WO2024044757A1 - Dérivés d'aminopyrimidine et d'aminotriazine utilisés en tant que modulateurs de la protéine myc - Google Patents

Dérivés d'aminopyrimidine et d'aminotriazine utilisés en tant que modulateurs de la protéine myc Download PDF

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WO2024044757A1
WO2024044757A1 PCT/US2023/072925 US2023072925W WO2024044757A1 WO 2024044757 A1 WO2024044757 A1 WO 2024044757A1 US 2023072925 W US2023072925 W US 2023072925W WO 2024044757 A1 WO2024044757 A1 WO 2024044757A1
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pyrimidin
amine
benzo
imidazol
compound
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PCT/US2023/072925
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Shubhankar DUTTA
Christian A. Hassig
Susanne HEYNEN-GENEL
Michael R. Jackson
Steven H. Olson
Anthony B. Pinkerton
Brad Savall
Robert WECHSLER-REYA
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Sanford Burnham Prebys Medical Discovery Institute
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
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Definitions

  • the present disclosure generally relates to compounds of Formula (I), (Ia), (Ib), or (II), or pharmaceutically acceptable salts thereof, and compositions comprising compounds of Formula (I), (Ia), (Ib), or (II), or pharmaceutically acceptable salts thereof, that are useful in treating various diseases and disorders, such as cancer.
  • Oncoproteins c-Myc, N-Myc, and L-Myc encoded by MYC proto-oncogene C-MYC, MYCN, and MYCL respectively, belong to a family of transcription factors that regulate the transcription of more than 15% of the entire genome.
  • MYC proto-oncogene C-MYC, MYCN, and MYCL belong to a family of transcription factors that regulate the transcription of more than 15% of the entire genome.
  • Recent mouse model studies have suggested that the modulation and regulation of oncogenic Myc proteins could potentially lead to the development of therapeutics useful for treating various cancers.
  • amplification and overexpression of N-Myc can lead to tumorigenesis and poor health outcomes in patients, and excess amounts of N-Myc proteins are associated with a variety of tumors, such as neuroblastomas.
  • CDKs cyclin-dependent protein kinases
  • CDK9 is a cyclin-dependent kinase associated with P- TEFb (positive transcription elongation factor b).
  • P- TEFb positive transcription elongation factor b
  • CDK9/P-TEFb phosphorylates the C-terminal domain of RNA polymerase II to regulate transcription elongation. Inhibition of CDK9 results in depletion of mRNA transcripts and associated proteins, including c-Myc.
  • inhibitors of CDK9 may be useful anti-cancer therapeutics.
  • the present disclosure fulfills these and other needs, as evident in reference to the following disclosure.
  • the present disclosure provides compounds and compositions that are useful as Myc protein modulators, and methods of using the same for treating various proliferative diseases, such as cancer.
  • the compounds are inhibitors of Myc.
  • the compounds described herein may be useful in the treatment of a Myc- mediated disease or disorder, such as cancers.
  • the present disclosure provides compounds and compositions that are useful as CDK protein modulators, and methods of using the same for treating various proliferative diseases, such as cancer.
  • the compounds are modulators of CDK.
  • the compounds are inhibitors of CDK.
  • the compounds described herein may be useful in the treatment of a CDK-mediated disease or disorder, such as cancer.
  • the CDK is CDK7, CDK8, CDK9, CDK11, CDK12, CDK13, CDK20.
  • the CDK is CDK9.
  • Some embodiments provide a compound of Formula (I): Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder mediated by a Myc protein, wherein: X 1 , X 2 , and X 3 are each independently N or CR 1 , wherein at least one of X 1 , X 2 , and X 3 is N; Y 1 is a bond, -O-, -S-, -CH2-, or -N(R 2 )(CH2)n-; Y 2 is -O-, -S-, -CH2-, or -N(R 2 )(CH2)n-; wherein the phenyl and 5-9 membered heteroaryl are each optionally substituted with 1-3 R 9 groups each independently selected from the group consisting of halogen, C 1 -C 5 alkyl, C 2 -C 5 - alkenyl, C2-C5-alkynyl, C1-C5 haloalkyl,
  • R 9 groups each independently selected from the group consisting of halogen, C1-C5 alkyl, C2-C5-alkenyl, C2-C5-alkynyl, C1-C5 haloalkyl, -(CH2)nOR 3 , and -NH2.
  • X 1 is CR 1
  • X 2 and X 3 are each independently N.
  • X 1 and X 2 are each independently CR 1
  • X 3 is N.
  • X 1 and X 3 are each independently CR 1
  • X 2 is N.
  • X 1 , X 2 and X 3 are each independently N.
  • Y 1 is a bond. In some embodiments, Y 1 is -O-, or -N(R 2 )(CH2)n-. In some embodiments, Y 1 is -N(R 2 )(CH 2 ) n -. In some embodiments, Y 1 is -CH 2 -, -S-, or -O-.
  • R 1 is hydrogen, or -CH 3 ; and B is aryl or heteroaryl each optionally substituted with 1-3 R 8 groups each independently selected from the group consisting of -CN, -OH, -NO2, -N(R 4 )2, -C(O)N(R 4 )2, -NR 4 C(O)R 4 , -NR 4 C(O)N(R 4 )2, -NR 4 (C 1 -C 5 )alkylene(O)R 4 , -C(O)R 4 , -CO 2 R 4 , -OC(O)R 4 , -OC(O)OR 4 , -O(C1-C5-alkylene)N(R 4 )2, -SR 4 , -S(O)R 4 , -S(O)2R 4 , -N(R 4 )S(O)2R 4 , -S(O)2N(R 4 )2, halogen
  • B is C1-C5 alkyl, C3-C9-cycloalkyl, or 5-9 membered heterocycloalkyl. In some embodiments, B is selected from , , , . [0017] In some embodiments, B is aryl optionally substituted with 1-3 groups each independently selected from the group consisting of -CN, -OH, -NO2, -N(R 4 )2, -C(O)N(R 4 )2, -NR 4 C(O)R 4 , -NR 4 C(O)N(R 4 ) 2 , -NR 4 (C 1 -C 5 )alkylene(O)R 4 , -C(O)R 4 , -CO 2 R 4 , -OC(O)R 4 , -OC(O)OR 4 , -O(C1-C5-alkylene)N(R 4 )2, -SR 4 , -S(O)R 4 ,
  • B is aryl substituted with 1 or 2 R 8 groups each independently selected from the group consisting of halogen, C1-C5-alkyl, aryl, C1-C5-alkoxy, heteroaryl, C3- C9-cycloalkyl, 5-9-membered heterocycloalkyl, -CO2R 4 , -C(O)R 4 , -NR 4 C(O)R 4 , -S(O)2R 4 , - S(O) 2 R 4 , -S(O) 2 NR 4 , -NR 4 C(O)R 4 , -NR 4 (C 1 -C 5 )alkylene(O)R 4A , and -O(C 1 -C 5 -alkylene)N(R 4 ) 2.
  • R 8 groups each independently selected from the group consisting of halogen, C1-C5-alkyl, aryl, C1-C5-alkoxy, heteroaryl, C3- C
  • B is phenyl substituted with 1 or 2 R 8 groups each independently selected from the group consisting of -F, -Cl, -Br, -CH3, -CF3, -CN, -CH(CH3)2, -C(CH3)3, -CH2CH2CH3, -OCF3, -OCH 3 , -CONH 2 ,-COOH, -COOCH 3 , pyridinyl, phenyl, pyrazolyl, ethynyl, cyclohexyl, cyclopentyl, morpholinyl, tetrahydropyranyl, piperidinyl, piperazinyl, -SO2NH2, -SO2CH3, , and .
  • B is aryl substituted with one R 8 group selected from halogen, C 1 -C 5 -alkyl, aryl, C 1 -C 5 -alkoxy, heteroaryl, C 5 -C 9 -cycloalkyl, 5-9-membered heterocycloalkyl, -CO2R 4 , -C(O)R 4 , -NR 4 C(O)R 4 , -S(O)2R 4 , -S(O)2R 4 , -S(O)2NR 4 , -NR 4 C(O)R 4 , -NR 4 (C1-C5)alkylene(O)R 4A , and -O(C1-C5-alkylene)N(R 4 )2.
  • R 8 group selected from halogen, C 1 -C 5 -alkyl, aryl, C 1 -C 5 -alkoxy, heteroaryl, C 5 -C 9 -cycloalkyl, 5-9
  • B is heteroaryl optionally substituted with 1-3 R 8 groups each independently selected from the group consisting of -CN, -OH, -N(R 4 )2, -C(O)N(R 4 )2, -NR 4 C(O)R 4 , -NR 4 C(O)N(R 4 )2, -NR 4 (C1-C5)alkylene(O)R 4A , -C(O)R 4 , -CO2R 4 , -OC(O)R 4 , -OC(O)OR 4 , -O(C 1 -C 5 -alkylene)N(R 4 ) 2 , -SR 4 , -S(O)R 4 , -S(O) 2 R 4 , -N(R 4 )S(O) 2 R 4 , -S(O) 2 N(R 4 ) 2 , halogen, C1-C5-alkyl, C1-C5-hal
  • B is heteroaryl substituted with 1-3 R 8 groups each independently selected from the group consisting of 4-9 membered heterocycloalkyl, C 1 -C 5 -haloalkyl, C 1 -C 5 -alkyl, aryl, heteroaryl, and alkylaryl.
  • B is heteroaryl substituted with 1 or 2 R 8 groups each independently -CF3, -OH, tetrahydropyranyl, isopropyl, pyridinyl, benzyl or phenyl.
  • B is selected from , , , [0022] In some embodiments, B is phenyl.
  • Some embodiments provide a compound of Formula (Ia): Formula (Ia), or a pharmaceutically acceptable salt thereof, wherein: B is aryl or heteroaryl each optionally substituted with 1-3 R 8 groups each independently selected from the group consisting of -(CH 2 )mCN, -(CH 2 )mOH, -(CH 2 )mN(R 4 ) 2 , -(CH 2 )mC(O)N(R 4 ) 2 , -(CH 2 )mNR 4 C(O)R 4 , -(CH 2 )mNR 4 C(O)N(R 4 ) 2 , -(CH 2 )mNR 4 (C 1 - C5)alkylene(O)R 4A , -(CH2)mC(O)R 4 , -(CH2)mCO2R 4 , -(CH2)mOC(O)R 4 , -(CH2)mOC(O)OR 4 , -(CH2)mO(C1
  • X 1 is N. In some embodiments, X 1 is CH. [0025] In some embodiments, X 4 is N. In some embodiments, X 4 is CH. [0026] In some embodiments, R 2 is hydrogen or -CH 3 . In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is -CH3. [0027] In some embodiments, each R 6 is independently hydrogen, halogen, or hydroxyl. [0028] In some embodiments, R 7 is hydrogen or -CH 3 .
  • B is phenyl substituted with 1-3 R 8 groups each independently selected from -OH, -NR 4 C(O)R 4 , -S(O)2R 4 , -S(O)2N(R 4 )2, halogen, C1-C5-alkyl, C1-C5- haloalkyl, aryl, heteroaryl, and 5-9 membered heterocycloalkyl.
  • B is pyridyl substituted with 1-3 R 8 groups each independently selected from halogen, C1-C5-alkyl, and C1-C5-haloalkyl.
  • B is pyrazolyl substituted with 1-3 R 8 groups each independently selected from halogen, C 1 -C 5 -alkyl, aryl, and heteroaryl.
  • R 8 is independently selected from the group consisting of -CN, -OH, -N(R 4 )2, -C(O)N(R 4 ) 2 , -NR 4 C(O)R 4 , -NR 4 C(O)N(R 4 ) 2 , -NR 4 (C 1 -C 5 )alkylene(O)R 4A , -C(O)R 4 ,
  • each R 10 is independently selected from halogen, C1-C5-alkyl, C1-C5-alkoxy, C1-C5- haloalkoxy, -CN, -OH, -N(R 12 ) 2 , -C(O)R 12 , -C(O)N(R 12 ) 2 , -NR 12 C(O)R 12 , -CO 2 R 12 , -OC(O)R 12 , -OC(O)OR 12 , -SR 12 , -S(O)R 12 , or -S(O) 2 R 12 ; each R 12 is independently hydrogen or C1-C5 alkyl; y is 0, 1, 2, 3, or 4; and R 11 is hydrogen, C 1 -C 5 alkyl, C 3 -C 6 -cycloalkyl, or aryl.
  • each R 10 is independently selected from halogen, C 1 -C 5 -alkyl, or - C(O)N(R 12 )2. In some embodiments, each R 10 is independently selected from -F, -Cl, -Br, -CH3, -CH(CH 3 ) 2 , -C(CH 3 ) 3 , or -CONH 2 . [0035] In some embodiments, y is 1 or 2. [0036] In some embodiments, R 11 is hydrogen, C1-C3 alkyl, C3-C6-cycloalkyl, or phenyl.
  • R 11 is hydrogen, -CH3, -CH(CH3)2, -C(CH3)3, cyclopropyl, or phenyl. .
  • a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and at least one diluent or excipient.
  • Some embodiments provide a method of treating a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • Some embodiments provide a method of treating a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition as described herein.
  • the disease or disorder is mediated by a Myc protein.
  • the Myc protein is selected from an N-Myc protein, a c-Myc protein, and an L- Myc protein.
  • Some embodiments provide a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • Some embodiments provide a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition as described herein.
  • the cancer is mediated by a Myc protein.
  • the Myc protein is selected from an N-Myc protein, a c-Myc protein, and an L-Myc protein.
  • the cancer is selected from head and neck cancer, nervous system cancer, brain cancer, neuroblastoma, medulloblastoma, lung/mediastinum cancer, breast cancer, esophageal cancer, stomach cancer, liver cancer, biliary tract cancer, pancreatic cancer, small bowel cancer, large bowel cancer, colorectal cancer, gynecological cancer, genitourinary cancer, ovarian cancer, thyroid gland cancer, adrenal gland cancer, skin cancer, melanoma, bone sarcoma, soft tissue sarcoma, pediatric malignancy, Hodgkin's disease, non-Hodgkin's lymphoma, myeloma, leukemia, and metastasis from an unknown primary site.
  • the cancer is medulloblastoma.
  • the subject is human.
  • Some embodiments provide a method of treating a disease or condition mediated by CDK9 in a subject comprising administering a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein to the subject.
  • the compound is a CDK9 inhibitor.
  • the compound inhibits activity of CDK9.
  • FIG.1 shows the set-up and workflow of high content screen for inhibitors of endogenous Myc.
  • FIGs.2A-2D show the compound profile for Compound A.
  • FIG.2A shows Myc expression inhibition in PDX511 medulloblastoma cells by Compound A with an IC50 of 11.7 ⁇ M.
  • FIG.2B shows that Compound A had no effect on the expression of the retinoblastoma (Rb) protein in PDX511 medulloblastoma cells.
  • Rb retinoblastoma
  • FIG.2C shows that Compound A had no effect on cell viability of PDX511 medulloblastoma cells at 4 hours.
  • FIG.2D shows images of immunofluorescence-based detection of Myc expression (top row), cell viability (middle row), and Rb protein expression (bottom row) of PDX511 medulloblastoma cells treated with Compound A at various concentrations.
  • FIGs.3A-3D show the compound profile for Compound 171.
  • FIG.3A shows Myc expression inhibition in PDX511 medulloblastoma cells by Compound 171.
  • FIG.3B shows that Compound 171 had no effect on expression of the retinoblastoma (Rb) protein in PDX511 medulloblastoma cells.
  • FIG.3C shows that Compound 171 had no effect on cell viability of PDX511 medulloblastoma cells at 4 hours.
  • FIG.3D shows images of immunofluorescence- based detection of Myc expressions (top row), cell viability (middle row), and Rb protein expressions (bottom row) of PDX511 medulloblastoma cells treated with Compound 171 at various concentrations.
  • FIG.4A shows Western Blot gel data from cultured cells treated with Compound 171 at various times.
  • FIG.4B and FIG.4C show inhibition of Myc expression in cells treated with 0.18 ⁇ M of Compound 171 after 48 hours and after 96 hours respectively using CellTiter Glo assay. The data suggest that Compound 171 cased an 80% reduction in cell viability by 48 hours, and 100% reduction in viability by 96 hours.
  • FIGs.5A-5D show inhibition of Myc expression in different cell lines derived from multiple types of cancer after treatment with various concentrations of Compound 171.
  • FIG. 5A shows the inhibition result from the THP-1 cell line derived from acute monocytic leukemia.
  • FIG.5B shows the inhibition result from the HL-60 cell line derived from acute promyelocytic leukemia.
  • FIG.5C shows the inhibition result from the BxPC-3 cell line derived from pancreatic adenocarcinoma.
  • FIG.5D shows the inhibition result from the H-82 cell line derived from small cell lung cancer.
  • FIG.6 shows concentrations of Compound 171 at various time points in the plasma and in the brain of non-tumor-bearing mice after systemic oral administration of the compound at 100 mg/kg.
  • FIG.7 shows reduction of Myc levels in intracranial tumors in mice transplanted with medulloblastoma PDX cells after oral administration of Compound 171 at 100 mg/kg.
  • the present disclosure provides novel Myc modulator compounds as described herein.
  • the Myc modulator compounds are Myc inhibitors.
  • the compounds of the present disclosure exhibit potent inhibitory activities against Myc- mediated disease or disorder, such as cancers.
  • the present disclosure provides novel CDK9 modulator compounds as described herein.
  • the CDK9 modulator compounds are CDK9 inhibitors.
  • the compounds of the present disclosure exhibit potent inhibitory activities against CDK9-mediated disease or disorder, such as cancers.
  • Some embodiments provide a compound of Formula (I): Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder mediated by a Myc protein, wherein: X 1 , X 2 , and X 3 are each independently N or CR 1 , wherein at least one of X 1 , X 2 , and X 3 is N; Y 1 is a bond, -O-, -S-, -CH2-, or -N(R 2 )(CH2)n-; Y 2 is -O-, -S-, -CH 2 -, or -N(R 2 )(CH 2 )n-; wherein the phenyl and 5-9 membered heteroaryl are each optionally substituted with 1-3 R 9 groups each independently selected from the group consisting of halogen, C1-C5 alkyl, C2-C5- alkenyl, C2-C5-alkynyl, C1-C5 hal
  • R 9 groups each independently selected from the group consisting of halogen, C1-C5 alkyl, C2-C5-alkenyl, C2-C5-alkynyl, C1-C5 haloalkyl, -(CH2)nOR 3 , and -NH2.
  • X 1 is CR 1
  • X 2 and X 3 are each independently N.
  • X 1 and X 2 are each independently CR 1
  • X 3 is N.
  • X 1 and X 3 are each independently CR 1
  • X 2 is N.
  • X 1 , X 2 and X 3 are each independently N.
  • Y 1 is a bond. In some embodiments, Y 1 is -O-, or -N(R 2 )(CH2)n-. In some embodiments, Y 1 is -N(R 2 )(CH2)n-. In some embodiments, Y 1 is -CH2-, -S-, or -O-. [0062] In some embodiments, R 1 is hydrogen, or -CH 3 .
  • B is C 1 -C 5 alkyl, C 3 -C 9 -cycloalkyl, or 5-9 membered heterocycloalkyl. In some embodiments, B is selected from , , , .
  • B is aryl optionally substituted with 1-3 groups independently selected from the group consisting of -CN, -OH, -N(R 4 ) 2 , -C(O)N(R 4 ) 2 , -NR 4 C(O)R 4 , -NR 4 C(O)N(R 4 )2, -NR 4 (C1-C5)alkylene(O)R 4A , -C(O)R 4 , -CO2R 4 , -OC(O)R 4 , -OC(O)OR 4 , -O(C1-C5-alkylene)N(R 4 )2, -SR 4 , -S(O)R 4 , -S(O)2R 4 , -N(R 4 )S(O)2R 4 , -S(O)2N(R 4 )2, halogen, C1- C 5 -alkyl, C 1 -C 5 -haloal
  • B is aryl substituted with 1 or 2 R 8 groups each independently selected from the group consisting of halogen, C1-C5-alkyl, aryl, C1-C5-alkoxy, heteroaryl, C5- C9-cycloalkyl, 5-9-membered heterocycloalkyl, -CO2R 4 , -C(O)R 4 , -NR 4 C(O)R 4 , -S(O)2R 4 , - S(O) 2 R 4 , -S(O) 2 NR 4 , -NR 4 C(O)R 4 , -NR 4 (C 1 -C 5 )alkylene(O)R 4A , and -O(C 1 -C 5 -alkylene)N(R 4 ) 2 , and wherein said aryl and heteroaryl are each optionally substituted with 1 or 2 C1-C5-alkyl, and said 5-9 membered heterocycl
  • B is phenyl substituted with 1 or 2 R 8 groups each independently selected from the group consisting of -F, - Cl, -Br, -CH 3 , -CF 3 , -CN, -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 CH 2 CH 3 , -OCF 3 , -OCH 3 , -CONH 2 ,-COOH, -COOCH3, pyridinyl, phenyl, pyrazolyl, ethynyl, cyclohexyl, cyclopentyl, morpholinyl, tetrahydropyranyl, piperidinyl, piperazinyl, -SO 2 NH 2 , -SO 2 CH 3 , , , ,
  • aryl is substituted with one R 8 group selected from halogen, C 1 -C 5 -alkyl, aryl, C 1 -C 5 -alkoxy, heteroaryl, C 5 -C 9 -cycloalkyl, 5-9-membered heterocycloalkyl, -CO2R 4 , -C(O)R 4 , -NR 4 C(O)R 4 , -S(O)2R 4 , -S(O)2R 4 , -S(O)2NR 4 , -NR 4 C(O)R 4 , -NR 4 (C1-C5)alkylene(O)R 4A , and -O(C1-C5-alkylene)N(R 4 )2, and wherein said aryl and heteroaryl are each optionally substituted with 1 or 2 C 1 -C 5 -alkyl, and said 5-9 membered heterocycloalkyl is optionally substituted
  • B is heteroaryl optionally substituted with 1-3 R 8 groups each independently selected from the group consisting of -CN, -OH, -N(R 4 ) 2 , -C(O)N(R 4 ) 2 , -NR 4 C(O)R 4 , -NR 4 C(O)N(R 4 ) 2 , -NR 4 (C 1 -C 5 )alkylene(O)R 4A , -C(O)R 4 , -CO 2 R 4 , -OC(O)R 4 , -OC(O)OR 4 , -O(C1-C5-alkylene)N(R 4 )2, -SR 4 , -S(O)R 4 , -S(O)2R 4 , -N(R 4 )S(O)2R 4 , -S(O)2N(R 4 )2, halogen, C1-C5-alkyl, C1-C
  • B is heteroaryl substituted with 1-3 R 8 groups each independently selected from the group consisting of 5-9 membered heterocycloalkyl, C1-C5-haloalkyl, C1-C5- alkyl, aryl, heteroaryl, and alkylaryl, and wherein said aryl and heteroaryl are each optionally substituted with 1 or 2 C 1 -C 5 -alkyl, and said 5-9 membered heterocycloalkyl is optionally substituted with 1 or 2 substituents each independently selected from C1-C5-alkyl and oxo.
  • B is heteroaryl substituted with 1 or 2 R 8 groups each independently -CF3, - OH, tetrahydropyranyl, isopropyl, pyridinyl, benzyl or phenyl. [0073] In some embodiments, B is selected from , , , [0074] In some embodiments, B is phenyl. In some embodiments, is pyridyl optionally substituted with 1-3 R 8 groups each independently selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, -OR 3 , and -NH2.
  • R 8 groups each independently selected from the group consisting of -OH and - OCH3.
  • B is aryl or heteroaryl each optionally substituted with 1-3 R 8 groups each independently selected from the group consisting of -(CH 2 )mCN, -(CH 2 )mOH, -(CH 2 )mN(R 4 ) 2 , - (CH 2 )mC(O)N(R 4 ) 2 , -(CH 2 )mNR 4 C(O)R 4 , -(CH 2 )mNR 4 C(O)N(R 4 ) 2 , -(CH 2 )mNR 4 (C 1 - C5)alkylene(O)R 4A , -(CH2)mC(O)R 4 , -(CH2)mCO2R 4
  • X 1 is N. In some embodiments, X 1 is CH. [0077] In some embodiments, X 4 is N. In some embodiments, X 4 is CH. [0078] In some embodiments, R 2 is hydrogen or -CH 3 . In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is -CH3. [0079] In some embodiments, each R 6 is independently hydrogen, halogen, or -OH. In some embodiments, each R 4A is independently C 1 -C 5 alkyl or C 3 -C 6 -cycloalkyl. In some embodiments, each R 4A is C 1 -C 5 alkyl. [0080] In some embodiments, R 7 is hydrogen or -CH3.
  • B is phenyl substituted with 1-3 R 8 groups each independently selected from -OH, -NR 4 C(O)R 4 , -S(O) 2 R 4 , -S(O) 2 N(R 4 ) 2 , halogen, C 1 -C 5 -alkyl, C 1 -C 5 - haloalkyl, aryl, heteroaryl, and 5-9 membered heterocycloalkyl.
  • B is pyridyl substituted with 1-3 R 8 groups each independently selected from halogen, C 1 -C 5 -alkyl, and C 1 -C 5 -haloalkyl.
  • B is pyrazolyl substituted with 1-3 R 8 groups each independently selected from halogen, C1-C5-alkyl, aryl, and heteroaryl.
  • R 8 is independently selected from the group consisting of -CN, -OH, -NO 2 , -N(R 4 ) 2 , -C(O)N(R 4 )2, -NR 4 C(O)R 4 , -NR 4 C(O)N(R 4 )2, -NR 4 (C1-C5)alkylene(O)R 4 , -C(O)R 4 , -CO2R
  • each R 10 is independently selected from halogen, C1-C5-alkyl, C1-C5-alkoxy, C1-C5- haloalkoxy, -CN, -OH, -N(R 12 ) 2 , -C(O)R 12 , -C(O)N(R 12 ) 2 , -NR 12 C(O)R 12 , -CO 2 R 12 , -OC(O)R 12 , -OC(O)OR 12 , -SR 12 , -S(O)R 12 , or -S(O) 2 R 12 ; each R 12 is independently hydrogen or C1-C5 alkyl; y is 0, 1, 2, 3, or 4; and R 11 is hydrogen, C 1 -C 5 alkyl, C 3 -C 6 -cycloalkyl, or aryl.
  • each R 10 is independently selected from halogen, C 1 -C 5 -alkyl, or - C(O)N(R 12 )2. In some embodiments, each R 10 is independently selected from -F, -Cl, -Br, -CH3, -CH(CH 3 ) 2 , -C(CH 3 ) 3 , or -CONH 2 . [0087] In some embodiments, y is 1 or 2. [0088] In some embodiments, R 11 is hydrogen, C1-C3 alkyl, C3-C6-cycloalkyl, or phenyl.
  • R 11 is hydrogen, -CH3, -CH(CH3)2, -C(CH3)3, cyclopropyl, or phenyl. .
  • the present disclosure provides a pharmaceutically acceptable salt of a compound described in Table 1.
  • the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of: N-(3-((4-(1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)amino)phenyl)benzamide (Compound 1), N-(3-((4-(1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)amino)phenyl)acetamide (Compound 2), 4-(1H-benzo[d]imidazol-5-yl)-N-(2',6'-dimethyl-[1,1'-biphenyl]-3-yl)pyrimidin-2-amine (Compound 3), 4-(1H-benzo[d]imidazol-5-yl)-N-(3-(2,5-dimethyl-1H-pyrrol-1-yl)phenyl)pyrimidin-2- amine (Compound 4), 4-(1H-benzobenzo
  • compounds described herein are in the form of pharmaceutically acceptable salts.
  • the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms of the compounds presented herein are also considered to be disclosed herein.
  • “Pharmaceutically acceptable,” as used herein refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic at the concentration or amount used, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • pharmaceutically acceptable salt refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation.
  • Handbook of Pharmaceutical Salts Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci.1977, 66, 1-19. P. H. Stahl and C. G.
  • pharmaceutically acceptable salts are obtained by reacting a compound of Formula (I) with an acid.
  • the compound of Formula (I) i.e. free base form
  • the term “acid” refers to a compound that is an electron pair acceptor in an acid-base reaction.
  • the term “inorganic acid” refers to an acid that does not include a carbon bond. Inorganic acids can be a strong acid or a weak acid.
  • Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, sulfamic acid, perchloric acid, boric acid, fluorophosphoric acid, and metaphosphoric acid.
  • organic acid refers to an acid including at least one C-H bond, C-F bond, or C-C bond.
  • Organic acids include, but are not limited to, acetic acid; benzenesulfonic acid; benzoic acid; camphor-10-sulfonic acid (+); citric acid; ethanesulfonic acid; formic acid; fumaric acid; glycolic acid; isobutyric acid; lactic acid (DL); maleic acid; malonic acid; methanesulfonic acid; oxalic acid; proprionic acid; salicylic acid; succinic acid; L-(+)-tartaric acid ; p-toluenesulfonic acid; trifluoroacetic acid; and trifluoromethanesulfonic acid.
  • a compound of Formula (I) is prepared as a chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt or phosphate salt.
  • pharmaceutically acceptable salts are obtained by reacting a compound of Formula (I) with a base.
  • base refers to a compound that is an electron pair donor in an acid-base reaction.
  • the base can be an inorganic base or an organic base.
  • the compound of Formula (I) is acidic and is reacted with a base.
  • inorganic base refers to a base that does not include at least one C-H bond and includes at least one alkali metal or alkaline earth metal.
  • examples of an inorganic base include, but are not limited to, sodium hydride, potassium hydride, lithium hydride, calcium hydride, barium carbonate, calcium carbonate, cesium carbonate, lithium carbonate, magnesium carbonate, potassium carbonate, sodium carbonate, cesium hydrogen carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, barium hydroxide, calcium hydroxide, cesium hydroxide, lithium hydroxide, magnesium hydroxide, potassium hydroxide, sodium hydroxide.
  • the compound of Formula (I) is acidic and is reacted with an inorganic base.
  • an acidic proton of the compound of Formula (I) is replaced by a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, barium, or a cesium ion.
  • a metal ion e.g., lithium, sodium, potassium, magnesium, calcium, barium, or a cesium ion.
  • organic base refers to a base including at least one C-H bond (e.g., an amine base).
  • the amine base can be a primary, secondary, or tertiary amine.
  • a reference to a pharmaceutically acceptable salt includes the solvent addition forms.
  • solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
  • Solvates of compounds described herein are conveniently prepared or formed during the processes described herein.
  • the compounds provided herein optionally exist in unsolvated as well as solvated forms.
  • Compounds described herein allow atoms at each position of the compound independently to have: 1) an isotopic distribution for a chemical element in proportional amounts to those usually found in nature or 2) an isotopic distribution in proportional amounts different to those usually found in nature unless the context clearly dictates otherwise.
  • a particular chemical element has an atomic number defined by the number of protons within the atom's nucleus. Each atomic number identifies a specific element, but not the isotope; an atom of a given element may have a wide range in its number of neutrons.
  • the number of both protons and neutrons in the nucleus is the atom's mass number, and each isotope of a given element has a different mass number.
  • a compound wherein one or more atoms have an isotopic distribution for a chemical element in proportional amounts different to those usually found in nature is commonly referred to as being an isotopically labeled compound.
  • Each chemical element as represented in a compound structure may include any isotopic distribution of said element.
  • a hydrogen atom can be explicitly disclosed or understood to be present in the compound.
  • the hydrogen atom can be an isotopic distribution of hydrogen, including but not limited to protium ( 1 H) and deuterium ( 2 H) in proportional amounts to those usually found in nature and in proportional amounts different to those usually found in nature.
  • protium ( 1 H) and deuterium ( 2 H) in proportional amounts to those usually found in nature and in proportional amounts different to those usually found in nature.
  • isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine chlorine, iodine, phosphorus, such as, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, 36 Cl, 123 I, 124 I, 125 I, 131 I, 32 P and 33 P.
  • isotopically labeled compounds described herein, for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
  • substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.
  • an atom in one position of the compound has an isotopic distribution for a chemical element in proportional amounts different to those usually found in nature (remainder atoms having an isotopic distribution for a chemical element in proportional amounts to those usually found in nature).
  • atoms in at least two positions of the compound independently have an isotopic distribution for a chemical element in proportional amounts different to those usually found in nature (remainder atoms having an isotopic distribution for a chemical element in proportional amounts to those usually found in nature).
  • atoms in at least three positions of the compound independently have an isotopic distribution for a chemical element in proportional amounts different to those usually found in nature (remainder atoms having an isotopic distribution for a chemical element in proportional amounts to those usually found in nature). In some embodiments, atoms in at least four positions of the compound independently have an isotopic distribution for a chemical element in proportional amounts different to those usually found in nature (remainder atoms having an isotopic distribution for a chemical element in proportional amounts to those usually found in nature).
  • atoms in at least five positions of the compound independently have an isotopic distribution for a chemical element in proportional amounts different to those usually found in nature (remainder atoms having an isotopic distribution for a chemical element in proportional amounts to those usually found in nature).
  • atoms in at least six positions of the compound independently have an isotopic distribution for a chemical element in proportional amounts different to those usually found in nature (remainder atoms having an isotopic distribution for a chemical element in proportional amounts to those usually found in nature).
  • Catalytic Reduction with Tritium Gas This procedure normally yields high specific activity products and requires halogenated or unsaturated precursors.
  • D. Tritium Gas Exposure Labeling This procedure involves exposing precursors containing exchangeable protons to tritium gas in the presence of a suitable catalyst.
  • a radiolabeled form of a compound described herein can be used in a screening assay to identify/evaluate compounds.
  • a newly synthesized or identified compound i.e., test compound
  • the ability of a test compound to compete with a radiolabeled form of a compound described herein for the binding correlates to its binding affinity.
  • the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be the (R)-configuration, or the (S)-configuration, or a mixture thereof.
  • the compounds provided herein can be enantiomerically pure, enantiomerically enriched (i.e., a scalemic mixture), a racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture.
  • the compounds of Formulae (I), (Ia), (Ib), or (II) possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration.
  • the compound of Formulae (I), (Ia), (Ib), or (II) exists in the R configuration.
  • the compound of Formulae (I), (Ia), (Ib), or (II) exists in the S configuration.
  • the compounds presented herein include all diastereomeric, individual enantiomers, atropisomers, and epimeric forms as well as the appropriate mixtures thereof.
  • the compounds and methods provided herein include all cis, trans, syn, anti,
  • Z isomers as well as the appropriate mixtures thereof.
  • Stereochemical definitions are available in E.L. Eliel, S.H. Wilen & L.N. Mander, Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, NY, 1994 which is incorporated herein by reference in its entirety.
  • the compound described herein is chiral or otherwise includes one or more stereocenters
  • the compound can be prepared with an enantiomeric excess or diastereomeric excess of greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 99%, or greater than 99.5%, or within a range defined by any of the preceding numbers.
  • Individual stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns or the separation of diastereomers by either non-chiral or chiral chromatographic columns or crystallization and recrystallization in a proper solvent or a mixture of solvents.
  • compounds of Formulae (I), (Ia), (Ib), or (II) are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds/salts, separating the diastereomers and recovering the optically pure individual enantiomers.
  • resolution of individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein.
  • diastereomers are separated by separation/resolution techniques based upon differences in solubility.
  • separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof.
  • a compound prepared by stereoselective synthesis can have at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%, or at least 99.9% enantiomeric excess, or an enantiomeric excess within a range defined by any of the preceding numbers.
  • compound as used herein is meant to include all stereoisomers, geometric isomers, and tautomers of the structures depicted.
  • the term is also meant to refer to compounds described herein, regardless of how they are prepared, e.g., synthetically, through biological process (e.g., metabolism or enzyme conversion), or a combination thereof. All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated. When in the solid state, the compounds described herein and salts thereof may occur in various forms and may, e.g., take the form of solvates, including hydrates.
  • the compounds can be in any solid-state form, such as a polymorph or solvate, so unless clearly indicated otherwise, reference in the specification to compounds and salts thereof should be understood as encompassing any solid-state form of the compound.
  • the compounds described herein, or salts thereof are substantially isolated.
  • substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, e.g., a composition enriched in the compounds described herein.
  • Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds described herein, or salts thereof.
  • the environment in which the compound was formed or detected can include, for example, a composition comprising one or more solvents and one or more chemical reagents.
  • heterocyclic rings may exist in tautomeric forms. In such situations, it is understood that the structures of said compounds are illustrated or named in one tautomeric form but could be illustrated or named in the alternative tautomeric form. The alternative tautomeric forms are expressly included in this disclosure.
  • composition refers to a compound, including but not limited to, salts, solvates, and hydrates of a compound described herein, in combination with at least one additional component. Some embodiments provide a pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient or diluent.
  • excipient refers to a substance that is added to a composition to provide, without limitation, consistency, stability, binding ability, lubrication, disintegrating ability, etc., to the composition.
  • a “diluent” refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but can be pharmaceutically necessary or desirable.
  • a diluent can be used to increase the bulk of a potent drug substance whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug substance to be administered by injection, ingestion, or inhalation.
  • a pharmaceutically acceptable excipient is a physiologically and pharmaceutically suitable non- toxic and inactive material or ingredient that does not interfere with the activity of the drug substance.
  • compositions formulated as liquid solutions include saline and sterile water, and may optionally include antioxidants, buffers, bacteriostats and other common additives.
  • the diluents can be a buffered aqueous solution such as, without limitation, phosphate buffered saline.
  • the compositions can also be formulated as capsules, granules, or tablets which contain, in addition to a compound as disclosed and described herein, diluents, dispersing and surface-active agents, binders, and lubricants.
  • diluents dispersing and surface-active agents, binders, and lubricants.
  • One skilled in this art may further formulate a compound as disclosed and described herein in an appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington, supra. [00115]
  • the compounds described herein are formulated into pharmaceutical compositions.
  • compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a summary of pharmaceutical compositions described herein is found, for example, in Remington, supra; Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999), herein incorporated by reference for such disclosure.
  • a compound or a pharmaceutical composition of the present disclosure is, in some embodiments, useful for the treatment of a Myc-mediated disease or disorder. In some embodiments, the pharmaceutical composition is effective at treating a disease or disorder wherein Myc is overexpressed. [00117] In some embodiments, a compound or a pharmaceutical composition of the present disclosure is useful for the treatment of a CDK9-mediated disease, condition, or disorder. In some embodiments, the pharmaceutical composition is effective at treating a disease, condition, or disorder wherein CDK9 is overexpressed. [00118] In some embodiments, the pharmaceutical composition is useful in the treatment of a disease or disorder. In some embodiments, the disease or disorder is mediated by a Myc protein.
  • the Myc protein is selected from a N-Myc protein, a c-Myc protein, and a L-Myc protein.
  • the disease, condition, or disorder is mediated by a CDK9 protein.
  • the disease or disorder is cancer.
  • the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition. Administration of the compounds and compositions described herein can be affected by any method that enables delivery of the compounds to the site of action.
  • a pharmaceutical composition is administered orally (e.g., in a liquid formulation, tablet, capsule, nebulized liquid, aerosolized liquid, dry powder spray).
  • compositions suitable for oral administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the drug substance; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • Pharmaceutical compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the drug substance in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and are formulated so as to provide slow or controlled release of the drug substance therein. All formulations for oral administration should be in dosages suitable for such administration.
  • the push-fit capsules can contain the drug substance in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the drug substance may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers are added.
  • pharmaceutical compositions are formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the compositions may be presented in unit-dose or multi- dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
  • sterile liquid carrier for example, saline or sterile pyrogen-free water
  • the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • Method of Treatment [00124] Some embodiments provide a method of treating a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. [00125] Some embodiments provide a method of treating a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition as described herein. [00126] In some embodiments, the disease or disorder is mediated by a Myc protein.
  • the Myc protein is selected from a N-Myc protein, a c-Myc protein, and a L-Myc protein.
  • the disease or disorder is cancer. [00127] In some embodiments, the disease or disorder is mediated by a CDK protein. In some embodiments, the disease or disorder is mediated by a transcriptional CDK protein. In some embodiments, the disease or disorder is mediated by a CDK7, CDK8, CDK9, CDK11, CDK12, CDK13, or CDK20 protein. In some embodiments, the disease or disorder is mediated by a CDK7 or CDK9 protein. In some embodiments, the disease or disorder is mediated by a CDK9 protein.
  • Some embodiments provide a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. [00129] Some embodiments provide a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition as described herein.
  • the cancer is selected from selected from head and neck cancer, nervous system cancer, brain cancer, neuroblastoma, medulloblastoma, lung/mediastinum cancer, breast cancer, esophageal cancer, stomach cancer, liver cancer, biliary tract cancer, pancreatic cancer, small bowel cancer, large bowel cancer, colorectal cancer, gynecological cancer, genito-urinary cancer, ovarian cancer, thyroid gland cancer, adrenal gland cancer, skin cancer, melanoma, bone sarcoma, soft tissue sarcoma, pediatric malignancy, Hodgkin's disease, non-Hodgkin's lymphoma, myeloma, leukemia, and metastasis from an unknown primary site.
  • the cancer is medulloblastoma.
  • the subject is human.
  • Some embodiments provide a method of treating a disease, disorder, or condition mediated by CDK9 in a subject comprising administering a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein to the subject.
  • the compound is a CDK9 inhibitor.
  • the compound inhibits activity of CDK9.
  • the present disclosure also provides the use of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition as described herein, to modulate the amount and activity of a Myc protein, such as in vitro or in a subject, wherein the Myc protein is selected from a N-Myc protein, a c-Myc protein, and a L- Myc protein.
  • the disclosure provides a method of modulating the amount (e.g., the concentration) and/or activity of a Myc protein such as (e.g., degrading a Myc protein, or modulating the rate of degradation of a Myc protein) that comprises administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, including embodiments or from any examples, tables or figures as described herein.
  • the method as described herein include methods of modulating the protein-protein interactions of the Myc family protein, or a method of decreasing the amount or decreasing the level of activity of a Myc protein.
  • the method of modulating the amount and activity of a Myc protein may include co-administering a compound described herein, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a second agent, e.g., a therapeutic agent.
  • a second agent e.g., a therapeutic agent.
  • Ca-Cb in which “a” and “b” are integers refer to the number of carbon atoms when indicated in an alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, or haloalkoxy group, or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclyl group.
  • a group designated as "C1-C6" indicates that there are one to six carbon atoms in the moiety.
  • “C1-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.
  • an “alkyl” group refers to a fully saturated straight or branched hydrocarbon group. In some embodiments, the “alkyl” group has 1 to 10 carbon atoms, i.e. a C1-C10alkyl.
  • an alkyl is a C 1 -C 6 alkyl.
  • the alkyl is methyl, ethyl, propyl, iso- propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.
  • an alkyl group can be unsubstituted or substituted.
  • An “alkylene” group refers to a divalent alkyl radical. Any of the monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. In some embodiments, an alkylene is a C1-C6 alkylene.
  • an alkylene is a C1- C 4 alkylene.
  • Typical alkylene groups include, but are not limited to, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, and the like.
  • an alkylene is -CH 2 -.
  • An “alkoxy” group refers to a RO- group, where R is an alkyl as defined herein. A non- limiting list of alkoxys are methoxy, ethoxy, n-propoxy, 1-methylethoxy (iso-propoxy), n- butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.
  • the alkoxy group can be designated as “C 1 -C 5 - alkoxy” or similar designations. In some embodiments, an alkoxy can be unsubstituted or substituted.
  • haloalkyl refers to an alkyl group, as defined herein, wherein one or more hydrogen atoms of the alkyl group have been replaced by a halogen atom (e.g., mono-haloalkyl, di-haloalkyl, and tri-haloalkyl). In some embodiments, the haloalkyl group can have 1 to 5 carbons (i.e., “C 1 -C 5 haloalkyl”).
  • the C 1 -C 5 haloalkyl can be fully halogen substituted in which case it can be represented by the formula C n L 2n+1 , wherein L is a halogen and “n” is 1, 2, 3, 4, or 5. When more than one halogen is present then they can be the same or different and selected from: fluorine, chlorine, bromine, and iodine.
  • haloalkyl contains 1 to 4 carbons (i.e., C 1 -C 4 haloalkyl).
  • haloalkyl contains 1 to 3 carbons (i.e., C 1 - C3 haloalkyl).
  • haloalkyl contains 1 or 2 carbons.
  • haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 1- fluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 4,4,4-trifluorobutyl, and the like.
  • An “haloalkoxy” refers to an alkoxy group in which one or more of the hydrogen atoms are replaced by a halogen.
  • Such groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy and 2- fluoroisobutoxy.
  • the haloalkoxy group may have 1 to 5 carbon atoms.
  • the haloalkoxy group can be designated as “C1-C5 haloalkoxy” or similar designations.
  • An “alkylthio” refers to a RS- group, where R is an alkyl as defined herein.
  • alkylthios are methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, 1- methylethylsulfanyl, n-butylsulfanyl, iso-butylsulfanyl, sec-butylsulfanyl, and tert-butylsulfanyl.
  • the alkylthiogroup can be designated as “C1-C5-alkylthio” or similar designations.
  • an alkylthio can be unsubstituted or substituted.
  • alkenyl refers to a straight or branched hydrocarbon group in which at least one carbon-carbon double bond is present.
  • an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like.
  • the alkenyl group can be designated as “C2-C5-alkenyl” or similar designations.
  • alkynyl refers to a straight or branched hydrocarbon group in which at least one carbon-carbon triple bond is present.
  • an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • Non-limiting examples of an alkynyl group include -C ⁇ CH, -C ⁇ CCH 3 -C ⁇ CCH 2 CH 3 , -CH 2 C ⁇ CH and -CH(CH 3 )(C ⁇ CH).
  • the alkynyl group can be designated as “C 2 -C 5 -alkynyl” or similar designations.
  • aryl refers to an aromatic ring system containing 6, 10 or 14 carbon atoms that can contain a single ring, two fused rings or three fused rings, such as phenyl, naphthalenyl and phenanthrenyl.
  • aryl group can have 6 or 10 carbon atoms (i.e ., C 6 or C 10 aryl).
  • an aryl is phenyl.
  • an aryl is naphthyl.
  • an aryl is a C6 or C10aryl.
  • an aryl group can be unsubstituted or substituted.
  • cycloalkyl refers to a monocyclic or polycyclic hydrocarbon including at least one fully or partially saturated ring (i.e., non-aromatic ring), wherein each of the atoms forming the ring is a carbon atom.
  • cycloalkyls are spirocyclic or bridged compounds.
  • cycloalkyls include at least one partially saturated ring fused with an aromatic ring (e.g., 1,2,3,4-tetrahydronaphthalenyl), and the point of attachment is at a carbon of either ring.
  • Cycloalkyl groups include groups having from 3 to 10 ring atoms.
  • cycloalkyl group can be designated as “C3-C10-cycloalkyl” or similar designations.
  • cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl, bicycle[1.1.1]pentyl, 2,3-dihydro-1H-indene and 1,2,3,4-tetrahydronaphthalenyl.
  • a cycloalkyl is a C3-C10-cycloalkyl. In some embodiments, a cycloalkyl is a C3- C 9 -cycloalkyl.
  • halogen refers to a fluoro, chloro, bromo or iodo group. In some embodiments, halogen or halo is fluoro, chloro, or bromo. In some embodiments, halogen or halo is fluoro.
  • heteroaryl refers to a monocyclic or fused multicyclic aromatic ring system and having at least one heteroatom in the ring system, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur.
  • heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls.
  • Monocyclic heteroaryls include, but are not limited to, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, 1,3,5-triazinyl, 1,3,4-oxadiazolyl, thiadiazolyl, and 1,2,5-oxadiazolyl.
  • Bicyclic heteroaryls include, but are not limited to, indolizinyl, indolyl, benzofuranyl, benzothiophene (i.e., benzothiofuranyl), indazolyl, benzimidazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, and pteridinyl.
  • a heteroaryl contains 1-4 nitrogen atoms in the ring.
  • a heteroaryl has 5 to 10 ring members or 5 to 9 ring members.
  • the heteroaryl group can be designated as “5-10 membered heteroaryl,” “5-9 membered heteroaryl,” or similar designations.
  • a heteroaryl can be an optionally substituted C 1 -C 13 five-, six-, seven, eight-, nine-, ten-, up to 14-membered monocyclic, bicyclic, or tricyclic ring system including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur.
  • a heteroaryl can be an optionally substituted C 1 -C 8 five-, six-, seven, eight-, or nine-membered monocyclic, or bicyclic ring system including 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur.
  • heteroaryl is a C1-C9heteroaryl.
  • monocyclic heteroaryl is a C 1 -C 5 heteroaryl.
  • monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl.
  • the C 1 -C 4 5-membered heteroaryl is furanyl, thienyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl, isothiazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, oxazolyl, pyrrolyl, triazolyl, or tetrazolyl.
  • the heteroaryl is a C 3 -C 5 6-membered heteroaryl.
  • the C 3 -C 5 6-membered heteroaryl is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl.
  • a heteroaryl can be an optionally substituted C6-C9 ten-membered bicyclic ring system including 1 to 4 nitrogen atoms.
  • a heteroaryl can be an optionally substituted C4-C8 eight- , or nine-membered bicyclic ring system including 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur.
  • a heteroaryl can be an optionally substituted C 5 -C 8 nine-membered bicyclic ring system including 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur.
  • a heteroaryl can be an optionally substituted C5-C8 nine-membered bicyclic ring system including 1 to 4 nitrogen atoms.
  • bicyclic heteroaryl is a C6-C9heteroaryl.
  • a heteroaryl group can be unsubstituted or substituted.
  • a “heterocycloalkyl” group refers to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic, and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system and optionally containing one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur in the monocyclic ring or in at least one ring of the bicyclic or tricyclic ring system.
  • the heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur, and nitrogen.
  • a heterocycloalkyl can be an C2-C12 three-, four-, five- , six-, seven-, eight-, nine-, ten-, up to 13 -membered monocyclic, bicyclic, or tricyclic ring system including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heterocyclyl can be a C 2 -C 6 three-, four-, five-, six-, or seven-membered monocyclic ring including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heterocyclyl can be a C 2 -C 10 four-, five-, six-, seven-, eight-, nine-, ten- or eleven-membered bicyclic ring system including 1 to 5 heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • the heterocyclyl can be a C7-C1212- or 13-membered tricyclic ring system including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heteroatom(s) of six membered monocyclic heterocyclyls are independently selected from one to three of oxygen, nitrogen and sulfur, and the heteroatom(s) of five membered monocyclic heterocyclyls are independently selected from oxygen, nitrogen and sulfur.
  • the heterocycloalkyl is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl.
  • a heterocycloalkyl is a C2- C10heterocycloalkyl.
  • a heterocycloalkyl is a C4-C10heterocycloalkyl.
  • a heterocycloalkyl is monocyclic or bicyclic.
  • a heterocycloalkyl is monocyclic and is a 3, 4, 5, 6, 7, or 8-membered ring. In some embodiments, a heterocycloalkyl is monocyclic and is a 3, 4, 5, or 6-membered ring. In some embodiments, a heterocycloalkyl is monocyclic and is a 3 or 4-membered ring. In some embodiments, a heterocycloalkyl contains 1 or 2 nitrogen atoms in the ring.
  • a heterocycloalkyl can be aziridinyl, azetidinyl, tetrahydrofuranyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4- dioxanyl, 1,2-dioxolanyl, 1,3-dioxolanyl, 1,3-oxathianyl, 1,4-oxathianyl, 1,3-oxathiolanyl, 1,3- dithiolyl, 1,3-dithiolanyl, 1,4-oxathianyl, tetrahydro-l,4-thiazinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isoindolinyl, indolinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, morph
  • a substituted heterocyclyl can be oxazolidinonyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl.
  • the substituent(s) can be bonded at any available carbon atom and/or heteroatom.
  • a heterocyclyl group can be unsubstituted or substituted.
  • bond refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.
  • bond when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups.
  • substituent(s) when a group is described as being “optionally substituted” that group can be unsubstituted, or can be substituted with one or more of the indicated substituents.
  • substituent(s) can be selected from one or more of the indicated substituents.
  • substituted groups can be substituted with substituents independently selected from halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CHF2, -CF3, -OCH3, -OCHF2, and -OCF3.
  • substituted groups are substituted with one or two of the preceding groups.
  • modulate means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.
  • modulator refers to a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, degrader, or combinations thereof.
  • a modulator is an antagonist.
  • a modulator is an inhibitor.
  • administer refers to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. In some embodiments, the compounds and compositions described herein are administered orally.
  • an “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, or an amount of a pharmaceutical composition comprising the compound described herein or a pharmaceutically acceptable salt thereof, being administered, which will relieve to some extent one or more of the symptoms of the disease, disorder or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • an appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.
  • the terms “enhance” as used herein, means to increase or prolong either in potency or duration a desired effect.
  • a health care practitioner can directly provide a compound described herein to a subject in the form of a sample or can indirectly provide a compound to a subject by providing an oral or written prescription for the compound. Also, for example, a subject can obtain a compound by themselves without the involvement of a health care practitioner. When the compound is administered to the subject, the body is transformed by the compound in some way.
  • “administration” is understood to include the compound and other agents are administered at the same time or at different times and includes both fixed and non-fixed combinations.
  • the term “fixed combination” means that a compound as disclosed and described herein, or a pharmaceutically acceptable salt thereof, and a co-agent, are both administered to a subject simultaneously in the form of a single entity or dosage.
  • the term “non-fixed combination” means that a compound as described herein, or a pharmaceutically acceptable salt thereof, and a co-agent, are administered to a subject as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits. [00161]
  • the term “subject” or “patient” refers to any animal, including mammals.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non- human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • the mammal is a human.
  • the subject can be a healthy volunteer or healthy participant without an underlying Myc-mediated or CDK9-mediated disorder or condition or a volunteer or participant that has received a diagnosis for a disorder or condition in need of medical treatment as determined by a health care professional.
  • a subject under the care of a health care professional who has received a diagnosis for a disorder or condition is typically described as a patient.
  • the terms “treat,” “treating” or “treatment,” as used herein, refer to medical management of a disease, disorder, or condition of a subject.
  • the compounds as described herein can include beneficial or desired clinical results that comprise, but are not limited to, alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development or progression of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a secondary condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
  • beneficial or desired clinical results comprise, but are not limited to, alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development or progression of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a secondary condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
  • Solvents ACS grade. Reagents: unless otherwise noted, from Combi Blocks, Alfa Aesar, Fisher and Aldrich highest quality available.
  • TLC silica gel 60 F254 aluminum plates, (WhatmanTM, type Al Sil G/UV, 250 ⁇ m layer); visualization by UV absorption. Redisep and Biotage Flash+ systems were used for medium-pressure column chromatography.
  • NMR 1 H spectra were obtained at Bruker 400 MHz spectrometer.
  • Step 1 Synthesis of tert-butyl 3-bromo-1H-pyrrolo[2,3-c]pyridine-1-carboxylate
  • Step 2 Synthesis of tert-butyl 3-(2-chloropyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-1- carboxylate
  • tert-butyl 3-bromo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate 0.1 g, 1 Eq, 0.3 mmol
  • 2-chloro-4-(tributylstannyl)pyrimidine 0.1 g, 1.1 Eq, 0.4 mmol
  • 1,4- dioxane 10 mL
  • Pd2(dba)3 0.06 g, 0.2 Eq, 0.07 mmol
  • the resulting mixture was treated with tert-butyl 3-bromo- 1H-pyrrolo[2,3-b]pyridine-1-carboxylate (0.1 g, 1 Eq, 0.3 mmol), and 2-chloro-4- (tributylstannyl)pyrimidine (0.1 g, 1.1 Eq, 0.4 mmol) and stirred until complete.
  • the mixture was filtered via celite and the filtrate was extracted with ethyl acetate, washed with water, then dried over brine. The crude organic layer was dried over Na 2 SO 4 and the solvent was removed.
  • Step 3 Synthesis of 4-(1H-pyrrolo[2,3-c]pyridin-3-yl)-N-(3- (trifluoromethyl)phenyl)pyrimidin-2-amine
  • 3-(2-chloropyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridine 20 mg, 1 Eq, 87 ⁇ mol
  • 3-(trifluoromethyl)aniline 28 mg, 22 ⁇ L, 2 Eq, 0.17 mmol
  • pTsOH ⁇ H2O 33 mg, 2 Eq, 0.17 mmol
  • Step 2 Synthesis of mixture of tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- benzol1-1-caroxylate and tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- benzo[d]imidazole-1-carboxylate [00170] To a mixture of potassium acetate (3.55 g, 3.0 Eq, 36.1 mmol), a mixture of tert-butyl 5- bromo-1H-benzo[d]imidazole-1-carboxylate and tert-butyl 6-bromo-1H-benzo[d]imidazole-1- carboxylate (3.58 g, 1 Eq, 12.0 mmol), and B 2 pin 2 (4.59 g, 1.5 Eq, 18.1 mmol) was added 1,4- dioxane (60 mL) in
  • the mixture was degassed for 10 min and then was treated with Pd(dppf)Cl2 (884 mg, 0.1 Eq, 1.20 mmol).
  • the reaction mixture was heated for 3 h at 90 °C under N 2 and then allowed to cool to rt.
  • the reaction mixture was diluted with ethyl acetate (100 mL) and water (100 mL), passed through a celite bed, organic layer was separated, the aqueous layer extracted with ethyl acetate (2 ⁇ 100 mL). The combined organic layer was washed with water, then brine, and finally, dried over Na2SO4. The organic layer was filtered and dried under reduced pressure.
  • Step 3 Synthesis of mixture of tert-butyl 5-(2-chloropyrimidin-4-yl)-1H-benzo[d]imidazole-1- carboxylate and tert-butyl 6-(2-chloropyrimidin-4-yl)-1H-benzo[d]imidazole-1-carboxylate [00171] To a solution of potassium carbonate (3.97 g, 2.5 Eq, 28.8 mmol) and a mixture of 2,4- dichloropyrimidine (2.40 g, 1.4 Eq, 16.1 mmol) in 1,4-dioxane (60 mL) under N2 was added tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole-1-carboxylate and tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)
  • the reaction mixture was purged with N 2 for 10 min and then was treated with Pd(dppf)Cl 2 (1.69 g, 0.2 Eq, 2.30 mmol).
  • the resulting mixture was heated at 100 °C for 3 h under nitrogen and then allowed to cool to rt.
  • the reaction mixture was diluted with ethyl acetate (100 ⁇ 2 mL), passed through a celite bed, and then washed with water (100 ⁇ 2 mL), and finally with brine.
  • the organic layer was dried over Na 2 SO 4 and filtered.
  • Step 2 Synthesis of 5-(2-chloropyrimidin-4-yl)benzo[d]thiazole
  • 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole 0.575 g, 1 Eq, 2.2 mmol
  • 2,4-dichloropyrimidine 394 mg, 1.2 Eq, 2.64 mmol
  • 1,4-dioxane 10 mL
  • potassium carbonate 609 mg, 2 Eq, 4.4 mmol
  • the reaction mixture was purged with N 2 for 10 min and then was treated with Pd(dppf)Cl 2 (162 mg, 0.1 Eq, 220 ⁇ mol).
  • the reaction mixture was heated at 90 °C for 2 h under nitrogen and then allowed to cool to rt.
  • the reaction mixture was diluted with ethyl acetate (10 X 2 mL), water (10 X 2 mL), and finally with brine.
  • the organic layer was removed under reduced pressure and the remainder was loaded on a 12 g silica column to elute in 100% hexane to 100% ethyl acetate to afford 5-(2-chloropyrimidin-4-yl)benzo[d]thiazole (0.027 g, 0.11 mmol, 5.0 %).
  • Step 3 Synthesis of 4-(benzo[d]thiazol-5-yl)-N-(3-(trifluoromethyl)phenyl)pyrimidin-2-amine (Compound 59) [00175] To solution of 5-(2-chloropyrimidin-4-yl)benzo[d]thiazole (0.06 g, 1 Eq, 0.2 mmol) in ethanol (1 mL) was added 3-(trifluoromethyl)aniline (0.08 g, 0.06 mL, 98% wt, 2 Eq, 0.5 mmol) and 4-methylbenzenesulfonic acid monohydrate (0.08 g, 2 Eq, 0.5 mmol).
  • the resulting mixture was heated at 80 °C for 12 h and then allowed to cool to rt.
  • the solvent was removed under reduced pressure, diluted with ethyl acetate (20 mL), then NaHCO 3 (20 mL) and then the mixture was portioned and the organic layer was maintained.
  • the organic layer was washed with water, dried over Na2SO4, and the solid removed by filtration. The solvent was removed under reduced pressure.
  • Step 2 Synthesis of N 4 -(2-(1H-imidazol-4-yl)ethyl)-N 2 -(3-(trifluoro methyl)phenyl)pyrimidine-2,4-diamine (Compound 111)
  • N-(2-(1H-imidazol-4-yl)ethyl)-2-chloropyrimidin-4-amine 339 mg, 1.5 mmol
  • EtOH 10 mL
  • 3-(trifluoromethyl)aniline 340 mg, 2.1 mmol
  • conc. HCl 0.1 mL
  • Step 2 Synthesis of 4-(2-((3-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenol (Compound 130) [00179] A solution of 4-(2-chloropyrimidin-4-yl)phenol (100 mg, 0.5 mmol), 3- (trifluoromethyl)aniline (97 mg, 0.6 mmol) and pTsOH (172 mg, 1 mmol) in EtOH (10 mL) was stirred at 80 °C overnight and then allowed to cool to rt.
  • Step 2 Synthesis of 2’-methoxy-N-phenyl-[4,4’-bipyrimidin]-2-amine (Compound 163)
  • Compound 163 A mixture of 4-bromo-N-phenylpyrimidin-2-amine (72 mg, 0.28 mmol), 2-methoxy-4- (tributylstannyl)pyrimidine (138 mg, 0.34 mmol) and Pd(PPh 3 ) 4 (33 mg, 0.03 mmol) in toluene (5 mL) was heated to reflux for 16 hrs.
  • Step 3 Synthesis of 4-(imidazo[1,2-a]pyrazin-6-yl)-N-(3-(trifluoromethyl)phenyl)pyrimidin-2- amine (Compound 107) [00186] To a solution of 6-(2-chloropyrimidin-4-yl)imidazo[1,2-a]pyrazine (20 mg, 0.09 mmol) in EtOH (10 mL) was added conc.
  • reaction mixture was stirred at room temperature for 30 mins.
  • the reaction mixture was then poured into ice water (350 mL) and extracted with ethyl acetate (400 mL).
  • the ethyl acetate layer was washed with brine (350 mL), dried over anhydrous sodium sulfate, filtered to remove solids and concentrated under reduced pressure.
  • Step 2 Synthesis of mixture of tert-butyl 5-bromo-1H-benzo[d][1,2,3]triazole-1-carboxylate and tert-butyl 6-bromo-1H-benzo[d][1,2,3]triazole-1-carboxylate
  • a solution of 5-bromo-1H-benzo[d][1,2,3]triazole (1.0 g, 5.1 mmol), Boc2O (1.7 g, 7.6 mmol) and NaOH (0.3 g, 7.6 mmol) in THF/water (5 mL/5 mL) was stirred at room temperature for 3 hrs.
  • Step 3 Synthesis of mixture of tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- benzo[d][1,2,3]triazole-1-carboxylate and tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-benzo[d][1,2,3]triazole-1-carboxylate [00189] A solution of a mixture of tert-butyl 5-bromo-1H-benzo[d][1,2,3]triazole-1-carboxylate and tert-butyl 6-bromo-1H-benzo[d][1,2,3]triazole-1-carboxylate (915 mg, 3.08 mmol), B2pin2 (858 mg, 3.38 mmol), Pd(dppf)Cl2 (220 mg, 0.31 mmol) and KOAc (604 mg, 6.16
  • Step 4 Synthesis of 4-bromo-2-(methylsulfonyl)pyrimidine
  • 4-bromo-2-(methylthio)pyrimidine 1.5 g, 7.32 mmol
  • methanol/water 15 mL/9 mL
  • potassium hydrogen monopersulfate 9.0 g, 14.6 mmol
  • the reaction mixture was stirred at room temperature for 2 hrs.
  • the reaction mixture was filtered to remove solids.
  • the filtrate was poured into H 2 O (100 mL) and extracted with ethyl acetate (100 mL).
  • Step 6 Synthesis of 4-(1H-benzo[d][1,2,3]triazol-5-yl)-N-(3- (trifluoromethyl)phenyl)pyrimidin-2-amine (Compound 139)
  • Step 3 Synthesis of 4-bromo-N-(3-(trifluoromethyl)phenyl)pyrimidin-2-amine
  • 3-(trifluoromethyl)aniline (680 mg, 4.2 mmol) in THF (20 mL) was added NaHMDS (2.5 M in hexane) (2.0 mL, 4.8 mmol) at -70 °C under N 2 atmosphere (balloon).
  • the mixture was stirred at -70 °C for 1 hr, then added a solution of 4-bromo-2- (methylsulfonyl)pyrimidine (1.0 g, 4.2 mmol) and the new mixture was stirred at -70 °C for 2 hrs.
  • Step 4 Synthesis of tert-butyl (5-(2-((3-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)thiazol- 2-yl)carbamate
  • Step 5 Synthesis of 5-(2-((3-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)thiazol-2-amine (Compound 119)
  • Step 2 Synthesis of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-bis((2- (trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2(3H)-one
  • a solution of 5-bromo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol- 2(3H)-one (342 mg, 0.192 mmol), B2pin2 (369 mg, 1.45 mmol), Pd(dppf)Cl2 (52.7 mg, 0.072 mmol) and AcOK (213 mg, 2.17 mmol) in 1,4-dioxane (6 mL) was stirred at 85 °C for 3 hrs under N 2 atmosphere (balloon) and then allowed to cool to rt.
  • Step 3 5-(2-chloropyrimidin-4-yl)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1H- benzo[d]imidazol-2(3H)-one
  • a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-bis((2- (trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2(3H)-one (424 mg, 0.8 mmol), 2,4- dichloropyrimidine (133 mg, 0.892 mmol), Pd(dppf)Cl 2 (52.7 mg, 0.072 mmoL) and K 2 CO 3 (213 mg, 2.17 mmol) in 1,4-dioxane/H 2 O (10 mL/2 mL) was stirred at 85 °C for 4 hrs and then allowed to cool to rt.
  • Step 4 Synthesis of 5-(2-((3-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)-1,3-bis((2- (trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2(3H)-one
  • a solution of 5-(2-chloropyrimidin-4-yl)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1H- benzo[d]imidazol-2(3H)-one 150 mg, 0.296 mmol
  • Step 5 Synthesis of 5-(2-((3-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)-1H- benzo[d]imidazol-2(3H)-one (Compound 116)
  • Step 2 Synthesis of N-(3-fluorophenyl)-4-(1H-indazol-5-yl)pyrimidin-2-amine (Compound 165)
  • N-(3-fluorophenyl)-4-(1H-indazol-5-yl)pyrimidin-2-amine Compound 165
  • Step 2 Synthesis of 2-benzyl-4-(2-methoxypyridin-4-yl)pyrimidine (Compound 230)
  • Step 2 Synthesis of 4-bromo-N-(3-(trifluoromethyl)phenyl)pyrimidin-2-amine
  • 3-(trifluoromethyl)aniline (1.08 g, 6.75 mmol) in THF (15 mL)
  • NaHMDS (6.8 mL, 13.5 mmol)
  • the mixture was stirred at -5 °C for 30 mins under N 2 (balloon).
  • the mixture was cooled to -70 °C and then treated with a solution of 4- bromo-2-(methylsulfonyl)pyrimidine (1.6 g, 6.75 mmol) in THF (20 mL).
  • the resulting mixture was stirred at -70 °C for 2 hrs under N2 (balloon).
  • the reaction mixture was quenched by sat. NH 4 Cl solution, extracted with ethyl acetate (150 mL).
  • the organic layer was dried over Na2SO4, filtered to remove solids and concentrated under reduced pressure.
  • the second isolate was purified by reverse flash to afford 4-bromo-N-(3-(trifluoromethyl)phenyl)pyrimidin-2-amine (0.98 g, yield: 45 %).
  • Step 3 Synthesis of N2’-(3-(trifluoromethyl)phenyl)-[2,4’-bipyrimidine]-2’,5-diamine (Compound 137)
  • reaction mixture was concentrated and the remainder was purified by silica gel column chromatography to give a mixture of tert-butyl 6-bromo-2-methyl-1H- benzo[d]imidazole-1-carboxylate and tert-butyl 5-bromo-2-methyl-1H-benzo[d]imidazole-1- carboxylate (1.2 g, yield: 80%).
  • Step 2 Synthesis of mixture of tert-butyl 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-benzo[d]imidazole-1-carboxylate and tert-butyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-benzo[d]imidazole-1-carboxylate [00212] A solution of a mixture of tert-butyl 6-bromo-2-methyl-1H-benzo[d]imidazole-1- carboxylate and tert-butyl 5-bromo-2-methyl-1H-benzo[d]imidazole-1-carboxylate (100 mg, 0.32 mmol), B 2 pin 2 (163 mg, 0.64 mmol), AcOK (63 mg, 0.64 mmol) and Pd(dppf)Cl 2 (23 mg, 0.032 mmol) in 1,4
  • Step 3 Synthesis of mixture of tert-butyl 2-methyl-6-(2-((3- (trifluoromethyl)phenyl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazole-1-carboxylate and tert- butyl 2-methyl-6-(2-((3-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazole- 1-carboxylate [00213] A mixture of tert-butyl 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- benzo[d]imidazole-1-carboxylate and tert-butyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-benzo[d]imidazole-1-carboxylate (4A and 4B, 115 mg, 0.
  • Step 4 Synthesis of 4-(2-methyl-1H-benzo[d]imidazol-6-yl)-N-(3- (trifluoromethyl)phenyl)pyrimidin-2-amine (Compound 142)
  • Step 2 Synthesis of 5-(2-((3-(trifluoromethyl)phenyl)amino)pyrimidin-1-ium-4-yl)-1H- benzo[d]imidazol-3-ium chloride (Compound 171)
  • 4-(1H-benzo[d]imidazol-5-yl)-N-(3-(trifluoromethyl)phenyl)pyrimidin- 2-amine 0.497 g, 95% Wt, 1 Eq, 1.33 mmol
  • hydrogen chloride 107 mg, 731 ⁇ L, 4 molar, 2.2 Eq, 2.92 mmol
  • the via was capped.
  • the reaction mixture was heated for 12h at 88 °C and then was cooled.
  • the mixture was diluted with ethyl acetate, washed with NaHCO 3 , dried over Na 2 SO 4 , and the solid removed by filtration.
  • the organic layer was removed under the reduced pressure and the remainder was loaded on a 24 g silica column.
  • the resulting mixture was stirred for 1 h at -70 °C, and then treated with 4-chloro-2-(methylsulfonyl)pyrimidine (0.9 g, 1 Eq, 4 mmol) in THF (20 mL). The resulting mixture was stirred for an additional 2 hr at -70 °C. The mixture was treated with ammonium chloride solution (20 mL). The resulting mixture was extracted with ethyl acetate, washed with water, and then washed with brine. The organic layer was dried over Na2SO4, solid removed by filtration and solvent removed under reduced pressure.
  • Step 2 Synthesis of mixture of 5-bromo-1-isopropyl-1H-benzo[d]imidazole and 6-bromo-1- isopropyl-1H-benzo[d]imidazole
  • 5-bromo-1H-benzo[d]imidazole (3 g, 1 Eq, 0.02 mol) and cesium carbonate (5 g, 1 Eq, 0.02 mol) were added to a 50 mL round bottom flask.
  • Acetonitrile (15 mL) was added to the flask, followed by the addition of 2-iodopropane (5 g, 3 mL, 1.8 Eq, 0.03 mol).
  • Step 3 Synthesis of mixture of 1-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-benzo[d]imidazole and 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- benzo[d]imidazole [00220]
  • a mixture of potassium acetate 294 mg, 3 Eq, 3.00 mmol
  • a mixture of 5-bromo-1- isopropyl-1H-benzo[d]imidazole and 6-bromo-1-isopropyl-1H-benzo[d]imidazole (239 mg, 1 Eq, 999 ⁇ mol)
  • B2pin2 (279 mg, 1.1 Eq, 1.10 mmol
  • Step 1 Synthesis of 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine
  • 6-bromo-1H-imidazo[4,5-b]pyridine 1 g, 5.1 mmol
  • THF 40 mL
  • SEMCl 1 g, 6.1 mmol
  • NaH 122 mg, 5.1 mmol
  • Step 2 Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine
  • a solution of 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine 500 mg, 1.53 mmol
  • B2pin2 777 mg, 3.06 mmol
  • Pd(dppf)Cl2 110 mg, 0.15 mmol
  • AcOK 300 mg, 3.06 mmol
  • Step 3 Synthesis of 4-chloro-N-(3-(trifluoromethyl)phenyl)-6-(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-6-yl)-1,3,5-triazin-2-amine
  • a solution of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine 100 mg, 0.27 mmol
  • 4,6-dichloro- N-(3-(trifluoromethyl)phenyl)-1,3,5-triazin-2-amine 99 mg, 0.32 mmol
  • Pd(dppf)Cl 2 23 mg, 0.1 mmol
  • K2CO3 75 mg, 0.54 mmol
  • Step 4 Synthesis of N-(3-(trifluoromethyl)phenyl)-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazo[4,5-b]pyridin-6-yl)-1,3,5-triazin-2-amine
  • 4-chloro-N-(3-(trifluoromethyl)phenyl)-6-(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-6-yl)-1,3,5-triazin-2-amine (20 mg, 0.04 mmol) in MeOH (10 mL) was added Pd/C (20 mg).
  • Step 5 Synthesis of 4-(1H-imidazo[4,5-b]pyridin-6-yl)-N-(3-(trifluoromethyl)phenyl)-1,3,5- triazin-2-amine (Compound 105) [00226] To a solution of N-(3-(trifluoromethyl)phenyl)-4-(1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-imidazo[4,5-b]pyridin-6-yl)-1,3,5-triazin-2-amine (17 mg, 0.03 mmol) in MeOH (3 mL) was added conc. HCl (3 mL). The mixture was stirred at room temperature overnight under N 2 atmosphere.
  • Step 2 Synthesis of 4-chloro-6-(2-methoxypyridin-4-yl)-N-phenyl-1,3,5-triazin-2-amine
  • 4-chloro-6-(2-methoxypyridin-4-yl)-N-phenyl-1,3,5-triazin-2-amine 240 mg, 1.0 mmol
  • 1,4-dioxane/H 2 O 20 mL/5 mL
  • 2,4-dichloropyrimidine 153 mg, 1.0 mmol
  • Pd(dppf)Cl 2 73 mg, 0.1 mmol
  • K 2 CO 3 414 g, 3.0 mmol
  • Step 3 Synthesis of 4-(2-methoxypyridin-4-yl)-N-phenyl-1,3,5-triazin-2-amine (Compound 240) [00229] To a solution of 4-chloro-6-(2-methoxypyridin-4-yl)-N-phenyl-1,3,5-triazin-2-amine (167 mg, 0.53 mmol) in MeOH (20 mL) was added Pd/C (50 mg). The resulting mixture was stirred for 4 hrs under H2 atmosphere (balloon) and then the H2 was replaced with N2.
  • the resulting mixture was purged with N2 for 10 min, and then treated with Pd(dppf)Cl 2 (294 mg, 0.1 Eq, 400 ⁇ mol).
  • the resulting mixture was heated at 90 °C for 4 h under nitrogen and then allowed to cool to rt. Subsequently, the mixture was diluted with ethyl acetate (50 mL) and the organic layer separated. The aqueous layer was extracted with ethyl acetate (10 X 2 mL). The combined organic layer was washed with water (10 X 2 mL), and brine (20 mL). The organic layer was dried over Na 2 SO 4 and filtered to remove solid.
  • Step 2 Synthesis of 6-(1H-benzo[d]imidazol-5-yl)-N-(3-(trifluoromethyl)phenyl)pyridin-2- amine (Compound 50) [00232] To a solution of a mixture of tert-butyl 5-(6-fluoropyridin-2-yl)-1H-benzo[d]imidazole- 1-carboxylate and tert-butyl 6-(6-fluoropyridin-2-yl)-1H-benzo[d]imidazole-1-carboxylate (5A and 5B, 0.11 g, 1 Eq, 0.35 mmol) and 3-(trifluoromethyl)aniline (0.11 g, 88 ⁇ L, 2 Eq, 0.70 mmol) in DMF (3 mL) and NaH ( 42 mg, 2 eq, 1.8 mmol, 60% wet) was heated at 135 °C for 1 h in microwave.
  • Step 2 Synthesis of 4-(1H-benzo[d]imidazol-5-yl)-N-(3-(trifluoromethyl)phenyl)pyridin-2- amine (Compound 52) [00234] To a solution of tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- benzo[d]imidazole-1-carboxylate (0.07 g, 1 Eq, 0.2 mmol) and 4-bromo-N-(3- (trifluoromethyl)phenyl)pyridin-2-amine (0.08 g, 1.2 Eq, 0.2 mmol) under nitrogen in 1,4- dioxane (5 mL) was added potassium carbonate (0.06 g, 2 Eq, 0.4 mmol), and water ( 1.25 mL).
  • the reaction mixture was purged with N2 for 10 min and then was treated with Pd(dppf)Cl2 (0.01 g, 0.1 Eq, 0.02 mmol).
  • the resulting mixture was heated at 90 °C for 4 h under nitrogen and then allowed to cool to rt.
  • the reaction mixture was diluted with ethyl acetate (2 ⁇ 10 mL), washed with water (2 ⁇ 10 mL), and brine (1 ⁇ 10 mL).
  • the organic layer was dried over anhydrous Na2SO4, filtered to remove solids, and concentrated under reduced pressure.
  • Step 2 Synthesis of 6-(3-methoxyphenyl)-N-phenylpyridin-2-amine (Compound 245)
  • Step 2 Synthesis of 4-(3-methoxyphenyl)-N-phenylpyridin-2-amine (Compound 246)
  • a mixture of 2-fluoro-4-(3-methoxyphenyl)pyridine (182 mg, 0.897 mmol) and aniline (100.1 mg, 1.08 mmol) in DMSO (3 mL) was stirred at 200 °C under microwave irradiation for 2 hrs and then allowed to cool to rt.
  • the reaction mixture was combined with H 2 O (10 mL) and extracted with ethyl acetate (10 mL ⁇ 3).
  • the combined ethyl acetate phases were dried over anhydrous Na2SO4, filtered to remove solids and concentrated under reduced pressure.
  • Step 2 Synthesis of N-(4-(1H-benzo[d]imidazol-5-yl)pyridin-2-yl)-6-(difluoromethyl)pyridin- 2-amine
  • a mixture of sodium carbonate (0.3 mL, 1 molar, 3 Eq, 0.3 mmol) tert-butyl 5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole-1-carboxylate and tert-butyl 6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole-1-carboxylate (1A and 1B, 0.03 g, 1.0 Eq, 0.09 mmol), and 4-bromo-N-(6-(difluoromethyl)pyridin-2-yl)pyridin-2-amine (0.03 g, 1.1 E
  • the resulting mixture was purged with N2 and treated with added Pd2(dba)3 (0.24 g, 0.06 Eq, 0.27 mmol).
  • the vessel was then purged with N2 for 10 min and then capped.
  • the mixture was heated at 100 °C for 5 h.
  • the mixture was passed via celite, diluted with ethyl acetate, and the dilutant washed with water and brine, and dried over Na 2 SO 4 .
  • the solid was removed by filtration and the solvent was removed under reduced pressure.
  • Step 2 Synthesis of N-(4-(1H-benzo[d]imidazol-6-yl)pyridin-2-yl)-6-(trifluoromethyl)pyridin- 2-amine
  • a mixture of sodium carbonate (5.13 mL, 1 molar, 3 Eq, 5.13 mmol), tert-butyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole-1-carboxylate and tert- butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole-1-carboxylate (1A and 1B, 589 mg, 1 Eq, 1.71 mmol), and 4-chloro-N-(6-(trifluoromethyl)pyridin-2-yl)pyridin-2- amine (515 mg, 1.1 Eq, 1.88
  • Step 2 Synthesis of 4-(1H-benzo[d]imidazol-6-yl)-5-fluoro-N-(6-(trifluoromethyl)pyridin-2- yl)pyridin-2-amine
  • a mixture of 4-bromo-5-fluoro-N-(6-(trifluoromethyl)pyridin-2-yl)pyridin-2-amine (0.09 g, 1.1 Eq, 0.3 mmol)
  • tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- benzo[d]imidazole-1-carboxylate and tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-benzo[d]imidazole-1-carboxylate (1A and 1B, 0.08 g, 1.0 Eq, 0.2 mmol), and potassium carbonate (0.1
  • the reaction was heated at 50 °C for 2 h to afford 5-bromo-N-cyclopropyl-3-fluoro-2-nitroaniline (2.2 g, 8.0 mmol, 100 %) as the major product.
  • the reaction mixture was dried under reduced pressure and loaded on a silica column, and purified with 100% hexane to 100% ethyl acetate to furnish 5-bromo-N-cyclopropyl-3-fluoro- 2-nitroaniline (2.2 g, 8.0 mmol, 100%).
  • Step 2 Synthesis of 5-bromo-N 1 -cyclopropyl-3-fluorobenzene-1,2-diamine
  • 5-bromo-N-cyclopropyl-3-fluoro-2-nitroaniline (2.21 g, 1 Eq, 8.03 mmol) in EtOH/water (10 mL/2 mL)
  • ammonium chloride (2.15 g, 5 Eq, 40.2 mmol)
  • iron 2.24 g, 5 Eq, 40.2 mmol
  • Step 3 Synthesis of 6-bromo-1-cyclopropyl-4-fluoro-2-methyl-1H-benzo[d]imidazole
  • 1,1,1-trimethoxymethane (0.54 g, 10 mL, 1 Eq, 4.5 mmol) was added to 5-bromo-N1- cyclopropyl-3-fluorobenzene-1,2-diamine (1.1 g, 1 Eq, 4.5 mmol) and heated for 2 h at 100 °C. The reaction was cooled and dried under reduced pressure.
  • Step 4 Synthesis of 4-(1-cyclopropyl-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-N-(6- (trifluoromethyl)pyridin-2-yl)pyridin-2-amine [00248] To a solution of potassium acetate (71 mg, 3 Eq, 0.72 mmol) in EtOH (2 mL) was added hypodiboric acid (65 mg, 3 Eq, 0.72 mmol), 6-bromo-1-cyclopropyl-4-fluoro-2-methyl- 1H-benzo[d]imidazole (65 mg, 1 Eq, 0.24 mmol), XPhos (3.5 mg, 0.03 Eq, 7.2 ⁇ mol), and XPhos-Pd_G2 (5.7 mg, 0.03 Eq, 7.2 ⁇ mol).
  • hypodiboric acid 65 mg, 3 Eq, 0.72 mmol
  • the reaction mixture was degassed for 4 minutes and heated at 85 °C until the color turned orange.
  • the reaction mixture was cooled, and 4- chloro-N-(6-(trifluoromethyl)pyridin-2-yl)pyridin-2-amine (73 mg, 1.1 Eq, 0.27 mmol) and K 2 CO 3 (0.10 g, 0.40 mL, 1.8 molar, 3 Eq, 0.72 mmol) were added under nitrogen.
  • the reaction mixture was heated at 85 °C overnight.
  • the reaction mixture was cooled and passed through celite, then dried under reduced pressure.
  • Step 1 Synthesis of 5-bromo-N-cyclopropyl-2-nitroaniline
  • 4-bromo-2-fluoro-1-nitrobenzene (2 g, 1 Eq, 9 mmol) in ACN (10 mL) was added cyclopropanamine (2 g, 4 Eq, 0.04 mol) and DIEA (1 g, 2 mL, 1 Eq, 9 mmol).
  • the reaction mixture was heated at 80 °C for 2 h, dried under reduced pressure, and purified via column chromatography with a gradient 20% DCM in methanol to afford 5-bromo-N- cyclopropyl-2-nitroaniline (2 g, 8 mmol, 90%).
  • Step 2 Synthesis of 5-bromo-N 1 -cyclopropylbenzene-1,2-diamine
  • 5-bromo-N-cyclopropyl-2-nitroaniline 2 g, 1 Eq, 8 mmol
  • ammonium chloride 2 g, 5 Eq, 0.04 mol
  • iron 2 g, 5 Eq, 0.04 mol
  • the crude was dried under reduced pressure and loaded in a silica column.
  • the crude was purified with 100% hexane to 100% ethyl acetate to afford 6-bromo-1-cyclopropyl-2-methyl-1H- benzo[d]imidazole (292 mg, 1.16 mmol, 74.4%).
  • Step 4 Synthesis of 4-(1-cyclopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-N-(6- (trifluoromethyl)pyridin-2-yl)pyridin-2-amine [00252]
  • hypodiboric acid 138 mg, 3 Eq, 1.54 mmol
  • 6-bromo-1-cyclopropyl-2-methyl-1H- benzo[d]imidazole 129 mg, 1 Eq, 514 ⁇ mol
  • XPhos (7 mg, 0.03 Eq, 15 ⁇ mol)
  • XPhos- Pd_G2 (12 mg, 0.03 Eq, 15 ⁇ mol).
  • the reaction mixture was degassed for 4 minutes and heated at 85 °C until the color turned orange.
  • the reaction mixture was cooled, and 4-chloro-N-(6- (trifluoromethyl)pyridin-2-yl)pyridin-2-amine (155 mg, 1.1 Eq, 565 ⁇ mol) and K2CO3 (213 mg, 856 ⁇ L, 1.8 molar, 3 Eq, 1.54 mmol) were added under nitrogen.
  • the reaction mixture was heated at 85 °C overnight.
  • the reaction mixture was cooled and passed through celite, then dried under reduced pressure.
  • the reaction was degassed, sealed, and heated at 85 °C until the color changed from orange to yellow.
  • the reaction mixture was cooled, and 4-chloro-N-(6- (trifluoromethyl)pyridin-2-yl)pyridin-2-amine (125 mg, 1.1 Eq, 458 ⁇ mol) and potassium carbonate (173 mg, 694 ⁇ L, 1.8 molar, 3 Eq, 1.25 mmol) were added under nitrogen.
  • the reaction was degassed and heated 15 h at 85 °C.
  • Step 1 Synthesis of 5-bromo-2-methyl-2H-indazole
  • 5-bromo-2-nitrobenzaldehyde 564 mg, 1 Eq, 2.45 mmol
  • methylamine solution 209 mg, 0.34 mL, 40% Wt in water, 1.1 Eq, 2.70 mmol
  • 2- propanol 10 mL
  • the reaction mixture was heated at 80 °C for 4 h.
  • the reaction was cooled and tributylphosphane (1.49 g, 1.80 mL, 3 Eq, 7.36 mmol) was added under nitrogen.
  • the reaction was heated to reflux at 80 °C for 4 days.
  • Step 3 Synthesis of 5-bromo-3-isopropyl-2-methyl-2H-indazole [00257] To a solution of 2-(5-bromo-2-methyl-2H-indazol-3-yl)propan-2-ol (84 mg, 1 Eq, 0.31 mmol) in DCM (6 mL) was added triethylsilane (0.36 g, 0.50 mL, 10 Eq, 3.1 mmol) and trifluoroacetic acid (0.36 g, 0.24 mL, 10 Eq, 3.1 mmol). The reaction mixture was stirred for 12 h at 25 °C.
  • reaction mixture was diluted with NaHCO3, extracted with ethyl acetate, and the combined organic layer was dried over Na2SO4.
  • the crude was loaded on silica gel and purified with 10% MeOH in DCM to afford the compound 5-bromo-3-isopropyl-2-methyl-2H-indazole (61.4 mg, 243 ⁇ mol, 78%).
  • Step 4 Synthesis of 4-(3-isopropyl-2-methyl-2H-indazol-5-yl)-N-(6-(trifluoromethyl)pyridin- 2-yl)pyridin-2-amine [00258] To a solution of potassium acetate (72 mg, 3 Eq, 0.73 mmol) in EtOH (2 mL) was added hypodiboric acid (66 mg, 3 Eq, 0.73 mmol), 5-bromo-3-isopropyl-2-methyl-2H-indazole (62 mg, 1 Eq, 0.24 mmol), XPhos (3.5 mg, 0.03 Eq, 7.3 ⁇ mol), and XPhos-Pd_G2 (5.8 mg, 0.03 Eq, 7.3 ⁇ mol).
  • the reaction mixture was degassed for 4 minutes and heated at 85 °C until color turned orange.
  • the reaction mixture was cooled, and 4-chloro-N-(6-(trifluoromethyl)pyridin-2- yl)pyridin-2-amine (74 mg, 1.1 Eq, 0.27 mmol) and K 2 CO 3 (0.10 g, 0.41 mL, 1.8 molar, 3 Eq, 0.73 mmol) were added under nitrogen.
  • the reaction mixture was heated at 85 °C o/n.
  • the reaction mixture was cooled and passed through a celite pad, then dried under reduced pressure.
  • Step 1 Synthesis of 5-bromo-N-isopropyl-2-nitroaniline
  • 4-bromo-2-fluoro-1-nitrobenzene (2 g, 1 Eq, 9 mmol)
  • propan-2-amine (2 g, 3 mL, 4 Eq, 0.04 mol)
  • DIPEA 5 g, 6 mL, 4 Eq, 0.04 mol
  • the reaction mixture was heated at 80 °C for 3 h.
  • the solution turned deep brown and was filtered, washed with water, and dried over Na2SO4.
  • the crude was passed through a silica column to afford 5-bromo-N1-isopropylbenzene-1,2-diamine (1.75 g, 7.64 mmol, 50%).
  • Step 3 Synthesis of 6-bromo-1-isopropyl-2-methyl-1H-benzo[d]imidazole
  • Step 4 Synthesis of 4-(1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-N-(6- (trifluoromethyl)pyridin-2-yl)pyridin-2-amine [00262]
  • sodium carbonate 116 mg, 1.10 mL, 1 molar, 3 Eq, 1.10 mmol
  • 1- isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole 121 mg, 1.1 Eq, 402 ⁇ mol
  • 4-chloro-N-(6-(trifluoromethyl)pyridin-2-yl)pyridin-2-amine 100 mg, 1.0 Eq, 365 ⁇ mol
  • degassed DME 10 mL
  • sodium carbonate 116 mg, 1.10 mL, 1 molar, 3 Eq, 1.10 mmol
  • the reaction was degassed for 4 minutes and heated at 85 °C until the color turned orange.
  • the reaction mixture was cooled, and 4-chloro-N-(6- (trifluoromethyl)pyridin-2-yl)pyridin-2-amine (142 mg, 1.1 Eq, 519 ⁇ mol) and K2CO3 (196 mg, 786 ⁇ L, 1.8 molar, 3 Eq, 1.41 mmol) were added under nitrogen.
  • the reaction was heated at 85 °C o/n.
  • the reaction mixture was cooled, passed through celite, and dried under reduced pressure.
  • the reaction mixture was heated at 50 °C for 2 h.
  • the crude was dried under reduced pressure, loaded in a column, and purified by 100% hexane to 100% ethyl acetate to furnish 5-bromo-2- nitro-N-phenylaniline (2 g, 7 mmol, 80%).
  • Step 2 Synthesis of 5-bromo-N1-phenylbenzene-1,2-diamine
  • 5-bromo-2-nitro-N-phenylaniline 3 g, 1 Eq, 0.01 mol
  • iron 3 g, 5 Eq, 0.05 mol
  • ammonium chloride 3 g, 5 Eq, 0.05 mol
  • Step 4 Synthesis of 4-(2-methyl-1-phenyl-1H-benzo[d]imidazol-5-yl)-N-(6- (trifluoromethyl)pyridin-2-yl)pyridin-2-amine [00267] To a mixture of potassium acetate (175 mg, 3 Eq, 1.79 mmol), Pd(dppf)Cl 2 (43.6 mg, 0.1 Eq, 59.5 ⁇ mol), and 5-bromo-2-methyl-1-phenyl-1H-benzo[d]imidazole (171 mg, 1 Eq, 595 ⁇ mol) was added 1,4-dioxane (10 mL) under nitrogen.
  • the mixture was degassed and Pd(dppf)Cl 2 (43.6 mg, 0.1 Eq, 59.5 ⁇ mol) was added.
  • the reaction mixture was degassed and heated to reflux at 90 °C for 12 h under nitrogen.
  • the mixture was passed via celite and purified by column chromatography with 100% hexane to 100% ethyl acetate to furnish 2-methyl-1- phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (190 mg, 568 ⁇ mol, 95.5 %).
  • the mixture was degassed and heated at 85 °C until the color turned orange.
  • the mixture was cooled, and 5-bromo-3-isopropyl-2-methyl-2H-indazole (62 mg, 1 Eq, 0.24 mmol) and K 2 CO 3 (0.10 g, 0.41 mL, 1.8 molar, 3 Eq, 0.73 mmol) were added under nitrogen.
  • the mixture was heated to 85 °C o/n.
  • the reaction mixture was cooled and passed via celite pad, and dried under reduced pressure.
  • reaction mixture was heated at 70 °C for 2 h.
  • the reaction mixture was dried under reduced pressure and loaded in a silica column and purified with 100% hexane to 100% ethyl acetate to furnish 5-bromo-3-fluoro-N- isopropyl-2-nitroaniline.
  • Step 2 Synthesis of 5-bromo-3-fluoro-N1-isopropylbenzene-1,2-diamine
  • 5-bromo-3-fluoro-N-isopropyl-2-nitroaniline 2 g, 1 Eq, 7 mmol
  • iron 2 g, 5 Eq, 0.04 mol
  • ammonium chloride 2 g, 5 Eq, 0.04 mol
  • Step 3 Synthesis of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole
  • 5-bromo-3-fluoro-N1-isopropylbenzene-1,2-diamine 503 mg, 1 Eq, 2.04 mmol
  • 1,1,1-triethoxyethane 330 mg, 6 mL, 1 Eq, 2.04 mmol
  • Step 4 Synthesis of 4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-N-(6- (trifluoromethyl)pyridin-2-yl)pyridin-2-amine [00272]
  • hypodiboric acid 28 mg, 3 Eq, 0.31 mmol
  • XPhos 1.5 mg, 0.03 Eq, 3.1 ⁇ mol
  • XPhos 1.5 mg, 0.03 Eq, 3.1 ⁇ mol
  • XPhos-Pd_G2 2.4 mg, 0.03 Eq, 3.1 ⁇ mol
  • 6-bromo-4-fluoro- 1-isopropyl-2-methyl-1H-benzo[d]imidazole 28 mg, 1 Eq, 0.10 mmol.
  • the mixture was degassed for 4 minutes and heated at 85 °C until color turned orange.
  • the reaction mixture was cooled, and 4-chloro-N-(6-(trifluoromethyl)pyridin-2-yl)pyridin-2-amine (31 mg, 1.1 Eq, 0.11 mmol) and potassium carbonate (43 mg, 0.17 mL, 1.8 molar, 3 Eq, 0.31 mmol) were added under nitrogen.
  • the reaction was heated at 85 °C o/n.
  • the reaction mixture was cooled, passed through celite, and concentrated.
  • the crude was loaded in a reverse phase column and purified with 10% MeOH to 100% MeOH to afford the title compound in 20% yield.
  • * IC50 less than 0.2 ⁇ M
  • A IC50 greater than or equal to 0.2 ⁇ M and less than 1 ⁇ M
  • B IC 50 greater than or equal to 1 ⁇ M and less than 10 ⁇ M
  • C IC 50 greater than or equal to 10 ⁇ M and less than 100 ⁇ M.
  • PDXs patient-derived orthotopic xenografts
  • NSG immunodeficient mice
  • Tumor tissues were isolated from tumor-bearing animals, dissociated into a single-cell suspension, resuspended in serum-free media, and immediately plated in 384 well plates.
  • FIG.1 shows the experimental set-up and workflow of the Myc inhibition assay.
  • FIGs.2A-2D shows the compound profile for Compound A as shown below.
  • FIG.2A shows Myc expression inhibition in PDX511 medulloblastoma cells by Compound A with an IC 50 of 11.7 ⁇ M.
  • FIG.2B shows that Compound A had no effect on the expression of the retinoblastoma (Rb) protein in PDX511 medulloblastoma cells.
  • FIG.2C shows that Compound A had no effect on cell viability of PDX511 medulloblastoma cells at 4 hours.
  • FIG.2D shows images of immunofluorescence-based detection of Myc expression (top row), cell viability (middle row), and Rb protein expression (bottom row) of PDX511 medulloblastoma cells treated with Compound A at various concentrations.
  • FIGs.3A-3D show the compound profile for Compound 171.
  • FIG.3A shows Myc expression inhibition in PDX511 medulloblastoma cells by Compound 171.
  • FIG.3B shows that Compound 171 had no effect on expression of the retinoblastoma (Rb) protein in PDX511 medulloblastoma cells.
  • FIG.3C shows that Compound 171 had no effect on cell viability of PDX511 medulloblastoma cells at 4 hours.
  • FIG.3D shows images of immunofluorescence- based detection of Myc expression (top row), cell viability (middle row), and Rb protein expression (bottom row) of PDX511 medulloblastoma cells treated with Compound 171 at various concentrations.
  • Example 5 Inhibition of Myc Expression with Treatment of Compound 171 in Medulloblastoma PDX Cells in Mice Experimental Procedure [00279] Medulloblastoma PDX cells were harvested from the brains of tumor-bearing mice, cultured overnight, and then treated with Compound 171 for various amounts of time. Cells cultured for time points of 1 hour, 2 hours, and 4 hours were lysed and subjected to Western blotting with antibodies specific for Myc or GAPDH as control, as shown in FIG.4A. Cells cultured for longer time points of 48 hours and 96 hours were assayed for viability using the CellTiter Glo assay, as shown in FIG.4B and FIG.4C.
  • Example 6 Inhibition of Myc Expression with Treatment of Compound 171 in Cell Lines Derived from Various Cancers Experimental Procedure [00282] Cell lines derived from acute monocytic leukemia, acute promyelocytic leukemia, pancreatic adenocarcinoma and small cell lung cancer were treated with vehicle (DMSO) or the indicated concentrations of Compound 171 for 4 hours, and then lysed and subjected to Western blotting using antibodies specific for Myc or GAPDH as control. Results [00283] As shown in FIGs.5A-5D, all cell lines tested showed substantial inhibition of Myc at both 0.18 ⁇ M and 1.0 ⁇ M concentrations of Compound 171.
  • FIG.5A shows the inhibition result from the THP-1 cell line derived from acute monocytic leukemia.
  • FIG.5B shows the inhibition result from the HL-60 cell line derived from acute promyelocytic leukemia.
  • FIG.5C shows the inhibition result from the BxPC-3 cell line derived from pancreatic adenocarcinoma.
  • FIG.5D shows the inhibition result from the H-82 cell line derived from small cell lung cancer.
  • Example 7 Accumulation of Compound 171 in the Brain of Mice Following Oral Administration of the Compound Experimental Procedure
  • NSG Non-tumor-bearing NOD-SCID-IL2Rgamma knockout mice were treated with Compound 171 at 100 mg/kg via oral administration. Blood was collected retro-orbitally or by cardiac puncture for measuring compound concentrations. For measurements of compound concentration in the brain, animals were sacrificed, and brain tissue was harvested and homogenized. Compound concentration was determined by liquid chromatography-mass spectrometry (LCMS). Results [00286] As shown in FIG.6, concentrations of Compound 171 remained above the IC90 level in both plasma and brain for more than 6 hours following oral administration of the compound.
  • LCMS liquid chromatography-mass spectrometry
  • Compound 171 demonstrated the ability to cross the blood-brain-barrier with good retention in the brain following oral administration in mice.
  • Example 8 Reduction of Myc Levels with Oral Administration of Compound 171 in Intracranial Tumors in Mice Experimental Procedure [00288] NSG mice transplanted with medulloblastoma PDX cells were treated by oral administration with either vehicle (10% DMSO, 10% Tween 80) or Compound 171 (100 mg/kg). After 5.5 hours, animals were sacrificed, and tumors were harvested, dissociated, lysed and subjected to Western blotting with antibodies specific for Myc or GAPDH as control.

Abstract

La présente divulgation concerne des composés et des compositions qui sont utiles en tant que modulateurs de la protéine MYC et des méthodes d'utilisation de ceux-ci pour traiter des maladies ou des troubles médiés par MYC.
PCT/US2023/072925 2022-08-26 2023-08-25 Dérivés d'aminopyrimidine et d'aminotriazine utilisés en tant que modulateurs de la protéine myc WO2024044757A1 (fr)

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