WO2023146512A1 - Compounds and methods of use thereof - Google Patents
Compounds and methods of use thereof Download PDFInfo
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- WO2023146512A1 WO2023146512A1 PCT/US2022/013749 US2022013749W WO2023146512A1 WO 2023146512 A1 WO2023146512 A1 WO 2023146512A1 US 2022013749 W US2022013749 W US 2022013749W WO 2023146512 A1 WO2023146512 A1 WO 2023146512A1
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- compound
- substituted
- unsubstituted
- pharmaceutically acceptable
- solvate
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- 229960000553 somatostatin Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- DUYSYHSSBDVJSM-KRWOKUGFSA-N sphingosine 1-phosphate Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)COP(O)(O)=O DUYSYHSSBDVJSM-KRWOKUGFSA-N 0.000 description 1
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- 239000000375 suspending agent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 201000011080 telangiectatic osteogenic sarcoma Diseases 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- IBVAPXYQTAUIMB-UHFFFAOYSA-N tert-butyl 2-(5-bromopyrimidin-2-yl)-2-cyanoacetate Chemical compound CC(C)(C)OC(=O)C(C#N)C1=NC=C(Br)C=N1 IBVAPXYQTAUIMB-UHFFFAOYSA-N 0.000 description 1
- BFNYNEMRWHFIMR-UHFFFAOYSA-N tert-butyl 2-cyanoacetate Chemical compound CC(C)(C)OC(=O)CC#N BFNYNEMRWHFIMR-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- IRRRVCLDPODLJG-UHFFFAOYSA-N tert-butyl n-(4-bromopyridin-2-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC(Br)=CC=N1 IRRRVCLDPODLJG-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
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- LBLYYCQCTBFVLH-UHFFFAOYSA-M toluenesulfonate group Chemical group C=1(C(=CC=CC1)S(=O)(=O)[O-])C LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
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- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
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- 230000028973 vesicle-mediated transport Effects 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/76—Nitrogen atoms to which a second hetero atom is attached
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- YAP and TAZ are transcriptional co-activators of the Hippo pathway network and regulate cell proliferation, migration, and apoptosis. Inhibition of the Hippo pathway promotes YAP/TAZ translocation to the nucleus, wherein YAP/TAZ interact with transcriptional enhancer associate domain (TEAD) transcription factors and coactivate the expression of target genes and promote cell proliferation.
- TEAD transcriptional enhancer associate domain
- Hyperactivation of YAP and TAZ and/or mutations in one or more members of the Hippo pathway network have been implicated in numerous cancers. Described herein are inhibitors associated with one or more members of the Hippo pathway network, such as inhibitors of YAP/TAZ or inhibitors that modulate the interaction between YAP/TAZ and TEAD.
- compositions comprising said compounds.
- the subject compounds are useful for the treatment of diseases or disorders.
- the disease or disorder is cancer.
- the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof: wherein, ring A is monocyclic heteroaryl;
- X 1 is N or CR X1 ;
- X 2 is N or CR X2 ;
- X 3 is N or CR X3 ;
- X 4 is N or CR X4 ;
- R 4 and R 5 taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C 3 -C8cycloalkyl or substituted or unsubstituted 3- to 8- membered heterocycloalkyl having 1 or 2 heteroatoms each independently selected from N, O, and S; or
- R 7 and R 8 taken together with the atom to which they are attached to form a substituted or unsubstituted N- or P-containing 3- to 8-membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, or 4.
- the present disclosure provides a compound described in Table 1, or a pharmaceutically acceptable salt or solvate thereof.
- the present disclosure provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient.
- the present disclosure provides a method of inhibiting one or more of proteins encompassed by, or related to, the Hippo pathway in a subject, comprising administering to a subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.
- the present disclosure provides a method of inhibiting transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP) in a subject comprising administering to a subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.
- the subject has cancer, polycystic kidney disease, or liver fibrosis.
- the cancer is selected from mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwannoma, lung cancer, bladder carcinoma, cutaneous neurofibromas, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, and breast cancer.
- the present disclosure provides a method of treating cancer in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.
- the cancer is selected from mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwannoma, lung cancer, bladder carcinoma, cutaneous neurofibromas, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, and breast cancer.
- the present disclosure provides a method of treating polycystic kidney disease or liver fibrosis in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.
- ranges and amounts are expressed as “about” a particular value or range. About also includes the exact amount. Hence “about 5 ⁇ L” means “about 5 ⁇ L” and also “5 ⁇ L.” Generally, the term “about” includes an amount that is expected to be within experimental error.
- the terms “individual(s)”, “subject(s)” and “patient(s)” mean any mammal.
- the mammal is a human.
- the mammal is a nonhuman. None of the terms require or are limited to situations characterized by the supervision (e.g., constant or intermittent) of a health care worker (e.g., a doctor, a registered nurse, a nurse practitioner, a physician’s assistant, an orderly, or a hospice worker).
- a health care worker e.g., a doctor, a registered nurse, a nurse practitioner, a physician’s assistant, an orderly, or a hospice worker.
- Amino refers to the -NH2 radical.
- Niro refers to the -NO2 radical.
- Oxa refers to the -O- radical.
- Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C 1 -C 15 alkyl).
- an alkyl comprises one to thirteen carbon atoms (e.g., C 1 -C13 alkyl).
- an alkyl comprises one to eight carbon atoms (e.g., C 1 -C8 alkyl).
- an alkyl comprises one to five carbon atoms (e.g., C 1 -C5 alkyl).
- an alkyl comprises one to four carbon atoms (e.g., C 1 -C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C 1 -C 3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C 1 -C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C 5 -C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8 alkyl).
- an alkyl comprises two to five carbon atoms (e.g., C 2 -C 5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C 3 -C 5 alkyl).
- the alkyl group is selected from methyl, ethyl, 1 -propyl (n-propyl), 1 -methylethyl (iso-propyl), 1 -butyl (//-butyl), 1 -methylpropyl (sec- butyl), 2-methylpropyl (iso-butyl), 1,1 -dimethylethyl (tert-butyl), 1 -pentyl (//-pentyl).
- the alkyl is attached to the rest of the molecule by a single bond.
- an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, OR a , -SR a , OC(O)R a , N(R a )2, C(O)R a , C(O)OR a , C(O)N(R a ) 2 , N(R a )C(O)OR f , OC(O) NR a R f , N(R a )C(O)R f , N(R a )S(O) t R f (where t is 1 or 2), S(O)tOR a (where t is 1 or 2), S(O)tR f (where t is 1 or 2), and S(O)tN(R a )2 (where t is 1
- Alkoxy refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.
- alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like.
- ethenyl i.e., vinyl
- prop-l-enyl i.e., allyl
- but-l-enyl pent-l-enyl, penta- 1,4-dienyl, and the like.
- an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, OR a , -SR a , OC(O) R a , N(R a )2, C(O)R a , C(O)OR a , C(O)N(R a ) 2 , N(R a )C(O)OR f , OC(O) NR a R f , N(R a )C(O)R f , N(R a )S(O)tR f (where t is 1 or 2), S(O)tOR a (where t is 1 or 2), S(O)tR f (where t is 1 or 2), S(O)tR f (where t is 1 or 2), and S(O)tN(R a
- Alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms.
- an alkynyl comprises two to eight carbon atoms.
- an alkynyl has two to four carbon atoms.
- the alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
- an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, OR a , -SR a , OC(O) R a , N(R a )2, C(O)R a , C(O)OR a , C(O)N(R a ) 2 , N(R a )C(O)OR f , OC(O) NR a R f , N(R a )C(O)R f , N(R a )S(O) t R f (where t is 1 or 2), S(O)tOR a (where t is 1 or 2), S(O)tR f (where t is 1 or 2), and S(O)tN(R a )2 (where t
- Alkylene or "alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, ⁇ -butylene, and the like.
- the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
- the points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain.
- an alkylene comprises one to eight carbon atoms (e.g., C 1 -Cs alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C 1 -C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C 1 -C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C 1 -C 3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C 1 -C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., Ci alkylene).
- an alkylene comprises five to eight carbon atoms (e.g., Cs-Cs alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C 2 -C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C 3 -C5 alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -
- Aryl refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom.
- the aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ⁇ -electron system in accordance with the Hiickel theory.
- the ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene.
- aryl or the prefix “ar-” (such as in “aralkyl”) is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -CN, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a ,
- Aryloxy refers to a radical bonded through an oxygen atom of the formula -O-aryl, where aryl is as defined above.
- Aralkyl refers to a radical of the formula -R c -aryl where R c is an alkylene chain as defined above, for example, methylene, ethylene, and the like.
- the alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain.
- the aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
- alkenyl refers to a radical of the formula -R d -aryl where R d is an alkenylene chain as defined above.
- the aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group.
- the alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.
- Aralkynyl refers to a radical of the formula -R e -aryl, where R e is an alkynylene chain as defined above.
- the aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group.
- the alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.
- Carbocyclyl or “carbocycle” refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclyl from “heterocyclyl” rings or “heterocycles” in which the ring backbone contains at least one atom which is different from carbon.
- a carbocyclyl is a monocyclic carbocyclyl or a bicyclic carbocyclyl.
- a carbocyclyl is a monocyclic carbocyclyl.
- Carbocyclyls are non-aromatic or aromatic.
- Non-aromatic carbocyclyls are saturated or partially unsaturated.
- a carbocyclyl is a bicyclic carbocyclyl.
- at least one of the two rings of a bicyclic carbocyclyl is aromatic.
- both rings of a bicyclic carbocyclyl are aromatic.
- Carbocyclyl include aryls and cycloalkyls.
- Cycloalkyl refers to a monocyclic or polycyclic aliphatic, fully saturated non-aromatic carbocyclyl, wherein each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom.
- cycloalkyls are spirocyclic or bridged compounds.
- cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom.
- Cycloalkyl groups include groups having from 3 to 10 ring atoms. In some embodiments, cycloalkyl groups include groups having from 3 to 6 ring atoms.
- cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl and bicyclefl .1. l]pentyl.
- a cycloalkyl is a C3-C 6 cycloalkyl.
- Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
- a cycloalkyl comprises three to eight carbon atoms (e.g., C3-C8 cycloalkyl).
- a cycloalkyl comprises three to seven carbon atoms (e.g., C 3 -C7 cycloalkyl).
- a cycloalkyl comprises three to six carbon atoms (e.g., C 3 -C6 cycloalkyl).
- a cycloalkyl comprises three to five carbon atoms (e.g., C 3 -C5 cycloalkyl). In other embodiments, a cycloalkyl comprises three to four carbon atoms (e.g., C 3 -C4 cycloalkyl).
- An unsaturated carbocyclyl is also referred to as "cycloalkenyl.” Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
- Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.
- cycloalkyl is meant to include cycloalkyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -CN, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R
- Carbocycloalkylalkyl refers to a radical of the formula -R c - cycloalkyl where R c is an alkylene chain as defined above.
- R c is an alkylene chain as defined above.
- the alkylene chain and the cycloalkyl radical are optionally substituted as defined above.
- Halo or "halogen” refers to bromo, chloro, fluoro, or iodo substituents.
- Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like.
- the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.
- Heterocyclyl or “heterocycle” refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms.
- Non-aromatic heterocyclic groups also known as heterocycloalkyls
- aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system.
- the heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which include fused, spiro, or bridged ring systems in some embodiments.
- the heteroatoms in the heterocyclyl radical are optionally oxidized.
- One or more nitrogen atoms, if present, are optionally quaternized.
- the heterocyclyl radical is partially or fully saturated.
- the heterocyclyl is attached to the rest of the molecule through any atom of the ring(s).
- Heterocycloalkyl refers to a cycloalkyl group in which one or more skeletal atoms of the cycloalkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, - N(alkyl)-, sulfur, or combinations thereof.
- a heterocycloalkyl is fused with an aryl or heteroaryl.
- heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxoxo
- heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides.
- a heterocycloalkyl is a C 2 -C 10 heterocycloalkyl.
- a heterocycloalkyl is a 5- to 10-membered C 4 -C 9 heterocycloalkyl.
- a heterocycloalkyl is a 4- to 7-membered C 3 -C 6 heterocycloalkyl.
- a heterocycloalkyl contains 0-2 N atoms in the ring.
- a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.
- heterocycloalkyl is meant to include heterocycloalkyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -CN, -R
- Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-, sulfur, or combinations thereof.
- a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
- a heteroalkyl is a C 1 -C 6 heteroalkyl.
- the alkyl part of the heteroalkyl radical is optionally substituted as defined for an alkyl group.
- Heterocycloalkylalkyl refers to a radical of the formula -R c -heterocycloalkyl where R c is an alkylene chain as defined above. If the heterocycloalkyl is a nitrogen-containing heterocycloalkyl, the heterocycloalkyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocycloalkylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocycloalkyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocycloalkyl group.
- Heterocycloalkylalkoxy refers to a radical bonded through an oxygen atom of the formula -O-R c - heterocycloalkyl where R c is an alkylene chain as defined above. If the heterocycloalkyl is a nitrogen-containing heterocycloalkyl, the heterocycloalkyl is optionally attached to the alkyl radical at the nitrogen atom.
- the alkylene chain of the heterocycloalkylalkoxy radical is optionally substituted as defined above for an alkylene chain.
- the heterocycloalkyl part of the heterocycloalkylalkoxy radical is optionally substituted as defined above for a heterocycloalkyl group.
- Heteroaryl refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur.
- the heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, z.e., it contains a cyclic, delocalized (4n+2) ⁇ -electron system in accordance with the Hiickel theory.
- Heteroaryl includes fused or bridged ring systems.
- the heteroatom(s) in the heteroaryl radical is optionally oxidized.
- heteroaryl is attached to the rest of the molecule through any atom of the ring(s).
- heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodi oxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (
- heteroaryl is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-R a , -R b -
- heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical.
- An A-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
- C-heteroaryl refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical.
- a C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
- Heteroaryloxy refers to radical bonded through an oxygen atom of the formula -O- heteroaryl, where heteroaryl is as defined above.
- Heteroarylalkyl refers to a radical of the formula -R c -heteroaryl, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom.
- the alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain.
- the heteroaryl part of the heteroaryl alkyl radical is optionally substituted as defined above for a heteroaryl group.
- Heteroarylalkoxy refers to a radical bonded through an oxygen atom of the formula -O- R c -heteroaryl, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom.
- the alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain.
- the heteroaryl part of the heteroaryl alkoxy radical is optionally substituted as defined above for a heteroaryl group.
- the compounds disclosed herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (A)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or irons'). Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included.
- geometric isomer refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond.
- positional isomer refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.
- a "tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible.
- Optional or “optionally” means that a subsequently described event or circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not.
- optionally substituted aryl means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
- optional substituents are independently selected from D, halogen, -CN, -NH2, -OH, - NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3.
- substituted groups are substituted with one to six of the preceding groups. In some embodiments, substituted groups are substituted with one to four of the preceding groups. In some embodiments, substituted groups are substituted with one to three of the preceding groups. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, substituted groups are substituted with one of the preceding groups.
- “Pharmaceutically acceptable salt” includes both acid and base addition salts.
- a pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms.
- Pharmaceutically acceptable salts of the compounds described herein are optionally pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
- “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
- acetic acid trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
- Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like.
- salts of amino acids such as arginates, gluconates, and galacturonates
- acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.
- “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like.
- Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N, N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N- methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge
- treatment or “treating” or “palliating” or “ameliorating” are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including, but not limited to, therapeutic benefit and/or a prophylactic benefit.
- therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
- a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is afflicted with the underlying disorder in some embodiments.
- the compositions are administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
- Prodrug is meant to indicate a compound that is converted under physiological conditions or by solvolysis to a biologically active compound described herein.
- prodrug refers to a precursor of a biologically active compound that is pharmaceutically acceptable.
- a prodrug is inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis.
- the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).
- prodrugs are provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein.
- prodrug is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject.
- prodrugs of an active compound, as described herein are prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound.
- Prodrugs include compounds wherein a hydroxy, amino, or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino, or free mercapto group, respectively.
- prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol or amine functional groups in the active compounds and the like.
- the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
- ring A is monocyclic heteroaryl
- X 1 is N or CR X1 ;
- X 2 is N or CR X2 ;
- X 3 is N or CR X3 ;
- X 4 is N or CR X4 ;
- R 4 and R 5 taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C 3 -C 8 cycloalkyl or substituted or unsubstituted 3- to 8- membered heterocycloalkyl having 1 or 2 heteroatoms each independently selected from N, O, and S; or
- R 7 and R 8 taken together with the atom to which they are attached to form a substituted or unsubstituted N- or P-containing 3- to 8-membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, or 4.
- ring A is a 5-, 6-, or 7-membered monocyclic heteroaryl. In some embodiments, ring A is a 5- or 6-membered monocyclic heteroaryl. In some embodiments, ring A is a 6- or 7-membered monocyclic heteroaryl. In some embodiments, ring A is a 6-membered monocyclic heteroaryl.
- ring A is a monocyclic heteroaryl having 1-4 N atoms. In some embodiments, ring A is a monocyclic heteroaryl having 1-3 N atoms. In some embodiments, ring A is a monocyclic heteroaryl having 1-2 N atoms. In some embodiments, ring A is a monocyclic heteroaryl having 1 N atom. In some embodiments, ring A is a monocyclic heteroaryl having 2 N atoms. In some embodiments, ring A is a monocyclic heteroaryl having 3 N atoms. In some embodiments, ring A is a monocyclic heteroaryl having 4 N atoms.
- ring A is a monocyclic 6-membered heteroaryl having 1-4 N atoms.
- ring A is pyridinyl, pyrimidinyl, or pyrazinyl.
- ring A is selected from
- the compound has a structure of Formula (Il-a), or a pharmaceutically acceptable salt or solvate thereof:
- the compound has a structure of Formula (Il-b), or a pharmaceutically acceptable salt or solvate thereof: [0070] In some embodiments, the compound has a structure of Formula (II-c), or a pharmaceutically acceptable salt or solvate thereof:
- the compound has a structure of Formula (Il-d), or a pharmaceutically acceptable salt or solvate thereof: wherein m is 0, 1, or 2.
- the compound has a structure of Formula (Il-e), or a pharmaceutically acceptable salt or solvate thereof: wherein m is 0, 1, or 2.
- the compound has a structure of Formula (Il-f), or a pharmaceutically acceptable salt or solvate thereof:
- the compound has a structure of Formula (Il-g), or a pharmaceutically acceptable salt or solvate thereof: wherein m is 0, 1, or 2.
- each of R X1 , R X2 , R X3 , and R X4 when present, is independently hydrogen, halogen, -OR 7 , -SR 7 , -CN, -NR 7 R 8 , substituted or unsubstituted C 1 -C4alkyl, substituted or unsubstituted C 2 -C4alkenyl, substituted or unsubstituted C 2 -C4alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl.
- each of R X1 , R X2 , R X3 , and R X4 when present, is independently hydrogen, halogen, -OR 7 , -SR 7 , -CN, -NR 7 R 8 , substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl.
- each of R X1 , R X2 , R X3 , and R X4 when present, is independently hydrogen, F, Cl, Br, I, -CH 3 , -CH 2 CH 3 , cyclopropyl, -OCH 3 , or -OCF 3 .
- each of R X1 , R X2 , R X3 , and R X4 when present, is independently hydrogen, F, Cl, or -CH 3 .
- each of R X1 , R X2 , R X3 , and R X4 when present, is independently hydrogen or F.
- each of R X1 , R X2 , R X3 , and R X4 when present, is hydrogen.
- the compound has a structure of Formula (Ill-a), or a pharmaceutically acceptable salt or solvate thereof:
- the compound has a structure of Formula (Ill-b), or a pharmaceutically acceptable salt or solvate thereof: [0079] In some embodiments, the compound has a structure of Formula (III-c), or a pharmaceutically acceptable salt or solvate thereof:
- the compound has a structure of Formula (Ill-d), or a pharmaceutically acceptable salt or solvate thereof:
- the compound has a structure of Formula (Ill-e), or a pharmaceutically acceptable salt or solvate thereof:
- the compound has a structure of Formula (Ill-f), or a pharmaceutically acceptable salt or solvate thereof:
- the compound has a structure of Formula (Ill-g), or a pharmaceutically acceptable salt or solvate thereof:
- the compound has a structure of Formula (Ill-h), or a pharmaceutically acceptable salt or solvate thereof:
- the compound has a structure of Formula (Ill-i), or a pharmaceutically acceptable salt or solvate thereof:
- the compound has a structure of Formula (Ill-j), or a pharmaceutically acceptable salt or solvate thereof:
- the compound has a structure of Formula (Ill-k), or a pharmaceutically acceptable salt or solvate thereof:
- the compound has a structure of Formula (III-l), or a pharmaceutically acceptable salt or solvate thereof:
- the compound has a structure of Formula (Ill-m), or a pharmaceutically acceptable salt or solvate thereof:
- the compound has a structure of Formula (Ill-n), or a pharmaceutically acceptable salt or solvate thereof:
- the compound has a structure of Formula (III-o), or a pharmaceutically acceptable salt or solvate thereof:
- the compound has a structure of Formula (III-p), or a pharmaceutically acceptable salt or solvate thereof: [0093] In some embodiments, the compound has a structure of Formula (Ill-q), or a pharmaceutically acceptable salt or solvate thereof:
- the compound has a structure of Formula (Ill-r), or a pharmaceutically acceptable salt or solvate thereof:
- the compound has a structure of Formula (III-s), or a pharmaceutically acceptable salt or solvate thereof:
- the compound has a structure of Formula (Ill-t), or a pharmaceutically acceptable salt or solvate thereof:
- the compound has a structure of Formula (III-u), or a pharmaceutically acceptable salt or solvate thereof:
- the compound has a structure of Formula (III-v), or a pharmaceutically acceptable salt or solvate thereof:
- the compound of Formula (I) is a compound having a structure selected from Formulas (Ill-a), (Ill-b), (III-c), (Ill-d), (Ill-e), (Ill-f), (IILg), (Ill-h), (Ill-i), (Ill-j), (Ill-k), (III-l), (in-m), (ni-n), (III-o), (III-p), (Ill-q), (Ill-r), (III-s), (IH-t), (III-u), and (III-v).
- R 3 is substituted or unsubstituted C5-C10 aryl. In some embodiments, R 3 is substituted or unsubstituted phenyl. In some embodiments, R 3 is phenyl.
- R 3 is -NH2.
- R 3 is cyclopropyl.
- R 3 is 1 -CN- cycloprop-l-yl.
- R 3 is -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, or -OCH(CH 3 ) 2 .
- R 3 is -OH.
- R 3 is -OCH3.
- R 3 is -OCH2CH3.
- R 3 is -OCH2CH2CH3.
- R 3 is -OCH 2 F, -OCHF 2 , -OCF3, -OCF2CH3, or -OCH2CF3.
- each R 7 and R 8 is independently hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, or substituted or unsubstituted 3- to 10-membered heterocycloalkyl; or R 7 and R 8 taken together with the atom to which they are attached to form a substituted or unsubstituted
- R is F, Cl, - CN, -OCF3, -CHF2, -SCF3, or -CF3. In some embodiments, R is F, Cl, -OCF3, -CHF2, -SCF3, or - CF3. In some embodiments, R is F, Cl, -SF5, -SCF3, or -CF3. In some embodiments, R is F, Cl, - SF5, -OCF3, -SCF3, or -CF3. In some embodiments, R is -SF5, -SCF3, or -OCF3. In some embodiments, R is -SF5, -SCF3, or -CF3. 1 n some embodiments, R is -CF3, -SCF3, or -OCF3. In some embodiments, R is -OCF3. In some embodiments, R is -CF3. In some embodiments, R is -SF5. In some embodiments, R is -SCF3.
- each R 1 is independently F, Cl, -OCH3, - OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, - OCH2CH2F, -OCH2C ⁇ H, -OCH2CH2CH2F, or -OCH2CH2C ⁇ H.
- each R 1 is independently F, Cl, -OH, -OCH3, or -OCH2CH3.
- m is 0, 1, 2, 3, or 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 1 or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.
- each R 2 is independently F, Cl, -OCF3, or -CF3.
- each R 2 is independently F or Cl.
- n is 0, 1, 2, 3, or 4. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 1 or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. [00117] In some embodiments, Y is CR 4 R 5 , O, S, or NR 6 . In some embodiments, Y is O, S, or NR 6 . In some embodiments, Y is CR 4 R 5 , S, or NR 6 . In some embodiments, Y is CR 4 R 5 , O, or NR 6 .
- Y is CR 4 R 5 , O, or S. In some embodiments, Y is CR 4 R 5 or O. In some embodiments, Y is CR 4 R 5 or S. In some embodiments, Y is CR 4 R 5 or NR 6 . In some embodiments, Y is O or S. In some embodiments, Y is O or NR 6 . In some embodiments, Y is S or NR 6 .
- Y is CR 4 R 5 .
- each R 4 and R 5 is independently hydrogen or C 1 -C4 alkyl.
- each R 4 and R 5 is hydrogen.
- each R 4 is hydrogen and R 5 is -CH3.
- each R 4 and R 5 is - CH 3 .
- Y is O or S. In some embodiments, Y is O. In some embodiments, Y is S.
- Y is NR 6 .
- R 6 is hydrogen or C 1 -C4 alkyl.
- R 6 is hydrogen or -CH3.
- R 6 is hydrogen.
- R 6 is -CH3.
- R 6 is -OCH3.
- R 6 is -OCH2CH3.
- ring A is monocyclic 6-membered heteroaryl
- X 1 is N or CR X1 ;
- X 2 is N or CR X2 ;
- X 3 is N or CR X3 ;
- X 4 is N or CR X4 ;
- R 7 and R 8 taken together with the atom to which they are attached to form a substituted or unsubstituted N- or P-containing 3- to 8-membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, or 4.
- the present disclosure provides a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof: wherein, ring A is monocyclic 6-membered heteroaryl;
- X 1 is N or CR X1 ;
- X 2 is N or CR X2 ;
- X 3 is N or CR X3 ;
- X 4 is N or CR X4 ;
- R 7 and R 8 taken together with the atom to which they are attached to form a substituted or unsubstituted N- or P-containing 3- to 8-membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, or 4.
- the present disclosure provides a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof:
- R 7 and R 8 taken together with the atom to which they are attached to form a substituted or unsubstituted N- or P-containing 3- to 8-membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, or 4.
- the present disclosure provides a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof: wherein, ring A is monocyclic 6-membered heteroaryl;
- X 1 is N or CR X1 ;
- X 2 is N or CR X2 ;
- X 3 is N or CR X3 ;
- X 4 is N or CR X4 ;
- R 7 and R 8 taken together with the atom to which they are attached to form a substituted or unsubstituted N- or P-containing 3- to 8-membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, or 4.
- the compound of Formula (I) is selected from the group consisting of: [00126]
- the present disclosure provides a compound or pharmaceutically acceptable salt thereof, wherein the compound is a compound from Table 1.
- the compounds described herein exist as geometric isomers.
- the compounds described herein possess one or more double bonds.
- the compounds presented herein include all cis, trans, syn, anti,
- Z) isomers as well as the corresponding mixtures thereof.
- the compounds described herein include all possible tautomers within the formulas described herein.
- the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration.
- the compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
- mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
- the compounds described herein 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, separating the diastereomers, and recovering the optically pure enantiomers.
- dissociable complexes e.g., crystalline diastereomeric salts.
- the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities.
- the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
- the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that does not result in racemization.
- the compounds described herein exist in their isotopically-labeled forms.
- the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds.
- the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions.
- the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
- examples of isotopes that are incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 C1, respectively.
- Compounds described herein, and the metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates, or derivatives thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this disclosure.
- C 6 rtain isotopically-labeled compounds 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.
- Tritiated, i. e., 3 H and carbon-14, i. e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
- substitution with heavy isotopes such as deuterium, i.e.., 2 H produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
- the isotopically labeled compounds, pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof is prepared by any suitable method.
- the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
- the compounds described herein exist as their pharmaceutically acceptable salts.
- the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts.
- the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
- the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
- these salts are prepared in situ during the final isolation and purification of the compounds of the disclosure, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
- the compounds described herein exist as solvates.
- the disclosure provides for methods of treating diseases by administering such solvates.
- the disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.
- Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, 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 the compounds described herein are conveniently prepared or formed during the processes described herein.
- hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or methanol.
- the compounds provided herein exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
- the compounds described herein exist in prodrug form.
- the disclosure provides for methods of treating diseases by administering such prodrugs.
- the disclosure further provides for methods of treating diseases by administering such prodrugs as pharmaceutical compositions.
- prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e. g., two, three, or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy, or carboxylic acid group of compounds of the present disclosure.
- the amino acid residues include, but are not limited to, the 20 naturally occurring amino acids and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, ornithine, and methionine sulfone.
- prodrugs include compounds wherein a nucleic acid residue, or an oligonucleotide of two or more (e. g., two, three or four) nucleic acid residues is covalently joined to a compound of the present disclosure.
- Pharmaceutically acceptable prodrugs of the compounds described herein also include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, metal salts, and sulfonate esters.
- compounds having free amino, amido, hydroxy, or carboxylic groups are converted into prodrugs.
- free carboxyl groups are derivatized as amides or alkyl esters.
- all of these prodrug moieties incorporate groups including, but not limited to, ether, amine, and carboxylic acid functionalities.
- Hydroxy prodrugs include esters such as, though not limited to, acyloxyalkyl (e.g. acyloxymethyl, acyloxyethyl) esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, sulfonate esters, sulfate esters and disulfide containing esters, ethers, amides, carbamates, hemisuccinates, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews 1996, 19, 115.
- esters such as, though not limited to, acyloxyalkyl (e.g. acyloxymethyl, acyloxyethyl) esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, sulfonate esters, sulfate esters and disulfide containing esters, ethers, amides, carba
- Amine derived prodrugs include, but are not limited to, the following groups and combinations of groups: as well as sulfonamides and phosphonamides.
- compounds described herein are susceptible to various metabolic reactions. Therefore, in some embodiments, incorporation of appropriate substituents into the structure will reduce, minimize, or eliminate a metabolic pathway.
- the appropriate substituent to decrease or eliminate the susceptibility of an aromatic ring to metabolic reactions is, by way of example only, a halogen or an alkyl group.
- the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.
- the compounds disclosed herein are prepared as described in the Examples section.
- the compound as described herein is administered as a pure chemical.
- the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)), the disclosure of which is hereby incorporated herein by reference in its entirety.
- a pharmaceutical composition comprising at least one compound described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof, together with one or more pharmaceutically acceptable carriers.
- the carrier(s) or excipient(s) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject) of the composition.
- One embodiment provides a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I), (Il-a), (Il-b), (II-c), (Il-d), (II- e), (Il-f), (Il-g), (Ill-a), (Ill-b), (III-c), (Ill-d), (Ill-e), (Ill-f), (Ill-g), (Ill-h), (Ill-i), (Ill-j), (Ill-k), (III-l), (Ill-m), (Ill-n), (III-o), (III-p), (Ill-q), (Ill-r), (III-s), (Ill-t), (III-u), (III-v), (IV), (V), (VI), or (VII), or a pharmaceutically acceptable salt or solvate thereof.
- Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (I), (Il-a), (Il-b), (II-c), (Il-d), (Il-e), (Il-f), (Il-g), (Ill-a), (Ill-b), (III-c), (Ill-d), (Ill-e), (Ill-f), (Ill-g), (Ill-h), (Ill-i), (Ill-j), (Ill-k), (III-l), (Ill-m), (Ill-n), (III-o), (III-p), (Ill-q), (Ill-r), (III-s), (Ill-t), (III-u), (III-v), (IV), (V), (VI), or (VII), or a pharmaceutically acceptable salt or solvate thereof.
- a pharmaceutically acceptable carrier consisting essentially of Formula (I), (Il-a), (Il-b), (II-
- the compound as described herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as contaminating intermediates or by-products that are created, for example, in one or more of the steps of a synthesis method.
- compositions include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.
- parenteral e.g., subcutaneous, intramuscular, intradermal, or intravenous
- rectal vaginal
- aerosol administration although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.
- disclosed compositions are formulated as a unit dose, and/or are formulated for oral or subcutaneous administration.
- exemplary pharmaceutical compositions are used in the form of a pharmaceutical preparation, for example, in solid, semisolid, or liquid form, which includes one or more of a disclosed compound, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral, or parenteral applications.
- the active ingredient is compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.
- the active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.
- the principal active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a disclosed compound or a non-toxic pharmaceutically acceptable salt thereof.
- a pharmaceutical carrier e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gums
- other pharmaceutical diluents e.g., water
- the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example,
- compositions also comprise buffering agents in some embodiments.
- Solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
- the liquid dosage forms contain optionally inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers.
- Suspensions in addition to the subject composition, optionally contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
- suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
- the doses of the composition comprising at least one compound as described herein differ, depending upon the patient's (e.g., human) condition, that is, stage of the disease, general health status, age, and other factors that a person skilled in the medical art will use to determine dose.
- compositions are administered in a manner appropriate to the disease to be treated (or prevented) as determined by persons skilled in the medical arts.
- An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration.
- an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity.
- Optimal doses are generally determined using experimental models and/or clinical trials. In some embodiments, the optimal dose depends upon the body mass, weight, or blood volume of the patient.
- oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.
- the Hippo signaling network (also known as the Salvador/Warts/Hippo (SWH) pathway) is a master regulator of cell proliferation, death, and differentiation.
- the main function of the Hippo signaling pathway is to regulate negatively the transcriptional co-activators Yes-associated protein (YAP) and its paralogue, the transcriptional co- activator with PDZ-binding motif (TAZ; also known as WWTR1).
- YAP transcriptional co-activators Yes-associated protein
- TEZ transcriptional co- activator with PDZ-binding motif
- the Hippo kinase cascade phosphorylates and inhibits YAP/TAZ by promoting its cytoplasmic retention and degradation, thereby inhibiting the growth promoting function regulated under the YAP/TAZ control.
- YAP also known as YAP1 or YAP65
- TAZ TEAD family of transcription factors to upregulate genes that promote proliferation and migration, and inhibit apoptosis.
- Pnregulated upregulation of these genes involved in proliferation, migration, and anti-apoptosis leads to development of cancer.
- overexpression of YAP/TAZ is associated with cancer.
- Additional core members of the Hippo signaling pathway comprise the serine/threonine kinases MST1/2 (homologues of Hippo/Hpo in Drosophila), Latsl/2 (homologues of Warts/Wts), and their adaptor proteins Savl (homologue of Salvador/Sav) and Mob (MOBKL1 A and MOBKL1B; homologues of Mats), respectively.
- MST1/2 kinase complexes with the scaffold protein Savl, which in turn phosphorylates and activates Latsl/2 kinase.
- Latsl/2 is also activated by the scaffold protein Mob.
- the activated Latsl/2 then phosphorylates and inactivates YAP or its paralog TAZ.
- the phosphorylation of YAP/TAZ leads to their nuclear export, retention within the cytoplasm, and degradation by the ubiquitin proteasome system.
- Latsl/2 phosphorylates YAP at the [HXRXXS] consensus motifs.
- YAP comprises five [HXRXXS] consensus motifs, wherein X denotes any amino acid residue.
- Latsl/2 phosphorylates YAP at one or more of the consensus motifs.
- Latsl/2 phosphorylates YAP at all five of the consensus motifs.
- Latsl/2 phosphorylate at the S127 amino acid position. The phosphorylation of YAP S127 promotes 14-3-3 protein binding and results in cytoplasmic sequestration of YAP. Mutation of YAP at the S127 position thereby disrupts its interaction with 14-3-3 and subsequently promotes nuclear translocation.
- Latsl/2 phosphorylates TAZ at the [HXRXXS] consensus motifs.
- TAZ comprises four [HXRXXS] consensus motifs, wherein X denotes any amino acid residues.
- Latsl/2 phosphorylates TAZ at one or more of the consensus motifs.
- Latsl/2 phosphorylates TAZ at all four of the consensus motifs.
- Latsl/2 phosphorylate at the S89 amino acid position. The phosphorylation of TAZ S89 promotes 14-3-3 protein binding and results in cytoplasmic sequestration of TAZ. Mutation of TAZ at the S89 position thereby disrupts its interaction with 14-3-3 and subsequently promotes nuclear translocation.
- phosphorylated YAP/TAZ accumulates in the cytoplasm, and undergoes SCF ⁇ -TRCP-Pediated ubiquitination and subsequent proteasomal degradation.
- the Skp, Cullin, F-box containing complex is a multi-protein E3 ubiquitin ligase complex that comprises a F-box family member protein (e.g. Cdc4), Skpl, a bridging protein, and RBX1, which contains a small RING Finger domain which interacts with E2 -ubiquitin conjugating enzyme.
- the F-box family comprises more than 40 members, in which exemplary members include F-box/WD repeat-containing protein 1A (FBXW1A, ⁇ -TRCPl, Fbxwl, hsSlimb, plkappaBalpha-E3 receptor subunit) and S-phase kinase-associated proteins 2 (SKP2).
- exemplary members include F-box/WD repeat-containing protein 1A (FBXW1A, ⁇ -TRCPl, Fbxwl, hsSlimb, plkappaBalpha-E3 receptor subunit) and S-phase kinase-associated proteins 2 (SKP2).
- the SCF complex e.g. SCF ⁇ -TR 1
- Exemplary El ubiquitin-activating enzymes include those encoded by the following genes: UBA1, UBA2, UBA3, UBA5, UBA5, UBA7, ATG7, NAE1, and SAE1.
- Exemplary E2 ubiquitin-conjugating enzymes include those encoded by the following genes: UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE2G1, UBE2G2, UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE2L3, UBE2L6, UBE2M, UBE2N, UBE2O, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2Z, ATG2, BIRC5, and UFC1.
- the Hippo pathway is regulated upstream by several different families of regulators.
- the Hippo pathway is regulated by the G-protein and its coupled receptors, the Crumbs complex, regulators upstream of the MST kinases, and the adherens junction.
- un-phosphorylated and/or dephosphorylated YAP/TAZ accumulates in the nucleus.
- YAP/TAZ interacts with the TEAD family of transcription factors (e.g. TEAD1, TEAD2, TEAD3, or TEAD4) to activate genes involved in anti- apoptosis and proliferation, such as for example CTFG, Cyr61. and FGF1.
- TEAD1, TEAD2, TEAD3, or TEAD4 TEAD1, TEAD2, TEAD3, or TEAD4
- the compounds disclosed herein modulate the interaction between YAP/TAZ and TEAD. In some embodiments, the compounds disclosed herein bind to TEAD, YAP, or TAZ and prevent the interaction between YAP/TAZ and TEAD.
- the Hippo pathway is regulated by the G protein-coupled receptor (GPCR) and G protein (also known as guanine nucleotide-binding proteins) family of proteins.
- G proteins are molecular switches that transmit extracellular stimuli into the cell through GPCRs.
- monomeric small GTPases and heterotrimeric G protein complexes.
- the latter class of complexes comprise of alpha (G ⁇ ), beta (G ⁇ ), and gamma (G y ) subunits.
- G a subunits Gq/ 11 a, Gi ⁇ na, Gi/ O a (G inhibitory, G other), and G s ⁇ (G stimulatory).
- G i ⁇ (G inhibitory), G o a (G other), Gq/ 11 a, and Gu/ua coupled GPCRs activate YAP/TAZ and promote nuclear translocation.
- G s ⁇ (G stimulatory) coupled GPCRs suppress YAP/TAZ activity, leading to YAP/TAZ degradation.
- G i ⁇ (G inhibitory), G o ⁇ (G other), Gq/ 11 a, and Gu/ua coupled GPCRs activate YAP/TAZ through repression of Latsl/2 activities.
- G s ⁇ in some embodiments, induces Latsl/2 activity, thereby promoting YAP/TAZ degradation.
- G q ⁇ (also known as Gq/ 11 protein), participates in the inositol trisphosphate (IP3) signal transduction pathway and calcium (Ca 2+ ) release from intracellular storage through the activation of phospholipase C (PLC).
- PLC phospholipase C
- PLC phospholipase C
- PIP2 phosphatidylinositol 4,5- bisphosphate
- DAG diacyl glycerol
- IP3 then diffuses through the cytoplasm into the ER or the sarcoplasmic reticulum (SR) in the case of muscle cells, and then binds to inositol trisphosphate receptor (InsP3R), which is a Ca 2+ channel.
- the binding triggers the opening of the Ca 2+ channel, and thereby increases the release of Ca 2+ into the cytoplasm.
- the GPCRs that interact with G q ⁇ include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HT2 and 5-HT3; alpha-1 adrenergic receptor; vasopressin type 1 receptors 1A and IB; angiotensin II receptor type 1; calcitonin receptor; histamine Hl receptor; metabotropic glutamate receptor, group I; muscarinic receptors Mi, M3, and M5; and trace amine-associated receptor 1.
- 5-HT receptor 5-hydroxytryptamine receptor
- 5-HT2 and 5-HT3 alpha-1 adrenergic receptor
- vasopressin type 1 receptors 1A and IB angiotensin II receptor type 1
- calcitonin receptor histamine Hl receptor
- metabotropic glutamate receptor group I
- muscarinic receptors Mi, M3, and M5 and trace amine-associated receptor 1.
- G q ⁇ there are several types of G q ⁇ : G q , Gq/ 11 , Gq/14, and Gq/15.
- the G q protein is encoded by GNAQ.
- Gq/ 11 is encoded by GNA11.
- Gq/14 is encoded by GNA14.
- Gq/15 is encoded by GNA15.
- G q ⁇ genes have been associated with cancer. Indeed, studies have shown that mutations in G q ⁇ promote uveal melanoma (UM) tumorigenesis. In some instances, about 80% of UM cases have been detected to contain a mutation in GNAQ and/or GNA11.
- G q ⁇ genes have been associated with congenital diseases.
- mutations of G q ⁇ have been observed in congenital diseases such as Port-Wine Stain and/or Sturge-Weber Syndrome.
- congenital diseases such as Port-Wine Stain and/or Sturge-Weber Syndrome.
- Port-Wine Stain and/or Sturge-Weber Syndrome.
- about 92% of Port-Wine stain cases harbors a mutation in GNAQ.
- Sturge-Weber Syndrome harbors a mutation in GNAQ.
- G12/13 ⁇ modulates actin cytoskeletal remodeling in cells and regulates cell processes through guanine nucleotide exchange factors (GEFs).
- GEFs participate in the activation of small GTPases which acts as molecular switches in a variety of intracellular signaling pathways.
- small GTPases include the Ras-related GTPase superfamily (e.g. Rho family such as Cdc42), which is involved in cell differentiation, proliferation, cytoskeletal organization, vesicle trafficking, and nuclear transport.
- the GPCRs that interact with G12/n/ include, but are not limited to, purinergic receptors (e.g. P2Yi, P2Y2, P2Y4, P2Ye); muscarinic acetylcholine receptors Ml and M3; receptors for thrombin [protease-activated receptor (PAR)-l, PAR-2]; thromboxane (TXA2); sphingosine 1 -phosphate (e.g. SIP2, SIP3, SIP4 and SIP5); lysophosphatidic acid (e.g.
- purinergic receptors e.g. P2Yi, P2Y2, P2Y4, P2Ye
- muscarinic acetylcholine receptors Ml and M3 receptors for thrombin [protease-activated receptor (PAR)-l, PAR-2]
- thromboxane TXA2
- sphingosine 1 -phosphate e.g.
- LPAi LPA2, LPA3; angiotensin II (ATI); serotonin (5-HT2 C and 5-HT4); somatostatin (ssts); endothelin (ETA and ETB); cholecystokinin (CCKi); Via vasopressin receptors; D5 dopamine receptors; fMLP formyl peptide receptors; GAL2 galanin receptors; EP3 prostanoid receptors; Ai adenosine receptors; on adrenergic receptors; BB2 bombesin receptors; B2 bradykinin receptors; calcium-sensing receptors; KSHV-ORF74 chemokine receptors; NKi tachykinin receptors; and thyroid-stimulating hormone (TSH) receptors.
- TSHV-ORF74 thyroid-stimulating hormone
- G12/1301 is further subdivided into G12 and G13 types which are encoded by GNA12 and GNA13, respectively.
- Gi/o ⁇ G inhibitory, G other
- Gi/Go or Gi protein suppresses the production of 3’,5’-cyclic AMP (cAMP) from adenosine triphosphate (ATP) through an inhibition of adenylate cyclase activity, which converts ATP to cAMP.
- cAMP 3’,5’-cyclic AMP
- the GPCRs that interact with G i ⁇ include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HTi and 5-HTs; muscarinic acetylcholine receptors such as M2 and M4; adenosine receptors such as Ai and A3; adrenergic receptors such as a2A, a2B, and a2c; apelin receptors; calcium-sensing receptor; cannabinoid receptors CB1 and CB2; chemokine CXCR4 receptor; dopamines D2, D3, and D4; GAB AB receptor; glutamate receptors such as metabotropic glutamate receptor 2 (mGluR2), metabotropic glutamate receptor 3 (mGluR3), metabotropic glutamate receptor 4 (mGluR4), metabotropic glutamate receptor 6 (mGluR6), metabotropic glutamate receptor 7 (mGluR7), and metabotropic glutamate receptor
- 5-HT receptor 5-hydroxy
- G i ⁇ there are several types of G i ⁇ : G i ⁇ l, G i ⁇ 2, G i ⁇ 3, G i ⁇ 4, G o a, Gt, Ggust, and G z .
- G i ⁇ l is encoded by GNAI1.
- G i ⁇ 2 is encoded by GNAI2.
- G i ⁇ 3 is encoded by GN Al 3.
- G o a the a 0 subunit, is encoded by GNAO1.
- Gt is encoded by GNAT1 and GNAT2.
- Ggust is encoded by GNAT3.
- G z is encoded by GNAZ.
- G s ⁇ also known as G stimulatory, G s alpha subunit, or G s protein
- G s ⁇ activates the cAMP-dependent pathway through the activation of adenylate cyclase, which convers adenosine triphosphate (ATP) to 3 ’,5 ’-cyclic AMP (cAMP) and pyrophosphate.
- ATP adenosine triphosphate
- cAMP cyclic AMP
- the GPCRs that interact with G s a include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HT4, 5-HT6, and 5-HT7; adrenocorticotropic hormone receptor (ACTH receptor) (also known as melanocortin receptor 2 or MC2R); adenosine receptor types A2a and Ait,; arginine vasopressin receptor 2 (AVPR2); ⁇ -adrenergic receptors Pi, P2, and P3; calcitonin receptor; calcitonin gene-related peptide receptor; corticotropin-releasing hormone receptor; dopamine receptor Di-like family receptors such as Di and D5; follicle-stimulating hormone receptor (FSH- receptor); gastric inhibitory polypeptide receptor; glucagon receptor; histamine EE receptor; luteinizing hormone/choriogonadotropin receptor; melanocortin receptors such as MC1R, MC2R, MC 3
- G s a there are two types of G s a: ⁇ G s and G o if.
- G s is encoded by GNAS.
- Goif is encoded by GN AL.
- the additional regulator of the Hippo signaling pathway is the Crumbs (Crb) complex.
- the Crumbs complex is a key regulator of cell polarity and cell shape.
- the Crumbs complex comprises transmembrane CRB proteins which assemble multi-protein complexes that function in cell polarity.
- CRB complexes recruit members of the Angiomotin (AMOT) family of adaptor proteins that interact with the Hippo pathway components.
- AMOT Angiomotin
- studies have shown that AMOT directly binds to YAP, promotes YAP phosphorylation, and inhibits its nuclear localization.
- the additional regulator of the Hippo signaling pathway comprises regulators of the MST kinase family. MST kinases monitor actin cytoskeletal integrity.
- the regulators include TAO kinases and cell polarity kinase PAR-1.
- the additional regulator of the Hippo signaling pathway comprises molecules of the adherens junction.
- E-Cadherin (E-cad) suppresses YAP nuclear localization and activity through regulating MST activity.
- E- cad-associated protein a-catenin regulates YAP through sequestering YAP/14-3-3 complexes in the cytoplasm.
- Ajuba protein family members interact with Latsl/2 kinase activity, thereby preventing inactivation of YAP/TAZ.
- additional proteins that interact with YAP/TAZ either directly or indirectly include, but are not limited to, Merlin, protocadherin Fat 1, MASK1/2, HIPK2, PTPN14, RASSF, PP2A, Salt-inducible kinases (SIKs), Scribble (SCRIB), the Scribble associated proteins Discs large (Dig), KIBRA, PTPN14, NPHP3, LKB1, Ajuba, and ZO1/2.
- the compounds described herein are inhibitors of transcriptional coactivator with PDZ binding motif/Yes- associated protein transcriptional coactivator (TAZ/YAP). In some embodiments, the compounds described herein increase the phosphorylation of transcriptional coactivator with PDZ binding motif/ Yes- associated protein transcriptional coactivator (TAZ/YAP) or decrease the dephosphorylation of transcriptional coactivator with PDZ binding motif/ Yes- associated protein transcriptional coactivator (TAZ/YAP).
- the compounds increase the ubiquitination of transcriptional coactivator with PDZ binding motif/ Yes- associated protein transcriptional coactivator (TAZ/YAP) or decrease the deubiquitination of transcriptional coactivator with PDZ binding motif/ Yes- associated protein transcriptional coactivator (TAZ/YAP).
- the compounds disclosed herein are inhibitors of one or more of the proteins encompassed by, or related to, the Hippo pathway.
- the one or more proteins comprise a protein described above.
- an inhibitor of the Hippo pathway is an inhibitor of a G-protein and/or its coupled GPCR.
- an inhibitor of the Hippo pathway is an inhibitor of a G-protein.
- an inhibitor of the Hippo pathway is an inhibitor of the G q ⁇ family proteins such as G q , G q /u, G q /i4, and G q /is; the G12/13 ⁇ family of proteins such as G12 and G13; or the G i ⁇ family of proteins such as G i ⁇ l, G i ⁇ 2, G i ⁇ 3, G i ⁇ 4, G o a, Gt, Ggust, and G z .
- an inhibitor of the Hippo pathway is an inhibitor of G q .
- an inhibitor of the Hippo pathway is an inhibitor of G q /u.
- an inhibitor of the Hippo pathway is an inhibitor of G q /i4. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G q /i5. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G12. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G13. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G i ⁇ 1. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G i ⁇ 2. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G i ⁇ 3. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G i ⁇ 4.
- an inhibitor of the Hippo pathway is an inhibitor of G o a. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gt. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Ggust. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G z . [00192] In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a core protein of the Hippo pathway. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Savl. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Mob. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of YAP. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of TAZ. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of TEAD.
- an inhibitor of the Hippo pathway is an inhibitor of a protein associated with the ubiquitination and proteasomal degradation pathway.
- an inhibitor of the Hippo pathway is an inhibitor of a proteasomal degradation pathway protein (e.g. 26S proteasome).
- an inhibitor of the Hippo pathway is an inhibitor of a protein of the Ras superfamily of proteins. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a protein of the Rho family of proteins. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Cdc42.
- Cdc42 is a member of the Ras superfamily of small GTPases. Specifically, Cdc42 belongs to the Rho family of GTPases, in which the family members participate in diverse and critical cellular processes such as gene transcription, cell-cell adhesion, and cell cycle progression. Cdc42 is involved in cell growth and polarity, and in some instances, Cdc42 is activated by guanine nucleotide exchange factors (GEFs). In some cases, an inhibitor of Cdc42 is a compound disclosed herein.
- GEFs guanine nucleotide exchange factors
- an inhibitor of the Hippo pathway is an inhibitor of a deubiquitinating enzyme.
- an inhibitor of the Hippo pathway is an inhibitor of a cysteine protease or a metalloprotease.
- an inhibitor of the Hippo pathway is an inhibitor of an ubiquitin-specific protease.
- USP47 is a member of the ubiquitinspecific protease (USP/UBP) superfamily of cysteine proteases.
- the compounds disclosed herein are inhibitors of USP47.
- the present disclosure provides a method of inhibiting one or more of proteins encompassed by, or related to, the Hippo pathway in a subject, comprising administering to a subject a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.
- the present disclosure provides a method of inhibiting transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP) in a subject comprising administering to a subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.
- the subject has cancer, polycystic kidney disease, or liver fibrosis.
- the cancer is selected from mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwannoma, lung cancer, bladder carcinoma, cutaneous neurofibromas, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, and breast cancer.
- the present disclosure provides a method of treating cancer in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.
- the cancer is selected from mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwannoma, lung cancer, bladder carcinoma, cutaneous neurofibromas, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, and breast cancer.
- the present disclosure provides a method of treating polycystic kidney disease or liver fibrosis in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.
- the present disclosure provides a method of treating or preventing a disease or disorder amenable to treatment with a compound that inhibits the activity of one or more of proteins encompassed by, or related to, the Hippo pathway in a subject, comprising administering to a subject in need thereof a therapeutically acceptable amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.
- the present disclosure provides a method of treating or preventing a disease or disorder amenable to treatment with a compound that inhibits transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP) in a subject comprising administering to a subject in need thereof a therapeutically acceptable amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.
- a compound that inhibits transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator TEZ/YAP
- a compound disclosed herein is for use in a method of treating a disease or disorder (e.g., a disease or disorder amenable to treatment with a compound that inhibits one or more of proteins encompassed by, or related to, the Hippo pathway; or a disease or disorder conducive to treatment to prevention by inhibiting transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP)) in a subject in need thereof, such cancer.
- a disease or disorder e.g., a disease or disorder amenable to treatment with a compound that inhibits one or more of proteins encompassed by, or related to, the Hippo pathway; or a disease or disorder conducive to treatment to prevention by inhibiting transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP)
- Such a compound is, for example, a compound of Formula (I), (Il-a), (Il-b), (II-c), (II- d), (Il-e), (Il-f), (Il-g), (Ill-a), (Ill-b), (III-c), (Ill-d), (Ill-e), (IILf), (IILg), (IILh), (IILi), (Ill-j), (III- k), (IILI), (IILm), (Ill-n), (III-o), (III-p), (IILq), (IILr), (IILs), (IH-t), (IILu), (III-v), (IV), (V), (VI), or (VII), as disclosed herein, or a pharmaceutical composition comprising the compound disclosed herein, and a pharmaceutically acceptable excipient, as disclosed herein.
- a pharmaceutical composition comprising the compound disclosed herein, and a pharmaceutically acceptable excipient, as disclosed herein.
- compositions comprising a compound Formula (I), (ILa), (Il-b), (II-c), (ILd), (Il-e), (ILf), (Il-g), (IILa), (Ill-b), (III-c), (Ill-d), (Ill-e), (IILf), (IILg), (IILh), (IILi), (IILj), (IILk), (III-l), (IILm), (IILn), (IILo), (III-p), (IILq), (IILr), (IILs), (IILt), (IILu), (III-v), (IV), (V), (VI), or (VII), as disclosed herein or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder (e.g., a disease or disorder amenable to treatment with a compound that inhibits one or more of proteins encompassed by, or related to, the Hippo pathway; or a disease
- the compounds disclosed herein are useful for treating cancer.
- a method for treating a cancer in a subject in need thereof comprising administering a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof.
- a compound for use in treating a cancer in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof.
- the cancer is mediated by activation of transcriptional coactivator with PDZ binding motif/Yes- associated protein transcription coactivator (TAZ/YAP).
- the cancer is mediated by modulation of the interaction of YAP/TAZ with TEAD.
- the cancer is characterized by a mutant G ⁇ -protein.
- the mutant G ⁇ -protein is selected from G12, G13, Gq, G11, Gi, Go, and Gs.
- the mutant G ⁇ -protein is G12.
- the mutant G ⁇ -protein is G13.
- the mutant G ⁇ - protein is Gq.
- the mutant G ⁇ -protein is Gl 1.
- the mutant G ⁇ -protein is Gi.
- the mutant G ⁇ -protein is Go.
- the mutant G ⁇ -protein is Gs.
- the cancer is a solid tumor.
- the cancer is a hematologic malignancy.
- the solid tumor is a sarcoma or carcinoma.
- the solid tumor is a sarcoma.
- the solid tumor is a carcinoma.
- Exemplary sarcoma includes, but is not limited to, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastoma, angiosarcoma, chondrosarcoma, chordoma, clear cell sarcoma of soft tissue, dedifferentiated liposarcoma, desmoid, desmoplastic small round cell tumor, embryonal rhabdomyosarcoma, epithelioid fibrosarcoma, epithelioid hemangioendothelioma, epithelioid sarcoma, esthesioneuroblastoma, Ewing sarcoma, extrarenal rhabdoid tumor, extraskeletal myxoid chondrosarcoma, extraskeletal osteosarcoma, fibrosarcoma, giant cell tumor, hemangiopericytoma, infantile fibrosarcoma, inflammatory myofibroblastic tumor,
- Exemplary carcinoma includes, but is not limited to, adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, anal cancer, appendix cancer, bile duct cancer (i.e., cholangiocarcinoma), bladder cancer, brain tumor, breast cancer, cervical cancer, colon cancer, cancer of Unknown Primary (CUP), esophageal cancer, eye cancer, fallopian tube cancer, gastroenterological cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer.
- the liver cancer is primary liver cancer.
- the cancer is selected from uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neck cancer, prostate cancer, and meningioma.
- the cancer is uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neck cancer, prostate cancer, or meningioma.
- the cancer is uveal melanoma, mesothelioma, esophageal cancer, or liver cancer.
- the cancer is uveal melanoma.
- the cancer is mesothelioma.
- the cancer is esophageal cancer.
- the cancer is liver cancer.
- the cancer is primary liver cancer.
- the cancer is a hematologic malignancy.
- a hematologic malignancy is a leukemia, a lymphoma, a myeloma, a non-Hodgkin’s lymphoma, a Hodgkin’s lymphoma, a T-cell malignancy, or a B-cell malignancy.
- a hematologic malignancy is a T-cell malignancy.
- Exemplary T-cell malignancy includes, but is not limited to, peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, angioimmunoblastic lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia/lymphoma (ATLL), blastic NK-cell lymphoma, enteropathy -type T-cell lymphoma, hematosplenic gamma-delta T-cell lymphoma, lymphoblastic lymphoma, nasal NK/T-cell lymphomas, and treatment-related T-cell lymphomas.
- PTCL-NOS peripheral T-cell lymphoma not otherwise specified
- anaplastic large cell lymphoma angioimmunoblastic lymphoma
- ATLL adult T-cell leukemia/lymphoma
- blastic NK-cell lymphoma enteropathy -type T-cell lymphoma
- a hematologic malignancy is a B-cell malignancy.
- Exemplary B- cell malignancy includes, but is not limited to, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, and a non-CLL/SLL lymphoma.
- the cancer is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt’ s lymphoma, nonBurkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.
- FL follicular lymphoma
- the cancer is a relapsed or refractory cancer.
- the relapsed or refractory cancer is a relapsed or refractory solid tumor.
- the relapsed or refractory solid tumor is a relapsed or refractory sarcoma or a relapsed or refractory carcinoma.
- the relapsed or refractory carcinoma includes adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, anal cancer, appendix cancer, bile duct cancer (i.e., cholangiocarcinoma), bladder cancer, brain tumor, breast cancer, cervical cancer, colon cancer, cancer of Unknown Primary (CUP), esophageal cancer, eye cancer, fallopian tube cancer, gastroenterological cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer.
- bile duct cancer i.e., cholangiocarcinoma
- bladder cancer i.e.,
- the relapsed or refractory cancer is selected from relapsed or refractory uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neck cancer, prostate cancer, and meningioma.
- the relapsed or refractory cancer is relapsed or refractory uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neck cancer, prostate cancer, or meningioma.
- the relapsed or refractory cancer is relapsed or refractory uveal melanoma, mesothelioma, esophageal cancer, or liver cancer. In some cases, the relapsed or refractory cancer is relapsed or refractory uveal melanoma. In some cases, the relapsed or refractory cancer is relapsed or refractory mesothelioma. In some cases, the relapsed or refractory cancer is relapsed or refractory esophageal cancer. In some cases, the relapsed or refractory cancer is relapsed or refractory liver cancer. In some cases, the relapsed or refractory cancer is relapsed or refractory primary liver cancer.
- the relapsed or refractory cancer is a relapsed or refractory hematologic malignancy.
- a relapsed or refractory hematologic malignancy is a relapsed or refractory leukemia, a relapsed or refractory lymphoma, a relapsed or refractory myeloma, a relapsed or refractory non-Hodgkin’s lymphoma, a relapsed or refractory Hodgkin’s lymphoma, a relapsed or refractory T-cell malignancy, or a relapsed or refractory B-cell malignancy.
- a relapsed or refractory hematologic malignancy is a relapsed or refractory T-cell malignancy.
- a relapsed or refractory hematologic malignancy is a relapsed or refractory B-cell malignancy, such as for example, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, or a non-CLL/SLL lymphoma.
- CLL chronic lymphocytic leukemia
- SLL small lymphocytic lymphoma
- high risk CLL or a non-CLL/SLL lymphoma.
- the cancer is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt’s lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.
- FL follicular lymphoma
- the cancer is a metastasized cancer.
- the metastasized cancer is a metastasized solid tumor.
- the metastasized solid tumor is a metastasized sarcoma or a metastasized carcinoma.
- the metastasized carcinoma includes adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, anal cancer, appendix cancer, bile duct cancer (i.e., cholangiocarcinoma), bladder cancer, brain tumor, breast cancer, cervical cancer, colon cancer, cancer of Unknown Primary (CUP), esophageal cancer, eye cancer, fallopian tube cancer, gastroenterological cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer.
- CUP Unknown Primary
- the metastasized cancer is selected from metastasized uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neck cancer, prostate cancer, and meningioma.
- the metastasized cancer is metastasized uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neck cancer, prostate cancer, or meningioma.
- the metastasized cancer is metastasized uveal melanoma, mesothelioma, esophageal cancer, or liver cancer.
- the metastasized cancer is metastasized uveal melanoma. In some cases, the metastasized cancer is metastasized mesothelioma. In some cases, the metastasized cancer is metastasized esophageal cancer. In some cases, the metastasized cancer is metastasized liver cancer. In some cases, the metastasized cancer is metastasized primary liver cancer.
- the metastasized cancer is a metastasized hematologic malignancy.
- the metastasized hematologic malignancy is a metastasized leukemia, a metastasized lymphoma, a metastasized myeloma, a metastasized non-Hodgkin’s lymphoma, a metastasized Hodgkin’s lymphoma, a metastasized T-cell malignancy, or a metastasized B-cell malignancy.
- a metastasized hematologic malignancy is a metastasized T-cell malignancy.
- a metastasized hematologic malignancy is a metastasized B-cell malignancy, such as for example, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, or a non-CLL/SLL lymphoma.
- CLL chronic lymphocytic leukemia
- SLL small lymphocytic lymphoma
- high risk CLL or a non-CLL/SLL lymphoma.
- the cancer is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt’ s lymphoma, nonBurkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.
- FL follicular lymphoma
- the compounds disclosed herein are useful for treating a congenital disease.
- the congenital disease is mediated by activation of transcriptional coactivator with PDZ binding motif/Yes- associated protein transcription coactivator (TAZ/YAP).
- the congenital disease is characterized by a mutant G ⁇ -protein.
- the mutant G ⁇ -protein is selected from G12, G13, Gq, G11, Gi, Go, and Gs.
- the mutant G ⁇ -protein is G12.
- the mutant G ⁇ -protein is G13.
- the mutant G ⁇ -protein is Gq.
- the mutant G ⁇ - protein is Gl 1.
- the mutant G ⁇ -protein is Gi.
- the mutant G ⁇ -protein is Go.
- the mutant G ⁇ -protein is Gs.
- the congenital disease is the result of a genetic abnormality, an intrauterine environment, errors related to morphogenesis, infection, epigenetic modifications on a parental germline, or a chromosomal abnormality.
- exemplary congenital diseases include, but are not limited to, Sturge-Weber Syndrome, Port-Wine stain, Holt-Oram syndrome, abdominal wall defects, Becker muscular dystrophy (BMD), biotinidase deficiency, Charcot-Marie-Tooth (CMT), cleft lip, cleft palate, congenital adrenal hyperplasia, congenital heart defects, congenital hypothyroidism, congenital muscular dystrophy, cystic fibrosis, Down syndrome, Duchenne muscular dystrophy, Fragile X syndrome, Friedreich’s ataxia, galactosemia, hemoglobinopathies, Krabbe disease, limb-girdle muscular dystrophy, medium chain acyl-CoA dehydrogenase defici
- Example 8 2-(2-(Azetidin-l-yl)pyridin-4-yl)-N-(4-(trifluoromethyl)phenyl)aniline (Compound 8)
- reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash chromatography on silica gel (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-42% Ethyl acetate/Petroleum ether gradient @20 mL/min) and prep-HPLC (column: Xtimate C18 100x30mmx3um; mobile phase: [water(0.05%HCl)-ACN]; B%: 50%-80%, 8.5 min) to give Compound 20 (2.1 mg, 2.4% yield) as a yellow solid.
- silica gel ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-42% Ethyl acetate/Petroleum ether gradient @20 mL/min
- prep-HPLC columnumn: Xtimate C18 100x30mmx3um; mobile phase: [water(0.05%HCl)-ACN]; B%: 50%-80%, 8.5 min
- Example 23 N-(5-(3-(4-(trifluoromethyl)phenoxy)pyrazin-2-yl)pyrimidin-2- yl)methanesulfonamide (Compound 23) N[5-[3-[4-(trifluoromethyl)phenoxy]pyrazin-2-yl]pyrimidin-2-yl]methanesulfonamide [00275] To a solution of compound 23A (40 mg, 0.12 mmol, 1 eq) in THF (0.5 mL) at 0°C was added MsCl (27.5 mg, 0.24 mmol, 18 uL, 2.0 eq) and NaH (7.2 mg, 0.18 mmol, 60%, 1.5 eq).
- Example 29 l-(5-(3-((4-(trifluoromethyl)phenyl)thio)pyrazin-2-yl)pyrimidin-2- yl)cyclopropane-l-carbonitrile (Compound 29) l-[5-[3-[4-(trifluoromethyl)phenyl]sulfanylpyrazin-2-yl]pyrimidin-2- yljcyclopropanecarbonitrile
- reaction mixture was diluted with H 2 O (10 mL) and the reaction mixture was extracted with EtOAc (20mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-30% PE/EtOAc@ 35 mL/min). Intermediate 33B (500 mg, 2.10 mmol, 61.7% yield) was obtained as white solid.
- reaction mixture was diluted with H 2 O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (lOmL x 2), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®;20 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate/Petroleum ether gradient @35 mL/min).
- reaction mixture was diluted with H 2 O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-55% PEZEtOAc@ 35 mL/min).
- N-[3-cyano-5-[3-[4-(trifluoromethyl)phenoxy]pyrazin-2-yl]-2-pyridyl]methanesulfonamide [00304] NaH (134.3 mg, 0.55 mmol, 10%, 2 eq) was added at the reaction mixture of intermediate 35C (100.0 mg, 0.27 mmol, 1 eq) in THF (3 mL) at 25 °C. The reaction mixture was stirred at 70°C for 1 hr. MsCl (32.0 mg, 0.27 mmol, 21.6 uL, 1 eq) was added at the reaction mixture at 25 °C. Then the reaction mixture was stirred at 70°C for another 16 hr.
- reaction mixture was cooled to - 20 °C and tert-butyl nitrite (39.7 mg, 0.39 mmol, 46 uL, 1 eq in DCM (0.5 mL) was added into the reaction mixture.
- the reaction mixture was stirred at 0 °C for 0.5 hr. Brown solid formed.
- the reaction mixture was filtered, and the filter cake was washed with DCM give intermediate 44B (120 mg, crude) as a brown solid. The crude intermediate 44B was used into the next step without further purification.
- reaction mixture was diluted with H 2 O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrousNa 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-10% PE/EtOAc@ 35 mL/min) to afford Compound 52 (7.1 mg, 17% yield) was obtained as white solid.
- silica gel ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-10% PE/EtOAc@ 35 mL/min
- reaction mixture was diluted with H 2 O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-10% PEZEtOAc @ 35mL/min) to afford Compound 53 (9.83 mg, 19% yield) as a white solid.
- silica gel ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-10% PEZEtOAc @ 35mL/min
- reaction mixture was diluted with H 2 O (5 mL) and the reaction mixture was extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous ISfeSCU, filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 40 g SepaFlash ® Silica Flash Column, Eluent of 0-50% PEZEtOAc@ 35 mL/min) to afford Compound 55 (150 mg, 52.9% yield) as a yellow solid.
- silica gel ISCO®; 40 g SepaFlash ® Silica Flash Column, Eluent of 0-50% PEZEtOAc@ 35 mL/min
- reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate/Petroleum ether gradient @ 20 mL/min), and was further purified by prep- HPLC (column: 3_Phenomenex Luna C18 75x30mmx3um; mobile phase: [water(0.05%HCl)- ACN];B%: 40%-70%,6.5min) to afford Compound 57 (19.3 mg, 35.9% yield, HC1) as a yellow solid.
- silica gel ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate/Petroleum ether gradient @ 20 mL/min
- prep- HPLC columnumn: 3_Phenomenex Luna C18 75x30mmx3um; mobile phase: [water(0.05%HCl)- A
- the reaction mixture was degassed with N2 for 3 times and Cui (2.4 mg, 12.8 pmol, 0.05 eq ⁇ and Pd(PPh 3 )2Ch (17.9 mg, 25.5 pmol, 0.1 eq ⁇ were added.
- the reaction mixture was further degassed with N2 for 3 times and then was stirred and heated to 120 °C for 1 h under N2.
- the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3).
- reaction mixture was degassed with N2 for 3 times and Cui (2.7 mg, 14 pmol, 0.05 eq) and Pd(PPh3)2Ch (20.0 mg, 28 pmol, 0.1 eq) were added.
- the reaction mixture was further degassed with N2 for 3 times and then was stirred and heated to 120 °C for 0.5 hr under N2.
- the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3).
- reaction mixture was degassed with N2 for 3 times and Cui (2.7 mg, 14.2 pmol, 0.05 eq) and Pd(PPh3)2Cl 2 (20.0 mg, 28.4 pmol, 0.1 eq) were added.
- the reaction mixture was further degassed with N2 for 3 times and then was stirred and heated to 120 °C for 1 h under N2.
- the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3).
- Example 62 l-Methyl-2'-((4-(trifluoromethyl)phenyl)thio)-[3,3'-bipyridin]-6(lH)-one (Compound 62) dioxane/ H 2 O
- reaction mixture was diluted with H 2 O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum.
- Example 63 l-Methyl-2'-((4-(pentafluoro-k6-sulfaneyl)phenyl)thio)-[3,3'-bipyridin]-6(lH)- one (Compound 63) [4-[(3-bromo-2-pyridyl)sulfanyl]phenyl]-pentafluoro-sulfane
- Example 64 l-Methyl-5-(2-(4-(pentafluoro-L6-sulfaneyl)phenoxy)pyridin-3-yl)pyrimidin-
- Example 65 l-ethyl-2'-(4-(pentafluoro-L6-sulfaneyl)phenoxy)-[3,3'-bipyridin]-6(lH)-one
- 5-Bromo-l-ethyl-pyridin-2-one [00365] The mixture of 5-bromo-lH-pyridin-2-one (62A, 500.0 mg, 2.87 mmol, 1 eq) and iodoethane (448.1 mg, 2.87 mmol, 0.22 mL, 1 eq), CS2CO3 (1.87 g, 5.75 mmol, 2 eq) in DMF (2 mL) was stirred at 25°C for 1 hr. The reaction mixture was diluted with H 2 O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3).
- reaction mixture was diluted with H 2 O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate/Petroleum ether gradient @ 35mL/min) to give intermediate 65B (295 mg, 1.18 mmol, 78.7% yield) was obtained as a yellow oil.
- silica gel ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate/Petroleum ether gradient @ 35mL/min
- Example 68 l-Isopropyl-2'-((4-(pentafluoro-L6-sulfaneyl)phenyl)amino)-[3,3'-bipyridin]-
- Example 69 l-Cyclopropyl-2'-(4-(pentafluoro-L6-sulfaneyl)pheno y)-[3,3'-bipyridin]-6(lH)- one (Compound 69) O 2 , DCE
- Example 70 2'-(4-(Pentafluoro-L6-sulfaneyl)pheno y)-l-propyl-[3,3'-bipyridin]-6(lH)-one
- reaction mixture was diluted with H 2 O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate/Petroleum ether gradient @ 35mL/min) to give intermediate 70B (182 mg, 0.69 mmol, 66.1% yield) as a yellow oil.
- silica gel ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate/Petroleum ether gradient @ 35mL/min
- Example 71 l-(2-Aminoethyl)-2'-(4-(pentafluoro-L6-sulfaneyl)phenoxy)-[3,3'-bipyridin]-
- reaction mixture was diluted with H 2 O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous TsfeSCh, filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 12g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 80%PE/EtOAc@30 mL/min) to give intermediate 71B (343 mg, 0.81 mmol, 43.0% yield) as a white solid.
- silica gel ISCO®; 12g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 80%PE/EtOAc@30 mL/min
- Example 74 (£')-5-(3-(4-(Pentafluoro-k6-sulfaneyl)phenoxy)pyrazin-2-yl)-2-(3,3,3- trifluoroprop-l-en-l-yl)pyrimidine (Compound 74)
- Example 76 (E)-5-(2-(4-(pentafluoro-k6-sulfaneyl)phenoxy)pyridin-3-yl)-2-(3,3,3- trifluoroprop-l-en-l-yl)pyrimidine (Compound 76) pentafluoro- [4- [ [3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-2-pyridyl] oxy] phenyl] - sulfane
Abstract
Provided herein are compounds and pharmaceutical compositions comprising said compounds that are useful for treating diseases. Specific diseases include those that are mediated by YAP/TAZ or those that are modulated by the interaction between YAP/TAZ and TEAD.
Description
COMPOUNDS AND METHODS OF USE THEREOF
BACKGROUND OF THE DISCLOSURE
[0001] YAP and TAZ are transcriptional co-activators of the Hippo pathway network and regulate cell proliferation, migration, and apoptosis. Inhibition of the Hippo pathway promotes YAP/TAZ translocation to the nucleus, wherein YAP/TAZ interact with transcriptional enhancer associate domain (TEAD) transcription factors and coactivate the expression of target genes and promote cell proliferation. Hyperactivation of YAP and TAZ and/or mutations in one or more members of the Hippo pathway network have been implicated in numerous cancers. Described herein are inhibitors associated with one or more members of the Hippo pathway network, such as inhibitors of YAP/TAZ or inhibitors that modulate the interaction between YAP/TAZ and TEAD.
SUMMARY OF THE DISCLOSURE
[0002] Provided herein are compounds of Formula (I) and pharmaceutical compositions comprising said compounds. In some embodiments, the subject compounds are useful for the treatment of diseases or disorders. In some embodiments, the disease or disorder is cancer.
[0003] In one aspect, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
wherein, ring A is monocyclic heteroaryl;
X1 is N or CRX1; X2 is N or CRX2; X3 is N or CRX3; X4 is N or CRX4;
Y is CR4R5, O, S, or NR6; each of RX1, RX2, RX3, and RX4, when present, is independently hydrogen, halogen, nitro, - OR7, -SR7, -CN, -C(=O)R7, -C(=O)NR7R8, -C(=O)OR7, -S(=O)R7, -S(=O)2R7, -NR7R8, - NR7S(=O)2R8, -NR7C(=O)R8, -NR7C(=O)OR8, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl,
substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3- Cvcycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;
R is halogen, nitro, -CN, -OR7, -SR7, -S(R7)5, -C(=O)R7, -C(=O)NR7R8, -C(=O)OR7, - S(=O)R7, -S(=O)2R7, -NR7R8, -NR7S(=O)2R8, -NR7C(=O)R8, -NR7C(=O)OR8, or substituted or unsubstituted C1-C6fluoroalkyl; each of R1 and R2 is independently halogen, nitro, -CN, -OR7, -SR7, -S(=O)R7, -S(=O)2R7, - S(=O)2NR7R8, -NR7R8, -C(=O)R7, -C(=O)OR7, -C(=O)NR7R8, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R3 is halogen, nitro, -OR7, -SR7, -CN, -C(=O)R7, -OC(=O)R7, -C(=O)NR7R8, -C(=O)OR7, - S(=O)R7, -S(=O)NR7R8, -S(=NR7)R8, -S(=NR7)NR7R8, -S(=O)2R7, -S(=O)2NR7R8, - S(=O)(=NR7)R7, -S(=O)(=NR7)NR7R8, -NR7R8, -NR7S(=O)2R8, -NR7S(=O)(=NR7)R8, - NR7C(=O)R8, -N[C(=O)R8]2, -NR7C(=O)NR7R8, NR7CH2C(=O)NR7R8, NR7CH2CH2C(=O)NR7R8, -NR7C(=O)OR8, -P(=O)(OR7)R8, -P(=O)(OR7)(OR8), - P(=O)R7R8, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2- C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1- C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted C5-C10 aryl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl; each R4, R5, R6, R7, and R8 is independently hydrogen, halogen, -CN, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R4 and R5 taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C3-C8cycloalkyl or substituted or unsubstituted 3- to 8- membered heterocycloalkyl having 1 or 2 heteroatoms each independently selected from N, O, and S; or
R7 and R8 taken together with the atom to which they are attached to form a substituted or unsubstituted N- or P-containing 3- to 8-membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S; m is 0, 1, 2, or 3; and
n is 0, 1, 2, 3, or 4.
[0004] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.
[0005] In another aspect, the present disclosure provides a compound described in Table 1, or a pharmaceutically acceptable salt or solvate thereof.
[0006] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient.
[0007] In another aspect, the present disclosure provides a method of inhibiting one or more of proteins encompassed by, or related to, the Hippo pathway in a subject, comprising administering to a subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.
[0008] In another aspect, the present disclosure provides a method of inhibiting transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP) in a subject comprising administering to a subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the subject has cancer, polycystic kidney disease, or liver fibrosis. In some embodiments, the cancer is selected from mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwannoma, lung cancer, bladder carcinoma, cutaneous neurofibromas, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, and breast cancer.
[0009] In another aspect, the present disclosure provides a method of treating cancer in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cancer is selected from mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwannoma, lung cancer, bladder carcinoma, cutaneous neurofibromas, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, and breast cancer. [0010] In another aspect, the present disclosure provides a method of treating polycystic kidney disease or liver fibrosis in a subject in need thereof comprising administering to the subject in need
thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.
DETAILED DESCRIPTION OF THE DISCLOSURE Ce rtain Terminology
[0011] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. In this application, the use of “or” means “and/or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting.
[0012] As used herein, in some embodiments, ranges and amounts are expressed as “about” a particular value or range. About also includes the exact amount. Hence “about 5 μL” means “about 5 μL” and also “5 μL.” Generally, the term “about” includes an amount that is expected to be within experimental error.
[0013] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.
[0014] As used herein, the terms “individual(s)”, “subject(s)” and “patient(s)” mean any mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is a nonhuman. None of the terms require or are limited to situations characterized by the supervision (e.g., constant or intermittent) of a health care worker (e.g., a doctor, a registered nurse, a nurse practitioner, a physician’s assistant, an orderly, or a hospice worker).
[0015] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.
[0016] " Amino" refers to the -NH2 radical.
[0017] "Cyano" refers to the -CN radical.
[0018] "Nitro" refers to the -NO2 radical.
[0019] " Oxa" refers to the -O- radical.
[0020] " Oxo" refers to the =0 radical.
[0021] " Thioxo" refers to the =S radical.
[0022] " Imino" refers to the =N-H radical.
[0023] " Oximo" refers to the =N-OH radical.
[0024] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C1-C8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1 -propyl (n-propyl), 1 -methylethyl (iso-propyl), 1 -butyl (//-butyl), 1 -methylpropyl (sec- butyl), 2-methylpropyl (iso-butyl), 1,1 -dimethylethyl (tert-butyl), 1 -pentyl (//-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, ORa, -SRa, OC(O)Ra, N(Ra)2, C(O)Ra, C(O)ORa, C(O)N(Ra)2, N(Ra)C(O)ORf, OC(O) NRaRf, N(Ra)C(O)Rf, N(Ra)S(O)tRf (where t is 1 or 2), S(O)tORa (where t is 1 or 2), S(O)tRf (where t is 1 or 2), and S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each Rf is independently alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.
[0025] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.
[0026] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the
following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, ORa, -SRa, OC(O) Ra, N(Ra)2, C(O)Ra, C(O)ORa, C(O)N(Ra)2, N(Ra)C(O)ORf, OC(O) NRaRf, N(Ra)C(O)Rf, N(Ra)S(O)tRf (where t is 1 or 2), S(O)tORa (where t is 1 or 2), S(O)tRf (where t is 1 or 2), and S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each Rf is independently alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.
[0027] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl has two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, ORa, -SRa, OC(O) Ra, N(Ra)2, C(O)Ra, C(O)ORa, C(O)N(Ra)2, N(Ra)C(O)ORf, OC(O) NRaRf, N(Ra)C(O)Rf, N(Ra)S(O)tRf (where t is 1 or 2), S(O)tORa (where t is 1 or 2), S(O)tRf (where t is 1 or 2), and S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each Rf is independently alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.
[0028] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, ^-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In some embodiments, the points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., C1-Cs alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., Ci alkylene). In
other embodiments, an alkylene comprises five to eight carbon atoms (e.g., Cs-Cs alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5 alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -
SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORf, -OC(O)- NRaRf, -N( Ra)C(O)Rf, -N(Ra)S(O)tRf (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRf (where t is 1 or 2), and -S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each Rf is independently alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.
[0029] "Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ^-electron system in accordance with the Hiickel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-CN, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra) C(O)Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a
straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.
[0030] "Aryloxy" refers to a radical bonded through an oxygen atom of the formula -O-aryl, where aryl is as defined above.
[0031] "Aralkyl" refers to a radical of the formula -Rc-aryl where Rc is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
[0032] "Aralkenyl" refers to a radical of the formula -Rd-aryl where Rd is an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.
[0033] "Aralkynyl" refers to a radical of the formula -Re-aryl, where Re is an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.
[0034] "Carbocyclyl" or “carbocycle” refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclyl from “heterocyclyl” rings or “heterocycles” in which the ring backbone contains at least one atom which is different from carbon. In some embodiments, a carbocyclyl is a monocyclic carbocyclyl or a bicyclic carbocyclyl. In some embodiments, a carbocyclyl is a monocyclic carbocyclyl. Carbocyclyls are non-aromatic or aromatic. Non-aromatic carbocyclyls are saturated or partially unsaturated. In some embodiments, a carbocyclyl is a bicyclic carbocyclyl. In some embodiments, at least one of the two rings of a bicyclic carbocyclyl is aromatic. In some embodiments, both rings of a bicyclic carbocyclyl are aromatic. Carbocyclyl include aryls and cycloalkyls.
[0035] “Cycloalkyl” refers to a monocyclic or polycyclic aliphatic, fully saturated non-aromatic carbocyclyl, wherein each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls are spirocyclic or bridged compounds. In some embodiments, cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having from 3 to 10 ring atoms. In some embodiments, cycloalkyl groups include groups having from 3 to 6 ring atoms. In some embodiments, cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl and bicyclefl .1. l]pentyl. In some embodiments, a cycloalkyl is a C3-C6cycloalkyl.
Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In certain embodiments, a cycloalkyl comprises three to eight carbon atoms (e.g., C3-C8 cycloalkyl). In other embodiments, a cycloalkyl comprises three to seven carbon atoms (e.g., C3-C7 cycloalkyl). In other embodiments, a cycloalkyl comprises three to six carbon atoms (e.g., C3-C6 cycloalkyl). In other embodiments, a cycloalkyl comprises three to five carbon atoms (e.g., C3-C5 cycloalkyl). In other embodiments, a cycloalkyl comprises three to four carbon atoms (e.g., C3-C4 cycloalkyl). An unsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term " cycloalkyl" is meant to include cycloalkyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -CN, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb -C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O )Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.
[0036] "Carbocycloalkylalkyl" refers to a radical of the formula -Rc- cycloalkyl where Rc is an alkylene chain as defined above. The alkylene chain and the cycloalkyl radical are optionally substituted as defined above.
[0037] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo substituents.
[0038] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.
[0039] "Heterocyclyl" or “heterocycle” refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings having 3 to 10 atoms in its ring system and aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which include fused, spiro, or bridged ring systems in some embodiments. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. In some embodiments, the heterocyclyl is attached to the rest of the molecule through any atom of the ring(s).
[0040] “Heterocycloalkyl” refers to a cycloalkyl group in which one or more skeletal atoms of the cycloalkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, - N(alkyl)-, sulfur, or combinations thereof. In some embodiments, a heterocycloalkyl is fused with an aryl or heteroaryl. Examples of such heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. In one aspect, a heterocycloalkyl is a C2-C10heterocycloalkyl. In another aspect, a heterocycloalkyl is a 5- to 10-membered C4-C9heterocycloalkyl. In another aspect, a heterocycloalkyl is a 4- to 7-membered C3-C6heterocycloalkyl. In some embodiments, a heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring. Unless stated otherwise specifically in the specification, the term "heterocycloalkyl" is meant to include heterocycloalkyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, -CN, -Rb-CN
, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)O Ra, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)t Ra (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.
[0041] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-, sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6heteroalkyl. In some embodiments, the alkyl part of the heteroalkyl radical is optionally substituted as defined for an alkyl group.
[0042] "Heterocycloalkylalkyl" refers to a radical of the formula -Rc-heterocycloalkyl where Rc is an alkylene chain as defined above. If the heterocycloalkyl is a nitrogen-containing heterocycloalkyl, the heterocycloalkyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocycloalkylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocycloalkyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocycloalkyl group.
[0043] "Heterocycloalkylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O-Rc- heterocycloalkyl where Rc is an alkylene chain as defined above. If the heterocycloalkyl is a nitrogen-containing heterocycloalkyl, the heterocycloalkyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocycloalkylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocycloalkyl part of the heterocycloalkylalkoxy radical is optionally substituted as defined above for a heterocycloalkyl group.
[0044] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, in some embodiments, the heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, z.e., it contains a cyclic, delocalized (4n+2) ^-electron system in accordance with the Hiickel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally
quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodi oxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,
5.6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H- benzo[6,7]cyclohepta[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,
1.6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1 -phenyl- 177-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl,
5.6.7.8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,
6.7.8.9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O )Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, - Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or
2), and -Rb-S(0)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.
[0045] "/'/-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An A-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
[0046] " C-heteroaryl" refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
[0047] "Heteroaryloxy" refers to radical bonded through an oxygen atom of the formula -O- heteroaryl, where heteroaryl is as defined above.
[0048] "Heteroarylalkyl" refers to a radical of the formula -Rc-heteroaryl, where Rc is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroaryl alkyl radical is optionally substituted as defined above for a heteroaryl group.
[0049] "Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O- Rc-heteroaryl, where Rc is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroaryl alkoxy radical is optionally substituted as defined above for a heteroaryl group.
[0050] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (A)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or irons'). Likewise, all possible isomers, as well as their racemic and optically pure forms,
and all tautomeric forms are also intended to be included. The term "geometric isomer" refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term "positional isomer" refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.
[0051] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:
[0052] "Optional" or "optionally" means that a subsequently described event or circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
[0053] The term “optionally substituted” or “substituted” means that the referenced group is optionally substituted with one or more additional group(s). In some other embodiments, optional substituents are individually and independently selected from D, halogen, -CN, -NEb, -NH(alkyl), - N(alkyl)2, -OH, =0, -CO2H, -CO2alkyl, -C(=0)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, - S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, -CH2CO2H, -CH2CO2alkyl, -CH2C(=O)NH2, - CH2C(=O)NH(alkyl), -CH2C(=O)N(alkyl)2, -CH2S(=O)2NH2, - CH2S(=O)2NH(alkyl), - CH2S(=O)2N(alkyl)2, alkyl, alkenyl, alkynyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide,
arylsulfoxide, alkylsulfone, and arylsulfone. In some embodiments, optional substituents are individually and independently selected from D, halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, - S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, =0, -CO2H, - CO2(C1-C4alkyl), -C(=0)NH2, -C(=O)NH(C1-C4alkyl), -C(=O)N(C1-C4alkyl)2, -S(=O)2NH2, - S(=O)2NH(C1-C4alkyl), -S(=O)2N(C1-C4alkyl)2, C1-C4alkyl, C3-C6cycloalkyl, C1-C4fluoroalkyl, C1- C4heteroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, -SC1-C4alkyl, -S(=O)C1-C4alkyl, and -S(=0)2C1- C4alkyl. In some embodiments, optional substituents are independently selected from D, halogen, - CN, -NH2, -OH, =0, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -0CH3, and -OCF3. In some embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2, -OH, - NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, optional substituents are independently selected from D, F, Cl, -CN, -NH2, -OH, =0, -NH(CH3), -N(CH3)2, - CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, substituted groups are substituted with one to six of the preceding groups. In some embodiments, substituted groups are substituted with one to four of the preceding groups. In some embodiments, substituted groups are substituted with one to three of the preceding groups. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, substituted groups are substituted with one of the preceding groups.
[0054] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Pharmaceutically acceptable salts of the compounds described herein are optionally pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
[0055] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic
acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997), which is hereby incorporated by reference in its entirety). In some embodiments, acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.
[0056] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N, N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N- methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra.
[0057] As used herein, "treatment" or "treating " or "palliating" or "ameliorating" are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including, but not limited to, therapeutic benefit and/or a prophylactic benefit. By "therapeutic benefit" is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is
observed in the patient, notwithstanding that the patient is afflicted with the underlying disorder in some embodiments. For prophylactic benefit, in some embodiments, the compositions are administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
[0058] "Prodrug" is meant to indicate a compound that is converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharmaceutically acceptable. In some embodiments, a prodrug is inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).
[0059] A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein.
[0060] The term "prodrug" is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. In some embodiments, prodrugs of an active compound, as described herein, are prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino, or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino, or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol or amine functional groups in the active compounds and the like.
Compounds
[0061] In one aspect, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
X1 is N or CRX1; X2 is N or CRX2; X3 is N or CRX3; X4 is N or CRX4;
Y is CR4R5, O, S, or NR6; each of RX1, RX2, RX3, and RX4, when present, is independently hydrogen, halogen, nitro, - OR7, -SR7, -CN, -C(=O)R7, -C(=O)NR7R8, -C(=O)OR7, -S(=O)R7, -S(=O)2R7, -NR7R8, - NR7S(=O)2R8, -NR7C(=O)R8, -NR7C(=O)OR8, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3- C?cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;
R is halogen, nitro, -CN, -OR7, -SR7, -S(R7)5, -C(=O)R7, -C(=O)NR7R8, -C(=O)OR7, - S(=O)R7, -S(=O)2R7, -NR7R8, -NR7S(=O)2R8, -NR7C(=O)R8, -NR7C(=O)OR8, or substituted or unsubstituted C1-C6fluoroalkyl; each of R1 and R2 is independently halogen, nitro, -CN, -OR7, -SR7, -S(=O)R7, -S(=O)2R7, - S(=O)2NR7R8, -NR7R8, -C(=O)R7, -C(=O)OR7, -C(=O)NR7R8, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R3 is halogen, nitro, -OR7, -SR7, -CN, -C(=O)R7, -OC(=O)R7, -C(=O)NR7R8, -C(=O)OR7, - S(=O)R7, -S(=O)NR7R8, -S(=NR7)R8, -S(=NR7)NR7R8, -S(=O)2R7, -S(=O)2NR7R8, - S(=O)(=NR7)R7, -S(=O)(=NR7)NR7R8, -NR7R8, -NR7S(=O)2R8, -NR7S(=O)(=NR7)R8, - NR7C(=O)R8, -N[C(=O)R8]2, -NR7C(=O)NR7R8, NR7CH2C(=O)NR7R8, NR7CH2CH2C(=O)NR7R8, -NR7C(=O)OR8, -P(=O)(OR7)R8, -P(=O)(OR7)(OR8), - P(=O)R7R8, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2- C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-
C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted C5-C10 aryl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl; each R4, R5, R6, R7, and R8 is independently hydrogen, halogen, -CN, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R4 and R5 taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C3-C8cycloalkyl or substituted or unsubstituted 3- to 8- membered heterocycloalkyl having 1 or 2 heteroatoms each independently selected from N, O, and S; or
R7 and R8 taken together with the atom to which they are attached to form a substituted or unsubstituted N- or P-containing 3- to 8-membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, or 4.
[0062] In some embodiments, ring A is a 5-, 6-, or 7-membered monocyclic heteroaryl. In some embodiments, ring A is a 5- or 6-membered monocyclic heteroaryl. In some embodiments, ring A is a 6- or 7-membered monocyclic heteroaryl. In some embodiments, ring A is a 6-membered monocyclic heteroaryl.
[0063] In some embodiments, ring A is a monocyclic heteroaryl having 1-4 N atoms. In some embodiments, ring A is a monocyclic heteroaryl having 1-3 N atoms. In some embodiments, ring A is a monocyclic heteroaryl having 1-2 N atoms. In some embodiments, ring A is a monocyclic heteroaryl having 1 N atom. In some embodiments, ring A is a monocyclic heteroaryl having 2 N atoms. In some embodiments, ring A is a monocyclic heteroaryl having 3 N atoms. In some embodiments, ring A is a monocyclic heteroaryl having 4 N atoms.
[0064] In some embodiments, ring A is a monocyclic 6-membered heteroaryl having 1-4 N atoms. [0065] In some embodiments, ring A is pyridinyl, pyrimidinyl, or pyrazinyl.
[0068] In some embodiments, the compound has a structure of Formula (Il-a), or a pharmaceutically acceptable salt or solvate thereof:
Formula (Il-a).
[0069] In some embodiments, the compound has a structure of Formula (Il-b), or a pharmaceutically acceptable salt or solvate thereof:
[0070] In some embodiments, the compound has a structure of Formula (II-c), or a pharmaceutically acceptable salt or solvate thereof:
Formula (II-c).
[0071] In some embodiments, the compound has a structure of Formula (Il-d), or a pharmaceutically acceptable salt or solvate thereof:
wherein m is 0, 1, or 2.
[0072] In some embodiments, the compound has a structure of Formula (Il-e), or a pharmaceutically acceptable salt or solvate thereof:
wherein m is 0, 1, or 2.
[0073] In some embodiments, the compound has a structure of Formula (Il-f), or a pharmaceutically acceptable salt or solvate thereof:
Formula (Il-f).
[0074] In some embodiments, the compound has a structure of Formula (Il-g), or a pharmaceutically acceptable salt or solvate thereof:
wherein m is 0, 1, or 2.
[0075] In some embodiments, X1 is CRX1; X2 is CRX2; X3 is CRX3; and X4 is CRX4. In some embodiments, X1 is N; X2 is CRX2; X3 is CRX3; and X4 is CRX4. In some embodiments, X1 is CRX1; X2 is N; X3 is CRX3; and X4 is CRX4. In some embodiments, X1 is CRX1; X2 is CRX2; X3 is N; and X4 is CRX4. In some embodiments, X1 is CRX1; X2 is CRX2; X3 is CRX3; and X4 is N. In some embodiments, X1 is N; X2 is CRX2; X3 is CRX3; and X4 is N. In some embodiments, X1 is N; X2 is CRX2; X3 is N; and X4 is CRX4. In some embodiments, X1 is N; X2 is N; X3 is CRX3; and X4 is CRX4. In some embodiments, X1 is CRX1; X2 is N; X3 is N; and X4 is CRX4. In some embodiments, X1 is CRX1; X2 is N; X3 is X3 is CRX3; and X4 is N. In some embodiments, X1 is N; X2 is N; X3 is CRX3; and X4 is N. In some embodiments, X1 is N; X2 is CRX2; X3 is N; and X4 is N.
[0076] In some embodiments, each of RX1, RX2, RX3, and RX4, when present, is independently hydrogen, halogen, -OR7, -SR7, -CN, -NR7R8, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C2-C4alkenyl, substituted or unsubstituted C2-C4alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl. In some embodiments, each of RX1, RX2, RX3, and RX4, when present, is independently hydrogen, halogen, -OR7, -SR7, -CN, -NR7R8, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl.
In some embodiments, each of RX1, RX2, RX3, and RX4, when present, is independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2CN, -CH2C(=O)OH, - CH2C(=O)OCH3, -CH2C(=O)OCH2CH3, -CH2C(=O)NH2, -CH2C(=O)NHCH3, - CH2C(=O)N(CH3)2, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2F, -CHF2, -CF3, -CH=CH2, - C=CH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -OH, -OCH3, -OCH2CH3, -OCH2F, -OCHF2, -OCF3, -NH2, -NHCH3, -N(CH3)2, -NHC(=O)CH3, -N(CH3)C(=O)CH3, -NHC(=O)OCH3, - N(CH3)C(=O)OCH3, -S(=O)CH3, -S(=O)2CH3, -NHS(=O)2CH3, or -N(CH3)S(=O)2CH3. In some embodiments, each of RX1, RX2, RX3, and RX4, when present, is independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, cyclopropyl, -C=CH, -OCH3, -NH2, -NHC(=O)CH3, -N(CH3)C(=O)CH3, - NHS(=O)2CH3, -N(CH3)S(=O)2CH3, -S(=O)CH3, or -S(=O)2CH3. In some embodiments, each of RX1, RX2, RX3, and RX4, when present, is independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, cyclopropyl, -OCH3, or -OCF3. In some embodiments, each of RX1, RX2, RX3, and RX4, when present, is independently hydrogen, F, Cl, or -CH3. In some embodiments, each of RX1, RX2, RX3, and RX4, when present, is independently hydrogen or F. In some embodiments, each of RX1, RX2, RX3, and RX4, when present, is hydrogen.
[0077] In some embodiments, the compound has a structure of Formula (Ill-a), or a pharmaceutically acceptable salt or solvate thereof:
Formula (Ill-a).
[0078] In some embodiments, the compound has a structure of Formula (Ill-b), or a pharmaceutically acceptable salt or solvate thereof:
[0079] In some embodiments, the compound has a structure of Formula (III-c), or a pharmaceutically acceptable salt or solvate thereof:
Formula (III-c).
[0080] In some embodiments, the compound has a structure of Formula (Ill-d), or a pharmaceutically acceptable salt or solvate thereof:
[0081] In some embodiments, the compound has a structure of Formula (Ill-e), or a pharmaceutically acceptable salt or solvate thereof:
Formula (Ill-e).
[0082] In some embodiments, the compound has a structure of Formula (Ill-f), or a pharmaceutically acceptable salt or solvate thereof:
Formula (III-F).
[0083] In some embodiments, the compound has a structure of Formula (Ill-g), or a pharmaceutically acceptable salt or solvate thereof:
Formula (Ill-g).
[0084] In some embodiments, the compound has a structure of Formula (Ill-h), or a pharmaceutically acceptable salt or solvate thereof:
[0085] In some embodiments, the compound has a structure of Formula (Ill-i), or a pharmaceutically acceptable salt or solvate thereof:
Formula (Ill-i).
[0086] In some embodiments, the compound has a structure of Formula (Ill-j), or a pharmaceutically acceptable salt or solvate thereof:
Formula (Ill-j ).
[0087] In some embodiments, the compound has a structure of Formula (Ill-k), or a pharmaceutically acceptable salt or solvate thereof:
[0088] In some embodiments, the compound has a structure of Formula (III-l), or a pharmaceutically acceptable salt or solvate thereof:
Formula (III-l).
[0089] In some embodiments, the compound has a structure of Formula (Ill-m), or a pharmaceutically acceptable salt or solvate thereof:
[0090] In some embodiments, the compound has a structure of Formula (Ill-n), or a pharmaceutically acceptable salt or solvate thereof:
[0091] In some embodiments, the compound has a structure of Formula (III-o), or a pharmaceutically acceptable salt or solvate thereof:
Formula (III-o).
[0092] In some embodiments, the compound has a structure of Formula (III-p), or a pharmaceutically acceptable salt or solvate thereof:
[0093] In some embodiments, the compound has a structure of Formula (Ill-q), or a pharmaceutically acceptable salt or solvate thereof:
Formula (Ill-q).
[0094] In some embodiments, the compound has a structure of Formula (Ill-r), or a pharmaceutically acceptable salt or solvate thereof:
Formula (Ill-r).
[0095] In some embodiments, the compound has a structure of Formula (III-s), or a pharmaceutically acceptable salt or solvate thereof:
Formula (III-s).
[0096] In some embodiments, the compound has a structure of Formula (Ill-t), or a pharmaceutically acceptable salt or solvate thereof:
Formula (Ill-t).
[0097] In some embodiments, the compound has a structure of Formula (III-u), or a pharmaceutically acceptable salt or solvate thereof:
Formula (III-u).
[0098] In some embodiments, the compound has a structure of Formula (III-v), or a pharmaceutically acceptable salt or solvate thereof:
[0099] In some embodiments, the compound of Formula (I) is a compound having a structure selected from Formulas (Ill-a), (Ill-b), (III-c), (Ill-d), (Ill-e), (Ill-f), (IILg), (Ill-h), (Ill-i), (Ill-j), (Ill-k), (III-l), (in-m), (ni-n), (III-o), (III-p), (Ill-q), (Ill-r), (III-s), (IH-t), (III-u), and (III-v). [00100] In some embodiments, R3 is halogen, nitro, -OR7, -SR7, -CN, -OC(=O)R7, - C(=O)R7, -C(=O)NR7R8, -C(=O)OR7, -S(=O)R7, -S(=O)NR7R8, -S(=O)2R7, -S(=O)2NR7R8, - NR7R8, -NR7S(=O)2R8, -NR7C(=O)R8, -N[C(=O)R8]2, -NR7C(=O)NR7R8, NR7CH2C(=O)NR7R8, NR7CH2CH2C(=O)NR7R8, -NR7C(=O)OR8, -P(=O)(OR7)R8, -P(=O)(OR7)(OR8), -P(=O)R7R8, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or
unsubstituted C3-C7cycloalkyl, substituted or unsubstituted C5-C10 aryl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl; and each R7 and R8 is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or substituted or unsubstituted 3- to 10-membered heterocycloalkyl; or R7 and R8 taken together with the atom to which they are attached to form a substituted or unsubstituted N- or P-containing 3- to 8-membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S.
[00101] In some embodiments, R3 is halogen, -OR7, -SR7, -C(=O)R7, -OC(=O)R7, - C(=O)NR7R8, -C(=O)OR7, -NR7R8, -NR7S(=O)2R8, -NR7C(=O)R8, -N[C(=O)R8]2, NR7C(=O)NR7R8, NR7CH2C(=O)NR7R8, NR7CH2CH2C(=O)NR7R8, -NR7C(=O)OR8, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, or substituted or unsubstituted C1-C6heteroalkyl; and each R7 and R8 is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1- C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3- C10cycloalkyl, substituted or unsubstituted C5-C10 aryl, or substituted or unsubstituted 3- to 8- membered heterocycloalkyl; or R7 and R8 taken together with atom to which they are attached to form a substituted or unsubstituted N-containing 3- to 10-membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S.
[00102] In some embodiments, R3 is -OR7, -SR7, -C(=O)R7, -OC(=O)R7, -C(=O)NR7R8, - C(=O)OR7, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; and each R7 and R8 is independently hydrogen, substituted or unsubstituted C1- C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1- C6heteroalkyl, substituted or unsubstituted C3-C10 ycloalkyl, or substituted or unsubstituted 3- to 10-membered heterocycloalkyl.
[00103] In some embodiments, R3 is -OR7, -SR7, -C(=O)R7, -OC(=O)R7, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; and each R7 and R8 is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1- C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or substituted or unsubstituted 3- to 10-membered heterocycloalkyl.
[00104] In some embodiments, R3 is -OR7, -SR7, -C(=O)R7, or -OC(=O)R7; and each R7 and R8 is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C3-C10cycloalkyl.
[00105] In some embodiments, R3 is -NR7R8, -NR7S(=O)2R7, or -NR7C(=O)R7; and each R7 and R8 is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, or C3-C10cycloalkyl.
[00106] In some embodiments, R3 is substituted or unsubstituted C5-C10 aryl. In some embodiments, R3 is substituted or unsubstituted phenyl. In some embodiments, R3 is phenyl. [00107] In some embodiments, R3 is F, Cl, Br, I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -Cμ H, -CH2Cμ H, -CH2CH2Cμ H, -CH2CN, -CH=CH2, -CH2C(=O)OH, -CH2C(=O)OCH3, -CH2C(=O)OCH2CH3, -CH2C(=O)NH2, -CH2C(=O)NHCH3, -CH2C(=O)N(CH3)2, -CH2NH2, - CH2CH2NH2, -CH2CH2CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2F, -CHF2, -CF3, -CH2CH2F, - CH=CH2, -CH=CHCF3, -C=CH, -CH2OCH, cyclopropyl, -CN-cycloprop-l-yl, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, oxetanyloxy, tetrahydrofuranyloxy, tetrahydropyranyloxy, azetidinyl, pyrrolidinyl, tetrazolyl, piperazin-2-one-yl, phenyl, -CN, -OH, -OCH3, -OCH2CH3, - OCH2Cμ H, -OCH2CH=CH2, -OCH=CHCH3, -OCH2C=CH, -0CH2CN, -0CF3, -C(=O)OH, - C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -NH2, -NHCH3, - NHCH2CH3, -N(CH3)2, -NHC(=O)CH3, NHCH2CH2OH, NCH3CH2Cμ H, NHCH2C(=O)NH2, NHCH2CH2C(=O)NH2, N[C(=O)CH=CH2]2, -N(CH3)C(=O)CH3, -NHC(=O)OCH3, - NHC(=O)CH=CH2, -NHC(=O)O-t-butyl, -N(CH3)C(=O)OCH3, -S(=O)CH3, -S(=O)2CH3, - S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NHS(=O)2CH3, or -N(CH3)S(=O)2CH3.
[00108] In some embodiments, R3 is -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, - NHCH2Cμ H, -N(CH3)CH2Cμ H, azetidinyl, pyrrolidinyl, piperazin-2-one-4-yl, phenyl, - NHCH2CH2C(=O)NH2, -NHCH2C(=O)NH2, -NHC(=O)CH3, -NHC(=O)CH=CH2, - N(C(=O)CH=CH2)2, or -NHS(=O)2CH3. In some embodiments, R3 is -NH2. In some embodiments, R3 is -NHCH3. In some embodiments, R3 is -NHCH2CH3. In some embodiments, R3 is -N(CH3)2. In some embodiments, R3 is -NHCH2Cμ H. In some embodiments, R3 is - N(CH3)CH2Cμ H. In some embodiments, R3 is azetidinyl. In some embodiments, R3 is pyrrolidinyl. In some embodiments, R3 is piperazin-2-one-4-yl. In some embodiments, R3 is phenyl. In some embodiments, R3 is -NHCH2CH2C(=O)NH2. In some embodiments, R3 is - NHCH2C(=O)NH2. In some embodiments, R3 is -NHC(=O)CH3. In some embodiments, R3 is - NHC(=O)CH=CH2. In some embodiments, R3 is -N(C(=O)CH=CH2)2. In some embodiments, R3 is -NHS(=O)2CH3.
[00109] In some embodiments, R3 is -CH=CH2, -C=CH, -CH=CHCF3, cyclopropyl, 1 -CN- cycloprop-l-yl, 1-F-cycloprop-l-yl, -C(=O)NHCH3, -C(=O)N(CH3)2, or -S(=O)2CH3. In some embodiments, R3 is -CH=CH2. In some embodiments, R3 is -C=CH. In some embodiments, R3 is - CH=CHCF3. In some embodiments, R3 is cyclopropyl. In some embodiments, R3 is 1 -CN- cycloprop-l-yl. In some embodiments, R3 is 1-F-cycloprop-l-yl. In some embodiments, R3 is -
C(=0)NHCH3. In some embodiments, R3 is -C(=O)N(CH3)2. In some embodiments, R3 is - S(=O)2CH3.
[00110] In some embodiments, R3 is -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, - OCH(CH3)2, -OCH=CH2, -OCH2CH=CH2, -OCH=CHCH3, -OCH2OCH, or -OOCCH3. In some embodiments, R3 is -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, or -OCH(CH3)2. In some embodiments, R3 is -OH, -OCH=CH2, -OCH2CH=CH2, -OCH=CHCH3, -OCH2C=CH, or - OOCCH3. In some embodiments, R3 is -OH, -OCH3, -OCH2CH3, -OCH=CH2, -OCH2CH=CH2, - OCH=CHCH3, -OCH2C=CH, or -OOCCH3. In some embodiments, R3 is -OH. In some embodiments, R3 is -OCH3. In some embodiments, R3 is -OCH2CH3. In some embodiments, R3 is -OCH2CH2CH3. In some embodiments, R3 is -OCH(CH3)2. In some embodiments, R3 is - OCH=CH2. In some embodiments, R3 is -OCH2CSHCH2. In some embodiments, R3 is - OCH=CHCH3. In some embodiments, R3 is -OCH2C=CH. In some embodiments, R3 is - OOCCH3.
[00111] In some embodiments, R3 is -OCH2F, -OCHF2, -OCF3, -OCF2CH3, or -OCH2CF3.
[00112] In some embodiments, R is halogen, nitro, -CN, -OR7, -SR7, -S(R7)5, -C(=O)R7, -
C(=O)NR7R8, -C(=O)OR7, -S(=O)R7, -S(=O)2R7, -NR7S(=O)2R7, -NR7C(=O)R7, -NR7C(=O)OR7, or substituted or unsubstituted C1-C6fluoroalkyl; and each R7 and R8 is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or substituted or unsubstituted 3- to 10-membered heterocycloalkyl; or R7 and R8 taken together with the atom to which they are attached to form a substituted or unsubstituted N-containing 3- to 8-membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S. In some embodiments, R is F, Cl, Br, I, nitro, -CN, -SF5, -SCF3, -OCH2F, -OCHF2, - 0CF3, -C(=O)CH3, -C(=O)OCH3 -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -S(=O)CH3, - S(=O)2CH3, -NHS(=O)2CH3, -N(CH3)S(=O)2CH3, -NHC(=O)CH3, -N(CH3)C(=O)CH3, - NHC(=O)OCH3, -N(CH3)C(=O)OCH3, -CH2F, -CHF2, or -CF3. In some embodiments, R is F, Cl, - CN, -OCF3, -CHF2, -SCF3, or -CF3. In some embodiments, R is F, Cl, -OCF3, -CHF2, -SCF3, or - CF3. In some embodiments, R is F, Cl, -SF5, -SCF3, or -CF3. In some embodiments, R is F, Cl, - SF5, -OCF3, -SCF3, or -CF3. In some embodiments, R is -SF5, -SCF3, or -OCF3. In some embodiments, R is -SF5, -SCF3, or -CF3. 1 n some embodiments, R is -CF3, -SCF3, or -OCF3. In some embodiments, R is -OCF3. In some embodiments, R is -CF3. In some embodiments, R is -SF5. In some embodiments, R is -SCF3.
[00113] In some embodiments, each R1 is independently halogen, -CN, -OR7, -SR7, - S(=O)R7, -S(=O)2R7, -S(=O)2NR7R8, -C(=O)R7, substituted or unsubstituted C1-C6alkyl, substituted
or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted -3 to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and each R7 and R8 is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1- C6fluoroalkyl, or substituted or unsubstituted C1-C6heteroalkyl; or R7 and R8 taken together with the atom to which they are attached to form a substituted or unsubstituted N-containing 3- to 8- membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S. In some embodiments, each R1 is independently halogen, -CN, -OR7, - S(=O)2NR7R8, -C(=O)R7, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1- C6fluoroalkyl, or substituted or unsubstituted C1-C6heteroalkyl; and each R7 and R8 is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1- C6fluoroalkyl, or substituted or unsubstituted C1-C6heteroalkyl; or R7 and R8 taken together with the atom to which they are attached to form a substituted or unsubstituted N-containing 3- to 8- membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S. In some embodiments, each R1 is independently F, Cl, -CN, -OH, - OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, -OCH=CH2, -OCH=CHCH3, -OCH2CH=CH2, -OCH2CH2F, -OCH2Cμ H, -OCH2CH2CH2F, - OCH2CH2Cμ H, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2NHCH2CH3, -S(=O)2NHCH(CH3)2, - S(=O)2NCH3CH2C=CH, -S(=O)2NHcyclopropyl, -S(=O)2NHCH2CH2F, -S(=O)2NHCH2CH2OH, or -S(=O)2N(CH3)CH2CH3. In some embodiments, each R1 is independently F, Cl, -OCH3, - OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, - OCH2CH2F, -OCH2Cμ H, -OCH2CH2CH2F, or -OCH2CH2Cμ H. In some embodiments, each R1 is independently F, Cl, -OH, -OCH3, or -OCH2CH3.
[00114] In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 1 or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.
[00115] In some embodiments, each R2 is independently halogen, nitro, -CN, -OR7, -SR7, - S(=O)R7, -S(=O)2R7, -S(=O)2NR7R8, -NR7R8, -C(=O)R7, -C(=O)OR7, -C(=O)NR7R8, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, each R2 is independently halogen, nitro, -CN, -OR7, -SR7, - S(=O)2R7, -NR7R8, -C(=O)OR7, substituted or unsubstituted C1-C6alkyl, or substituted or
unsubstituted C1-C6fluoroalkyl; and each R7 and R8 is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl; or R7 and R8 taken together with the atom to which they are attached to form a substituted or unsubstituted N-containing 3- to 8-membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S. In some embodiments, each R2 is independently F, Cl, Br, -CN, -OH, -OCH3, -OCH2CH3, -OCH2Cμ H, -OCH2CN, - OCF3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, -C(=O)OCH3, -CH3, -CH2CH3, -CH2F, -CHF2, or - CF3. In some embodiments, each R2 is independently F, Cl, -CN, -OCH3, -OCF3, -C(=0)0CH3, - CH3, or -CF3. In some embodiments, each R2 is independently F, Cl, -OCF3, or -CF3. In some embodiments, each R2 is independently F or Cl.
[00116] In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 1 or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. [00117] In some embodiments, Y is CR4R5, O, S, or NR6. In some embodiments, Y is O, S, or NR6. In some embodiments, Y is CR4R5, S, or NR6. In some embodiments, Y is CR4R5, O, or NR6. In some embodiments, Y is CR4R5, O, or S. In some embodiments, Y is CR4R5 or O. In some embodiments, Y is CR4R5 or S. In some embodiments, Y is CR4R5 or NR6. In some embodiments, Y is O or S. In some embodiments, Y is O or NR6. In some embodiments, Y is S or NR6.
[00118] In some embodiments, Y is CR4R5. In some embodiments, each R4 and R5 is independently hydrogen or C1-C4 alkyl. In some embodiments, each R4 and R5 is hydrogen. In some embodiments, each R4 is hydrogen and R5 is -CH3. In some embodiments, each R4 and R5 is - CH3.
[00119] In some embodiments, Y is O or S. In some embodiments, Y is O. In some embodiments, Y is S.
[00120] In some embodiments, Y is NR6. In some embodiments, R6 is hydrogen or C1-C4 alkyl. In some embodiments, R6 is hydrogen or -CH3. In some embodiments, R6 is hydrogen. In some embodiments, R6 is -CH3. In some embodiments, R6 is -OCH3. In some embodiments, R6 is -OCH2CH3.
[00121] In another aspect, provided herein are compounds having a structure of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof:
X1 is N or CRX1; X2 is N or CRX2; X3 is N or CRX3; X4 is N or CRX4; each of RX1, RX2, RX3, and RX4, when present, is independently hydrogen, halogen, nitro, - OR7, -SR7, -CN, -C(=O)R7, -C(=O)NR7R8, -C(=O)OR7, -S(=O)R7, -S(=O)2R7, -NR7R8, - NR7S(=O)2R8, -NR7C(=O)R8, -NR7C(=O)OR8, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3- C?cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;
R is halogen, nitro, -CN, -OR7, -SR7, -S(R7)5, -C(=O)R7, -C(=O)NR7R8, -C(=O)OR7, - S(=O)R7, -S(=O)2R7, -NR7R8, -NR7S(=O)2R8, -NR7C(=O)R8, -NR7C(=O)OR8, or substituted or unsubstituted C1-C6fluoroalkyl; each of R1 and R2 is independently halogen, nitro, -CN, -OR7, -SR7, -S(=O)R7, -S(=O)2R7, - S(=O)2NR7R8, -NR7R8, -C(=O)R7, -C(=O)OR7, -C(=O)NR7R8, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R3 is halogen, nitro, -OR7, -SR7, -CN, -C(=O)R7, -OC(=O)R7, -C(=O)NR7R8, -C(=O)OR7, - S(=O)R7, -S(=O)NR7R8, -S(=NR7)R8, -S(=NR7)NR7R8, -S(=O)2R7, -S(=O)2NR7R8, - S(=O)(=NR7)R7, -S(=O)(=NR7)NR7R8, -NR7R8, -NR7S(=O)2R8, -NR7S(=O)(=NR7)R8, - NR7C(=O)R8, -N[C(=O)R8]2, -NR7C(=O)NR7R8, NR7CH2C(=O)NR7R8, NR7CH2CH2C(=O)NR7R8, -NR7C(=O)OR8, -P(=O)(OR7)R8, -P(=O)(OR7)(OR8), - P(=O)R7R8, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2- C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1- C6heteroalkyl, substituted or unsubstituted C3-C?cycloalkyl, substituted or unsubstituted C5-C10 aryl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;
each R7 and R8 is independently hydrogen, halogen, -CN, substituted or unsubstituted C1- C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2- C6alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3- C10cycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or
R7 and R8 taken together with the atom to which they are attached to form a substituted or unsubstituted N- or P-containing 3- to 8-membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, or 4.
[00122] In another aspect, the present disclosure provides a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof:
wherein, ring A is monocyclic 6-membered heteroaryl;
X1 is N or CRX1; X2 is N or CRX2; X3 is N or CRX3; X4 is N or CRX4; each of RX1, RX2, RX3, and RX4, when present, is independently hydrogen, halogen, nitro, - OR7, -SR7, -CN, -C(=O)R7, -C(=O)NR7R8, -C(=O)OR7, -S(=O)R7, -S(=O)2R7, -NR7R8, - NR7S(=O)2R8, -NR7C(=O)R8, -NR7C(=O)OR8, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3- C?cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;
R is halogen, nitro, -CN, -OR7, -SR7, -S(R7)5, -C(=O)R7, -C(=O)NR7R8, -C(=O)OR7, - S(=O)R7, -S(=O)2R7, -NR7R8, -NR7S(=O)2R8, -NR7C(=O)R8, -NR7C(=O)OR8, or substituted or unsubstituted C1-C6fluoroalkyl; each of R1 and R2 is independently halogen, nitro, -CN, -OR7, -SR7, -S(=O)R7, -S(=O)2R7, - S(=O)2NR7R8, -NR7R8, -C(=O)R7, -C(=O)OR7, -C(=O)NR7R8, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or
unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R3 is halogen, nitro, -OR7, -SR7, -CN, -C(=O)R7, -OC(=O)R7, -C(=O)NR7R8, -C(=O)OR7, - S(=O)R7, -S(=O)NR7R8, -S(=NR7)R8, -S(=NR7)NR7R8, -S(=O)2R7, -S(=O)2NR7R8, - S(=O)(=NR7)R7, -S(=O)(=NR7)NR7R8, -NR7R8, -NR7S(=O)2R8, -NR7S(=O)(=NR7)R8, - NR7C(=O)R8, -N[C(=O)R8]2, -NR7C(=O)NR7R8, NR7CH2C(=O)NR7R8, NR7CH2CH2C(=O)NR7R8, -NR7C(=O)OR8, -P(=O)(OR7)R8, -P(=O)(OR7)(OR8), - P(=O)R7R8, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2- C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1- C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted C5-C10 aryl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl; each R7 and R8 is independently hydrogen, halogen, -CN, substituted or unsubstituted C1- C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2- C6alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3- C10cycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or
R7 and R8 taken together with the atom to which they are attached to form a substituted or unsubstituted N- or P-containing 3- to 8-membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, or 4.
[00123] In another aspect, the present disclosure provides a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof:
Formula (VI) wherein, ring A is monocyclic 6-membered heteroaryl;
X1 is N or CRX1; X2 is N or CRX2; X3 is N or CRX3; X4 is N or CRX4; each of RX1, RX2, RX3, and RX4, when present, is independently hydrogen, halogen, nitro, - OR7, -SR7, -CN, -C(=O)R7, -C(=O)NR7R8, -C(=O)OR7, -S(=O)R7, -S(=O)2R7, -NR7R8, - NR7S(=O)2R8, -NR7C(=O)R8, -NR7C(=O)OR8, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3- C?cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;
R is halogen, nitro, -CN, -OR7, -SR7, -S(R7)5, -C(=O)R7, -C(=O)NR7R8, -C(=O)OR7, - S(=O)R7, -S(=O)2R7, -NR7R8, -NR7S(=O)2R8, -NR7C(=O)R8, -NR7C(=O)OR8, or substituted or unsubstituted C1-C6fluoroalkyl; each of R1 and R2 is independently halogen, nitro, -CN, -OR7, -SR7, -S(=O)R7, -S(=O)2R7, - S(=O)2NR7R8, -NR7R8, -C(=O)R7, -C(=O)OR7, -C(=O)NR7R8, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R3 is halogen, nitro, -OR7, -SR7, -CN, -C(=O)R7, -OC(=O)R7, -C(=O)NR7R8, -C(=O)OR7, - S(=O)R7, -S(=O)NR7R8, -S(=NR7)R8, -S(=NR7)NR7R8, -S(=O)2R7, -S(=O)2NR7R8, - S(=O)(=NR7)R7, -S(=O)(=NR7)NR7R8, -NR7R8, -NR7S(=O)2R8, -NR7S(=O)(=NR7)R8, - NR7C(=O)R8, -N[C(=O)R8]2, -NR7C(=O)NR7R8, NR7CH2C(=O)NR7R8, NR7CH2CH2C(=O)NR7R8, -NR7C(=O)OR8, -P(=O)(OR7)R8, -P(=O)(OR7)(OR8), - P(=O)R7R8, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2- C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1- C6heteroalkyl, substituted or unsubstituted C3-C?cycloalkyl, substituted or unsubstituted C5-C10 aryl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl; each R7 and R8 is independently hydrogen, halogen, -CN, substituted or unsubstituted C1- C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2- C6alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3- C10cycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or
R7 and R8 taken together with the atom to which they are attached to form a substituted or unsubstituted N- or P-containing 3- to 8-membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S; m is 0, 1, 2, or 3; and
n is 0, 1, 2, 3, or 4.
[00124] In another aspect, the present disclosure provides a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof:
wherein, ring A is monocyclic 6-membered heteroaryl;
X1 is N or CRX1; X2 is N or CRX2; X3 is N or CRX3; X4 is N or CRX4; each of RX1, RX2, RX3, and RX4, when present, is independently hydrogen, halogen, nitro, - OR7, -SR7, -CN, -C(=O)R7, -C(=O)NR7R8, -C(=O)OR7, -S(=O)R7, -S(=O)2R7, -NR7R8, - NR7S(=O)2R8, -NR7C(=O)R8, -NR7C(=O)OR8, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3- C?cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;
R is halogen, nitro, -CN, -OR7, -SR7, -S(R7)5, -C(=O)R7, -C(=O)NR7R8, -C(=O)OR7, - S(=O)R7, -S(=O)2R7, -NR7R8, -NR7S(=O)2R8, -NR7C(=O)R8, -NR7C(=O)OR8, or substituted or unsubstituted C1-C6fluoroalkyl; each of R1 and R2 is independently halogen, nitro, -CN, -OR7, -SR7, -S(=O)R7, -S(=O)2R7, - S(=O)2NR7R8, -NR7R8, -C(=O)R7, -C(=O)OR7, -C(=O)NR7R8, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R3 is halogen, nitro, -OR7, -SR7, -CN, -C(=O)R7, -OC(=O)R7, -C(=O)NR7R8, -C(=O)OR7, - S(=O)R7, -S(=O)NR7R8, -S(=NR7)R8, -S(=NR7)NR7R8, -S(=O)2R7, -S(=O)2NR7R8, - S(=O)(=NR7)R7, -S(=O)(=NR7)NR7R8, -NR7R8, -NR7S(=O)2R8, -NR7S(=O)(=NR7)R8, - NR7C(=O)R8, -N[C(=O)R8]2, -NR7C(=O)NR7R8, NR7CH2C(=O)NR7R8, NR7CH2CH2C(=O)NR7R8, -NR7C(=O)OR8, -P(=O)(OR7)R8, -P(=O)(OR7)(OR8), -
P(=O)R7R8, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2- C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1- C6heteroalkyl, substituted or unsubstituted C3-C?cycloalkyl, substituted or unsubstituted C5-C10 aryl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl; each R7 and R8 is independently hydrogen, halogen, -CN, substituted or unsubstituted C1- C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2- C6alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3- C10cycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or
R7 and R8 taken together with the atom to which they are attached to form a substituted or unsubstituted N- or P-containing 3- to 8-membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, or 4.
[00125] In some embodiments, the compound of Formula (I) is selected from the group consisting of:
[00126] In another aspect, the present disclosure provides a compound or pharmaceutically acceptable salt thereof, wherein the compound is a compound from Table 1.
[00127] In some embodiments, provided is a pharmaceutically acceptable salt or solvate thereof of a compound described in Table 1.
Further Forms of Compounds
Isomers
[00128] Furthermore, in some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (£), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single
preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein 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, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, disclosed herein are dissociable complexes (e.g., crystalline diastereomeric salts). In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that does not result in racemization.
Labeled compounds
[00129] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. In some embodiments, examples of isotopes that are incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 170, 31P, 32P, 35S, 18F, and 36C1, respectively. Compounds described herein, and the metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates, or derivatives thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this disclosure. C6rtain isotopically-labeled compounds, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i. e., 3H and carbon-14, i. e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e.., 2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compounds, pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof is prepared by any suitable method.
[00130] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
Pharmaceutically acceptable salts
[00131] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
[00132] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds of the disclosure, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
Solvates
[00133] In some embodiments, the compounds described herein exist as solvates. The disclosure provides for methods of treating diseases by administering such solvates. The disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.
[00134] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, 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. In some embodiments, solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or methanol. In some embodiments, the compounds provided herein exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
Prodrugs
[00135] In some embodiments, the compounds described herein exist in prodrug form. The disclosure provides for methods of treating diseases by administering such prodrugs. The disclosure
further provides for methods of treating diseases by administering such prodrugs as pharmaceutical compositions.
[00136] In some embodiments, prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e. g., two, three, or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy, or carboxylic acid group of compounds of the present disclosure. The amino acid residues include, but are not limited to, the 20 naturally occurring amino acids and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, ornithine, and methionine sulfone. In other embodiments, prodrugs include compounds wherein a nucleic acid residue, or an oligonucleotide of two or more (e. g., two, three or four) nucleic acid residues is covalently joined to a compound of the present disclosure. [00137] Pharmaceutically acceptable prodrugs of the compounds described herein also include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, metal salts, and sulfonate esters. In some embodiments, compounds having free amino, amido, hydroxy, or carboxylic groups are converted into prodrugs. For instance, free carboxyl groups are derivatized as amides or alkyl esters. In certain instances, all of these prodrug moieties incorporate groups including, but not limited to, ether, amine, and carboxylic acid functionalities.
[00138] Hydroxy prodrugs include esters such as, though not limited to, acyloxyalkyl (e.g. acyloxymethyl, acyloxyethyl) esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, sulfonate esters, sulfate esters and disulfide containing esters, ethers, amides, carbamates, hemisuccinates, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews 1996, 19, 115.
[00139] Amine derived prodrugs include, but are not limited to, the following groups and combinations of groups:
as well as sulfonamides and phosphonamides.
[00140] In certain instances, sites on any aromatic ring portions are susceptible to various metabolic reactions, therefore incorporation of appropriate substituents on the aromatic ring structures reduce, minimize, or eliminate this metabolic pathway.
Metabolites
[00141] In some embodiments, compounds described herein are susceptible to various metabolic reactions. Therefore, in some embodiments, incorporation of appropriate substituents into the structure will reduce, minimize, or eliminate a metabolic pathway. In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of an aromatic ring to metabolic reactions is, by way of example only, a halogen or an alkyl group.
[00142] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.
Preparation of the Compounds
[00143] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).
[00144] Methods known to one of ordinary skill in the art are identified through various reference books and databases. Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed.,
Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471- 60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871- 1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley- Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.
[00145] In some instances, specific and analogous reactants are identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (the American Chemical Society, Washington, D.C., is contacted for more details). Chemicals that are known but not commercially available in catalogs are prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.
[00146] In some embodiments, the compounds disclosed herein are prepared as described in the Examples section.
Pharmaceutical Compositions
[00147] In certain embodiments, the compound as described herein is administered as a pure chemical. In other embodiments, the compound described herein is combined with a
pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)), the disclosure of which is hereby incorporated herein by reference in its entirety.
[00148] Accordingly, provided herein is a pharmaceutical composition comprising at least one compound described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject) of the composition.
[00149] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I), (Il-a), (Il-b), (II-c), (Il-d), (II- e), (Il-f), (Il-g), (Ill-a), (Ill-b), (III-c), (Ill-d), (Ill-e), (Ill-f), (Ill-g), (Ill-h), (Ill-i), (Ill-j), (Ill-k), (III-l), (Ill-m), (Ill-n), (III-o), (III-p), (Ill-q), (Ill-r), (III-s), (Ill-t), (III-u), (III-v), (IV), (V), (VI), or (VII), or a pharmaceutically acceptable salt or solvate thereof.
[00150] Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (I), (Il-a), (Il-b), (II-c), (Il-d), (Il-e), (Il-f), (Il-g), (Ill-a), (Ill-b), (III-c), (Ill-d), (Ill-e), (Ill-f), (Ill-g), (Ill-h), (Ill-i), (Ill-j), (Ill-k), (III-l), (Ill-m), (Ill-n), (III-o), (III-p), (Ill-q), (Ill-r), (III-s), (Ill-t), (III-u), (III-v), (IV), (V), (VI), or (VII), or a pharmaceutically acceptable salt or solvate thereof.
[00151] In certain embodiments, the compound as described herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as contaminating intermediates or by-products that are created, for example, in one or more of the steps of a synthesis method.
[00152] These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used. For example, disclosed compositions are formulated as a unit dose, and/or are formulated for oral or subcutaneous administration.
[00153] In some instances, exemplary pharmaceutical compositions are used in the form of a pharmaceutical preparation, for example, in solid, semisolid, or liquid form, which includes one or
more of a disclosed compound, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral, or parenteral applications. In some embodiments, the active ingredient is compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.
[00154] For preparing solid compositions such as tablets in some instances, the principal active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a disclosed compound or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition is readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.
[00155] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions also comprise buffering agents in some embodiments. Solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
[00156] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject
composition, the liquid dosage forms contain optionally inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers.
[00157] Suspensions, in addition to the subject composition, optionally contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
[00158] In some embodiments, the doses of the composition comprising at least one compound as described herein differ, depending upon the patient's (e.g., human) condition, that is, stage of the disease, general health status, age, and other factors that a person skilled in the medical art will use to determine dose.
[00159] In some instances, pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented) as determined by persons skilled in the medical arts. An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and/or clinical trials. In some embodiments, the optimal dose depends upon the body mass, weight, or blood volume of the patient.
[00160] In some embodiments, oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.
The Hippo Signaling Network
[00161] The Hippo signaling network (also known as the Salvador/Warts/Hippo (SWH) pathway) is a master regulator of cell proliferation, death, and differentiation. In some embodiments, the main function of the Hippo signaling pathway is to regulate negatively the transcriptional co-activators Yes-associated protein (YAP) and its paralogue, the transcriptional co- activator with PDZ-binding motif (TAZ; also known as WWTR1). The Hippo kinase cascade phosphorylates and inhibits YAP/TAZ by promoting its cytoplasmic retention and degradation, thereby inhibiting the growth promoting function regulated under the YAP/TAZ control. In an un- phosphorylated/de-phosphorylated state, YAP, also known as YAP1 or YAP65, together with TAZ, are transported into the nucleus where they interact with TEAD family of transcription factors to upregulate genes that promote proliferation and migration, and inhibit apoptosis. In some instances,
Pnregulated upregulation of these genes involved in proliferation, migration, and anti-apoptosis leads to development of cancer. In some instances, overexpression of YAP/TAZ is associated with cancer.
[00162] Additional core members of the Hippo signaling pathway comprise the serine/threonine kinases MST1/2 (homologues of Hippo/Hpo in Drosophila), Latsl/2 (homologues of Warts/Wts), and their adaptor proteins Savl (homologue of Salvador/Sav) and Mob (MOBKL1 A and MOBKL1B; homologues of Mats), respectively. In general, MST1/2 kinase complexes with the scaffold protein Savl, which in turn phosphorylates and activates Latsl/2 kinase. Latsl/2 is also activated by the scaffold protein Mob. The activated Latsl/2 then phosphorylates and inactivates YAP or its paralog TAZ. The phosphorylation of YAP/TAZ leads to their nuclear export, retention within the cytoplasm, and degradation by the ubiquitin proteasome system.
[00163] In some instances, Latsl/2 phosphorylates YAP at the [HXRXXS] consensus motifs. YAP comprises five [HXRXXS] consensus motifs, wherein X denotes any amino acid residue. In some instances, Latsl/2 phosphorylates YAP at one or more of the consensus motifs. In some instances, Latsl/2 phosphorylates YAP at all five of the consensus motifs. In some instances, Latsl/2 phosphorylate at the S127 amino acid position. The phosphorylation of YAP S127 promotes 14-3-3 protein binding and results in cytoplasmic sequestration of YAP. Mutation of YAP at the S127 position thereby disrupts its interaction with 14-3-3 and subsequently promotes nuclear translocation.
[00164] Additional phosphorylation occurs at the S381 amino acid position in YAP. Phosphorylation of YAP at the S381 position and on the corresponding site in TAZ primes both proteins for further phosphorylation events by CK16/s in the degradation motif, which then signals for interaction with the β-TRCP E3 ubiquitin ligase, leading to polyubiquitination and degradation of YAP.
[00165] In some instances, Latsl/2 phosphorylates TAZ at the [HXRXXS] consensus motifs. TAZ comprises four [HXRXXS] consensus motifs, wherein X denotes any amino acid residues. In some instances, Latsl/2 phosphorylates TAZ at one or more of the consensus motifs. In some instances, Latsl/2 phosphorylates TAZ at all four of the consensus motifs. In some instances, Latsl/2 phosphorylate at the S89 amino acid position. The phosphorylation of TAZ S89 promotes 14-3-3 protein binding and results in cytoplasmic sequestration of TAZ. Mutation of TAZ at the S89 position thereby disrupts its interaction with 14-3-3 and subsequently promotes nuclear translocation.
[00166] In some embodiments, phosphorylated YAP/TAZ accumulates in the cytoplasm, and undergoes SCF β-TRCP-Pediated ubiquitination and subsequent proteasomal degradation. In some
instances, the Skp, Cullin, F-box containing complex (SCF complex) is a multi-protein E3 ubiquitin ligase complex that comprises a F-box family member protein (e.g. Cdc4), Skpl, a bridging protein, and RBX1, which contains a small RING Finger domain which interacts with E2 -ubiquitin conjugating enzyme. In some cases, the F-box family comprises more than 40 members, in which exemplary members include F-box/WD repeat-containing protein 1A (FBXW1A, β-TRCPl, Fbxwl, hsSlimb, plkappaBalpha-E3 receptor subunit) and S-phase kinase-associated proteins 2 (SKP2). In some embodiments, the SCF complex (e.g. SCF β-TR1)C iPnteracts with an El ubiquitin-activating enzyme and an E2 ubiquitin-conjugating enzyme to catalyze the transfer of ubiquitin to the YAP/TAZ substrate. Exemplary El ubiquitin-activating enzymes include those encoded by the following genes: UBA1, UBA2, UBA3, UBA5, UBA5, UBA7, ATG7, NAE1, and SAE1. Exemplary E2 ubiquitin-conjugating enzymes include those encoded by the following genes: UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE2G1, UBE2G2, UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE2L3, UBE2L6, UBE2M, UBE2N, UBE2O, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2Z, ATG2, BIRC5, and UFC1. In some embodiments, the ubiquitinated YAP/TAZ further undergoes the degradation process through the 26S proteasome.
[00167] In some embodiments, the Hippo pathway is regulated upstream by several different families of regulators. In some instances, the Hippo pathway is regulated by the G-protein and its coupled receptors, the Crumbs complex, regulators upstream of the MST kinases, and the adherens junction.
YAP/TAZ Interaction with TEAD
[00168] In some embodiments, un-phosphorylated and/or dephosphorylated YAP/TAZ accumulates in the nucleus. Within the nucleus, YAP/TAZ interacts with the TEAD family of transcription factors (e.g. TEAD1, TEAD2, TEAD3, or TEAD4) to activate genes involved in anti- apoptosis and proliferation, such as for example CTFG, Cyr61. and FGF1.
[00169] In some embodiments, the compounds disclosed herein modulate the interaction between YAP/TAZ and TEAD. In some embodiments, the compounds disclosed herein bind to TEAD, YAP, or TAZ and prevent the interaction between YAP/TAZ and TEAD.
YAP/TAZ regulation mediated by G-proteins/GPCRs
[00170] In some embodiments, the Hippo pathway is regulated by the G protein-coupled receptor (GPCR) and G protein (also known as guanine nucleotide-binding proteins) family of proteins. G proteins are molecular switches that transmit extracellular stimuli into the cell through GPCRs. In some instances, there are two classes of G proteins: monomeric small GTPases and heterotrimeric G protein complexes. In some instances, the latter class of complexes comprise of
alpha (Gα), beta (Gβ), and gamma (Gy) subunits. In some cases, there are several classes of Ga subunits: Gq/11a, Gi^na, Gi/Oa (G inhibitory, G other), and Gsα (G stimulatory).
[00171] In some instances, Giα (G inhibitory), Goa (G other), Gq/11a, and Gu/ua coupled GPCRs activate YAP/TAZ and promote nuclear translocation. In other instances, Gsα (G stimulatory) coupled GPCRs suppress YAP/TAZ activity, leading to YAP/TAZ degradation.
[00172] In some cases, Giα (G inhibitory), Goα (G other), Gq/11a, and Gu/ua coupled GPCRs activate YAP/TAZ through repression of Latsl/2 activities. In contrast, Gsα, in some embodiments, induces Latsl/2 activity, thereby promoting YAP/TAZ degradation.
Gq Family
[00173] Gqα (also known as Gq/11 protein), participates in the inositol trisphosphate (IP3) signal transduction pathway and calcium (Ca2+) release from intracellular storage through the activation of phospholipase C (PLC). The activated PLC hydrolyzes phosphatidylinositol 4,5- bisphosphate (PIP2) to diacyl glycerol (DAG) and IP3. In some instances, IP3 then diffuses through the cytoplasm into the ER or the sarcoplasmic reticulum (SR) in the case of muscle cells, and then binds to inositol trisphosphate receptor (InsP3R), which is a Ca2+ channel. In some cases, the binding triggers the opening of the Ca2+ channel, and thereby increases the release of Ca2+ into the cytoplasm.
[00174] In some embodiments, the GPCRs that interact with Gqα include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HT2 and 5-HT3; alpha-1 adrenergic receptor; vasopressin type 1 receptors 1A and IB; angiotensin II receptor type 1; calcitonin receptor; histamine Hl receptor; metabotropic glutamate receptor, group I; muscarinic receptors Mi, M3, and M5; and trace amine-associated receptor 1.
[00175] In some instances, there are several types of Gqα : Gq, Gq/11, Gq/14, and Gq/15. The Gq protein is encoded by GNAQ. Gq/11 is encoded by GNA11. Gq/14 is encoded by GNA14. Gq/15 is encoded by GNA15.
[00176] In some instances, mutations or modifications of the Gqα genes have been associated with cancer. Indeed, studies have shown that mutations in Gqα promote uveal melanoma (UM) tumorigenesis. In some instances, about 80% of UM cases have been detected to contain a mutation in GNAQ and/or GNA11.
[00177] In some instances, mutations or modifications of the Gqα genes have been associated with congenital diseases. In some instances, mutations of Gqα have been observed in congenital diseases such as Port-Wine Stain and/or Sturge-Weber Syndrome. In some instances, about 92% of Port-Wine stain cases harbors a mutation in GNAQ. In some instances, about 88% of Sturge-Weber Syndrome harbors a mutation in GNAQ.
G 12/13 Family
[00178] G12/13α modulates actin cytoskeletal remodeling in cells and regulates cell processes through guanine nucleotide exchange factors (GEFs). GEFs participate in the activation of small GTPases which acts as molecular switches in a variety of intracellular signaling pathways. Examples of small GTPases include the Ras-related GTPase superfamily (e.g. Rho family such as Cdc42), which is involved in cell differentiation, proliferation, cytoskeletal organization, vesicle trafficking, and nuclear transport.
[00179] In some embodiments, the GPCRs that interact with G12/n/ include, but are not limited to, purinergic receptors (e.g. P2Yi, P2Y2, P2Y4, P2Ye); muscarinic acetylcholine receptors Ml and M3; receptors for thrombin [protease-activated receptor (PAR)-l, PAR-2]; thromboxane (TXA2); sphingosine 1 -phosphate (e.g. SIP2, SIP3, SIP4 and SIP5); lysophosphatidic acid (e.g. LPAi, LPA2, LPA3); angiotensin II (ATI); serotonin (5-HT2C and 5-HT4); somatostatin (ssts); endothelin (ETA and ETB); cholecystokinin (CCKi); Via vasopressin receptors; D5 dopamine receptors; fMLP formyl peptide receptors; GAL2 galanin receptors; EP3 prostanoid receptors; Ai adenosine receptors; on adrenergic receptors; BB2 bombesin receptors; B2 bradykinin receptors; calcium-sensing receptors; KSHV-ORF74 chemokine receptors; NKi tachykinin receptors; and thyroid-stimulating hormone (TSH) receptors.
[00180] In some instances, G12/1301 is further subdivided into G12 and G13 types which are encoded by GNA12 and GNA13, respectively.
Gi/o Family
[00181] Gi/oα. (G inhibitory, G other) (also known as Gi/Go or Gi protein) suppresses the production of 3’,5’-cyclic AMP (cAMP) from adenosine triphosphate (ATP) through an inhibition of adenylate cyclase activity, which converts ATP to cAMP.
[00182] In some embodiments, the GPCRs that interact with Giα include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HTi and 5-HTs; muscarinic acetylcholine receptors such as M2 and M4; adenosine receptors such as Ai and A3; adrenergic receptors such as a2A, a2B, and a2c; apelin receptors; calcium-sensing receptor; cannabinoid receptors CB1 and CB2; chemokine CXCR4 receptor; dopamines D2, D3, and D4; GAB AB receptor; glutamate receptors such as metabotropic glutamate receptor 2 (mGluR2), metabotropic glutamate receptor 3 (mGluR3), metabotropic glutamate receptor 4 (mGluR4), metabotropic glutamate receptor 6 (mGluR6), metabotropic glutamate receptor 7 (mGluR7), and metabotropic glutamate receptor 8 (mGluR8); histamine receptors such as EE and EU receptors; melatonin receptors such as melatonin receptor type 1 (MT1), melatonin receptor type 2 (MT2), and melatonin receptor type 3 (MT3); niacin receptors such as NIACR1 and NIACR2; opioid receptors such as 6, K, p, and nociceptin
receptors; prostaglandin receptors such as prostaglandin E receptor 1 (EPi), prostaglandin E receptor 3 (EP3), prostaglandin F receptor (FP), and thromboxane receptor (TP); somatostatin receptors sstl, sst2, sst3, sst4, and sst5; and trace amine-associated receptor 8.
[00183] In some instances, there are several types of Giα : Giα l, Giα2, Giα3, Giα4, Goa, Gt, Ggust, and Gz. Giα l is encoded by GNAI1. Giα2 is encoded by GNAI2. Giα3 is encoded by GN Al 3. Goa, the a0 subunit, is encoded by GNAO1. Gt is encoded by GNAT1 and GNAT2. Ggust is encoded by GNAT3. Gzis encoded by GNAZ.
Gs Family
[00184] Gsα (also known as G stimulatory, Gs alpha subunit, or Gs protein) activates the cAMP-dependent pathway through the activation of adenylate cyclase, which convers adenosine triphosphate (ATP) to 3 ’,5 ’-cyclic AMP (cAMP) and pyrophosphate. In some embodiments, the GPCRs that interact with Gsa include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HT4, 5-HT6, and 5-HT7; adrenocorticotropic hormone receptor (ACTH receptor) (also known as melanocortin receptor 2 or MC2R); adenosine receptor types A2a and Ait,; arginine vasopressin receptor 2 (AVPR2); β-adrenergic receptors Pi, P2, and P3; calcitonin receptor; calcitonin gene-related peptide receptor; corticotropin-releasing hormone receptor; dopamine receptor Di-like family receptors such as Di and D5; follicle-stimulating hormone receptor (FSH- receptor); gastric inhibitory polypeptide receptor; glucagon receptor; histamine EE receptor; luteinizing hormone/choriogonadotropin receptor; melanocortin receptors such as MC1R, MC2R, MC3 R, MC4R, and MC5R; parathyroid hormone receptor 1; prostaglandin receptor types D2 and I2; secretin receptor; thyrotropin receptor; trace amine-associated receptor 1; and box jellyfish opsin.
[00185] In some instances, there are two types of Gsa:α Gs and Goif. Gs is encoded by GNAS. Goif is encoded by GN AL.
Additional Regulators of the Hippo signaling network
[00186] In some embodiments, the additional regulator of the Hippo signaling pathway is the Crumbs (Crb) complex. The Crumbs complex is a key regulator of cell polarity and cell shape. In some instances, the Crumbs complex comprises transmembrane CRB proteins which assemble multi-protein complexes that function in cell polarity. In some instances, CRB complexes recruit members of the Angiomotin (AMOT) family of adaptor proteins that interact with the Hippo pathway components. In some instances, studies have shown that AMOT directly binds to YAP, promotes YAP phosphorylation, and inhibits its nuclear localization.
[00187] In some instances, the additional regulator of the Hippo signaling pathway comprises regulators of the MST kinase family. MST kinases monitor actin cytoskeletal integrity. In some instances, the regulators include TAO kinases and cell polarity kinase PAR-1.
[00188] In some instances, the additional regulator of the Hippo signaling pathway comprises molecules of the adherens junction. In some instances, E-Cadherin (E-cad) suppresses YAP nuclear localization and activity through regulating MST activity. In some embodiments, E- cad-associated protein a-catenin regulates YAP through sequestering YAP/14-3-3 complexes in the cytoplasm. In other instances, Ajuba protein family members interact with Latsl/2 kinase activity, thereby preventing inactivation of YAP/TAZ.
[00189] In some embodiments, additional proteins that interact with YAP/TAZ either directly or indirectly include, but are not limited to, Merlin, protocadherin Fat 1, MASK1/2, HIPK2, PTPN14, RASSF, PP2A, Salt-inducible kinases (SIKs), Scribble (SCRIB), the Scribble associated proteins Discs large (Dig), KIBRA, PTPN14, NPHP3, LKB1, Ajuba, and ZO1/2.
[00190] In some embodiments, the compounds described herein are inhibitors of transcriptional coactivator with PDZ binding motif/Yes- associated protein transcriptional coactivator (TAZ/YAP). In some embodiments, the compounds described herein increase the phosphorylation of transcriptional coactivator with PDZ binding motif/ Yes- associated protein transcriptional coactivator (TAZ/YAP) or decrease the dephosphorylation of transcriptional coactivator with PDZ binding motif/ Yes- associated protein transcriptional coactivator (TAZ/YAP). In some embodiments, the compounds increase the ubiquitination of transcriptional coactivator with PDZ binding motif/ Yes- associated protein transcriptional coactivator (TAZ/YAP) or decrease the deubiquitination of transcriptional coactivator with PDZ binding motif/ Yes- associated protein transcriptional coactivator (TAZ/YAP).
[00191] In some embodiments, the compounds disclosed herein are inhibitors of one or more of the proteins encompassed by, or related to, the Hippo pathway. In some instances, the one or more proteins comprise a protein described above. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a G-protein and/or its coupled GPCR. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a G-protein. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of the Gqα family proteins such as Gq, Gq/u, Gq/i4, and Gq/is; the G12/13α family of proteins such as G12 and G13; or the Giα family of proteins such as Giα l, Giα2, Giα3, Giα4, Goa, Gt, Ggust, and Gz. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gq. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gq/u. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gq/i4. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gq/i5. In some embodiments, an
inhibitor of the Hippo pathway is an inhibitor of G12. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G13. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Giα1. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Giα2. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Giα3. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Giα4. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Goa. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gt. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Ggust. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gz. [00192] In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a core protein of the Hippo pathway. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Savl. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Mob. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of YAP. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of TAZ. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of TEAD.
[00193] In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a protein associated with the ubiquitination and proteasomal degradation pathway. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a proteasomal degradation pathway protein (e.g. 26S proteasome).
[00194] In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a protein of the Ras superfamily of proteins. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a protein of the Rho family of proteins. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Cdc42.
[00195] Cdc42 is a member of the Ras superfamily of small GTPases. Specifically, Cdc42 belongs to the Rho family of GTPases, in which the family members participate in diverse and critical cellular processes such as gene transcription, cell-cell adhesion, and cell cycle progression. Cdc42 is involved in cell growth and polarity, and in some instances, Cdc42 is activated by guanine nucleotide exchange factors (GEFs). In some cases, an inhibitor of Cdc42 is a compound disclosed herein.
[00196] In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a deubiquitinating enzyme. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a cysteine protease or a metalloprotease. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of an ubiquitin-specific protease. USP47 is a member of the ubiquitinspecific protease (USP/UBP) superfamily of cysteine proteases. In some embodiments, the compounds disclosed herein are inhibitors of USP47.
[00197] Further embodiments provided herein include combinations of one or more of the particular embodiments set forth above.
[00198] In another aspect, the present disclosure provides a method of inhibiting one or more of proteins encompassed by, or related to, the Hippo pathway in a subject, comprising administering to a subject a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.
[00199] In another aspect, the present disclosure provides a method of inhibiting transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP) in a subject comprising administering to a subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the subject has cancer, polycystic kidney disease, or liver fibrosis. In some embodiments, the cancer is selected from mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwannoma, lung cancer, bladder carcinoma, cutaneous neurofibromas, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, and breast cancer.
[00200] In another aspect, the present disclosure provides a method of treating cancer in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cancer is selected from mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwannoma, lung cancer, bladder carcinoma, cutaneous neurofibromas, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, and breast cancer.
[00201] In another aspect, the present disclosure provides a method of treating polycystic kidney disease or liver fibrosis in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.
[00202] In yet another aspect, the present disclosure provides a method of treating or preventing a disease or disorder amenable to treatment with a compound that inhibits the activity of one or more of proteins encompassed by, or related to, the Hippo pathway in a subject, comprising administering to a subject in need thereof a therapeutically acceptable amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.
[00203] In yet another aspect, the present disclosure provides a method of treating or preventing a disease or disorder amenable to treatment with a compound that inhibits transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP) in a subject comprising administering to a subject in need thereof a therapeutically acceptable amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.
[00204] In yet another aspect, provided herein are uses of a compound of Formula (I), (Il-a), (Il-b), (II-c), (ILd), (Il-e), (Il-f), (n-g), (in-a), (IH-b), (III-c), (IH-d), (Ill-e), (IILf), (IILg), (IILh), (IILi), (IH-j), (IILk), (III-l), (in-m), (Ill-n), (III-o), (III-p), (IH-q), (IILr), (IILs), (IH-t), (IILu), (III- v), (IV), (V), (VI), or (VII), as disclosed herein or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof as described herein, in the preparation of a medicament for treating a disease or disorder (e.g., a disease or disorder conducive to treatment to prevention by inhibiting one or more of proteins encompassed by, or related to, the Hippo pathway; or a disease or disorder conducive to treatment to prevention by inhibiting transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP)) in a subject in need thereof.
[00205] In another aspect, a compound disclosed herein is for use in a method of treating a disease or disorder (e.g., a disease or disorder amenable to treatment with a compound that inhibits one or more of proteins encompassed by, or related to, the Hippo pathway; or a disease or disorder conducive to treatment to prevention by inhibiting transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP)) in a subject in need thereof, such cancer. Such a compound is, for example, a compound of Formula (I), (Il-a), (Il-b), (II-c), (II- d), (Il-e), (Il-f), (Il-g), (Ill-a), (Ill-b), (III-c), (Ill-d), (Ill-e), (IILf), (IILg), (IILh), (IILi), (Ill-j), (III- k), (IILI), (IILm), (Ill-n), (III-o), (III-p), (IILq), (IILr), (IILs), (IH-t), (IILu), (III-v), (IV), (V), (VI), or (VII), as disclosed herein, or a pharmaceutical composition comprising the compound disclosed herein, and a pharmaceutically acceptable excipient, as disclosed herein.
[00206] In another aspect, provided herein are pharmaceutical compositions comprising a compound Formula (I), (ILa), (Il-b), (II-c), (ILd), (Il-e), (ILf), (Il-g), (IILa), (Ill-b), (III-c), (Ill-d), (Ill-e), (IILf), (IILg), (IILh), (IILi), (IILj), (IILk), (III-l), (IILm), (IILn), (IILo), (III-p), (IILq), (IILr), (IILs), (IILt), (IILu), (III-v), (IV), (V), (VI), or (VII), as disclosed herein or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder (e.g., a disease or disorder amenable to treatment with a compound that inhibits one or more of proteins encompassed by, or related to, the Hippo pathway; or a disease or disorder conducive to treatment to prevention
by inhibiting transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP)) in a subject in need thereof.
Diseases
Cancer
[00207] In some embodiments, the compounds disclosed herein are useful for treating cancer. In some embodiments, disclosed herein is a method for treating a cancer in a subject in need thereof comprising administering a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, disclosed herein is a compound for use in treating a cancer in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cancer is mediated by activation of transcriptional coactivator with PDZ binding motif/Yes- associated protein transcription coactivator (TAZ/YAP). In some embodiments, the cancer is mediated by modulation of the interaction of YAP/TAZ with TEAD. In some embodiments, the cancer is characterized by a mutant Gα-protein. In some embodiments, the mutant Gα-protein is selected from G12, G13, Gq, G11, Gi, Go, and Gs. In some embodiments, the mutant Gα-protein is G12. In some embodiments, the mutant Gα-protein is G13. In some embodiments, the mutant Gα- protein is Gq. In some embodiments, the mutant Gα-protein is Gl 1. In some embodiments, the mutant Gα-protein is Gi. In some embodiments, the mutant Gα-protein is Go. In some embodiments, the mutant Gα-protein is Gs.
[00208] In some embodiments, the cancer is a solid tumor. In some instances, the cancer is a hematologic malignancy. In some instances, the solid tumor is a sarcoma or carcinoma. In some instances, the solid tumor is a sarcoma. In some instances, the solid tumor is a carcinoma.
[00209] Exemplary sarcoma includes, but is not limited to, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastoma, angiosarcoma, chondrosarcoma, chordoma, clear cell sarcoma of soft tissue, dedifferentiated liposarcoma, desmoid, desmoplastic small round cell tumor, embryonal rhabdomyosarcoma, epithelioid fibrosarcoma, epithelioid hemangioendothelioma, epithelioid sarcoma, esthesioneuroblastoma, Ewing sarcoma, extrarenal rhabdoid tumor, extraskeletal myxoid chondrosarcoma, extraskeletal osteosarcoma, fibrosarcoma, giant cell tumor, hemangiopericytoma, infantile fibrosarcoma, inflammatory myofibroblastic tumor, Kaposi sarcoma, leiomyosarcoma of bone, liposarcoma, liposarcoma of bone, malignant fibrous histiocytoma (MFH), malignant fibrous histiocytoma (MFH) of bone, malignant mesenchymoma, malignant peripheral nerve sheath tumor, mesenchymal chondrosarcoma, myxofibrosarcoma, myxoid liposarcoma, myxoinflammatory fibroblastic sarcoma, neoplasms with perivascular
epithelioid cell differentiation, osteosarcoma, parosteal osteosarcoma, neoplasm with perivascular epithelioid cell differentiation, periosteal osteosarcoma, pleomorphic liposarcoma, pleomorphic rhabdomyosarcoma, PNET/extraskeletal Ewing tumor, rhabdomyosarcoma, round cell liposarcoma, small cell osteosarcoma, solitary fibrous tumor, synovial sarcoma, and telangiectatic osteosarcoma.
[00210] Exemplary carcinoma includes, but is not limited to, adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, anal cancer, appendix cancer, bile duct cancer (i.e., cholangiocarcinoma), bladder cancer, brain tumor, breast cancer, cervical cancer, colon cancer, cancer of Unknown Primary (CUP), esophageal cancer, eye cancer, fallopian tube cancer, gastroenterological cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer. In some instances, the liver cancer is primary liver cancer.
[00211] In some instances, the cancer is selected from uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neck cancer, prostate cancer, and meningioma. In some cases, the cancer is uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neck cancer, prostate cancer, or meningioma. In some cases, the cancer is uveal melanoma, mesothelioma, esophageal cancer, or liver cancer. In some cases, the cancer is uveal melanoma. In some cases, the cancer is mesothelioma. In some cases, the cancer is esophageal cancer. In some cases, the cancer is liver cancer. In some cases, the cancer is primary liver cancer.
[00212] In some instances, the cancer is a hematologic malignancy. In some embodiments, a hematologic malignancy is a leukemia, a lymphoma, a myeloma, a non-Hodgkin’s lymphoma, a Hodgkin’s lymphoma, a T-cell malignancy, or a B-cell malignancy. In some instances, a hematologic malignancy is a T-cell malignancy. Exemplary T-cell malignancy includes, but is not limited to, peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, angioimmunoblastic lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia/lymphoma (ATLL), blastic NK-cell lymphoma, enteropathy -type T-cell lymphoma,
hematosplenic gamma-delta T-cell lymphoma, lymphoblastic lymphoma, nasal NK/T-cell lymphomas, and treatment-related T-cell lymphomas.
[00213] In some instances, a hematologic malignancy is a B-cell malignancy. Exemplary B- cell malignancy includes, but is not limited to, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, and a non-CLL/SLL lymphoma. In some embodiments, the cancer is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt’ s lymphoma, nonBurkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.
[00214] In some instances, the cancer is a relapsed or refractory cancer. In some embodiments, the relapsed or refractory cancer is a relapsed or refractory solid tumor. In some embodiments, the relapsed or refractory solid tumor is a relapsed or refractory sarcoma or a relapsed or refractory carcinoma. In some embodiments, the relapsed or refractory carcinoma includes adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, anal cancer, appendix cancer, bile duct cancer (i.e., cholangiocarcinoma), bladder cancer, brain tumor, breast cancer, cervical cancer, colon cancer, cancer of Unknown Primary (CUP), esophageal cancer, eye cancer, fallopian tube cancer, gastroenterological cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer.
[00215] In some instances, the relapsed or refractory cancer is selected from relapsed or refractory uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neck cancer, prostate cancer, and meningioma. In some cases, the relapsed or refractory cancer is relapsed or refractory uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neck cancer, prostate cancer, or meningioma. In
some cases, the relapsed or refractory cancer is relapsed or refractory uveal melanoma, mesothelioma, esophageal cancer, or liver cancer. In some cases, the relapsed or refractory cancer is relapsed or refractory uveal melanoma. In some cases, the relapsed or refractory cancer is relapsed or refractory mesothelioma. In some cases, the relapsed or refractory cancer is relapsed or refractory esophageal cancer. In some cases, the relapsed or refractory cancer is relapsed or refractory liver cancer. In some cases, the relapsed or refractory cancer is relapsed or refractory primary liver cancer.
[00216] In some instances, the relapsed or refractory cancer is a relapsed or refractory hematologic malignancy. In some embodiments, a relapsed or refractory hematologic malignancy is a relapsed or refractory leukemia, a relapsed or refractory lymphoma, a relapsed or refractory myeloma, a relapsed or refractory non-Hodgkin’s lymphoma, a relapsed or refractory Hodgkin’s lymphoma, a relapsed or refractory T-cell malignancy, or a relapsed or refractory B-cell malignancy. In some instances, a relapsed or refractory hematologic malignancy is a relapsed or refractory T-cell malignancy. In some instances, a relapsed or refractory hematologic malignancy is a relapsed or refractory B-cell malignancy, such as for example, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, or a non-CLL/SLL lymphoma. In some embodiments, the cancer is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt’s lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.
[00217] In some instances, the cancer is a metastasized cancer. In some instances, the metastasized cancer is a metastasized solid tumor. In some instances, the metastasized solid tumor is a metastasized sarcoma or a metastasized carcinoma. In some embodiments, the metastasized carcinoma includes adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, anal cancer, appendix cancer, bile duct cancer (i.e., cholangiocarcinoma), bladder cancer, brain tumor, breast cancer, cervical cancer, colon cancer, cancer of Unknown Primary (CUP), esophageal cancer, eye cancer, fallopian tube cancer, gastroenterological cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer,
pituitary tumor, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer.
[00218] In some instances, the metastasized cancer is selected from metastasized uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neck cancer, prostate cancer, and meningioma. In some cases, the metastasized cancer is metastasized uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neck cancer, prostate cancer, or meningioma. In some cases, the metastasized cancer is metastasized uveal melanoma, mesothelioma, esophageal cancer, or liver cancer. In some cases, the metastasized cancer is metastasized uveal melanoma. In some cases, the metastasized cancer is metastasized mesothelioma. In some cases, the metastasized cancer is metastasized esophageal cancer. In some cases, the metastasized cancer is metastasized liver cancer. In some cases, the metastasized cancer is metastasized primary liver cancer.
[00219] In some instances, the metastasized cancer is a metastasized hematologic malignancy. In some embodiments, the metastasized hematologic malignancy is a metastasized leukemia, a metastasized lymphoma, a metastasized myeloma, a metastasized non-Hodgkin’s lymphoma, a metastasized Hodgkin’s lymphoma, a metastasized T-cell malignancy, or a metastasized B-cell malignancy. In some instances, a metastasized hematologic malignancy is a metastasized T-cell malignancy. In some instances, a metastasized hematologic malignancy is a metastasized B-cell malignancy, such as for example, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, or a non-CLL/SLL lymphoma. In some embodiments, the cancer is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt’ s lymphoma, nonBurkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.
Congenital Diseases
[00220] In some embodiments, the compounds disclosed herein are useful for treating a congenital disease. In some embodiments, the congenital disease is mediated by activation of transcriptional coactivator with PDZ binding motif/Yes- associated protein transcription coactivator (TAZ/YAP). In some embodiments, the congenital disease is characterized by a mutant Gα-protein. In some embodiments, the mutant Gα-protein is selected from G12, G13, Gq, G11, Gi, Go, and Gs. In some embodiments, the mutant Gα-protein is G12. In some embodiments, the mutant Gα-protein is G13. In some embodiments, the mutant Gα-protein is Gq. In some embodiments, the mutant Gα- protein is Gl 1. In some embodiments, the mutant Gα-protein is Gi. In some embodiments, the mutant Gα-protein is Go. In some embodiments, the mutant Gα-protein is Gs.
[00221] In some embodiments, the congenital disease is the result of a genetic abnormality, an intrauterine environment, errors related to morphogenesis, infection, epigenetic modifications on a parental germline, or a chromosomal abnormality. Exemplary congenital diseases include, but are not limited to, Sturge-Weber Syndrome, Port-Wine stain, Holt-Oram syndrome, abdominal wall defects, Becker muscular dystrophy (BMD), biotinidase deficiency, Charcot-Marie-Tooth (CMT), cleft lip, cleft palate, congenital adrenal hyperplasia, congenital heart defects, congenital hypothyroidism, congenital muscular dystrophy, cystic fibrosis, Down syndrome, Duchenne muscular dystrophy, Fragile X syndrome, Friedreich’s ataxia, galactosemia, hemoglobinopathies, Krabbe disease, limb-girdle muscular dystrophy, medium chain acyl-CoA dehydrogenase deficiency, myasthenia gravis, neural tube defects, phenylketonuria, Pompe disease, severe combined immunodeficiency (SCID), Stickler syndrome (or hereditary progressive arthro- ophthalmopathy), spinal muscular atrophy, and trisomy 18. In some embodiments, the congenital disease is Sturge-Weber Syndrome or Port-Wine stain. In some embodiments, the congenital disease is Sturge-Weber Syndrome. In some embodiments, the congenital disease is Port-Wine stain.
EXAMPLES
[00222] These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.
List of abbreviations
[00223] As used above, and throughout the disclosure, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:
ACN or MeCN acetonitrile Ac acetyl
BOC or Boc tert-butyl carbamate
Z-Bu tert-butyl
°C degrees C6lsius
DBA or dba dib enzy li deneacetone
DCE di chloroethane (CICH2CH2CI)
DCM dichloromethane (CH2CI2)
DIPEtOAc or DIEtOAc diisopropylethylamine
DMF dimethylformamide
DMSO dimethylsulfoxide
EtO Ac or EtOAc ethyl acetate
Et ethyl
EtOH ethanol g gram(s) h, hr, hrs hour(s)
HPLC high performance liquid chromatography
Hz hertz
LCMS liquid chromatography mass spectrometry m/z mass-to-charge ratio
M molar
Me methyl
MeOH methanol mg milligram(s)
MHz megahertz pmol micromole(s) uL microliter(s) mL milliliter(s) mmol millimole(s)
MS mass spectroscopy
NMR nuclear magnetic resonance
PE petroleum ether
Ph phenyl prep-HPLC preparative high pressure liquid chromatography prep-TLC preparative thin layer chromatography
Py pyridine
RT retention time
TEA triethylamine
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography
I. Chemical Synthesis
[00224] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for synthetic transformations sensitive to moisture and/or oxygen. Yields were not optimized. Reaction times were approximate and were not optimized. Column chromatography and thin layer chromatography (TLC) were performed on silica gel unless otherwise noted.
Example 1: 2-[[4-[2-[4-(trifluoromethyl)anilino]phenyl]-2-pyridyl]amino]ethanol
2-[(4-bromo-2-pyridyl)amino]ethanol
[00225] To a solution of 4-bromo-2-fluoropyridine (1A, 200.0 mg, 1.1 mmol, 1.0 eq) in DMF (5.0 mL) was added K2CO3 (315.1 mg, 2.3 mmol, 2.0 eq) and 2-aminoethan-l-ol (6 9.6 mg, 1.1 mmol, 68.9 uL, 1.0 eq). The reaction mixture was stirred at 80 °C for 16 hrs under N2 atmosphere. The reaction was filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography over silica gel and eluted with petroleum ether/ethyl acetate=l/O to 10/1 to give intermediate IB (100.0 mg, 0.46 mmol, 40.4% yield) as a colorless oil. LCMS (ESI): RT = 0.627 min, mass calc, for C7H9BrN 215.99m/z found 218.9 [M+H+2]+; 1HNMR (400 MHz, CDCl3-d) δ 7.87 (d, J= 5.5 Hz, 1H), 6.75 (dd, J= 1.5, 5.5 Hz, 1H), 6.64 (d, J= 1.5 Hz, 1H), 3.83 - 3.78 (m, 2H), 3.54 - 3.50 (m, 2H).
2- [ [4- [2- [4-(trifluoromethyl)anilino] phenyl] -2-pyridyl] amino] ethanol
[00226] To a solution of 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-N-(4-
(trifluoromethyl)phenyl)aniline (intermediate 4E, 100.0 mg, 0.14 mmol, 1.0 eq) and intermediate
IB (35.9 mg, 0.17 mmol, 1.2 eq) in dioxane (5.0 mL) was added H2O (0.5 mL), Pd(dppf)C12 (10.1 mg, 13.8 pmol, 0.1 eq) and Na2CO3 (29.2 mg, 0.28 mmol, 2.0 eq). The reaction mixture was stirred at 100 °C for 16 hrs under N2 atmosphere. The reaction was filtered through celite and concentrated under reduced pressure to give a residue. The crude product was purified by preparative HPLC (Condition: water(0.05%HCl)-ACN. ColummPhenomenex Gemini 150x25mmxl0um. Begin B:25. End B:55) to afford Compound 1 as a white solid (14.73 mg, 28.37% yield). LCMS (ESI): RT = 0.702 min, mass calc, for C2oH18F3N30 373.14, m/z found 374.0 [M+H]+; 1HNMR (400 MHz, DMSOd6) δ 8.84 (s, 1H), 8.33 (s, 1H), 7.85 (d, J= 6.8 Hz, 1H), 7.54 - 7.40 (m, 5H), 7.33 - 7.25 (m, 1H), 7.13 (s, 1H), 6.94 (d, J= 8.3 Hz, 2H), 6.79 (d, J= 5.8 Hz, 1H), 3.65 - 3.55 (m, 2H), 3.44 (d, J= 4.3 Hz, 2H).
Example 2: 2-((6-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)pyrimidin-4-yl)amino)ethanol
2-((6-chloropyrimidin-4-yl)amino)ethanol
[00227] To a mixture of 2-aminoethan-l-ol (98.2 mg, 1.6 mmol, 97 uL, 1.20 eq) and TEA
(176.3 mg, 1.7 mmol, 0.2 mL, 1.3 eq) in z-PrOH (3.0 mL), was added 4,6-dichloropyrimidine (200.0 mg, 1.3 mmol, 1.0 eq). The resulted mixture was stirred at 85 °C for 2 h. The reaction mixture was concentrated in vacuum. The residue was diluted with water (20 mL), extracted with DCM (20 mL x2). The organic layer was dried over anhydrouNas2SO4 , concentrated in vacuum. Intermediate 2A was obtained as light yellow solid (200.0 mg, 1.2 mmol, 86.0% yield), which was confirmed by 1NMR. 1H NMR (400MHz, DMSO-t/6) 8 8.25 (s, 1H), 7.77 (s, 1H), 6.55 (s, 1H), 4.79 (s, 1H), 3.50 (q, J= 5.4 Hz, 2H), 3.35 - 3.38 (m, 2H).
2-((6-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)pyrimidin-4-yl)amino)ethanol
[00228] To a mixture of intermediate 2A (35.9 mg, 0.2 mmol, 1.50 eq), intermediate 4E (50.0 mg, 0.1 mmol, 1.00 eq) and Na2CO3 (29.2 mg, 0.3 mmol, 2.00 eq) in dioxane (3.0 mL) and H2O (1.0 mL), was added Pd(dppf)C12 (10.1 mg, 13.8 pmol, 0.10 eq). The reaction mixture was
degassed under vacuum and purged with N2 for 3 times. The resulted mixture was stirred at 100 °C under N2 for 17 h. The reaction mixture was filtered, and the solid was washed with DCM (10 mL x2). The filtrate was concentrated in vacuum. The residue was purified by prep-HPLC (acidic HC1 condition). Compound 2 was obtained as brown oil (0.65 mg, 1.2% yield, HC1), which was combined with the previous batch (1.69 mg, HC1), and confirmed by LC-MS and 1HNMR. LCMS (ESI): RT = 0.681 min, mass calcd. for C19H17F3N4O 374.14, m/z found 375.0 [M+H]+. 1HNMR (400MHz, DMSO-d6) δ 8.81 (s, 1H), 7.58 - 7.47 (m, 6H), 7.26 - 7.18 (m, 1H), 7.13 - 7.06 (m, 2H), 6.84 (s, 1H), 3.60 - 3.51 (m, 4H).
Example 3: 2-(Methyl(4-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)pyridin-2- yl)amino)ethan-l-ol (Compound 3)
2-[(4-bromo-2-pyridyl)-methyl-amino]ethanol
[00229] To a solution of 4-bromo-2-fhioropyridine (1A, 200.0 mg, 1.1 mmol, 1.0 eq) in DMF (5.0 mL) was added K2CO3 (315.1 mg, 2.3 mmol, 2.0 eq) and 2-(methylamino)ethan-l-ol. The reaction mixture was stirred at 80 °C for 16 hrs under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel eluted with petroleum ether/ethyl acetate=l/O to 10/1 to give intermediate 3A (100.0 mg, 0.46 mmol, 40.4% yield) as a colorless oil. LCMS (ESI): RT = 0.792 min, mass calc, for C8H11BrN2O 230.01m/z found 232.9 [M+H+2]+; 1HNMR (400 MHz, CDCl3-d6) δ 7.88 (d, J= 5.5 Hz, 1H), 6.75 - 6.68 (m, 2H), 3.87 - 3.81 (m, 2H), 3.75 - 3.70 (m, 2H), 3.06 (s, 3H).
2-[methyl-[4-[2-[4-(trifluoromethyl)anilino]phenyl]-2-pyridyl]amino]ethanol
[00230] To a solution of 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-N-(4-
(trifluoromethyl)phenyl)aniline (intermediate 4E, 100.0 mg, 0.14mmol, 1.0 eq) and intermediate 3A (38.2 mg, 0.16 mmol, 1.2 eq) in dioxane (5.0 mL) was added H2O (0.5 mL) Pd(dppf)C12 (10.1
mg, 13.8 pmol, 0.1 eq) and NazCOs (29.2 mg, 0.28 mmol, 2.0 eq). The reaction mixture was stirred at 100 °C for 16 hrs under N2 atmosphere. The reaction was filtered through celite and concentrated under reduced pressure to give a residue. The crude product was purified by prep- HPLC (Condition: water(0.05%HCl)-ACN. ColummPhenomenex Gemini 150x25mmxl0um. Begin B:26. End B:56) to give Compound 3 (21.18 mg, 39.32% yield) as a white solid. LCMS (ESI): RT = 0.714 min, mass calc, for C21H20F3N3O 387.16, m/z found 388.1 [M+H]+; 1HNMR (400 MHz, DMSO-d6) 8 8.43 (s, 1H), 7.89 (d, J= 6.5 Hz, 1H), 7.56 - 7.49 (m, 2H), 7.43 (d, J= 8.5 Hz, 3H), 7.32 (t, J= 7.3 Hz, 1H), 7.27 (s, 1H), 6.92 - 6.85 (m, 3H), 3.73 (d, J= 4.3 Hz, 2H), 3.63 (d, J= 4.3 Hz, 2H), 3.22 (s, 3H).
4
2-bromo-N-[4-(trifluoromethyl)phenyl]aniline
[00231] To a solution of 2-bromoaniline (4A, 1.5 g, 8.72 mmol, 1 eq) and (4- (trifluoromethyl)phenyl)boronic acid (4B, 2.48 g, 13.08 mmol, 1.5 eq) in DCM (30.0 mL) was added DIEtOAc (4.5 g, 34.9 mmol, 6.1 mL, 4.0 eq) and Cu(OAc)2 (2.38 g, 13.1 mmol, 1.5 eq). The reaction mixture was stirred at 20 °C for 16 hrs under O2 atmosphere. The reaction mixture was filtered to give a crude product. The crude product was purified by column chromatography on silica gel eluted with petroleum ether/ethyl acetate=l/O to 10/1 to give 2-bromo-N-[4- (trifluoromethyl)phenyl]aniline (0.5 g, 1.58 mmol, 18.14% yield) as a yellow oil. LCMS (ESI): RT = 0.844 min, mass calc, for C 13H9BrF3N 314.99 m/z found 315.8 [M+H]+.
2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-N-[4-(trifluoromethyl)phenyl]aniline [00232] To a solution of 2compound 4C (0.5 g, 1.58 mmol, 1 eq) and 4, 4, 4', 4', 5, 5,5', 5'- octamethyl-2,2'-bi(l,3,2-dioxaborolane) (4D, 0.44 g, 1.74 mmol, 1.1 eq) in dioxane (20 mL) was
added Pd(dppf)C12 (0.12 g, 0.16 mmol, 0.1 eq) and AcOK (0.31 g, 3.16 mmol, 2.0 eq). The reaction mixture was stirred at 100 °C for 16 hrs under N2 atmosphere. The reaction mixture was filtered through celite and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography on silica gel eluted with petroleum ether/ethyl acetate=l/O to 10/1 to give crude compound 4E (0.34 g, 936.17 pmol, 59.19% yield) as a yellow solid.
The residue was directly used without further purification. LCMS (ESI): RT = 0.957 min, mass calc, for C19H21BF3NO2 363.16 m/z found 364.0 [M+H]+.
4-[2-[4-(trifluoromethyl)anilino]phenyl]pyridin-2-amine
[00233] To a solution of compound 4E (50 mg, 0.14 mmol, 1.0 eq) and 4-bromopyridin-2- amine (4F, 35.7 mg, 0.21 mmol, 1.5 eq) in dioxane (5.0 mL) was added H2O (0.5 mL), Pd(dppf)Cl2 (10.1 mg, 13.8 pmol, 0.1 eq) and Na2CO3 (29.2 mg, 0.28 mmol, 2.0 eq). The reaction mixture was stirred at 90 °C for 16 hrs under N2 atmosphere. The reaction mixture was filtered through celite and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (Condition: water (0.05% ammonia hydroxide v/v)-ACN. Column: Waters Xbridge 150x25 5u. Begin B:45. End B:75) to give the Compound 4 (6 .51 mg, 13.64% yield) was obtained as a white solid. LCMS (ESI): RT = 0.678 min, mass calc, for C18H14F3N3 329.11, m/z found 329.9 [M+H]+; 1HNMR (400 MHz, CDCl2-)d ) 8 8.12 (d, J= 5.0 Hz, 1H), 7.50 - 7.43 (m, 3H), 7.39 - 7.33 (m, 1H), 7.31 (dd, J= 1.5, 7.8 Hz, 1H), 7.17 - 7.12 (m, 1H), 7.02 (d, J= 8.5 Hz, 2H), 6.69 (dd, J= 1.3, 5.3 Hz, 1H), 6.53 (s, 1H), 5.72 (s, 1H), 4.50 (s, 2H).
Example 5: N-methyl-4-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)pyridin-2-amine
4-bromo-N-methyl-pyridin-2-amine
[00234] 4 -Bromo-2-fluoropyridine (1A, 0.1 g, 0.5 mmol, 1.0 eq) and methylamine (2 M,
1.14 mL, 4.0 eq) were taken up into a microwave tube in THF (1.0 mL). The sealed tube was heated at 70 °C for 0.5 hr under microwave. The reaction mixture was filtered to give a crude
product. The crude product was purified by column chromatography on silica gel eluted with petroleum ether/ethyl acetate=l/O to 10/1 to give intermediate 5A (6 0 mg, 0.32 mmol, 56.5% yield) as a white solid. LCMS (ESI): RT = 2.482 min, mass calc, for C6HvBrlSb 185.98 m/z found 188.9 [M+H+2]+.
N-methyl-4- [2- [4-(trifluoromethyl)anilino] phenyl]pyridin-2-amine
[00235] To a solution of intermediate 4E (50 mg, 0.14 mmol, 1.0 eq) and intermediate 5A (38.6 mg, 0.21 mmol, 1.5 eq) in dioxane (5.0 mL) was added H2O (0.5 mL), Pd(dppf)C12 (10.1 mg, 13.8 pmol, 0.1 eq) and Na2CO3 (29.2 mg, 0.28 mmol, 2.0 eq). The reaction mixture was stirred at 90 °C for 16 hrs under N2 atmosphere. The crude product was purified by prep-HPLC (Condition: water (0.05% ammonia hydroxide v/v)-acetonitrile. Column: Waters Xbridge 150x25 5u. Begin B:48. End B:78) to give Compound 5 (1.94 mg, 4.10% yield) as a white solid. LCMS (ESI): RT = 0.685 min, mass calc, for C19H16F3N3 343.13, m/z found 343.9 [M+H]+; 1HNMR (400 MHz, CDCl2d- d) 6 8.13 (d, J= 5.3 Hz, 1H), 7.50 - 7.42 (m, 3H), 7.40 - 7.31 (m, 2H), 7.17 - 7.11 (m, 1H), 7.01 (d, J= 8.5 Hz, 2H), 6.61 (dd, J= 1.4, 5.1 Hz, 1H), 6.38 (s, 1H), 5.75 (s, 1H), 4.62 (d, J= 4.0 Hz, 1H), 2.89 (d, J= 5.3 Hz, 3H).
Example 6: N, N-Dimethyl-4-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)pyridin-2-amine
4-bromo-N,N-dimethyl-pyridin-2-amine
[00236] 4-Bromo-2-fluoropyridine (1A, 0.1 g, 0.57 mmol, 1.0 eq) and dimethylamine (0.31 g, 2.3 mmol, 4.0 eq) were taken up into a microwave tube in THF (1 mL) and H2O (1 mL). The sealed tube was heated at 70 °C for 0.5 hr under microwave. The reaction mixture was filtered to give a crude product. The crude product was purified by column chromatography on silica gel eluted with petroleum ether/ethyl acetate=l/O to 10/1 to give intermediate 6A (6 0 mg, 0.32 mmol, 56.5% yield) as a white solid. LC-MS (ESI): RT = 0.991 min, mass calc, for C7H9BrN2 199.99 m/z found 202.9 [M+H+2]+.
N,N-dimethyl-4-[2-[4-(trifluoromethyl)anilino]phenyl]pyridin-2-amine
[00237] To a solution of compound 4E (50 mg, 0.14 mmol, 1.0 eq) and intermediate 6A (41.5 mg, 0.21 mmol, 1.5 eq) in dioxane (5.0 mL) was added H2O (500.00 uL), Pd(dppf)C12 (10.1 mg, 13.8 pmol, 0.1 eq), and Na2CO3 (29.2 mg, 0.28 mmol, 2.0 eq). The reaction mixture was stirred at 90 °C for 16 hrs under N2 atmosphere. The crude product was purified by prep-HPLC (Condition: water (0.05% ammonia hydroxide v/v)-ACN. Column: Waters Xbridge 150x25 5u. Begin B: 55. End B: 75) to give Compound 6 (8.90 mg, 17.91% yield) as a white solid. LCMS (ESI): RT = 0.683 min, mass calc, for C2OHI8F3N3 357.15, m/z found 358.0 [M+H]+; 1HNMR (400 MHz, DMSO-tfe) 6 8.12 - 7.98 (m, 2H), 7.48 - 7.34 (m, 5H), 7.32 - 7.24 (m, 1H), 6.83 (br d, J=8.3 Hz, 2H), 6.57 (s, 2H), 2.93 (s, 6H).
2-bromo-N-(4-(trifluoromethoxy)phenyl)aniline
[00238] To a solution of compound 4A (1 g, 5.81 mmol, 1 eq) in DCM (10 mL) were added Cu(OAc)2 (1.58 g, 8.72 mmol, 1.5 eq), DIPEtOAc (1.50 g, 11.63 mmol, 2.0 mL, 2 eq) and (4- (trifluoromethoxy)phenyl)boronic acid (7 A, 1.80 g, 8.72 mmol, 1.5 eq). The reaction mixture was stirred at 25 °C for 16 hrs under O2 (15 psi) atmosphere. The reaction mixture was filtered, and the filtrate was concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-10% Ethyl acetate/Petr oleum ether gradient). Intermediate 7B (900 mg, 2.2 mmol, 38.2% yield) was obtained as a light yellow oil. LCMS (ESI): RT = 0.943 min, mass calcd. for Ci3H9BrF3NO 330.98, m/z found 333.9 [M+H]+.
4-(2-((4-(trifluoromethoxy)phenyl)amino)phenyl)pyridin-2-amine
[00239] To a solution of intermedaite 7B (80 mg, 0.24 mmol, 1 eq) in dioxane (5 mL) and H2O (1 mL) were added Pd(dppf)C12 (8.8 mg, 12.0 μmol, 0.05 eq), Na2CO3 (51.0 mg, 0.48 mmol, 2 eq) and 4-(4,4,5-trimethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine (7C, 79.5 mg, 0.36 mmol, 1.5 eq). The reaction mixture was stirred at 90 °C for 2 hrs. The reaction mixture was filtered, and the filtrate was concentrated in vacuum. The residue was purified by prep-HPLC (column: Waters
Xbridge 150x25 5u; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 55%-85%, 6.5min). Compound 7 was obtained as a yellow solid (7.28 mg, 21.1 pmol, 8.8% yield). LCMS (ESI): RT = 0.722 min, mass calcd. for CI8HI4F3N3O 345.11, m/z found 345.9 [M+H]+; 1H NMR (400 MHz, CDC13) 8 7.94 (d, J= 5.8 Hz, 1H), 7.35 (d, J= 3.8 Hz, 2H), 7.29 - 7.28 (m, 1H), 7.27 - 7.25 (m, 1H), 7.14 - 7.11 (m, 1H), 7.15 - 7.10 (m, 1H), 7.10 - 7.06 (m, 1H), 7.10 - 7.06 (m, 1H), 7.02 (d, J= 8.8 Hz, 2H), 6.82 (d, J= 4.8 Hz, 1H), 6.75 (s, 1H), 5.67 (s, 2H).
[00240] A solution of 2-(2-fluoropyridin-4-yl)-N-(4-(trifluoromethyl)phenyl)aniline (8A, 30 mg, 90 μmol, 1.0 eq) and azetidine (8B, 26 mg, 0.45 mmol, 5 eq) in DMF (1 mL) was stirred at 100 °C for 6 hrs. The reaction mixture was concentrated under reduced pressure. The reaction mixture was diluted with water (30 mL) and the resultant mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were dried overNa2SO4 , filtered and concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25 5u; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 60%-90%, 9.5min) to obtain a crude product. The crude product Compound 8 was purified by prep-HPLC (column: Xtimate C18 150x25mmx5um; mobile phase: [water (0.05%HCl)-ACN]; B%: 30%-60%, 6.5min) to obtain Compound 8 (5.40 mg, 14% yield) as a yellow solid. LCMS (ESI): RT = 0.878 min, mass calcd. For C21H18F3N3 369.15, m/z found 370.4 [M+H]+; 1H NMR (400MHz, DMSO4) 8 8.38 (s, 1H), 7.91 - 7.86 (m, 1H), 7.57 - 7.50 (m, 2H), 7.48 - 7.42 (m, 3H), 7.36 - 7.29 (m, 1H), 6.91 - 6.81 (m, 4H), 4.24 (t, J=7.7 Hz, 4H), 2.47 - 2.39 (m, 2H).
Example 9: 4-(4-(2-((4-(Trifluoromethyl)phenyl)amino)phenyl)pyridin-2-yl)piperazin-2-one (Compound 9)
4-(4-Bromopyridin-2-yl)piperazin-2-one
[00241] A solution of compound 1A (100 mg, 0.568 mmol, 1.0 eq) and piperazin-2-one (9 A, 171 mg, 1.70 mmol, 3.0 eq) in DMSO (1 mL) was stirred at 120 °C for 2 hrs. The reaction mixture was diluted with water (20 mL) and the resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried overNa2SO4 , filtered and concentrated to dryness under reduced pressure to affording intermediate 9B (110 mg, 76% yield) as a light yellow solid.
4-(4-(2-((4-(Trifluoromethyl)phenyl)amino)phenyl)pyridin-2-yl)piperazin-2-one
[00242] To a solution of intermediate 4E (50 mg, 0.14 pmol, 1.0 eq), intermediate 9B (35 mg, 0.14 mmol, 1.0 eq), Na2CO3 (29 mg, 0.28 mmol, 2.0 eq) in dioxane (2 mL) and H2O (0.4 mL) was added Pd(dppf)C12 (5.0 mg, 6.9 μmol, 0.05 eq) under N2. The reaction suspension was degassed under vacuum and purged with N2 several times. The reaction mixture was stirred under N2 at 90°C for 3 hrs. The reaction mixture was concentrated under reduced pressure. The reaction mixture was diluted with water (10 mL) and the resultant mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were dried overNa2SO4 , filtered and concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25 5u; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 45%-75%, 7.8 min) to afford Compound 9 as a white solid (17.13 mg, 30% yield). LC-MS (ESI): RT = 0.701 min, mass calcd. For C22H19F3N4O 412.15, m/z found 413.0 [M+H]+; 1H NMR (400MHz, CDCl3) 8 8.25 (d, J= 5.0 Hz, 1H), 7.52 - 7.43 (m, 3H), 7.43 - 7.37 (m, 1H), 7.34 (dd, J= 1.3, 7.5 Hz, 1H), 7.22 - 7.16 (m, 1H), 7.00 (d, J= 8.5 Hz, 2H), 6.77 - 6.72 (m, 1H), 6.59 (s, 1H), 6.35 (s, 1H), 5.73 (s, 1H), 4.14 (s, 2H), 3.87 (t, J= 5.3 Hz, 2H), 3.53 - 3.47 (m, 2H).
[00243] To a solution of intermediate 4E (100 mg, 0.27 mmol, 1.0 eq) in dioxane (5 mL) and H2O (1 mL) were added Pd(dppf)C12 (10.0 mg, 13.7 pmol, 0.05 eq), CS2CO3 (179.4 mg, 0.55 mmol, 2.0 eq) and 6-bromopyrimidin-4-amine (10A, 71.8 mg, 0.41 mmol, 1.5 eq). The reaction mixture was stirred at 90 °C for 16 hrs. The reaction mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25 5u;mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN];B%: 50%-80%,9.5min). Compound 10 was obtained as a yellow solid (14.86 mg, 16.34% yield). LC-MS (ESI): RT = 0.679 min, mass calcd. for C17H13F3N4330.11, m/z found 330.9 [M+H]+; 1H NMR (400MHz, CDCl2) 8 10.44 (br s, 1H), 8.66 (s, 1H), 7.59 (d, J= 6.5 Hz, 1H), 7.50 (dd, J= 8.5, 11.5 Hz, 4H), 7.35 (t, J= 7.8 Hz, 1H), 7.21 (d, J= 8.5 Hz, 2H), 7.03 - 6.98 (m, 1H), 6.77 (s, 1H), 4.95 (br s, 2H).
(2-bromophenyl)(4-(trifluoromethyl)phenyl)sulfane
[00244] The mixture of l-bromo-2-iodo-benzene (HA, 2 g, 7.07 mmol, 0.90 mL, 1 eq), 4- (trifhioromethyl)benzenethiol (11B, 1.26 g, 7.07 mmol, 1 eq), ethylene glycol (877.6 mg, 14.14 mmol, 0.79 mL, 2 eq), Cui (134.6 mg, 0.70 mmol, 0.1 eq) and t-BuONa (1.36 g, 14.14 mmol, 2
eq) in isopropanol (2 mL) was stirred at 90 °C under N2 for 16 hrs. The reaction mixture was diluted with H2O (6 mL) and the reaction mixture was extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (10 mL x 3), dried over anhydrouNas2SO4 , filtered and concentrated in vacuum. The residue was purified by column chromatography (SiCh, Petroleum ether/Ethyl acetate=l/0). Intermediate 11C (was obtained as colorless oil 2 g, 6.00 mmol, 84.9% yield) .
4,4,5,5-tetramethyl-2-(2-((4-(trifluoromethyl)phenyl)thio)phenyl)-l,3,2-dioxaborolane
[00245] A mixture of intermediate 11C (1 g, 3.00 mmol, 1 eq), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (4D, 1.14 g, 4.50 mmol, 1.5 eq), Pd(dppf)C12 (109.8 mg, 0.15 mmol, 0.05 eq) and AcOK (589.1 mg, 6.00 mmol, 2 eq) in dioxane (10 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90 °C for 3 hr under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (15 mL x 3). The combined organic phase was washed with brine (10 mL x 3), dried over anhydrouNas2SO4 , filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=l/O to 5: 1 ). Intermediate 11D was obtained as yellow oil (6 00 mg, 1.58 mmol, 52.5% yield) . tert-butyl (4-(2-((4-(trifluoromethyl)phenyl)thio)phenyl)pyridin-2-yl)carbamate
[00246] The mixture of intermediate 11D (50 mg, 0.13 mmol, 1 eq), tert-butyl N-(4-bromo- 2-pyridyl)carbamate (11E, 35.9 mg, 0.13 mmol, 1 eq), CS2CO3 (85.6 mg, 0.26 mmol, 2 eq) and Pd(dppf)C12 (4.8 mg, 6.5 pmol, 0.05 eq) in dioxane (1 mL) and H2O (1 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 80 °C for 2 hrs under N2 atmosphere. The reaction mixture was diluted with H2O (6 mL) and the reaction mixture was extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (10 mL x 3), dried over anhydrouNas2SO4 , filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=l/O to 5: 1). Intermediate 11F was obtained as yellow oil (40 mg, 89.5 pmol, 68.1% yield).
4-(2-((4-(trifluoromethyl)phenyl)thio)phenyl)pyridin-2-amine
[00247] The mixture of intermediate 11F (40 mg, 89.5 pmol, 1 eq) in HCl/dioxane (2 mL) was stirred at 50 °C for 1 hr. The reaction mixture was diluted with H2O (5 mL) and the reaction mixture was extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (10 mL x 3), dried over anhydrouNas2SO4 , filtered and concentrated in vacuum. The
residue was purified by prep-HPLC (column: Xtimate C18 150x25mmx5um;mobile phase: [water(0.05%HCl)-ACN];B%: 28%-58%,7.8min). Compound 11 (8 mg, 25.5% yield) was obtained as a yellow solid. LC-MS (ESI): RT = 0.828 min, mass calc, for C18H13F3N2S 346.37, m/z found 347.1 [M+H]+; 1H NMR (400MHz, DMSO-d6) δ = 8.08 - 8.04 (m, 1H), 8.06 (br s, 1H), 7.94 (d, J= 6.5 Hz, 1H), 7.64 - 7.59 (m, 1H), 7.65 - 7.59 (m, 4H), 7.55 - 7.49 (m, 1H), 7.25 (br d, J= 8.1 Hz, 2H), 6.89 - 6.80 (m, 2H).
(2-bromophenyl)-[4-(trifluoromethyl)phenyl]methanol
[00248] To a solution of 2-bromobenzaldehyde (12A, 10.9 g, 48.6 mmol, 6.7 mL, 1 eq) in THF (200 mL) was added drop-wise n-BuLi (2.5 M, 17.5 mL, 0.9 eq) at -78°C. After addition, the reaction mixture was stirred at this temperature for 1 hr, and then l-bromo-4- (trifluoromethyl)benzene (9 g, 48.6 mmol, 5.6 mL, 1 eq) in THF (30 mL) was added dropwise at - 78 °C. And the reaction mixture was allowed to warm to 20 °C was stirred for 2 hrs. The residue was poured into NH4CI (300 mL) and stirred for 5 min. The aqueous phase was extracted with EtOAc (150 mL x 3). The combined organic phase was washed with brine (250 mL), dried over anhydrous Na2CO3 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (120 g SepaFlash® Silica Flash Column, EtOAc/PE: 0-10%) to afford intermediate 12B as a colorless oil (23.8 g, 71.9 mmol, 73.9% yield).
l-bromo-2-[[4-(trifluoromethyl)phenyl]methyl]benzene
[00249] To a solution of intermediate 12B (10 g, 30.2 mmol, 1 eq) in DCM (200 mL) was added dropwise TFA (13.8 g, 120.8 mmol, 8.94 mL, 4 eq) at 0 °C under N2. After addition, the reaction mixture was stirred at this temperature for 0.5 hr, and then EtsSiH (7.02 g, 60.4 mmol, 9.6 mL, 2 eq) was added dropwise at 0 °C. The resulting mixture was stirred at 50 °C for 15.5 hrs. The residue was poured into H2O (300 mL) and stirred for 5 min. The aqueous phase was extracted with EtOAc (150 mL x 3). The combined organic phase was washed with brine (250 mL), dried over anhydrous Na2CO3 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (120 g SepaFlash® Silica Flash Column, EtOAc/PE: 0~l%) to give intermediate 12C (15.2 g, 48.2 mmol, 79.8% yield) as a colorless oil.
4,4,5,5-tetramethyl-2-[2-[[4-(trifluoromethyl)phenyl]methyl]phenyl]-l,3,2-dioxaborolane [00250] A mixture of intermediate 12C (3 g, 9.5 mmol, 1 eq), compound 4D (3.6 g, 14.3 mmol, 1.5 eq) , KO Ac (1.9 g, 19.0 mmol, 2 eq) , Pd(dppf)C12 (348.3 mg, 0.5 mmol, 0.05 eq) in dioxane (30 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90 °C for 3 hr under N2 atmosphere. The reaction mixture was poured into H2O (50 mL) and stirred for 5 min. The aqueous phase was extracted with EtOAc (30 mL x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrouNas2SO4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (40 g SepaFlash® Silica Flash Column, EtOAc/PE: 0~5%) to give intermediate 12D (1.85 g, 5.1 mmol, 53.6% yield) as a yellow oil.
4-[2-[[4-(trifluoromethyl)phenyl]methyl]phenyl]pyridin-2-amine
[00251] A mixture of intermediate 12D (180 mg, 0.5 mmol, 1 eq), compound 4F (90.3 mg, 0.5 mmol, 1.05 eq), CS2CO3 (161.9 mg, 0.5 mmol, 1 eq), Pd(dppf)C12 (18.2 mg, 24.9 pmol, 0.05 eq) in dioxane (10 mL) and H2O (2 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 110 °C for 3 hr under N2 atmosphere. The reaction mixture was poured into H2O (100 mL) and stirred for 5 min. The aqueous phase was extracted with EtOAc (50 mL x 3). The combined organic phase was washed with brine (100 mL), dried over anhydrouNas2SO4 , filtered and concentrated in vacuum. The residue was purified by prep- HPLC (column: Xtimate C18 150x25mmx5um; mobile phase: [water (0.05%HCl)-ACN]; B%: 25%-55%, 7.8 min) to give Compound 12 as a white solid (48.3 mg, 26.1% yield, HC1). LC-MS (ESI): RT = 0.72 min, mass calc, for C19H15F3N2 328.1, m/z found 328.9 [M+H]+; 1H NMR (400MHz, DMSO-de)d6 δ 8.15 (s, 2H), 7.96 (d, J= 6.5 Hz, 1H), 7.59 (d, J= 8.0 Hz, 2H), 7.50 - 7.44
(m, 1H), 7.44 - 7.38 (m, 1H), 7.34 (d, J= 7.5 Hz, 1H), 7.29 (dd, J= 1.3, 7.5 Hz, 1H), 7.20 (d, J = 8.0 Hz, 2H), 6.83 (s, 1H), 6.78 (dd, J= 1.4, 6.7 Hz, 1H), 4.11 (s, 2H).
2-(4-bromopyridin-2-yl)ethanol
[00252] To a solution of 4-bromo-2-methyl-pyridine (13A, 1.8 g, 10.46 mmol, 1 eq) in THF (20 mL) was added dropwise LDA (2 M, 6.28 mL, 1.2 eq) at -78 °C under N2. After addition, the reaction mixture was stirred at this temperature for 1 hr, and then benzotriazol-l-ylmethanol (13B, 1.87 g, 12.56 mmol, 1.2 eq) was added at -78 °C. The resulting reaction mixture was stirred at -78 °C for 2 hrs and the reaction mixture was warmed to 0 °C was stirred for 1 hr. The residue was poured into H2O (60 mL) and stirred for 5 min. The aqueous phase was extracted with EtAOc (30 mL x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (20 g SepaFlash® Silica Flash Column, EtOAc/PE: 0-50%). Intermediate 13C (0.65 g, 3.22 mmol, 30.7% yield) was obtained as a yellow solid.
2-(4-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)pyridin-2-yl)ethanol
[00253] A mixture of intermediate 4E (200 mg, 0.55 mmol, 1 eq), intermediate 13C (133.5 mg, 0.66 mmol, 1.2 eq), Pd(dppf)C12 (20.1 mg, 27.5 pmol, 0.05 eq), CS2CO3 (358.85 mg, 1.10 mmol, 2 eq) in dioxane (5 mL) and H2O (1 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 110 °C for 3 hr under N2 atmosphere. The reaction mixture was poured into H2O (30 mL) and stirred for 5 min. The aqueous phase was extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Xtimate C18 150x25mmx5um;mobile phase: [water(0.05%HCl)-ACN];B%: 18%-48%,5.5min).
Compound 13 was obtained as a yellow solid (53.2 mg, 24.0% yield, HC1). LC-MS (ESI): RT = 0.696 min, mass calcd for C20H17F3N2O 358.36, m/z found 359.0 [M+H]+, 1H NMR (400MHz, METHANOL-d4) 6 = 8.62 (d, J= 6.3 Hz, 1H), 8.12 (d, J= 1.8 Hz, 1H), 8.03 (dd, J= 1.8, 6.3 Hz, 1H), 7.61 (ddd, J= 1.4, 7.7, 14.1 Hz, 2H), 7.55 - 7.50 (m, 1H), 7.44 - 7.35 (m, 3H), 6.90 (d, J= 8.5 Hz, 2H), 3.92 (t, J= 5.9 Hz, 2H), 3.19 (t, J= 5.9 Hz, 2H).
Example 14: 2-((4-(2-((4-(Trifluoromethyl)phenyl)amino)phenyl)pyridin-2- yl)amino)acetamide (Compound 14)
[00254] To a solution of methyl 2-[[4-[2-[4-(trifluoromethyl)anilino]phenyl]-2- pyridyl]amino]acetate (14A, 20 mg, 49.8 pmol, 1 eq) in NH3.H2O (1 mL) was stirred at 80 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Xtimate Cl 8 150x25mmx5um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 45%-75%,7.8min). Compound 14 was obtained as a white solid (1.1 mg, 5.7% yield). LC-MS (ESI): RT = 0.701 min, mass calc, for C20H17F3N4O 386.37, m/z found 386.9 [M+H]+; 1H NMR (400MHz, METHANOL-d4) 8 = 7.95 (d, J= 5.5 Hz, 1H), 7.44 - 7.35 (m, 5H), 7.27 - 7.21 (m, 1H), 6.90 (d, J= 8.6 Hz, 2H), 6.69 (dd, J= 1.4, 5.4 Hz, 1H), 6.66 (s, 1H), 3.94 (s, 2H).
Example 15: 3-((4-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)pyridin-2- yl)amino)propanamide (Compound 15)
[00255] To a solution of 3-[[4-[2-[4-(trifluoromethyl)anilino]phenyl]-2- pyridyl]amino]propanoic acid (15A, 10 mg, 24.9 μmol, 1 eq) in DMF (1 mL) was added ammonium; 1-oxidobenzotriazole (HOBt.NH4) (7.5 mg, 49.8 pmol, 2 eq) and EDCI (14.3 mg, 74.7 pmol, 3 eq). The reaction mixture was stirred at 25 °C for 1 hr. The reaction mixture was extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (7 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Xtimate Cl 8 150 x 25mm x 5um; mobile phase: [water(0.05%HCl)-ACN]; B%: 20%-50%,7min). The residue was re-purified by prep-HPLC (column: Waters Xbridge 150x25 5u;mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 45%-85%,7.8min). Compound 15 was obtained as a white solid (1.8 mg, 18.4% yield). LC- MS (ESI): RT = 0.704 min, mass calc, for C21H19F3N4O 400.40, m/z found 400.9 [M+H]+; 1H NMR (400MHz, METHANOL-d4) 8 = 7.91 (d, J= 5.4 Hz, 1H), 7.44 - 7.34 (m, 4H), 7.44 - 7.34 (m, 1H), 7.28 - 7.21 (m, 1H), 6.88 (d, J= 8.6 Hz, 2H), 6.66 - 6.59 (m, 2H), 3.53 (t, J= 6.8 Hz, 2H), 2.48 (t, J = 6.8 Hz, 2H).
Example 16: N-ethyl-4-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)pyridin-2-amine
2-(2-fluoropyridin-4-yl)-N-(4-(trifluoromethyl)phenyl)aniline
[00256] A mixture of intermediate 4E (12 g, 33.04 mmol, 1 eq), 4-bromo-2 -fluoro-pyridine (1A, 8.72 g, 49.56 mmol, 1.5 eq), Na2CO3 (7.00 g, 66.08 mmol, 2 eq), Pd(dppf)Cl2 (1.21 g, 1.65 mmol, 0.05 eq) in dioxane (150 mL) and H2O (30 mL) was degassed and purged with N2 for 3
times, and then the reaction mixture was stirred at 110 °C for 16 hr under N2 atmosphere. The reaction mixture was poured into H2O (150 mL) and stirred for 5 min. The aqueous phase was extracted with EtOAc (80 mL x 3). The combined organic phase was washed with brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel ( 330 g SepaFlash® Silica Flash Column, EtOAc/PE: 0-20%). Intermediate 16A (3.8 g, 11.44 mmol, 34.61% yield) was obtained as a yellow solid.
N-ethyl-4-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)pyridin-2-amine
[00257] To a solution of intermediate 16A (150 mg, 0.45 mmol, 1 eq) in dioxane (0.5 mL) was added ethanamine (203.5 mg, 4.51 mmol, 0.29 mL, 10 eq) in a sealed tube. The reaction mixture was stirred at 120 °C for 16 hrs. The reaction mixture was poured into H2O (20 mL) and stirred for 5 min. The aqueous phase was extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrouNas2SO4 , filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Xtimate C18 150 x 25mm x 5um; mobile phase: [water(0.05%HCl)-ACN]; B%: 30%-55.5%,9.5min). Compound 16 was obtained as a yellow solid (34.6 mg, 19.5% yield, HC1). LC-MS (ESI): RT = 0.753 min, mass calcd for C20H18F3N3 357.37, m/z found 358.0 [M+H]+, 1H NMR (400MHz, METHANOL-d4) 8 = 7.74 (d, J= 6.8 Hz, 1H), 7.56 - 7.44 (m, 3H), 7.40 (d, J= 8.5 Hz, 2H), 7.36 - 7.30 (m, 1H), 7.08 (d, J= 1.0 Hz, 1H), 6.96 (dd, J= 1.6, 6.8 Hz, 1H), 6.87 (d, J= 8.5 Hz, 2H), 3.40 - 3.35 (m, 2H), 1.32 (t, J= 13 Hz, 3H).
Example 17: N-(4-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)pyridin-2-yl)acetamide
2-bromo-N-(4-methoxybenzyl)-N-(4-(trifluoromethyl)phenyl)aniline
[00258] To a solution of intermediate 4C (1 g, 3.16 mmol, 1 eq) in DMF (10 mL) was added NaH (151.8 mg, 3.80 mmol, 60%, 1.2 eq) at 0 °C under N2. After addition, the reaction mixture was stirred at 0°C for 1 hr, and then PMB-C1 (594.5 mg, 3.80 mmol, 0.51 mL, 1.2 eq) in DMF (5 mL) was added dropwise at 0°C. The resulting mixture was stirred at 20 °C for 2 hrs. The reaction mixture was poured into NH4CI (50 mL) and stirred for 5 min. The aqueous phase was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (40 mL), dried over anhydrous NA2SO4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (40 g SepaFlash® Silica Flash Column, EtOAc/PE: 0-20%). Intermediate 17A (920 mg, 2.11 mmol, 66.6% yield) was obtained as a colorless oil.
N-(4-methoxybenzyl)-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-N-(4- (trifluoromethyl)phenyl)aniline
[00259] A mixture of intermediate 17A (700 mg, 1.60 mmol, 1 eq), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (4D, 11.1 mg, 2.41 mmol, 1.5 eq), Pd(dppf)C12 (58.7 mg, 80.2 pmol, 0.05 eq), AcOK (314.9 mg, 3.21 mmol, 2 eq) in dioxane (6 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90 °C for 3 hr under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (10 mLx2), dried over anhydrouNas2SO4 , filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=l/O to 20/1). Intermediate 17B (300 mg, 0.62 mmol, 38.6% yield) was obtained as yellow oil.
4-(2-((4-methoxybenzyl)(4-(trifluoromethyl)phenyl)amino)phenyl)pyridin-2-amine
[00260] The mixture of intermediate 17B (300 mg, 0.62 mmol, 1 eq), 4-bromopyridin-2- amine (4F, 128.8 mg, 0.74 mmol, 1.2 eq), CS2CO3 (404.4 mg, 1.24 mmol, 2 eq) and Pd(dppf)C12 (22.7 mg, 31.0 pmol, 0.05 eq) in dioxane (3 mL) was stirred at 90 °C for 2 hrs. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (15 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=l/O to 0/1). Intermediate 17C (200 mg, 0.20 ,mmol, 32.2% yield) was obtained as yellow solid.
N-(4-(2-((4-methoxybenzyl)(4-(trifluoromethyl)phenyl)amino)phenyl)pyridin-2-yl)acetamide
[00261] The mixture of intermediate 17C (100 mg, 0.22 mmol, 1 eq), TEA (67.5 mg, 0.66 mmol, 92.9 uL, 3 eq) and AC2O (34.0 mg, 0.33 mmol, 31.2 uL, 1.5 eq) in DCM (2 mL) was stirred at 50 °C for 2 hrs. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (30 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. Intermediate 17D (100 mg, crude) was obtained as yellow oil, which was used into the next step without further purification.
N-(4-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)pyridin-2-yl)acetamide
[00262] The mixture of crude intermediate 17D (100 mg, 0.20 mmol, 1 eq) and HCl/MeOH
(4 M, 50.8 uL, 1 eq) was stirred at 50 °C for 2 hrs. The reaction mixture was diluted with μ (10 mL) and the reaction mixture was adjusted to pH of 9 with NaOH (4 M). The reaction mixture was extracted with EtOAc (30 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Xtimate C18 150 x 25mm x 5um; mobile phase: [water(0.225%FA)-ACN];B%: 47%-77%,7min). Compound 17 was obtained as a white solid (10 mg, 11.6% yield, HCOOH). LC-MS (ESI): RT = 0.859 min, mass calcd for C20H16F3N3O 371.36, m/z found 372.1 [M+H]+, 1H NMR (400MHz, METHANOL-d4) δ = 8.23 - 8.17 (m, 2H), 7.45 - 7.42 (m, 3H), 7.33 (d, J= 8.5 Hz, 2H), 7.31 - 7.25 (m, 1H), 7.17 (dd, J= 1.5, 5.3 Hz, 1H), 6.83 (d, J= 8.5 Hz, 2H), 2.17 (s, 3H).
[00263] Methanesulfonyl chloride (0.34 g, 2.97 mmol, 0.22 mL, 13.34 eq) was added at the reaction mixture of intermediate 17C (100 mg, 0.22 mmol, 1 eq) and TEA (6 7.5 mg, 0.66 mmol, 92.9 uL, 3 eq) in DCM (3 mL) was stirred at 0 °C. Then the reaction mixture was stirred at 25 °C for 16 hr. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (10 mL x 3), dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. The residue was purified by prep-TLC (SiO2, Petroleum ether/Ethyl acetate= 1: 1). A mixture of intermediates 18A and 18B (50 mg, 82.5 pmol, 37.1% yield) was obtained as yellow solid.
N-(4-(2-((4-methoxybenzyl)(4-(trifluoromethyl)phenyl)amino)phenyl)pyridin-2- yl)methanesulfonamide
[00264] The mixture of intermediates 18A and 18B (50 mg, 82.5 pmol, 1 eq) and NaOH (4 M, 20.64 uL, 1 eq) in MeOH (3 mL) was stirred at 40 °C for 20 min. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (10 mLx3), dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. Intermediate 18B (50 mg, crude) was obtained as yellow solid, which was used into the next step without further purification.
N-(4-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)pyridin-2-yl)methanesulfonamide
[00265] The mixture of intermediate 18B (80 mg, 0.15 mmol, 1 eq) and Pd/C (0.15 mmol, 40%, 1 eq) in DCM (5 mL) was degassed and purged with H2 for 3 times, and then the reaction mixture was stirred at 25°C for 16 hr under H2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (30 mL x 3). The combined organic phase was washed with brine (10 mL x 3), dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Xtimate C18 150 x 25mm x 5um;mobile phase: [water(0.05%HCl)-ACN];B%: 50%-80%,7.8min). Compound 18 (8 mg, 11.7% yield, HC1) was obtained as a white solid. LCMS (ESI): RT = 0.913 min, mass calcd for C19H16F3N3O2S 407.41, m/z found 308.0 [M+H]+, 1H NMR (400MHz, METHANOL-d4) 8 = 8.13 (d, J= 5.9 Hz, 1H), 7.54 - 7.42 (m, 3H), 7.41 - 7.35 (m, 3H), 7.35 - 7.30 (m, 1H), 7.24 (dd, J = 1.4, 6.0 Hz, 1H), 6.87 (d, J= 8.5 Hz, 2H), 3.20 - 3.14 (m, 3H).
3-bromo-N-(4-(trifluoromethyl)phenyl)pyridin-2-amine
[00266] To a solution of intermediate 4B, (8.2 g, 43.3 mmol, 1.5 eq) in DCM (20 mL) were added Cu(OAc)2 (7.8 g, 43.3 mmol, 1.5 eq), DIPEtOAc (7.4 g, 57.8 mmol, 10.0 mL, 2.0 eq) and 3- bromopyridin-2-amine (19A, 5.0 g, 28.9 mmol, 1.0 eq). The reaction mixture was stirred at 25 °C for 16 hr under O2 atmosphere. The reaction mixture was filtered, and the filtrate was concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 24 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate/Petroleum ether gradient) to give intermediate 19B (1.5 g, 2.8 mmol, 9.8% yield) as a light yellow oil. LCMS (ESI): RT = 1.012 min, mass calcd. for Ci2H8BrF3N2 315.98, m/z found 317 [M+H]+; 1H NMR (400 MHz, CDCl3) 6 8.21 (dd, J= 1.5, 4.8 Hz, 1H), 7.80 (dd, J= 1.5, 7.8 Hz, 1H), 7.76 (d, J= 8.5 Hz, 2H), 7.58 (d, J= 8.8 Hz, 2H), 6.74 (dd, J= 5.0, 7.8 Hz, 1H).
N2-(4-(trifluoromethyl)phenyl)-[3,4'-bipyridine]-2,2'-diamine
[00267] To a solution of intermediate 19B (100 mg, 0.3 mmol, 1.0 eq) in dioxane (5 mL) and H2O (1 mL) were added Pd(dppf)C12 (11.5 mg, 15.7 pmol, 0.05 eq), Na2CO3 (6 6.8 mg, 0.6 mmol,
2.0 eq) and 4-(4,4,5-trimethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine (intermediate 7C, 83.2 mg, 0.4 mmol, 1.2 eq). The reaction mixture was stirred at 90 °C for 2 hrs. The reaction mixture was filtered, and the filtrate was concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate/Petroleum ether gradient ) to give Compound 19 (10.82 mg, 9.87% yield) as a light yellow solid. LC-MS (ESI): RT = 0.773 min, mass calcd. for C17H13F3N4 330.11, m/z found 331.1 [M+H]+; 1H NMR (400 MHz, DMSO-tL) 8 8.37 (s, 1H), 8.24 (dd, J= 1.8, 4.8 Hz, 1H), 7.98 (d, J= 5.3 Hz, 1H), 7.73 (d, J= 8.8 Hz, 2H), 7.59 (dd, J= 1.9, 7.4 Hz, 1H), 7.54 (d, J= 8.5 Hz, 2H), 7.03 (dd, J= 4.8, 7.5 Hz, 1H), 6.58 (dd, J= 1.5, 5.3 Hz, 1H), 6.55 (s, 1H), 6.02 (s, 2H).
Example 20: N-(4-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)pyridin-2-yl)acrylamide
N-(4-bromo-2-pyridyl)prop-2-enamide
[00268] To a solution of compound 4F (300 mg, 1.73 mmol, 1 eq) in THF (3 mL) were added TEA (701.8 mg, 6.94 mmol, 0.96 mL, 4.0 eq) and acryloyl chloride (313.8 mg, 3.4 mmol, 0.28 mL, 2.0 eq). The reaction mixture was stirred at 25 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (SiO2, Petroleum ether/Ethyl acetate = 100/1 to 5/1) to give intermediate 20A (250 mg, 0.85 mmol, 49% yield) as a light yellow solid. LC-MS (ESI): RT = 0.940 min, mass calcd. for CsH7BrN2O 225.97, m/z found 226.9 [M+H]+.
N-[4-[2-[4-(trifluoromethyl)anilino]phenyl]-2-pyridyl]prop-2-enamide
[00269] To a solution of intermediate 4E (100 mg, 0.27 mmol, 1 eq) in H2O (1 mL) and dioxane (5 mL) were added Pd(dppf)C12 (20.1 mg, 27.5 pmol, 0.1 eq), intermediate 20A (93.7 mg, 0.41 mmol, 1.5 eq) and CS2CO3 (269.1 mg, 0.82 mmol, 3.0 eq). The reaction mixture was stirred at 90 °C for 16 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25 5u;mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN];B%: 65%-95%,7.8min) to give Compound 20 (5.2 mg, 4% yield) as a white solid. LC-MS (ESI): RT = 0.904 min, mass calcd. for C21H16F3N3O 383.12, m/z found 383.9 [M+H]+; 1H NMR (400 MHz, CDCl3) 68.40 (s, 1H), 8.29 (d, J= 5.1 Hz, 1H), 8.26 - 8.20 (m, 1H), 7.45 (d, J = 8.6 Hz, 3H), 7.41 - 7.35 (m, 2H), 7.18 (dt, J= 1.1, 7.4 Hz, 1H), 7.11 (dd, J= 1.5, 5.1 Hz, 1H), 6.98 (d, J= 8.5 Hz, 2H), 6.52 - 6.43 (m, 1H), 6.35 - 6.20 (m, 1H), 5.89 - 5.80 (m, 2H).
Example 21 : 2-Ethoxy-5-(3-(4-(trifluoromethyl)phenoxy)pyrazin-2-yl)pyrimidine
2-methoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine
[00270] A solution of 5-bromo-2-ethoxypyrimidine (20A, 50.0 mg, 0.25 mmol, 1 eq), compound 4D (75.0 mg, 0.30 mmol, 1.2 eq), Pd(dppf)C12 (18.0 mg, 25 pmol, 0.1 eq) and potassium acetate (48.3 mg, 0.49 mmol, 2 eq) in 1,4-dioxane (2 mL) at 20°C was purged and degassed with N2 and then stirred at 100 °C for 6 hrs. The crude intermediate 20B (61.6 mg) was obtained as black oil.
2-ethoxy-5-(3-(4-(trifluoromethyl)phenoxy)pyrazin-2-yl)pyrimidine
[00271] A solution of 2-chl oro-3 -(4-(trifluoromethyl)phenoxy)pyrazine (21C, 79.1 mg, 0.29 mmol, 1.2 eq), intermediate 20B (60.0 mg, 0.24 mmol, 1 eq), Pd(dppf)C12 (17.6 mg, 24 pmol, 0.1 eq) and Na2CO3 (50.9 mg, 0.48 mmol, 2 eq) in 1,4-di oxane (2 mL) and H2O (0.2 mL) at 20 °C was purged and degassed with N2 and then stirred at 100 °C for 16 hrs. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash chromatography on silica gel (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-42% Ethyl
acetate/Petroleum ether gradient @20 mL/min) and prep-HPLC (column: Xtimate C18 100x30mmx3um; mobile phase: [water(0.05%HCl)-ACN]; B%: 50%-80%, 8.5 min) to give Compound 20 (2.1 mg, 2.4% yield) as a yellow solid. LC-MS (ESI): RT = 0.954 min, mass calc, for C17H13F3N4O2 362.10, m/z found 363.1 [M+H]+; 1H NMR (400 MHz, CDCl3) 8 9.37 (s, 2H), 8.44 (d, J= 2.4 Hz, 1H), 8.08 (d, J= 2.4 Hz, 1H), 7.73 (d, J= 8.4 Hz, 2H), 7.31 (d, J= 8.5 Hz, 2H), 4.54 (q, J= 7.0 Hz, 2H), 1.49 (t, J= 7.0 Hz, 3H).
Example 22: 2-propoxy-5-(3-(4-(trifluoromethyl)phenoxy)pyrazin-2-yl)pyrimidine
5-Bromo-2-propoxypyrimidine
[00272] A mixture of 5-bromo-2-chloropyrimidine (22A, 200.0 mg, 1.03 mmol, 1 eq) and KOH (116.0 mg, 2.07 mmol, 2 eq) in //-PrOH (2 mL) was stirred at 20 °C for 3 hrs. The residue was filtered and diluted with water (10 mL), and then extracted with EtOAc (10 mL x 3). The combined organic layers were washed with water (10 mL x 2) and brine (10 mL x 2), dried over anhydrousNa2SO4 , filtered and concentrated under reduced pressure to give intermediate 22B (320.0 mg, 1.46 mmol, 94.1% yield) as colorless oil. LC-MS (ESI): RT = 0.845 min, mass calc, for C7H9BrN2O 215.99, m/z found 218.8 [M+H]+.
2-Propoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine
[00273] A solution of intermediate 22B (100.0 mg, 0.46 mmol, 1 eq), compound 4D (140.4 mg, 0.55 mmol, 1.2 eq), Pd(dppf)C12 (33.7 mg, 46 pmol, 0.1 eq) and AcOK (90.4 mg, 0.92 mmol, 2 eq) in dioxane (1 mL) at 20°C was purged and degassed with N2 and then stirred at 90 °C for 5 hrs. The crude intermediate 22C was obtained (121.0 mg, 0.46 mmol, 99.4% yield) as black oil.
2-propoxy-5-(3-(4-(trifluoromethyl)phenoxy)pyrazin-2-yl)pyrimidine
[00274] A solution of 2-chloro-3-(4-(trifluoromethyl)phenoxy)pyrazine (21C, 121.0 mg, 0.46 mmol, 1.2 eq), intermediate 22C (104.8 mg, 0.38 mmol, 1 eq), Pd(dppf)C12 (27.9 mg, 38 pmol, 0.1 eq) and Na2CO3 (80.9 mg, 0.76 mmol, 2.0 eq) in dioxane (1 mL) and H2O (0.1 mL) at 20 °C was purged and degassed with N2 and then stirred at 90 °C for 16 hrs. The residue was concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-35% Ethyl acetate/Petroleum ether gradient @ 20/min), prep-HPLC :(column: Xtimate C18 100x30mmx3um; mobile phase: [water(0.05%HCl)-ACN]; B%: 55%-85%, 8.5min) and prep-TLC (SiCh, PE:EtOAc = 3:1, UV) to give Compound 22 (12.7 mg, 8.8% yield) as a white solid. LC-MS (ESI): RT = 1.007 min, mass calc, for C18H15F3N4O2 376.11, m/z found 376.9 [M+H]+; XH NMR (400 MHz, CDCL) 8 9.35 (s, 2H), 8.44 (d, J= 2.5 Hz, 1H), 8.08 (d, J= 2.5 Hz, 1H), 7.72 (d, J= 8.6 Hz, 2H), 7.31 (d, J= 8.5 Hz, 2H), 4.42 (t, J= 6.8 Hz, 2H), 1.94 - 1.85 (m, 2H), 1.07 (t, J= 7.4 Hz, 3H).
Example 23: N-(5-(3-(4-(trifluoromethyl)phenoxy)pyrazin-2-yl)pyrimidin-2- yl)methanesulfonamide (Compound 23)
N[5-[3-[4-(trifluoromethyl)phenoxy]pyrazin-2-yl]pyrimidin-2-yl]methanesulfonamide [00275] To a solution of compound 23A (40 mg, 0.12 mmol, 1 eq) in THF (0.5 mL) at 0°C was added MsCl (27.5 mg, 0.24 mmol, 18 uL, 2.0 eq) and NaH (7.2 mg, 0.18 mmol, 60%, 1.5 eq). The reaction mixture was stirred at 25 °C for 4 h. The residue was diluted with H2O (10 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Xtimate C18 100x30mmx3um; mobile phase: [water (0.05% HC1)-ACN]; B%: 40%-70%, 8.5min) to give Compound 23 (1.5 mg, 3.0% yield) as a white solid. LC-MS (ESI): RT = 0.807 min, mass calc, for C16H12F3N5O3S 411.06, m/z found 411.9 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 2H), 8.54 (d, J= 2.5 Hz, 1H), 8.20 (d, J= 2.6 Hz, 1H),
7.81 (d, J= 8.6 Hz, 2H), 7.51 (d, J= 8.6 Hz, 2H), 6.15 (br s, 1H), 6.16 - 6.13 (m, 1H), 3.44 - 3.31 (m, 3H).
2-chloro-5-[3-[4-(trifluoromethyl)phenoxy]pyrazin-2-yl]pyrimidine
[00276] To a solution of intermediate 21C (200 mg, 0.73 mmol, 1 eq) in dioxane (2 mL) and H2O (0.2 mL) were added Pd(dppf)C12 (53.2 mg, 72.8 pmol, 0.1 eq), Na2CO3 (154.3 mg, 1.46 mmol, 2 eq) and compound (2-chloropyrimidin-5-yl)boronic acid (la, 115.3 mg, 0.73 mmol, 1 eq). The reaction mixture was degassed and purged with N2 for 3 times and stirred at 110°C for 1 hr. The reaction mixture was concentrated in vacuum. The residue was diluted with EtOAc (20 mL), filtered and the filtrate was washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4 , filtered and concentrated in vacuum. The crude product was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate/Petroleum ether gradient @ 30 mL/min). Intermediate 24B (80 mg, 0.21 mmol, 29.2% yield) was obtained as a yellow solid.
2-[4-(trifluoromethyl)phenoxy]-3-(2-vinylpyrimidin-5-yl)pyrazine
[00277] To a solution of intermediate 24B (50 mg, 0.14 mmol, 1 eq) and 4,4,5,5-tetramethyl-
2-vinyl-l,3,2-dioxaborolane (24C, 26.2 mg, 0.17 mmol, 28 uL, 1.2 eq) in dioxane (2 mL) and μ (0.2 mL) were added Pd(dppf)C12 (10.3 mg, 14.1 pmol, 0.1 eg) and Na2CO3 (30.0 mg, 0.28 mmol, 2 eq). The reaction mixture was degassed and purged with N2 for 3 times and stirred at 110°C for 1 hr. The residue was filtered, and the filtrate was concentrated in vacuum. The crude product was checked by HPLC and purified by prep-HPLC (column: Waters Xbridge C18 150x50mmx 10um;mobile phase: [water(0.04%NH3H20+10mM NH4HCO3)-ACN];B%: 51%-81%,9.3min). to afford Compound 24 (20.1 mg, 40.9% yield) was obtained as a white solid. LCMS (ESI): RT = 0.910 min, mass calc, for C17H11F3N4O 344.09, m/z found 344.9 [M+H]+; 1H NMR (400 MHz, CDCl3) 8 9.54 (s, 2H), 8.49 (d, J= 2.5 Hz, 1H), 8.13 (d, J= 2.3 Hz, 1H), 7.73 (d, J= 8.5 Hz, 2H),
7.32 (d, J= 8.3 Hz, 2H), 6.98 (dd, J= 10.5, 17.3 Hz, 1H), 6.75 (dd, J= 1.5, 17.3 Hz, 1H), 5.85 (dd, J= 1.8, 10.5 Hz, 1H).
5-bromo-2-ethoxypyrimidine
[00278] To a solution of 5-bromo-2-chloro-pyrimidine (25A, 1 g, 5.17 mmol, 1 eq) in EtOH (10 mL) was added KOH (580.1 mg, 10.34 mmol, 2 eq) in H2O (2 mL). The reaction mixture was stirred at 25 °C for 16 hrs. The reaction mixture was concentrated under reduced pressure to remove EtOH. Then the residue was diluted with H2O (5 mL) and neutralized to pH = 6-7 with 2M HC1, then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure to give a residue. It was used into next step without further purification. Compound 5-bromo-2- ethoxy -pyrimidine (intermediate 25B, 800 mg, 3.94 mmol, 76.2% yield) was obtained as a yellow solid.
2-ethoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine
[00279] A mixture of intermediate 25B (100 mg, 0.49 mmol, 1 eq), intermediate 4D (125.0 mg, 0.49 mmol, 1 eq), KO Ac (96.6 mg, 0.98 mmol, 2 eq), Pd(dppf)C12 (36.0 mg, 49.2 pmol, 0.1 eq) in dioxane (5 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 100 °C for 4 hr under N2 atmosphere. After removing solvent in vacuo, crude intermediate 25C (123 mg, 0.49 mmol, 99.8% yield) was obtained as a black oil, and was used for the next step without further purification.
3-(2-ethoxypyrimidin-5-yl)-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine
[00280] A mixture of 3-chloro-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine (25D, 110 mg, 0.40 mmol, 1 eq), intermediate 25C (120.6 mg, 0.48 mmol, 1.2 eq), KO Ac (78.9 mg, 0.80 mmol, 2
eq), Pd(dppf)C12 (29.4 mg, 40.2 pmol, 0.1 eq) in dioxane (5 mL) and H2O (0.2 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 100 °C for 16 hr under N2 atmosphere. The reaction mixture was filtered and added H2O (10 mL), then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrousNa2SO4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Xtimate C18 100x30mmx3um;mobile phase: [water(0.05%HCl)-ACN];B%: 45%-75%,8.5min). Compound 25 (5.4 mg, 3.5% yield) was obtained as a yellow solid. LC-MS (ESI): RT = 0.930 min, mass calcd for C17H14F3N5O 361.32 m/z found 380.9[M+H]+, 1H NMR (400 MHz, CD3OD) 8 8.95 (s, 2H), 8.22 (dd, J= 2.6, 12.8 Hz, 2H), 7.69 (d, J= 8.6 Hz, 2H), 7.56 (d, J= 8.6 Hz, 2H), 4.56 (q, J= 7.1 Hz, 2H), 1.46 (t, J= 7.1 Hz, 3H).
Example 26: N-(4-(Trifluoromethyl)phenyl)-3-(2-vinylpyrimidin-5-yl)pyrazin-2-amine
3-(2-chloropyrimidin-5-yl)-N-(4-(trifluoromethyl)phenyl)pyrazin-2-amine
[00281] A mixture of 3-chloro-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine (25D, 100 mg, 0.36 mmol, 1 eq), (2-chloropyrimidin-5-yl)boronic acid (24A, 6 3.6 mg, 0.40 mmol, 1.1 eq), Pd(dppf)C12 (26.7 mg, 36.5 pmol, 0.1 eq) and K2CO3 (101.0 mg, 0.73 mmol, 2 eq) in dioxane (3 mL) and H2O (0.2 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 110 °C for 4 hrs under N2 atmosphere. The reaction mixture was added H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-25% Ethyl acetate/Petroleum ether gradient @ 25 mL/min). Intermediate 26A (70 mg, 0.19 mmol, 52.8% yield) was obtained as a yellow solid.
N-(4-(trifluoromethyl)phenyl)-3-(2-vinylpyrimidin-5-yl)pyrazin-2-amine
[00282] A mixture of intermediate 26A (70 mg, 0.19 mmol, 1 eq), 4,4,5,5-tetramethyl-2- vinyl-l,3,2-dioxaborolane (24C, 33.7 mg, 0.21 mmol, 37 uL, 1.1 eq), K2CO3 (55.0 mg, 0.39 mmol,
2 eq) and Pd(dppf)C12 (14.5 mg, 19.9 pmol, 0.1 eq) in dioxane (3 mL) and H2O (0.3 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 100 °C for 4 hrs under N2 atmosphere. The reaction mixture was added H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Xtimate C18 100x30mmx3um;mobile phase: [water(0.05%HCl)- ACN];B%: 42%-72%,8.5min) to give 13 mg crude product. Then the residue was purified by prep- HPLC (column: Welch Xtimate Cl 8 150x25mmx5um;mobile phase: [water(0.05%HCl)- ACN];B%: 42%-72%,8.5min). Compound 26 (3.3 mg, 4.9% yield) was obtained as a yellow solid. LC-MS (ESI): RT = 0.928 min, mass calcd for C17H12F3N5343.31 m/z found 344.0[M+H]+, 1H NMR (400 MHz, CDCl3) 8 9.12 (s, 2H), 8.29 - 8.24 (m, 2H), 7.65 - 7.57 (m, 4H), 6.99 (dd, J= 10.6, 17.3 Hz, 1H), 6.82 - 6.73 (m, 2H), 5.88 (dd, J= 1.4, 10.6 Hz, 1H).
5-bromo-2-cyclopropylpyrimidine
[00283] To a solution of 5-bromo-2-iodopyrimidine (27A, 200 mg, 0.70 mmol, 1 eq) and Pd(PPh3)4 (162.3 mg, 0.14 mmol, 0.2 eq) in THF (2 mL) at 20°C was added cyclopropylmagnesium bromide (0.5 M, 2.81 mL, 2 eq), and the reaction mixture was purged and degassed with N2 for 3 times and then stirred at 70°C under N2 for 16 hrs. The reaction mixture was quenched with water (0.5 mL) and then concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give intermediate 27B (80 mg, 0.39 mmol, 56.1% yield) as colorless oil. LCMS (ESI): RT = 0.752 min, mass calc, for CvHvBrlS 197.98, m/z found 200.8 [M+H]+.
2-cyclopropyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine
[00284] The mixture of intermediate 27B (40 mg, 0.20 mmol, 1 eq}, 4D (6 6.3 mg, 0.26 mmol, 1.3 eq}, Pd(dppf)C12 (7.4 mg, 10.1 pmol, 0.05 eq} and AcOK (39.4 mg, 0.40 mmol, 2 eq in dioxane (2 mL) at 20°C was purged and degassed with N2 for 3 times and then stirred at 100°C under N2 for 2 hrs. The reaction mixture was concentrated under reduced pressure to give intermediate 27C (49 mg, 0.20 mmol, 99.1% yield) as black oil, which was used directly for next step without further purification.
2-cyclopropyl-5-(3-(4-(trifluoromethyl)phenoxy)pyrazin-2-yl)pyrimidine
[00285] The mixture of intermediate 21C (40 mg, 0.15 mmol, 1 eq), intermediate 27C (43.0 mg, 0.17 mmol, 1.2 eq), Pd(dppf)C12 (5.3 mg, 7.3 pmol, 0.05 eq) and Na2CO3 (30.9 mg, 0.29 mmol, 2 eq) in dioxane (2 mL) and H2O (0.2 mL) at 20°C was purged and degassed with N2 for 3 times and then stirred at 100°C under N2 for 16 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate/Petroleum ether gradient @ 20 mL/min) to give 50 mg crude product, which was purified further by prep-HPLC (column: Xtimate C18 100x30mmx3um; mobile phase: [water (0.05%HCl)-ACN]; B%: 45%-75%, 8.5min) to give the title compound (23.7 mg, 45.5% yield) as a white solid. LC-MS (ESI): RT = 0.925 min, mass calc, for CI8HI3F3N4O 358.10, m/z found 358.9 [M+H]+; 1H NMR (400 MHz, CDC13) 8 9.40 (s, 2H), 8.47 (d, J= 2.5 Hz, 1H), 8.11 (d, J= 2.5 Hz, 1H), 7.72 (d, J= 8.5 Hz, 2H), 7.30 (d, J= 8.3 Hz, 2H), 2.43 - 2.35 (m, 1H), 1.31 - 1.24 (m, 2H), 1.23 - 1.16 (m, 2H).
Example 28: l-(5-(3-(4-(Trifluoromethyl)phenoxy)pyrazin-2-yl)pyrimidin-2-yl)cyclopropane-
[00286] To a solution of NaH (413.5 mg, 10.34 mmol, 60%, 2 eq) in THF (20 mL) were added 5-bromo-2-chloropyrimidine (28A, 802.8 mg, 5.69 mmol, 0.81 mL, 1.1 eq) at 0°C and stirred for 1 hr. Then tert-butyl 2-cyanoacetate (1.00 g, 5.17 mmol, 1 eq) was added to the reaction mixture and stirred at 20 °C for 16 hrs. The reaction mixture was quenched with H2O (20 mL), extracted with EtOAc (20 mL). The aqueous phase was adjusted pH = 4 with IN.aq.HCl and extracted with EtOAc (20 mL x 3). Then the combined organic phase was washed with H2O (10 mL), brine (10 mL) and dried over Na2SO4 , filtered and concentrated in vacuum. The crude product was used for the next step directly. Intermediate 28B (1.50 g, 3.27 mmol, 63.2% yield) was obtained as a yellow solid.
2-(5-bromopyrimidin-2-yl)acetonitrile
[00287] To a solution of intermediate 28B (1.50 g, 3.27 mmol, 1 eq) in DCM (20 mL) was added TFA (4 mL). The reaction mixture was stirred at 20 °C for 1 hr. LCMS showed that the starting material was consumed completely and 67% of the desired product was detected. The reaction mixture was concentrated in vacuum. The residue was diluted with H2O (10 mL), adjusted pH = 7 with saturated aq.NaHCO3 and extracted with EtOAc (15 mL x 3). The combined organic phase was washed with H2O (10 mL), brine (10 mL) and dried over Na2SO4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate/Petroleum ether gradient @ 40 mL/min). Intermediate 28C (300.0 mg, 1.51 mmol, 46.3% yield) was obtained as a yellow solid. l-(5-bromopyrimidin-2-yl)cyclopropanecarbonitrile
[00288] To a solution of Intermediate 28C (300.0 mg, 1.51 mmol, 1 eq), 1,2-dibromoethane (1.14 g, 6.06 mmol, 0.45 mL, 4 eq) and benzyl(triethyl)ammonium chloride (TEBAC, 34.5 mg, 0.15 mmol, 0.1 eq) in toluene (6 mL) was added NaOH (1.62 g, 12.12 mmol, 1.5 mL, 30%, 8 eq) at 20°C. Then the reaction mixture was stirred at 25°C for 16 hr. The colorless solution had turn into a red one. Then the reaction mixture was stirred at 25°C for 24 hr. The reaction mixture was poured into ice water (20 mL), extracted with EtOAc (15 mL x 3). The combined organic phase was washed with H2O (10 mL), brine (10 mL) and dried over Na2SO4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-10% Ethyl acetate/Petroleum ether gradient @ 40
mL/min). Intermediate 28D (110.0 mg, 0.48 mmol, 32.0% yield) was obtained as a white solid. 1H NMR (400 MHz, CDCl3) 6 8.70 (s, 2H), 1.90 - 1.82 (m, 4H). l-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]cyclopropanecarbonitrile [00289] To a solution of intermediate 28D (30.0 mg, 0.13 mmol, 1 eq) and intermediate 4D
(51.0 mg, 0.2 mmol, 1.5 eq) in dioxane (1 mL) were added Pd(dppf)C12 (9.8 mg, 13.3 pmol, 0.1 eq) and AcOK (26.2 mg, 0.27 mmol, 2 eq). The reaction mixture was degassed and purged with N2 for 3 times and stirred at 100 °C for 2 hr. The reaction mixture was concentrated in vacuum and diluted with EtOAc (20 mL), filtered and the filtrate was concentrated in vacuum. The crude product was used for the next step directly. Crude intermediate 28E (36.0 mg, crude) was obtained as a yellow oil, and used for the next step without further purification. l-[5-[3-[4-(trifluoromethyl)phenoxy]pyrazin-2-yl]pyrimidin-2-yl]cyclopropanecarbonitrile [00290] To a solution of intermediate 21C (43.7 mg, 0.16 mmol, 1.2 eq) and intermediate
28E (36.0 mg, 0.13 mmol, 1 eq) in dioxane (1 mL) were added Pd(dppf)C12 (9.7 mg, 13.2 pmol, 0.1 eq), Na2CO3 (28.1 mg, 0.26 mmol, 2 eq) and H2O (0.2 mL). The reaction mixture was degassed and purged with N2 for 3 times and stirred at 100 °C for 2 hr. The reaction mixture was concentrated in vacuum. The residue was checked by HPLC and purified by prep-HPLC (column: Xtimate C18 100x30mmx3um; mobile phase: [water (0.225%FA)-ACN]; B%: 55%-85%, 7.8min). Compound 28 (16.7 mg, 32.9% yield) was obtained as a white solid. LC-MS (ESI): RT = 0.907 min, mass calc, for C19H12F3N5O 383.10, m/z found 383.9 [M+H]+; 1H NMR (400 MHz, CDCl3) 8 9.49 (s, 2H), 8.49 (d, J= 2.5 Hz, 1H), 8.14 (d, J= 2.4 Hz, 1H), 7.74 (d, J= 8.6 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 2.03 - 1.87 (m, 4H).
Example 29: l-(5-(3-((4-(trifluoromethyl)phenyl)thio)pyrazin-2-yl)pyrimidin-2- yl)cyclopropane-l-carbonitrile (Compound 29)
l-[5-[3-[4-(trifluoromethyl)phenyl]sulfanylpyrazin-2-yl]pyrimidin-2- yljcyclopropanecarbonitrile
[00291] To a solution of intermediate 28E (47.1 mg, 0.16 mmol, 1.1 eq and 2-chloro-3-((4- (trifluoromethyl)phenyl)thio)pyrazine (29A, 40 mg, 0.15 mmol, 1 eq in dioxane (2 mL) and μ (0.2 mL) were added Pd(dppf)C12 (10.8 mg, 14.7 pmol, 0.1 e ) and Na2CO3 (31.2 mg, 0.29 mmol, 2 eq . The reaction mixture was degassed and purged with N2 for 3 times and stirred at 100 °C for 2 hr. The reaction mixture was concentrated in vacuum. The residue was diluted with EtOAc (20 mL), filtered and the filtrate was concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate/Petroleum ether gradient @ 20 mL/min). Compound 29 (8.3 mg, 14.1% yield) was obtained as a white solid. LC-MS (ESI): RT = 0.909 min, mass calc, for C19H12F3N5S 399.08, m/z found 399.9 [M-H]'; 1H NMR (400 MHz, CDCl3) 6 9.11 (s, 2H), 8.46 (d, J= 2.4 Hz, 1H), 8.35 (d, J= 2.4 Hz, 1H), 7.67 (d, J= 8.4 Hz, 2H), 7.61 (d, J= 8.4 Hz, 2H), 2.01 - 1.92 (m, 4H).
Example 30: 5-(3-((4-(Trifluoromethyl)phenyl)thio)pyrazin-2-yl)pyrimidin-2-amine
(Compound 30) and tert-butyl (5-(3-((4-(trifluoromethyl)phenyl)thio)pyrazin-2-yl)pyrimidin- 2-yl)carbamate Compound 30a)
5-(3-((4-(trifluoromethyl)phenyl)thio)pyrazin-2-yl)pyrimidin-2-amine
[00292] To a solution of 2-chloro-3-[4-(trifluoromethyl)phenyl]sulfanyl-pyrazine (29A, 100 mg, 0.34 mmol, 1 eq and [2-(tert-butoxycarbonylamino)pyrimidin-5-yl]boronic acid (30A, 82.2 mg, 0.34 mmol, 1 eq) in dioxane (3 mL) were added Pd(dppf)C12 (25.1 mg, 34.4 pmol, 0.1 eq and CS2CO3 (168.1 mg, 0.51 mmol, 1.5 eq . The reaction mixture was stirred at 110 °C for 16 hr under N2 atmosphere. The reaction mixture was added H2O (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was
purified by prep-HPLC (column: Waters Xbridge Cl 8 150x50mmx 10um;mobile phase: [water(0.04%NH3H20+10mM NH4HCO3)-ACN];B%: 43%-73%,l Imin). Compound 30 (6 .8 mg, 5.7% yield) was obtained as a white solid. LC-MS (ESI): RT = 0.833 min, mass calcd for CI5HIOF3N5S 349.33 m/z found 350.0[M+H]+, 1H NMR (400 MHz, CDC13) 8 8.79 (s, 2H), 8.40 (d, J= 2.5 Hz, 1H), 8.26 (d, J= 2.5 Hz, 1H), 7.68 - 7.60 (m, 4H), 5.31 (br s, 2H). Compound 30a (8.9 mg, 5.7% yield) was obtained as a white solid. LCMS (ESI): RT = 0.954 min, mass calcd for C2OHI8F3N502S 449.45 m/z found 450.0[M+H]+, 1H NMR (400 MHz, CDC13) 8 9.06 (s, 2H), 8.43 (d, J= 2.3 Hz, 1H), 8.31 (d, J= 2.5 Hz, 1H), 7.71 (s, 1H), 7.68 - 7.60 (m, 4H), 1.58 (s, 9H).
Example 31: N-(5-(3-((4-(Trifluoromethyl)phenyl)amino)pyrazin-2-yl)pyrimidin-2- yl)acrylamide (Compound 31)
N-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)pyrimidin-2-yl)acrylamide
[00293] To a solution of 3-(2-aminopyrimidin-5-yl)-N-[4-(trifluoromethyl)phenyl]pyrazin-2- amine (31A, 80 mg, 0.24 mmol, 1 eq) and TEA (73.0mg, 0.72 mmol, 0.1 mL, 3 eq) in DCM (2 mL) was added prop-2-enoyl chloride (32.6 mg, 0.36 mmol, 29 uL, 1.5 eq) under N2. Then the reaction mixture was stirred at 25 °C for 16 hrs. The reaction mixture was added H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge C18 150x50mmx 10um;mobile phase: [water(0.04%NH3H20)-ACN];B%: 46%-46%,9.5min) to afford Compound 31 (2.8 mg, 2.9% yield) as a yellow solid. LCMS (ESI): RT = 0.789 min, mass calcd for Ci8Hi3F3NeO 386.33 m/z found 386.9[M+H]+, 1H NMR (400 MHz, CD3OD) 8 8.95 - 8.85 (m, 2H), 8.12 (q, J= 2.6 Hz, 2H), 7.60 (d, J= 8.5 Hz, 2H), 7.45 (d, J= 8.6 Hz, 2H), 6.57 - 6.35 (m, 2H), 5.83 - 5.74 (m, 1H).
Example 32: N-Acryloyl-N-(5-(3-(4-(trifluoromethyl)phenoxy)pyrazin-2-yl)pyrimidin-2- yl)acrylamide (Compound 32)
[00294] To a solution of 5-(3-(4-(trifluoromethyl)phenoxy)pyrazin-2-yl)pyrimidin-2-amine (32A, 20 mg, 60.0 μmol, 1 eq) in DCM (0.5 mL) was added prop-2-enoyl chloride (6 .5 mg, 72.0 pmol, 5 uL, 1.2 eq) and TEA (18.2 mg, 0.18 mmol, 25 uL, 3.0 eq). The solution was stirred at 25°C for 16 hrs. The residue was purified by prep-HPLC (column: Xtimate C18 100x30mmx3um; mobile phase: [water (0.05% HC1) -ACN]; B%: 45%-75%, 8.5min) to give Compound 32 (4.7 mg, 17.3% yield) as a yellow solid. LCMS (ESI): RT = 0.896 min, mass calc, for C21H14F3N5O3 441.10, m/z found 441.9 [M+H]+; 1H NMR (400 MHz, CDCl3) 8 9.66 (s, 2H), 8.52 (d, J= 2.5 Hz, 1H), 8.18 (d, J= 2.5 Hz, 1H), 7.75 (d, J= 8.6 Hz, 2H), 7.33 (d, J= 8.5 Hz, 2H), 6.60 - 6.53 (m, 2H), 6.52 - 6.42 (m, 2H), 5.86 (dd, J= 1.6, 9.9 Hz, 2H).
Example 33: N-(3-fluoro-5-(3-(4-(trifluoromethyl)phenoxy)pyrazin-2-yl)pyridin-2- yl)methanesulfonamide (Compound 33)
3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine
[00295] A mixture of 5-bromo-3-fluoro-pyridin-2-amine (33A, 650 mg, 3.40 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (4D, 1.30 g, 5.10 mmol, 1.5 eq), Pd(dppf)C12 (124.51 mg, 0.17mmol, 0.05 eq), AcOK (1.00 g, 10.21 mmol, 3 eq) in dioxane (10 mL)was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90 °C for 10 hr under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (20mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 20 g
SepaFlash® Silica Flash Column, Eluent of 0-30% PE/EtOAc@ 35 mL/min). Intermediate 33B (500 mg, 2.10 mmol, 61.7% yield) was obtained as white solid.
3-fluoro-5-[3-[4-(trifluoromethyl)phenoxy]pyrazin-2-yl]pyridin-2-amine
[00296] A mixture of intermediate 33B (208.0 mg, 0.87 mmol, 1.2 eq), intermediate 21C (200 mg, 0.72 mmol, 1 eq), Pd(dppf)C12 (26.6 mg, 36.4 pmol, 0.05 eq), K2CO3 (301.9 mg, 2.18 mmol, 3 eq) in dioxane (2 mL)and H2O (0.5 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90 °C for 10 hr under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate/Petr oleum ether gradient @ 25 mL/min). Intermediate 33C (170 mg, 0.45 mmol, 61.9% yield) was obtained as a yellow solid.
N-[3-fluoro-5-[3-[4-(trifluoromethyl)phenoxy]pyrazin-2-yl]-2-pyridyl]methanesulfonamide [00297] NaH (137.04 mg, 0.57mmol, 10%, 2 eq) was added at the reaction mixture of Intermediate 33C (100 mg, 0.28mmol, 1 eq) in THF (3 mL) at 25°C. The reaction mixture was stirred at 70°C for 1 hr. MsCl (32.70 mg, 0.28 mmol, 22.1 uL, 1 eq) was added at the reaction mixture at 25°C. Then the reaction mixture was stirred at 70°C for another 16 hrs. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75x30mmx3um;mobile phase: [water(0.05%HCl)-ACN];B%: 45%- 75%,6.5min) to afford Compound 33 (7.31 mg, 5.9% yield) was obtained as yellow solid. LC-MS (ESI): RT = 0.891 min, mass calcd for C17H12F4N4O3S 428.36 m/z found 429.2 [M+H]+. 1H NMR (400 MHz, CD3OD) 8 ppm 3.45 (s, 3 H) 7.43 (d, J= 8.50 Hz, 2 H) 7.77 (d, J= 8.63 Hz, 2 H) 8.12 (d, 2.50 Hz, 1 H) 8.36 (dd, J= 11.63, 1.88 Hz, 1 H) 8.47 (d, J= 2.63 Hz, 1 H) 8.98 (d, J= 1.38
Hz, 1 H).
Example 34: A-(3-Chloro-5-(3-(4-(trifluoromethyl)phenoxy)pyrazin-2-yl)pyridin-2- yl)methanesulfonamide (Compound 34)
3-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine
[00298] A mixture of 5-bromo-3-chloro-pyridin-2-amine (34A, 1 g, 4.82 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (4D, 1.84 g, 7.23 mmol, 1.5 eq), Pd(dppf)C12 (176.3 mg, 0.24 mmol, 0.05 eq), AcOK (1.42 g, 14.4 mmol, 3 eq) in dioxane (10 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90 °C for 10 hr under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (lOmL x 2), dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®;20 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate/Petroleum ether gradient @35 mL/min).
Intermediate 34B (1.2 g, 4.71 mmol, 97.8% yield) was obtained as yellow oil.
3-chloro-5-[3-[4-(trifluoromethyl)phenoxy]pyrazin-2-yl]pyridin-2-amine
[00299] A mixture of intermediate 34B (400 mg, 1.46 mmol, 1 eq), intermediate 21C (556.0 mg, 2.18 mmol, 1.5 eq), Pd(dppf)C12 (53.2 mg, 72.8 pmol, 0.05 eq), K2CO3 (6 03.9 mg, 4.37 mmol, 3 eq) in dioxane (3 mL) and H2O (0.5 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90 °C for 10 hr under N2 atmosphere. The reaction mixture was
diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-30% PEZEtOAc@ 35 mL/min). Intermediate 34C (300 mg, 0.81 mmol, 56.1% yield) was obtained as a yellow solid.
N-[3-chloro-5-[3-[4-(trifluoromethyl)phenoxy]pyrazin-2-yl]-2-pyridyl]-N-methylsulfonyl- methanesulfonamide
[00300] NaH (261.7 mg, 1.09 mmol, 10%, 2 eq) was added at the reaction mixture of Intermediate 34C (200 mg, 0.54 mmol, 1 eq) in THF (3 mL) at 25°C. The reaction mixture was stirred at 70 °C for 1 hr. MsCl (6 2.4 mg, 0.54 mmol, 42.2 uL, 1 eq was added at the reaction mixture at 25 °C. Then the reaction mixture was stirred at 70 °C for another 16 hr. LC-MS showed the desired compound was detected. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. Crude intermediate 34D (200 mg, crude) was obtained as yellow solid which was used into the next step without further purification.
N-[3-chloro-5-[3-[4-(trifluoromethyl)phenoxy]pyrazin-2-yl]-2-pyridyl]methanesulfonamide [00301] The mixture intermediate 34D (200 mg, 0.38 mmol, 1 eq) and KOH (2 M, 0.19 mL, 1 eq) in THF (2 mL) was stirred at 25°C for 15 min. The reaction mixture was diluted with μ (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna Cl 8 75x30mmx3um;mobile phase: [water(0.05%HCl)-ACN];B%: 50%-80%,6.5min) to afford Compound 34 (29.1 mg, 16.7% yield) was obtained white solid. LC-MS (ESI): RT = 0.918 min, mass calcd for C17H12CIF3N4O3S 444.82 m/z found 445.2 [M+H]+. 1H NMR (400 MHz, DMSO-t/6) 8 2.07 (s, 1 H) 3.43 (br s, 3 H) 7.54 (d, J= 8.53 Hz, 2 H) 7.85 (d, J= 8.53 Hz, 2 H) 8.22 (d, J= 2.51 Hz, 1 H) 8.55 (d, J= 2.51 Hz, 2 H) 9.00 (br s, 1 H) 10.59 (br s, 1 H).
Example 35: A-(3-Cyano-5-(3-(4-(trifluoromethyl)phenoxy)pyrazin-2-yl)pyridin-2- yl)methanesulfonamide (Compound 35)
2-amino-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine-3-carbonitrile
[00302] A mixture of 2-amino-5-bromo-pyridine-3-carbonitrile (35A, 6 00 mg, 3.03 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (4D, 1.15 g, 4.54 mmol, 1.5 eq), Pd(dppf)C12 (110.8 mg, 0.15 mmol, 0.05 eq), AcOK (892.0 mg, 9.09 mmol, 3 eq) in dioxane (10 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90 °C for 10 hr under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-55% PEZEtOAc@ 35 mL/min).
Intermediate 35B (580 mg, 2.30 mmol, 75.76% yield) was obtained as a white solid.
2-amino-5-[3-[4-(trifluoromethyl)phenoxy]pyrazin-2-yl]pyridine-3-carbonitrile
[00303] A mixture of intermediate 35B (214.1 mg, 0.87mmol, 1.2 eq), intermediate 21C (200 mg, 0.72mmol, 1 eq), Pd(dppf)C12 (26.6 mg, 36.4 pmol, 0.05 eq), K2CO3 (301.9 mg, 2.18 mmol, 3 eq) in dioxane (2 mL)and H2O (0.5 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90 °C for 10 hrs under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate/Petroleum ether gradient @ 25 mL/min). Intermediate 35C (200 mg, 548.58 pmol, 75.33% yield) was obtained as a yellow solid.
N-[3-cyano-5-[3-[4-(trifluoromethyl)phenoxy]pyrazin-2-yl]-2-pyridyl]methanesulfonamide [00304] NaH (134.3 mg, 0.55 mmol, 10%, 2 eq) was added at the reaction mixture of intermediate 35C (100.0 mg, 0.27 mmol, 1 eq) in THF (3 mL) at 25 °C. The reaction mixture was stirred at 70°C for 1 hr. MsCl (32.0 mg, 0.27 mmol, 21.6 uL, 1 eq) was added at the reaction
mixture at 25 °C. Then the reaction mixture was stirred at 70°C for another 16 hr. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75x30mmx3um;mobile phase: [water(0.05%HCl)-ACN];B%: 40%- 70%,6.5min) to afford Compound 35 (9.2 mg, 7.5% yield) was obtained as a white solid. LC-MS (ESI): RT = 0.883 min, mass calcd for C18H12F3N5O3S 435.38 m/z found 436.2 [M+H]+. 1H NMR (400 MHz, CD3OD) 8 3.44 (s, 3 H) 7.46 (d, J= 8.53 Hz, 2 H) 7.79 (d, J= 8.78 Hz, 2 H) 8.16 (d, J = 2.51 Hz, 1 H) 8.50 (d, J= 2.51 Hz, 1 H) 8.94 (d, J= 2.01 Hz, 1 H) 9.30 (s, 1 H).
Example 36: 2-(Prop-2-yn-l-yloxy)-5-(3-(4-(trifluoromethyl)phenoxy)pyrazin-2- yl)pyrimidine (Compound 36)
2-chloro-5-[3-[4-(trifluoromethyl)phenoxy]pyrazin-2-yl]pyrimidine
[00305] To a solution of intermediate 21C (5 g, 18.21 mmol, 1 eq in dioxane (40 mL) and H2O (0.4 mL) was added (2-chloropyrimidin-5-yl)boronic acid (24A, 2.88 g, 18.21 mmol, 1.2 eq , Na2CO3 (3.86 g, 36.41 mmol, 2 eq and Pd(dppf)C12 (6 66.1 mg, 0.91 mmol, 0.05 eq . The reaction mixture was degassed and purged with N2 for 3 times. The solution was stirred at 110°C for 3 hr under N2. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate/Petroleum ether gradient @ 50 mL/min) to give intermediate 36A (1.7 g, 4.48 mmol, 24.6% yield) as a yellow solid. LCMS (ESI): RT = 0.914 min, mass calc, for CI5H8C1F3N4O 352.03, m/z found 352.9 [M+H]+; 1H NMR (400 MHz, CDCl3) 8 9.58 - 9.41 (m, 1H), 9.53 - 9.41 (m, 1H), 8.50 (d, J= 2.4 Hz, 1H), 8.17 (d, J= 2.4 Hz, 1H), 7.74 (d, J= 8.5 Hz, 2H), 7.32 (d, J= 8.5 Hz, 2H).
2-prop-2-ynoxy-5-[3-[4-(trifluoromethyl)phenoxy]pyrazin-2-yl]pyrimidine
[00306] To a solution of intermediate 36A (350 mg, 0.99 mmol, 1 eq) in MeCN (3 mL) was added 3 -(trimethyl silyl)prop-2-yn-l-ol (36B, 127.3 mg, 0.99 mmol, 0.1 mL, 1 eq) and K^CCL (411.5 mg, 2.98 mmol, 3.0 eq). The solution was stirred at 80°C for 16 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with H2O (40 mL) and extracted with EtOAc (45 mL x 3). The combined organic layers were washed with brine (45 mL), dried over Na2SO4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-15% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to afford Compound 36 (97.4 mg, 25.3% yield) as a white solid. LC-MS (ESI): RT = 0.946 min, mass calc, for C18H11F3N4O2 372.08, m/z found 373.0 [M+H]+; 1H NMR (400 MHz, CDCl3) 8 9.43 - 9.43 (m, 1H), 9.42 (s, 1H), 8.45 (d, J= 2.5 Hz, 1H), 8.10 (d, J= 2.5 Hz, 1H), 7.73 (d, J= 8.5 Hz, 2H), 7.31 (d, J= 8.3 Hz, 2H), 5.13 (d, J= 2.3 Hz, 2H), 2.51 (t, J= 2.4 Hz, 1H).
3-(2-chloropyrimidin-5-yl)-A-[4-(trifluoromethyl)phenyl]pyridin-2-amine
[00307] To a solution of intermediate 19B (300.0 mg, 0.95 mmol, 1.0 eq), (2- chloropyrimidin-5-yl)boronic acid (24A, 179.8 mg, 1.14 mmol, 1.2 eq) and K2CO3 (261.5 mg, 1.89 mmol, 2.0 eq) in dioxane (3 mL) and H2O (0.3 mL) was added Pd(dppf)C12 (6 9.2 mg, 94.6 pmol, 0.1 eq). The reaction mixture was degassed and purged with N2 for three times. The reaction mixture was stirred at 90 °C for 3 hr under N2 atmosphere. Crude intermediate 37A (330.0 mg, crude) was obtained as black oil, which was used for the next step without further purification. N-[4-(trifluoromethyl)phenyl]-3-(2-vinylpyrimidin-5-yl)pyridin-2-amine
[00308] To a solution of intermediate 37A (330.0 mg, 0.33 mmol, 1.0 eq), 4, 4,5,5- tetramethyl-2 -vinyl-1, 3, 2-dioxaborolane (24C, 60.8 mg, 0.40 mmol, 67 uL, 1.2 eq) and K2CO3 (91.0 mg, 0.66 mmol, 2.0 eq) in dioxane (1 mL) and H2O (0.1 mL) was added Pd(dppf)C12 (12.0 mg, 16 pmol, 0.05 eq). The reaction mixture was degassed and purged with N2 for three times. The
reaction mixture was stirred at 90 °C for 12 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: Welch Xtimate C18 150x25mmx5um; mobile phase: [water (0.05% NFLFLO+ I OmM NH4HCO3) - ACN]; B%: 55 %-85 %, 9.5 min) to afford Compound 37 (12.9 mg, 37.2 pmol, 11.2 % yield) as a yellow solid. LC-MS (ESI): RT = 0.849 min, mass calc, for C18H13F3N4 342.11, m/z found 343.0 [M+H]+; 1H NMR (400 MHz, DMSO-t/6) 8 8.95 - 8.80 (m, 2H), 8.67 (s, 1H), 8.30 (dd, J= 1.5, 4.8 Hz, 1H), 7.76 - 7.67 (m, 3H), 7.55 (d, J= 8.8 Hz, 2H), 7.09 (dd, J= 4.9, 7.4 Hz, 1H), 6.91 (dd, J= 10.4, 17.4 Hz, 1H), 6.61 (dd, J= 1.8, 17.6 Hz, 1H), 5.80 (dd, J= 1.8, 10.5 Hz, 1H).
5-bromo-2-vinyl-pyrimidine
[00309] To a solution of 5-bromo-2-chloropyrimidine (25A, 320 mg, 1.12 mmol, 1 eq) in dioxane (3 mL) and H2O (0.3 mL) was added intermediate 24C (207.6 mg, 1.35 mmol, 0.3 mL, 1.2 eq), Pd(dppf)C12 (41.1 mg, 56.2 pmol, 0.05 eq) and K2CO3 (310.5 mg, 2.25 mmol, 2.0 eq). The reaction mixture was degassed and purged with N2 for three times. The reaction mixture was stirred at 80°C for 16 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 100% Petroleum ether gradient @ 30 mL/min) to give intermediate 38A (110 mg, 0.56 mmol, 49.7% yield) as a colorless oil. LC-MS (ESI): RT = 0.699 min, mass calc, for C6H5BrN2 183.96, m/z found 186.7 [M+H]+.
5-[2-[4-(trifluoromethyl)phenoxy]-3-pyridyl]-2-vinyl-pyrimidine
[00310] To a solution of intermediate 38A (98.7 mg, 0.27 mmol, 1 eq) in dioxane (1 mL) and H2O (0.1 mL) was added 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-(4-
(trifluoromethyl)phenoxy)pyridine (38B, 50 mg, 0.27 mmol, 1 eq), Pd(dppf)C12 (19.8 mg, 27 pmol, 0.1 eq) and K2CO3 (74.7 mg, 0.54 mmol, 2.0 eq). The reaction mixture was degassed and purged
with N2 for three times. The reaction mixture was stirred at 90°C for 16 hrs under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with H2O (10 mL) and extracted with EtOAc (15 mL x3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4 , filtered and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: Welch Xtimate Cl 8 150x25mmx5um; mobile phase: [water (0.05% HC1)-ACN]; B%: 50%-80%, 8.5min) to afford Compound 38 (17.7 mg, 17.1% yield, HC1) as a yellow solid. LC-MS (ESI): RT = 0.968 min, mass calc, for C18H12F3N3O 343.09, m/z found 344.2 [M+H]+; 1H NMR (400 MHz, CDCl3) 8 9.07 (s, 2H), 8.26 (d, J= 4.0 Hz, 1H), 7.87 (br d, J= 6.8 Hz, 1H), 7.68 (d, J= 8.5 Hz, 2H), 7.26 - 7.21 (m, 2H), 7.03 (dd, J= 10.5, 17.3 Hz, 1H), 6.77 (dd, J= 1.4, 17.2 Hz, 1H), 5.88 (dd, J= 1.3, 10.5 Hz, 1H), 4.93 (br s, 1H).
Example 39: (E)-A-(4-(Trifluoromethyl)phenyl)-3-(2-(3,3,3-trifluoroprop-l-en-l- yl)pyrimidin-5-yl)pyrazin-2-amine (Compound 39)
[00311] To a solution of Compound 26 (120 mg, 0.35 mmol, 1 eq) and 3, 3 -dimethyl- 1-
(trifhioromethyl)-l,3-dihydro-113-benzo[d][l,2]iodaoxole (39A, 288.5 mg, 0.87 mmol, 2.5 eq) in DMF (0.5 mL) were added DBU (106.4 mg, 0.70 mmol, 0.11 mL, 2 eq) and Cu(MeCN)4PF6 (26.1 mg, 69.9 pmol, 0.2 eq). The reaction mixture was stirred at 60 °C for 6 hrs. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: Waters Xbridge 150x25mmx 5um; mobile phase: [water (0.05%NH3H20)-ACN]; B%: 57%-87%, 9.5 min) to give the title compound (12 mg, yellow solid) to afford Compound 39(5.9 mg, 4.1% yield) as a yellow solid. LC-MS (ESI): RT = 1.009 min, mass calc, for C18H11F6N5 411.09, m/z found 412.3 [M+H]+; 1H NMR (400 MHz, CDCl3) 6 9.19 (s, 2H), 8.29 (d, J= 6.3 Hz, 2H), 7.59 (s, 4H), 7.39 - 7.31 (m, 1H), 7.25 - 7.14 (m, 1H), 6.67 (s, 1H)
Example 40: (E)-5-(3-(4-(Trifluoromethyl)phenoxy)pyrazin-2-yl)-2-(3,3,3-trifluoroprop-l-en- l-yl)pyrimidine (Compound 40)
2-methyl-5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) pyrimidine
[00312] A mixture of 5-bromo-2-methylpyrimidine (40A, 5 g, 28.90 mmol, 1 eq), 4D (8.81 g, 34.68 mmol, 1.2 eq), Pd(dppf)Cl2 (2.11 g, 2.89 mmol, 0.1 eq), KOAc (4.25 g, 43.35 mmol, 1.5 eq) in dioxane (50 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90 °C for 16 hr under N2 atmosphere. The residue was poured into H2O (50 mL) and stirred for 5 min. The aqueous phase was extracted with EtOAc (30 mL x 3). The combined organic phase was washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give intermediate 40B (6 .2 g, crude) as a yellow solid. The crude intermediate 40B was used for next step without further purification.
2-chloro-3-(2-methylpyrimidin-5-yl) pyrazine
[00313] A mixture of intermediate 40B (6 .1 g, 27.72 mmol, 1 eq), 2,3 -di chloropyrazine (4.96 g, 33.26 mmol, 1.2 eq), Pd(dppf)Cl2 (1.01 g, 1.39 mmol, 0.05 eq), K2CO3 (5.75 g, 41.58 mmol, 1.5 eq) in dioxane (50 mL) and H2O (10 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90 °C for 3 hr under N2 atmosphere. The reaction mixture was diluted with H2O (80 mL) and stirred for 5 min. The aqueous phase was extracted with EtOAc (50 mL x 3). The combined organic phase was washed with brine (60 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (40 g SepaFlash® Silica Flash Column, EtOAc/PE: 0-30%) to give intermediate 40C (4.8 g, 21.37 mmol, 77% yield) as a yellow solid.
2-(bromomethyl)-5-(3-chloropyrazin-2-yl) pyrimidine
[00314] A mixture of intermediate 40C (1.5 g, 7.26 mmol, 1 eq), NBS (1.55 g, 8.71 mmol, 1.2 eq), AIBN (238.4 mg, 1.45 mmol, 0.2 eq) in CCU (10 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 70 °C for 16 hr under N2 atmosphere. The reaction mixture was diluted with H2O (50 mL) and stirred for 5 min. The aqueous phase was extracted with EtOAc (30 mL x 3). The combined organic phase was washed with brine (40 mL), dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (20 g SepaFlash® Silica Flash Column, EtOAc/PE: 0-30%) to give intermediate 40D (318 mg, 1.08 mmol, 15% yield) as a yellow solid.
2-chloro-3-[2-(diethoxyphosphorylm ethyl) pyrimidin-5-yl] pyrazine
[00315] To a solution of intermediate 40D (280 mg, 0.98 mmol, 1 eq) and triethyl phosphite (195.5 mg, 1.18 mmol, 0.20 mL, 1.2 eq) in MeCN (3 mL) and the reaction mixture was stirred at 100 °C for 3 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent to give intermediate 40E (318 mg, crude) as a yellow oil. The crude intermediate 40E was used for next step without further purification.
2-chloro-3-[2-[(E)-3, 3, 3-trifluoroprop-l-enyl] pyrimidin-5-yl] pyrazine
[00316] To a solution of intermediate 40E (285 mg, 0.83 mmol, 1 eq) in THF (3 mL) was added NaOMe (6 7.4 mg, 1.25 mmol, 1.5 eq). After addition, the reaction mixture was stirred at this temperature for 0.5 hr, and then 2,2,2-trifluoroacetaldehyde (174.7 mg, 1.25 mmol, 1.5 eq) was added. The resulting mixture was stirred at 25 °C for 2.5 hr. The reaction mixture was diluted with H2O (30 mL) and stirred for 5 min. The aqueous phase was extracted with EtOAc (15 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (12 g SepaFlash® Silica Flash Column, EtOAc/PE: 0-20%) to give intermediate 40F (156 mg, 0.54 mmol, 65.5% yield) as a yellow solid.
2-chloro-3-[2-[(E)-3, 3, 3-trifluoroprop-l-enyl] pyrimidin-5-yl] pyrazine
[00317] To a solution of intermediate 40F (120 mg, 0.42 mmol, 1 eq) in DMF (2 mL) were added 4-(trifluoromethyl)phenol (40G, 74.7 mg, 0.46 mmol, 1.1 eq), CS2CO3 (204.6 mg, 0.63 mmol, 1.5 eq). The reaction mixture was stirred at 110 °C for 3 hr. The reaction mixture was diluted with H2O (30 mL) and stirred for 5 min. The aqueous phase was extracted with EtOAc (15
mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mmx 5um; mobile phase: [water (0.04%NH3H20+10mM NH4HCO3)- ACN]; B%: 63%-73%, 9.5min) to afford Compound 40 (36.7 mg, 21.3% yield) as a white solid. LC-MS (ESI): RT = 0.981 min, mass calcd for CI8HIOF6N40 412.08, m/z found 412.9 [M+H]+; 1H NMR (400 MHz, CD3OD) 8 9.59 (s, 2H), 8.53 (d, J= 2.5 Hz, 1H), 8.20 (d, J= 2.3 Hz, 1H), 7.78 (d, J= 8.5 Hz, 2H), 7.46 (d, J= 8.5 Hz, 2H), 7.38 - 7.20 (m, 2H).
Example 41: 5-(3-((4-(pentafluoro-k6-sulfaneyl)phenyl)thio)pyrazin-2-yl)pyrimidin-2-ol
4-(pentafluoro-sulfanyl)benzenethiol
[00318] To a solution of pentafluoro(4-fluorophenyl)-X6-sulfane (41A, 0.15 g, 0.67 mmol,
1 eq) in DMF (4 mL) was added Na2S (131.7 mg, 1.6 mmol, 70.8 uL, 2.5 eq). The reaction mixture was stirred at 120 °C for 0.5 hr under the microwave. The reaction mixture was quenched by addition NaOH (2 M, 15 mL), and then washed with EtOAc (20 mL). The pH of the aqueous phase was adjusted with HC1 (2M) to 2-3, and then extracted with DCM (15 x 2). The combined organic layers were dried overNa2SO4 , filtered and concentrated under reduced pressure to give a residue. The crude intermediate 4 IB was used into the next step without further purification. pentafluoro-[4-[3-(2-methoxypyrimidin-5-yl)pyrazin-2-yl]sulfanylphenyl]-sulfane
[00319] To a solution of intermediate 41B (56.5 mg, 0.25 mmol, 1 eq) in DMF (6 mL) was added CS2CO3 (165.5 mg, 0.5 mmol, 2.0 eq) and 5-(3-chloropyrazin-2-yl)-2 -methoxypyrimidine (41C, 60 mg, 0.25 mmol, 1.0 eq). The reaction mixture was stirred at 100 °C for 1 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether/Ethyl acetate = 100/1 to 5/1) to give intermediate 41D (6 0 mg, 0.14 mmol, 55.9% yield) as a white solid. LCMS (ESI): RT = 0.950 min, mass calcd for C15H11F5N4OS2 422.03 m/z found 423.2 [M+H]+.
5-[3-[4-(pentafluoro-sulfanyl)phenyl]sulfanylpyrazin-2-yl]pyrimidin-2-ol
[00320] A solution of intermediate 41D (6 0 mg, 0.14 mmol, 1 eq) in HBr/AcOH (0.24 mmol, 3 mL) was stirred at 25 °C for 16 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75x30mmx3um; mobile phase: [water (0.05%HCl)-ACN]; B%: 30%-60%, 6.5min) to afford Compound 41 (4.3 mg, 7.3% yield) as a white solid. LC-MS (ESI): RT = 0.817 min, mass calcd for: C14H9F5N4OS2 408.01 m/z found 409.2[M+H]+; 1H NMR (400 MHz, DMSO4) 8 12.45 (s, 1H), 8.69 (s, 2H), 8.56 (d, J= 2.5 Hz, 1H), 8.45 (d, J= 2.5 Hz, 1H), 7.94 (d, J= 8.8 Hz, 2H), 7.70 (d, J= 8.5 Hz, 2H).
Example 42: 2-Methoxy-5-(3-(4-(pentafluoro-k6-sulfaneyl)phenoxy)pyrazin-2-yl)pyrimidine
[4-(3-chloropyrazin-2-yl)oxyphenyl]-pentafluoro-sulfane
[00321] To a solution of 2,3-dichloropyrazine (42A, 500 mg, 3.3 mmol, 1 eq) in DMF (6 mL) was added K2CO3 (927.6 mg, 6.7 mmol, 2.0 eq) and 4-(pentafluoro-X6-sulfaneyl)phenol (738.9 mg, 3.3 mmol, 1.0 eq). The reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography (SiCh, Petroleum ether/Ethyl acetate = 100/1 to 1/1) to give intermediate 42B (0.6 g, 1.80 mmol, 53.74% yield) as a white solid. pentafluoro-[4-[3-(2-methoxypyrimidin-5-yl)pyrazin-2-yl]oxyphenyl]-sulfane [00322] To a solution of intermediate 42B (300 mg, 0.90 mmol, 1 eq) and (2- methoxypyrimidin-5-yl)boronic acid (42C, 152.6 mg, 0.99 mmol, 1.1 eq) in dioxane (4 mL) and H2O (1 mL) was added Pd(dppf)C12 (6 5.9 mg, 90.1 pmol, 0.1 eq) and Na2CO3 (286.7 mg, 2.71 mmol, 3.0 eq). The reaction mixture was stirred at 90 °C for 16 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography (SiO2, Petroleum ether/Ethyl acetate = 100/1 to 1/1) to afford Compound 42 (250 mg, 68.2% yield) as a white solid. 50 mg of the compound was additionally purified by
prep-HPLC (column: Welch Xtimate Cl 8 150x25mmx5um;mobile phase: [water(0.05%HCl)- ACN];B%: 50%-80%,8.5min) to afford the desired Compound 42 (9.91 mg) as a white solid. LC- MS (ESI): RT = 0.955 min, mass calcd for C15H11F5N4O2S 406.05 m/z found 407.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.36 (s, 2H), 8.46 (d, J= 2.3 Hz, 1H), 8.09 (d, J= 2.5 Hz, 1H), 7.85 (d, J= 9.0 Hz, 2H), 7.29 (d, J= 9.0 Hz, 2H), 4.14 - 4.05 (m, 3H).
Example 43: 5-(3-(4-(pentafluoro-k6-sulfaneyl)phenoxy)pyrazin-2-yl)pyrimidin-2-ol
[00323] A solution of Compound 42(100 mg, 0.24 mmol, 1 eq) in HBr/AcOH (0.24 mmol, 3 mL) was stirred at 25 °C for 16 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: Welch Xtimate C18 150x25mmx5um;mobile phase: [water(0.05%HCl)-ACN];B%: 40%-70%,8.5min) to afford Compound 43 (29.7 mg, 30.8% yield) as a white solid. LC-MS (ESI): RT = 0.824 min, mass calcd for C14H9F5N4O2S 392.04 m/z found 393.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 8 9.02 (s, 2H), 8.48 (d, J= 2.8 Hz, 1H), 8.14 (d, J= 2.5 Hz, 1H), 8.05 - 7.99 (m, 2H), 7.53 (d, J= 9.0 Hz, 2H).
Example 44: 2-Methoxy-5-(3-((4-((trifluoromethyl)thio)phenyl)thio)pyrazin-2-yl)pyrimidine
(Compound 44) and 5-(3-((4-((trifluoromethyl)thio)phenyl)thio)pyrazin-2-yl)pyrimidin-2-ol
4-[3-(2-Methoxypyrimidin-5-yl)pyrazin-2-yl]sulfanylaniline
[00324] To a solution of 5-(3-chloropyrazin-2-yl)-2-methoxypyrimidine (45B, 200 mg, 0.90 mmol, 1 eq and 4-aminobenzenethiol (168.7 mg, 1.35 mmol, 1.5 eq in DMF (2 mL) was added CS2CO3 (585.4 mg, 1.80 mmol, 2 eq . The reaction mixture was stirred at 100 °C for 2 hrs. The reaction mixture was diluted with H2O (15 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous ISfeSCU, filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate/Petroleum ether gradient @ 35 mL/min) to give intermediate 44A (240 mg, 0.74 mmol, 82.3% yield) as a red solid. LC-MS (ESI): RT = 0.714 min, mass calc, for C15H13N5OS 311.08, m/z found 312.2 [M+H]+; XH NMR (400 MHz, CDCl3) 8 9.00 (s, 2H), 8.31 (d, J= 2.5 Hz, 1H), 8.27 (d, J= 2.5 Hz, 1H), 7.29 (s, 2H), 6.74 - 6.68 (m, 2H), 4.12 (s, 3H), 3.89 (br s, 2H).
Tetrafluoro-[4-[3-(2-methoxypyrimidin-5-yl)pyrazin-2-yl]sulfanylphenyl]iminoiminio-boron [00325] To a solution of intermediate 44A (120 mg, 0.39 mmol, 1 eq) in DCM (1.5 mL) was added BF3 Et2O (114.9 mg, 0.81 mmol, 99.9 pL, 2.1 eq). The reaction mixture was stirred at 25 °C for 5 min. THF (1 mL) was added into the reaction mixture. The reaction mixture was cooled to - 20 °C and tert-butyl nitrite (39.7 mg, 0.39 mmol, 46 uL, 1 eq in DCM (0.5 mL) was added into the reaction mixture. The reaction mixture was stirred at 0 °C for 0.5 hr. Brown solid formed. The reaction mixture was filtered, and the filter cake was washed with DCM give intermediate 44B (120 mg, crude) as a brown solid. The crude intermediate 44B was used into the next step without further purification.
2-Methoxy-5-[3-[4-(trifluoromethylsulfanyl)phenyl]sulfanylpyrazin-2-yl]pyrimidine [00326] To a mixture of intermediate 44B (120 mg, 0.29 mmol, 1 eq) and (trifluoromethylthio) silver (91.7 mg, 0.44 mmol, 1.5 eq) in acetonitrile (2 mL) were added Cui (55.7 mg, 0.29 mmol, 1 eq) and K2CO3 (80.9 mg, 0.59 mmol, 2 eq). The reaction mixture was stirred at 25 °C for 16 hr. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrousNa2SO4 , filtered and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75x30mmx3um; mobile phase: [water (0.05%HCl)-ACN]; B%: 45%-75%, 8.5 min) to afford Compound 44 (25 mg, 21.3% yield) as a white solid. LC-MS (ESI): RT = 0.714 min, mass calc, for C16H11F3N4OS2 396.03, m/z found 397.0 [M+H]+; 1H NMR (400 MHz, CDCl3) 8 8.99 (s, 2H), 8.44 (d, ./=2,5 Hz, 1H), 8.32 (d, ,/=2.5 Hz, 1H), 7.68 (d, J=8.3 Hz, 2H), 7.54 (d, J=8.5 Hz, 2H), 4.13 (s, 3H).
5-[3-[4-(Trifluoromethylsulfanyl)phenyl]sulfanylpyrazin-2-yl]pyrimidin-2-ol
[00327] A solution of Compound 44 (20 mg, 50.5 pmol, 1 eq) in HCl/di oxane (1 mL) was stirred at 70 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75x30mmx3um; mobile phase: [water (0.05%HCl)-ACN]; B%: 30%-60%, 6.5 min) to give Compound 44a (3.6 mg, 18.4% yield) as a white solid. LC-MS (ESI): RT = 0.818 min, mass calc, for C15H9F3N4OS2 382.02, m/z found 383.0 [M+H]+; 1H NMR (400 MHz, DMSO4) 6 8.73 (s, 2H), 8.55 (d, J= 2.3 Hz, 1H), 8.44 (d, J= 2.3 Hz, 1H), 7.74 (br d, J= 8.3 Hz, 2H), 7.62 (d, J= 8.3 Hz, 2H).
Example 45: 5-(3-(4-((Trifluoromethyl)thio)phenoxy)pyrazin-2-yl)pyrimidin-2-ol
5-(3-Chloropyrazin-2-yl)-2-methoxypyrimidine
[00328] A solution of 2,3 -di chloropyrazine (42A, 5.8 g, 38.98 mmol, 1.2 eq), (2- methoxypyrimidin-5-yl)boronic acid (45A, 5.0 g, 32.48 mmol, 1.0 eq), Pd(dppf)C12 (2.4 g, 3.25 mmol, 0.1 eq) and Na2CO 3 (6 .9 g, 64.96 mmol, 2.0 eq) in dioxane (50 mL) and H2O (5 mL) at
30 °C was purged and degassed with N2 for 3 times and then stirred at 90 °C under N2 for 16 hrs. The reaction mixture was quenched with water (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with H2O (50 mL) and brine (50 mL), dried over anhydrousNa2SO4 , filtered and concentrated under reduced pressure to give intermediate 45B (2.8 g, 11.81 mmol, 36.4% yield) as a white solid. LC-MS (ESI): RT = 0.712 min, mass calc, for C9H7CIN4O 222.03, m/z found 223.1 [M+H]+.
5-(3-Chloropyrazin-2-yl)pyrimidin-2-ol
[00329] A solution of intermediate 45B (1.0 g, 4.49 mmol, 1 eq) in HCl/dioxane (4 M, 10.0 mL, 8.91 eq) was stirred at 80 °C for 16 hrs. The reaction mixture was concentrated under reduced pressure to give intermediate 45C (930.0 mg, 4.41 mmol, 98.3% yield) as a brown solid.
5-(3-(4-((Trifluoromethyl)thio)phenoxy)pyrazin-2-yl)pyrimidin-2-ol
[00330] To a solution of 4-(pentafluoro-X6-sulfaneyl)phenol (51.2 mg, 0.26 mmol, 1.1 eq in DMSO (1 mL) was added intermediate 45C (50.0 mg, 0.24 mmol, 1.0 eq and CS2CO3 (117.1 mg, 0.36 mmol, 1.5 eq . The reaction mixture was stirred at 110 °C for 4 hrs. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC: (column: 3_Phenomenex Luna C18 75x30mmx3um; mobile phase: [water(0.05%HCl)-ACN];B%: 30%-60%, 6.5 min) to afford Compound 55 (270.0 mg, 46.8% yield) as a yellow oil. LCMS (ESI): RT = 0.827 min, mass calc, for C15H9F3N4O2S 366.04, m/z found 367.2 [M+H]+; 1H NMR (400 MHz, DMSO-t/6) 8 9.03 (brs, 2H), 8.47 (brs, 1H), 8.15 (brd, J= 1.8 Hz, 1H), 7.82 (brd, J= 8.3 Hz, 2H), 7.47 (brd, J= 8.4 Hz, 2H).
Example 46: 5-(3-((4-(Trifluoromethoxy)phenyl)thio)pyrazin-2-yl)pyrimidin-2-ol
5-(3-((4-(trifluoromethoxy)phenyl)thio)pyrazin-2-yl)pyrimidin-2-ol
[00331] To a solution of 4-(trifluoromethoxy)benzenethiol (69.8 mg, 0.36 mmol, 1.5 eq) in
DMSO (1 mL) was added intermediate 45C (50.0 mg, 0.24 mmol, 1.0 eq) and CS2CO3 (117.1 mg, 0.36 mmol, 1.5 eq). The solution was stirred at 110 °C for 4 hrs. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75x30mmx3um; mobile phase: [water(0.05%HCl)-ACN]; B%: 25%-55%, 6.5 min) to afford Compound 46 (17.55 mg, 19.8% yield) as a white solid. LC-MS (ESI): RT = 0.797 min, mass calc, for C15H9F3N4O2S 366.04, m/z found 367.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 8 8.74 (s, 2H), 8.50 (d, J= 2.5 Hz, 1H), 8.39 (d, J= 2.5 Hz, 1H), 7.66 - 7.62 (m, 2H), 7.44 (d, J= 8.0 Hz, 2H).
2-methoxy-5-[2-[4-(trifluoromethyl)phenyl]sulfanyl-3-pyridyl]pyrimidine
[00332] To a solution of 3-bromo-2-((4-(trifluoromethyl)phenyl)thio)pyridine (47A, 100 mg, 0.30 mmol, 1 eq) and (2-methoxypyrimidin-5-yl)boronic acid (45A, 55.3 mg, 0.36 mmol, 1.2 eq) in dioxane (2 mL) and H2O (0.2 mL) were added Pd(dppf)C12 (21.9 mg, 29.93 pmol, 0.1 eq) and Na2CO 3 (6 3.4 mg, 0.60 mmol, 2.0 eq) in one portion with N2 for 3 times. The reaction mixture was stirred at 100 °C for 5 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with H2O (6 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by prep-TLC (PE:EtOAc = 5: 1) to give intermediate 47B (21 mg, 36.9 pmol, 12.3% yield) as a yellow solid. LC-MS (ESI): RT = 0.877 min, mass calcd. For C17H12F3N3OS, 363.07 m/z found 363.9 [M+H]+. XH NMR (400 MHz, CDCl3) 6 4.10 (s, 3H) 7.21 - 7.26 (m, 2H) 7.48 - 7.56 (m, 3H) 7.57 - 7.63 (m, 2H) 8.45 (dd, J= 4.77, 1.76 Hz, 1H) 8.62 (s, 2 H) 8.94 (s, 1H).
5- [2- [4-(trifluoromethyl)phenyl] sulfanyl-3-pyridyl] pyrimidin-2-ol
[00333] To a solution of intermediate 47B (21 mg, 57.7 pmol, 1 eq) was added HCl/dioxane (2 mL) in one portion at 25 °C for 18 hrs, and at 60 °C for 19 hr. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75x30mmx3um; mobile phase: [water (0.05%HCl)-ACN]; B%: 25%- 55%, 6.5 min) to afford Compound 47 (3.7 mg, 18.3% yield). LC-MS (ESI): RT = 0.723 min, mass calcd. For C16H10F3N3OS, 349.05 m/z found 349.9 [M+H]+. XH NMR (400 MHz, CD3OD) 8 7.44 (dd, J= 7.65, 4.89 Hz, 1H) 7.56 (d, J= 8.03 Hz, 2H) 7.63 - 7.68 (m, 2 H) 7.86 (dd, J= 7.78, 1.76 Hz, 1H) 8.48 (br d, J= 3.26 Hz, 1H) 8.81 (br s, 2H).
2-methoxy-5- [2- [4-(trifluoromethyl)phenoxy]-3-pyridyl] pyrimidine
[00334] To a solution of 5-bromo-2-methoxypyrimidine (124.2 mg, 0.66 mmol, 1.2 eq) and intermediate 38B (200 mg, 0.55 mmol, 1 eq) in dioxane (4 mL) and H2O (0.4 mL) were added Pd(dppf)C12 (80.1 mg, 0.11 mmol, 0.2 eq) and Na2CO 3 (116.1 mg, 1.10 mmol, 2.0 eq) in one portion with N2 for 3 times and the reaction mixture was stirred at 100 °C for 4 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with H2O (10 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give intermediate 48A (95 mg, 0.26 mmol, 48.4% yield) as a white solid. LCMS (ESI): RT = 0.869 min, mass calcd. For C17H12F3N3O2, 347.09 m/z found 347.9 [M+H]+. XH NMR (400 MHz, CDCl3) 6 1.25 (s, 3 H) 4.08 (s, 3 H) 7.26 (s, 3 H) 7.67 (d, J= 8.53 Hz, 2 H) 7.81 (dd, J= 7.53, 1.76 Hz, 1 H) 8.21 (dd, J= 5.02, 1.76 Hz, 1 H) 8.82 (s, 2 H).
5-[2-[4-(trifluoromethyl)phenoxy]-3-pyridyl]pyrimidin-2-ol
[00335] To a solution of intermediate 48A (50 mg, 143.97 pmol, 1 eq) was added
HCl/di oxane (2 mL) in one portion at 60°C for 17 hr. The reaction mixture was concentrated under
reduced pressure to give a residue, which was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75x30mmx3um; mobile phase: [water (0.05%HCl) -ACN]; B%: 25%-55%, 6.5min) to afford Compound 48 (5.1 mg, 10.7% yield). LC-MS (ESI): RT = 0.728 min, mass calcd. For C16H10F3N3O2, 333.07 m/z found 333.9 [M+H]+. 1H NMR (400 MHz, CD3OD) 8 7.30 (dd, J= 7.53, 5.02 Hz, 1H) 7.36 (d, J= 8.53 Hz, 2H) 7.74 (d, J= 8.53 Hz, 2H) 8.05 (br d, J= 7.53 Hz, 1H) 8.16 (br d, J= 3.76 Hz, 1H) 9.02 (br s, 2H).
[00336] To a solution of intermediate 19B (100 mg, 0.31 mmol, 1 eq) and 5-bromo-2- methoxypyrimidine (58.2 mg, 0.38 mmol, 1.2 eq) in dioxane (2 mL) and H2O (0.2 mL) were added Pd(dppf)C12 (46.1 mg, 63 pmol, 0.2 eq) and Na2CO 3 (6 6.8 mg, 0.63 mmol, 2.0 eq) in one portion with N2 for 3 times. And the reaction mixture was stirred at 100 °C for 2 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with H2O (6 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4 , filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to afford Compound 49 (42 mg, 37.6% yield) was obtained as a white solid. LC-MS (ESI): RT = 0.816 min, mass calcd. For C17H13F3N4O, 346.10 m/z found 346.9 [M+H]+. 1H NMR (400 MHz, CDCl3) 6 4.11 (s, 3H) 6.41 (s, 1H) 6.92 - 7.02 (m, 1H) 6.99 (dd, J= 7.40, 4.89 Hz, 1H) 7.46 (dd, J= 7.28, 1.76 Hz, 1H) 7.51 - 7.57 (m, 2H) 7.57 - 7.65 (m, 2H) 8.35 (dd, J= 4.89, 1.63 Hz, 1H) 8.64 (s, 2H).
[00337] To a solution of 2-(2-methoxypyrimidin-5-yl)pyridin-3-amine (50A, 35 mg, 0.17 mmol, 1 eq), l-iodo-4-(trifluoromethyl)benzene (70.6 mg, 0.26 mmol, 38 uL, 1.5 eq) and CS2CO3 (169.2 mg, 0.52 mmol, 3 eq) in dioxane (1 mL) at 20°C was added Pd2(dba)3 (7.9 mg, 8.7 pmol, 0.05 eq) and X-Phos (8.3 mg, 17.3 pmol, 0.1 eq), and the reaction mixture was purged and degassed with N2 for 3 times and then stirred at 100°C under N2 for 16 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (20 mL) and EtOAc (10 mL), and then filtered to remove the solid. The filtrate was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrousNa2SO4 , filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate/Petroleum ether gradient @ 20 mL/min) to afford Compound 50 (50 mg, 83.4% yield) as a yellow solid. LC-MS (ESI): RT = 0.775 min, mass calc, for C17H13F3N4O 346.10, m/z found 346.9 [M+l]+; 1H NMR (400 MHz, CDCl3) 8 8.89 (s, 2H), 8.49 (dd, J= 1.3, 4.6 Hz, 1H), 7.75 (dd, J= 1.1, 8.1 Hz, 1H), 7.51 (d, J= 8.5 Hz, 2H), 7.32 (dd, J= 4.6, 8.3 Hz, 1H), 6.95 (d, J= 8.5 Hz, 2H), 5.73 (s, 1H), 4.06 (s, 3H).
Example 51 : 2-(6-methoxypyridin-3-yl)-3-((4-(trifluoromethyl)phenyl)thio)pyrazine
[00338] To a mixture of 2-chl oro-3 -(6-m ethoxypyri din-3 -yl)pyrazine (51A, 100 mg, 0.45 mmol, 1 eq) and 4-(trifluoromethyl)benzenethiol (96.5 mg, 0.54 mmol, 1.2 eq) in DMF (2 mL) at 30°C was added K2CO3 (187.1 mg, 1.35 mmol, 3 eq). And the reaction mixture was degassed and purged with N2 for 3 times, and the reaction mixture was stirred at 80°C for 2 h under N2. The
reaction mixture was diluted with water (10 mL), and then extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous ISfeSCU and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to afford Compound 51 (120 mg, 71.7% yield) as a white solid. LC-MS (ESI): RT = 0.928 min, mass calc, for C17H12F3N3OS 363.07, m/z found 364.0 [M+l]+; 1H NMR (400 MHz, CDCI3) 8 8.64 (d, J= 2.5 Hz, 1H), 8.40 (d, J= 2.5 Hz, 1H), 8.25 (d, J= 2.5 Hz, 1H), 8.01 (dd, J= 2.5, 8.8 Hz, 1H), 7.63 (q, J= 8.4 Hz, 4H), 6.90 (d, J= 8.5 Hz, 1H), 4.04 (s, 3H).
[00339] A mixture of (6-m ethoxy-3 -pyridyl)boronic acid (95.0 mg, 0.62 mmol, 1.2 eq), intermediate 47A (173.0 mg, 0.51 mmol, 1 eq), CS2CO3 (506.1 mg, 1.55 mmol, 3 eq), Pd(dppf)C12 (37.8 mg, 51.7 pmol, 0.1 eq) in dioxane (2 mL) and H2O (0.1 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90 °C for 16 hr under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrousNa2SO4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-10% PE/EtOAc@ 35 mL/min) to afford Compound 52 (7.1 mg, 17% yield) was obtained as white solid. LC-MS (ESI): RT = 1.026 min, mass calcd for C18H13F3N2OS 362.37 m/z found 363.2 [M+H]+. 1H NMR (400 MHz, CD3OD) 8 3.96 (s, 3 H) 6.90 (d, J= 8.28 Hz, 1 H) 7.36 (dd, J= 7.65, 4.89 Hz, 1 H) 7.49 (d, J= 8.03 Hz, 2 H) 7.60 (d, J= 8.28 Hz, 2 H) 7.71 (dd, J= 7.53, 1.76 Hz, 1 H) 7.81 (dd, J= 8.66, 2.38 Hz, 1 H) 8.17 (d, J= 2.26 Hz, 1 H) 8.39 (dd, J= 4.89, 1.63 Hz, 1 H).
Example 53: 6'-Methoxy-2-(4-(trifluoromethyl)phenoxy)-3,3'-bipyridine (Compound 53)
2-methoxy-5- [2- [4-(trifluoromethyl)phenoxy]-3-pyridyl] pyridine
[00340] A mixture of 5-bromo-2-methoxy-pyridine (53A, 100 mg, 0.53 mmol, 68.9 uL, 1 eq), intermediate 38B (213.6 mg, 0.58 mmol, 1.1 eq), Pd(dppf)C12 (19.4 mg, 26.5 pmol, 0.05 eq), CS2CO3 (519.8 mg, 1.60 mmol, 3 eq) in dioxane (1 mL) and H2O (0.5 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90 °C for 16 hr under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-10% PEZEtOAc @ 35mL/min) to afford Compound 53 (9.83 mg, 19% yield) as a white solid. LC-MS (ESI): RT = 0.827 min, mass calcd for C17H11F3N2O2 332.28 m/z found 333.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 8 6.44 - 6.49 (m, 1 H) 7.26 (dd, J= 7.53, 4.77 Hz, 1 H) 7.37 (d, J= 8.28 Hz, 2 H) 7.78 (br d, J= 8.53 Hz, 3 H) 7.84 (dd, J= 9.41, 2.89 Hz, 1 H) 7.97 (dd, J= 7.53, 1.76 Hz, 1 H) 8.09 (dd, J= 4.89, 1.88 Hz, 1 H).
[00341] A mixture of 2-bromo-3-[4-(trifluoromethyl)phenoxy]pyridine (54A, 100 mg, 0.31 mmol, 1 eq), (6-methoxy-3-pyridyl)boronic acid (72.1 mg, 0.47 mmol, 1.5 eq), CS2CO3 (307.2 mg, 0.94 mmol, 3 eq), Pd(dppf)C12 (11.5 mg, 15.7 pmol, 0.05 eq) in dioxane (2 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90 °C for 16 hr under N2
atmosphere. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 25 g SepaFlash® Silica Flash Column, Eluent of 0-20% PEZEtOAc@ 35 mL/min) to afford Compound 54 (7.6 mg, 6.2% yield, HC1) was obtained as a white solid. LC-MS (ESI): RT = 0.941 min, mass calcd for C18H13F3N2O2 346.30 m/z found 347.1 [M+H]+. 1H NMR (400 MHz, CD3OD) 8 ppm 3.98 (s, 3 H) 6.98 (d, J= 8.78 Hz, 1 H) 7.25 (d, J= 8.53 Hz, 2 H) 7.30 (dd, J= 7.40, 4.89 Hz, 1 H) 7.68 (d, J= 8.53 Hz, 2 H) 7.97 (dd, J= 7.53, 1.76 Hz, 1 H) 8.08 (dd, J = 8.66, 2.38 Hz, 1 H) 8.14 (dd, J= 4.89, 1.88 Hz, 1 H) 8.42 (d, J= 2.26 Hz, 1 H).
Example 55: 6'-methoxy-N-(4-(trifluoromethyl)phenyl)-[2,3'-bipyridin]-3-amine (Compound
2-(6-Methoxy-3-pyridyl)-N- [4-(trifluoromethyl)phenyl] pyridin-3-amine (Compound 55) [00342] A mixture of 3 -bromo-2-(6-m ethoxy-3 -pyridyl)pyri dine (55A, 200 mg, 0.75mmol, 1 eq) , 4-(trifluoromethyl)aniline (145.8 mg, 0.90mmol, O.lmL, 1.2 eq , Pd2(dba)3 (34.5 mg, 37.7 pmol, 0.05 eq), Xantphos (43.6 mg, 75.4 pmol, 0.1 eq and t-BuOK (253.9 mg, 2.26 mmol, 3 eq in toluene (2 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 110 °C for 10 hr under N2 atmosphere. The reaction mixture was diluted with H2O (5 mL) and the reaction mixture was extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous ISfeSCU, filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 40 g SepaFlash ® Silica Flash Column, Eluent of 0-50% PEZEtOAc@ 35 mL/min) to afford Compound 55 (150 mg, 52.9% yield) as a yellow solid. LC-MS (ESI): RT = 0.818 min, mass calcd for C18H14F3N3O 345.32 m/z found 346.2 [M+H]+. XH NMR (400 MHz, CDCl3) 8 3.90 - 3.94 (m, 1H) 3.92 (s, 2H)
5.97 (br s, 1H) 6.83 (br s, 1H) 7.03 (br s, 2H) 7.34 (br s, 1H) 7.49 (br d, J= 5.38 Hz, 2H) 7.78 -
7.98 (m, 2H) 8.36 (br s, 1H) 8.50 (br s, 1H).
5-[3-[4-(Trifluoromethyl)phenyl]sulfanyl-2-pyridyl]pyridin-2-ol (Compound 55a) [00343] The mixture of Compound 55 (80 mg, 231.67 pmol, 1 eq) and HCl/dioxane (4 M, 3 mL, 51.80 eq) was stirred at 70 °C for 4 hr. The reaction mixture was diluted with H2O (3 mL) and the reaction mixture was adjusted pH to 8 with NaOH (4 M).The reaction mixture was extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (10 mL x 3), dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75x30mmx3um; mobile phase: [water (0.05%HCl)-ACN];B%: 20%-50%,6.5min) to afford Compound 55a as a yellow solid. LC-MS (ESI): RT = 0.753 min, mass calcd for C17H12F3N3O 331.29 m/z found 332.2 [M+H]+. 1H NMR (400 MHz, CD3OD ) 8 6.64 (d, J= 9.54 Hz, 1H) 7.20 (d, J= 8.28 Hz, 2H) 7.58 (d, J= 8.53 Hz, 2H) 7.76 (dd, J= 8.53, 5.52 Hz, 1H) 7.84 (dd, J= 9.66, 2.64 Hz, 1H) 7.98 (d, J= 2.01 Hz, 1H) 8.28 (dd, J= 8.53, 1.25 Hz, 1H) 8.36 (dd, J= 5.27, 1.26 Hz, 1H).
[00344] A solution of 2-(6-chloropyridin-3-yl)-3-(4-(trifluoromethyl)phenoxy)pyrazine
(56A, 150.0 mg, 0.43 mmol, 1.0 eq), 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (24C, 92.0 mg, 0.60 mmol, 0.1 mL, 1.4 eq), Pd(dppf)C12 (31.2 mg, 43 pmol, 0.1 eq) and Na2CO 3 (90.4 mg, 0.85 mmol, 2.0 eq) in dioxane (1.5 mL) and H2O (0.15 mL) at 20 °C was purged and degassed with N2 purged for 3 times and then stirred under N2 at 90 °C for 16 hrs. The residue was concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate/Petroleum ether gradient @ 20 mL/min) and purified by prep-HPLC (column: 3_Phenomenex Luna C18 75x30mmx3um;mobile phase: [water(0.05%HCl)-ACN]; B%: 40%-70%, 6.5 min) to afford Compound 56 (6.0 mg, 3.5% yield, HC1) as a white solid. LC-MS (ESI): RT = 0.872 min, mass calc, for C18H12F3N3O 343.09, m/z found 344.1 [M+H]+; 1H NMR (400 MHz, CD3OD) 8 9.47 (d, J = 1.5 Hz, 1H), 9.33 (dd, J= 1.8, 8.5 Hz, 1H), 8.58 (d, J= 2.5 Hz, 1H), 8.39 (d, J= 8.8 Hz, 1H), 8.27 (d, J= 2.3 Hz, 1H), 7.80 (d, J= 8.5 Hz, 2H), 7.49 (brd, J= 8.5 Hz, 2H), 7.09 (dd, J= 11.2, 17.7 Hz, 1H), 6.67 (d, J= 17.6 Hz, 1H), 6.15 (d, J= 11.3 Hz, 1H).
Example 57 : N-(4-(T rifluoromethyl)phenyl)-3-(6-vinylpyridin-3-yl)pyrazin-2-amine
[00345] To a solution of 3-(6-chloropyridin-3-yl)-N-(4-(trifluoromethyl)phenyl)pyrazin-2- amine (57A, 50 mg, 0.14 mmol, 1 eq), Na2CO 3 (30.2 mg, 0.29 mmol, 2 eq) and Pd(PPh3)4 (8.2 mg, 7.1 pmol, 0.05 eq) in dioxane (2 mL) and Water (0.2 mL) at 20°C was added 4,4,5,5-tetramethyl-2- vinyl-l,3,2-dioxaborolaner (24C, 32.9 mg, 0.21 mmol, 36 uL, 1.5 eq), and the resulting mixture was purged and degassed with N2 for 3 times and then stirred at 90°C under N2 for 16 hrs. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate/Petroleum ether gradient @ 20 mL/min), and was further purified by prep- HPLC (column: 3_Phenomenex Luna C18 75x30mmx3um; mobile phase: [water(0.05%HCl)- ACN];B%: 40%-70%,6.5min) to afford Compound 57 (19.3 mg, 35.9% yield, HC1) as a yellow solid. LC-MS (ESI): RT = 0.781 min, mass calc, for C18H13F3N4 342.11, m/z found 342.9 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 6 9.16 (s, 1H), 9.01 (d, J= 1.5 Hz, 1H), 8.45 - 8.39 (m, 1H), 8.34 - 8.27 (m, 2H), 7.97 (br d, J= 8.3 Hz, 1H), 7.74 (d, J= 8.5 Hz, 2H), 7.62 (d, J= 8.8 Hz, 2H), 7.02 (dd, J= 11.0, 17.3 Hz, 1H), 6.52 (d, J= 17.6 Hz, 1H), 5.79 (d, J= 10.8 Hz, 1H).
Example 58: 2-Ethynyl-5-(3-(4-(trifluoromethyl)phenoxy)pyrazin-2-yl)pyrimidine
2-chloro-5-(3-(4-(trifluoromethyl)phenoxy)pyrazin-2-yl)pyrimidine
[00346] A solution of 2-chl oro-3 -(4-(trifluoromethyl)phenoxy)pyrazine (21C, 1 g, 3.64 mmol, 1 eq}, (2-chloropyrimidin-5-yl)boronic acid (24A, 691.9 mg, 4.37 mmol, 1.2 eq}, Pd(dppf)C12 (266.4 mg, 0.36 mmol, 0.1 eq} and Na2CO3 (771.9 mg, 7.28 mmol, 2 eq} in dioxane (10 mL) and H2O (1 mL) at 20°C was purged and degassed with N2 purged for 3 times and then stirred under N2 at 90°C for 16 hrs. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-40% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give intermediate 58A (220 mg, 0.59 mmol, 16.2% yield) as a yellow solid. LCMS (ESI): RT = 0.963 min, mass calc, for CI5H8C1F3N4O 352.03, m/z found 353.1 [M+l]+.
5-(3-(4-(Trifluoromethyl)phenoxy)pyrazin-2-yl)-2-((trimethylsilyl)ethynyl)pyrimidine [00347] To a solution of intermediate 58A (90 mg, 0.26 mmol, 1 eq} and ethynyltrimethylsilane (50.1 mg, 0.51 mmol, 71 uL, 2 eq} in DMF (1 mL) was added TEA (90.4 mg, 0.89 mmol, 0.12 mL, 3.5 eq}. The reaction mixture was degassed with N2 for 3 times and Cui (2.4 mg, 12.8 pmol, 0.05 eq} and Pd(PPh3)2Ch (17.9 mg, 25.5 pmol, 0.1 eq} were added. The reaction mixture was further degassed with N2 for 3 times and then was stirred and heated to 120 °C for 1 h under N2. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate/Petroleum ether gradient @ 20 mL/min) to give intermediate 58B (65 mg, 0.12 mmol, 47.9% yield) as a yellow solid. LCMS (ESI): RT = 1.070 min, mass calc, for C2oHi7F3N4OSi 414.11, m/z found 415.1 [M+l]+.
2-Ethynyl-5-(3-(4-(trifluoromethyl)phenoxy)pyrazin-2-yl)pyrimidine
[00348] To a solution of intermediate 58B (40 mg, 96.5 pmol, 1 eq} in ACN (1 mL)at 20°C was added KF (11.2 mg, 0.19 mmol, 5 uL, 2 eq), and the reaction mixture was stirred at 20°C for 16 hrs. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to afford Compound 58 (10.2 mg, 30.6% yield) as a yellow solid. LCMS (ESI): RT = 0.848 min, mass calc, for C17H3N4O 342.07, m/z
found 342.9 [M+l]+; 1H NMR (400 MHz, CDCl3) 6 9.57 (s, 2H), 8.51 (d, J= 2.3 Hz, 1H), 8.16 (d, J= 2.5 Hz, 1H), 7.74 (d, J= 8.5 Hz, 2H), 7.32 (d, J= 8.3 Hz, 2H), 3.26 (s, 1H).
[00349] To a solution of 3-(2-chloropyrimidin-5-yl)-N-(4-(trifluoromethyl)phenyl)pyrazin-2- amine (26A, 100.0 mg, 0.28 mmol, 1.0 eq) and ethynyltrimethylsilane (55.9 mg, 0.57 mmol, 79 uL, 2.0 eq) in DMF (1 mL) was added TEA (100.7 mg, 1.0 mmol, 0.1 mL, 3.5 eq). The reaction mixture was degassed with N2 for 3 times and Cui (2.7 mg, 14 pmol, 0.05 eq) and Pd(PPh3)2Ch (20.0 mg, 28 pmol, 0.1 eq) were added. The reaction mixture was further degassed with N2 for 3 times and then was stirred and heated to 120 °C for 0.5 hr under N2. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 , filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate/Petroleum ether gradient @ 20 mL/min), and was further purified by prep-HPLC: (column: Welch Xtimate C18 150x25mmx5um; mobile phase: [water (0.05%NH3H20)-ACN]; B%: 51%-81%, 9.5 min) to afford Compound 59 (11.2 mg, 10.7% yield) as a yellow solid. LC-MS (ESI): RT = 0.896 min, mass calc, for C17H10F3N5341.09, m/z found 342.1 [M+H]+; 1H NMR (400 Hz, CDCl3) 8 9.15 (s, 2H), 8.30 - 8.27 (m, 2H), 7.60 (d, J .3 Hz, 4H), 6.94 (s, 1H), 3.25 (s, 1H).
2-(6-Chloropyridin-3-yl)-3-(4-(trifluoromethyl)phenoxy)pyrazine
[00350] A solution of 2-chl oro-3 -(4-(trifluoromethyl)phenoxy)pyrazine (21C, 1 g, 3.64 mmol, 1 eq), (6-methoxy-3-pyridyl)boronic acid (6 87.6 mg, 4.37 mmol, 1.2 eq), Pd(dppf)C12 (266.4 mg, 0.36 mmol, 0.1 eq) and Na2CO3 (771.9 mg, 7.28 mmol, 2 eq) in dioxane (10 mL) and H2O (1 mL) was degassed with N2 for 3 times and then was stirred and heated to 90 °C for 16 hrs under N2. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give intermediate 60A (330 mg, 0.90 mmol, 24.7% yield) as a yellow solid. LCMS (ESI): RT = 0.982 min, mass calc, for C16H9CIF3N3O 351.04, m/z found 352.0 [M+H]+.
2-(4-(Trifluoromethyl)phenoxy)-3-(6-((trimethylsilyl)ethynyl)pyridin-3-yl)pyrazine [00351] To a solution of intermediate 60A (100 mg, 0.28 mmol, 1 eq) and ethynyltrimethylsilane (55.85 mg, 0.57 mmol, 79 uL, 2 eq) in DMF (1 mL) was added TEA (100.7 mg, 1.00 mmol, 0.14 mL, 3.5 eq). The reaction mixture was degassed with N2 for 3 times and Cui (2.7 mg, 14.2 pmol, 0.05 eq) and Pd(PPh3)2Cl2 (20.0 mg, 28.4 pmol, 0.1 eq) were added. The reaction mixture was further degassed with N2 for 3 times and then was stirred and heated to 120 °C for 1 h under N2. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate/Petroleum ether gradient @ 20 mL/min) to give intermediate 60B(70 mg, 83.0 pmol, 29.2% yield) as a yellow solid. LCMS (ESI): RT = 1.087 min, mass calc, for C2iHisF3N3OSi 413.12, m/z found 414.1 [M+H]+.
2-(6-ethynylpyridin-3-yl)-3-(4-(trifluoromethyl)phenoxy)pyrazine
[00352] To a solution of intermediate 60B (30 mg, 72.6 pmol, 1 eq) in ACN (1 mL) at 20°C was added KF (8.4 mg, 0.15 mmol, 3.4 uL, 2 eq), and the reaction mixture was stirred at 20°C for
16 hrs. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to afford Compound 60 (9.0 mg, 36.4% yield) as a white solid. LC-MS (ESI): RT = 0.864 min, mass calc, for C18H10F3N3O 341.08, m/z found 341.9 [M+H]+; XH NMR (400 MHz, CDCl3) 8 9.43 (s, 1H), 8.52 - 8.45 (m, 2H), 8.12 (s, 1H), 7.73 (br d, J= 8.4 Hz, 2H), 7.63 (d, J= 8.0 Hz, 1H), 7.31 (br d, J= 8.8 Hz, 2H), 3.28 (s, 1H).
Example 61 : 3-(6-ethynylpyridin-3-yl)-N-(4-(trifluoromethyl)phenyl)pyrazin-2-amine
5-Bromo-2-((trimethylsilyl)ethynyl)pyridine
[00353] To a solution of 5-bromo-2-iodopyridine (61A, 1 g, 3.52 mmol, 1 eq), Cui (6 7.1 mg, 0.35 mmol, 0.1 eq) and Pd(PPh3)2C12 (247.2 mg, 0.35 mmol, 0.1 eq) in THF (10 mL) at 20°C were added TEA (1.07 g, 10.57 mmol, 1.47 mL, 3 eq) and ethynyltrimethyl silane (415.2 mg, 4.23 mmol, 0.59 mL, 1.2 eq). And the resulting mixture was purged and degassed with N2 for 3 times, and then stirred at 20°C under N2 for 16 hrs. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~5% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give intermediate 61B (6 50 mg, 2.40 mmol, 68.1% yield) as a gray solid. LCMS (ESI): RT = 0.932 min, mass calc, for C10HuBrNSi 252.99, m/z found 253.8 [M+H]+.
5-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)-2-((trimethylsilyl)ethynyl)pyridine
[00354] The mixture of intermediate 61B (200 mg, 0.79 mmol, 1 eq), 4D (299.7 mg, 1.18 mmol, 1.5 eq), KO Ac (154.4 mg, 1.57 mmol, 2 eq) and Pd(dppf)C12 (28.8 mg, 39.3 pmol, 0.05 eq) in dioxane (2 mL) at 20°C was purged and degassed with N2 for 3 times, and then stirred at 100°C
under N2 for 3 hrs. The reaction mixture was concentrated under reduced pressure to give crude intermediate 61C (237 mg, 0.79 mmol, 100 % yield) as black oil, which was used directly for next step.
A-(4-(Trifluoromethyl)phenyl)-3-(6-((trimethylsilyl)ethynyl)pyridin-3-yl)pyrazin-2-amine [00355] The mixture of intermediate 61C (170 mg, 0.62 mmol, 1 eq), intermediate 25D (224.6 mg, 0.75 mmol, 1.2 eq), Na2CO 3 (131.7 mg, 1.24 mmol, 2 eq) and Pd(dppf)C12 (22.7 mg, 31.1 pmol, 0.05 eq) in dioxane (4 mL) and Water (0.4 mL) at 20°C was purged and degassed with N2 for 3 times, and then stirred at 100°C under N2 for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give intermediate 61D (60 mg, 0.12 mmol, 19.0% yield) as a yellow oil. LC-MS (ESI): RT = 0.990 min, mass calc, for C2iHi9F3N4Si 412.13, m/z found 413.0 [M+H]+.
3-(6-Ethynylpyridin-3-yl)-N-(4-(trifluoromethyl)phenyl)pyrazin-2-amine
[00356] To a solution of intermediate 61D (6 0 mg, 0.15 mmol, 1 eq) in ACN (1 mL) at 20°C was added KF (16.9 mg, 0.29 mmol, 7 uL, 2 eq), and the reaction mixture was stirred at 20°C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure to give a residue, which was purified by prep-TLC (SiO2, PE: EtOAc = 2: 1, UV) to afford Compound 61 (15.4 mg, 29.7% yield) as a yellow solid. LC-MS (ESI): RT = 0.854 min, mass calc, for C18H11F3N4 340.09, m/z found 340.9 [M+H]+; XH NMR (400 MHz, CDCl3) 8 8.99 (d, J= 2.0 Hz, 1H), 8.24 (q, J= 2.5 Hz, 2H), 8.08 (dd, J= 2.0, 8.0 Hz, 1H), 7.74 - 7.62 (m, 3H), 7.62 - 7.54 (m, 2H), 6.88 (brs, 1H), 3.29 (s, 1H).
Example 62: l-Methyl-2'-((4-(trifluoromethyl)phenyl)thio)-[3,3'-bipyridin]-6(lH)-one (Compound 62)
dioxane/ H2O
5-Bromo-l-methyl-pyridin-2-one
[00357] The mixture of 5-bromo-lH-pyridin-2-one (62A, 1 g, 5.75 mmol, 1 eq), Mel (815.7 mg, 5.75 mmol, 0.35 mL, 1 eq) and CS2CO3 (3.75 g, 11.49 mmol, 2 eq) in DMF (1 mL) was stirred at 25°C for 2 hr. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-100% PEZEtOAc@ 35 mL/min) to give intermediate 62B as a white solid. l-Methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one
[00358] A mixture of intermediate 62B (520 mg, 2.77 mmol, 1 eq), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (4D, 1.40 g, 5.53 mmol, 2 eq), AcOK (814.2 mg, 8.30 mmol, 3 eq), Pd(dppf)C12 (101.1 mg, 0.13 mmol, 0.05 eq) in dioxane (5 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90 °C for 4 hr under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~65%PE/EtOAc@ 35 mL/min) to give intermediate 62C, l-methyl-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one (781 mg, 1.89 mmol, 68.4% yield) as a yellow oil.
3-bromo-2-[4-(trifluoromethyl)phenyl]sulfanyl-pyridine
[00359] The mixture of 3-bromo-2-fluoro-pyridine (62D, 200 mg, 1.14 mmol, 1 eq), 4- (trifluoromethyl)benzenethiol (202.4 mg, 1.14 mmol, 1 eq) and CS2CO3 (740.5 mg, 2.27 mmol, 2 eq) in DMF (2 mL) was stirred at 100°C for 1 hr. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-10% PEZEtOAc@ 35mL/min) to give intermediate 62E (293 mg, 0.87 mmol, 77.1% yield) as a yellow oil. l-methyl-5-[2-[4-(trifluoromethyl)phenyl]sulfanyl-3-pyridyl]pyridin-2-one
[00360] A mixture of intermediate 62C (296.2 mg, 0.71 mmol, 0.29 mL, 1.2 eq), intermediate 62E (200 mg, 0.59 mmol, 1 eq), Pd(dppf)C12 (21.9 mg, 29.9 pmol, 0.05 eq), K2CO3 (248.1 mg, 1.80 mmol, 3 eq) in dioxane (2 mL) and H2O (1 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90 °C for 16 hrs under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrousNa2SO4 , filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75x30mmx3um;mobile phase: [water(0.05%HCl)-ACN];B%: 35%-65%,6.5min) to afford Compound 62 (8.3 mg, 3.8% yield) as a yellow solid. LC-MS (ESI): RT = 0.842 min, mass calcd for C18H13F3N2OS 362.37 m/z found 363.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.40 - 8.33 (m, 1H), 7.90 (d, J= 2.3 Hz, 1H), 7.76 - 7.69 (m, 3H), 7.61 (br d, J = 7.8 Hz, 3H), 7.34 (dd, J= 4.8, 7.5 Hz, 1H), 6.48 (d, J= 9.3 Hz, 1H), 5.19 (br s, 5H), 5.25 - 5.09 (m, 1H), 3.50 - 3.42 (m, 3H), 2.50 (br s, 4H)
Example 63: l-Methyl-2'-((4-(pentafluoro-k6-sulfaneyl)phenyl)thio)-[3,3'-bipyridin]-6(lH)- one (Compound 63)
[4-[(3-bromo-2-pyridyl)sulfanyl]phenyl]-pentafluoro-sulfane
[00361] A mixture of 3-bromo-2-fluoro-pyridine (62D, 374.7 mg, 2.13 mmol, 1 eq), 4- (pentafhioro-sulfanyl)benzenethiol (41B, 503 mg, 2.13 mmol, 1 eq), CS2CO3 (1.39 g, 4.2 mmol, 2 eq) in DMF (5 mL) was stirred at 100 °C for 1 hr under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-10% PEZEtOAc@ 30mL/min) to give intermediate 63A (237 mg, 0.60 mmol, 28.3% yield) as a yellow oil. l-Methyl-5-[2-[4-(pentafluoro-sulfanyl)phenyl]sulfanyl-3-pyridyl]pyridin-2-one
[00362] A mixture of intermediate 62C (89.9 mg, 0.38 mmol, 89 uL, 1.5 eq), intermediate
63A (100 mg, 0.25 mmol, 1 eq), Pd(dppf)C12 (55.9 mg, 76.4 pmol, 0.3 eq) N, a2CO 3 (54.0 mg, 0.50 mmol, 2 eq) in dioxane (2 mL) and H2O (0.5 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90 °C for 16 hrs under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75x30mmx3um;mobile phase: [water(0.05%HCl)-ACN];B%: 34%- 64%,8.5min) to afford Compound 63 (3.2 mg, 3.0% yield) as white solid. LC-MS (ESI): RT = 0.865 min, mass calcd for C17H13F5N2OS2 420.42 m/z found 421.0 [M+H]+. 1H NMR (400 MHz, CD3OD) 6 8.77 (d, J= 4.5 Hz, 1H), 8.33 (d, J= 8.0 Hz, 1H), 8.11 (s, 1H), 7.88 - 7.79 (m, 4H), 7.48 (br d, J= 8.5 Hz, 2H), 6.64 (d, J= 9.5 Hz, 1H), 3.61 (s, 3H).
Example 64: l-Methyl-5-(2-(4-(pentafluoro-L6-sulfaneyl)phenoxy)pyridin-3-yl)pyrimidin-
2(lH)-one (Compound 64)
pentafluoro- [4- [ [3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-2-pyridyl] oxy] phenyl] - sulfane
[00363] To a solution of 3-bromo-2-(4-(pentafluoro-X6-sulfaneyl)phenoxy)pyridine (65C, 150 mg, 0.39 mmol, 1 eq) and 4D (121.5 mg, 0.47 mmol, 1.2 eq) in dioxane (3 mL) was added AcOK (78.2 mg, 0.79 mmol, 2.0 eq) and Pd(dppf)C12 (29.1 mg, 39.8 pmol, 0.1 eq). The reaction mixture was stirred at 90 °C for 1 hr under N2. The reaction mixture was filtered and concentrated under reduced pressure to give crude intermediate 64A (170 mg, crude) as a black solid, which was used in the next step without further purification. l-Methyl-5-[2-[4-(pentafluoro-sulfanyl)phenoxy]-3-pyridyl]pyrimidin-2-one
[00364] To a solution of intermediate 64A (50 mg, 0.11 mmol, 1 eq) and 5-bromo-l- methylpyrimidin-2(lH)-one (64B, 24.5 mg, 0.12 mmol, 1.1 eq) in dioxane (3.0 mL) and H2O (0.5 mL) was added Pd(dppf)C12 (8.6 mg, 11.8 pmol, 0.1 eq) and Na2CO 3 (25.0 mg, 0.23 mmol, 2.0 eq). The reaction mixture was stirred at 90 °C for 1 hr under N2. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75x30mmx3um; mobile phase: [water (0.05%HCl)-ACN]; B%: 35%- 65%, 6.5 min) to afford Compound 64 (4.2 mg, 8.6% yield as a white solid. LC-MS (ESI): RT = 0.823 min, mass calcd for: C16H12F5N3O2S 405.06 m/z found 406.1 [M+H]+; XH NMR (400 MHz, DMSO-d6) 69.04 (d, J= 3.1 Hz, 1H), 8.93 (d, J = 3.0 Hz, 1H), 8.17 (dd, J= 1.6, 4.8 Hz, 1H), 8.07 (dd, J= 1.6, 7.4 Hz, 1H), 7.98 (d, J= 9.1 Hz, 2H), 7.44 (d, J= 8.9 Hz, 2H), 7.34 (dd, J= 4.9, 7.4 Hz, 1H), 3.68 - 3.63 (m, 1H), 3.59 (s, 2H). h
Example 65: l-ethyl-2'-(4-(pentafluoro-L6-sulfaneyl)phenoxy)-[3,3'-bipyridin]-6(lH)-one
5-Bromo-l-ethyl-pyridin-2-one
[00365] The mixture of 5-bromo-lH-pyridin-2-one (62A, 500.0 mg, 2.87 mmol, 1 eq) and iodoethane (448.1 mg, 2.87 mmol, 0.22 mL, 1 eq), CS2CO3 (1.87 g, 5.75 mmol, 2 eq) in DMF (2 mL) was stirred at 25°C for 1 hr. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-50% PEZEtOAc @ 35 mL/min) to give intermediate 65A (304.0 mg, 1.50 mmol, 52.3% yield) was obtained as a yellow solid. l-Ethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one
[00366] A mixture of intermediate 65A (304.0 mg, 1.50 mmol, 1 eq), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (4D, 573.1 mg, 2.26 mmol, 1.5 eq), Pd(dppf)C12 (55.0 mg, 75.2 pmol, 0.05 eq), AcOK (442.9 mg, 4.51 mmol, 3 eq) in dioxane (2 mL) was degassed and purged with N2 for 3 times and then the reaction mixture was stirred at 90 °C for 16 hrs under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate/Petroleum ether gradient @ 35mL/min) to give intermediate 65B (295 mg, 1.18 mmol, 78.7% yield) was obtained as a yellow oil.
[4-[(3-Bromo-2-pyridyl)oxy]phenyl]-pentafluoro-sulfane
[00367] The mixture of 4-(pentafluoro-sulfanyl)phenol (1 g, 4.54 mmol, 1 eq), 3-bromo-2- fluoro-pyridine (62D, 799.3 mg, 4.54 mmol, 1 eq) and CS2CO3 (2.96 g, 9.08 mmol, 2 eq) in DMF (6 mL) was stirred at 100°C for 1 hr. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-10% PEZEtOAc@ 35 mL/min) to give intermediate 65C (1.26 g, 3.35 mmol, 73.7% yield) as a white solid. l-Ethyl-5-[2-[4-(pentafluoro-sulfanyl)phenoxy]-3-pyridyl]pyridin-2-one
[00368] A mixture of intermediate 65B (6 6.2 mg, 0.26 mmol, 1 eq), intermediate 65C (100 mg, 0.26mmol, 1 eq), Pd(dppf)C12 (9.7 mg, 13.2 pmol, 0.05 eq), K2CO3 (110.2 mg, 0.79 mmol, 3
eq) in dioxane (2 mL) and H2O (0.5 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90 °C for 5 hrs under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75x30mmx3um; mobile phase: [water(0.05%HCl)-ACN];B%: 50%-80%,6.5min) to afford Compound 65 (6.7 mg, 16.2 pmol, 6.1% yield) as a white solid. LC-MS (ESI): RT = 0.906 min, mass calcd for C18H15F5N2O2S 418.38 m/z found 419.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.16 (dd, J= 1.5, 4.8 Hz, 1H), 8.05 (d, J= 2.0 Hz, 1H), 7.98 (dd, J= 1.6, 7.4 Hz, 1H), 7.93 - 7.85 (m, 3H), 7.35 - 7.25 (m, 3H), 6.66 (d, J= 9.3 Hz, 1H), 4.14 (q, J= 7.0 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H).
Example 66: l-Ethyl-2'-((4-(pentafluoro-L6-sulfaneyl)phenyl)amino)-[3,3'-bipyridin]-6(lH)- one (Compound 66)
3-bromo-N-[4-(pentafluoro-sulfanyl)phenyl]pyridin-2-amine
[00369] The mixture of 4-(pentafluoro-sulfanyl)aniline (1 g, 4.56 mmol, 1 eq), 3-bromo-2- fluoro-pyridine (62D, 802.9 mg, 4.56 mmol, 1 eq) and CS2CO3 (2.97 g, 9.13 mmol, 2 eq) in DMF (6 mL) was stirred at 100 °C for 1 hr. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 25 g SepaFlash® Silica Flash Column, Eluent of 0-40% PEZEtOAc@35 mL/min) to give intermediate 66A (1 g, 2.45 mmol, 53.7% yield) as a white solid.
l-Ethyl-5-[2-[4-(pentafluoro-sulfanyl)anilino]-3-pyridyl]pyridin-2-one
[00370] A mixture of intermediate 65B (6 6.4 mg, 0.26 mmol, 1 eq), intermediate 66A (100 mg, 0.26 mmol, 1 eq), Pd(dppf)C12 (9.75 mg, 13.3 pmol, 0.05 eq), K2CO3 (110.5 mg, 0.79 mmol, 3 eq) in dioxane (2 mL) and H2O (0.5 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90 °C for 5 hrs under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75x30mmx3um; mobile phase: [ water(0.05%HCl)-ACN];B%: 40%-70%,6.5min) to afford Compound 66 (15.2 mg, 13.5% yield) as a white solid. LC-MS (ESI): RT = 0.864 min, mass calcd for C18H16F5N3OS 417.40 m/z found 418.1 [M+H]+. XH NMR (400 MHz, CD3OD) 8 8.09 (d, J= 5.3 Hz, 1H), 8.02 - 7.95 (m, 2H), 7.88 (d, J= 8.8 Hz, 2H), 7.67 (br d, J= 9.0 Hz, 1H), 7.59 (br d, J= 8.8 Hz, 2H), 7.25 (t, J= 6.5 Hz, 1H), 6.66 (d, J= 9.0 Hz, 1H), 4.12 (q, J= 7.0 Hz, 2H), 1.40 (t, J = 7.0 Hz, 3H).
Example 67: l-Isopropyl-2'-(4-(pentafluoro-L6-sulfaneyl)phenoxy)-[3,3'-bipyridin]-6(lH)-one (Compound 67)
[00371] A mixture of l-isopropyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2- one (68B, 83.9 mg, 0.31 mmol, 1.2 eq), intermediate 65C (100 mg, 0.26 mmol, 1 eq), Pd(dppf)C12 (9.7 mg, 13.2 pmol, 0.05 eq), K2CO3 (110.2 mg, 0.79 mmol, 3 eq) in dioxane (2 mL)and μ (0.5 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90 °C for 16 hr under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75x30mmx3um;mobile phase: [water(0.05%HCl)-ACN];B%: 50%-80%,6.5min) to afford Compound 67 (16.2 mg, 14.0% yield) as a white solid. LC-MS (ESI): RT = 0.926 min, mass calcd for C19H17F5N2O2S 432.41 m/z
found 433.0 [M+H]+. 1H NMR (400 MHz, CD3OD) 8 8.15 (br d, J= 5.3 Hz, 1H), 8.02 - 7.94 (m, 2H), 7.89 - 7.78 (m, 3H), 7.34 - 7.24 (m, 3H), 6.63 (d, J=9.5 Hz, 1H), 5.23 (quin, J= 6.8 Hz, 1H), 1.41 (d, J = 6.8 Hz, 6H).
Example 68: l-Isopropyl-2'-((4-(pentafluoro-L6-sulfaneyl)phenyl)amino)-[3,3'-bipyridin]-
5-Bromo-l-isopropyl-pyridin-2-one
[00372] The mixture of 5-bromo-lH-pyridin-2-one (62A, 1 g, 5.75 mmol, 1 eq) and 2- iodopropane (976.9 mg, 5.75 mmol, 0.5 mL, 1 eq), CS2CO3 (3.75 g, 11.49 mmol, 2 eq) in DMF (6 mL) was stirred at 25°C for 1 hr. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~65%PE/EtOAc@30 mL/min) to give intermediate 68A (259 mg, 1.17 mmol, 20.4% yield) as a white solid. l-Isopropyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one
[00373] A mixture of intermediate 68A (259 mg, 1.20 mmol, 1 eq), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (4D, 365.2 mg, 1.44 mmol, 1.2 eq), Pd(dppf)C12 (43.8 mg, 59.9 pmol, 0.05 eq), AcOK (352.9 mg, 3.60 mmol, 3 eq) in dioxane (3 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90 °C for 5 hr under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; X g SepaFlash® Silica Flash Column, Eluent of 0-65% PEZEtOAc@ 35 mL/min) to give intermediate 68B (231 mg, 0.82 mmol, 68.8% yield) was obtained as yellow solid.
l-Isopropyl-5-[2-[4-(pentafluoro-sulfanyl)anilino]-3-pyridyl]pyridin-2-one
[00374] A mixture of intermediate 68B (84.1 mg, 0.31 mmol, 1.2 eq), intermediate 66A (100 mg, 0.26 mmol, 1 eq), Pd(dppf)C12 (9.7 mg, 13.3 pmol, 0.05 eq), K2CO3 (110.5 mg, 0.79 mmol, 3 eq) in dioxane (2 mL)and H2O (0.5 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90 °C for 16 hr under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75x30mmx3um;mobile phase: [water(0.05%HCl)-ACN];B%: 40%-70%,6.5min) to afford Compound 68 (18.3 mg, 15.9% yield) as a white solid. LC-MS (ESI): RT = 0.896 min, mass calcd for CI9HI8F5N3OS 431.42 m/z found 432.1 [M+H]+. XH NMR (400 MHz, DMSO-d6) 8 9.03 (br s, 1H), 8.22 (dd, J= 1.4, 5.1 Hz, 1H), 7.89 (d, J= 2.5 Hz, 1H), 7.80 - 7.73 (m, 3H), 7.64 (d, J= 9.0 Hz, 2H), 7.48 (dd, J= 2.5, 9.3 Hz, 1H), 7.14 (dd, J= 5.3, 7.3 Hz, 1H), 6.48 (d, J= 9.3 Hz, 1H), 5.12 - 5.02 (m, 1H), 1.32 (d, J = 7.0 Hz, 6H).
Example 69: l-Cyclopropyl-2'-(4-(pentafluoro-L6-sulfaneyl)pheno y)-[3,3'-bipyridin]-6(lH)- one (Compound 69)
O2, DCE
5-Bromo-l-cyclopropyl-pyridin-2-one
[00375] A mixture of 5-bromo-lH-pyridin-2-one (62A, 500 mg, 2.87 mmol, 1 eq), cyclopropylboronic acid (493.6 mg, 5.75 mmol, 2 eq), Cu(OAc)2 (6 26.3 mg, 3.45 mmol, 1.2 eq) and Na2CO3 (6 70.0 mg, 6.32 mmol, 2.2 eq) , 2-(2-pyridyl)pyridine (538.5 mg, 3.45 mmol, 1.2 eq) in DCE (5 mL)was degassed and purged with O2 for 3 times, and then the reaction mixture was stirred at 70 °C for 16 hr under O2 atmosphere. The reaction mixture was filtered to remove the insoluble. The filter liquor was concentrated in vacuo, and was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~80%PE/EtOAc@35 mL/min) to give intermediate 69A (393 mg, 1.84 mmol, 63.8% yield) as a yellow oil.
Cyclopropyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one
[00376] A mixture of intermediate 69A (393 mg, 1.84 mmol, 1 eq), 4,4,5,5-tetramethyl-2-
(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (4D, 559.4 mg, 2.20 mmol, 1.2 eq), AcOK (540.5 mg, 5.51 mmol, 3 eq), Pd(dppf)C12 (6 7.1 mg, 91.8 pmol, 0.05 eq) in dioxane (15 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90 °C for 4 hr under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous TsfeSCh, filtered and concentrated in vacuum to give crude intermediate 69B (515 mg, crude) as a yellow oil, which was used in the next step without further purification. l-Cyclopropyl-5-[2-[4-(pentafluoro-k6-sulfanyl)phenoxy]-3-pyridyl]pyridin-2-one
[00377] A mixture of intermediate 69B (104.1 mg, 0.39 mmol, 1.5 eq), intermediate 65C
(100 mg, 0.26 mmol, 1 eq), CS2CO3 (259.8 mg, 0.79 mmol, 3 eq), Pd(dppf)C12 (9.7 mg, 13.2 pmol, 0.05 eq) in dioxane (5 mL) and H2O (0.5 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90 °C for 16 hrs under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75x30mmx3um;mobile phase: [water(0.05%HCl)-ACN];B%: 40%- 70%,8.5min) to afford Compound 69 (10.0 mg, 8.6% yield) as a white solid. LC-MS (ESI): RT = 0.902 min, mass calcd for C19H15F5N2O2S 430.39 m/z found 431.0[M+H]+. XH NMR (400 MHz, CD3OD) 6 8.17 (dd, J= 1.8, 5.0 Hz, 1H), 8.10 (d, = 1.8 Hz, 1H), 8.05 - 7.99 (m, 2H), 7.91 - 7.87 (m, 2H), 7.35 - 7.27 (m, 3H), 6.79 (d, J= 9.3 Hz, 1H), 3.52 (td, J= 3.5, 7.2 Hz, 1H), 1.24 - 1.17 (m, 2H), 1.07 - 0.99 (m, 2H).
Example 70: 2'-(4-(Pentafluoro-L6-sulfaneyl)pheno y)-l-propyl-[3,3'-bipyridin]-6(lH)-one
[00378] A mixture of 5-bromo-lH-pyridin-2-one (62A, 500.0 mg, 2.87 mmol, 1 eq), 1- iodopropane (488.5 mg, 2.87 mmol, 0.28 mL, 1 eq), CS2CO3 (1.87 g, 5.75 mmol, 2 eq) in DMF (2 mL) was stirred at 25°C for 1 hr under N2 atmosphere. The reaction mixture was diluted with μ (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 25 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate/Petroleum ether gradient @ 35 mL/min) to give intermediate 70A (226 mg, 0.99 mmol, 34.5% yield) as a yellow oil. l-Propyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one
[00379] A mixture of intermediate 70A (226 mg, 1.0 mmol, 1 eq), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (4D, 398.4 mg, 1.5 mmol, 1.5 eq), Pd(dppf)C12 (38.2 mg, 52.3 pmol, 0.05 eq), AcOK (307.9 mg, 3.14 mmol, 3 eq) in dioxane (2 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90 °C for 16 hr under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate/Petroleum ether gradient @ 35mL/min) to give intermediate 70B (182 mg, 0.69 mmol, 66.1% yield) as a yellow oil.
5-[2-[4-(pentafluoro-sulfanyl)phenoxy]-3-pyridyl]-l-propyl-pyridin-2-one
[00380] A mixture of intermediate 65C (100.2 mg, 0.26 mmol, 1 eq), intermediate 70B (98.2 mg, 0.37 mmol, 1.4 eq), Pd(dppf)C12 (9.7 mg, 13.3 pmol, 0.05 eq), K2CO3 (110.5 mg, 0.79 mmol, 3 eq) in dioxane (10 mL) and H2O (1 mL) was degassed and purged with N2 for 3 times and then the reaction mixture was stirred at 90 °C for 16 hrs under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0% PEZEtOAc@ 35 mL/min) to afford Compound 70 (11.0 mg, 9.4% yield) as a white solid. LC-MS (ESI): RT = 0.922 min, mass calcd for C19H17F5N2O2S 432.41 m/z found 433.1 [M+H]+. 1H NMR (400 MHz, CD3OD) 8 8.16 (dd, J = 1.9, 4.9 Hz, 1H), 8.01 (d, J= 2.5 Hz, 1H), 7.97 (dd, J= 1.8, 7.5 Hz, 1H), 7.90 - 7.84 (m, 3H), 7.34 -
7.26 (m, 3H), 6.64 (d, J= 9.3 Hz, 1H), 4.04 (t, J= 7.3 Hz, 2H), 1.81 (sxt, J= 7.4 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H).
Example 71: l-(2-Aminoethyl)-2'-(4-(pentafluoro-L6-sulfaneyl)phenoxy)-[3,3'-bipyridin]-
[00381] The mixture of 5-bromo-lH-pyridin-2-one (62A, 1 g, 5.75 mmol, 1 eq}, tert-butyl N-(2-bromoethyl)carbamate (1.67 g, 7.47 mmol, 1.3 eq} and CS2CO3 (3.75 g, 11.49 mmol, 2 eq in DMF (6 mL) was stirred at 25°C for 2 hrs. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®;12 g SepaFlash® Silica Flash Column, Eluent of 0-100% PEZEtOAc@35 mL/min) to give intermediate 71A (725 mg, 1.90 mmol, 33.0% yield) as a white solid. tert-Butyl N-[2-[2-oxo-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l- py r idyl] ethyl] carbarn ate
[00382] A mixture of intermediate 71A (725 mg, 1.90 mmol, 1 eq), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (4D, 579.9 mg, 2.28 mmol, 1.2 eq), Pd(dppf)C12 (6 9.6 mg, 95.1 pmol, 0.05 eq), AcOK (560.3 mg, 5.71 mmol, 3 eq) in dioxane (7 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90 °C for 10 hr under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed
with brine (10 mL x 2), dried over anhydrous TsfeSCh, filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 12g SepaFlash® Silica Flash Column, Eluent of 0~80%PE/EtOAc@30 mL/min) to give intermediate 71B (343 mg, 0.81 mmol, 43.0% yield) as a white solid. tert-Butyl N- [2- [2-oxo-5- [2- [4-(pentafluoro-sulfanyl)phenoxy]-3-pyridyl]-l- py r idyl] ethyl] carbarn ate
[00383] A mixture of intermediate 71B (139.4 mg, 0.38 mmol, 1.2 eq), intermediate 65C (120 mg, 0.31 mmol, 1 eq), K2CO3 (132.2 mg, 0.95 mmol, 3 eq), Pd(dppf)C12 (11.6 mg, 15.9 pmol, 0.05 eq) in dioxane (2 mL) and H2O (0.05 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90 °C for 16 hr under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. Crude intermediate 71C (159 mg, crude) was obtained as yellow oil, which was used in the next step without further purification. l-(2-Aminoethyl)-5-[2-[4-(pentafluoro-sulfanyl)phenoxy]-3-pyridyl]pyridin-2-one
[00384] Intermediate 71C (159 mg, 0.29 mmol, 1 eq) in HCl/dioxane (4 M, 3 mL, 40.26 eq) was stirred at 25°C for 1 hr. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was adjusted pH to 8 with NaOH (4 M). The reaction mixture was extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (10 mLx3), dried over anhydrousNa2SO4 , filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150x25mmx5um;mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN];B%: 45%-75%,7.8min) to afford Compound 71 (48.9 mg, 36.5% yield) as a white solid. LC-MS (ESI): RT = 0.789 min, mass calcd for Ci8Hi7F5N4OS 432.41 m/z found 434.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 8 8.13 (d, J= 5.0 Hz, 1H), 8.05 (br s, 1H), 8.02 - 7.93 (m, 3H), 7.83 (dd, J= 2.5, 9.5 Hz, 1H), 7.40 (br d, J= 8.5 Hz, 2H), 7.32 (dd, J= 4.8, 7.3 Hz, 1H), 6.50 (d, J= 9.3 Hz, 1H), 4.07 - 3.97 (m, 2H), 2.95 (br t, J= 6.0 Hz, 1H), 2.99 - 2.90 (m, 1H).
Example 72: l-(2-Hydroxyethyl)-2'-(4-(pentafluoro-L6-sulfaneyl)phenoxy)-[3,3'-bipyridin]- 6(lH)-one (Compound 72)
5-Bromo-l-(2-hydroxyethyl)pyridin-2-one
[00385] A mixture of 5-bromo-lH-pyridin-2-one (62A, 500 mg, 2.87 mmol, 1 eq), 2- bromoethanol (359.1 mg, 2.87 mmol, 0.20 mL, 1 eq) CS2CO3 (1.87 g, 5.75 mmol, 2 eq) in DMF (6 mL) was stirred at 25 °C for 1 hr. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®;4 g SepaFlash® Silica Flash Column, Eluent of 0~100%PE/EtOAc@ 30 mL/min) to give intermediate 72A (312 mg, 1.39 mmol, 48.3% yield) as a yellow solid. l-(2-hydroxyethyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one
[00386] A mixture of intermediate 72A (312 mg, 1.43 mmol, 1 eq), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (4D, 545.0 mg, 2.15 mmol, 1.5 eq), Pd(dppf)C12 (52.3 mg, 71.5 pmol, 0.05 eq), AcOK (421.2 mg, 4.29 mmol, 3 eq) in dioxane (3 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90 °C for 16 hr under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (lOmL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~100%PE/EtOAc@30 mL/min) to give intermediate 72B (66 mg, 0.24 mmol, 17.4% yield) as a white solid. l-(2-Hydroxyethyl)-5-[2-[4-(pentafluoro-sulfanyl)phenoxy]-3-pyridyl]pyridin-2-one
[00387] A mixture of intermediate 72B (6 2.0 mg, 0.23mmol, 1.1 eq), intermediate 65C (80 mg, 0.21mmol, 1 eq), K2CO3 (88.1 mg, 0.63mmol, 3 eq), Pd(dppf)C12 (7.7 mg, 10.6 pmol, 0.05 eq) in dioxane (2 mL) and H2O (0.05 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90 °C for 5 hrs under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4 , filtered
and concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®;4 g SepaFlash® Silica Flash Column, Eluent of 0-100% PE/EtOAc@ 20 mL/min) and was further separated by prep-HPLC (column: 3_Phenomenex Luna C18 75x30mmx3um;mobile phase: [water(0.05%HCl)-ACN];B%: 35%-65%,6.5min) to afford Compound 72 (10.8 mg, 11.7% yield) as a white solid. LC-MS (ESI): RT = 0.844 min, mass calcd for C18H15F5N2O3S 434.38 m/z found 435.1 [M+H]+. 1H NMR (400 MHz, CD3OD) 8 8.20 (d, J= 2.0 Hz, 1H), 8.16 (dd, J= 1.6, 4.9 Hz, 1H), 8.10 (dd, J= 2.3, 9.3 Hz, 1H), 8.00 (dd, J= 1.5, 7.5 Hz, 1H), 7.88 - 7.84 (m, 2H), 7.34 - 7.28 (m, 3H), 6.86 (d, J= 9.3 Hz, 1H), 4.29 (t, J= 5.0 Hz, 2H), 3.89 (t, J= 5.0 Hz, 2H).
Example 73: 5-Fluoro-2'-(4-(pentafluoro-L6-sulfaneyl)phenoxy)-[3,3'-bipyridin]-6-ol
[00388] To a solution of intermediate 65C (350 mg, 0.93 mmol, 1 eq) and (5-fluoro-6- methoxypyri din-3 -yl)boronic acid (159.1 mg, 0.93 mmol, 1 eq) in dioxane (2 mL) and H2O (0.5 mL) were added K2CO3 (385.8 mg, 2.79 mmol, 3 eq) and Pd(dppf)C12 (6 8.1 mg, 93.1 pmol, 0.1 eq). The reaction mixture was degassed under vacuum and purged with N2 3 times. The reaction mixture was stirred at 90 °C for 6 hrs. The reaction mixture was diluted with H2O (15 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-15% Ethyl acetate/Petroleum ether gradient @ 20 mL/min) to give intermediate 73A (300 mg, 0.69 mmol, 74.4% yield) as a yellow oil. LC-MS (ESI): RT = 1.043 min, mass calc, for C17H12F6N2O2S 422.05, m/z found 423.1 [M+H]+.
3-fluoro-5-[2-[4-(pentafluoro-sulfanyl)phenoxy]-3-pyridyl]pyridin-2-ol
[00389] A solution of intermediate 73A (250 mg, 0.59 mmol, 1 eq) in HCl/dioxane (1 mL) was stirred at 70 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75x30mmx3um;
mobile phase: [water (0.05%HCl)-ACN]; B%: 40%-70%, 6.5 min) to afford Compound 73 (172.4 mg, 69.3% yield) as a white solid. LC-MS (ESI): RT = 0.863 min, mass calc, for C16H10F6N2O2S 408.04, m/z found 409.0 [M+H]+; 1H NMR (400 MHz, DMSO-t/6) 8 12.46 (br s, 1H), 8.10 (dd, J= 1.8, 5.0 Hz, 1H), 8.00 (dd, J= 1.8, 7.5 Hz, 1H), 7.98 - 7.93 (m, 2H), 7.84 (dd, J= 2.3, 12.3 Hz, 1H), 7.63 (d, J= 2.0 Hz, 1H), 7.41 (d, J= 8.8 Hz, 2H), 7.28 (dd, J= 5.0, 7.5 Hz, 1H).
Example 74: (£')-5-(3-(4-(Pentafluoro-k6-sulfaneyl)phenoxy)pyrazin-2-yl)-2-(3,3,3- trifluoroprop-l-en-l-yl)pyrimidine (Compound 74)
[00390] To a solution of intermediate 40F (120 mg, 0.42 mmol, 1 eq) in DMF (1.5 mL) were added 4-(pentafluoro-X6-sulfaneyl)phenol (101.4 mg, 0.46 mmol, 1.1 eq), CS2CO3 (204.6 mg, 0.63 mmol, 1.5 eq). The reaction mixture was stirred at 110 °C for 3 hrs. The reaction mixture was diluted with H2O (30 mL) and stirred for 5 min. The aqueous phase was extracted with EtOAc (15 mLx3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150x25mmx5um; mobile phase: [water (0.04%NH3H20+10mM NH4HCO3)- ACN]; B%: 60%-90%, 7.8min) to afford Compound 74 (58.7 mg, 29.8% yield) as a yellow solid. LCMS (ESI): RT = 1.000 min, mass calcd for CI7HIOF8N4OS 470.04, m/z found470.9 [M+H]+; 1H NMR (400 MHz, CD3OD) 8 9.58 (s, 2H), 8.55 (d, J= 2.5 Hz, 1H), 8.22 (d, J= 2.5 Hz, 1H), 7.94 (d, J= 9.0 Hz, 2H), 7.46 (d, J= 9.0 Hz, 2H), 7.38 - 7.20 (m, 2H).
Example 75: (Zi)-5-(2-(4-(Trifluoromethyl)phenoxy)pyridin-3-yl)-2-(3,3,3-trifluoroprop-l-en- l-yl)pyrimidine (Compound 75)
[00391] To a solution of Compound 38 (150 mg, 0.44 mmol, 1 eq) and 39A (360.6 mg, 1.09 mmol, 2.5 eq) in DMF (1 mL) were added DBU (133.0 mg, 0.87 mmol, 0.13 mL, 2 eq) and Cu(MeCN)4PFe (32.6 mg, 87.4 pmol, 0.2 eq). The reaction mixture was stirred at 60 °C for
6 hrs. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure to give a residue, which was purified by prep- HPLC (column: 3_Phenomenex Luna C18 75x30mmx3um; mobile phase: [water (0.05%HCl)- ACN]; B%: 60%-90%, 6.5 min) to Compound 75 (18.7 mg, 10.4% yield) as a white solid. LC-MS (ESI): RT = 0.967 min, mass calc, for C19H11F6N3O 411.08 found 412.0 [M+H]+; XH NMR (400 MHz, CDCl3) 8 9.11 (s, 2H), 8.33 - 8.26 (m, 1H), 7.90 (dd, J= 1.5, 7.3 Hz, 1H), 7.72 (d, J= 8.5 Hz, 2H), 7.36 (dd, J= 1.6, 15.9 Hz, 1H), 7.32 - 7.27 (m, 3H), 7.23 - 7.12 (m, 1H).
Example 76 : (E)-5-(2-(4-(pentafluoro-k6-sulfaneyl)phenoxy)pyridin-3-yl)-2-(3,3,3- trifluoroprop-l-en-l-yl)pyrimidine (Compound 76)
pentafluoro- [4- [ [3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-2-pyridyl] oxy] phenyl] - sulfane
[00392] To a solution of intermediate 65C (0.5 g, 1.33 mmol, 1 eq) and 4D (337.6 mg, 1.33 mmol, 1 eq) in dioxane (5 mL) were added AcOK (260.9 mg, 2.66 mmol, 2 eq) and Pd(dppf)C12 (97.3 mg, 0.13 mmol, 0.1 eq). The reaction mixture was degassed and purged with N2 for 3 times, then the reaction mixture was stirred at 100 °C for 2 hr under N2. Crude intermediate 76A (562 mg, crude, black oil) was obtained and used in the next step without further purification.
[4-[[3-(2-chloropyrimidin-5-yl)-2-pyridyl]oxy]phenyl]-pentafluoro-sulfane
[00393] To a solution of intermediate 76A (560 mg, 1.32 mmol, 1 eq) and 5-bromo-2- methylpyrimidine (40A, 256.0 mg, 1.32 mmol, 1 eq) in dioxane (3 mL) and H2O (1 mL) were added Pd(dppf)C12 (96.8 mg, 0.13 mmol, 0.1 eq) and K2CO3 (365.8 mg, 2.65 mmol, 2 eq). The reaction mixture was degassed and purged with N2 for 3 times, then the reaction mixture was stirred at 100 °C for 2 hrs under N2. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (ISCO®; 24 g SepaFlash® Silica Flash Column, Eluent of 0-35% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give intermediate 76B (290 mg, 0.68 mmol, 51.3% yield) as a white solid. LC-MS (ESI): RT = 0.978 min, mass calc, for C15H9CIF5N3OS 409.01 found 410.0 [M+H]+. pentafluoro-[4-[[3-(2-vinylpyrimidin-5-yl)-2-pyridyl]oxy]phenyl]-sulfane
[00394] To a solution of intermediate 76B (290 mg, 0.71 mmol, 1 eq) and 24C (119.9 mg, 0.78 mmol, 0.13 mL, 1.1 eq) in dioxane (3 mL) and HO (0.3 mL) were added Pd(dppf)C12 (51.8 mg, 70.8 pmol, 0.1 eq) and K2CO3 (195.6 mg, 1.42 mmol, 2 eq). The reaction mixture was degassed and purged with N2 for 3 times, then the reaction mixture was stirred at 100 °C for 3 hrs under N2. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-40% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give intermediate 76C (220 mg, 0.50 mmol, 70.5% yield) as a yellow solid. LC-MS (ESI): RT = 0.970 min, mass calc. for CI5H8C1F3N4O 401.06 found 402.0 [M+H]+.
Pentafluoro-[4-[[3-[2-[(E)-3,3,3-ti’ifluoroprop-l-enyl]pyrimidin-5-yl]-2-pyridyl]oxy]phenyl]- sulfane
[00395] To a solution of intermediate 76C (180 mg, 0.45 mmol, 1 eq) and 39A (370.1 mg, 1.12 mmol, 2.5 eq) in DMF (3 mL) were added DBU (136.6 mg, 0.90 mmol, 0.14 mL, 2 eq) and Cu(MeCN)4PFe (33.4 mg, 89.7 pmol, 0.2 eq). The reaction mixture was stirred at 60 °C for 3.5 hrs. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure to give a residue, which was purified by prep- HPLC (column: 3_Phenomenex Luna C18 75x30mmx3um; mobile phase: [water (0.05%HCl)- ACN]; B%: 65%-95%, 6.5 min) to afford Compound 76 (16.8 mg, 8.0% yield) as a yellow solid. LC-MS (ESI): RT = 1.064 min, mass calc, for CI8HUF8N3OS 469.05 found 470.1 [M+H]+; 1H NMR (40 0MHz, CDCl3) 8 9.06 (s, 2H), 8.28 (dd, J= 1.8, 4.8 Hz, 1H), 7.88 (dd, J= 1.8, 7.5 Hz, 1H), 7.82 (d, J= 9.0 Hz, 2H), 7.36 - 7.27 (m, 2H), 7.24 (d, J= 9.0 Hz, 2H), 7.20 - 7.09 (m, 1H).
Example 77: l-(3-Hydroxypropyl)-2'-(4-(pentafluoro-L6-sulfaneyl)phenoxy)-[3,3'-bipyridin]- 6(lH)-one (Compound 77)
3-(5-bromo-2-oxo-l-pyridyl)propyl acetate
[00396] To a solution of 5-bromo-lH-pyridin-2-one (62A, 1 g, 5.75 mmol, 1 eq) and 3- chloropropyl acetate (1.1 g, 8.63 mmol, 1.06 mL, 1.5 eq) in DMF (5 mL) was added CS2CO3 (3.7 g, 11.50 mmol, 2 eq). The reaction mixture was stirred at 25 °C for 16 hr. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x3). The combined organic layers were washed with brine (30 mL x2), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 30% Ethyl acetate/Petroleum ether
gradient @ 30 mL/min) to give intermediate 77A (6 84 mg, 2.38 mmol, 41.3% yield) as a white solid.
3-[2-oxo-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-pyridyl]propyl acetate
[00397] A mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (4D, 236.1 mg, 0.92 mmol, 1.2 eq), intermediate 77A (212.4 mg, 0.77 mmol, 1 eq), KOAc (152.0 mg, 1.55 mmol, 2 eq), Pd(dppf)C12 (28.3 mg, 38.7 pmol, 0.05 eq) in dioxane (10 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90°C for 16 hrs under N2 atmosphere. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL x3). The combined organic layers were washed with brine (50 mL x2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude intermediate 77B (200 mg, crude) as a white solid.
3-[2-oxo-5-[2-[4-(pentafluoro-sulfanyl)phenoxy]-3-pyridyl]-l-pyridyl]propyl acetate
[00398] A mixture of intermediate 65C (150 mg, 0.39 mmol, 1 eq), intermediate 77B (153.7 mg, 0.47 mmol, 1.2 eq), K2CO3 (165.3 mg, 1.20 mmol, 3 eq), Pd(dppf)C12 (29.1 mg, 39.8 pmol, 0.1 eq) in dioxane (2 mL) and H2O (0.5 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90 °C for 6 hr under N2 atmosphere. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x3). The combined organic layers were washed with brine (30 mL x2), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (ISCO®; 24 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 90% Ethyl acetate/Petroleum ether gradient @ 35 mL/min) to give intermediate 77C (139 mg, 0.27 mmol, 68.2% yield) as a yellow solid. l-(3-hydroxypropyl)-5-[2-[4-(pentafluoro-sulfanyl)phenoxy]-3-pyridyl]pyridin-2-one
[00399] To a solution of intermediate 77C (70 mg, 0.14 mmol, 1 eq) in THF (2 mL) and μ (0.2 mL) was added NaOH (28.5 mg, 0.71 mmol, 5 eq). The reaction mixture was stirred at 25 °C for 16 hr. The reaction mixture was diluted with H2O (30 mL) and HC1 (2 mL, 2 M) extracted with EtOAc (30 mL x3). The combined organic layers were washed with brine (30 mL x2), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: Welch Xtimate Cl 8 150x25mmx5um;mobile phase: [water(0.05%HCl)-ACN];B%: 35%-65%,6.5min) to afford Compound 77 (11.20 mg, 17.4% yield) as a white solid. LC-MS (ESI): RT = 0.858 min, mass calcd for C19H17F5N2O3S
448.41 m/z, found 449.1 [M+H]+, XH NMR (400 MHz, DMSO4) 8 ppm 1.81 (quin, J= 6.53 Hz, 2 H) 3.42 (t, J= 6.15 Hz, 2 H) 4.00 (t, J= 6.90 Hz, 2 H) 6.47 (d, J= 9.29 Hz, 1 H) 7.30 (dd, J= 7.40, 4.89 Hz, 1 H) 7.39 (br d, J= 8.78 Hz, 2 H) 7.79 (dd, J= 9.29, 2.51 Hz, 1 H) 7.95 (d, J= 9.29 Hz, 2 H) 7.98 (dd, J = 7.53, 1.51 Hz, 1 H) 8.04 (d, J = 2.26 Hz, 1 H) 8.12 (dd, J= 4.77, 1.51 Hz, 1 H).
Example 78: l-(3-Aminopropyl)-2'-(4-(pentafluoro-L6-sulfaneyl)phenoxy)-[3,3'-bipyridin]- 6(lH)-one (Compound 78)
dioxane/ H2O
Tert-butyl N-[3-(5-bromo-2-oxo-l-pyridyl)propyl]carbamate
[00400] To a solution of 5-bromo-lH-pyridin-2-one (62A, 3 g, 17.24 mmol, 1 eq) and tert- butyl N-(3-bromopropyl)carbamate (6 .1 g, 25.86 mmol, 1.5 eq) in DMF (5 mL) was added CS2CO3 (11.2 g, 34.48 mmol, 2 eq). The reaction mixture was stirred at 25 °C for 16 hrs. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x3). The combined organic layers were washed with brine (30 mL x2), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (ISCO®; 24 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 30% Ethyl acetate/Petroleum ether gradient @ 35 mL/min) to give intermediate 78A (2.7 g, 8.11 mmol, 47.0% yield) as a white solid. tert-butyl N-[3-[2-oxo-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l- pyridyl] propyl] carbamate
[00401] A mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (4D, 184.0 mg, 0.72 mmol, 1.2 eq), intermediate 78A (200 mg, 0.60 mmol, 1 eq), KOAc (118.5 mg, 1.21 mmol, 2 eq), Pd(dppf)C12 (22.0 mg, 30.1 pmol, 0.05 eq) in dioxane (10
mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90 °C for 16 hrs under N2 atmosphere. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL x3). The combined organic layers were washed with brine (50 mL x2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude intermediate 78B (200 mg, crude) as a white solid. tert-butyl N-[3-[2-oxo-5-[2-[4-(pentafluoro-sulfanyl)phenoxy]-3-pyridyl]-l- pyridyl] propyl] carbamate
[00402] A mixture of intermediate 65C (150 mg, 398.79 pmol, 1 eq), intermediate 78B
(181.0 mg, 0.47 mmol, 1.2 eq), K2CO3 (165.3 mg, 1.20 mmol, 3 eq), Pd(dppf)C12 (29.1 mg, 39.8 pmol, 0.1 eq) in dioxane (2 mL) and H2O (0.5 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90 °C for 6 hr under N2 atmosphere. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x3). The combined organic layers were washed with brine (30 mL x2), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 80% Ethyl acetate/Petroleum ether gradient @ 35 mL/min) to give intermediate 78C (150 mg, 0.21 mmol, 54.6% yield) as a white solid. l-(3-aminopropyl)-5-[2-[4-(pentafluoro-sulfanyl)phenoxy]-3-pyridyl]pyridin-2-one
[00403] To a solution of intermediate 78C (70 mg, 0.12 mmol, 1 eq) was added HCl/dioxane (4 M, 4.20 mL, 131.4 eq). The reaction mixture was stirred at 25 °C for 16 hrs. The reaction mixture was diluted with H2O (30 mL) and HC1 (2 mL, 2 M) extracted with EtOAc (30 mL x3). The combined organic layers were washed with brine (30 mL x2), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure to give a residue, which was purified by prep- HPLC (column: Welch Xtimate Cl 8 150x25mmx5um;mobile phase: [water(0.05%HCl)- ACN];B%: 20%-50%,6.5min) to afford Compound 78 (35.88 mg, 57.8% yield, HC1) as a white solid. LC-MS (ESI): RT = 0.795 min, mass calcd for Ci9Hi8F5N3O2S 447.42 m/z, found 448.1 [M+H]+, 1HNMR (400 MHz, CDCl3) ppm 2.42 (br s, 1 H) 3.22 (br s, 1 H) 4.44 (br s, 1 H) 7.03 - 7.23 (m, 2 H) 7.74 (br d, J= 7.78 Hz, 1 H) 8.09 (br s, 1 H) 8.47 (br s, 2 H).
Example 79: 2'-(4-(Pentafluoro-L6-sulfaneyl)phenoxy)-l-phenyl-[3,3'-bipyridin]-6(lH)-one (Compound 79)
WSGR Docket No.47612-741.601
79A [00404] A mixture of [4-[(3-bromo-2-pyridyl)oxy]phenyl]-pentafluoro-λ6-sulfane (65C, 83.1 mg, 0.22 mmol, 1 eq), 1-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (79A, 90 mg, 0.22 mmol, 1 eq), Pd(dppf)Cl2 (8.0 mg, 11.0 µmol, 0.05 eq), Na2CO3 (70.3 mg, 0.66 mmol, 3 eq)and H2O (0.2 mL) in dioxane (1 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 100 °C for 3 hr under N2 atmosphere. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with saturated brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (4 g SepaFlash® Silica Flash Column, EtOAc/PE: 0~60%) to afford Compound 79 (9.2 mg, 8.8 % yield) as a white solid. LC-MS (ESI): RT = 0.873 min, mass calcd for C22H15F5N2O2S 466.42 m/z, found 467.1[M+H]+.1H NMR (400 MHz, CD3OD) δ 6.72 (dd, J = 9.51, 0.63 Hz, 1 H) 7.23 - 7.32 (m, 3 H) 7.41 - 7.59 (m, 6 H) 7.82 - 7.88 (m, 2 H) 7.93 - 8.02 (m, 3 H) 8.14 (dd, J = 4.88, 1.88 Hz, 1 H). Example 80: 2'-(4-(Pentafluoro-λ6-sulfaneyl)phenoxy)-1-(pyrrolidin-3-yl)-[3,3'-bipyridin]- 6(1H)-one (Compound 80)
Tert-butyl 3-(5-bromo-2-oxo-1-pyridyl)pyrrolidine-1-carboxylate [00405] The mixture of 5-bromo-1H-pyridin-2-one (62A, 347.8 mg, 2.00 mmol, 1 eq), tert- butyl 3-bromopyrrolidine-1-carboxylate (500 mg, 2.00 mmol, 1 eq) and Cs2CO3 (651.3 mg, 2.00 mmol, 1 eq) in DMF (3 mL) was stirred at 60 °C for 16 hr. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered and 181
concentrated in vacuum. The residue was purified by flash chromatography on silica gel (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~50 % Ethyl acetate/Petroleum ether gradient @20 mL/min) to give intermediate 80A (45 mg, 0.12 mmol, 6.4% yield) as a white solid. Cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one [00406] A mixture of intermediate 80A (42.0 mg, 0.12 mmol, 1 eq), intermediate 76A (77.6 mg, 0.18 mmol, 1.5 eq), Pd(dppf)Cl2 (4.48 mg, 6.1 µmol, 0.05 eq), K2CO3 (50.7 mg, 0.36 mmol, 3.0 eq) in dioxane (1 mL) and H2O (0.5 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 90 °C for 8 hr under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and the reaction mixture was extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give crude intermediate 80B (68 mg, crude) as a yellow oil, which was used into next step without further purification. 5-[2-[4-(pentafluoro-λ6-sulfanyl)phenoxy]-3-pyridyl]-1-pyrrolidin-3-yl-pyridin-2-one [00407] intermediate 80B (68 mg, 0.12 mmol, 1 eq) in HCl/dioxane (4 M, 30 uL, 1 eq) was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to remove to give a residue, which was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75x30mmx3um; mobile phase: [water (0.05%HCl)-ACN]; B%: 25%-55%, 6.5 min) to afford Compound 80 (7.2 mg, 12.0 % yield, HCl) as a white solid. LC-MS (ESI): RT = 0.787 min, mass calcd for C20H18F5N3O2S 459.4 m/z found 460.0 [M+H]+.1H NMR (400 MHz, CD3OD) δ 8.17 (d, J = 4.0 Hz, 1H), 8.08 - 8.02 (m, 2H), 7.94 (br d, J = 9.3 Hz, 1H), 7.88 (d, J = 9.0 Hz, 2H), 7.37 - 7.28 (m, 3H), 6.68 (d, J=9.3 Hz, 1H), 5.18 (br s, 1H), 3.89 - 3.76 (m, 2H), 3.74 - 3.63 (m, 1H), 3.41 - 3.34 (m, 1H), 2.75 - 2.64 (m, 1H), 2.54 - 2.43 (m, 1H). Example 81: 1-(2-Fluoroethyl)-2'-(4-(pentafluoro-λ6-sulfaneyl)phenoxy)-[3,3'-bipyridin]- 6(1H)-one (Compound 81)
5-bromo-1-(2-fluoroethyl)pyridin-2-one [00408] To a solution of 5-bromo-1H-pyridin-2-one (62A, 500 mg, 2.87 mmol, 1 eq) and 1- bromo-2-fluoro-ethane (364.8 mg, 2.87 mmol, 1 eq) in DMF (5 mL) was added Cs2CO3 (1.8 g, 5.75 mmol, 2 eq). The reaction mixture was stirred at 25 °C for 16 hr. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x3). The combined organic layers were washed with brine (30 mL x2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 45% Ethyl acetate/Petroleum ether gradient @ 35mL/min) to give intermediate 81A (334 mg, 1.50 mmol, 52.2% yield) as a white solid. 1-(2-fluoroethyl)-5-[2-[4-(pentafluoro-λ6-sulfanyl)phenoxy]-3-pyridyl]pyridin-2-one [00409] A mixture of intermediate 81A (50 mg, 0.22 mmol, 1 eq), intermediate 76A (115.4 mg, 0.27 mmol, 1.2 eq), K2CO3 (62.8 mg, 0.45 mmol, 2 eq), Pd(dppf)Cl2 (8.3 mg, 11.3 µmol, 0.05 eq) in dioxane (2 mL) and H2O (0.5 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 100 °C for 6 hr under N2 atmosphere. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x3). The combined organic layers were washed with brine (30 mL x2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: 3_Phenomenex Luna C1875x30mmx3um;mobile phase: [water(0.05%HCl)-ACN];B%: 40%-70%,6.5min) to afford Compound 81 (45.11 mg, 22.5% yield) as a white solid. LC-MS (ESI): RT = 0.898 min, mass calcd for C18H14F6N2O2S 436.37 m/z, found 437.0 [M+H]+, 1H NMR (400 MHz, CD3OD) ppm 4.33 - 4.47 (m, 2 H) 4.67 (t, J = 4.52 Hz, 1 H) 4.79 (t, J = 4.52 Hz, 1 H) 6.68 (d, J = 9.29 Hz, 1 H) 7.22 - 7.32 (m, 3 H) 7.84 (d, J = 9.29 Hz, 2 H) 7.93 (td, J = 8.22, 1.63 Hz, 2 H) 8.01 (s, 1 H) 8.13 (dd, J = 4.77, 1.51 Hz, 1 H). Example 82: 1-(2,2-difluoroethyl)-2'-(4-(pentafluoro-λ6-sulfaneyl)phenoxy)-[3,3'-bipyridin]- 6(1H)-one (Compound 82)
5-bromo-1-(2,2-difluoroethyl)pyridin-2-one [00410] To a solution of 5-bromo-1H-pyridin-2-one (62A, 500 mg, 2.87 mmol, 1 eq) and 2- bromo-1,1-difluoro-ethane (416.5 mg, 2.87 mmol, 1 eq) in DMF (5 mL) was added Cs2CO3 (1.87 g, 5.75 mmol, 2 eq). The reaction mixture was stirred at 25 °C for 16 hrs. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x3). The combined organic layers were washed with brine (30 mL x2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 35% Ethyl acetate/Petroleum ether gradient @ 35 mL/min) to give intermediate 82A (248 mg, 1.03 mmol, 35.8% yield) as a white solid. 1-(2,2-difluoroethyl)-5-[2-[4-(pentafluoro-λ6-sulfanyl)phenoxy]-3-pyridyl]pyridin-2-one [00411] A mixture of intermediate 82A (50 mg, 0.21 mmol, 1 eq), intermediate 76A (106.6 mg, 0.25 mmol, 1.2 eq), K2CO3 (58.0 mg, 0.42 mmol, 2 eq), Pd(dppf)Cl2 (7.6 mg, 10.5 µmol, 0.05 eq) in dioxane (2 mL) and H2O (0.5 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 100 °C for 6 hr under N2 atmosphere. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x3). The combined organic layers were washed with brine (30 mL x2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: 3_Phenomenex Luna C1875x30mmx3um;mobile phase: [water(0.05%HCl)-ACN];B%: 40%-70%,6.5min) to afford Compound 82 (13.37 mg, 13.9% yield) as a white solid. LC-MS (ESI): RT = 0.919 min, mass calcd for C18H14F7N3OS 454.36 m/z, found 455.0 [M+H]+, 1H NMR (400 MHz,CD3OD) δ ppm 4.47 (td, J = 14.18, 4.02 Hz, 2 H) 6.04 - 6.37 (m, 1 H) 6.65
= 9.29 Hz, 1 H) 7.23 - 7.32 (m, 3 H) 7.82 - 7.88 (m, 2 H) 7.88 - 7.95 (m, 2 H) 7.98 (d, J = 2.26 Hz, 1 H) 8.13 (dd, J = 4.89, 1.88 Hz, 1 H). Example 83: 2-(4-(Trifluoromethyl)phenoxy)-6'-vinyl-3,3'-bipyridine (Compound 83)
2-chloro-5-[2-[4-(trifluoromethyl)phenoxy]-3-pyridyl]pyridine [00412] A mixture of 5-bromo-2-chloro-pyridine (62A, 200 mg, 1.04 mmol, 1 eq), intermediate 38B (455.4 mg, 1.25 mmol, 1.2 eq), K2CO3 (287.2 mg, 2.08 mmol, 2 eq), Pd(dppf)Cl2 (38.0 mg, 51.9 µmol, 0.05 eq) in dioxane (2 mL) and H2O (0.5 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 100 °C for 6 hrs under N2 atmosphere. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x3). The combined organic layers were washed with brine (30 mL x2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~5% Ethyl acetate/Petroleum ether gradient @ 20 mL/min) to give intermediate 83B (234 mg, 0.61 mmol, 59.0% yield) as a white solid. 2-[4-(trifluoromethyl)phenoxy]-3-(6-vinyl-3-pyridyl)pyridine [00413] A mixture of intermediate 83B (50 mg, 0.14 mmol, 1 eq), 4,4,5,5-tetramethyl-2- vinyl-1,3,2-dioxaborolane (24C, 26.3 mg, 0.17 mmol, 29.0 µL, 1.2 eq), K2CO3 (39.4 mg, 0.28 mmol, 2 eq), Pd(dppf)Cl2 (5.2 mg, 7.1 µmol, 0.05 eq) in dioxane (2 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 100 °C for 6 hrs under N2 atmosphere. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x3). The combined organic layers were washed with brine (30 mL x2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: 3_Phenomenex Luna C1875x30mmx3um;mobile phase: [water(0.05%HCl)- ACN];B%: 37%-67%,8.5min) to afford Compound 83 (3.52 mg, 7.1% yield) as a white solid. LC- MS (ESI): RT = 0.873 min, mass calcd for C19H13F3N2O 342.31 m/z, found 343.1 [M+H]+, 1H NMR (400 MHz, CD3OD) ppm 6.12 (d, J = 11.13 Hz, 1 H) 6.62 (d, J = 17.64 Hz, 1 H) 7.05 (dd, J = 17.64, 11.26 Hz, 1 H) 7.34 - 7.40 (m, 3 H) 7.74 (d, J = 8.50 Hz, 2 H) 8.17 (dd, J = 7.63, 1.88 Hz, 1 H) 8.26 (dd, J = 4.94, 1.81 Hz, 1 H) 8.34 (d, J = 8.63 Hz, 1 H) 8.87 (dd, J = 8.63, 2.13 Hz, 1 H) 9.09 (d, J = 1.63 Hz, 1 H).
Example 84: N-(4-(Trifluoromethyl)phenyl)-6'-vinyl-[3,3'-bipyridin]-2-amine (Compound 84)
3-(6-chloro-3-pyridyl)-N-[4-(trifluoromethyl)phenyl]pyridin-2-amine [00414] A mixture of (6-chloro-3-pyridyl)boronic acid (84A, 300 mg, 1.91 mmol, 1 eq), intermediate 19B (604.5 mg, 1.91 mmol, 1 eq), K2CO3 (526.9 mg, 3.81 mmol, 2 eq), Pd(dppf)Cl2 (69.7 mg, 95.3 µmol, 0.05 eq) in dioxane (2 mL) and H2O (0.5 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 100 °C for 6 hrs under N2 atmosphere. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x3). The combined organic layers were washed with brine (30 mL x2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 30% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give intermediate 84B (402 mg, 0.87 mmol, 45.8% yield) as a white solid. N-[4-(trifluoromethyl)phenyl]-3-(6-vinyl-3-pyridyl)pyridin-2-amine [00415] A mixture of intermediate 84B (100 mg, 0.28 mmol, 1 eq), 4,4,5,5-tetramethyl-2- vinyl-1,3,2-dioxaborolane (24C, 52.8 mg, 0.34 mmol, 58.2 µL, 1.2 eq), K2CO3 (79.0 mg, 0.57 mmol, 2 eq), Pd(dppf)Cl2 (10.4 mg, 14.3 µmol, 0.05 eq) in dioxane (2 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 100 °C for 6 hr under N2 atmosphere. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x3). The combined organic layers were washed with brine (30 mL x2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: 3_Phenomenex Luna C1875x30mmx3um;mobile phase: [water(0.05%HCl)- ACN];B%: 30%-60%,6.5min) to afford Compound 84 (25.31 mg, 25.9% yield) as a yellow solid. LC-MS (ESI): RT = 0.776 min, mass calcd for C19H14F3N3341.33 m/z, found 341.9 [M+H]+, 1H NMR (400 MHz, CD3OD) ppm 6.15 (d, J = 11.04 Hz, 1 H) 6.67 (d, J = 17.57 Hz, 1 H) 7.09 (dd, J
= 17.57, 11.29 Hz, 1 H) 7.33 (dd, J = 7.28, 6.02 Hz, 1 H) 7.63 (d, J = 8.53 Hz, 2 H) 7.79 (d, J = 8.53 Hz, 2 H) 8.15 (ddd, J = 13.87, 6.71, 1.51 Hz, 2 H) 8.38 (d, J = 8.53 Hz, 1 H) 8.69 (dd, J = 8.41, 1.63 Hz, 1 H) 9.03 (d, J = 1.26 Hz, 1 H). [00416] Example 85: 1-Methyl-5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)pyridin- 2(1H)-one (Compound 85)
[00417] 2-Bromo-N-(4-(trifluoromethyl)phenyl)aniline (7B, 1 eq) and (1-methylpyridin- 2(1H)-one-5-yl)boronic acid (62C, 1.2 eq) were suspended in 1:42M K2CO3 /dioxane, and the reaction mixture was purged with N2 for 10 min. To this reaction mixture was added Pd(dppf)Cl2 (0.1 eq), and the reaction mixture was heated to 100 °C until LCMS indicated starting materials were consumed. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with NH4Cl, H2O, and brine. The organic layers were dried over Na2SO4, concentrated, and purified by flash chromatography to afford Compound 85 (84% yield). LCMS Calcd.: 344.1, m/z found: 345.0 ([M+H]+).1H NMR (600 MHz, DMSO-d6) δ ppm: 3.41 (s, 3 H) 6.32 (d, J=9.35 Hz, 1 H) 6.85 (d, J=8.62 Hz, 2 H) 7.17 - 7.22 (m, 1 H) 7.31 - 7.41 (m, 6 H) 7.77 (d, J=2.48 Hz, 1 H) 8.09 (s, 1 H). Example 86: N-Methyl-5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)picolinamide (Compound 86)
[00418] Compound 86 was prepared by employing the procedure for Compound 85 using N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide in lieu of 1-methylpyridin- 2(1H)-one-5-yl)boronic acid (62C). LC-MS Calcd.: 371.1 m/z found: 372.1 ([M+H]+).1H NMR (600 MHz, DMSO-d6) δ ppm 2.81 (d, J=4.77 Hz, 3 H) 6.83 (d, J=8.44 Hz, 2 H) 7.34 (t, J=7.40 Hz, 1 H) 7.39 - 7.44 (m, 3 H) 7.45 - 7.54 (m, 2 H) 7.99 - 8.04 (m, 2 H) 8.25 (s, 1 H) 8.61 (s, 1 H) 8.77 (q, J=4.40 Hz, 1 H). Example 87: N,N-Dimethyl-5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)picolinamide (Compound 87)
[00419] Compound 87 was prepared by employing the procedure for Compound 85 using N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide in lieu of 1- methylpyridin-2(1H)-one-5-yl)boronic acid (62C). LC-MS Calcd.: 385.1 m/z found: 386.1 ([M+H]+).1H NMR (600 MHz, DMSO-d6) δ ppm 2.70 (s, 5 H) 2.82 (s, 3 H) 2.99 (s, 3 H) 6.76 (d, J=8.44 Hz, 2 H) 7.31 - 7.37 (m, 3 H) 7.40 (d, J=8.07 Hz, 1 H) 7.46 - 7.51 (m, 3 H) 7.90 (dd, J=8.07, 2.20 Hz, 1 H) 8.34 (s, 1 H) 8.58 (s, 1 H). Example 88: N-Methyl-6-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)nicotinamide (Compound 88)
[00420] Compound 88 was prepared by employing the procedure for Compound 85 using N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide in lieu of 1-methylpyridin- 2(1H)-one-5-yl)boronic acid (62C). LC-MS Calcd.: 371.1 m/z found: 372.1 ([M+H]+).1H NMR (600 MHz, DMSO-d6) δ ppm 2.83 (d, J=4.40 Hz, 3 H) 7.12 (d, J=8.44 Hz, 2 H) 7.20 (t, J=7.51 Hz, 1 H) 7.43 - 7.51 (m, 4 H) 7.81 (dd, J=7.89, 1.28 Hz, 1 H) 7.89 (d, J=8.07 Hz, 1 H) 8.24 (dd, J=8.44, 2.20 Hz, 1 H) 8.65 - 8.70 (m, 1 H) 9.11 (d, J=1.83 Hz, 1 H) 9.86 (s, 1 H). Example 89: N,N-Dimethyl-6-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)nicotinamide (Compound 89)
[00421] Compound 89 was prepared by employing the procedure for Compound 85 using N,N-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide in lieu of 1- methylpyridin-2(1H)-one-5-yl)boronic acid (62C). LC-MS Calcd.: 385.1 m/z found: 386.1 ([M+H]+).1H NMR (600 MHz, DMSO-d6) δ ppm 2.94 (s, 3 H) 3.02 (s, 3 H) 7.07 (d, J=8.80 Hz, 2 H) 7.21 (t, J=7.36 Hz, 1 H) 7.43 - 7.49 (m, 4 H) 7.77 - 7.82 (m, 2 H) 7.90 (dd, J=8.07, 2.20 Hz, 1 H) 8.72 (s, 1 H) 9.69 (s, 1 H). Example 90: 5-(Methylsulfonyl)-2-(2-(4-(trifluoromethyl)phenoxy)phenyl)pyridine (Compound 90)
[00422] 1-Iodo-2-(4-(trifluoromethyl)phenoxy)benzene (90A, 36 mg, 0.1 mmol, 1 eq) and (5-(methylsulfonyl)pyridine-2-yl)boronic acid (24 mg, 0.12 mmol, 1.2 eq.) were suspended in 1:4 2M K2CO3 /dioxane, and the reaction mixture was purged with N2 for 10 min. To the reaction mixture was added Pd(dppf)Cl2 (0.1 eq), and the reaction mixture was heated to 100 °C until LCMS indicated starting materials were consumed. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with NH4Cl, H2O, and brine. The organic layers were dried over Na2SO4, concentrated, and purified by flash chromatography (DCM/EtOAc gradient) to afford Compound 90 (34 mg, 87%). LCMS Calcd.: 393.1 m/z found: 394.0 ([M+H]+).1H NMR (600 MHz, DMSO-d6) δ ppm 3.33 - 3.35 (m, 3 H) 7.15 (m, J=8.80 Hz, 2 H) 7.22 (d, J=8.15 Hz, 1 H) 7.46 (td, J=7.52, 1.10 Hz, 1 H) 7.60 (td, J=7.70, 1.83 Hz, 1 H) 7.72 (m, J=8.80 Hz, 2 H) 7.97 (dd, J=7.89, 1.65 Hz, 1 H) 8.05 (d, J=8.44 Hz, 1 H) 8.33 (dd, J=8.44, 2.57 Hz, 1 H) 9.12 (d, J=2.20 Hz, 1 H). Example 91: 6-Hydroxy-2'-(4-(trifluoromethyl)phenoxy)-[3,3'-bipyridine]-5-carbonitrile (Compound 91)
3-Bromo-2-(4-(trifluoromethyl)phenoxy)pyridine [00423] 3-Bromo-2-fluoropyridine (91A, 20.6 g, 117 mmol, 1 eq.), 4- (trifluoromethyl)phenol (19.02 g, 117 mmol, 1 eq.), Cs2CO3 (45.8 g, 141 mmol, 1.2 eq.), and DMF (292 mL) were heated to 100 °C for 6 hrs until LC-MS indicated the completion of reaction. The reaction mixture was added to rapidly stirring water, and the solid was filtered to give intermediate 91B (26.3g, 71%). LC-MS Calcd.: 318 ([M+H]+), m/z found: 318.
6-Hydroxy-2'-(4-(trifluoromethyl)phenoxy)-[3,3'-bipyridine]-5-carbonitrile [00424] Intermediate 91B (1 eq.) and (2-hydroxy-3-cyanopyridin-5-yl)boronic acid (1.1 eq.) were suspended in 1:42M K2CO3 /dioxane, and the reaction mixture was purged with N2 for 10 min. To the reaction mixture was added Pd(dppf)Cl2 (0.1 eq), and the reaction mixture was heated to 100 °C until LCMS indicated reaction completion. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with NH4Cl, H2O, and brine. The organic layers were dried over Na2SO4, concentrated, and purified by flash chromatography to afford Compound 91. LCMS mass calcd., C18H10F3N3O2, 357. m/z found, 358 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ ppm 7.29 (dd, J=7.52, 4.95 Hz, 1 H) 7.43 (d, J=8.44 Hz, 2 H) 7.81 (d, J=8.44 Hz, 2 H) 8.03 (dd, J=7.34, 1.83 Hz, 1 H) 8.12 (dd, J=4.77, 1.83 Hz, 1 H) 8.17 (d, J=2.20 Hz, 1 H) 8.57 (d, J=2.93 Hz, 1 H) 12.90 (br d, J=1.83 Hz, 1 H). Example 92: 5-Fluoro-2'-(4-(trifluoromethyl)phenoxy)-[3,3'-bipyridin]-6-ol (Compound 92)
[00425] Compound 92 was prepared by employing the procedure for Compound 91 using (2-hydroxy-3-fluoropyridin-5-yl)boronic acid in lieu of (2-hydroxy-3-cyanopyridin-5-yl)boronic acid. LC-MS Calcd.: 351 ([M+H]+), m/z found: 351.0.1H NMR (600 MHz, DMSO-d6) δ ppm: 7.27 (dd, J=7.34, 4.77 Hz, 1 H) 7.41 (m, J=8.44 Hz, 2 H) 7.64 (s, 1 H) 7.79 (m, J=8.44 Hz, 2 H) 7.85 (dd, J=12.10, 2.20 Hz, 1 H) 8.00 (dd, J=7.34, 1.83 Hz, 1 H) 8.10 (dd, J=4.77, 1.83 Hz, 1 H) 12.44 (br s, 1 H). Example 93: 3-Chloro-5-(3-(4-(trifluoromethyl)phenoxy)pyrazin-2-yl)pyridin-2-ol (Compound 93)
[00426] Intermediate 21C (20 mg, 0.07 mmol, 1 eq.) and (2-hydroxy-3-chloropyridin-5- yl)boronic acid (23 mg, 0.087 mmol, 1.2 equiv.) were suspended in 1:42M K2CO3 /dioxane, and this mixture was purged with N2 for 10 min. To this mixture was added Pd(dppf)Cl2 (0.1 eq), and the reaction mixture was heated to 100 °C until LCMS indicated starting materials were consumed. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with NH4Cl, H2O, and brine. The organic layers were dried over Na2SO4, concentrated, and purified by flash chromatography to afford Compound 93 (5 mg). LCMS mass calcd. C16H9ClF3N3O2, 367. m/z found, 368 [M+H]+.1H NMR (600 MHz, DMSO-d6) δ ppm 7.54 (d, J=8.44 Hz, 2 H) 7.86 (d, J=8.80 Hz, 2 H) 8.11 (d, J=2.57 Hz, 1 H) 8.30 - 8.33 (m, 1 H) 8.47 (d, J=2.57 Hz, 1 H) 8.50 (d, J=2.57 Hz, 1 H) 12.57 (br s, 1 H). Example 94: 2-Hydroxy-5-(3-(4-(trifluoromethyl)phenoxy)pyrazin-2-yl)nicotinonitrile (Compound 94)
[00427] Compound 94 was prepared by employing the procedure for Compound 93 using (2-hydroxy-3-cyanopyridin-5-yl)boronic acid in lieu of (2-hydroxy-3-chloropyridin-5-yl)boronic acid. LC-MS mass calcd., C17H9F3N4O2, 358. m/z found, 359 [M+H]+.1H NMR (600 MHz, DMSO-d6) δ ppm 7.54 (d, J=8.44 Hz, 2 H) 7.87 (d, J=8.80 Hz, 2 H) 8.14 (d, J=2.57 Hz, 1 H) 8.48 (d, J=2.57 Hz, 1 H) 8.57 (d, J=2.57 Hz, 1 H) 8.84 (d, J=2.57 Hz, 1 H) 13.00 (br s, 1 H). Example 95: 3-Fluoro-5-(3-(4-(trifluoromethyl)phenoxy)pyrazin-2-yl)pyridin-2-ol (Compound 95)
[00428] Compound 95 was prepared by employing the procedure for Compound 93 using (2-hydroxy-3-fluoropyridin-5-yl)boronic acid in lieu of (2-hydroxy-3-chloropyridin-5-yl)boronic acid. LC-MS mass calcd., C16H9F4N3O2, 351. m/z found, 352 [M+H]+.1H NMR (600 MHz, DMSO-d6) δ ppm 7.54 (d, J=8.44 Hz, 2 H) 7.86 (d, J=8.44 Hz, 2 H) 8.09 - 8.20 (m, 3 H) 8.47 (d, J=2.57 Hz, 1 H) 12.55 (br s, 1 H). Example 96: 2-Methoxy-5-(3-(4-(trifluoromethyl)phenoxy)pyrazin-2-yl)pyrimidine (Compound 96)
[00429] Compound 96 was prepared by employing the procedure for Compound 93 using (2-methoxy-pyrimidin-5-yl)boronic acid in lieu of (2-hydroxy-3-chloropyridin-5-yl)boronic acid. LC-MS calcd.: 348.1, m/z found: 349.0 ([M+H]+).1H NMR (600 MHz, DMSO-d6) δ ppm 3.95 - 4.05 (m, 3 H) 7.56 (d, J=8.44 Hz, 2 H) 7.86 (d, J=8.80 Hz, 2 H) 8.24 (d, J=2.57 Hz, 1 H) 8.57 (d, J=2.57 Hz, 1 H) 9.29 (s, 2 H). Example 97: 3-Chloro-5-(3-((4-(trifluoromethyl)phenyl)thio)pyrazin-2-yl)pyridin-2-ol (Compound 97)
[00430] Intermediate 29A (2.35 g, 8 mmol, 1 eq.) and (2-hydroxy-3-chloropyridin-5- yl)boronic acid (1.81 g, 9.6 mmol, 1.2 equiv.) were suspended in 1:42M K2CO3 /dioxane, and this reaction mixture was purged with N2 for 10 min. To this reaction mixture was added Pd(dppf)Cl2 (0.1 eq), and the reaction mixture was heated to 100 °C until LCMS indicated starting materials were consumed. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with NH4Cl, H2O, and brine. The organic layers were dried over Na2SO4, concentrated, and purified by flash chromatography to afford Compound 97. LC-MS mass calcd., C16H9ClF3N3OS, 383. m/z found, 384 [M+H]+.1H NMR (600 MHz, DMSO-d6) δ ppm 7.71 (m ,J=8.44 Hz, 2 H) 7.80 (m, J=8.44 Hz, 2 H) 7.95 (br s, 1 H) 8.14 (d, J=2.57 Hz, 1 H) 8.40 (d, J=2.20 Hz, 1 H) 8.52 (d, J=2.57 Hz, 1 H) 12.62 (br s, 1 H). Example 98: 2-Hydroxy-5-(3-((4-(trifluoromethyl)phenyl)thio)pyrazin-2-yl)nicotinonitrile (Compound 98)
[00431] Compound 98 was prepared by employing the procedure for Compound 97 using (2-hydroxy-3-cyanopyridin-5-yl)boronic acid in lieu of (2-hydroxy-3-chloropyridin-5-yl)boronic acid. LC-MS mass calcd., C17H9F3N4OS, 374. m/z found, 375 [M+H]+.1H NMR (600 MHz, DMSO-d6) δ ppm 7.70 (d, J=8.07 Hz, 2 H) 7.79 (d, J=8.44 Hz, 2 H) 8.30 (d, J=2.57 Hz, 1 H) 8.41 (d, J=2.57 Hz, 1 H) 8.47 (d, J=2.57 Hz, 1 H) 8.53 (d, J=2.57 Hz, 1 H). Example 99: 5-(3-((4-(Trifluoromethyl)phenyl)thio)pyrazin-2-yl)pyrimidin-2-ol (Compound 99)
[00432] Compound 99 was prepared by employing the procedure for Compound 97 using (2-hydroxy-pyrimidin-5-yl)boronic acid in lieu of (2-hydroxy-3-chloropyridin-5-yl)boronic acid. LC-MS Calcd.: 351 ([M+H]+), m/z found: 351.0.1H NMR (600 MHz, DMSO-d6) δ ppm: 7.71 (m, J=8.07 Hz, 2 H) 7.79 (m, J=8.07 Hz, 2 H) 8.44 (d, J=2.57 Hz, 1 H) 8.56 (d, J=2.57 Hz, 1 H) 8.71 (br s, 2 H). Example 100: 2-Methoxy-5-(3-((4-(Trifluoromethyl)phenyl)thio)pyrazin-2-yl)pyrimidine (Compound 100)
[00433] Compound 100 was prepared by employing the procedure for Compound 97 using (2-methoxy-pyrimidin-5-yl)boronic acid in lieu of (2-hydroxy-3-chloropyridin-5-yl)boronic acid. LC-MS Calcd.: 364.1 m/z found: 365.0 ([M+H]+).1H NMR (600 MHz, DMSO-d6) δ ppm 4.03 (s, 3 H) 7.71 (m, J=8.07 Hz, 2 H) 7.79 (m, J=8.07 Hz, 2 H) 8.51 (d, J=2.57 Hz, 1 H) 8.62 (d, J=2.20 Hz, 1 H) 9.01 (s, 2 H). Example 101: 3-Fluoro-5-(3-((4-(trifluoromethyl)phenyl)thio)pyrazin-2-yl)pyridin-2-ol (Compound 101)
[00434] Compound 101 was prepared by employing the procedure for Compound 97 using (2-hydroxy-3-fluoropyridin-5-yl)boronic acid in lieu of (2-hydroxy-3-chloropyridin-5-yl)boronic acid. LC-MS Calcd.: 368 ([M+H]+), m/z found: 368.0.1H NMR (600 MHz, DMSO-d6) δ ppm: 7.71 (d, J=8.07 Hz, 2 H) 7.78 - 7.84 (m, 4 H) 8.39 (d, J=2.57 Hz, 1 H) 8.51 (d, J=2.57 Hz, 1 H) 12.59 (br s, 1 H).
Example 102: 2-(Prop-2-yn-1-yloxy)-5-(3-((4-(trifluoromethyl)phenyl)thio)pyrazin-2- yl)pyrimidine (Compound 102)
[00435] Compound 102 was prepared by employing the procedure for Compound 97 using 2-(prop-2-yn-1-yloxy)pyrimidin-5-yl)boronic acid in lieu of (2-hydroxy-3-chloropyridin-5- yl)boronic acid. LC-MS Calcd.: 389 ([M+H]+), m/z found: 389. Example 103: 3-(2-(Prop-2-yn-1-yloxy)pyrimidin-5-yl)-N-(4- (trifluoromethyl)phenyl)pyrazin-2-amine (Compound 103)
[00436] Intermediate 19B (1 eq.) and 2-(prop-2-yn-1-yloxy)pyrimidin-5-yl)boronic acid (1.2 equiv.) were suspended in 1:42M K2CO3 /dioxane, and this mixture was purged with N2 for 10 min. To this reaction mixture was added Pd(dppf)Cl2 (0.1 eq), and the reaction mixture was heated to 100 °C until LCMS indicated starting materials were consumed. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with NH4Cl, H2O, and brine. The organic layers were dried over Na2SO4, concentrated, and purified by flash chromatography to afford Compound 103. LC-MS Calcd.: 371.1, m/z found: 372.0 ([M+H]+).1H NMR (600 MHz, DMSO-d6) δ ppm 3.61 (t, J=2.38 Hz, 1 H) 5.12 (d, J=2.40 Hz, 2 H) 7.63 (m, J=8.71 Hz, 2 H) 7.74 - 7.78 (m, 2 H) 8.27 (s, 2 H) 8.97 (s, 2 H) 9.12 (s, 1 H).
Example 104: 6-Hydroxy-2'-(4-(pentafluoro-λ6-sulfaneyl)phenoxy)-[3,3'-bipyridine]-5- carbonitrile (Compound 104)
dioxane/ H2O [00437] Intermediate 65C (1 eq.) and (2-hydroxy-3-cyanopyridin-5-yl)boronic acid (1.2 equiv.), were suspended in 1:42M K2CO3 /dioxane, and this mixture was purged with N2 for 10 min. To this mixture was added Pd(dppf)Cl2 (0.1 eq), and the reaction mixture was heated to 100 °C until LCMS indicated starting materials were consumed. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with NH4Cl, H2O, and brine. The organic layers were dried over Na2SO4, concentrated, and purified by flash chromatography to afford Compound 104. LC-MS Calcd.: 416 ([M+H]+), m/z found: 416.1H NMR (600 MHz, DMSO-d6) δ ppm 7.28 - 7.31 (m, 1 H) 7.43 (d, J=9.17 Hz, 2 H) 7.95 - 8.00 (m, 2 H) 8.04 (dd, J=7.34, 1.83 Hz, 1 H) 8.13 (dd, J=4.77, 1.83 Hz, 1 H) 8.17 (d, J=2.57 Hz, 1 H) 8.56 (d, J=2.57 Hz, 1 H) 12.71 - 13.08 (m, 1 H). Example 105: 5-Chloro-2'-(4-(pentafluoro-λ6-sulfaneyl)phenoxy)-[3,3'-bipyridin]-6-ol (Compound 105)
[00438] Compound 105 was prepared by employing the procedure for Compound 104 using (2-hydroxy-3-chloropyridin-5-yl)boronic acid in lieu of (2-hydroxy-3-cyanopyridin-5- yl)boronic acid. LC-MS Calcd.: 425 ([M+H]+), m/z found: 425.1H NMR (600 MHz, DMSO-d6) δ ppm 7.26 - 7.30 (m, 1 H) 7.41 (d, J=8.80 Hz, 2 H) 7.79 (d, J=2.20 Hz, 1 H) 7.95 - 7.99 (m, 2 H)
8.02 (dd, J=7.34, 1.83 Hz, 1 H) 8.11 (dd, J=5.13, 1.83 Hz, 1 H) 8.15 (d, J=2.20 Hz, 1 H) 12.47 (br s, 1 H). Example 106: 1-Methyl-2'-(4-(pentafluoro-λ6-sulfaneyl)phenoxy)-[3,3'-bipyridin]-6(1H)-one (Compound 106)
[00439] Compound 106 was prepared by employing the procedure for Compound 104 using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one in lieu of (2- hydroxy-3-cyanopyridin-5-yl)boronic acid. LC-MS Calcd.: 405 ([M+H]+), m/z found: 405.1H NMR (600 MHz, DMSO-d6) δ ppm 3.50 (s, 3 H) 6.48 (d, J=9.54 Hz, 1 H) 7.30 (dd, J=7.34, 4.77 Hz, 1 H) 7.39 (d, J=9.17 Hz, 2 H) 7.80 (dd, J=9.35, 2.75 Hz, 1 H) 7.94 - 7.99 (m, 4 H) 8.09 (d, J=2.57 Hz, 1 H) 8.12 (dd, J=4.77, 1.83 Hz, 1 H). Example 107: 5-Fluoro-2'-((4-(pentafluoro-λ6-sulfaneyl)phenyl)amino)-[3,3'-bipyridin]-6-ol (Compound 107)
dioxane/ H2O [00440] Intermediate 66A (1 eq.) and (2-hydroxy-3-fluoropyridin-5-yl)boronic acid (1.2 equiv.) were suspended in 1:42M K2CO3 /dioxane, and this mixture was purged with N2 for 10 min. To this mixture was added Pd(dppf)Cl2 (0.1 eq), and the reaction mixture was heated to 100 °C until LCMS indicated starting materials were consumed. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with NH4Cl, H2O, and brine. The organic layers were dried over Na2SO4, concentrated, and purified by flash chromatography to afford
Compound 107. LCMS Calcd.: 408 ([M+H]+), m/z found: 408.0.1H NMR (600 MHz, DMSO- d6) δ ppm: 7.03 (dd, J=7.52, 4.95 Hz, 1 H) 7.36 (s, 1 H) 7.50 (dd, J=11.74, 2.20 Hz, 1 H) 7.62 (dd, J=7.34, 1.83 Hz, 1H) 7.69 - 7.75 (m, 4 H) 8.22 (dd, J=4.77, 1.83 Hz, 1 H) 8.55 (s, 1 H) 12.35 (br s, 1 H). Example 108: 6-Hydroxy-2'-((4-(pentafluoro-λ6-sulfaneyl)phenyl)amino)-[3,3'-bipyridine]-5- carbonitrile (Compound 108)
dioxane/ H2O [00441] Compound 108 was prepared by employing the procedure for Compound 107 using (2-hydroxy-3-cyanopyridin-5-yl)boronic acid in lieu of (2-hydroxy-3-fluoropyridin-5- yl)boronic acid. LCMS Calcd.: 415 ([M+H]+), m/z found: 415.0. Example 109: 1-Methyl-2'-((4-(pentafluoro-λ6-sulfaneyl)phenyl)amino)-[3,3'-bipyridin]- 6(1H)-one (Compound 109)
dioxane/ H2O : [00442] Compound 109 was prepared by employing the procedure for Compound 107 using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one in lieu of (2- hydroxy-3-fluoropyridin-5-yl)boronic acid. LCMS Calcd.: 435 ([M+H]+), m/z found: 435.0. II. Biological Evaluation Example A1: YAP Reporter Assay
[00443] HEK293T cells stably transfected with 8XTBD luciferase reporter and pRLTK in 384-well plates were treated with the test compounds, starting from 3 µM (final concentration in assay plate), 1:3 dilution, and 10 points in quadruplicates. Post 24-hr incubation with compounds at 37 °C and 5% CO2, cells were lysed, and 8XTBD-driven firefly luciferase and control TK-driven renilla luciferase activities were measured using Promega Dual-Luciferase Reporter Assay System. [00444] Reagents: The reagents used for this study were: DMEM: Invitrogen# 11960077, Dual-Glo Luciferase Assay System: Promega-E2980, Puromycin Dihydrochloride: Invitrogen- A1113803, 384-well plate: PerkinElmer-6007480, L-GLUTAMINE: Invitrogen-25030164, Hygromycin B: Invitrogen-10687010 , and Penicillin-Streptomycin: Merk-TMS-AB2-C. [00445] Media: The media used for this assay were: Culture Medium: DMEM+ 1ug/mL puromycin + 200 ug/mL hygromycin (with 10% FBS + 1mM L-glutamine); and Assay Medium: DMEM (with 10% FBS + 1mM L-glutamine + 1x P/S). [00446] Cell Plating: The appropriate media was warmed at 37 °C by water bath: Culture Medium, Assay Medium, 1x D-PBS, 0.05% trypsin-EDTA. The cells were trypsinized after removing all media, then washed with 1x sterile D-PBS and then with 2 ml 0.05% trypsin-EDTA. The cells were then incubated at RT for one minute. Then 10 mL/75 cm2 flask Assay Medium was added to each flask. Using a 10 mL pipette, the cells were then gently resuspended in the media, until the clumps completely disappeared. The cells were then transferred into 50 mL centrifuge tubes and were centrifuged at 800 rpm for 5 mins. The medium was removed, and the cells were resuspended with Assay Medium. An aliquot of cells was used to count the cell density (cells/mL). The cell suspension was then diluted with Assay Medium to a concentration of 6x104 cells/mL. 50 µL cells suspension was then plated to 384-well plate (PerkinElmer-6007480), 3x103 cells/well and the cells were incubated in an incubator at 37 °C, 5% CO2. [00447] Compound Treatment: In the afternoon (incubation of the plate with 3-4 hrs), the test compounds were added by Echo, starting from 3 µM (final concentration in the assay plate), 1:3 dilution, 10 points, quadruplicates. The plate was placed at 37°C, 5% CO2 incubator for 24hrs. [00448] Detection: The Dual-Glo Luciferase Reagent was prepared by transferring the contents of one bottle of Dual-Glo Luciferase Buffer to one bottle of Dual-Glo Luciferase Substrate to create the Dual-Glo Luciferase Reagent. Mixing was performed by inversion until the substrate was thoroughly dissolved. After mixing, the reagent was aliquoted into 15 mL tubes. In the afternoon (24 hrs post-compound treatment), the DMEM+ medium in the 384 well plates were aspirated by Microplate Washer. [00449] Measuring firefly luciferase activity: 20 µL Dual-Glo Luciferase Reagent was added to the 384-well plates. The plates were protected from light to prevent interference with the assay.
The plates were shaken for 1 min followed centrifuging plates at 1000 rpm for 30 seconds. After waiting at least 10 minutes, the firefly luminescence was measured by Envision. [00450] Measuring renilla luciferase activity: 20 µL Stop-Glo Reagent was added to the 384- well plates. The plates were shaken for 1 min and then centrifuged at 1000rpm for 30 seconds. After waiting at least 10 minutes, the renilla luminescence was measured by Envision. [00451] Compounds’ IC50 and maximum inhibition on the firefly luciferase and renilla luciferase activities were reported separately. IC50’s for firefly luciferase activity of the tested compounds are shown in Table 2. TABLE 2
Note: Biochemical assay IC50 data are designated within the following ranges: A: ≤ 0.1 µM C: > 0.2 µM to ≤ 1.0 µM B: > 0.1 µM to ≤ 0.2 µM D: > 1.0 µM ≤ 10 µM N.D.: Not determined Example A2: Tumor Suppression Assay [00452] The procedures described herein for the tumor suppression assay is as described in PCT/US2013/043752 (WO 2013/188138). Mouse procedures are performed according to the guidelines of approved animal protocol and based on the methods. After the cells are grown to 90%> confluence, these cells are harvested by trypsinization, washed in phosphate-buffered saline (PBS), and resuspended in PBS supplemented with 50% Matrigel (BD Biosciences). An appropriate amount of cells is prepared for administration, such as 200 μL per injection site. Immuno-compromised mice are injected on the dorsolateral sites subcutaneously. Any one of the compounds described herein is formulated accordingly and is then administered at a suitable dose. Control mice received vehicle alone. The average tumor diameter (two perpendicular axes of the tumor are measured) are recorded. The data are expressed in tumor volume estimated by ([width]2 x length/2). Paired, two-tailed Student's t-test is performed to access the statistical significance. Example A3: Cell Proliferation Assay [00453] Cancer cell lines are plated in 384-well plates 24 hrs before drug treatment. Post incubation for various time periods with the test compounds, starting from 3 µM (final
concentration in assay plate), 1:3 dilution, and 10 points in duplicates, the number of viable cells and proliferative cells are determined using CellTiter-Glo® Luminescent Cell Viability Assay Kit (Promega) and Click-iT EdU HCS Assay Kit (Invitrogen) according to the manufacturers’ protocols. The IC50 values and maximum % inhibition of the test compounds are calculated using the dose response curves. [00454] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.
Claims
CLAIMS WHAT IS CLAIMED IS: 1. A compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
wherein, ring A is monocyclic heteroaryl; X1 is N or CRX1; X2 is N or CRX2; X3 is N or CRX3; X4 is N or CRX4; Y is CR4R5, O, S, or NR6; each of RX1, RX2, RX3, and RX4, when present, is independently hydrogen, halogen, nitro, - OR7, -SR7, -CN, -C(=O)R7, -C(=O)NR7R8, -C(=O)OR7, -S(=O)R7, -S(=O)2R7, -NR7R8, - NR7S(=O)2R8, -NR7C(=O)R8, -NR7C(=O)OR8, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3- C7cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl; R is halogen, nitro, -CN, -OR7, -SR7, -S(R7)5, -C(=O)R7, -C(=O)NR7R8, -C(=O)OR7, - S(=O)R7, -S(=O)2R7, -NR7R8, -NR7S(=O)2R8, -NR7C(=O)R8, -NR7C(=O)OR8, or substituted or unsubstituted C1-C6fluoroalkyl; each of R1 and R2 is independently halogen, nitro, -CN, -OR7, -SR7, -S(=O)R7, -S(=O)2R7, - S(=O)2NR7R8, -NR7R8, -C(=O)R7, -C(=O)OR7, -C(=O)NR7R8, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3 is halogen, nitro, -OR7, -SR7, -CN, -C(=O)R7, -OC(=O)R7, -C(=O)NR7R8, -C(=O)OR7, - S(=O)R7, -S(=O)NR7R8, -S(=NR7)R8, -S(=NR7)NR7R8, -S(=O)2R7, -S(=O)2NR7R8, - S(=O)(=NR7)R7, -S(=O)(=NR7)NR7R8, -NR7R8, -NR7S(=O)2R8, -NR7S(=O)(=NR7)R8, - NR7C(=O)R8, -N[C(=O)R8]2, -NR7C(=O)NR7R8, NR7CH2C(=O)NR7R8,
NR7CH2CH2C(=O)NR7R8, -NR7C(=O)OR8, -P(=O)(OR7)R8, -P(=O)(OR7)(OR8), - P(=O)R7R8, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2- C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1- C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted C5-C10 aryl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl; each R4, R5, R6, R7, and R8 is independently hydrogen, halogen, -CN, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R4 and R5 taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C3-C8cycloalkyl or substituted or unsubstituted 3- to 8- membered heterocycloalkyl having 1 or 2 heteroatoms each independently selected from N, O, and S; or R7 and R8 taken together with the atom to which they are attached to form a substituted or unsubstituted N- or P-containing 3- to 8-membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, or 4.
2. The compound of claim 1, wherein ring A is a monocyclic 6-membered heteroaryl having 1-4 N atoms.
7. The compound of claim 1 or claim 2, wherein the compound has a structure of Formula (II-e), or a pharmaceutically acceptable salt or solvate thereof:
10. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is CRX1; X2 is CRX2; X3 is CRX3; and X4 is CRX4.
11. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is N; X2 is CRX2; X3 is CRX3; and X4 is CRX4.
12. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is CRX1; X2 is N; X3 is CRX3; and X4 is CRX4.
13. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is CRX1; X2 is CRX2; X3 is N; and X4 is CRX4.
14. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is CRX1; X2 is CRX2; X3 is CRX3; and X4 is N.
15. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is N; X2 is CRX2; X3 is CRX3; and X4 is N.
16. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is CRX1; X2 is N; X3 is N; and X4 is CRX4.
17. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is N; X2 is N; X3 is CRX3; and X4 is N.
18. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is N; X2 is CRX2; X3 is N; and X4 is N.
19. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein each RX1, RX2, RX3, and RX4, when present, is independently hydrogen, halogen, -OR7, -SR7, -CN, -NR7R8, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C2-C4alkenyl, substituted or unsubstituted C2-C4alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl.
20. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein each RX1, RX2, RX3, and RX4, when present, is independently hydrogen, halogen, -OR7, -SR7, -CN, -NR7R8, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl.
21. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein each RX1, RX2, RX3, and RX4, when present, is independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2CN, -CH2C(=O)OH, - CH2C(=O)OCH3, -CH2C(=O)OCH2CH3, -CH2C(=O)NH2, -CH2C(=O)NHCH3, - CH2C(=O)N(CH3)2, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2F, -CHF2, -CF3, -CH=CH2, -C≡CH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -OH, -OCH3, -OCH2CH3, -OCH2F, - OCHF2, -OCF3, -NH2, -NHCH3, -N(CH3)2, -NHC(=O)CH3, -N(CH3)C(=O)CH3, - NHC(=O)OCH3, -N(CH3)C(=O)OCH3, -S(=O)CH3, -S(=O)2CH3, -NHS(=O)2CH3, or - N(CH3)S(=O)2CH3.
22. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein each RX1, RX2, RX3, and RX4, when present, is independently hydrogen, F, Cl,
Br, I, -CH3, -CH2CH3, cyclopropyl, -C≡CH, -OCH3, -NH2, -NHC(=O)CH3, - N(CH3)C(=O)CH3, -NHS(=O)2CH3, -N(CH3)S(=O)2CH3, -S(=O)CH3, or -S(=O)2CH3.
23. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein each RX1, RX2, RX3, and RX4, when present, is independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, cyclopropyl, -OCH3, or -OCF3.
24. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein each RX1, RX2, RX3, and RX4, when present, is independently hydrogen, F, Cl, or -CH3.
25. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein each RX1, RX2, RX3, and RX4, when present, is independently hydrogen or F.
26. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein each RX1, RX2, RX3, and RX4, when present, is hydrogen.
49. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is halogen, nitro, -OR7, -SR7, -CN, -OC(=O)R7, -C(=O)R7, -C(=O)NR7R8, -C(=O)OR7, -S(=O)R7, -S(=O)NR7R8, -S(=O)2R7, -S(=O)2NR7R8, -NR7R8, -NR7S(=O)2R8, - NR7C(=O)R8, -N[C(=O)R8]2, -NR7C(=O)NR7R8, NR7CH2C(=O)NR7R8, NR7CH2CH2C(=O)NR7R8, -NR7C(=O)OR8, -P(=O)(OR7)R8, -P(=O)(OR7)(OR8), - P(=O)R7R8, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2- C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1- C6heteroalkyl, substituted or unsubstituted C3-C7cycloalkyl, substituted or unsubstituted C5- C10 aryl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl; and each R7 and R8 is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1- C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or substituted or unsubstituted 3- to 10-membered heterocycloalkyl; or R7 and R8 taken together with the atom to which they are attached to form a substituted or unsubstituted N- or P-containing
3- to 8-membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S.
50. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is halogen, -OR7, -SR7, -C(=O)R7, -OC(=O)R7, -C(=O)NR7R8, - C(=O)OR7, -NR7R8, -NR7S(=O)2R8, -NR7C(=O)R8, -N[C(=O)R8]2, NR7C(=O)NR7R8, NR7CH2C(=O)NR7R8, NR7CH2CH2C(=O)NR7R8, -NR7C(=O)OR8, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, or substituted or unsubstituted C1-C6heteroalkyl; and each R7 and R8 is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1- C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or substituted or unsubstituted 3- to 10-membered heterocycloalkyl; or R7 and R8 taken together with atom to which they are attached to form a substituted or unsubstituted N-containing 3- to 8- membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S.
51. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -OR7, -SR7, -C(=O)R7, -OC(=O)R7, -C(=O)NR7R8, -C(=O)OR7, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; and each R7 and R8 is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1- C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or substituted or unsubstituted 3- to 10-membered heterocycloalkyl.
52. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -OR7, -SR7, -C(=O)R7, -OC(=O)R7, substituted or unsubstituted C1- C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; and each R7 and R8 is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1- C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or substituted or unsubstituted 3- to 10-membered heterocycloalkyl.
53. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -OR7, -SR7, -C(=O)R7, or -OC(=O)R7; and each R7 and R8 is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C3- C10cycloalkyl.
54. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -NR7R8, -NR7S(=O)2R7, or -NR7C(=O)R7; and each R7 and R8 is independently hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, or C3-C10cycloalkyl.
55. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is F, Cl, Br, I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2OH, - CH2CH2OH, -CH2CH2CH2OH, -CH2CN, -CH=CH2, -CH2C(=O)OH, -CH2C(=O)OCH3, - CH2C(=O)OCH2CH3, -CH2C(=O)NH2, -CH2C(=O)NHCH3, -CH2C(=O)N(CH3)2, -CH2NH2, - CH2CH2NH2, -CH2CH2CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2F, -CHF2, -CF3, - CH2CH2F, -CH=CH2, -CH=CHCF3, -C≡CH, -CH2C≡CH, cyclopropyl, -CN-cycloprop-1-yl, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, oxetanyloxy, tetrahydrofuranyloxy, tetrahydropyranyloxy, azetidinyl, pyrrolidinyl, tetrazolyl, piperazin-2-one-yl, phenyl, -CN, - OH, -OCH3, -OCH2CH3, -OCH2CH2OH, -OCH2CH=CH2, -OCH=CHCH3, -OCH2C≡CH, - OCH2CN, -OCF3, -C(=O)OH, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, -NHC(=O)CH3, NHCH2CH2OH, NCH3CH2CH2OH, NHCH2C(=O)NH2, NHCH2CH2C(=O)NH2, N[C(=O)CH=CH2]2, - N(CH3)C(=O)CH3, -NHC(=O)OCH3, -NHC(=O)CH=CH2, -NHC(=O)O-t-butyl, - N(CH3)C(=O)OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, - S(=O)2N(CH3)2, -NHS(=O)2CH3, or -N(CH3)S(=O)2CH3.
56. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, -NHCH2CH2OH, - N(CH3)CH2CH2OH, azetidinyl, pyrrolidinyl, piperazin-2-one-4-yl, phenyl, - NHCH2CH2C(=O)NH2, -NHCH2C(=O)NH2, -NHC(=O)CH3, -NHC(=O)CH=CH2, - N(C(=O)CH=CH2)2, or -NHS(=O)2CH3.
57. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -CH=CH2, -C≡CH, -CH=CHCF3, cyclopropyl, 1-CN-cycloprop-1-yl, 1-F-cycloprop-1-yl, -C(=O)NHCH3, -C(=O)N(CH3)2, or -S(=O)2CH3.
58. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH=CH2, - OCH2CH=CH2, -OCH=CHCH3, -OCH2C≡CH, or -OC≡CCH3.
59. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -OCH2F, -OCHF2, -OCF3, -OCF2CH3, or -OCH2CF3.
60. The compound of any one of claims 1-59, or a pharmaceutically acceptable salt or solvate thereof, wherein R is halogen, nitro, -CN, -OR7, -SR7, -S(R7)5, -C(=O)R7, -C(=O)NR7R8, -
C(=O)OR7, -S(=O)R7, -S(=O)2R7, -NR7S(=O)2R8, -NR7C(=O)R8, -NR7C(=O)OR8, or substituted or unsubstituted C1-C6fluoroalkyl; and each R7 and R8 is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1- C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, or substituted or unsubstituted 3- to 10-membered heterocycloalkyl; or R7 and R8 taken together with the atom to which they are attached to form a substituted or unsubstituted N-containing 3- to 8-membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S.
61. The compound of any one of claims 1-59, or a pharmaceutically acceptable salt or solvate thereof, wherein R is F, Cl, Br, I, nitro, -CN, -CF3, -SF5, -SCF3, -OCH2F, -OCHF2, -OCF3, - C(=O)CH3, -C(=O)OCH3 -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -S(=O)CH3, - S(=O)2CH3, -NHS(=O)2CH3, -N(CH3)S(=O)2CH3, -NHC(=O)CH3, -N(CH3)C(=O)CH3, - NHC(=O)OCH3, -N(CH3)C(=O)OCH3, -CH2F, -CHF2, or -CF3.
62. The compound of any one of claims 1-59, or a pharmaceutically acceptable salt or solvate thereof, wherein R is F, Cl, -CN, -OCF3, -CHF2, -SCF3, or -CF3.
63. The compound of any one of claims 1-59, or a pharmaceutically acceptable salt or solvate thereof, wherein R is F, Cl, -OCF3, -CHF2, -SCF3, or -CF3.
64. The compound of any one of claims 1-59, or a pharmaceutically acceptable salt or solvate thereof, wherein R is F, Cl, -SF5, -SCF3, or -CF3.
65. The compound of any one of claims 1-59, or a pharmaceutically acceptable salt or solvate thereof, wherein R is F, Cl, -SF5, -OCF3, -SCF3, or -CF3.
66. The compound of any one of claims 1-59, or a pharmaceutically acceptable salt or solvate thereof, wherein R is -CF3.
67. The compound of any one of claims 1-59, or a pharmaceutically acceptable salt or solvate thereof, wherein R is -OCF3.
68. The compound of any one of claims 1-59, or a pharmaceutically acceptable salt or solvate thereof, wherein R is -SF5.
69. The compound of any one of claims 1-59, or a pharmaceutically acceptable salt or solvate thereof, wherein R is -SCF3.
70. The compound of any one of claims 1-69, or a pharmaceutically acceptable salt or solvate thereof, wherein each R1 is independently halogen, -CN, -OR7, -SR7, -S(=O)R7, -S(=O)2R7, - S(=O)2NR7R8, -C(=O)R7, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted
C3-C10cycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and each R7 and R8 is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C1- C6heteroalkyl; or R7 and R8 taken together with the atom to which they are attached to form a substituted or unsubstituted N-containing 3- to 8-membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S.
71. The compound of any one of claims 1-69, or a pharmaceutically acceptable salt or solvate thereof, wherein each R1 is independently halogen, -CN, -OR7, -S(=O)2NR7R8, -C(=O)R7, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C1-C6heteroalkyl; and each R7 and R8 is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C1- C6heteroalkyl; or R7 and R8 taken together with the atom to which they are attached to form a substituted or unsubstituted N-containing 3- to 8-membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S.
72. The compound of any one of claims 1-69, or a pharmaceutically acceptable salt or solvate thereof, wherein each R1 is independently F, Cl, Br, -CN, -OH, -OCH3, -OCH2CH3, - OCH2CH2CH3, -OCH(CH3)2, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, -OCH=CH2, - OCH=CHCH3, -OCH2CH=CH2, -OCH2CH2F, -OCH2CH2OH, -OCH2CH2CH2F, - OCH2CH2CH2OH.
73. The compound of any one of claims 1-69, or a pharmaceutically acceptable salt or solvate thereof, wherein each R1 is independently F, Cl, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, cyclopropyl, cyclobutyl, or cyclopentyl.
74. The compound of any one of claims 1-69, or a pharmaceutically acceptable salt or solvate thereof, wherein each R1 is independently F, Cl, -OCH3, -OCH2CH3, -OCH2CH2CH3, - OCH(CH3)2, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, -OCH2CH2F, -OCH2CH2OH, - OCH2CH2CH2F, or -OCH2CH2CH2OH.
75. The compound of any one of claims 1-69, or a pharmaceutically acceptable salt or solvate thereof, wherein each R1 is independently -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CF3, -OCH2F, -OCHF2, -OCF3, -OCF2CH3, or -OCH2CF3.
76. The compound of any one of claims 1-75, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0, 1, or 2.
77. compound of any one of claims 1-76, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0 or 1.
78. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1.
79. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0.
80. The compound of any one of claims 1-79, or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently halogen, nitro, -CN, -OR7, -SR7, -S(=O)2R7, - NR7R8, -C(=O)OR7, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6fluoroalkyl; and each R7 and R8 is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1- C6heteroalkyl; or R7 and R8 taken together with the atom to which they are attached to form a substituted or unsubstituted N-containing 3- to 8-membered heterocycloalkyl optionally having 1 or 2 additional heteroatoms each independently selected from N, O, and S.
81. The compound of any one of claims 1-79, or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently F, Cl, Br, -CN, -OH, -OCH3, -OCH2CH3, - OCH2CH2OH, -OCH2CN, -OCF3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, -C(=O)OCH3, - CH3, -CH2CH3, -CH2F, -CHF2, or -CF3.
82. The compound of any one of claims 1-79, or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently F, Cl, -CN, -OCH3, -OCF3, -C(=O)OCH3, -CH3, or -CF3.
83. The compound of any one of claims 1-79, or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently F, Cl, -OCF3, or -CF3.
84. The compound of any one of claims 1-79, or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently F or Cl.
85. The compound of any one of claims 1-84, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2.
86. The compound of any one of claims 1-85, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0 or 1.
87. The compound of any one of claims 1-86, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
88. The compound of any one of claims 1-86, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.
89. The compound of any one of claims 1-88, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is CR4R5.
90. The compound of claim 89, or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 and R5 is independently hydrogen or C1-C4 alkyl.
91. The compound of claim 89, or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 and R5 is hydrogen.
92. The compound of any one of claims 1-88, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is O.
93. The compound of any one of claims 1-88, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is S.
94. The compound of any one of claims 1-88, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is NR6.
95. The compound of claim 94, or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is hydrogen or C1-C4 alkyl.
96. The compound of claim 94, or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is hydrogen.
97. A compound or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is a compound from Table 1.
98. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt or solvate of any one of claims 1-97, and a pharmaceutically acceptable excipient.
99. A method of inhibiting one or more of proteins encompassed by, or related to, the Hippo pathway in a subject, comprising administering to the subject the compound or pharmaceutically acceptable salt or solvate of any one of claims 1-97, or a pharmaceutical composition of claim 98.
100. A method of inhibiting transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP) in a subject comprising administering to the subject the compound or pharmaceutically acceptable salt or solvate of any one of claims 1- 97, or the pharmaceutical composition of claim 98.
101. The method of claim 99 or claim 100, wherein the subject has cancer, polycystic kidney disease or liver fibrosis.
102. The method of claim 101, wherein the cancer is selected from mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwannoma, lung cancer, bladder carcinoma, cutaneous neurofibromas, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, and breast cancer.
103. A method of treating cancer in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of the compound or pharmaceutically acceptable salt or solvate of any one of claims 1-97, or the pharmaceutical composition of claim 98.
104. The method of claim 103, wherein the cancer is selected from mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwannoma, lung cancer, bladder carcinoma, cutaneous neurofibromas, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, and breast cancer.
105. A method of treating polycystic kidney disease or liver fibrosis in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of the compound or pharmaceutically acceptable salt or solvate of any one of claims 1-97, or the pharmaceutical composition of claim 98.
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20130331382A1 (en) * | 2012-06-12 | 2013-12-12 | Abbvie Inc | Pyridinone and Pyridazinone Derivatives |
WO2017047602A1 (en) * | 2015-09-18 | 2017-03-23 | 科研製薬株式会社 | Biaryl derivative and medicine containing same |
US9994581B2 (en) * | 2013-12-10 | 2018-06-12 | Abbvie Inc. | Bromodomain inhibitors |
JP2018145180A (en) * | 2017-03-01 | 2018-09-20 | 科研製薬株式会社 | Pharmaceuticals comprising biaryl derivatives or salts thereof |
WO2019113236A1 (en) * | 2017-12-06 | 2019-06-13 | Vivace Therapeutics, Inc. | Benzocarbonyl compounds |
-
2022
- 2022-01-25 WO PCT/US2022/013749 patent/WO2023146512A1/en unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20130331382A1 (en) * | 2012-06-12 | 2013-12-12 | Abbvie Inc | Pyridinone and Pyridazinone Derivatives |
US9994581B2 (en) * | 2013-12-10 | 2018-06-12 | Abbvie Inc. | Bromodomain inhibitors |
WO2017047602A1 (en) * | 2015-09-18 | 2017-03-23 | 科研製薬株式会社 | Biaryl derivative and medicine containing same |
JP2018145180A (en) * | 2017-03-01 | 2018-09-20 | 科研製薬株式会社 | Pharmaceuticals comprising biaryl derivatives or salts thereof |
WO2019113236A1 (en) * | 2017-12-06 | 2019-06-13 | Vivace Therapeutics, Inc. | Benzocarbonyl compounds |
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