Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4965—Non-condensed pyrazines
  • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

• R a7 is selected from H, C 1-3 alkyl, and C 1-3 haloalkyl; each R a10 , R b10 , R c10 and R d10 is independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl; each R a20 is independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl;
• R b20 is selected from NH 2 , C 1-3 alkyl, and C 1-3 haloalkyl; each R a30 , R b30 , R c30 and R d30 is independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl; each R a31 , R b31 , R c31 and R d31 is independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl; each R a60 , R b60 , R c60 and R d60 is independently selected from H, C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; wherein said C 1-3 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl are each optionally substituted with 1 or 2 substituents independently
• Cy 2 is each R 10 is independently selected from C 1-3 alkyl and halo; each R 30 is independently selected from C 1-3 alkyl, halo, OH, and C(O)NR c30 R d30 ; wherein said C 1-3 alkyl is optionally substituted with 1 substituent independently selected from R 31 ; each R 31 is independently selected from OH, O(C 1-3 alkyl), and N(C 1-3 alkyl) 2 ; each R 60 is independently selected from C 1-3 alkyl, 4-6 membered heterocycloalkyl, 5- 6 membered heteroaryl, halo, C(O)R b60 , C(O)NR c60 R d60 , NR c60 C(O)R b60 , C(O)OR a60 , NR c60 C(O)OR a60 , and NR c60 S(O) 2 R b60 ; wherein said C 1-3 alkyl, 4-6 membered heterocycloalky
• R j3 is selected from C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl; wherein said C 1-3 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are each optionally substituted with 1 , 2, or 3 substituents independently selected from R 30 ; or R c3 and R j3 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, or 6-membered heterocycloalkyl group optionally substituted with 1 , 2, or 3 substituents independently selected from R 30 ;
• R b20 is selected from NH 2 , C 1-3 alkyl, and C 1-3 haloalkyl; each R a30 , R b30 , R c30 and R d30 is independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl; each R a31 , R b31 , R c31 and R d31 is independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl; each R a60 , R b60 , R c60 and R d60 is independently selected from H, C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; wherein said C 1-3 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl are each optionally substituted with 1 or 2 substituents independently
• Y is CR 6 ;
• R 7 is halo
• C 1-3 alkyl is optionally substituted with 1 substituent selected from R 31 ; each R 31 is OR a31 ; each R 60 is independently selected from 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, C(O)R b60 , C(O)NR c60 R d60 , and C(O)OR a60 ; wherein said 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R 61 ; each R 61 is independently selected from C 1-3 alkyl, and halo; each R c30 and R d30 is independently selected from H and C 1-3 alkyl; each R a31 is independently selected from H and C 1-3 alkyl; and each R a60 , R b60 , R c60 and R d60 is independently selected from H, C 1-3 alkyl, and C 3-6 cycloalkyl; wherein said C 1-3 alky
• Cy 2 is selected from wherein n is 0, 1 , or 2; each R 10 is independently selected from C 1-3 alkyl, C 1-3 haloalkyl, halo, D, CN, OR a10 , C(O)R b10 , C(O)NR c10 R d10 , C(O)OR a10 , NR c10 R d10 , and S(O) 2 R b10 ; each R 20 is independently selected from C 1-3 alkyl, C 1-3 haloalkyl, halo, D, CN, and
• Y is N or CR 6 ;
• Cy 1 is selected from C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6- 10 aryl, and 6-10 membered heteroaryl; wherein the 4-10 membered heterocycloalkyl and 6-10 membered heteroaryl each has at least one ring-forming carbon atom and 1 , 2, 3, or 4 ring- forming heteroatoms independently selected from N, O, and S; wherein a ring-forming carbon atom of 6-10 membered heteroaryl and 4-10 membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; and wherein the C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6- 10 aryl, and 6-10 membered heteroaryl are each optionally substituted with 1 , 2, 3, or 4 substituents independently selected from R 10 ;
• R 33 is selected from C 2-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, OR a30 , C(O)NR c30 R d30 , and NR c30 R d30 ; wherein said C 2-3 alkyl, C 3-6 cycloalkyl, 4- membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R 31 ; each R 60 is independently selected from C 1-3 alkyl, C 1-3 haloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halo, D, CN, OR a60 , C(O)R b60 , C
• R f3 is selected from wherein R x is H or C 1-2 alkyl and R y is C 1-2 alkyl; or R x and R y , together with the C atom to which they are attached, form a 3-, or 4- membered cycloalkyl group;
• R f3 is selected from wherein R x is H or C 1-2 alkyl and R y is C 1-2 alkyl; each R a10 is independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl;
• Cy 2 is selected from each R 10 is independently selected from C 1-3 alkyl, C 1-3 haloalkyl, halo, CN, and OR a10 ; each R 30 is independently selected from C 1-3 alkyl, C 1-3 haloalkyl, 4-6 membered heterocycloalkyl, halo, and NR c30 R d30 ; wherein said C 1-3 alkyl and 4-6 membered heterocycloalkyl are each optionally substituted with 1 or 2 substituents independently selected from R 31 ; each R 31 is independently selected from C 1-3 alkyl, C 1-3 haloalkyl, halo, and NR c31 R d131 ;
• R 5 is H
• R 6 is selected from H, C 1-3 alkyl, C 1-3 haloalkyl, and 5-6 membered heteroaryl; wherein said C 1-3 alkyl and 5-6 membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R 60 .
• R 2 is CH 2 CH 2 CN.
• R 10 is Cl
• substituted means that an atom or group of atoms formally replaces hydrogen as a “substituent” attached to another group.
• substituted refers to any level of substitution, e.g., mono-, di-, tri-, tetra- or penta-substitution, where such substitution is permitted.
• the substituents are independently selected, and substitution may be at any chemically accessible position. It is to be understood that substitution at a given atom is limited by valency. It is to be understood that substitution at a given atom results in a chemically stable molecule.
• the phrase “optionally substituted” means unsubstituted or substituted.
• substituted means that a hydrogen atom is removed and replaced by a substituent.
• a single divalent substituent e.g., oxo, can replace two hydrogen atoms.
• alkylene groups include, but are not limited to, ethan-1 ,2-diyl, ethan-1 ,1- diyl, propan-1 , 3-diyl, propan-1 , 2-diyl, propan-1 , 1-diyl, butan-1 ,4-diyl, butan-1 ,3-diyl, butan- 1 ,2-diyl, 2-methyl-propan-1 , 3-diyl and the like.
• the heterocycloalkyl group is a monocyclic group having 1 , 2 or 3 heteroatoms independently selected from nitrogen, sulfur and oxygen. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally oxidized to form an oxo or sulfido group or other oxidized linkage (e.g., C(O), S(O), C(S) or S(O) 2 , N-oxide etc.) or a nitrogen atom can be quaternized.
• the heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring- forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds.
• resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of a-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N- methylephedrine, cyclohexylethylamine, 1 ,2-diaminocyclohexane and the like.
• such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol or butanol) or acetonitrile (MeCN) are preferred.
• non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol or butanol) or acetonitrile (MeCN) are preferred.
• suitable salts are found in Remington's Pharmaceutical Sciences, 17 th Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19 and in Stahl et al., Handbook of Pharmaceutical
• Compound 1-11 can then be prepared by coupling of 1-9 with an adduct of formula 1-10, in which M is a boronic acid, boronic ester or an appropriately substituted metal [e.g., M is B(OR) 2 , Sn(Alkyl)s, or Zn-Hal], under standard Suzuki Cross-Coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base), or standard Stille cross-coupling conditions (e.g., in the presence of a palladium catalyst), or standard Negishi cross-coupling conditions (e.g., in the presence of a palldium catalyst). Removal of the protecting group in 1-11 and subsequent functionalization of the resulting adduct (such as coupling with acid chloride, e.g. acryloyl chloride) affords the desired product 1-12.
• M is a boronic acid, boronic ester or an appropriately substituted metal
• M is B(OR) 2 , Sn(Alkyl
• the desired product 2-13 can be prepared by a cross coupling reaction between 2-11 and an adduct of formula 2-12, in which M is a boronic acid, boronic ester or an appropriately substituted metal [e.g., M is B(OR) 2 , Sn(Alkyl) 3 , or Zn-Hal], under standard Suzuki Cross-Coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base), or standard Stille cross-coupling conditions ⁇ e.g., in the presence of a palladium catalyst), or standard Negishi cross-coupling conditions ⁇ e.g., in the presence of a palldium catalyst).
• M is a boronic acid, boronic ester or an appropriately substituted metal
• M is B(OR) 2 , Sn(Alkyl) 3 , or Zn-Hal
• Suzuki Cross-Coupling conditions e.g., in the presence of a palladium catalyst and a suitable base
• a method of inhibiting KRAS activity comprising contacting a compound of the instant disclosure with KRAS.
• the contacting comprises administering the compound to a patient.
• a method of inhibiting a KRAS protein harboring a G12V mutation comprising contacting a compound of the instant disclosure with KRAS.
• a is method of treating a disease or disorder associated with inhibition of KRAS interaction, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any of the formulae disclosed herein, or pharmaceutically acceptable salt thereof.
• the cancer is selected from carcinomas, hematological cancers, sarcomas, and glioblastoma.
• the hematological cancer is selected from myeloproliferative neoplasms, myelodysplastic syndrome, chronic and juvenile myelomonocytic leukemia, acute myeloid leukemia, acute lymphocytic leukemia, and multiple myeloma.
• the carcinoma is selected from pancreatic, colorectal, lung, bladder, gastric, esophageal, breast, head and neck, cervical, skin, and thyroid.
• diseases and indications that are treatable using the compounds of the present disclosure include, but are not limited to hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.
• Exemplary gastrointestinal cancers include cancers of the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (exocrine pancreatic carcinoma, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colorectal cancer, gall bladder cancer and anal cancer.
• esophagus squa
• Exemplary gynecological cancers include cancers of the breast (ductal carcinoma, lobular carcinoma, breast sarcoma, triple-negative breast cancer, HER2-positive breast cancer, inflammatory breast cancer, papillary carcinoma), uterus (endometrial carcinoma), cervix (cervical carcinoma, pre -tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), and fallopian tubes (car
• contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
• “contacting” KRAS with a compound described herein includes the administration of a compound described herein to an individual or patient, such as a human, having KRAS, as well as, for example, introducing a compound described herein into a sample containing a cellular or purified preparation containing KRAS.
• Example Bcr-Abl inhibitors include imatinib mesylate (GLEEVACTM), nilotinib, dasatinib, bosutinib, and ponatinib, and pharmaceutically acceptable salts.
• Other example suitable Bcr-Abl inhibitors include the compounds, and pharmaceutically acceptable salts thereof, of the genera and species disclosed in U.S. Pat. No. 5,521 ,184, WO 04/005281 , and U.S. Ser. No. 60/578,491.
• the compounds of the present disclosure can be used in combination with one or more other inhibitors or one or more therapies for the treatment of infections.
• infections include viral infections, bacterial infections, fungus infections or parasite infections.
• Viruses causing infections treatable by methods of the present disclosure include, but are not limit to human papillomavirus, influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpes simplex viruses, human cytomegalovirus, severe acute respiratory syndrome virus, Ebola virus, measles virus, herpes virus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), flaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus.
• human papillomavirus influenza, hepatitis A, B
• Administration may be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral.
• Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
• Parenteral administration can be in the form of a single bolus dose, or may be, e.g., by a continuous perfusion pump.
• the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day.
• the dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
• topical formulations contain at least about 0.1 , at least about 0.25, at least about 0.5, at least about 1 , at least about 2 or at least about 5 wt % of the compound of the invention.
• the topical formulations can be suitably packaged in tubes of, e.g., 100 g which are optionally associated with instructions for the treatment of the select indication, e.g., psoriasis or other skin condition.
• Step 2 tert-Butyl ( 1R,4R,5S)-5-((7-bromo-8-fluoro-3-iodo-6-methyl-2-(methylthio)quinolin-4- yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2. 1. 1]hexane-2-carboxylate
• the vial was evacuated and backfilled with nitrogen, and THF (30 ml) was added.
• THF (30 ml) was added.
• the reaction mixture was heated to 70 °C for 1.5 h. After cooling to room temperature, triethylamine (1.5 ml, 10.8 mmol) and boc-anhydride (1.2 g, 5.5 mmol) were added, and the reaction mixture was stirred for 15 minutes.
• the reaction was quenched with saturated NaHCCh and diluted with EtOAc.
• the mixture was filtered through a pad of celite and the layers were separated.
• the organic layer was washed with saturated NaHCCh and brine, dried over MgSO 4 , filtered and concentrated.
• the product was purified by flash chromatography (0-10% MeOH/DCM) to afford the title compound (1.8 g, 90% yield).

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