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WO2025035205A1 - Pharmaceutical combinations comprising a substituted thiophene fused cyclohexanone derivative and a cyclooxygenase (cox) inhibitor, and their use for the treatment of pain - Google Patents

Pharmaceutical combinations comprising a substituted thiophene fused cyclohexanone derivative and a cyclooxygenase (cox) inhibitor, and their use for the treatment of pain Download PDF

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Publication number
WO2025035205A1
WO2025035205A1 PCT/CA2024/051045 CA2024051045W WO2025035205A1 WO 2025035205 A1 WO2025035205 A1 WO 2025035205A1 CA 2024051045 W CA2024051045 W CA 2024051045W WO 2025035205 A1 WO2025035205 A1 WO 2025035205A1
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Prior art keywords
pain
alkyl
compound
formula
pharmaceutically acceptable
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PCT/CA2024/051045
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French (fr)
Inventor
Giovanni MARTINO
Claudio Sturino
Youssef Laafiret Bennani
Joseph A. Mancini
Juliette SABBATANI
Kathleen Jessie BERGER
Patricia LAPLANTE
Vincent Guerin
Lorenzo SERNISSI
Maxim EPIFANOV
Catherine ST-GEORGES
Antoine Caron
Arkadii Vaisburg
Daniel Guay
Philippe Seguela
Ariel Ruben ASE
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Neurasic Therapeutics Inc
Royal Institution for the Advancement of Learning
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Neurasic Therapeutics Inc
Royal Institution for the Advancement of Learning
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Publication of WO2025035205A1 publication Critical patent/WO2025035205A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • 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
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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]

Definitions

  • the technical field generally relates to pharmaceutical combinations and their uses in the treatment of pain.
  • the pharmaceutical combinations comprise thiophene fused cyclohexanone derivatives and cyclooxygenase (COX) inhibitors.
  • COX cyclooxygenase
  • the thiophene fused cyclohexanone derivatives are acid-sensing ion channels (ASICs) inhibitors.
  • ASICs acid-sensing ion channels
  • ASICs are permeable to Na+ ions (and other cations), they are activated by low extracellular pH and widely expressed in the central nervous system (CNS) and the peripheral nervous system (PNS).
  • ASICs are formed by homo- and heterotrimeric assemblies of subunits including ASICIa, ASICIb, ASIC2a, ASIC2b and ASIC3.
  • ASICIa are expressed in the PNS and CNS, ASICI b in the PNS.
  • ASIC inhibitors might relieve pain in a variety of clinical conditions.
  • ASIC antagonists may provide new treatment options for patients who do not benefit from or do not tolerate the adverse side effects of certain current pain medications.
  • Developing new pharmaceutical combinations comprising small molecule inhibitors that are specific for ASICs is therefore important to provide alternative therapeutic treatments against ASICs-related disorders or conditions, such as pain.
  • the present application relates to a pharmaceutical combination
  • a pharmaceutical combination comprising a cyclooxygenase (COX) inhibitor and a compound which is a thiophene fused cyclohexanone derivative of Formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • COX cyclooxygenase
  • the pharmaceutical combination can be useful for the treatment of pain.
  • the present application relates to a pharmaceutical combination comprising:
  • R a is -NH 2 , -NH-OH, -OH, -NHR b or -NHR c R d ;
  • R b is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein C 1 -C 6 alkyl is optionally substituted with 1 to 3 halogens, 1 to 3 -OH, -O C 1 -C 3 alkyl, -COOH, or cyclopropyl optionally substituted with -OH, and wherein C 3 -C 6 cycloalkyl is optionally substituted with -ON;
  • R c and R d form with the nitrogen to which they are attached a 4-membered heterocycloalkyl, wherein the 4-membered heterocycloalkyl is optionally substituted with at least one of -OH and C 1 -C 3 alkyl; wherein:
  • R is H, C 1 -C 6 alkyl or phenyl;
  • R 1 and R 2 are independently -CN, C 6 -C 10 aryl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 - C 8 cycloalkyl, 4- to 14-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C(O)NH 2 , - C(O)NHR 5 , -C(O)R 6 , or -C(0)OR 5 , wherein each C 1 -C 6 alkyl is optionally substituted with 1 to 3 R 7 substituents, each C 6 -C 10 aryl is optionally substituted with 1 to 3 R 8 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 22 substituents, with the proviso that when R a is -OH, represents A o , and R 1
  • R 4 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 7- to 10-membered partially unsaturated heterocyclic group, or 5- to 10-membered heteroaryl, wherein C 1 -C 6 alkyl and C 3 -C 8 cycloalkyl are optionally substituted with 1 to 3 R 9 substituents, and C 6 -C 10 aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R 10 substituents, with the proviso that: (i) when R a is -OH, -NH 2 , each R 10 is independently C 1 -C 4 alkyl, halogen, -OC 1 -C 6 alkyl, -NH 2 , -NH(C 1 -C 4 alkyl), or -N(C 1 - C 4 alkyl)2, wherein each C 1 -C 4 alkyl is optionally substituted with 1 to 3 halogens
  • R 2a is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, or C 6 -C 10 aryl, wherein C 1 -C 6 alkyl and C 3 -C 8 cycloalkyl are optionally substituted with 1 to 3 R 9 substituents, and C 6 -C 10 aryl is optionally substituted with 1 to 3 R 10 substituents;
  • R 1a and R 2b are independently -CN, C 6 -C 10 aryl, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, -C(O)NH 2 , - C(O)NHR 5 , or -C(0)OC 1 -C 6 alkyl, wherein each C 1 -C 6 alkyl is optionally substituted with 1 to 3 R 16 substituents and each C 6 -C 10 aryl is optionally substituted with 1 to 3 R 17 substituents; each R 16 is independently -OH, -C(O)NH 2 , -C(O)NH(C 1 -C 4 alkyl), C 3 -C6cycloalkyl, -CN, C 6 -C 10 aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC 1 -C6alkyl), 4- to 6-membered heterocycloalkyl, -NH(
  • R 2d and R 4b form together with the carbon atoms to which they are attached a C 3 -C 8 cycloalkyl or 4- to 14-membered heterocycloalkyl, wherein C 3 -C 8 cycloalkyl is optionally substituted with 1 to 3 R 19 substituents; and
  • R 1c and R 3 form together with the carbon atoms to which they are attached a C 3 -C 8 cycloalkyl or 4- to 14-membered heterocycloalkyl, wherein C 3 -C 8 cycloalkyl is optionally substituted with 1 to 3 R 19 substituents.
  • the pharmaceutical combination can comprise a compound of Formula (I) which is a compound of Formula (la), of Formula (la’), of Formula (lb), of Formula (lb’), of Formula (Ic), of Formula (lc’), of Formula (Id), of Formula (Id’), of Formula (le), of Formula (le’), of Formula (If), of Formula (If’), or of Formula (Ig), as described herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • a compound of Formula (I) which is a compound of Formula (la), of Formula (la’), of Formula (lb), of Formula (lb’), of Formula (Ic), of Formula (lc’), of Formula (Id), of Formula (Id’), of Formula (le), of Formula (le’), of Formula (If), of Formula (If’), or of Formula (Ig), as described herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the pharmaceutical combination can comprise a compound of Formula (I) which is a compound of Table 1 of the present description, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the pharmaceutical combination is such that the COX inhibitor can comprise a Non-Steroidal Anti-Inflammatory Drug (NSAID). In some embodiments, the pharmaceutical combination is such that the COX inhibitor is acetaminophen.
  • NSAID Non-Steroidal Anti-Inflammatory Drug
  • the pharmaceutical combination can be a synergistic pharmaceutical combination.
  • Another aspect relates to a pharmaceutical combination as defined herein, for use in the treatment of pain in a subject in need thereof. Similarly, this aspect relates to the use of a pharmaceutical combination as defined herein, for the treatment of pain in a subject in need thereof. Furthermore, this aspect relates to a method for the treatment of pain, comprising administering to a subject in need thereof a pharmaceutical combination as defined herein.
  • the pain is inflammatory pain, neuropathic pain or cancer pain.
  • the pain is inflammatory pain.
  • the pain is neuropathic pain.
  • the pain is cancer pain.
  • the treatment is an oral treatment.
  • COX inhibitor can comprise a Non-Steroidal Anti-Inflammatory Drug (NSAID).
  • NSAID Non-Steroidal Anti-Inflammatory Drug
  • the COX inhibitor is acetaminophen.
  • the pain is inflammatory pain, neuropathic pain or cancer pain.
  • the pain is inflammatory pain.
  • the pain is neuropathic pain.
  • the pain is cancer pain.
  • the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof are administered orally.
  • kits comprising a first single dose form of a cyclooxygenase (COX) inhibitor and a second single dose form of a compound having the Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and instructions for use.
  • the kit can comprise a COX inhibitor which is a Non-Steroidal Anti-Inflammatory Drug (NSAID).
  • the COX inhibitor can be acetaminophen.
  • the kit is for use in the treatment of pain.
  • the pain is inflammatory pain, neuropathic pain or cancer pain.
  • the pain is inflammatory pain.
  • the pain is neuropathic pain.
  • the pain is cancer pain.
  • the treatment is an oral treatment.
  • Figure 1 shows: (A) the dose response curve of compound 61 , naproxen, and compound 61 :naproxen combination in the carrageenan-induced inflammation model.
  • Analysis of carrageenan-treated rats using linear regression analysis reveals that the ED50 of the combination is 1.4 mg/kg, with 95% confidence limits (CL) of 1.0 and 2.0 mg/kg as compared to compound 61 or naproxen alone, which produces an ED50 of 6.7 and 8.1 mg/kg, respectively. All compounds administered orally and tested 30 minutes later. Dose ratio of combination was 1 :0.83 (naproxen: compound 61).
  • % anti-hyperalgesia (PWL (dose) -PWL (vehicle) ) I (PWL (naive) -PWL (vehicle) ) X 100. Dotted lines represent 95% CL.
  • B the isobologram of compound 61 to naproxen. The isobolographic analysis was performed using normalized data. The data point representing the ED50 value of the combination therapy lies below the line of additivity (line connecting compound 61 and naproxen ED50 values) with its 95% CL never crossing the dotted line.
  • Figure 2 shows: (A) the dose response curve of compound 61 , naproxen, and compound 61 :naproxen combination in the carrageenan-induced inflammation model.
  • Analysis of carrageenan-treated rats using linear regression analysis reveals that the ED50 of the combination is 1.8 mg/kg, with 95% confidence limits (CL) of 1.4 and 2.3 mg/kg as compared to compound 61 or naproxen alone, which produces an ED50 of 6.7 and 8.1 mg/kg, respectively. All compounds administered orally and tested 30 minutes later. Dose ratio of combination was 1 :0.83 (naproxen: compound 61).
  • % anti-hyperalgesia (PWL (dose) -PWL (vehicle) ) I (PWL (naive) -PWL (vehicle) ) X 100. Dotted lines represent 95% CL.
  • B the isobologram of compound 61 to naproxen. The isobolographic analysis was performed using normalized data. The data point representing the ED50 value of the combination therapy lies below the line of additivity (line connecting compound 61 and naproxen ED50 values) with its 95% CL never crossing the dotted line.
  • Figure 3 shows: (A) the dose response curve of compound 61 , celecoxib, and compound 61 :celecoxib combination in the carrageenan-induced inflammation model.
  • Analysis of carrageenan-treated rats using linear regression analysis reveals that the ED50 of the combination is 2.3 mg/kg, with 95% confidence limits (CL) of 1.5 and 2.9 mg/kg as compared to compound 61 or celecoxib alone, which produces an ED50 of 6.7 and 12.9 mg/kg, respectively. All compounds administered orally and tested 30 minutes later. Dose ratio of combination was 1 :0.52 (celecoxib: compound 61).
  • % anti-hyperalgesia (PWL (dose) -PWL (vehicle) ) I (PWL (naive) -PWL (vehicle) ) X 100. Dotted lines represent 95% CL.
  • B the isobologram of compound 61 to celecoxib. The isobolographic analysis was performed using normalized data. The data point representing the ED50 value of the combination therapy lies below the line of additivity (line connecting compound 61 and celecoxib ED50 values) with its 95% CL never crossing the dotted line.
  • Figure 4 shows: (A) the dose response curve of compound 61 , ibuprofen, and compound 61 : ibuprofen combination in the carrageenan-induced inflammation model.
  • Analysis of carrageenan- treated rats using linear regression analysis reveals that the ED50 of the combination is 2.1 mg/kg, with 95% confidence limits (CL) of 1.1 and 4.6 mg/kg as compared to compound 61 or ibuprofen alone, which produces an ED50 of 6.7 and 12.6 mg/kg, respectively. All compounds administered orally and tested 30 minutes later. Dose ratio of combination was 1 :0.53 (ibuprofen: compound 61).
  • % anti-hyperalgesia (PWL (dose) -PWL (vehicle) ) / (PWL (naive) -PWL (vehicle) ) X 100. Dotted lines represent 95% CL.
  • B the isobologram of compound 61 to ibuprofen. The isobolographic analysis was performed using normalized data. The data point representing the ED50 value of the combination therapy lies below the line of additivity (line connecting compound 61 and ibuprofen ED50 values) with its 95% CL never crossing the dotted line.
  • Figure 5 shows: (A) the dose response curve of compound 61 , diclofenac, and compound 61 : diclofenac combination in the carrageenan-induced inflammation model.
  • Analysis of carrageenan-treated rats using linear regression analysis reveals that the ED50 of the combination is 1.6 mg/kg, with 95% confidence limits (CL) of 0.9 and 2.8 mg/kg as compared to compound 61 or diclofenac alone, which produces an ED50 of 6.7 and 11 .7 mg/kg, respectively. All compounds administered orally and tested 30 minutes later.
  • Dose ratio of combination was 1 :0.57 (diclofenac: compound 61).
  • % anti-hyperalgesia (PWL (dose) -PWL (vehicle) ) I (PWL (naive) -PWL (vehicle) ) X 100. Dotted lines represent 95% CL.
  • B the isobologram of compound 61 to diclofenac. The isobolographic analysis was performed using normalized data. The data point representing the ED50 value of the combination therapy lies below the line of additivity (line connecting compound 61 and diclofenac ED50 values) with its 95% CL never crossing the dotted line.
  • Figure 6 shows: (A) the dose response curve of compound 63, naproxen, and compound 63:naproxen combination in the carrageenan-induced inflammation model.
  • Analysis of carrageenan-treated rats using linear regression analysis reveals that the ED50 of the combination is 0.87 mg/kg, with 95% confidence limits (CL) of 0.4 and 2.0 mg/kg as compared to compound 63 or naproxen alone, which produces an ED50 of 1.4 and 8.1 mg/kg, respectively. All compounds administered orally and tested 30 minutes later. Dose ratio of combination was 1 :0.178 (naproxen: compound 63).
  • % anti-hyperalgesia (PWL (dose) -PWL (vehicle) ) I (PWL (naive) -PWL (vehicle) )X 100. Dotted lines represent 95% CL.
  • B the isobologram of compound 63 to naproxen. The isobolographic analysis was performed using normalized data. The data point representing the ED50 value of the combination therapy lies below the line of additivity (line connecting compound 63 and naproxen ED50 values) with its 95% CL never crossing the dotted line.
  • the term “about” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value. Where particular values are described in the application and claims, unless otherwise stated the term "about” meaning within an acceptable error range for the particular value should be assumed.
  • the present application relates to pharmaceutical combinations comprising thiophene fused cyclohexanone derivatives having ASIC inhibition properties, which are compounds of general Formula (I) or pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein R a and will be defined in further detail below.
  • the compounds described in the present application thus encompass those represented by the chemical structure of Formula I, with reference to any of the applicable embodiments described below, and exemplary compounds, such as Compounds 4, 8, 9, 14-39, 47-54, 59, 60a, 60b, 61- 72, 75, 81-84, 89, 91 , 97, 101 , 108, 109, 119-136, 138-150, 154, 155, 163, 168-170, 173-175, 178-181 , 183, 189-195, 197-202, 211-216, 219, 221 , 227-232, 237, 238, 239, 245-251 , 253, 254, 255, 257, 258, 263, 264, 271 , 272, 273, 278-281 , 287, 288, 290, 291 , 297, 298, 305, 306, 313, 314, 321 , 322, 330, 331 , 337-349, 352-358, 360, 362, 371
  • Compounds may be identified either by their chemical structure or their chemical name. In a case where the chemical structure and chemical name would conflict, the chemical structure will prevail.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the present description. Unless otherwise stated, all tautomeric forms of the compounds are within the scope of the present description.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of the present description.
  • Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present description.
  • the number of carbon atoms in a hydrocarbyl substituent can be indicated by the prefix “C x -C y ,” where x is the minimum and y is the maximum number of carbon atoms in the substituent.
  • C x -C y the number of carbon atoms in a hydrocarbyl substituent
  • x and y define respectively, the minimum and maximum number of atoms in the cyclic group, including carbons as well as heteroatom(s).
  • halogen refers to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon, more particularly oxygen, sulfur, or nitrogen.
  • alkyl refers to a saturated, straight- (linear) or branched-chain hydrocarbon radical. In some embodiments, the alkyl group can contain from 1 to 6 carbon atoms, although alkyl groups with more than 6 carbon atoms can be contemplated. For example, "C 1 - C 6 alkyl” contains from one to six carbon atoms.
  • alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, te/Y-butyl, neopentyl, n- hexyl, heptyl, octyl radicals and the like.
  • alkenyl denotes a straight- or branched-chain hydrocarbon radical containing one or more double bonds.
  • the alkenyl groups can contain from 2 to 6 carbon atoms, although alkenyl groups with more than 6 carbon atoms can be contemplated.
  • C 2 -C 6 alkenyl contains from two to six carbon atoms.
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, pentenyl, 1-methyl-2-buten- 1-yl, hexenyl, and the like.
  • alkynyl denotes a straight- or branched-chain hydrocarbon radical containing one or more triple bonds.
  • the alkynyl groups can contain from 2 to 6 carbon atoms, although alkynyl groups with more than 6 carbon atoms can be contemplated.
  • C 2 -C 6 alkynyl contains from two to six carbon atoms.
  • Alkynyl groups include, but are not limited to, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • cycloalkyl refers to a group comprising a saturated carbocyclic ring in a monocyclic or polycyclic ring system, including spiro (sharing one atom), fused (sharing at least one bond) or bridged (sharing two or more bonds) carbocyclic ring systems, having from three to fifteen ring members.
  • the cycloalkyl groups can contain from 3 to 8 carbon atoms.
  • C 3 -C 8 cycloalkyl contains from three to eight carbon atoms in the cyclic ring.
  • cycloalkyl groups can include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[4.2.0]octyl, norbornyl, and the like.
  • aryl refers to a monocyclic moiety or to a bicyclic or tricyclic fused ring system wherein the ring system is carbocyclic and fully aromatic.
  • the aryl groups can contain from 6 to 14 carbon atoms, such as 6 to 10 carbon atoms for instance.
  • a "C 6 -C 10 aryl” group contains from six to ten carbon atoms in the aromatic system.
  • "aryl” refers to an aromatic ring system which includes, without being limited to, phenyl, naphthyl, azulenyl, anthracyl, and the like.
  • heterocyclic group refers to a chemically stable, saturated, partially unsaturated, or fully aromatic monocyclic or polycyclic ring system, including spiro (sharing one atom), fused (sharing at least one bond) or bridged (sharing two or more bonds) carbocyclic ring system, including at least one heteroatom as defined above.
  • a heterocyclic group can be a heterocycloalkyl group, a heteroaryl group, or a partially unsaturated heterocyclic group, as defined herein.
  • heterocycloalkyl used alone or as part of a larger moiety, refers to a saturated cyclic group containing at least one heteroatom as defined herein, which can include a single ring, or two or more rings.
  • the heterocycloalkyl groups can include 3 to 14 ring atoms although heterocycloalkyl groups with more than 14 ring atoms can be contemplated.
  • the heterocycloalkyl groups can contain 4 to 14 ring atoms, or 4 to 6 ring atoms or 3 to 6 ring atoms for instance.
  • a "3- to 14-membered heterocycloalkyl group” contains from three to fourteen atoms, by counting the total number of carbon atoms and heteroatoms, in the saturated heterocyclic moiety.
  • the heterocycloalkyl group can contain from one to four heteroatoms.
  • Heterocycloalkyl groups can include, without limitation, oxiranyl, aziridinyl, oxetanyl, tetrahydropyranyl (oxanyl), tetrahydrofuranyl (oxolanyl), pyrrolidinyl (azolidinyl), piperidinyl, dioxanyl, morpholinyl, thietanyl, azetidinyl, diazetidinyl, oxathiolanyl, oxepanyl, azocanyl (octahydroazocinyl), thiocanyl, azonanyl (octahydroazoninyl), 1 ,3-dioxolanyl, pyrazolidinyl, imidazolidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidiny
  • heteroaryl used alone or as part of a larger moiety, refers to a fully aromatic cyclic group containing at least one heteroatom as defined herein, which can include a single ring, or two or more fused rings.
  • the heteroaryl groups can include from 5 to 10 ring atoms although heteroaryl groups with more than 10 ring atoms can be contemplated.
  • the heteroaryl group can contain from one to four heteroatoms.
  • Heteroaryl groups can include, without limitation, thienyl, furanyl (furyl), pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, benzofuranyl, dibenzofuranyl, benzimidazolyl, benzothiazolyl, benzothienyl (benzothiophenyl), benzoxazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, furopyridinyl, indolyl, indazolyl, isoindolyl, indolizinyl, purinyl, quinolyl (quinolinyl), isoquinolyl (isoquinolinyl), acridin
  • the term “partially unsaturated heterocyclic group” refers to a carbocyclic ring system including at least one double bond between ring atoms but is not fully aromatic and comprises at least one heteroatom.
  • the "partially unsaturated heterocyclic group” is intended to encompass ring systems, which can be mono, bi or tricyclic and having one or multiple sites of unsaturation.
  • the partially unsaturated heterocyclic group can include a multicyclic ring system where at least one ring is aromatic while at least another ring is not aromatic.
  • the partially unsaturated heterocyclic group can include an aryl fused with a heterocycloalkyl, a heteroaryl fused with a cycloalkyl, or a heteroaryl fused with a heterocycloalkyl, where each of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl can itself be monocyclic or bicyclic.
  • the partially unsaturated heterocyclic groups can contain from 7 to 14 carbon atoms, such as 7 to 10 carbon atoms or 8 to 14 carbon atoms for instance.
  • a "7- to 10-membered partially unsaturated heterocyclic group” contains from seven to ten atoms, by counting the total number of carbon atoms and heteroatoms, in the heterocyclic moiety.
  • the partially unsaturated heterocyclic group can contain, in some embodiments, from one to four heteroatoms.
  • the partially unsaturated heterocyclic group can be attached to its pendant group at any heteroatom or carbon atom that results in a chemically stable structure.
  • Non-limiting examples of partially unsaturated heterocyclic group include pyrazolinyl, imidazolinyl, 1 , 2,3,6- tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2H-pyranyl, 4H-pyranyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, quinolizinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, 1 ,3- benzodioxolyl, chromanyl, chromenyl, indolinyl, quinolonyl, isoquinolonyl, oxazepinyl, diazepinyl, thiazepinyl, phthalazinyl, quinoxalinyl, pyrido[2,3-b]-l,4-oxazin-3(4H)-one, .
  • nitrogen When used in reference to a ring atom of a heterocyclic group, the term "nitrogen” includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR 0 (as in N- substituted pyrrolidinyl).
  • the term “partially unsaturated carbocyclic group” refers to a carbocyclic ring system including at least one double bond between ring atoms but is not fully aromatic.
  • the "partially unsaturated carbocyclic group” is intended to encompass ring systems, which comprise only carbon atoms within the ring, said ring being mono, bi or tricyclic and having one or multiple sites of unsaturation.
  • the partially unsaturated carbocyclic group can include a multicyclic ring system where at least one ring is aromatic while at least another ring is not aromatic.
  • the partially unsaturated heterocyclic group can include an aryl fused with a cycloalkyl, where each of the aryl and cycloalkyl can itself be monocyclic or bicyclic.
  • the partially unsaturated carbocyclic groups can contain from 7 to 14 carbon atoms, such as 7 to 10 carbon atoms or 8 to 14 carbon atoms for instance.
  • a "8- to 14-membered partially unsaturated carbocyclic group" contains from eight to fourteen carbon atoms in the cyclic moiety.
  • the partially unsaturated carbocyclic group can be attached to its pendant group at any carbon atom that results in a chemically stable structure.
  • a non-limiting example of partially unsaturated carbocyclic group includes
  • various chemical groups present in the compounds of the present description can be optionally substituted.
  • substituted means that one or more hydrogen atoms of the designated moiety is replaced with a suitable substituent.
  • a substituted chemical group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position.
  • Combinations of substituents envisioned under the present description are preferably those that result in the formation of chemically stable or chemically feasible compounds.
  • chemically stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • salts refers to those salts of the compounds of the present description which are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art.
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the present description, or separately by reacting a free base function of the compound with a suitable organic or inorganic acid (acid addition salts) or by reacting an acidic function of the compound with a suitable organic or inorganic base (base-addition salts).
  • salts include, but are not limited to, nontoxic acid addition salts, or salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamo
  • Representative base addition alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, or magnesium salts, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, sulfonate and aryl sulfonate.
  • solvate refers to a physical association of one of the present compounds with one or more solvent molecules. This physical association includes hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solution-phase and isolable solvates. Exemplary solvates include, without limitation, hydrates, hemihydrates, ethanolates, hemiethanolates, n-propanolates, iso-propanolates, 1 -butanolates, 2- butanolate, and solvates of other physiologically acceptable solvents. The compounds as herein described also include each of their solvates and mixtures thereof.
  • prodrug refers to those prodrugs of the compounds of the present description which are suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
  • Prodrug as used herein means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to afford any compound delineated by the formulae of the instant description.
  • Various forms of prodrugs are known in the art.
  • the compounds of the present application may be prepared by conventional chemical synthesis, such as exemplified in the general schemes provided hereafter and in Examples 1 to 260 for instance. As can be appreciated by the skilled artisan, further methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. In addition, the solvents, temperatures, reaction duration, etc. delineated herein are for purposes of illustration only and one of ordinary skill in the art will recognize that variation of the reaction conditions can produce the desired products of the present description. Synthetic chemistry transformations and/or protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art. The synthesized compounds can be separated from a reaction mixture and further purified by standard methods such as column chromatography, high pressure liquid chromatography, or recrystallization.
  • the thiophene fused cyclohexanone derivatives such as the compounds of Formula (I) may be modified by appending various functionalities via any synthetic means delineated herein to enhance selective biological properties.
  • modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
  • the thiophene fused cyclohexanone derivative can thus be a compound having the Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
  • R a is -NH 2 , -NH-OH, -OH, -NHR b , or -NHR c R d ;
  • R b is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein C 1 -C 6 alkyl is optionally substituted with 1 to 3 halogens, 1 to 3 -OH, -OC 1 -C 3 alkyl, -COOH, or cyclopropyl optionally substituted with -OH, and wherein C 3 -C6cycloalkyl is optionally substituted with -ON;
  • R c and R d form with the nitrogen to which they are attached a 4-membered heterocycloalkyl, wherein the 4-membered heterocycloalkyl is optionally substituted with at least one of -OH and C 1 -C 3 alkyl; represents one of the following residues A o to A12 and wherein:
  • R is H, C 1 -C 6 alkyl or phenyl
  • R 1 and R 2 are independently -ON, C 6 -C 10 aryl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 - C 8 cycloalkyl, 4- to 14-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C(O)NH 2 , - C(O)NHR 5 , -C(O)R 6 , or -C(0)OR 5 , wherein each C 1 -C 6 alkyl is optionally substituted with 1 to 3 R 7 substituents, each C 6 -C 10 aryl is optionally substituted with 1 to 3 R 8 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 22 substituents, with the proviso that when R a is -OH, represents A o , and R 1 is then R 2 in residue A o is different than ; each R 5 is independently C 1
  • R 4 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, 7- to 10-membered partially unsaturated heterocyclic group, or 5- to 10-membered heteroaryl, wherein C 1 -C 6 alkyl and C 3 -C 8 cycloalkyl are optionally substituted with 1 to 3 R 9 substituents, and C 8 -C 10 aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R 10 substituents, with the proviso that: (i) when R a is -OH, -NH 2 , represents A 2 , then R 4 in residue A 2 is different than -CH 3 ; and (ii) when R a is -NH 2 and C A
  • each R 10 is independently C 1 -C 4 alkyl, halogen, -OC 1 -C 6 alkyl, -NH 2 , -NH(C 1 -C 4 alkyl), or -N(C 1 - C 4 alkyl) 2 , wherein each C 1 -C 4 alkyl is optionally substituted with 1 to 3 halogens;
  • R 2a is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, or C 6 -C 10 aryl, wherein C 1 -C 8 alkyl and C 3 -C 8 cycloalkyl are optionally substituted with 1 to 3 R 9 substituents, and C 6 -C 10 aryl is optionally substituted with 1 to 3 R 10 substituents;
  • R 1a and R 2b are independently -CN, C 6 -C 10 aryl, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, -C(O)NH 2 , - C(O)NHR 5 , or -C(0)OC 1 -C 6 alkyl, wherein each C 1 -C 6 alkyl is optionally substituted with 1 to 3 R 16 substituents and each C 6 -C 10 aryl is optionally substituted with 1 to 3 R 17 substituents; each R 16 is independently -OH, -C(O)NH 2 , -C(O)NH(C 1 -C 4 alkyl), C 3 -C6cycloalkyl, -CN, C 6 -C 10 aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC 1 -C 6 alkyl), 4- to 6-membered heterocycloalkyl, -NH(
  • R 4a is C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl, wherein each C 1 -C 6 alkyl and C 3 -C 8 cycloalkyl are optionally substituted with 1 to 3 R 19 substituents; each R 19 is independently halogen, -OH, -OC 1 -C 4 alkyl, -SC 1 -C 4 alkyl, -NH 2 , -NH(C 1 -C 4 alkyl), or - N(C 1 -C 4 alkyl) 2 ;
  • R 2d and R 4b form together with the carbon atoms to which they are attached a C 3 -C 3 cycloalkyl or 4- to 14-membered heterocycloalkyl, wherein C 3 -C 8 cycloalkyl is optionally substituted with 1 to 3 R 19 substituents; and
  • R 1c and R 3 form together with the carbon atoms to which they are attached a C 3 -C 8 cycloalkyl or 4- to 14-membered heterocycloalkyl, wherein C 3 -C 8 cycloalkyl is optionally substituted with 1 to 3 R 19 substituents.
  • the compound of Formula (I) is such that: (i) when R a is -OH, represents A o , and R 1 is , then R 2 in residue A o is different than (ii) when
  • R a is -OH and represents A 2 , then R 4 in residue A 2 is different than -CH 3 and -CH 2 CH 3 ; (iii) when R a is -NH 2 , and represents A 2 , then R 4 in residue A 2 is different than -CH 3 ; and (iv) when R a is -NH 2 and represents A 3 , then R 4 in residue A 3 is different than -C(CH 3 ) 3 .
  • the compound of Formula (I) is such that: (i) when R a is -OH, represents A o , and R 1 is , then R 2 in residue A o is different than O ; (ii) when
  • R a is -OH and represents A 2 , then R 4 in residue A 2 is different than -CH 3 and -CH 2 CH 3 ; (iii) when R a is -NH 2 , and represents A 2 , then R 4 in residue A 2 is different than -CH 3 ;
  • the compound of Formula (I) is such that: (i) when R a is -OH, represents A o , and R 1 is then R 2 in residue A o is different than (ii) when
  • R a is -OH and ⁇ represents A 2 , then R 4 in residue A 2 is different than alkyl; (iii) when R a is -
  • the compound of Formula (I) is such that: (i) when R a is -OH, represents A o , and R 1 is then R 2 in residue A o is different than ; (jj) when R a is -OH and represents A 2 , then R 4 in residue A 2 is different than alkyl; (iii) when R a is - NH 2 , and represents A 2 , then R 4 in residue A 2 is different than -CH 3 ; (iv) when R a is and represents A 2 , then R 4 in residue A 2 is different than -CH 3 ; and (v) when
  • R a is -NH 2 and represents A 3 , then R 4 in residue A 3 is different than -C(CH 3 ) 3 .
  • the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof is such that R is H.
  • the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof is such that R a is -NHR b and R b represents C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein C 1 -C 6 alkyl is optionally substituted with 1 to 3 halogens, 1 to 3 -OH, -OC 1 -C 3 alkyl , -COOH , or cyclopropyl optionally substituted with - OH, and wherein C 3 -C6cycloalkyl is optionally substituted with -ON.
  • the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof is such that R a is -NHR b and R b represents:
  • the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof is such that R a is -NHR b and R b represents -CH 3
  • R a is -NHR b and R b represents In other embodiments, R a is -NR c R d and R c and R d form with the nitrogen to which they are attached a 4-membered heterocycloalkyl, wherein the 4-membered heterocycloalkyl is optionally substituted with at least one of -OH and C 1 -C 3 alkyl.
  • R a is
  • R a is
  • R a is -OH.
  • R a is -NH2.
  • R a is -NH-OH.
  • the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof can be in the form of a racemate or any enantiomer thereof.
  • the compound of Formula (I) can have the following structures (la), (la’), (lb), (lb’), (Ic), (lc’), (Id), (Id’), (le), (le’), (If), (If’), or (lg): where R 1 , R 2 , R 3 , R 4 , R 1a , R 1b , R 1c , R 2a , R 2b , R 2c , R 2d , R 4a , R 4b , R and R a are as defined herein.
  • the compound is of Formula (la) or (la’), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • R, R a , R 1 and R 2 can be as defined for the general Formula (I) above.
  • the compound is of Formula (la), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • R a , R 1 and R 2 can be as defined for the general Formula (I) above.
  • R 1 and R 2 can independently represent -CN, C 6 -C 10 aryl, C 1 -C 6 alkyl, C 2 - C 6 alkynyl, C 3 -C 8 cycloalkyl, 5- to 10-membered heteroaryl, -C(O)NH 2 , -C(O)NHR 5 , -C(O)R 6 , or - C(O)OR 5 , wherein each C 1 -C 6 alkyl is optionally substituted with 1 to 3 R 7 substituents, each C 6 -C 10 aryl is optionally substituted with 1 to 3 R 8 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 22 substituents, and R 5 , R 6 , R 7 , R 8 and R 22 are as defined herein.
  • R 1 and R 2 are independently -CN, C 6 -C 10 aryl, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 3 - C 8 cycloalkyl, 5- to 10-membered heteroaryl, or -C(O)NH 2 , wherein each C 1 -C 6 alkyl is optionally substituted with 1 to 3 R 7 substituents, each C 6 -C 10 aryl is optionally substituted with 1 to 3 R 8 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 22 substituents, and R 7 , R 8 and R 22 are as defined herein.
  • R 1 and R 2 can independently represent -CN, phenyl, C 1 -C 4 alkyl, C 2 - C 4 alkynyl, C 3 -C 6 cycloalkyl, 5-membered heteroaryl, or -C(O)NH 2 , wherein each C 1 -C 4 alkyl is optionally substituted with 1 or 2 R 7 substituents, each phenyl is optionally substituted with 1 or 2 halogens, and each 5-membered heteroaryl is optionally substituted with 1 or 2 -CH 3 .
  • R 1 and R 2 independently represent -CN, C 6 -C 10 aryl, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, or -C(O)NH 2 , wherein each C 1 -C 6 alkyl is optionally substituted with 1 to 2 R 7 substituents as defined herein.
  • each R 5 can be C 1 -C 6 alkyl.
  • each R 6 can be a 4- to 6-membered heterocycloalkyl.
  • each R 7 can independently represent -OH, -C(O)R 11 , C 3 -C 6 cycloalkyl, -CN, C 6 - C 10 aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC 1 -C 6 alkyl), -N(C 1 - C 4 alkyl)(C(O)OC 1 -C 6 alkyl), -NH(C(O)C 1 -C 6 alkyl), 4- to 6-membered heterocycloalkyl, -OR 20 , -SC- 1 -C 6 alkyl, -NH 2 , or -N(C 1 -C 4 alkyl) 2 , wherein each C 3 -C 6 cycloalkyl is optionally substituted with 1 to 3 R 12 substituents
  • R 7 can independently represent -OH, -C(O)R 11 , -OR 20 , C 3 -C 6 cycloalkyl, - CN, C 6 -C 10 aryl, halogen, -C(O)OH, or 5- to 10-membered heteroaryl, wherein each C 3 - C 6 cycloalkyl is optionally substituted with 1 to 3 R 12 substituents and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 13 substituents.
  • R 7 can independently represent -OH, -C(O)NH 2 , -OR 20 , C 3 -C 6 cycloalkyl, -CN, phenyl, halogen, -C(O)OH, or 5-membered heteroaryl, wherein each C 3 -C 6 cycloalkyl is optionally substituted with -CH 3 .
  • R 7 can independently represent -OH, -C(O)NH 2 , C 3 -C 6 cycloalkyl, -CN, C 6 -C 10 aryl, halogen, or 5- to 8-membered heteroaryl, wherein each C 3 -C 6 cycloalkyl is optionally substituted with 1 to 2 C 1 -C 4 alkyl, and each 5- to 8-membered heteroaryl is optionally substituted with 1 to 2 R 13 substituents.
  • the R 11 substituents mentioned above can independently represent -NH 2 , -NH(C 1 -C 4 alkyl), or 4- to 6-membered heterocycloalkyl. In some particular embodiments, R 11 can represent -NH 2 . In some embodiments, the R 12 substituents mentioned above can independently represent C 1 -C 4 alkyl, -SC 1 -C 4 alkyl, -Ph, -OC 1 -C 4 alkyl, or -SPh, wherein each C 1 -C 4 alkyl is optionally substituted with -OH. In some particular embodiments, R 12 is C 1 -C 4 alkyl.
  • the R 13 substituents mentioned above can independently represent halogen, C 1 -C 4 alkyl, or C 3 -C 6 cycloalkyl. In some particular embodiments, R 13 is independently halogen or C 1 -C 4 alkyl.
  • the R 14 substituents mentioned above can independently represent halogen, -OC 1 -C 4 alkyl, or C 3 -C 6 cycloalkyl. In some particular embodiments, R 14 is halogen.
  • the R 20 substituents mentioned above can independently represent C 1 - C 6 alkyl or 5- to 10-membered heteroaryl, wherein each C 1 -C 6 alkyl is optionally substituted with 1 to 3 R 14 substituents as defined herein, and each 5- to 10-membered heteroaryl is optionally substituted with -OH or -NH(cyclopropyl).
  • R 20 is C 1 -C 6 alkyl, wherein each C 1 -C 6 alkyl is optionally substituted with 1 to 3 R 14 substituents as defined herein.
  • R 20 is C 1 -C 6 alkyl, wherein each C 1 -C 6 alkyl is optionally substituted with 1 to 3 halogens.
  • R 20 is 5- to 10-membered heteroaryl substituted with -OH or -NH(cyclopropyl). In certain embodiments, R 20 is 5- to 10-membered heteroaryl substituted with - OH. In other embodiments, R 20 is 5- or 6-membered heteroaryl substituted with -OH.
  • the R 22 substituents mentioned above can independently represent C 1 - C 4 alkyl.
  • each R 8 can independently represent halogen, C 1 -C 6 alkyl, or -OC 1 -C 6 alkyl, wherein each -OC 1 -C 6 alkyl is optionally substituted with -OC 1 -C 4 alkyl.
  • R 8 is a halogen.
  • each R 22 when R 1 and/or R 2 represent 5- to 10- membered heteroaryl substituted with 1 to 3 R 22 substituents, then each R 22 can independently represent C 1 -C 6 alkyl optionally substituted with phenyl. In some embodiments, R 22 is C 1 -C2alkyl substituted with phenyl.
  • R 1 and R 2 are independently -CN, C 6 -C 10 aryl, C 1 -C 6 alkyl, C2-Cealkynyl, C3- C 8 cycloalkyl, 5- to 10-membered heteroaryl, -C(O)NH 2 , -C(O)NHR 5 , -C(O)R 6 , or -C(O)OR 5 , wherein each C 1 -C 6 alkyl is optionally substituted with 1 to 3 R 7 substituents, each C 6 -C 10 aryl is optionally substituted with 1 to 3 R 8 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 22 substituents, and each R 5 is independently C 1 -C 6 alkyl; each R 6 is independently a 4- to 6-membered heterocycloalkyl; each R 7 is independently -OH, -C(O)R 11 , C 3 -C 6 cycloalkyl
  • R 1 and R 2 are independently -ON, C 6 -C 10 aryl, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 3 - C 8 cycloalkyl, 5- to 10-membered heteroaryl, or -C(O)NH 2 , wherein each C 1 -C 6 alkyl is optionally substituted with 1 to 3 R 7 substituents, each C 6 -C 10 aryl is optionally substituted with 1 to 3 R 8 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 22 substituents, and each R 7 is independently -OH, -C(O)R 11 , C 3 -C 6 cycloalkyl, -ON, C 6 -C 10 aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC 1 -C 6 alkyl), -N(C 1 -
  • R 1 and R 2 are independently -CN, C 6 -C 10 aryl, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 3 - Cscycloalkyl, 5- to 10-membered heteroaryl, or -C(0)NH 2 , wherein each C 1 -C 6 alkyl is optionally substituted with 1 to 3 R 7 substituents, each C 6 -C 10 aryl is optionally substituted with 1 to 3 R 8 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R 22 substituents, and each R 7 is independently -OH, -C(O)R 11 , -OR 20 , C 3 -C 6 cycloalkyl, -CN, C 6 -C 10 aryl, halogen, - C(O)OH, or 5- to 10-membered heteroaryl, wherein each C 3 -C 6 cycloalkyl is optionally substituted with 1
  • R 1 and R 2 independently represent -CN, phenyl, C 1 -C 4 alkyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, 5-membered heteroaryl, or -C(O)NH 2 , wherein each C 1 -C 4 alkyl is optionally substituted with 1 or 2 R 7 substituents, each phenyl is optionally substituted with 1 or 2 halogens, and each 5-membered heteroaryl is optionally substituted with 1 or 2 -CH 3 , and each R 7 is independently -OH, -C(O)NH 2 , -OR 20 , C 3 -C 6 cycloalkyl, -CN, phenyl, halogen, - C(O)OH, or 5-membered heteroaryl, wherein each C 3 -C 6 cycloalkyl is optionally substituted with -CH 3 ; and each R 20 is C 1 -C 6 alkyl
  • R 1 and R 2 independently represent -CN, C 6 -C 10 aryl, C 1 -C 6 alkyl, C3- C 8 cycloalkyl, 5-membered heteroaryl, or -C(O)NH 2 , wherein each C 1 -C 6 alkyl is optionally substituted with 1 to 2 R 7 substituents; each R 7 is independently -OH, -C(O)NH 2 , C 3 -C 6 cycloalkyl, -CN, C 6 -C 10 aryl, halogen, or 5- to 8-membered heteroaryl, wherein each C 3 -C 6 cycloalkyl is optionally substituted with 1 to 2 C 1 - C 4 alkyl, and each 5- to 8-membered heteroaryl is optionally substituted with 1 to 2 R 13 substituents; and each R 13 is independently halogen or C 1 -C 4 alkyl.
  • R 1 and R 2 which can be identical or different
  • R 1 and R 2 which can be identical or different, can represent:
  • R 1 and R 2 which can be identical or different, can represent:
  • R 1 and R 2 which can be identical or different, can represent:
  • R 1 and R 2 which can be identical or different, can represent:
  • R 1 and R 2 which can be identical or different, can represent:
  • R 1 and R 2 which can be identical or different, can represent:
  • R 1 and R 2 which can be identical or different, can represent:
  • R 1 and R 2 which can be identical or different, can represent:
  • R 1 and R 2 which can be identical or different, can represent:
  • R 1 and R 2 which can be identical or different, can represent:
  • R 1 and R 2 are different. In another particular embodiment, one of R 1 and R 2 is -CN.
  • Other embodiments include compounds of Formula (la) or (la’), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, where one of R 1 and R 2 is of Formula
  • the compound is of Formula (lb) or (lb’), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • R, R a , and R 4 can be as defined for the general Formula (I) above.
  • the compound is of Formula (lb), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • R a and R 4 can be as defined for the general Formula (I) above.
  • R 4 can represent C 1 -C 6 alkyl, C 6 -C 10 aryl, 7- to 10-membered partially unsaturated heterocyclic group, or 5- to 10-membered heteroaryl, wherein C 1 -C 6 alkyl is optionally substituted with 1 to 3 R 9 substituents, and C 6 -C 10 aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R 10 substituents, and wherein R 9 and R 10 are as defined herein.
  • R 4 can represent C 1 -C 6 alkyl, C 6 -C 10 aryl, 7- to 10-membered partially unsaturated heterocyclic group, or 5- to 10-membered heteroaryl, wherein C 6 -C 10 aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R 10 substituents, and wherein the R 10 substituents are as defined herein.
  • R 4 can represent C 1 -C 4 alkyl, phenyl, 9-membered partially unsaturated heterocyclic group, or 5- to 6-membered heteroaryl, wherein phenyl and 5- to 6-membered heteroaryl are optionally substituted with 1 or 2 R 10 substituents, and wherein the R 10 substituents are as defined herein.
  • the R 10 substituents can independently represent C 1 -C 4 alkyl, halogen, - O C 1 -C 6 alkyl, -NH2, -NH(C 1 -C 4 alkyl), or -N(C 1 -C 4 alkyl)2, wherein each C 1 -C 4 alkyl is optionally substituted with 1 to 3 halogens.
  • the R 10 substituents can independently represent C 1 -C 4 alkyl, halogen, - OC 1 -C 6 alkyl, or -N(C 1 -C 4 alkyl) 2 , wherein each C 1 -C 4 alkyl is optionally substituted with 1 to 3 halogens.
  • the R 10 substituents can independently represent -CF 3 , halogen, -OCH 3 , or -N(CH 3 ) 2 .
  • R 4 is C 1 -C 6 alkyl, C 6 -C 10 aryl, 7- to 10-membered partially unsaturated heterocyclic group, or 5- to 10-membered heteroaryl, wherein C 6 -C 10 aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R 10 substituents, and each R 10 is independently C 1 -C 4 alkyl, halogen, -OC 1 -C 6 alkyl, -NH 2 , -NH(C 1 -C 4 alkyl), or -N(C 1 - C 4 alkyl)2, wherein each C 1 -C 4 alkyl is optionally substituted with 1 to 3 halogens.
  • R 4 is C 1 -C 6 alkyl, C 6 -C 10 aryl, 7- to 10-membered partially unsaturated heterocyclic group, or 5- to 10-membered heteroaryl, wherein C 6 -C 10 aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R 10 substituents, and each R 10 is independently C 1 -C 4 alkyl, halogen, -OC 1 -C 6 alkyl, or -N(C 1 -C 4 alkyl) 2 , wherein each C 1 - C 4 alkyl is optionally substituted with 1 to 3 halogens.
  • R 4 is C 1 -C 4 alkyl, phenyl, 9-membered partially unsaturated heterocyclic group, or 5- to 6-membered heteroaryl, wherein phenyl and 5- to 6-membered heteroaryl are optionally substituted with 1 or 2 R 10 substituents, and each R 10 is independently -CF 3 , halogen, -OCH 3 , or -N(CH 3 ) 2 .
  • R 4 groups can include:
  • the compound is of Formula (Ic) or (lc’), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the groups R, R a and R 2a can be as defined for the general Formula (I) above.
  • the compound is of Formula (Ic), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • R a and R 2a can be as defined for the general Formula (I) above.
  • R 2a can represent C 1 -C 6 alkyl orC 6 -C 10 aryl, wherein C 1 -C 6 alkyl is optionally substituted with 1 to 3 R 9 substituents and C 6 -C 10 aryl is optionally substituted with 1 to 3 R 10 substituents, and R 9 and R 10 are as defined herein.
  • R 2a can represent C 1 -C 6 alkyl orC 6 -C 10 aryl, wherein C 1 -C 6 alkyl is optionally substituted with 1 to 3 halogens. In some embodiments, R 2a is C 1 -C 6 alkyl, such as C 1 -C 4 alkyl or preferably ethyl.
  • the compound is of Formula (Id) or (Id’), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • R, R a , R 1a , R 2b , and R 4a can be as defined for the general Formula (I) above.
  • the compound is of Formula (Id), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • R a , R 1a , R 2b , and R 4a can be as defined for the general Formula (I) above.
  • R 1a and R 2b can independently represent -CN, C 6 -C 10 aryl, C 1 -C 6 alkyl, C 3 - C 8 cycloalkyl, or -C(O)NH 2 , wherein each C 1 -C 6 alkyl is optionally substituted with 1 to 2 R 16 substituents as defined herein.
  • R 1a and R 2b can independently represent -CN or C 6 -C 10 aryl.
  • R 4a can represent C 1 -C 6 alkyl.
  • the substituents R 16 can independently represent -OH, -C(O)NH 2 , C 3 - C 6 cycloalkyl, -CN, C 6 -C 10 aryl, halogen, or 5- to 8-membered heteroaryl, wherein each C 3 - C 6 cycloalkyl is optionally substituted with 1 to 2 C 1 -C 4 alkyl, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 2 R 21 substituents as defined herein.
  • each R 21 can represent independently halogen or C 1 -C 4 alkyl.
  • R 1a and R 2b are independently -CN, C 6 -C 10 aryl, C 1 -C 6 alkyl, C 3 - C 8 cycloalkyl, or -C(O)NH 2 , wherein each C 1 -C 6 alkyl is optionally substituted with 1 to 2 R 16 substituents; each R 16 is independently -OH, -C(O)NH 2 , C 3 -C 6 cycloalkyl, -CN, C 6 -C 10 aryl, halogen, or 5- to 8- membered heteroaryl, wherein each C 3 -C 6 cycloalkyl is optionally substituted with 1 to 2 C 1 - C 4 alkyl, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 2 R 21 substituents; and each R 21 is independently halogen or C 1 -C 4 alkyl.
  • the compound is of Formula (le) or (le’), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • R, R a , R 1 b , and R 2c can be as defined for the general Formula (I) above.
  • the compound is of Formula (le), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • R a , R 1 b , and R 2c can be as defined for the general Formula (I) above.
  • R 1b and R 2c can form together with the carbon atom to which they are attached a C 4 -C 6 cycloalkyl, or a group selected from wherein the dashed lines represent the portion of the cyclohexanone moiety of the compound of formula (le) or (le’) bearing R 1b and R 2c
  • R 1b and R 2c form together with the carbon atom to which they are attached a cyclopentyl, or a group selected from wherein the dashed lines represent the portion of the cyclohexanone moiety of the compound of formula (le) or (le’) bearing R 1b and R 2c .
  • R 1b and R 2c can form together with the carbon atom to which they are attached a group selected from , wherein the dashed lines represent the portion of the cyclohexanone moiety of the compound of formula (le) or (le’) bearing R 1b and R 2c .
  • R 1b and R 2c can form together with the carbon atom to which they are attached a cyclopentyl.
  • the compound is of (If) or (If’), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • R, R a , R 2d , and R 4b can be as defined for the general Formula (I) above.
  • the compound is of Formula (If), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • R a , R 2d , and R 4b can be as defined for the general Formula (I) above.
  • R 2d and R 4b can form together with the carbon atoms to which they are attached a C 3 -C 8 cycloalkyl, wherein each C 3 -C 8 cycloalkyl is optionally substituted with 1 to 3 R 19 substituents as defined herein.
  • R 2d and R 4b can form together with the carbon atoms to which they are attached a C 3 -C 8 cycloalkyl.
  • R 2d and R 4b can form together with the carbon atoms to which they are attached a cyclohexyl.
  • the compound is of Formula (Ig), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • R a , R 1c and R 3 can be as defined for the general Formula (I) above.
  • R 1c and R 3 can form together with the carbon atoms to which they are attached a C 3 -C 8 cycloalkyl, wherein each C 3 -C 8 cycloalkyl is optionally substituted with 1 to 3 R 19 substituents as defined herein.
  • R 1c and R 3 can form together with the carbon atoms to which they are attached a C 3 -C 8 cycloalkyl.
  • R 1c and R 3 can form together with the carbon atoms to which they are attached a cyclohexyl.
  • the compound of Formula (I) as described herein can be selected from Compound 4, 8, 9, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 47, 48, 49, 50, 51 , 52, 53, 54, 59, 60a, 60b, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 75, 81 , 82, 83, 84, 89, 91 , 97, 101 , 108, 109, 119, 120, 121 , 122, 123, 124, 125, 126, 127, 128, 129, 130, 131 , 132, 133, 134, 135, 136, 138, 139, 140, 141 , 142, 143, 144, 145,
  • the compound of Formula (I) as described herein is Compound 4, 9, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 47, 48, 49, 50, 51, 52, 53, 54, 59, 60a, 60b, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 75, 81, 82, 83, 84, 89, 91, 97, 101, 109, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132,
  • the compound of Formula (I) as described herein is Compound 4, 9, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 47, 48, 49, 50, 51, 52, 53, 54, 59, 60b, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 75, 81, 82, 83, 84, 89, 91, 97, 101, 109, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141, 143, 144, 145, 146, 147, 148, 149, 150, 155, 163, 168, 169,
  • the compound of Formula (I) as described herein is Compound 4, 9, 15, 16, 17, 18, 19, 20, 21, 22, 24, 25, 26, 27, 29, 30, 31, 32, 33, 34, 36, 37, 38, 39, 47, 48, 49, 50, 51, 52, 53, 54, 59, 60b, 61 , 62, 63, 64, 65, 66, 67, 68, 71 , 72, 75, 81 , 82, 83, 84, 89, 91 , 97, 101 , 109, 119, 120, 121, 122, 123, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141,
  • the compound of Formula (I) as described herein is Compound 4, 9, 15, 16, 17, 18, 19, 20, 21, 22, 24, 25, 26, 27, 29, 30, 31, 32, 33, 34, 36, 37, 38, 39, 47, 48, 49, 50, 51, 52, 53, 54, 59, 60b, 61 , 62, 63, 64, 65, 66, 67, 68, 71 , 72, 75, 81 , 82, 83, 84, 89, 91 , 97, 101 , 109, 119, 120, 121, 122, 123, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141,
  • the compound of Formula (I) as described herein is Compound 4, 15, 16, 17, 20, 24, 25, 26, 27, 29, 30, 31, 32, 33, 34, 36, 37, 47, 48, 49, 50, 51, 52, 53, 54, 59, 60b, 61,
  • the compound of Formula (I) as described herein is Compound 4, 15, 16, 20, 25, 26, 29, 30, 31, 32, 33, 34, 37, 47, 48, 49, 50, 51, 52, 54, 59, 60b, 61, 62, 63, 64, 65, 72, 75, 82, 83, 84, 89, 91, 97, 101, 109, 119, 121, 123, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141, 143, 144, 145, 146, 147, 148, 149, 150, 155, 163, 168, 169, 170, 173, 174, 175, 179, 180, 181, 183, 191, 192, 194, 195, 201, 212, 213, 214, 215, 216, 230, 231, 232, 238, 239, 246, 248, 250, 251, 253, 254, 255, 258, 263,
  • the compound of Formula (I) as described herein is Compound 4, 15, 16, 20, 25, 26, 29, 30, 31, 32, 33, 34, 37, 47, 48, 49, 50, 51, 52, 54, 59, 60b, 61, 62, 63, 64, 65, 72, 75, 82, 83, 84,89, 91, 97, 101, 109, 119, 121, 123, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141, 143, 144, 145, 146, 147, 148, 149, 150, 155, 163, 168, 169, 170, 173,
  • the compound of Formula (I) as described herein is Compound 4, 15, 25, 32, 33, 47, 48, 49, 50, 52, 54, 59, 60b, 61 , 62, 63, 72, 75, 82, 83, 89, 97, 101 , 109, 119, 121 , 127, 128, 129, 130, 131 , 132, 133, 134, 135, 136, 138, 139, 140, 141 , 143, 144, 145, 146, 147, 148,
  • the compound of Formula (I) as described herein is Compound 15, 25, 32, 48, 49, 50, 52, 54, 59, 60b, 61 , 62, 63, 72, 75, 82, 83, 97, 101 , 109, 119, 127, 128, 129, 130, 135, 136, 140, 141 , 143, 144, 145, 146, 147, 148, 149, 150, 163, 169, 170, 174, 179, 181 , 183,
  • the compound of Formula (I) as described herein is Compound 15, 25, 32, 48, 49, 50, 52, 54, 59, 60b, 61 , 62, 63, 72, 75, 82, 83, 97, 101 , 109, 119, 127, 128, 129, 130, 135, 136, 140, 141 , 143, 144, 145, 146, 147, 148, 149, 150, 163, 169, 170, 174, 179, 181 , 183,
  • the compound of Formula (I) as described herein is Compound 48, 50, 54, 60b, 61 , 63, 72, 75, 83, 97, 101 , 109, 127, 135, 140, 141 , 143, 144, 145, 146, 147, 149, 163, 169, 170, 174, 179, 181 , 191 , 194, 195, 212, 215, 230, 231 , 232, 238, 246, 248, 250, 251 , 255, 258, 272, 273, 279, 281 , 291 , 306, 314, 321 , 322, 331 , 338, 339, 340, 341 , 342, 345, 353, 355,
  • the compound of Formula (I) as described herein is Compound 48, 50, 54, 60b, 61 , 63, 75, 83, 97, 101 , 127, 135, 140, 141 , 143, 144, 146, 147, 149, 163, 170, 174, 181 , 191 , 195, 215, 230, 231 , 232, 238, 246, 248, 250, 251 , 255, 258, 272, 273, 279, 281 , 306, 314, 322, 338, 339, 340, 345, 353, 355, 356, 391 , 393, 397, 402, 428, 430, 431 , 434, 446, 447, 450, 463, 465, 466, 489, 512, 514, 515, or 524 ofTable 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 54, 61 , 63, 75, 140, 143, 146, 174, 215, 230, 250, 251 , 273, 306, 322, 430, 446, 463, or 512 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 61 , 63, 75, 143, 146, 174, 230, 250, 273, or 306 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 4 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 33 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 47 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 89 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 121 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 131 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 132 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 133 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 134 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 138 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 139 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 214 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 253 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 264 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 278 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 280 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 298 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 305 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 408 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 413 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 422 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 429 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 451 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 472 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 475 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 479 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 481 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 486 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 495 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 498 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 520 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 15 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 25 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 32 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 49 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 52 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 59 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 62 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 72 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 82 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 109 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 119 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 128 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 129 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 130 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 136 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 145 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 148 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 150 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 169 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 179 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 183 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 192 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 194 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 212 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 213 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 239 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 254 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 263 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 288 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 291 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 313 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 321 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 331 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 341 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 342 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 343 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 344 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 358 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 392 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 394a of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 394b of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 395a of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 395b of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 396 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 403 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 407 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 418 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 445 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 448 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 449 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 454 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 464 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 476 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 48 of Table
  • the compound of Formula (I) as described herein is Compound 50 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 54 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 60b of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 61 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 63 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 75 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 83 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 97 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 101 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 127 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 135 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 140 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 141 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 143 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 144 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 146 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 147 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 149 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 163 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 170 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 174 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 181 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 191 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 195 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 215 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 230 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 231 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 232 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 238 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 246 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 248 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 250 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 251 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 255 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 258 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 272 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 273 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 279 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 281 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 306 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 314 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 322 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 338 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 339 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 340 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 345 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 353 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 355 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 356 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 391 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 393 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 397 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 402 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 428 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 430 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 431 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 434 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 446 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 447 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 450 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 463 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 465 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 466 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 489 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 512 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 514 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 515 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula (I) as described herein is Compound 524 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the present application relates to pharmaceutical combinations comprising a thiophene fused cyclohexanone derivative ASIC inhibitor, which is a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a cyclooxygenase (COX) inhibitor.
  • the pharmaceutical combinations can further include pharmaceutically acceptable carriers, diluents, or excipients, as will be detailed below.
  • ASICs inhibitor as used herein means a compound that can inhibit acid-sensing ion channels, such as the acid-sensing ion channel 1a (ASICIa) or the acid-sensing ion channel 1 b (ASICI b).
  • the COX inhibitor can affect both COX-1 and COX- 2 enzymes. However, in some embodiments, the COX inhibitor can primarily affect the COX-2 enzyme or the COX-1 enzyme.
  • the COX inhibitor can comprise an NSAID, which can be highly selective for the COX-2 enzyme, such as coxibs or can be non-selective and affect both COX-1 and COX-2 enzymes, such as ibuprofen.
  • the COX inhibitor can be acetaminophen.
  • the pharmaceutical combinations of the present disclosure can include an NSAID which can be Bromfenac, Celecoxib, Diclofenac, Etodolac, Flurbiprofen, Ibuprofen, Indomethacin, Ketoprofen, Ketorolac, Mefenamic acid, Meloxicam, Nabumetone, Naproxen, Nepafenac, Piroxicam, Sulindac, Tenoxicam, Tiaprofenic acid, Diflunisal, Etoricoxib, Fenoprofen, Floctafenine, Lumiracoxib, Oxaprozin, Parecoxib, Rofecoxib, Tolmetin, Valdecoxib, Meclofenamic acid, Dexketoprofen, Licofelone, Lornoxicam, Loxoprofen, Nimesulide, Tolfenamic acid, Phenylbutazone, Firocoxib, Salsalate, Choline Magnes,
  • the pharmaceutical combinations of the present disclosure can further include a proton-pump inhibitor (PPI).
  • PPI proton-pump inhibitor
  • the pharmaceutical combinations of the present disclosure can include preferably, an NSAID selected from Naproxen, Celecoxib, Diclofenac, Ibuprofen, a pharmaceutically acceptable salt thereof, or any combination thereof.
  • an NSAID selected from Naproxen, Celecoxib, Diclofenac, Ibuprofen, a pharmaceutically acceptable salt thereof, or any combination thereof.
  • the pharmaceutical combinations of the present disclosure can be synergistic.
  • the therapeutically active compounds namely the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, can produce a therapeutic effect that is more than the sum of their individual therapeutic effects.
  • lower doses of at least one of the therapeutically active ingredients preferably both, can be used. In some embodiments, this can provide combination therapies that are much safer than the corresponding monotherapies.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is an NSAID.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is an NSAID selected from Bromfenac, Celecoxib, Diclofenac, Etodolac, Flurbiprofen, Ibuprofen, Indomethacin, Ketoprofen, Ketorolac, Mefenamic acid, Meloxicam, Nabumetone, Naproxen, Nepafenac, Piroxicam, Sulindac, Tenoxicam, Tiaprofenic acid, Diflunisal, Etoricoxib, Fenoprofen, Floctafenine, Lumiracoxib, Oxaprozin, Parecoxib, Rofecoxib, Tolmetin, Valdecoxib, Meclofenamic acid, Dexketoprofen, Licofelone, Lornoxicam, Loxoprof
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is an NSAID selected from Naproxen, Celecoxib, Diclofenac, Ibuprofen, a pharmaceutically acceptable salt thereof, or any combination thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Bromfenac or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Etodolac or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Flurbiprofen or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Indomethacin or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Ketoprofen or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Ketorolac or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Mefenamic acid or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Meloxicam or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Nabumetone or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Nepafenac or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Piroxicam or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Sulindac or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Tenoxicam or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Tiaprofenic acid or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Diflunisal or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Etoricoxib or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Fenoprofen or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Floctafenine or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Lumiracoxib or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Oxaprozin or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Parecoxib or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Rofecoxib or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Tolmetin or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Valdecoxib or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Meclofenamic acid or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Dexketoprofen or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Licofelone or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Lornoxicam or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Loxoprofen or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Nimesulide or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Tolfenamic acid or an pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Phenylbutazone or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Firocoxib or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Salsalate or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Choline Magnesium Trisalicylate or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Acetylsalicylic acid or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Naproxen or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Celecoxib or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Diclofenac or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Ibuprofen or a pharmaceutically acceptable salt thereof.
  • a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is acetaminophen.
  • the pharmaceutical combination of the present disclosure can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in a single dosage form.
  • Single dosage form refers to a mixture of the therapeutically active ingredients, namely the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, that are packaged in a single dosage form.
  • a dosage form can include a pill, a tablet, a capsule, a drink or a syrup.
  • the pharmaceutical combination of the present disclosure can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, each being in an individual dosage form.
  • the pharmaceutical combination can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, each in an amount ranging from about 1 mg to about 1000 mg.
  • the pharmaceutical combination can comprise from about 1 mg to about 1000 mg of the COX inhibitor and from about 1 mg to about 1000 mg of the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the pharmaceutical combination can comprise the COX inhibitor in an amount of from about 1 mg to about 900 mg, or from about 1 mg to about 800 mg, or from about 1 mg to about 700 mg, or from about 1 mg to about 600 mg, or from about 1 mg to about 500 mg, or from about 1 mg to about 400 mg, or from about 1 mg to about 300 mg, or from about 1 mg to about 200 mg, or from about 1 mg to about 100 mg, or from about 1 mg to about 50 mg, or any range value in between these ranges.
  • the pharmaceutical combination can comprise the COX inhibitor in an amount of about 1 mg, 1 .5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg,
  • the pharmaceutical combination can comprise the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in an amount of from about 1 mg to about 900 mg, or from about 1 mg to about 800 mg, or from about 1 mg to about 700 mg, or from about 1 mg to about 600 mg, or from about 1 mg to about 500 mg, or from about 1 mg to about 400 mg, or from about 1 mg to about 300 mg, or from about 1 mg to about 200 mg, or from about 1 mg to about 100 mg, or from about 1 mg to about 50 mg, or any range value in between these ranges.
  • the pharmaceutical combination can comprise the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in an amount of about 1 mg, 1 .5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg,
  • the pharmaceutical combination can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, of from 1:0.1 to 1:10 by weight.
  • the ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof can be from 1:0.1 to 1:9 by weight, or from 1:0.1 to 1:8 by weight, or from 1:0.1 to 1:7 by weight, or from 1 :0.1 to 1 :6 by weight, or from 1 :0.1 to 1 :5 by weight, or from 1:0.1 to 1 :4 by weight, or from 1:0.1 to 1:3 by weight, or from 1:0.1 to 1:2 by weight, or from 1:0.1 to 1:1 by weight.
  • the ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof can be from 1:0.1 to 1:1 by weight, or from 1:0.1 to 1:0.9 by weight, or from 1:0.1 to 1 :0.8 by weight, or from 1:0.1 to 1 :0.7 by weight, or from 1:0.1 to 1:0.6 by weight, or from 1:0.1 to 1:0.5 by weight, or from 1:0.1 to 1:0.4 by weight, or from 1:0.1 to 1:0.3 by weight, or from 1:0.1 to 1:0.2 by weight.
  • the ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof can be from 1:0.1 to 1:1 by weight, or from 1:0.2 to 1:1 by weight, or from 1:0.3 to 1:1 by weight, or from 1:0.4 to 1:1 by weight, or from 1:0.5 to 1:1 by weight, or from 1:0.6 to 1:1 by weight, or from 1:0.7 to 1:1 by weight, or from 1:0.8 to 1:1 by weight, or from 1:0.9 to 1:1 by weight.
  • the ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof can be from 1:1 to 1:2 by weight, or from 1:1 to 1:1.9 by weight, or from 1:1 to 1:1.8 by weight, or from 1:1 to 1:1.7 by weight, or from 1:1 to 1:1.6 by weight, or from 1:1 to 1:1.5 by weight, or from 1:1 to 1:1.4 by weight, or from 1:1 to 1:1.3 by weight, or from 1:1 to 1:1.2 by weight, or from 1:1 to 1:1.1 by weight.
  • the pharmaceutical combination can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, of from 1:0.1 to 1:2 by weight.
  • the pharmaceutical combination can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, of from 1:0.1 to 1:1 by weight.
  • the pharmaceutical combination can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, of from about 1 :0.2 to about 1 : 1 by weight, or from about 1 :0.18 to about 1 : 1 by weight, or from about 1:0.2 to about 1:0.83 by weight, or from about 1:0.18 to about 1:0.83 by weight.
  • the pharmaceutical combination can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof in a ratio by weight of COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof that results in a synergistic pharmaceutical combination.
  • the pharmaceutical combination can be synergistic and can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, of from 1 :0.1 to 1 :10 by weight.
  • the synergistic pharmaceutical combination can have a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, ranging from 1 :0.1 to 1 :9 by weight, or from 1 :0.1 to 1 :8 by weight, or from 1 :0.1 to 1 :7 by weight, or from 1 :0.1 to 1 :6 by weight, or from 1 :0.1 to 1 :5 by weight, or from 1 :0.1 to 1 :4 by weight, or from 1 :0.1 to 1 :3 by weight, or from 1 :0.1 to 1 :2 by weight, or from 1 :0.1 to 1 :1 by weight.
  • a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof ranging from 1 :0.1 to 1 :9 by weight, or from 1 :0.1 to 1 :8 by weight, or from 1 :0.1 to 1 :7 by weight, or from 1 :0.1 to 1 :6 by weight, or from
  • the synergistic pharmaceutical combination can have a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, ranging from 1 :0.1 to 1 :1 by weight, or from 1 :0.1 to 1 :0.9 by weight, or from 1 :0.1 to 1 :0.8 by weight, or from 1 :0.1 to 1 :0.7 by weight, or from 1 :0.1 to 1 :0.6 by weight, or from 1 :0.1 to 1 :0.5 by weight, or from 1 :0.1 to 1 :0.4 by weight, or from 1 :0.1 to 1 :0.3 by weight, or from 1 :0.1 to 1 :0.2 by weight.
  • a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof ranging from 1 :0.1 to 1 :1 by weight, or from 1 :0.1 to 1 :0.9 by weight, or from 1 :0.1 to 1 :0.8 by weight, or from 1 :0.1 to 1 :0.7 by weight, or from
  • the synergistic pharmaceutical combination can have a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, ranging from 1 :0.1 to 1 : 1 by weight, or from 1 :0.2 to 1 :1 by weight, or from 1 :0.3 to 1 :1 by weight, or from 1 :0.4 to 1 :1 by weight, or from 1 :0.5 to 1 :1 by weight, or from 1 :0.6 to 1 :1 by weight, or from 1:0.7 to 1 :1 by weight , or from 1 :0.8 to 1 :1 by weight, or from 1 :0.9 to 1 :1 by weight.
  • a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof ranging from 1 :0.1 to 1 : 1 by weight, or from 1 :0.2 to 1 :1 by weight, or from 1 :0.3 to 1 :1 by weight, or from 1 :0.4 to 1 :1 by weight, or from
  • the synergistic pharmaceutical combination can have a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, ranging from 1 :1 to 1 :2 by weight, or from 1 :1 to 1:1.9 by weight, or from 1 :1 to 1 :1.8 by weight, or from 1 :1 to 1 :1.7 by weight, or from 1 :1 to 1 :1.6 by weight, or from 1 :1 to 1 :1.5 by weight, or from 1 :1 to 1 :1.4 by weight, or from 1 :1 to 1 :1.3 by weight, or from 1 :1 to 1 :1.2 by weight, or from 1 :1 to 1 :1.1 by weight.
  • the pharmaceutical combination can be synergistic and can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, of from 1 :0.1 to 1 :2 by weight.
  • the pharmaceutical combination can be synergistic and can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, of from 1:0.1 to 1:1 by weight.
  • the pharmaceutical combination can be synergistic and can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, of from about 1 :0.2 to about 1 : 1 by weight, or from about 1:0.18 to about 1:1 by weight, or from about 1:0.2 to about 1:0.83 by weight, or from about 1:0.18 to about 1:0.83 by weight.
  • the pharmaceutical combination can comprise an NSAID as the COX inhibitor, and a ratio of the NSAID to the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be of from 1:0.1 to 1:10 by weight.
  • the ratio NSAID to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof can be from 1:0.1 to 1:9 by weight, or from 1:0.1 to 1:8 by weight, or from 1:0.1 to 1:7 by weight, or from 1:0.1 to 1:6 by weight, or from 1:0.1 to 1:5 by weight, or from 1:0.1 to 1:4 by weight, orfrom 1:0.1 to 1:3 by weight, or from 1:0.1 to 1:2 by weight, or from 1:0.1 to 1:1 by weight.
  • the ratio NSAID to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof can be from 1:0.1 to 1:1 by weight, orfrom 1:0.1 to 1:0.9 by weight, or from 1:0.1 to 1:0.8 by weight, orfrom 1:0.1 to 1:0.7 by weight, orfrom 1:0.1 to 1:0.6 by weight, or from 1:0.1 to 1:0.5 by weight, orfrom 1:0.1 to 1:0.4 by weight, orfrom 1:0.1 to 1:0.3 by weight, or from 1:0.1 to 1:0.2 by weight.
  • the ratio NSAIDto compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof can be from 1:0.1 to 1:1 by weight, or from 1:0.2 to 1:1 by weight, orfrom 1:0.3 to 1:1 by weight, orfrom 1:0.4 to 1:1 by weight, orfrom 1:0.5 to 1:1 by weight, orfrom 1:0.6 to 1:1 by weight, orfrom 1:0.7 to 1:1 by weight, orfrom 1:0.8 to 1:1 by weight, orfrom 1:0.9 to 1:1 by weight.
  • the ratio NSAIDto compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof can be from 1:1 to 1:2 by weight, orfrom 1:1 to 1:1.9 by weight, orfrom 1:1 to 1:1.8 by weight, orfrom 1:1 to 1:1.7 by weight, orfrom 1:1 to 1:1.6 by weight, orfrom 1:1 to 1:1.5 by weight, orfrom 1:1 to 1:1.4 by weight, orfrom 1:1 to 1:1.3 by weight, orfrom 1:1 to 1:1.2 by weight, orfrom 1:1 to 1:1.1 by weight.
  • the pharmaceutical combination can comprise an NSAID as the COX inhibitor, and a ratio of the NSAID to the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be of from 1:0.1 to 1:2 by weight. In some embodiments, the pharmaceutical combination can comprise an NSAID as the COX inhibitor, and a ratio of the NSAID to the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be of from 1:0.1 to 1:1 by weight.
  • the pharmaceutical combination can comprise an NSAID as the COX inhibitor, and a ratio of the NSAID to the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be of from about 1 :0.2 to about 1 :1 by weight, or from about 1 :0.18 to about 1:1 by weight, or from about 1:0.2 to about 1:0.83 by weight, or from about 1:0.18 to about 1 :0.83 by weight.
  • the pharmaceutical combination can comprise an NSAID as the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof are provided in a ratio by weight of NSAID to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof that results in a synergistic pharmaceutical combination.
  • the pharmaceutical combination can be synergistic and comprise an NSAID as the COX inhibitor, and a ratio of the NSAID to the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be of from 1 :0.1 to 1:10 by weight.
  • the synergistic pharmaceutical combination can have a ratio NSAID to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, ranging from 1:0.1 to 1:9 by weight, or from 1:0.1 to 1:8 by weight, or from 1:0.1 to 1:7 by weight, or from 1:0.1 to 1:6 by weight, or from 1:0.1 to 1:5 by weight, or from 1:0.1 to 1:4 by weight, orfrom 1:0.1 to 1:3 by weight, or from 1:0.1 to 1:2 by weight, or from 1:0.1 to 1:1 by weight.
  • NSAID to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof ranging from 1:0.1 to 1:9 by weight, or from 1:0.1 to 1:8 by weight, or from 1:0.1 to 1:7 by weight, or from 1:0.1 to 1:6 by weight, or from 1:0.1 to 1:5 by weight, or from 1:0.1 to 1:4 by weight, orfrom 1:0.1 to 1:3 by weight
  • the synergistic pharmaceutical combination can have a ratio NSAID to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, ranging from 1:0.1 to 1:1 by weight, orfrom 1:0.1 to 1:0.9 by weight, orfrom 1:0.1 to 1:0.8 by weight, orfrom 1:0.1 to 1:0.7 by weight, orfrom 1:0.1 to 1:0.6 by weight, orfrom 1:0.1 to 1:0.5 by weight, orfrom 1:0.1 to 1:0.4 by weight, or from 1:0.1 to 1:0.3 by weight, or from 1:0.1 to 1:0.2 by weight.
  • NSAID to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof ranging from 1:0.1 to 1:1 by weight, orfrom 1:0.1 to 1:0.9 by weight, orfrom 1:0.1 to 1:0.8 by weight, orfrom 1:0.1 to 1:0.7 by weight, orfrom 1:0.1 to 1:0.6 by weight, orfrom 1:0.1 to 1:0.5 by weight, orfrom 1:0.1 to 1:0.4 by weight
  • the synergistic pharmaceutical combination can have a ratio NSAID to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, ranging from 1:0.1 to 1:1 by weight, orfrom 1:0.2 to 1:1 by weight, orfrom 1:0.3 to 1:1 by weight, orfrom 1:0.4 to 1:1 by weight, orfrom 1:0.5 to 1:1 by weight, orfrom 1:0.6 to 1:1 by weight, orfrom 1:0.7 to 1:1 by weight , orfrom 1:0.8 to 1:1 by weight, orfrom 1:0.9 to 1:1 by weight.
  • a ratio NSAID to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof ranging from 1:0.1 to 1:1 by weight, orfrom 1:0.2 to 1:1 by weight, orfrom 1:0.3 to 1:1 by weight, orfrom 1:0.4 to 1:1 by weight, orfrom 1:0.5 to 1:1 by weight, orfrom 1:0.6 to 1:1 by weight, orfrom 1:0.7 to 1:1 by weight , orfrom 1:0.8 to 1:1 by weight, orfrom 1:0.9 to 1:1 by weight.
  • the synergistic pharmaceutical combination can have a ratio NSAID to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, ranging from 1:1 to 1:2 by weight, or from 1:1 to 1:1.9 by weight, orfrom 1:1 to 1:1.8 by weight, orfrom 1:1 to 1:1.7 by weight, orfrom 1:1 to 1:1.6 by weight, orfrom 1:1 to 1:1.5 by weight, orfrom 1:1 to 1:1.4 by weight, orfrom 1:1 to 1:1.3 by weight, orfrom 1:1 to 1:1.2 by weight, orfrom 1:1 to 1:1.1 by weight.
  • a ratio NSAID to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof ranging from 1:1 to 1:2 by weight, or from 1:1 to 1:1.9 by weight, orfrom 1:1 to 1:1.8 by weight, orfrom 1:1 to 1:1.7 by weight, orfrom 1:1 to 1:1.6 by weight, orfrom 1:1 to 1:1.5 by weight, orfrom 1:1 to 1:1.4 by weight, orfrom 1:1 to 1:1.3 by weight, orfrom 1:1 to 1:1.2 by
  • the pharmaceutical combination can be synergistic and comprise an NSAID as the COX inhibitor, and a ratio of the NSAID to the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be of from 1:0.1 to 1:2 by weight. In some embodiments, the pharmaceutical combination can be synergistic and comprise an NSAID as the COX inhibitor, and a ratio of the NSAID to the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be of from 1:0.1 to 1:1 by weight.
  • the pharmaceutical combination can be synergistic and comprise an NSAID as the COX inhibitor, and a ratio of the NSAID to the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be of from about 1 :0.2 to about 1 :1 by weight, or from about 1 :0.18 to about 1 :1 by weight, or from about 1 :0.2 to about 1 :0.83 by weight, or from about 1 :0.18 to about 1 :0.83 by weight.
  • the pharmaceutical combinations of the present disclosure comprising a COX inhibitor and a thiophene fused cyclohexanone derivative, i.e., a compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, can be useful for the treatment of disorders or conditions including pain.
  • the treatment can involve using, or can be potentiated by using, a pharmaceutical combination of the present disclosure which can be synergistic.
  • the present description thus provides a method for treating pain, comprising administering to a patient or subject identified as in need thereof, a COX inhibitor and a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, as disclosed herein.
  • the method for treating pain can comprise administering to a patient or subject identified as in need thereof, an effective amount of the COX inhibitor and of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the administration results in a synergistic effect thereof.
  • the term “effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, one can also refer to “therapeutically effective amount” which means any amount which, as compared to a corresponding subject who has not received such amount, results in treatment, healing, prevention, or amelioration of a disorder, disorder, or side effect, or a decrease in the rate of advancement of a disorder or disorder. The term also includes within its scope amounts that are effective to enhance normal physiological function.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disorder or disorder, or one or more symptoms thereof, as described herein.
  • treatment may be administered after one or more symptoms have developed.
  • treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • patient or “subject” as used herein generally refer to a mammal.
  • a subject therefore refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, and the like.
  • the subject is a human.
  • the subject may be either a patient or a healthy human.
  • pharmaceutically acceptable carrier diluent, or excipient
  • pharmaceutically acceptable carrier refers to a non-toxic carrier, diluent, or excipient that does not destroy the pharmacological activity of the compound with which it is formulated.
  • compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate,
  • the disorders or conditions that can be treated using the pharmaceutical combination comprising the COX inhibitor and the thiophene fused cyclohexanone derivative i.e., the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, can include pain.
  • the pain can include acute pain or chronic pain.
  • the pain can include inflammatory pain, neuropathic pain or cancer pain.
  • the pain can include nociceptive pain, inflammatory pain, neuropathic pain, cancer pain, idiopathic pain, musculoskeletal pain, visceral pain, or abdominal pain.
  • the pain can include inflammatory pain.
  • the pain can include neuropathic pain.
  • the pain can include cancer pain.
  • the pain can include arthritis pain, pain associated with musculoskeletal trauma or soft tissue trauma, post-operative pain, dental pain, dysmenorrhea pain, episiotomy pain, endometriosis pain, post-partum pain, headache pain, ocular pain, bursitis pain, tendinitis pain, tenosynovitis pain, or polymyalgia rheumatica pain.
  • the pain can include arthritis pain, pain associated with musculoskeletal trauma or soft tissue trauma, post-operative pain, dental pain, dysmenorrhea pain, episiotomy pain, endometriosis pain, post-partum pain, headache pain, ocular pain, bursitis pain, or tendinitis pain.
  • the pain can include a rheumatic disorder-related pain.
  • the pain can include arthritis pain. In some embodiments, the pain can include adult arthritis pain or juvenile arthritis pain. In certain embodiments, the pain can include adult arthritis pain. In some embodiments, the pain can include juvenile arthritis pain.
  • the pain can include osteoarthritis pain, rheumatoid arthritis pain, ankylosing spondylitis pain, gout pain, psoriatic arthritis pain, or periarthritis pain. In certain embodiments, the pain can include osteoarthritis pain, rheumatoid arthritis pain, ankylosing spondylitis pain, gout pain, or periarthritis pain.
  • the pain can include osteoarthritis pain.
  • the pain can include osteoarthritis inflammatory pain.
  • the pain can include osteoarthritis pain of the hip, osteoarthritis pain of the knee, osteoarthritis pain of the spine, osteoarthritis pain of the shoulder, osteoarthritis pain of the hand, osteoarthritis pain of the finger, osteoarthritis pain of the thumb, osteoarthritis pain of the foot, or osteoarthritis pain of the toe.
  • the pain can include rheumatoid arthritis pain. In certain embodiments, the pain can include adult rheumatoid arthritis pain or juvenile rheumatoid arthritis pain. In some embodiments, the pain can include adult rheumatoid arthritis pain. In certain embodiments, the pain can include juvenile rheumatoid arthritis pain. In certain embodiments, the pain can include rheumatoid arthritis inflammatory pain.
  • the pain can include rheumatoid arthritis pain of the hand, rheumatoid arthritis pain of the finger, rheumatoid arthritis pain of the thumb, rheumatoid arthritis pain of the foot, rheumatoid arthritis pain of the toe, rheumatoid arthritis pain of the wrist, rheumatoid arthritis pain of the knee, rheumatoid arthritis pain of the ankle, rheumatoid arthritis pain of the elbow, rheumatoid arthritis pain of the hip, or rheumatoid arthritis pain of the shoulder.
  • the pain can include ankylosing spondylitis pain.
  • the pain can include gout pain. In some embodiments, the pain can include gout pain of the foot, gout pain of the toe, gout pain of the ankle, gout pain of the knee, or gout pain of the elbow. In certain embodiments, the pain can include gouty arthritis pain. In certain embodiments, the pain can include psoriatic arthritis pain.
  • the pain can include bursitis pain. In some embodiments, the pain can include bursitis pain of the shoulder or bursitis pain of the hip.
  • the pain can include tendinitis pain.
  • the pain can include tendinitis pain of the shoulder, tendinitis pain of the elbow, tendinitis pain of the hip, tendinitis pain of the wrist, tendinitis pain of the knee, or tendinitis pain of the heel.
  • the pain can include periarthritis pain. In certain embodiments, the pain can include periarthritis pain of the shoulder or periarthritis pain of the hip.
  • the pain can include pain associated with musculoskeletal trauma or soft tissue trauma including pain associated with a sprain, a strain, swelling or stiffness. In certain embodiments, the pain can include pain associated with musculoskeletal trauma or soft tissue trauma including pain associated with a sprain or a strain. In certain embodiments, the pain can include pain associated with musculoskeletal trauma or soft tissue trauma of the back, shoulder, or ankle. In certain embodiments, the pain can include myofascial pain syndrome. In other embodiments, the pain can include exercise-induced pain, repetitive motion injury pain, or pain due to a bone fracture. In other embodiments, the pain can include temporomandibular joint disorder pain.
  • the pain can include ocular pain.
  • the ocular pain can include post-operative pain after cataract surgery, post-operative pain after refractive surgery, ocular pain from a non-penetrating wound, foreign body sensation ocular pain, burning or stinging of the eye, uveitis pain, ulceris pain, retinopathy pain or optic neuritis pain.
  • the pain can include dental pain.
  • the dental pain can include toothache or post-operative pain after dental surgery.
  • the dental pain can include pain after dental extraction.
  • the pain can include post-operative pain.
  • the pain can include post-operative pain following minor surgery, post-operative pain following general surgery, post-operative pain following orthopaedic surgery, post-operative pain following bunionectomy, post-operative pain following hernioplasty, post-operative pain following herniorrhaphy, post-operative pain following arthroplasty including pain following knee arthroplasty or pain following hip arthroplasty, post-operative pain following gynecological surgery, postoperative pain following caesarean section, post-mastectomy pain syndrome (PMPS), postoperative pain following abdominoplasty, post-operative pain following laminectomy, post-operative pain following hemorrhoid removal, or post-operative pain following thoracotomy.
  • PMPS post-mastectomy pain syndrome
  • the pain can include dysmenorrhea pain, episiotomy pain, endometriosis pain, or post-partum pain. In certain embodiments, the pain can include dysmenorrhea pain, episiotomy pain, endometriosis pain, or post-partum cramping pain.
  • the pain can include headache pain.
  • the pain can include migraine pain, tension headache pain, or cluster headache pain.
  • the pain can include migraine pain including migraine with aura pain or migraine without aura pain.
  • the pain can include pain due to the common cold, pain due to the flu, sore throat pain, sinus pain including sinusitis pain, pain due to immunization, earache pain, fever pain, body pain, muscle pain, bone pain, joint pain, back pain, neck pain, or nighttime pain.
  • the pain can include mucositis pain or stomatitis pain. In certain embodiments, the pain can include pain associated with lupus including lupus-related inflammatory pain.
  • the pain can include osteoarthritis neuropathic pain. In certain embodiments, the pain can include rheumatoid arthritis neuropathic pain.
  • the pain can include neuralgia.
  • that pain can include trigeminal neuralgia, postherpetic neuralgia, occipital neuralgia, post-surgical neuralgia, pudendal neuralgia, diabetic neuralgia, glossopharyngeal neuralgia, intercostal neuralgia, or drug therapy-induced neuralgia including cancer chemotherapy-induced neuralgia or anti-retroviral therapy-induced neuralgia.
  • the pain can include nerve injury pain, peripheral nerve injury pain, nerve compression pain, nerve avulsion injury pain, nerve entrapment injury pain, radiculopathy pain, brachial plexus injury pain, burning mouth syndrome pain, complex regional pain syndrome type 1 , complex regional pain syndrome type 2, neuroma pain, Morton’s neuroma pain, spinal cord injury pain, spinal cord compression pain, radicular pain, sciatica pain, spinal stenosis pain, cervical spine injury pain, brain injury pain, or post-stroke pain.
  • the pain can include neuropathy pain.
  • the pain can include peripheral neuropathy pain, polyneuropathy pain, mononeuropathy pain, multiple mononeuropathy pain, proximal neuropathy pain, sensory neuropathy pain, small fiber sensory neuropathy pain, idiopathic neuropathy pain, or distal sensory polyneuropathy pain.
  • the pain can include diabetic neuropathy pain.
  • the pain can include diabetic peripheral neuropathy pain, diabetic polyneuropathy pain, diabetic proximal neuropathy pain, or diabetic mononeuropathy pain.
  • the pain can include autoimmune disease neuropathy pain.
  • the pain can include Sjogren's syndrome neuropathy pain, Guillain-Barre syndrome neuropathy pain, chronic inflammatory demyelinating polyneuropathy pain, or vasculitis neuropathy pain.
  • the pain can include multiple sclerosis neuropathic pain.
  • the pain can include carpal tunnel syndrome pain.
  • the pain can include neuropathy pain associated with a bacterial infection or neuropathy pain associated with a viral infection.
  • the pain can include Lyme disease neuropathy pain, Epstein-Barr virus neuropathy pain, hepatitis B virus neuropathy pain, hepatitis C virus neuropathy pain, leprosy neuropathy pain, diphtheria neuropathy pain, or human immunodeficiency virus (HIV) neuropathy pain including HIV distal symmetric polyneuropathy pain.
  • the pain can include hereditary neuropathy pain.
  • the pain can include Charcot-Marie-Tooth disease neuropathy pain or hereditary neuropathy with pressure palsies (HNPP) pain.
  • the pain can include neuropathy pain caused by a malignant tumor, neuropathy pain caused by a benign tumor, or paraneoplastic neuropathy pain.
  • the pain can include myeloma neuropathy pain, lymphoma neuropathy pain, or amyloid neuropathy pain.
  • the pain can include liver disease neuropathy pain, uremic neuropathy pain, connective tissue disorder neuropathic pain, hypothyroidism neuropathy pain, alcohol use neuropathy pain, or vitamin deficiency neuropathy pain.
  • the pain can include vitamin B deficiency neuropathy pain including vitamin B1 , niacin, vitamin B6, or vitamin B12 deficiency neuropathy pain, or vitamin E deficiency neuropathy pain.
  • the pain can include toxic substance exposure neuropathy pain including neuropathy pain following lead exposure or neuropathy pain following mercury exposure.
  • the pain can include anti-retroviral therapy-induced neuropathy pain or neurotoxic drug-induced neuropathic pain.
  • the pain can include chemotherapy-induced neuropathy pain including platinum-based antineoplastic drug-induced neuropathic pain or chemotherapy-induced peripheral neuropathy (CIPN) pain, radiation therapy- induced pain including radiation therapy-induced neuropathy pain, cancer targeted therapy- induced neuropathy pain, or immunotherapy-induced neuropathy pain.
  • that pain can include central neuropathic pain.
  • the pain can include central post-stroke pain, spinal cord injury- related central neuropathic pain, brain injury-related central neuropathic pain, or multiple sclerosis-related central neuropathic pain.
  • the pain can include cancer pain.
  • the pain can include bone cancer pain, breakthrough pain, cancer nociceptive pain, cancer neuropathy pain including neuropathy caused by a tumor pressing on a nerve.
  • the pain can include post-amputation pain. In some embodiments, the pain can include phantom pain, phantom limb pain, or residual limb pain.
  • the pain can include Paget’s disease pain. In other embodiments, the pain can include pain associated with fibromyalgia. In certain embodiments, the pain can include pain associated with lupus including lupus-related inflammatory pain and lupus-related neuropathy pain. In some embodiments, the pain can include gastrointestinal motility disorder pain, irritable bowel syndrome pain, Crohn’s disease pain, ulcer-related pain, or ulcerative colitis pain. In other embodiments, the pain can include incontinence pain or interstitial cystitis pain. In certain embodiments, the pain can include herpes zoster pain. In certain embodiments, the pain can include angina-induced pain. In certain embodiments, the pain can include animal bite or sting pain, or pain caused by a burn including pain caused by a first-degree, second-degree or third-degree burn.
  • the pharmaceutical combination disclosed herein which comprises a therapeutically effective amount of at least one COX inhibitor and a therapeutically effective amount of at least one compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, can be administered to a patient or subject, alone, or admixed with a pharmaceutically acceptable carrier, diluent, or excipient.
  • the pharmaceutical combinations described herein are such that the COX inhibitor and the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, are administered each in an individual dosage form. In other embodiments, the pharmaceutical combinations described herein are such that the COX inhibitor and the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, are administered together in a single dosage form.
  • each separate individual dosage form can be administered either simultaneously or sequentially.
  • the individual dosage forms can be administered in any order.
  • oral treatment means a treatment that occurs by oral administration.
  • an “oral treatment” refers to a treatment where the pharmaceutical combinations of the present disclosure are administered orally for the indicated treatment.
  • parenteral includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Other modes of administration also include intradermal ortransdermal administration.
  • the pharmaceutical combinations described herein are administered orally, i.e., via the oral cavity, including buccally.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetra hydrofurfury I alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include excipients
  • sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3- butanediol.
  • acceptable carriers and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • biodegradable polymers examples include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the therapeutically active compound in liposomes or microemulsions that are compatible with body tissues.
  • Formulations for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the therapeutically active compounds of the present description with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone (PVP), sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and
  • Solid formulations of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the therapeutically active compounds can also be in micro- encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose.
  • additional substances other than inert diluents e.g., tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions that can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of the present description include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of the present description.
  • the description contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • compositions provided herein may also be formulated for administration by nasal aerosol or inhalation using inhalants.
  • Such formulations are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promotors to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • compositions provided herein may be formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutical combinations of this disclosure can be administered without food. In other embodiments, pharmaceutical combinations of this disclosure can be administered with food.
  • the amount of therapeutically active compounds that may be combined with carrier materials to produce a formulation in a single dosage form can vary depending upon the patient to be treated and the particular mode of administration.
  • the amount of individual therapeutically active compound that may be combined with carrier materials to produce individual dosage forms can vary depending upon the patient to be treated and the particular mode of administration.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disorder being treated.
  • the pharmaceutical combinations described herein may be administered using any amount and any route of administration effective for treating or lessening the severity of the disorders or disorders as contemplated herein.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disorder or condition, the particular agent, its mode of administration, and the like.
  • the COX inhibitor and the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof can be formulated in unit dose for ease of administration and uniformity of dosage.
  • unit dose or “single dose form” as used herein refers to a physically discrete unit of therapeutically active agent(s) in an amount appropriate for the patient to be treated.
  • each unit dose form can include both the required amount of COX inhibitor and of the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • separate unit doses can be prepared, a first unit dose including the required amount of COX inhibitor and a second unit dose including the required amount of the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof. It will be understood, however, that the total daily dosage of the therapeutically active compounds and/or combination thereof will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
  • each one of the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered at dosage levels of from about 0.01 mg/kg to about 50 mg/kg, or from about 0.01 mg/kg to about 40 mg/kg, or from about 0.01 mg/kg to about 30 mg/kg, or from about 0.1 mg/kg to about 50 mg/kg, or from about 0.1 mg/kg to about 40 mg/kg, or from about 0.1 mg/kg to about 30 mg/kg, or from about 0.1 mg/kg to about 20 mg/kg, or from about 0.1 mg/kg to about 10 mg/kg of subject body weight, one or more times a day, to obtain the desired therapeutic effect.
  • the COX inhibitor can be administered at dosage levels of from about 0.1 mg/kg to about 50 mg/kg, or from about 0.1 mg/kg to about 40 mg/kg, or from about 0.1 mg/kg to about 30 mg/kg, or from about 0.1 mg/kg to about 20 mg/kg, or from about 0.1 mg/kg to about 10 mg/kg of subject body weight, one or more times a day. In some preferred embodiments, the COX inhibitor can be administered at dosage levels of from about 0.1 to about 20 mg/kg.
  • the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered at dosage levels of from about 0.1 mg/kg to about 50 mg/kg, or from about 0.1 mg/kg to about 40 mg/kg, or from about 0.1 mg/kg to about 30 mg/kg, or from about 0.1 mg/kg to about 20 mg/kg, or from about 0.1 mg/kg to about 10 mg/kg of subject body weight, one or more times a day.
  • the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered at dosage levels of from about 0.1 to about 30 mg/kg, or from about 0.1 mg/kg to about 20 mg/kg, or from about 0.1 mg/kg to about 15 mg/kg.
  • the COX inhibitor can be administered at dosage levels of from about 0.1 to about 20 mg/kg and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, can be administered at dosage levels of from about 0.1 to about 30 mg/kg.
  • the COX inhibitor can be administered at dosage levels of from about 0.1 to about 20 mg/kg and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, can be administered at dosage levels of from about 0.1 mg/kg to about 20 mg/kg.
  • the COX inhibitor can be administered at dosage levels of from about 0.1 to about 20 mg/kg and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, can be administered at dosage levels of from about 0.1 mg/kg to about 15 mg/kg.
  • the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof are administered in a single dosage form. In other embodiments, the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, are administered each in an individual dosage form. In some embodiments, the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, are administered simultaneously or sequentially. In some embodiments, the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, are administered simultaneously.
  • the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof are administered sequentially. It is to be noted that when the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, are administered sequentially, they can be administered in any order. Hence, the COX inhibitor can be administered first and then the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered. Alternatively, the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered first and the COX inhibitor in second.
  • a maintenance dose of the pharmaceutical combination of the present description may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, treatment should cease.
  • the subject may, however, require intermittent treatment on a longterm basis upon any recurrence of disorder symptoms.
  • the total daily inhibitory dose of the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof as defined herein, administered to a subject in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight, or more usually from 0.1 to 30 mg/kg body weight.
  • Single dose formulations may contain such amounts or submultiples thereof to make up the daily dose.
  • treatment regimens according to the present description can comprise administration to a patient in need of such treatment of from about 1 mg to about 1000 mg per day in single or multiple doses, of the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the pharmaceutical combinations described herein may be commercialized in the form of a kit.
  • the kit can comprise at least one single dose form of the COX inhibitor (also referred to as “first single dose form of the COX inhibitor”) and at least one single dose form of the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein (also referred to as “second single dose form of the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof’).
  • first and second with reference to the single dose forms of each active ingredient, are used to differentiate the single dose forms and do not relate to any order for using/administering these dose forms. In fact, each of the first and second single dose forms can be administered in any order or even simultaneously.
  • the kit can thus comprise separate dose forms (dose units) of the COX inhibitor and of the compound having the Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • Each separate dose can include the same amount of the therapeutically active ingredients or different amounts thereof.
  • the kit can be tailored for a specific patient by selecting suitable amounts of each therapeutically active ingredient.
  • the kit generally also includes instructions for its proper use by a patient.
  • the kit is such that the first single dose form can include the COX inhibitor in any amount as described above with respect to the pharmaceutical combinations.
  • the kit is such that the second single dose form can include the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof in any amount as described above with respect to the pharmaceutical combinations.
  • the kit is such that the amount of the COX inhibitor in the first single dose form and the amount of the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof in the second single dose form, provide a ratio of the COX inhibitor to the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as described above with respect to the pharmaceutical combinations.
  • the kit can include a first single dose form of the COX inhibitor and a second single dose form of the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, and is useful for the treatment of a patient suffering from pain, such as any of the pain disclosed in the present disclosure.
  • the use of the kit can result in a synergistic effect of the COX inhibitor and of the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in alleviating pain.
  • Reagent grade chemicals and anhydrous solvents were purchased from commercial sources and, unless otherwise mentioned, were used without further purification.
  • the names of the products were determined using the naming software included in ChemDraw (PerkinElmer). Where it is stated that compounds were prepared analogously to earlier examples or intermediates, reaction time, number of equivalents of reagents, temperature, work-up and purification techniques may differ slightly from the described example.
  • Lithium hydroxide monohydrate (68.0 mg, 1.62 mmol) was added to 7 (86.6 mg, 324 umol) suspended in a mixture of MeOH (4.86 mL) and H 2 O (1 .62 mL). The resulting mixture was stirred under reflux for 2 hours, then allowed to cool to RT, diluted with water (20 mL) and washed with EA (20 mL). The organic phase was discarded and the aqueous phase was then acidified to pH 2-3 using 3 N HCI and extracted using EA (3 x 20 mL). The combined organics were washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated to afford title compound 8 as an off- white solid (60.5 mg, 78% yield). The crude product was used in Step 4 with no additional purification. (See table 6 for characterization)
  • Example 30 2-Amino-6-cyano-6-(cyclopentylmethyl)-7 -oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (49) and Example 31 2-Amino-6-cyano-6-(cyclopentylmethyl)-7 -oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (50)
  • Example 32 2-Amino-6-cyano-6-(cyclohexylmethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (51) and Example 33 2-Amino-6-cyano-6-(cyclohexylmethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (52)
  • Compound 53 (example 34) was synthesized similarly to compound 47 (example 28, scheme 4) starting from 1 ,4-dioxaspiro[4.5]decane-8-carbonitrile (40) and using in the first step (bromomethyl)cyclopropane instead of (bromomethyl)cyclobutane.
  • Step 1 Ethyl 2-amino-6-cyano-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate (56).
  • Racemic compound 59 (86.0 mg) was submitted to SFC chiral separation (isocratic 35% MeOH in CO 2 ) to afford enantioenriched compound 60a as a light-pink solid (33.1 mg, 38% separation yield) and 60b as a white solid (35.4 mg, 41% separation yield) (the absolute configurations were assigned based on resolved crystal structure of enantiomer 60a).
  • 60a 1 H NMR: same as racemic mixture (59).
  • LC-MS: rt 1.23 min, MS: 312.1 (calcd),
  • Step 1 2-Amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (61).
  • reaction mixture was stirred at RT for 16 hours and partitioned between EA and a saturated aqueous solution of NaHCO 3 . The layers were separated, and the organic phase was washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 20% to 100% of EA in hexane) and then by reverse-phase flash column chromatography (eluent gradient from 0% to 100% CH 3 CN in H 2 O with 0.1% (v/v) formic acid) to afford title compound 61 as a white solid (1 .20 g, 47% yield).
  • Aqueous hydrogen peroxide solution (170 uL) was added to a suspension of 61 (13.2 mg, 42.4 umol) and potassium carbonate (11.7 mg, 84.8 umol) in DMSO (569 uL). The mixture was stirred at RT for 3 hours, then partitioned between EA and water (5 mL each). The layers were separated, the organic phase was washed with 5 mL of water and the combined aqueous phase was extracted with EA (2 x 3 mL). The combined organics were washed with brine (5 mL), dried over Na 2 SO4, filtered and concentrated.
  • Racemic compound 61 (96.5 mg) was submitted to SFC chiral separation (isocratic: 45% of CH 3 CN/EtOH 1 :1 in CO 2 ) to yield enantioenriched compound 63 as a white solid (29.0 mg, 30% separation yield) and enantioenriched compound 64 as a white s olid (29.0 mg, 30% separation yield) (the absolute configurations were assigned based on resolved crystal structure of enantiomer 64).
  • Step 4 Ethyl 2-amino-6-(cyanomethyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (80).
  • Step 1 2-Amino-6-(cyanomethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene- 3-carboxamide (83).
  • a suspension of 81 (50.0 mg, 0.153 mmol) in anhydrous DMF (1.69 mL) was saturated with gaseous NH3.
  • PyBOP 120 mg, 0.230 mmol
  • N,N-diisopropylethylamine (53.4 uL, 0.306 mmol) were added and the reaction mixture was stirred at RT for 16 hours. Afterwards, the mixture was partitioned between EA and a saturated aqueous solution of NH 4 CI.
  • Step 3 4-(2,2-Difluoroethyl)-4-phenylcyclohexan-1-one (95) To a solution of 94 (213 mg, 0.75 mmol) in acetone (10.5 mL) was added HCI 2 N (1.89 mL, 3.77 mmol) and the reaction mixture was stirred at RT for 16 hours. Then, the mixture was neutralized by slowly adding saturated NaHCO 3 solution and concentrated to remove the organic solvent. The residue was extracted with EA and the organic layer was washed with brine, dried over Na 2 SO 4 , filtered and concentrated to dryness to afford title compound 95 (169 mg, 94% yield) as a colorless oil, which was not characterized and used directly for the next step.
  • Step 2 Ethyl 2-amino-6-(((tert-butyldimethylsilyl)oxy)methyl)-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (104)
  • a suspension of 103 (1.20 g, 3.77 mmol), morpholine (330 uL, 3.77 mmol), sulfur (121 mg, 473 umol) and ethyl 2-cyanoacetate (364 uL, 3.42 mmol) in EtOH (6.01 mL) was stirred at 60 °C for 16 hours. The mixture was then allowed to cool to RT and concentrated.
  • Step 1 8-Benzyl-1 ,4-dioxaspiro[4.51decane-8-carbonitrile (110).
  • 40 (scheme 4) (1.0 g, 5.98 mmol) in anhydrous THF (24.0 mL) at -78 °C was added dropwise LDA (6.58 mL, 1 M in THF/hexane, 6.58 mmol).
  • LDA 6.58 mL, 1 M in THF/hexane, 6.58 mmol
  • the reaction mixture was stirred at -78 °C for 45 min then benzyl bromide (0.870 mL, 7.18 mmol) was added dropwise.
  • the reaction mixture was allowed to reach RT and stirred for 2.5 hours. Afterwards, the reaction mixture was quenched with water and extracted with EA.
  • Diisobutylaluminum hydride (25% solution in toluene; 121 mL, 180.0 mmol) was added dropwise to a solution of 8-(cyclopropylmethyl)-1 ,4-dioxaspiro[4.5]decane-8-carbonitrile (112) (24.3 g, 110 mmol) (ACS Med. Chem. Lett. 2010, 350-354) in anhydrous toluene (600 mL) at -78 °C and the resulting mixture was stirred at -78 °C for 2 hours.
  • reaction mixture was then quenched with methanol (15 mL) at -78 °C and partitioned between saturated aqueous NH 4 CI solution (200 mL) and diethyl ether (300 mL). The mixture was allowed to slowly reach RT and a saturated aqueous solution of Rochelle’s salt (1 L) was added. The layers were separated and the organic phase was washed with brine (2 x 200 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was dissolved in THF (400 mL) and treated with 2 N aqueous HCI (27.5 mL, 54.9 mmol).
  • Example 82 (S)-2-Amino-6-(3-amino-3-oxopropyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (142) and Example 83 (R)-2-Amino-6-(3-amino-3-oxopropyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (143)
  • Example 84 2-Amino-6-(2-cyanoethyl)-N-cyclopropyl-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (144) and Example 85 2-Amino-6-(3-amino-3-oxopropyl)-N-cyclopropyl-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (145)
  • reaction mixture was quenched with a saturated NH 4 CI solution and extracted with EA.
  • organic layer was dried over Na 2 SO 4 , filtered and concentrated.
  • the residue was purified by reverse-phase flash column chromatography (eluent gradient from 0% to 100% of CH 3 CN in H 2 O with 0.1% (v/v) formic acid) to afford title compound 147 as a white solid (35 mg, 70% yield).
  • Step 1 Ethyl 2-amino-6-(3-hydroxypropyl)-6-phenyl-4,5,6,7-
  • 160 (scheme 30) (289 mg, 1.24 mmol) and ethyl 2-cyanoacetate (0.149 mL, 1.37 mmol) in EtOH (10.0 mL) were added morpholine (0.120 mL, 1.37 mmol) and sulfur (44 mg, 0.172 mmol).
  • the reaction mixture was stirred at 60 °C for 24 hours, then allowed to cool to RT and concentrated to dryness.
  • the residue was partitioned between EA and water. The layers were separated and the aqueous phase was extracted with EA. The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated.
  • reaction mixture was quenched with saturated NH 4 CI solution and extracted with EA.
  • organic layer was dried over Na 2 SO 4 , filtered and concentrated.
  • the residue was purified by flash column chromatography (eluent gradient from 0% to 50% of EA in hexane) to afford title compound 171 (753 mg, 77% yield) as a colorless oil, which was not characterized and used directly for the next step.
  • reaction mixture was quenched with a saturated NH 4 CI solution and extracted with EA.
  • organic layer was dried over Na 2 SO 4 , filtered and concentrated.
  • the residue was purified by reverse-phase flash column chromatography (eluent gradient from 0% to 100% of CH 3 CN in H 2 O with 0.1% (v/v) formic acid) to afford title compound 174 as a white solid (26 mg, 57% yield).
  • Step 1 3-(8-Phenyl-1 ,4-dioxaspiro[4.51decan-8-yl)propanal (176)
  • Step 1 (4-(2-Amino-3-carbamoyl-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b1]thiophen-6- yl)but-1-yn-1-yl)copper (182)
  • Step 6a 2-Amino-6-(2-cyanoethyl)-6-(cyclopropylmethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (189) and 2-Amino-6-(3-amino-3-oxopropyl)-6- (cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (190)
  • Step 6b 2-Amino-6-(2-cyanoethyl)-/V-cyclopropyl-6-(cyclopropylmethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (192)
  • Example 105 194 Example 106
  • Racemic compound 192 (scheme 40) (1.14 g) was submitted to SFC chiral separation (isocratic: 50% of MeOH 1 :1 in CO 2 ) to yield enantioenriched compound 193 as a orange solid (468.9 mg, 41% separation yield) and enantioenriched compound 194 as an off-white solid (424.5 mg, 37% separation yield) (the absolute configurations were assigned based on resolved crystal structure of enantiomer 194).

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Abstract

There is provided a pharmaceutical combination comprising a cyclooxygenase (COX) inhibitor and a compound having the Formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the COX inhibitor can comprise a Non-Steroidal Anti-Inflammatory Drug (NSAID). The pharmaceutical combination can be used in the treatment of pain in a subject in need thereof, such inflammatory pain. There is also provided a kit comprising a first single dose form of a cyclooxygenase (COX) inhibitor and a second single dose form of a compound having the Formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and instructions for use. (I)

Description

PHARMACEUTICAL COMBINATIONS COMPRISING A SUBSTITUTED THIOPHENE FUSED CYCLOHEXANONE DERIVATIVE AND A CYCLOOXYGENASE (COX) INHIBITOR, AND THEIR USE FOR THE TREATMENT OF PAIN
PRIORITY APPLICATION
The present application claims priority from U.S. provisional application No. 63/519.108, filed August 11 , 2023, which is incorporated herein by reference.
TECHNICAL FIELD
The technical field generally relates to pharmaceutical combinations and their uses in the treatment of pain. The pharmaceutical combinations comprise thiophene fused cyclohexanone derivatives and cyclooxygenase (COX) inhibitors. Particularly, the thiophene fused cyclohexanone derivatives are acid-sensing ion channels (ASICs) inhibitors.
BACKGROUND
Since the discovery of acid-sensing ion channels (ASICs) in 1997, their importance in the health of neurons and other non-neuronal cells has gained significant importance. ASICs play important roles in mediating pain sensation and their activity contributes to diseases such as stroke, inflammation, arthritis, cancer, and migraine.
ASICs are permeable to Na+ ions (and other cations), they are activated by low extracellular pH and widely expressed in the central nervous system (CNS) and the peripheral nervous system (PNS). ASICs are formed by homo- and heterotrimeric assemblies of subunits including ASICIa, ASICIb, ASIC2a, ASIC2b and ASIC3. ASICIa are expressed in the PNS and CNS, ASICI b in the PNS.
Tissue injury and inflammation cause acidosis and acidification is considered a significant contributor to associated pain. The literature indicates that ASIC inhibitors might relieve pain in a variety of clinical conditions. In addition, because their mechanism of action is distinct, ASIC antagonists may provide new treatment options for patients who do not benefit from or do not tolerate the adverse side effects of certain current pain medications.
Developing new pharmaceutical combinations comprising small molecule inhibitors that are specific for ASICs is therefore important to provide alternative therapeutic treatments against ASICs-related disorders or conditions, such as pain.
SUMMARY
The present application relates to a pharmaceutical combination comprising a cyclooxygenase (COX) inhibitor and a compound which is a thiophene fused cyclohexanone derivative of Formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof. The pharmaceutical combination can be useful for the treatment of pain.
According to one aspect, the present application relates to a pharmaceutical combination comprising:
(a) a cyclooxygenase (COX) inhibitor; and
(b) a compound having the Formula (I)
Figure imgf000004_0001
or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
Ra is -NH2, -NH-OH, -OH, -NHRbor -NHRcRd;
Rb is C1-C6 alkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein C1-C6 alkyl is optionally substituted with 1 to 3 halogens, 1 to 3 -OH, -O C1-C3alkyl, -COOH, or cyclopropyl optionally substituted with -OH, and wherein C3-C6cycloalkyl is optionally substituted with -ON;
Rc and Rd form with the nitrogen to which they are attached a 4-membered heterocycloalkyl, wherein the 4-membered heterocycloalkyl is optionally substituted with at least one of -OH and C1-C3alkyl;
Figure imgf000004_0002
wherein:
R is H, C1-C6alkyl or phenyl; R1 and R2 are independently -CN, C6-C10aryl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C8cycloalkyl, 4- to 14-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C(O)NH2, - C(O)NHR5, -C(O)R6, or -C(0)OR5, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R7 substituents, each C6-C10aryl is optionally substituted with 1 to 3 R8 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R22 substituents, with the proviso that when Ra is -OH,
Figure imgf000005_0002
represents Ao, and R1 is
Figure imgf000005_0003
, then R2 in residue Ao is different than
Figure imgf000005_0001
each R5 is independently C1-C6alkyl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R9 substituents; each R6 is independently C3-C6cycloalkyl, 4- to 6-membered heterocycloalkyl, or C6-C10aryl; each R7 is independently -OH, -C(O)R11, C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6alkyl), -N(C1-C4alkyl)(C(O)OC1-C6alkyl), 4- to 6- membered heterocycloalkyl, -NH(C(O)C1-C6alkyl), -OR20, -SC1-C6alkyl, -NH2, -NH(C1-C4alkyl), or -N(C1-C4alkyl)2, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 3 R12 substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R13 substituents, and each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl or oxo; each R8 is independently halogen, C1-C6alkyl, -OC1-C6alkyl, C3-C6cycloakyl, or 5- to 10- membered heteroaryl, wherein each -OC1-C6alkyl is optionally substituted with -OC1-C4alkyl, and each 5- to 10-membered heteroaryl is optionally substituted with C1-C4alkyl; each R22 is independently C1-C6alkyl optionally substituted with phenyl; each R9 is independently -OH, -C(O)R15, C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, -C(O)OH, 4- to 6-membered heterocycloalkyl, -NH(C(O)C1-C6alkyl), -OC1-C6alkyl, -SC1-C6alkyl, -NH2, -NH(C1- C4alkyl), or -N(C1-C4alkyl)2, wherein each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl, and each -OC1-C6alkyl is optionally substituted with -OC1-C4alkyl; each R11 is independently -NH2, -NH(C1-C4alkyl), -N(C1-C4alkyl)2, or 4- to 6-membered heterocycloalkyl; each R20 is independently C1-C6alkyl or 5- to 10-membered heteroaryl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R14 substituents and each 5- to 10-membered heteroaryl is optionally substituted with -OH or -NH(cyclopropyl); each R12 is independently C1-C4alkyl, -SC1-C4alkyl, -Ph, -OC1-C4alkyl, or -SPh, wherein each C1- C4alkyl is optionally substituted with -OH; each R13 is independently halogen, C1-C4alkyl, C3-C6cycloalkyl, -OH, -OC1-C6alkyl, -SC1-C6alkyl, -S(O)2C1-C6alkyl, -NH2, -NH(C1-C4alkyl), or -N(C1-C4alkyl)2, wherein each -OC1-C8alkyl, -SC1- C6alkyl, -S(O)2C1-C6alkyl, -NH(C1-C4alkyl), and -N(C1-C4alkyl)2 is optionally substituted with 1 to 3 R9 substituents; each R14 is independently halogen, -OC1-C4alkyl, or C3-C6cycloalkyl; each R15 is independently -NH2, -NH(C1-C4alkyl), -N(C1-C4alkyl)2, or 4- to 6-membered heterocycloalkyl;
R4 is C1-C6alkyl, C3-C8cycloalkyl, C6-C10aryl, 7- to 10-membered partially unsaturated heterocyclic group, or 5- to 10-membered heteroaryl, wherein C1-C6alkyl and C3-C8cycloalkyl are optionally substituted with 1 to 3 R9 substituents, and C6-C10aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R10 substituents, with the proviso that: (i) when Ra is -OH, -NH2,
Figure imgf000006_0001
each R10 is independently C1-C4alkyl, halogen, -OC1-C6alkyl, -NH2, -NH(C1-C4alkyl), or -N(C1- C4alkyl)2, wherein each C1-C4alkyl is optionally substituted with 1 to 3 halogens;
R2a is C1-C6alkyl, C3-C8cycloalkyl, or C6-C10aryl, wherein C1-C6alkyl and C3-C8cycloalkyl are optionally substituted with 1 to 3 R9 substituents, and C6-C10aryl is optionally substituted with 1 to 3 R10 substituents;
R1a and R2b are independently -CN, C6-C10aryl, C1-C6alkyl, C3-C8cycloalkyl, -C(O)NH2, - C(O)NHR5, or -C(0)OC1-C6alkyl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R16 substituents and each C6-C10aryl is optionally substituted with 1 to 3 R17 substituents; each R16 is independently -OH, -C(O)NH2, -C(O)NH(C1-C4alkyl), C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6alkyl), 4- to 6-membered heterocycloalkyl, -NH(C(O)C1-C6alkyl), or -OC1-C4alkyl(OC1-C4alkyl), wherein each C3- C6cycloalkyl is optionally substituted with 1 to 3 R18 substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R21 substituents, and each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl; each R17 is independently halogen, C1-C6alkyl, -OC1-C6alkyl, or 5- to 10-membered heteroaryl, wherein each 5- to 10-membered heteroaryl is optionally substituted with C1-C4alkyl; each R18 is independently C1-C4alkyl, -SC1-C4alkyl, -Ph, or -OC1-C4alkyl; each R21 is independently halogen or C1-C4alkyl; R4a is C1-C6alkyl or C3-C8cycloalkyl, wherein each C1-C6alkyl and C3-C8cycloalkyl are optionally substituted with 1 to 3 R19 substituents; each R19 is independently halogen, -OH, -OC1-C4alkyl, -SC1-C4alkyl, -NH2, -NH(C1-C4alkyl), or - N(C1-C4alkyl)2;
R1b and R2c form together with the carbon atom to which they are attached a C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, 8- to 14-membered partially unsaturated heterocyclic group, or 8- to 14-membered partially unsaturated carbocyclic group, wherein C3-C8cycloalkyl is optionally substituted with 1 to 3 R9 substituents, and wherein 4- to 14-membered heterocycloalkyl, 8- to 14- membered partially unsaturated heterocyclic group, or 8- to 14-membered partially unsaturated carbocyclic group is optionally substituted with oxo (=0), oxime (=N-OH), C1-C3alkoxyoxime (=N- OC1-C3alkyl), or 1 to 3 substituents independently selected from -OH and -CF3;
R2d and R4b form together with the carbon atoms to which they are attached a C3-C8cycloalkyl or 4- to 14-membered heterocycloalkyl, wherein C3-C8cycloalkyl is optionally substituted with 1 to 3 R19 substituents; and
R1c and R3 form together with the carbon atoms to which they are attached a C3-C8cycloalkyl or 4- to 14-membered heterocycloalkyl, wherein C3-C8cycloalkyl is optionally substituted with 1 to 3 R19 substituents.
In some embodiments, the pharmaceutical combination can comprise a compound of Formula (I) which is a compound of Formula (la), of Formula (la’), of Formula (lb), of Formula (lb’), of Formula (Ic), of Formula (lc’), of Formula (Id), of Formula (Id’), of Formula (le), of Formula (le’), of Formula (If), of Formula (If’), or of Formula (Ig), as described herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
In some embodiments, the pharmaceutical combination can comprise a compound of Formula (I) which is a compound of Table 1 of the present description, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
In some embodiments, the pharmaceutical combination is such that the COX inhibitor can comprise a Non-Steroidal Anti-Inflammatory Drug (NSAID). In some embodiments, the pharmaceutical combination is such that the COX inhibitor is acetaminophen.
In some embodiments, the pharmaceutical combination can be a synergistic pharmaceutical combination.
Another aspect relates to a pharmaceutical combination as defined herein, for use in the treatment of pain in a subject in need thereof. Similarly, this aspect relates to the use of a pharmaceutical combination as defined herein, for the treatment of pain in a subject in need thereof. Furthermore, this aspect relates to a method for the treatment of pain, comprising administering to a subject in need thereof a pharmaceutical combination as defined herein. In some embodiments, the pain is inflammatory pain, neuropathic pain or cancer pain. In some embodiments, the pain is inflammatory pain. In another embodiment, the pain is neuropathic pain. In yet another embodiment, the pain is cancer pain. In some embodiments, the treatment is an oral treatment.
Another aspect relates to a method for the treatment of pain, comprising administering to a subject in need thereof a cyclooxygenase (COX) inhibitor and a compound having the Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein. In some embodiments, the COX inhibitor can comprise a Non-Steroidal Anti-Inflammatory Drug (NSAID). In some embodiments, the COX inhibitor is acetaminophen. In some embodiments, the pain is inflammatory pain, neuropathic pain or cancer pain. In some embodiments, the pain is inflammatory pain. In another embodiment, the pain is neuropathic pain. In yet another embodiment, the pain is cancer pain. In some embodiments, the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof are administered orally.
Another aspect relates to a kit comprising a first single dose form of a cyclooxygenase (COX) inhibitor and a second single dose form of a compound having the Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and instructions for use. In some embodiments, the kit can comprise a COX inhibitor which is a Non-Steroidal Anti-Inflammatory Drug (NSAID). In some embodiments, the COX inhibitor can be acetaminophen. In some embodiments, the kit is for use in the treatment of pain. In some embodiments, the pain is inflammatory pain, neuropathic pain or cancer pain. In some embodiments, the pain is inflammatory pain. In another embodiment, the pain is neuropathic pain. In yet another embodiment, the pain is cancer pain. In some embodiments, the treatment is an oral treatment.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 shows: (A) the dose response curve of compound 61 , naproxen, and compound 61 :naproxen combination in the carrageenan-induced inflammation model. Analysis of carrageenan-treated rats using linear regression analysis reveals that the ED50 of the combination is 1.4 mg/kg, with 95% confidence limits (CL) of 1.0 and 2.0 mg/kg as compared to compound 61 or naproxen alone, which produces an ED50 of 6.7 and 8.1 mg/kg, respectively. All compounds administered orally and tested 30 minutes later. Dose ratio of combination was 1 :0.83 (naproxen: compound 61). Non-linear regression analysis using the variable slope sigmoidal equation model. % anti-hyperalgesia = (PWL(dose)-PWL(vehicle)) I (PWL(naive)-PWL (vehicle)) X 100. Dotted lines represent 95% CL. (B) the isobologram of compound 61 to naproxen. The isobolographic analysis was performed using normalized data. The data point representing the ED50 value of the combination therapy lies below the line of additivity (line connecting compound 61 and naproxen ED50 values) with its 95% CL never crossing the dotted line.
Figure 2 shows: (A) the dose response curve of compound 61 , naproxen, and compound 61 :naproxen combination in the carrageenan-induced inflammation model. Analysis of carrageenan-treated rats using linear regression analysis reveals that the ED50 of the combination is 1.8 mg/kg, with 95% confidence limits (CL) of 1.4 and 2.3 mg/kg as compared to compound 61 or naproxen alone, which produces an ED50 of 6.7 and 8.1 mg/kg, respectively. All compounds administered orally and tested 30 minutes later. Dose ratio of combination was 1 :0.83 (naproxen: compound 61). Non-linear regression analysis using the variable slope sigmoidal equation model. % anti-hyperalgesia = (PWL(dose)-PWL(vehicle)) I (PWL(naive)-PWL (vehicle)) X 100. Dotted lines represent 95% CL. (B) the isobologram of compound 61 to naproxen. The isobolographic analysis was performed using normalized data. The data point representing the ED50 value of the combination therapy lies below the line of additivity (line connecting compound 61 and naproxen ED50 values) with its 95% CL never crossing the dotted line.
Figure 3 shows: (A) the dose response curve of compound 61 , celecoxib, and compound 61 :celecoxib combination in the carrageenan-induced inflammation model. Analysis of carrageenan-treated rats using linear regression analysis reveals that the ED50 of the combination is 2.3 mg/kg, with 95% confidence limits (CL) of 1.5 and 2.9 mg/kg as compared to compound 61 or celecoxib alone, which produces an ED50 of 6.7 and 12.9 mg/kg, respectively. All compounds administered orally and tested 30 minutes later. Dose ratio of combination was 1 :0.52 (celecoxib: compound 61). Non-linear regression analysis using the variable slope sigmoidal equation model. % anti-hyperalgesia = (PWL(dose)-PWL(vehicle)) I (PWL(naive)-PWL(vehicle)) X 100. Dotted lines represent 95% CL. (B) the isobologram of compound 61 to celecoxib. The isobolographic analysis was performed using normalized data. The data point representing the ED50 value of the combination therapy lies below the line of additivity (line connecting compound 61 and celecoxib ED50 values) with its 95% CL never crossing the dotted line.
Figure 4 shows: (A) the dose response curve of compound 61 , ibuprofen, and compound 61 : ibuprofen combination in the carrageenan-induced inflammation model. Analysis of carrageenan- treated rats using linear regression analysis reveals that the ED50 of the combination is 2.1 mg/kg, with 95% confidence limits (CL) of 1.1 and 4.6 mg/kg as compared to compound 61 or ibuprofen alone, which produces an ED50 of 6.7 and 12.6 mg/kg, respectively. All compounds administered orally and tested 30 minutes later. Dose ratio of combination was 1 :0.53 (ibuprofen: compound 61). Non-linear regression analysis using the variable slope sigmoidal equation model. % anti-hyperalgesia = (PWL(dose)-PWL(vehicle)) / (PWL(naive)-PWL(vehicle)) X 100. Dotted lines represent 95% CL. (B) the isobologram of compound 61 to ibuprofen. The isobolographic analysis was performed using normalized data. The data point representing the ED50 value of the combination therapy lies below the line of additivity (line connecting compound 61 and ibuprofen ED50 values) with its 95% CL never crossing the dotted line.
Figure 5 shows: (A) the dose response curve of compound 61 , diclofenac, and compound 61 : diclofenac combination in the carrageenan-induced inflammation model. Analysis of carrageenan-treated rats using linear regression analysis reveals that the ED50 of the combination is 1.6 mg/kg, with 95% confidence limits (CL) of 0.9 and 2.8 mg/kg as compared to compound 61 or diclofenac alone, which produces an ED50 of 6.7 and 11 .7 mg/kg, respectively. All compounds administered orally and tested 30 minutes later. Dose ratio of combination was 1 :0.57 (diclofenac: compound 61). Non-linear regression analysis using the variable slope sigmoidal equation model. % anti-hyperalgesia = (PWL(dose)-PWL(vehicle)) I (PWL(naive)-PWL (vehicle)) X 100. Dotted lines represent 95% CL. (B) the isobologram of compound 61 to diclofenac. The isobolographic analysis was performed using normalized data. The data point representing the ED50 value of the combination therapy lies below the line of additivity (line connecting compound 61 and diclofenac ED50 values) with its 95% CL never crossing the dotted line.
Figure 6 shows: (A) the dose response curve of compound 63, naproxen, and compound 63:naproxen combination in the carrageenan-induced inflammation model. Analysis of carrageenan-treated rats using linear regression analysis reveals that the ED50 of the combination is 0.87 mg/kg, with 95% confidence limits (CL) of 0.4 and 2.0 mg/kg as compared to compound 63 or naproxen alone, which produces an ED50 of 1.4 and 8.1 mg/kg, respectively. All compounds administered orally and tested 30 minutes later. Dose ratio of combination was 1 :0.178 (naproxen: compound 63). Non-linear regression analysis using the variable slope sigmoidal equation model. % anti-hyperalgesia = (PWL(dose)-PWL(vehicle)) I (PWL(naive)-PWL (vehicle) )X 100. Dotted lines represent 95% CL. (B) the isobologram of compound 63 to naproxen. The isobolographic analysis was performed using normalized data. The data point representing the ED50 value of the combination therapy lies below the line of additivity (line connecting compound 63 and naproxen ED50 values) with its 95% CL never crossing the dotted line.
DETAILED DESCRIPTION
General Definitions
All technical and scientific terms used herein have the same meaning as commonly understood by one ordinary skilled in the art to which the present technology pertains. For convenience, the meaning of certain terms and phrases used herein are provided below.
To the extent the definitions of terms in the publications, patents, and patent applications incorporated herein by reference are contrary to the definitions set forth in this specification, the definitions in this specification control. The section headings used herein are for organizational purposes only, and are not to be construed as limiting the subject matter disclosed. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. It should be noted that, the singular forms "a", "an", and "the" include plural forms as well, unless the content clearly dictates otherwise. Thus, for example, reference to a composition containing "a compound" also contemplates a mixture of two or more compounds. It should also be noted that the term "or" is generally employed in its sense including "and/or" unless the content clearly dictates otherwise. Furthermore, to the extent that the terms “including”, "includes", "having", "has", "with", or variants thereof are used in either the detailed description and/or the claims, such terms are intended to be inclusive in a manner similar to the term "comprising”.
The term "about" means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, "about" can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value. Where particular values are described in the application and claims, unless otherwise stated the term "about" meaning within an acceptable error range for the particular value should be assumed.
Thiophene fused cyclohexanone derivative ASIC inhibitors
The present application relates to pharmaceutical combinations comprising thiophene fused cyclohexanone derivatives having ASIC inhibition properties, which are compounds of general Formula (I)
Figure imgf000011_0001
or pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein Ra and will
Figure imgf000011_0002
be defined in further detail below.
The compounds described in the present application thus encompass those represented by the chemical structure of Formula I, with reference to any of the applicable embodiments described below, and exemplary compounds, such as Compounds 4, 8, 9, 14-39, 47-54, 59, 60a, 60b, 61- 72, 75, 81-84, 89, 91 , 97, 101 , 108, 109, 119-136, 138-150, 154, 155, 163, 168-170, 173-175, 178-181 , 183, 189-195, 197-202, 211-216, 219, 221 , 227-232, 237, 238, 239, 245-251 , 253, 254, 255, 257, 258, 263, 264, 271 , 272, 273, 278-281 , 287, 288, 290, 291 , 297, 298, 305, 306, 313, 314, 321 , 322, 330, 331 , 337-349, 352-358, 360, 362, 371 , 378, 391-393, 394a, 394b, 395a, 395b, 396, 397, 401-403, 406-408, 412-414, 416, 418, 422, 427-431 , 433, 434, 445-454, 462- 466, 468-476, 478-483, 486, 488, 489, 492, 495-498, 511-515, 520, 523, 524, or 534 of Table 1 , as well as their pharmaceutically acceptable salts, solvates, and prodrugs when applicable.
Compounds may be identified either by their chemical structure or their chemical name. In a case where the chemical structure and chemical name would conflict, the chemical structure will prevail.
Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the present description. Unless otherwise stated, all tautomeric forms of the compounds are within the scope of the present description. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of the present description. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present description.
Definitions of specific functional groups and chemical terms are provided below.
The chemical structures herein are drawn according to the conventional standards known in the art. Thus, where an atom, such as a carbon atom, as drawn appears to have an unsatisfied valency, then that valency is assumed to be satisfied by a hydrogen atom even though that hydrogen atom is not necessarily explicitly drawn. Hydrogen atoms should be inferred to be part of the compound.
The number of carbon atoms in a hydrocarbyl substituent can be indicated by the prefix "Cx-Cy," where x is the minimum and y is the maximum number of carbon atoms in the substituent. When reference is made to “x to y membered” heterocyclic group (e.g., heterocycloalkyl, partially unsaturated heterocyclic group, or heteroaryl), then x and y define respectively, the minimum and maximum number of atoms in the cyclic group, including carbons as well as heteroatom(s).
The term "halogen" as used herein refers to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).
The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon, more particularly oxygen, sulfur, or nitrogen. The term "alkyl" as used herein, refers to a saturated, straight- (linear) or branched-chain hydrocarbon radical. In some embodiments, the alkyl group can contain from 1 to 6 carbon atoms, although alkyl groups with more than 6 carbon atoms can be contemplated. For example, "C1- C6alkyl" contains from one to six carbon atoms. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, te/Y-butyl, neopentyl, n- hexyl, heptyl, octyl radicals and the like.
The term "alkenyl" as used herein, denotes a straight- or branched-chain hydrocarbon radical containing one or more double bonds. In some embodiments, the alkenyl groups can contain from 2 to 6 carbon atoms, although alkenyl groups with more than 6 carbon atoms can be contemplated. For example, "C2-C6alkenyl" contains from two to six carbon atoms. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, pentenyl, 1-methyl-2-buten- 1-yl, hexenyl, and the like.
The term "alkynyl" as used herein, denotes a straight- or branched-chain hydrocarbon radical containing one or more triple bonds. In some embodiments, the alkynyl groups can contain from 2 to 6 carbon atoms, although alkynyl groups with more than 6 carbon atoms can be contemplated. For example, "C2-C6alkynyl" contains from two to six carbon atoms. Alkynyl groups include, but are not limited to, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
The term “cycloalkyl”, used alone or as part of a larger moiety, refers to a group comprising a saturated carbocyclic ring in a monocyclic or polycyclic ring system, including spiro (sharing one atom), fused (sharing at least one bond) or bridged (sharing two or more bonds) carbocyclic ring systems, having from three to fifteen ring members. In some embodiments, the cycloalkyl groups can contain from 3 to 8 carbon atoms. For example, "C3-C8cycloalkyl" contains from three to eight carbon atoms in the cyclic ring. Examples of cycloalkyl groups can include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[4.2.0]octyl, norbornyl, and the like.
The term "aryl" used herein refers to a monocyclic moiety or to a bicyclic or tricyclic fused ring system wherein the ring system is carbocyclic and fully aromatic. In some embodiments, the aryl groups can contain from 6 to 14 carbon atoms, such as 6 to 10 carbon atoms for instance. For example, a "C6-C10aryl" group contains from six to ten carbon atoms in the aromatic system. In certain embodiments, "aryl" refers to an aromatic ring system which includes, without being limited to, phenyl, naphthyl, azulenyl, anthracyl, and the like.
As used herein, the term "heterocyclic group" refers to a chemically stable, saturated, partially unsaturated, or fully aromatic monocyclic or polycyclic ring system, including spiro (sharing one atom), fused (sharing at least one bond) or bridged (sharing two or more bonds) carbocyclic ring system, including at least one heteroatom as defined above. A heterocyclic group can be a heterocycloalkyl group, a heteroaryl group, or a partially unsaturated heterocyclic group, as defined herein.
The term "heterocycloalkyl" used alone or as part of a larger moiety, refers to a saturated cyclic group containing at least one heteroatom as defined herein, which can include a single ring, or two or more rings. In some embodiments, the heterocycloalkyl groups can include 3 to 14 ring atoms although heterocycloalkyl groups with more than 14 ring atoms can be contemplated. In some embodiments, the heterocycloalkyl groups can contain 4 to 14 ring atoms, or 4 to 6 ring atoms or 3 to 6 ring atoms for instance. For example, a "3- to 14-membered heterocycloalkyl group" contains from three to fourteen atoms, by counting the total number of carbon atoms and heteroatoms, in the saturated heterocyclic moiety. In some embodiments, the heterocycloalkyl group can contain from one to four heteroatoms. Heterocycloalkyl groups can include, without limitation, oxiranyl, aziridinyl, oxetanyl, tetrahydropyranyl (oxanyl), tetrahydrofuranyl (oxolanyl), pyrrolidinyl (azolidinyl), piperidinyl, dioxanyl, morpholinyl, thietanyl, azetidinyl, diazetidinyl, oxathiolanyl, oxepanyl, azocanyl (octahydroazocinyl), thiocanyl, azonanyl (octahydroazoninyl), 1 ,3-dioxolanyl, pyrazolidinyl, imidazolidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothienyl, tetrahydrodithienyl, thiomorpholinyl, thioxanyl, homopiperidinyl, thiepanyl, dithianyl, dithiolanyl, 3- azabicyclo[3,1 ,0]hexanyl, 3-azabicyclo[4,1 ,0]heptanyl, quinuclidinyl, decahydroquinolinyl, octahydroindolyl, and the like. A heterocycloalkyl can be attached to its pendant group at any heteroatom or carbon atom that results in a chemically stable structure.
The term "heteroaryl" used alone or as part of a larger moiety, refers to a fully aromatic cyclic group containing at least one heteroatom as defined herein, which can include a single ring, or two or more fused rings. In some embodiments, the heteroaryl groups can include from 5 to 10 ring atoms although heteroaryl groups with more than 10 ring atoms can be contemplated. In some embodiments, the heteroaryl group can contain from one to four heteroatoms. Heteroaryl groups can include, without limitation, thienyl, furanyl (furyl), pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, benzofuranyl, dibenzofuranyl, benzimidazolyl, benzothiazolyl, benzothienyl (benzothiophenyl), benzoxazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, furopyridinyl, indolyl, indazolyl, isoindolyl, indolizinyl, purinyl, quinolyl (quinolinyl), isoquinolyl (isoquinolinyl), acridinyl, cinnolinyl, quinazolinyl, naphthyridinyl, carbazolyl, phenanthridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and pteridinyl. A heteroaryl group can be attached to its pendant group at any heteroatom or carbon atom that results in a chemically stable structure.
As used herein, the term "partially unsaturated heterocyclic group" refers to a carbocyclic ring system including at least one double bond between ring atoms but is not fully aromatic and comprises at least one heteroatom. The "partially unsaturated heterocyclic group" is intended to encompass ring systems, which can be mono, bi or tricyclic and having one or multiple sites of unsaturation. In some embodiments, the partially unsaturated heterocyclic group can include a multicyclic ring system where at least one ring is aromatic while at least another ring is not aromatic. For instance, the partially unsaturated heterocyclic group can include an aryl fused with a heterocycloalkyl, a heteroaryl fused with a cycloalkyl, or a heteroaryl fused with a heterocycloalkyl, where each of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl can itself be monocyclic or bicyclic. In some embodiments, the partially unsaturated heterocyclic groups can contain from 7 to 14 carbon atoms, such as 7 to 10 carbon atoms or 8 to 14 carbon atoms for instance. For example, a "7- to 10-membered partially unsaturated heterocyclic group" contains from seven to ten atoms, by counting the total number of carbon atoms and heteroatoms, in the heterocyclic moiety. The partially unsaturated heterocyclic group can contain, in some embodiments, from one to four heteroatoms. The partially unsaturated heterocyclic group can be attached to its pendant group at any heteroatom or carbon atom that results in a chemically stable structure. Non-limiting examples of partially unsaturated heterocyclic group include pyrazolinyl, imidazolinyl, 1 , 2,3,6- tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2H-pyranyl, 4H-pyranyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, quinolizinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, 1 ,3- benzodioxolyl, chromanyl, chromenyl, indolinyl, quinolonyl, isoquinolonyl, oxazepinyl, diazepinyl, thiazepinyl, phthalazinyl, quinoxalinyl, pyrido[2,3-b]-l,4-oxazin-3(4H)-one,
Figure imgf000015_0001
. When used in reference to a ring atom of a heterocyclic group, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR0 (as in N- substituted pyrrolidinyl).
As used herein, the term "partially unsaturated carbocyclic group" refers to a carbocyclic ring system including at least one double bond between ring atoms but is not fully aromatic. The "partially unsaturated carbocyclic group" is intended to encompass ring systems, which comprise only carbon atoms within the ring, said ring being mono, bi or tricyclic and having one or multiple sites of unsaturation. In some embodiments, the partially unsaturated carbocyclic group can include a multicyclic ring system where at least one ring is aromatic while at least another ring is not aromatic. For instance, the partially unsaturated heterocyclic group can include an aryl fused with a cycloalkyl, where each of the aryl and cycloalkyl can itself be monocyclic or bicyclic. In some embodiments, the partially unsaturated carbocyclic groups can contain from 7 to 14 carbon atoms, such as 7 to 10 carbon atoms or 8 to 14 carbon atoms for instance. For example, a "8- to 14-membered partially unsaturated carbocyclic group" contains from eight to fourteen carbon atoms in the cyclic moiety. The partially unsaturated carbocyclic group can be attached to its pendant group at any carbon atom that results in a chemically stable structure. A non-limiting example of partially unsaturated carbocyclic group includes
Figure imgf000016_0001
As described herein, various chemical groups present in the compounds of the present description, such as any of the above-defined groups, can be optionally substituted. In general, the term "substituted" means that one or more hydrogen atoms of the designated moiety is replaced with a suitable substituent. Unless otherwise indicated, a substituted chemical group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position. Combinations of substituents envisioned under the present description are preferably those that result in the formation of chemically stable or chemically feasible compounds. The term "chemically stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
In some particular embodiments, when any chemical group is substituted, it can be substituted by independent replacement of one, two, orthree or more of the hydrogen atoms with substituents including, but not limited to halogen (i.e., -F, -Cl, -Br,-I), -OH, -CO2H, alkoxy such as methoxy, ethoxy, or propyloxy, -OCHF2, -OCH2CHF2, -OCH2CF3, -OCH2CH2OCH3, protected alkoxy, alkyl groups as defined above such as methyl, ethyl, propyl, or -C(CH3)3, aryl groups as defined above such as phenyl, cycloalkyl groups as defined above such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, oxo (=0), thioxo (=s), oxime (=N-OH), C1-C3alkoxyoxime (=N-OC1-C3alkyl),-NO2, - CN, -NH2, -NHMe, -NHEt, -N(Me)2, -NHCOMe, -NH(COOtBu), -N(Et)(COOtBu), protected amino, -CH2OH, -COOH, -COOMe, -COOEt, -CONH2, -CONHMe, -CONHEt, -CF3, -CHF2, -CH2F, - Si(Me), -OSi(Me)2(fBu), -SMe, -SO2NH(CH2)3OH, -SO2Me, -SO2Ph, -SPh, pyrazolyl, pyrrolyl, pyridyl, piperidinyl, triazolyl, tetrazolyl, morpholinyl, isoxazolyl, oxazolyl, thiazolyl, imidazolyl, benzothiazolyl, benzimidazolyl,
Figure imgf000016_0002
Figure imgf000017_0001
The expression "pharmaceutically acceptable salt" refers to those salts of the compounds of the present description which are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of the present description, or separately by reacting a free base function of the compound with a suitable organic or inorganic acid (acid addition salts) or by reacting an acidic function of the compound with a suitable organic or inorganic base (base-addition salts). Examples of pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts, or salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, valerate salts, and the like. Representative base addition alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, or magnesium salts, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, sulfonate and aryl sulfonate.
The term “solvate” refers to a physical association of one of the present compounds with one or more solvent molecules. This physical association includes hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solution-phase and isolable solvates. Exemplary solvates include, without limitation, hydrates, hemihydrates, ethanolates, hemiethanolates, n-propanolates, iso-propanolates, 1 -butanolates, 2- butanolate, and solvates of other physiologically acceptable solvents. The compounds as herein described also include each of their solvates and mixtures thereof.
The term " prodrug" as used herein refers to those prodrugs of the compounds of the present description which are suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use. "Prodrug", as used herein means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to afford any compound delineated by the formulae of the instant description. Various forms of prodrugs are known in the art.
The compounds of the present application may be prepared by conventional chemical synthesis, such as exemplified in the general schemes provided hereafter and in Examples 1 to 260 for instance. As can be appreciated by the skilled artisan, further methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. In addition, the solvents, temperatures, reaction duration, etc. delineated herein are for purposes of illustration only and one of ordinary skill in the art will recognize that variation of the reaction conditions can produce the desired products of the present description. Synthetic chemistry transformations and/or protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art. The synthesized compounds can be separated from a reaction mixture and further purified by standard methods such as column chromatography, high pressure liquid chromatography, or recrystallization.
The thiophene fused cyclohexanone derivatives such as the compounds of Formula (I) may be modified by appending various functionalities via any synthetic means delineated herein to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
In some embodiments, the thiophene fused cyclohexanone derivative can thus be a compound having the Formula (I),
Figure imgf000019_0001
or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
Ra is -NH2, -NH-OH, -OH, -NHRb, or -NHRcRd;
Rb is C1-C6 alkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein C1-C6 alkyl is optionally substituted with 1 to 3 halogens, 1 to 3 -OH, -OC1-C3alkyl, -COOH, or cyclopropyl optionally substituted with -OH, and wherein C3-C6cycloalkyl is optionally substituted with -ON;
Rc and Rd form with the nitrogen to which they are attached a 4-membered heterocycloalkyl, wherein the 4-membered heterocycloalkyl is optionally substituted with at least one of -OH and C1-C3alkyl; represents one of the following residues Ao to A12
Figure imgf000019_0002
Figure imgf000019_0005
and wherein:
R is H, C1-C6alkyl or phenyl;
R1 and R2 are independently -ON, C6-C10aryl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C8cycloalkyl, 4- to 14-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C(O)NH2, - C(O)NHR5, -C(O)R6, or -C(0)OR5, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R7 substituents, each C6-C10aryl is optionally substituted with 1 to 3 R8 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R22 substituents, with the proviso that when Ra is -OH,
Figure imgf000019_0003
represents Ao, and R1 is
Figure imgf000019_0004
then R2 in residue Ao is different than ;
Figure imgf000020_0001
each R5 is independently C1-C6alkyl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R9 substituents; each R6 is independently C3-C6cycloalkyl, 4- to 6-membered heterocycloalkyl, or C6-C10aryl; each R7 is independently -OH, -C(O)R11, C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6alkyl), -N(C1-C4alkyl)(C(O)OC1-C6alkyl), 4- to 6- membered heterocycloalkyl, -NH(C(O)C1-C6alkyl), -OR20, -SC1-C6alkyl, -NH2, -NH(C1-C4alkyl), or -N(C1-C4alkyl)2, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 3 R12 substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R13 substituents, and each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl or oxo; each R8 is independently halogen, C1-C6alkyl, -OC1-C6alkyl, C3-C6cycloakyl, or 5- to 10- membered heteroaryl, wherein each -OC1-C6alkyl is optionally substituted with -OC1-C4alkyl, and each 5- to 10-membered heteroaryl is optionally substituted with C1-C4alkyl; each R22 is independently C1-C6alkyl optionally substituted with phenyl; each R9 is independently -OH, -C(O)R15, C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, -C(O)OH, 4- to 6-membered heterocycloalkyl, -NH(C(O)C1-C6alkyl), -OC1-C6alkyl, -SC1-C6alkyl, -NH2, -NH(C1- C4alkyl), or -N(C1-C4alkyl)2, wherein each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl, and each -OC1-C6alkyl is optionally substituted with -OC1-C4alkyl; each R11 is independently -NH2, -NH(C1-C4alkyl), -N(C1-C4alkyl)2, or 4- to 6-membered heterocycloalkyl; each R20 is independently C1-C6alkyl or 5- to 10-membered heteroaryl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R14 substituents and each 5- to 10-membered heteroaryl is optionally substituted with -OH or -NH(cyclopropyl); each R12 is independently C1-C4alkyl, -SC1-C4alkyl, -Ph, -OC1-C4alkyl, or -SPh, wherein each C1- C4alkyl is optionally substituted with -OH; each R13 is independently halogen, C1-C4alkyl, C3-C6cycloalkyl, -OH, -OC1-C6alkyl, -SC1-C6alkyl, -S(O)2C1-C6alkyl, -NH2, -NH(C1-C4alkyl), or -N(C1-C4alkyl)2, wherein each -OC1-C6alkyl, -SC1- C6alkyl, -S(O)2C1-C6alkyl, -NH(C1-C4alkyl), and -N(C1-C4alkyl)2 is optionally substituted with 1 to 3 R9 substituents; each R14 is independently halogen, -OC1-C4alkyl, or C3-Cecycloalkyl; each R15 is independently -NH2, -NH(C1-C4alkyl), -N(C1-C4alkyl)2, or 4- to 6-membered heterocycloalkyl;
R4 is C1-C6alkyl, C3-C6cycloalkyl, C6-C10aryl, 7- to 10-membered partially unsaturated heterocyclic group, or 5- to 10-membered heteroaryl, wherein C1-C6alkyl and C3-C8cycloalkyl are optionally substituted with 1 to 3 R9 substituents, and C8-C10aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R10 substituents, with the proviso that: (i) when Ra is -OH, -NH2,
Figure imgf000021_0001
represents A2, then R4 in residue A2 is different than -CH3; and (ii) when Ra is -NH2 and C A
— - represents A3, then R4 in residue A3 is different than -C(CH3)3; each R10 is independently C1-C4alkyl, halogen, -OC1-C6alkyl, -NH2, -NH(C1-C4alkyl), or -N(C1- C4alkyl)2, wherein each C1-C4alkyl is optionally substituted with 1 to 3 halogens;
R2a is C1-C6alkyl, C3-C8cycloalkyl, or C6-C10aryl, wherein C1-C8alkyl and C3-C8cycloalkyl are optionally substituted with 1 to 3 R9 substituents, and C6-C10aryl is optionally substituted with 1 to 3 R10 substituents;
R1a and R2b are independently -CN, C6-C10aryl, C1-C6alkyl, C3-C8cycloalkyl, -C(O)NH2, - C(O)NHR5, or -C(0)OC1-C6alkyl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R16 substituents and each C6-C10aryl is optionally substituted with 1 to 3 R17 substituents; each R16 is independently -OH, -C(O)NH2, -C(O)NH(C1-C4alkyl), C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6alkyl), 4- to 6-membered heterocycloalkyl, -NH(C(O)C1-C6alkyl), or -OC1-C4alkyl(OC1-C4alkyl), wherein each C3- C6cycloalkyl is optionally substituted with 1 to 3 R18 substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R21 substituents, and each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl; each R17 is independently halogen, C1-C6alkyl, -OC1-C6alkyl, or 5- to 10-membered heteroaryl, wherein each 5- to 10-membered heteroaryl is optionally substituted with C1-C4alkyl; each R18 is independently C1-C4alkyl, -SC1-C4alkyl, -Ph, or -OC1-C4alkyl; each R21 is independently halogen or C1-C4alkyl;
R4a is C1-C6alkyl or C3-C8cycloalkyl, wherein each C1-C6alkyl and C3-C8cycloalkyl are optionally substituted with 1 to 3 R19 substituents; each R19 is independently halogen, -OH, -OC1-C4alkyl, -SC1-C4alkyl, -NH2, -NH(C1-C4alkyl), or - N(C1-C4alkyl)2;
R1b and R2c form together with the carbon atom to which they are attached a C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, 8- to 14-membered partially unsaturated heterocyclic group, or 8- to 14-membered partially unsaturated carbocyclic group, wherein C3-C8cycloalkyl is optionally substituted with 1 to 3 R9 substituents, and wherein 4- to 14-membered heterocycloalkyl, 8- to 14- membered partially unsaturated heterocyclic group, or 8- to 14-membered partially unsaturated carbocyclic group is optionally substituted with oxo (=0), oxime (=N-OH), C1-C3alkoxyoxime (=N- OC1-C3alkyl), or 1 to 3 substituents independently selected from -OH and -CF3;
R2d and R4b form together with the carbon atoms to which they are attached a C3-C3cycloalkyl or 4- to 14-membered heterocycloalkyl, wherein C3-C8cycloalkyl is optionally substituted with 1 to 3 R19 substituents; and
R1c and R3 form together with the carbon atoms to which they are attached a C3-C8cycloalkyl or 4- to 14-membered heterocycloalkyl, wherein C3-C8cycloalkyl is optionally substituted with 1 to 3 R19 substituents.
In some embodiments, the compound of Formula (I) is such that: (i) when Ra is -OH,
Figure imgf000022_0005
represents Ao, and R1 is
Figure imgf000022_0001
, then R2 in residue Ao is different than
Figure imgf000022_0019
(ii) when
Ra is -OH and represents A2, then R4 in residue A2 is different than -CH3 and -CH2CH3; (iii)
Figure imgf000022_0007
when Ra is -NH2, and
Figure imgf000022_0008
represents A2, then R4 in residue A2 is different than -CH3; and (iv) when Ra is -NH2 and
Figure imgf000022_0009
represents A3, then R4 in residue A3 is different than -C(CH3)3.
In some embodiments, the compound of Formula (I) is such that: (i) when Ra is -OH,
Figure imgf000022_0006
Figure imgf000022_0002
represents Ao, and R1 is
Figure imgf000022_0003
, then R2 in residue Ao is different than O ; (ii) when
Ra is -OH and
Figure imgf000022_0010
represents A2, then R4 in residue A2 is different than -CH3 and -CH2CH3; (iii) when Ra is -NH2, and
Figure imgf000022_0011
represents A2, then R4 in residue A2 is different than -CH3;
(iv) when Ra is
Figure imgf000022_0004
represents A2, then R4 in residue A2 is different than -CH3; and (v) when Ra is -NH2 and
Figure imgf000022_0012
represents A3, then R4 in residue A3 is different than -C(CH3)3.
In other embodiments, the compound of Formula (I) is such that: (i) when Ra is -OH,
Figure imgf000022_0013
represents Ao, and R1 is
Figure imgf000022_0014
then R2 in residue Ao is different than
Figure imgf000022_0015
(ii) when
Ra is -OH and < represents A2, then R4 in residue A2 is different than alkyl; (iii) when Ra is -
Figure imgf000022_0016
NH2, and
Figure imgf000022_0017
represents A2, then R4 in residue A2 is different than -CH3; and (iv) when Ra is -
NH2 and
Figure imgf000022_0018
represents A3, then R4 in residue A3 is different than -C(CH3)3. In other embodiments, the compound of Formula (I) is such that: (i) when Ra is -OH,
Figure imgf000023_0002
represents Ao, and R1 is
Figure imgf000023_0004
then R2 in residue Ao is different than
Figure imgf000023_0003
; (jj) when Ra is -OH and
Figure imgf000023_0005
represents A2, then R4 in residue A2 is different than alkyl; (iii) when Ra is - NH2, and
Figure imgf000023_0006
represents A2, then R4 in residue A2 is different than -CH3; (iv) when Ra is
Figure imgf000023_0007
and
Figure imgf000023_0008
represents A2, then R4 in residue A2 is different than -CH3; and (v) when
Ra is -NH2 and
Figure imgf000023_0009
represents A3, then R4 in residue A3 is different than -C(CH3)3.
In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is such that R is H.
In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is such that Ra is -NHRb and Rb represents C1-C6 alkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein C1-C6 alkyl is optionally substituted with 1 to 3 halogens, 1 to 3 -OH, -OC1-C3alkyl , -COOH , or cyclopropyl optionally substituted with - OH, and wherein C3-C6cycloalkyl is optionally substituted with -ON.
In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is such that Ra is -NHRb and Rb represents:
Figure imgf000023_0001
In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is such that Ra is -NHRb and Rb represents -CH3
Figure imgf000023_0012
Figure imgf000023_0010
In some embodiments, Ra is -NHRb and Rb represents
Figure imgf000023_0011
In other embodiments, Ra is -NRcRd and Rc and Rd form with the nitrogen to which they are attached a 4-membered heterocycloalkyl, wherein the 4-membered heterocycloalkyl is optionally substituted with at least one of -OH and C1-C3alkyl.
In other embodiments, Ra is
In other embodiments, Ra is
Figure imgf000024_0002
In other embodiments, Ra is -OH.
In other embodiments, Ra is -NH2.
In other embodiments, Ra is -NH-OH.
In some embodiments, the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, can be in the form of a racemate or any enantiomer thereof.
In some embodiments, the compound of Formula (I) can have the following structures (la), (la’), (lb), (lb’), (Ic), (lc’), (Id), (Id’), (le), (le’), (If), (If’), or (lg):
Figure imgf000024_0001
Figure imgf000025_0001
where R1, R2, R3, R4, R1a, R1b, R1c, R2a, R2b, R2c, R2d, R4a, R4b, R and Ra are as defined herein.
Compounds of Formula (la) and (la”)
In some embodiments, the compound is of Formula (la) or (la’), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
Figure imgf000025_0002
The groups R, Ra, R1 and R2 can be as defined for the general Formula (I) above.
In some embodiments, the compound is of Formula (la), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
Figure imgf000025_0003
The groups Ra, R1 and R2 can be as defined for the general Formula (I) above.
In some embodiments, R1 and R2 can independently represent -CN, C6-C10aryl, C1-C6alkyl, C2- C6alkynyl, C3-C8cycloalkyl, 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHR5, -C(O)R6, or - C(O)OR5, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R7 substituents, each C6-C10aryl is optionally substituted with 1 to 3 R8 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R22 substituents, and R5, R6, R7, R8 and R22 are as defined herein.
In some embodiments, R1 and R2 are independently -CN, C6-C10aryl, C1-C6alkyl, C2-C6alkynyl, C3- C8cycloalkyl, 5- to 10-membered heteroaryl, or -C(O)NH2, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R7 substituents, each C6-C10aryl is optionally substituted with 1 to 3 R8 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R22 substituents, and R7, R8 and R22 are as defined herein.
In further embodiments, R1 and R2 can independently represent -CN, phenyl, C1-C4alkyl, C2- C4alkynyl, C3-C6cycloalkyl, 5-membered heteroaryl, or -C(O)NH2, wherein each C1-C4alkyl is optionally substituted with 1 or 2 R7 substituents, each phenyl is optionally substituted with 1 or 2 halogens, and each 5-membered heteroaryl is optionally substituted with 1 or 2 -CH3.
According to some embodiments, R1 and R2 independently represent -CN, C6-C10aryl, C1-C6alkyl, C3-C8cycloalkyl, or -C(O)NH2, wherein each C1-C6alkyl is optionally substituted with 1 to 2 R7 substituents as defined herein.
In some embodiments, when R1 and/or R2 represent -C(O)NHR5 or -C(O)OR5, each R5 can be C1-C6alkyl. In other embodiments, when R1 and/or R2 represent -C(O)R6 each R6 can be a 4- to 6-membered heterocycloalkyl.
In some embodiments, when R1 and/or R2 represent C1-C6alkyl substituted with 1 to 3 R7 substituents, then each R7 can independently represent -OH, -C(O)R11, C3-C6cycloalkyl, -CN, C6- C10aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6alkyl), -N(C1- C4alkyl)(C(O)OC1-C6alkyl), -NH(C(O)C1-C6alkyl), 4- to 6-membered heterocycloalkyl, -OR20, -SC-1-C6alkyl, -NH2, or -N(C1-C4alkyl)2, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 3 R12 substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R13 substituents and each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl or oxo.
In some embodiments, R7 can independently represent -OH, -C(O)R11, -OR20, C3-C6cycloalkyl, - CN, C6-C10aryl, halogen, -C(O)OH, or 5- to 10-membered heteroaryl, wherein each C3- C6cycloalkyl is optionally substituted with 1 to 3 R12 substituents and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R13 substituents.
In further embodiments, R7 can independently represent -OH, -C(O)NH2, -OR20, C3-C6cycloalkyl, -CN, phenyl, halogen, -C(O)OH, or 5-membered heteroaryl, wherein each C3-C6cycloalkyl is optionally substituted with -CH3.
In another embodiment, R7 can independently represent -OH, -C(O)NH2, C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, or 5- to 8-membered heteroaryl, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 2 C1-C4alkyl, and each 5- to 8-membered heteroaryl is optionally substituted with 1 to 2 R13 substituents.
In some embodiments, the R11 substituents mentioned above can independently represent -NH2, -NH(C1-C4alkyl), or 4- to 6-membered heterocycloalkyl. In some particular embodiments, R11 can represent -NH2. In some embodiments, the R12 substituents mentioned above can independently represent C1-C4alkyl, -SC1-C4alkyl, -Ph, -OC1-C4alkyl, or -SPh, wherein each C1-C4alkyl is optionally substituted with -OH. In some particular embodiments, R12 is C1-C4alkyl.
In some embodiments, the R13 substituents mentioned above can independently represent halogen, C1-C4alkyl, or C3-C6cycloalkyl. In some particular embodiments, R13 is independently halogen or C1-C4alkyl.
In some embodiments, the R14 substituents mentioned above can independently represent halogen, -OC1-C4alkyl, or C3-C6cycloalkyl. In some particular embodiments, R14 is halogen.
In some embodiments, the R20 substituents mentioned above can independently represent C1- C6alkyl or 5- to 10-membered heteroaryl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R14 substituents as defined herein, and each 5- to 10-membered heteroaryl is optionally substituted with -OH or -NH(cyclopropyl). In some particular embodiments, R20 is C1-C6alkyl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R14 substituents as defined herein. In further embodiments, R20 is C1-C6alkyl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 halogens. In some embodiments, R20 is 5- to 10-membered heteroaryl substituted with -OH or -NH(cyclopropyl). In certain embodiments, R20 is 5- to 10-membered heteroaryl substituted with - OH. In other embodiments, R20 is 5- or 6-membered heteroaryl substituted with -OH.
In some embodiments, the R22 substituents mentioned above can independently represent C1- C4alkyl.
In some embodiments, when R1 and/or R2 represent C6-C10aryl substituted with 1 to 3 R8 substituents, then each R8 can independently represent halogen, C1-C6alkyl, or -OC1-C6alkyl, wherein each -OC1-C6alkyl is optionally substituted with -OC1-C4alkyl. In some particular embodiments, R8 is a halogen. In some embodiments, when R1 and/or R2 represent 5- to 10- membered heteroaryl substituted with 1 to 3 R22 substituents, then each R22 can independently represent C1-C6alkyl optionally substituted with phenyl. In some embodiments, R22 is C1-C2alkyl substituted with phenyl.
In some embodiments, R1 and R2 are independently -CN, C6-C10aryl, C1-C6alkyl, C2-Cealkynyl, C3- C8cycloalkyl, 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHR5, -C(O)R6, or -C(O)OR5, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R7 substituents, each C6-C10aryl is optionally substituted with 1 to 3 R8 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R22 substituents, and each R5 is independently C1-C6alkyl; each R6 is independently a 4- to 6-membered heterocycloalkyl; each R7 is independently -OH, -C(O)R11, C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6alkyl), -N(C1-C4alkyl)(C(O)OC1-C6alkyl), 4- to 6-membered heterocycloalkyl, -NH(C(O)C1-C6alkyl), -OR20, -SC1-C6alkyl, -NH2, or -N(C1- C4alkyl)2, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 3 R12 substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R13 substituents, and each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl or oxo; each R8 is independently halogen, C1-C6alkyl, or -OC1-C6alkyl, wherein each -OC1-C6alkyl is optionally substituted with -OC1-C4alkyl; each R22 is independently C1-C6alkyl optionally substituted with phenyl; each R11 is independently -NH2, -NH(C1-C4alkyl), or 4- to 6-membered heterocycloalkyl; each R20 is independently C1-C6alkyl or 5- to 10-membered heteroaryl, wherein each C1- C6alkyl is optionally substituted with 1 to 3 R14 substituents and each 5- to 10-membered heteroaryl is optionally substituted with -OH or -NH(cyclopropyl); each R12 is independently C1-C4alkyl, -SC1-C4alkyl, -Ph, -OC1-C4alkyl, or -SPh, wherein each C1-C4alkyl is optionally substituted with -OH; each R13 is independently halogen, C1-C4alkyl, or C3-C6cycloalkyl; and each R14 is independently halogen, -OC1-C4alkyl, or C3-C6cycloalkyl.
In some embodiments, R1 and R2 are independently -ON, C6-C10aryl, C1-C6alkyl, C2-C6alkynyl, C3- C8cycloalkyl, 5- to 10-membered heteroaryl, or -C(O)NH2, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R7 substituents, each C6-C10aryl is optionally substituted with 1 to 3 R8 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R22 substituents, and each R7 is independently -OH, -C(O)R11, C3-C6cycloalkyl, -ON, C6-C10aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6alkyl), -N(C1-C4alkyl)(C(O)OC1-C6alkyl), - NH(C(O)C1-C6alkyl), 4- to 6-membered heterocycloalkyl, -OR20, -SC1-C6alkyl, -NH2, or -N(C1- C4alkyl)2, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 3 R12 substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R13 substituents, and each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl or oxo; each R8 is independently halogen, C1-C6alkyl, or -OC1-C6alkyl, wherein each -OC1-C6alkyl is optionally substituted with -OC1-C4alkyl; each R11 is independently -NH2, -NH(C1-C4alkyl), or 4- to 6-membered heterocycloalkyl; each R20 is independently C1-C6alkyl or 5- to 10-membered heteroaryl, wherein each C1- Cealkyl is optionally substituted with 1 to 3 R14 substituents and each 5- to 10-membered heteroaryl is optionally substituted with -OH or -NH(cyclopropyl); each R12 is independently C1-C4alkyl, -SC1-C4alkyl, -Ph, -OC1-C4alkyl, or -SPh, wherein each C1-C4alkyl is optionally substituted with -OH; each R13 is independently halogen, C1-C4alkyl, or C3-C6cycloalkyl; each R14 is independently halogen, -OC1-C4alkyl, or C3-C6cycloalkyl; and each R22 is independently C1-C4alkyl. In some embodiments, R1 and R2are independently -CN, C6-C10aryl, C1-C6alkyl, C2-C6alkynyl, C3- Cscycloalkyl, 5- to 10-membered heteroaryl, or -C(0)NH2, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R7 substituents, each C6-C10aryl is optionally substituted with 1 to 3 R8 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R22 substituents, and each R7 is independently -OH, -C(O)R11, -OR20, C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, - C(O)OH, or 5- to 10-membered heteroaryl, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 3 R12 substituents and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R13 substituents; each R8 is a halogen; each R11 is -NH2; each R20 is C1-C6alkyl or 5- or 6-membered heteroaryl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R14 substituents and each 5- or 6-membered heteroaryl is optionally substituted with -OH or -NH(cyclopropyl); each R12 is C1-C4alkyl; each R13 is independently halogen or C1-C4alkyl; each R14 is halogen; and each R22 is independently C1-C4alkyl.
In some embodiments, R1 and R2 independently represent -CN, phenyl, C1-C4alkyl, C2-C4alkynyl, C3-C6cycloalkyl, 5-membered heteroaryl, or -C(O)NH2, wherein each C1-C4alkyl is optionally substituted with 1 or 2 R7 substituents, each phenyl is optionally substituted with 1 or 2 halogens, and each 5-membered heteroaryl is optionally substituted with 1 or 2 -CH3, and each R7 is independently -OH, -C(O)NH2, -OR20, C3-C6cycloalkyl, -CN, phenyl, halogen, - C(O)OH, or 5-membered heteroaryl, wherein each C3-C6cycloalkyl is optionally substituted with -CH3; and each R20 is C1-C6alkyl or 5- or 6-membered heteroaryl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 halogen and each 5- or 6-membered heteroaryl is optionally substituted with -OH.
In some embodiments, R1 and R2 independently represent -CN, C6-C10aryl, C1-C6alkyl, C3- C8cycloalkyl, 5-membered heteroaryl, or -C(O)NH2, wherein each C1-C6alkyl is optionally substituted with 1 to 2 R7 substituents; each R7 is independently -OH, -C(O)NH2, C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, or 5- to 8-membered heteroaryl, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 2 C1- C4alkyl, and each 5- to 8-membered heteroaryl is optionally substituted with 1 to 2 R13 substituents; and each R13 is independently halogen or C1-C4alkyl. In some embodiments, R1 and R2, which can be identical or different, can represent:
Figure imgf000030_0001
In some embodiments, R1 and R2, which can be identical or different, can represent:
Figure imgf000031_0001
In some embodiments, R1 and R2, which can be identical or different, can represent:
Figure imgf000031_0002
Figure imgf000032_0001
10 In some embodiments, R1 and R2, which can be identical or different, can represent:
Figure imgf000032_0002
Figure imgf000033_0001
In some embodiments, R1 and R2, which can be identical or different, can represent:
Figure imgf000033_0002
Figure imgf000034_0001
Figure imgf000035_0001
In some embodiments, R1 and R2, which can be identical or different, can represent:
Figure imgf000035_0002
In some embodiments, R1 and R2, which can be identical or different, can represent:
Figure imgf000035_0003
Figure imgf000036_0001
In some embodiments, R1 and R2, which can be identical or different, can represent:
Figure imgf000036_0002
Figure imgf000037_0001
In some embodiments, R1 and R2, which can be identical or different, can represent:
Figure imgf000037_0002
In some embodiments, R1 and R2, which can be identical or different, can represent:
Figure imgf000037_0003
Figure imgf000038_0001
In some embodiments, R1 and R2, which can be identical or different, can represent:
Figure imgf000038_0002
In some particular embodiments, R1 and R2 are different. In another particular embodiment, one of R1 and R2 is -CN. Other embodiments include compounds of Formula (la) or (la’), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, where one of R1 and R2 is
Figure imgf000038_0003
of Formula
In some embodiments, the compound is of Formula (lb) or (lb’), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
Figure imgf000038_0004
(lb) (lb’)
The groups R, Ra, and R4 can be as defined for the general Formula (I) above.
In some embodiments, the compound is of Formula (lb), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
Figure imgf000038_0005
The groups Ra and R4 can be as defined for the general Formula (I) above.
In some embodiments, R4 can represent C1-C6alkyl, C6-C10aryl, 7- to 10-membered partially unsaturated heterocyclic group, or 5- to 10-membered heteroaryl, wherein C1-C6alkyl is optionally substituted with 1 to 3 R9 substituents, and C6-C10aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R10 substituents, and wherein R9 and R10 are as defined herein.
In some embodiments, R4 can represent C1-C6alkyl, C6-C10aryl, 7- to 10-membered partially unsaturated heterocyclic group, or 5- to 10-membered heteroaryl, wherein C6-C10aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R10 substituents, and wherein the R10 substituents are as defined herein.
In some embodiments, R4 can represent C1-C4alkyl, phenyl, 9-membered partially unsaturated heterocyclic group, or 5- to 6-membered heteroaryl, wherein phenyl and 5- to 6-membered heteroaryl are optionally substituted with 1 or 2 R10 substituents, and wherein the R10 substituents are as defined herein.
In some embodiments, the R10 substituents can independently represent C1-C4alkyl, halogen, - O C1-C6alkyl, -NH2, -NH(C1-C4alkyl), or -N(C1-C4alkyl)2, wherein each C1-C4alkyl is optionally substituted with 1 to 3 halogens.
In other embodiments, the R10 substituents can independently represent C1-C4alkyl, halogen, - OC1-C6alkyl, or -N(C1-C4alkyl)2, wherein each C1-C4alkyl is optionally substituted with 1 to 3 halogens.
In further embodiments, the R10 substituents can independently represent -CF3, halogen, -OCH3, or -N(CH3)2.
In some embodiments, R4 is C1-C6alkyl, C6-C10aryl, 7- to 10-membered partially unsaturated heterocyclic group, or 5- to 10-membered heteroaryl, wherein C6-C10aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R10 substituents, and each R10 is independently C1-C4alkyl, halogen, -OC1-C6alkyl, -NH2, -NH(C1-C4alkyl), or -N(C1- C4alkyl)2, wherein each C1-C4alkyl is optionally substituted with 1 to 3 halogens.
In some embodiments, R4 is C1-C6alkyl, C6-C10aryl, 7- to 10-membered partially unsaturated heterocyclic group, or 5- to 10-membered heteroaryl, wherein C6-C10aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R10 substituents, and each R10 is independently C1-C4alkyl, halogen, -OC1-C6alkyl, or -N(C1-C4alkyl)2, wherein each C1- C4alkyl is optionally substituted with 1 to 3 halogens.
In some embodiments, R4 is C1-C4alkyl, phenyl, 9-membered partially unsaturated heterocyclic group, or 5- to 6-membered heteroaryl, wherein phenyl and 5- to 6-membered heteroaryl are optionally substituted with 1 or 2 R10 substituents, and each R10 is independently -CF3, halogen, -OCH3, or -N(CH3)2.
Examples of particular R4 groups can include:
Figure imgf000040_0001
Compounds of Formula (Ic) and (Ic’) In some embodiments, the compound is of Formula (Ic) or (lc’), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
Figure imgf000040_0002
(Ic) (lc’)
The groups R, Ra and R2a can be as defined for the general Formula (I) above. In some embodiments, the compound is of Formula (Ic), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
Figure imgf000040_0003
The groups Ra and R2a can be as defined for the general Formula (I) above. In some embodiments, R2a can represent C1-C6alkyl orC6-C10aryl, wherein C1-C6alkyl is optionally substituted with 1 to 3 R9 substituents and C6-C10aryl is optionally substituted with 1 to 3 R10 substituents, and R9 and R10 are as defined herein.
In some embodiments, R2a can represent C1-C6alkyl orC6-C10aryl, wherein C1-C6alkyl is optionally substituted with 1 to 3 halogens. In some embodiments, R2a is C1-C6alkyl, such as C1-C4alkyl or preferably ethyl.
Compounds of Formula (Id) and (Id”)
In some embodiments, the compound is of Formula (Id) or (Id’), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
Figure imgf000041_0001
The groups R, Ra, R1a, R2b, and R4a can be as defined for the general Formula (I) above.
In some embodiments, the compound is of Formula (Id), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
Figure imgf000041_0002
The groups Ra, R1a, R2b, and R4a can be as defined for the general Formula (I) above.
In some embodiments, R1a and R2b can independently represent -CN, C6-C10aryl, C1-C6alkyl, C3- C8cycloalkyl, or -C(O)NH2, wherein each C1-C6alkyl is optionally substituted with 1 to 2 R16 substituents as defined herein.
In some embodiments, R1a and R2b can independently represent -CN or C6-C10aryl.
In some embodiments, R4a can represent C1-C6alkyl.
In some embodiments, the substituents R16 can independently represent -OH, -C(O)NH2, C3- C6cycloalkyl, -CN, C6-C10aryl, halogen, or 5- to 8-membered heteroaryl, wherein each C3- C6cycloalkyl is optionally substituted with 1 to 2 C1-C4alkyl, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 2 R21 substituents as defined herein.
In some embodiments, each R21 can represent independently halogen or C1-C4alkyl.
In some embodiments, R1a and R2b are independently -CN, C6-C10aryl, C1-C6alkyl, C3- C8cycloalkyl, or -C(O)NH2, wherein each C1-C6alkyl is optionally substituted with 1 to 2 R16 substituents; each R16 is independently -OH, -C(O)NH2, C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, or 5- to 8- membered heteroaryl, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 2 C1- C4alkyl, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 2 R21 substituents; and each R21 is independently halogen or C1-C4alkyl.
Compounds of Formula (le) and de”)
In some embodiments, the compound is of Formula (le) or (le’), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
Figure imgf000042_0001
The groups R, Ra, R1 b, and R2c can be as defined for the general Formula (I) above.
In some embodiments, the compound is of Formula (le), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
Figure imgf000042_0002
The groups Ra, R1 b, and R2c can be as defined for the general Formula (I) above.
In some embodiments, R1b and R2c can form together with the carbon atom to which they are attached a C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, 8- to 14-membered partially unsaturated heterocyclic group, or 8- to 14-membered partially unsaturated carbocyclic group, wherein each 4- to 14-membered heterocycloalkyl, 8- to 14-membered partially unsaturated heterocyclic group, or 8- to 14-membered partially unsaturated carbocyclic group is optionally substituted with oxo (=0), oxime (=N-OH), C1-C3alkoxyoxime (=N-OC1-C3alkyl), or 1 to 3 substituents independently selected from -OH and -CF3.
In some embodiments, R1b and R2c can form together with the carbon atom to which they are attached a C3-C8cycloalkyl or a 8- to 10-membered partially unsaturated carbocyclic group, wherein 8- to 10-membered partially unsaturated carbocyclic group is optionally substituted with oxo (=0), oxime (=N-OH), methoxyoxime (=N-OCH3), or 1 to 2 substituents independently selected from -OH and -CF3.
In some embodiments, R1b and R2c can form together with the carbon atom to which they are attached a C4-C6cycloalkyl, or a group selected from
Figure imgf000043_0001
wherein the dashed lines represent the portion of the cyclohexanone moiety of the compound of formula (le) or (le’) bearing R1b and R2c
In some embodiments, R1b and R2c form together with the carbon atom to which they are attached a cyclopentyl, or a group selected from
Figure imgf000043_0002
wherein the dashed lines represent the portion of the cyclohexanone moiety of the compound of formula (le) or (le’) bearing R1b and R2c.
In some embodiments, R1b and R2c can form together with the carbon atom to which they are attached a group selected from
Figure imgf000043_0003
, wherein the dashed lines represent the portion of the cyclohexanone moiety of the compound of formula (le) or (le’) bearing R1b and R2c.
In some embodiments, R1b and R2c can form together with the carbon atom to which they are attached a cyclopentyl.
Compounds of Formula (If) and (If’)
In some embodiments, the compound is of
Figure imgf000043_0004
(If) or (If’), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
Figure imgf000044_0001
The groups R, Ra, R2d, and R4b can be as defined for the general Formula (I) above.
In some embodiments, the compound is of Formula (If), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
Figure imgf000044_0002
The groups Ra, R2d, and R4b can be as defined for the general Formula (I) above.
In some embodiments, R2d and R4b can form together with the carbon atoms to which they are attached a C3-C8cycloalkyl, wherein each C3-C8cycloalkyl is optionally substituted with 1 to 3 R19 substituents as defined herein.
In some embodiments, R2d and R4b can form together with the carbon atoms to which they are attached a C3-C8cycloalkyl.
In some embodiments, R2d and R4b can form together with the carbon atoms to which they are attached a cyclohexyl.
Compound of Formula (Iq)
In some embodiments, the compound is of Formula (Ig), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
Figure imgf000044_0003
The groups Ra, R1cand R3 can be as defined for the general Formula (I) above.
In some embodiments, R1c and R3 can form together with the carbon atoms to which they are attached a C3-C8cycloalkyl, wherein each C3-C8cycloalkyl is optionally substituted with 1 to 3 R19 substituents as defined herein.
In some embodiments, R1c and R3 can form together with the carbon atoms to which they are attached a C3-C8cycloalkyl.
In some embodiments, R1c and R3 can form together with the carbon atoms to which they are attached a cyclohexyl.
In some embodiments, the compound of Formula (I) as described herein can be selected from Compound 4, 8, 9, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 47, 48, 49, 50, 51 , 52, 53, 54, 59, 60a, 60b, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 75, 81 , 82, 83, 84, 89, 91 , 97, 101 , 108, 109, 119, 120, 121 , 122, 123, 124, 125, 126, 127, 128, 129, 130, 131 , 132, 133, 134, 135, 136, 138, 139, 140, 141 , 142, 143, 144, 145,
146, 147, 148, 149, 150, 154, 155, 163, 168, 169, 170, 173, 174, 175, 178, 179, 180, 181 , 183,
189, 190, 191 , 192, 193, 194, 195, 197, 198, 199, 200, 201 , 202, 211 , 212, 213, 214, 215, 216, 219, 221 , 227, 228, 229, 230, 231 , 232, 237, 238, 239, 245, 246, 247, 248, 249, 250, 251 , 253,
254, 255, 257, 258, 263, 264, 271 , 272, 273, 278, 279, 280, 281 , 287, 288, 290, 291 , 297, 298,
305, 306, 313, 314, 321 , 322, 330, 331 , 337, 338, 339, 340, 341 , 342, 343, 344, 345, 346, 347,
348, 349, 352, 353, 354, 355, 356, 357, 358, 360, 362, 371 , 378, 391 , 392, 393, 394a, 394b, 395a, 395b, 396, 397, 401 , 402, 403, 406, 407, 408, 412, 413, 414, 416, 418, 422, 427, 428, 429, 430, 431 , 433, 434, 445, 446, 447, 448, 449, 450, 451 , 452, 453, 454, 462, 463, 464, 465, 466, 468, 469, 470, 471 , 472, 473, 474, 475, 476, 478, 479, 480, 481 , 482, 483, 486, 488, 489, 492, 495, 496, 497, 498, 511 , 512, 513, 514, 515, 520, 523, 524, and 534 of Table 1 below, or can be any pharmaceutically acceptable salt, solvate, or prodrug thereof.
Table 1
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000063_0002
Figure imgf000063_0003
In some embodiments, the compound of Formula (I) as described herein is Compound 4, 9, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 47, 48, 49, 50, 51, 52, 53, 54, 59, 60a, 60b, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 75, 81, 82, 83, 84, 89, 91, 97, 101, 109, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132,
133, 134, 135, 136, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 155, 163,
168, 169, 170, 173, 174, 175, 179, 180, 181, 183, 189, 191, 192, 193, 194, 195, 197, 198, 199,
200, 201, 202, 211, 212, 213, 214, 215, 216, 219, 221, 228, 229, 230, 231, 232, 237, 238, 239,
246, 247, 248, 249, 250, 251, 253, 254, 255, 258, 263, 264, 271, 272, 273, 278, 279, 280, 281, 287, 288, 291, 297, 298, 305, 306, 313, 314, 321, 322, 331, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 352, 353, 354, 355, 356, 357, or 358 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
In some embodiments, the compound of Formula (I) as described herein is Compound 4, 9, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 47, 48, 49, 50, 51, 52, 53, 54, 59, 60b, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 75, 81, 82, 83, 84, 89, 91, 97, 101, 109, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141, 143, 144, 145, 146, 147, 148, 149, 150, 155, 163, 168, 169,
170, 173, 174, 175, 179, 180, 181, 183, 189, 191, 192, 193, 194, 195, 198, 199, 200, 201, 202,
211, 212, 213, 214, 215, 216, 219, 228, 230, 231, 232, 237, 238, 239, 246, 247, 248, 249, 250,
251, 253, 254, 255, 258, 263, 264, 271, 272, 273, 278, 279, 280, 281, 287, 288, 291, 297, 298,
305, 306, 313, 314, 321, 322, 331, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348,
349, 352, 353, 354, 355, 356, 357 or 358 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
In some embodiments, the compound of Formula (I) as described herein is Compound 4, 9, 15, 16, 17, 18, 19, 20, 21, 22, 24, 25, 26, 27, 29, 30, 31, 32, 33, 34, 36, 37, 38, 39, 47, 48, 49, 50, 51, 52, 53, 54, 59, 60b, 61 , 62, 63, 64, 65, 66, 67, 68, 71 , 72, 75, 81 , 82, 83, 84, 89, 91 , 97, 101 , 109, 119, 120, 121, 122, 123, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141,
143, 144, 145, 146, 147, 148, 149, 150, 155, 163, 168, 169, 170, 173, 174, 175, 179, 180, 181,
183, 189, 191, 192, 194, 195, 198, 199, 201, 202, 212, 213, 214, 215, 216, 228, 230, 231, 232, 237, 238, 239, 246, 248, 249, 250, 251, 253, 254, 255, 258, 263, 264, 271, 272, 273, 278, 279,
280, 281, 287, 288, 291, 297, 298, 305, 306, 313, 314, 321, 322, 331, 338, 339, 340, 341, 342,
343, 344, 345, 346, 347, 348, 352, 353, 354, 355, 356, 357, or 358 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
In some embodiments, the compound of Formula (I) as described herein is Compound 4, 9, 15, 16, 17, 18, 19, 20, 21, 22, 24, 25, 26, 27, 29, 30, 31, 32, 33, 34, 36, 37, 38, 39, 47, 48, 49, 50, 51, 52, 53, 54, 59, 60b, 61 , 62, 63, 64, 65, 66, 67, 68, 71 , 72, 75, 81 , 82, 83, 84, 89, 91 , 97, 101 , 109, 119, 120, 121, 122, 123, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141,
143, 144, 145, 146, 147, 148, 149, 150, 155, 163, 168, 169, 170, 173, 174, 175, 179, 180, 181,
183, 189, 191, 192, 194, 195, 198, 199, 201, 202, 212, 213, 214, 215, 216, 228, 230, 231, 232, 237, 238, 239, 245, 246, 248, 249, 250, 251, 253, 254, 255, 258, 263, 264, 271, 272, 273, 278,
279, 280, 281, 287, 288, 291, 297, 298, 305, 306, 313, 314, 321, 322, 331, 338, 339, 340, 341,
342, 343, 344, 345, 346, 347, 352, 353, 354, 355, 356, 357, 358, 391, 392, 393, 394a, 394b, 395a, 395b, 396, 397, 401, 402, 403, 406, 407, 408, 413, 414, 416, 418, 422, 427, 428, 429, 430, 431, 434, 445, 446, 447, 448, 449, 450, 451, 453, 454, 462, 463, 464, 465, 466, 468, 470, 472, 474, 475, 476, 478, 479, 480, 481, 482, 486, 489, 492, 495, 496, 498, 511, 512, 513, 514, 515, 520, or 524 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
In some embodiments, the compound of Formula (I) as described herein is Compound 4, 15, 16, 17, 20, 24, 25, 26, 27, 29, 30, 31, 32, 33, 34, 36, 37, 47, 48, 49, 50, 51, 52, 53, 54, 59, 60b, 61,
62, 63, 64, 65, 66, 67, 71, 72, 75, 81, 82, 83, 84, 89, 91, 97, 101, 109, 119, 120, 121, 122, 123,
127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141, 143, 144, 145, 146, 147,
148, 149, 150, 155, 163, 168, 169, 170, 173, 174, 175, 179, 180, 181, 183, 191, 192, 194, 195,
198, 199, 201, 202, 212, 213, 214, 215, 216, 228, 230, 231, 232, 237, 238, 239, 246, 248, 250, 251, 253, 254, 255, 258, 263, 264, 271, 272, 273, 278, 279, 280, 281, 287, 288, 291, 298, 305, 306, 313, 314, 321, 322, 331, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 352, 353, 354,
355, 356, 357, 358, 391, 392, 393, 394a, 394b, 395a, 395b, 396, 397, 401, 402, 403, 406, 407,
408, 413, 414, 416, 418, 422, 428, 429, 430, 431, 434, 445, 446, 447, 448, 449, 450, 451, 453,
454, 462, 463, 464, 465, 466, 468, 470, 472, 474, 475, 476, 479, 480, 481, 482, 486, 489, 495,
496, 498, 511, 512, 513, 514, 515, 520, or 524 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
In some embodiments, the compound of Formula (I) as described herein is Compound 4, 15, 16, 20, 25, 26, 29, 30, 31, 32, 33, 34, 37, 47, 48, 49, 50, 51, 52, 54, 59, 60b, 61, 62, 63, 64, 65, 72, 75, 82, 83, 84, 89, 91, 97, 101, 109, 119, 121, 123, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141, 143, 144, 145, 146, 147, 148, 149, 150, 155, 163, 168, 169, 170, 173, 174, 175, 179, 180, 181, 183, 191, 192, 194, 195, 201, 212, 213, 214, 215, 216, 230, 231, 232, 238, 239, 246, 248, 250, 251, 253, 254, 255, 258, 263, 264, 271, 272, 273, 278, 279, 280, 281,
288, 291, 298, 305, 306, 313, 314, 321, 322, 331, 338, 339, 340, 341, 342, 343, 344, 345, 346,
352, 353, 354, 355, 356, 358, 391, 392, 393, 394a, 394b, 395a, 395b, 396, 397, 401, 402, 403,
406, 407, 408, 413, 414, 416, 418, 422, 428, 429, 430, 431, 434, 445, 446, 447, 448, 449, 450,
451, 453, 454, 462, 463, 464, 465, 466, 468, 470, 472, 474, 475, 476, 479, 480, 481, 482, 486,
489, 495, 496, 498, 511, 512, 513, 514, 515, 520, or 524 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
In some embodiments, the compound of Formula (I) as described herein is Compound 4, 15, 16, 20, 25, 26, 29, 30, 31, 32, 33, 34, 37, 47, 48, 49, 50, 51, 52, 54, 59, 60b, 61, 62, 63, 64, 65, 72, 75, 82, 83, 84,89, 91, 97, 101, 109, 119, 121, 123, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141, 143, 144, 145, 146, 147, 148, 149, 150, 155, 163, 168, 169, 170, 173,
174, 175, 179, 180, 181, 183, 191, 192, 194, 195, 201, 212, 213, 214, 215, 216, 230, 231, 232,
238, 239, 245, 246, 248, 250, 251, 253, 254, 255, 258, 263, 264, 271, 272, 273, 278, 279, 280,
281, 288, 291, 298, 305, 306, 313, 314, 321, 322, 331, 338, 339, 340, 341, 342, 343, 344, 345,
346, 352, 353, 354, 355, 356, 358, 391, 392, 393, 394a, 394b, 395a, 395b, 396, 397, 402, 403,
407, 408, 413, 414, 416, 418, 422, 428, 429, 430, 431, 434, 445, 446, 447, 448, 449, 450, 451, 453, 454, 462, 463, 464, 465, 466, 468, 472, 475, 476, 479, 480, 481 , 482, 486, 489, 495, 496, 498, 511 , 512, 514, 515, 520, or 524 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
In some embodiments, the compound of Formula (I) as described herein is Compound 4, 15, 25, 32, 33, 47, 48, 49, 50, 52, 54, 59, 60b, 61 , 62, 63, 72, 75, 82, 83, 89, 97, 101 , 109, 119, 121 , 127, 128, 129, 130, 131 , 132, 133, 134, 135, 136, 138, 139, 140, 141 , 143, 144, 145, 146, 147, 148,
149, 150, 163, 169, 170, 174, 179, 181 , 183, 191 , 192, 194, 195, 212, 213, 214, 215, 230, 231 ,
232, 238, 239, 246, 248, 250, 251 , 253, 254, 255, 258, 263, 264, 272, 273, 278, 279, 280, 281 ,
288, 291 , 298, 305, 306, 313, 314, 321 , 322, 331 , 338, 339, 340, 341 , 342, 343, 344, 345, 353,
355, 356, 358, 391 , 392, 393, 394a, 394b, 395a, 395b, 396, 397, 402, 403, 407, 408, 413, 418,
422, 428, 429, 430, 431 , 434, 445, 446, 447, 448, 449, 450, 451 , 454, 463, 464, 465, 466, 472,
475, 476, 479, 481 , 486, 489, 495, 498, 512, 514, 515, 520, or 524 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
In some embodiments, the compound of Formula (I) as described herein is Compound 15, 25, 32, 48, 49, 50, 52, 54, 59, 60b, 61 , 62, 63, 72, 75, 82, 83, 97, 101 , 109, 119, 127, 128, 129, 130, 135, 136, 140, 141 , 143, 144, 145, 146, 147, 148, 149, 150, 163, 169, 170, 174, 179, 181 , 183,
191 , 192, 194, 195, 212, 213, 215, 230, 231 , 232, 238, 239, 246, 248, 250, 251 , 254, 255, 258,
263, 272, 273, 279, 281 , 288, 291 , 306, 313, 314, 321 , 322, 331 , 338, 339, 340, 341 , 342, 343,
344, 345, 353, 355, 356, 358, 391 , 392, 393, 394a, 394b, 395a, 395b, 396, 397, 402, 403, 407,
408, 413, 418, 422, 428, 429, 430, 431 , 434, 445, 446, 447, 448, 449, 450, 451 , 454, 463, 464, 465, 466, 472, 475, 476, 479, 481 , 486, 489, 495, 498, 512, 514, 515, 520, or 524 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
In some embodiments, the compound of Formula (I) as described herein is Compound 15, 25, 32, 48, 49, 50, 52, 54, 59, 60b, 61 , 62, 63, 72, 75, 82, 83, 97, 101 , 109, 119, 127, 128, 129, 130, 135, 136, 140, 141 , 143, 144, 145, 146, 147, 148, 149, 150, 163, 169, 170, 174, 179, 181 , 183,
191 , 192, 194, 195, 212, 213, 215, 230, 231 , 232, 238, 239, 246, 248, 250, 251 , 254, 255, 258,
263, 272, 273, 279, 281 , 288, 291 , 306, 313, 314, 321 , 322, 331 , 338, 339, 340, 341 , 342, 343,
344, 345, 353, 355, 356, 358, 391 , 392, 393, 394a, 394b, 395a, 395b, 396, 397, 402, 403, 407,
418, 428, 430, 431 , 434, 445, 446, 447, 448, 449, 450, 454, 463, 464, 465, 466, 476, 489, 512,
514, 515, or 524 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
In some embodiments, the compound of Formula (I) as described herein is Compound 48, 50, 54, 60b, 61 , 63, 72, 75, 83, 97, 101 , 109, 127, 135, 140, 141 , 143, 144, 145, 146, 147, 149, 163, 169, 170, 174, 179, 181 , 191 , 194, 195, 212, 215, 230, 231 , 232, 238, 246, 248, 250, 251 , 255, 258, 272, 273, 279, 281 , 291 , 306, 314, 321 , 322, 331 , 338, 339, 340, 341 , 342, 345, 353, 355,
356, 391 , 393, 395a, 395b, 397, 402, 428, 430, 431 , 434, 446, 447, 448, 450, 463, 464, 465, 466, 489, 512, 514, 515, or 524 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
In some embodiments, the compound of Formula (I) as described herein is Compound 48, 50, 54, 60b, 61 , 63, 75, 83, 97, 101 , 127, 135, 140, 141 , 143, 144, 146, 147, 149, 163, 170, 174, 181 , 191 , 195, 215, 230, 231 , 232, 238, 246, 248, 250, 251 , 255, 258, 272, 273, 279, 281 , 306, 314, 322, 338, 339, 340, 345, 353, 355, 356, 391 , 393, 397, 402, 428, 430, 431 , 434, 446, 447, 450, 463, 465, 466, 489, 512, 514, 515, or 524 ofTable 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
In some embodiments, the compound of Formula (I) as described herein is Compound 54, 61 , 63, 75, 140, 143, 146, 174, 215, 230, 250, 251 , 273, 306, 322, 430, 446, 463, or 512 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 61 , 63, 75, 143, 146, 174, 230, 250, 273, or 306 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
In some embodiments, the compound of Formula (I) as described herein is Compound 4 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 33 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 47 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 89 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 121 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 131 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 132 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 133 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 134 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 138 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 139 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 214 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 253 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 264 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 278 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 280 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 298 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 305 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 408 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 413 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 422 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 429 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 451 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 472 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 475 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 479 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 481 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 486 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 495 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 498 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 520 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
In some embodiments, the compound of Formula (I) as described herein is Compound 15 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 25 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 32 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 49 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 52 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 59 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 62 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 72 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 82 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 109 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 119 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 128 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 129 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 130 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 136 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 145 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 148 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 150 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 169 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 179 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 183 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 192 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 194 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 212 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 213 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 239 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 254 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 263 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 288 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 291 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 313 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 321 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 331 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 341 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 342 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 343 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 344 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 358 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 392 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 394a of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 394b of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 395a of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 395b of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 396 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 403 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 407 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 418 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 445 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 448 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 449 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 454 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 464 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 476 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
In some embodiments, the compound of Formula (I) as described herein is Compound 48 of Table
1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 50 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 54 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 60b of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 61 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 63 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 75 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 83 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 97 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 101 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 127 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 135 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 140 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 141 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 143 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 144 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 146 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 147 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 149 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 163 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 170 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 174 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 181 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 191 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 195 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 215 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 230 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 231 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 232 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 238 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 246 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 248 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 250 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 251 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 255 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 258 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 272 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 273 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 279 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 281 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 306 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 314 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 322 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 338 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 339 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 340 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 345 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 353 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 355 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 356 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 391 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 393 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 397 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 402 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 428 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 430 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 431 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 434 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 446 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 447 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 450 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 463 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 465 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 466 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 489 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 512 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 514 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 515 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula (I) as described herein is Compound 524 of Table 1 above, or is any pharmaceutically acceptable salt, solvate, or prodrug thereof.
Pharmaceutical combinations
The present application relates to pharmaceutical combinations comprising a thiophene fused cyclohexanone derivative ASIC inhibitor, which is a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a cyclooxygenase (COX) inhibitor. In some embodiments, the pharmaceutical combinations can further include pharmaceutically acceptable carriers, diluents, or excipients, as will be detailed below.
The term “ASICs inhibitor” as used herein means a compound that can inhibit acid-sensing ion channels, such as the acid-sensing ion channel 1a (ASICIa) or the acid-sensing ion channel 1 b (ASICI b). A “cyclooxygenase (COX) inhibitor” as used in the pharmaceutical combinations of the present application, refers to a drug enabling inhibition of COX enzymes, such as COX-1 and COX-2 enzymes, for instance. In some embodiments, the COX inhibitor can affect both COX-1 and COX- 2 enzymes. However, in some embodiments, the COX inhibitor can primarily affect the COX-2 enzyme or the COX-1 enzyme. In some embodiments, the COX inhibitor can comprise an NSAID, which can be highly selective for the COX-2 enzyme, such as coxibs or can be non-selective and affect both COX-1 and COX-2 enzymes, such as ibuprofen. In other embodiments, the COX inhibitor can be acetaminophen.
In some embodiments, the pharmaceutical combinations of the present disclosure can include an NSAID which can be Bromfenac, Celecoxib, Diclofenac, Etodolac, Flurbiprofen, Ibuprofen, Indomethacin, Ketoprofen, Ketorolac, Mefenamic acid, Meloxicam, Nabumetone, Naproxen, Nepafenac, Piroxicam, Sulindac, Tenoxicam, Tiaprofenic acid, Diflunisal, Etoricoxib, Fenoprofen, Floctafenine, Lumiracoxib, Oxaprozin, Parecoxib, Rofecoxib, Tolmetin, Valdecoxib, Meclofenamic acid, Dexketoprofen, Licofelone, Lornoxicam, Loxoprofen, Nimesulide, Tolfenamic acid, Phenylbutazone, Firocoxib, Salsalate, Choline Magnesium Trisalicylate, Acetylsalicylic acid, any pharmaceutically acceptable salt thereof, or any combination thereof.
Due to their COX-1 inhibition effect, certain NSAIDs can cause side effects such as bleeding and gastrointestinal irritation for instance. Side effects tend to be more common at high doses for a long time. Accordingly, NSAIDs are often co-administered with proton-pump inhibitors (PPIs) to reduce NSAID-induced gastrointestinal (Gl) adverse events. Hence, in some embodiments, the pharmaceutical combinations of the present disclosure can further include a proton-pump inhibitor (PPI). However, in other embodiments, one can achieve pain reduction using a combination of the ASIC inhibitor of Formula (I) and the NSAID, in which the dosage of NSAID can be reduced, thanks to the pain reduction potency of the ASIC inhibitor. Then, the use of a PPI can be avoided or at least the PPI can be used in more limited dosage, thus eliminating or at least reducing side effects associated with NSAIDs.
In some embodiments, the pharmaceutical combinations of the present disclosure can include preferably, an NSAID selected from Naproxen, Celecoxib, Diclofenac, Ibuprofen, a pharmaceutically acceptable salt thereof, or any combination thereof.
In some embodiments, the pharmaceutical combinations of the present disclosure can be synergistic. In other words, the therapeutically active compounds, namely the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, can produce a therapeutic effect that is more than the sum of their individual therapeutic effects. In some embodiments, thanks to the synergy that can be observed between the two therapeutically active compounds, lower doses of at least one of the therapeutically active ingredients, preferably both, can be used. In some embodiments, this can provide combination therapies that are much safer than the corresponding monotherapies.
In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is an NSAID.
In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is an NSAID selected from Bromfenac, Celecoxib, Diclofenac, Etodolac, Flurbiprofen, Ibuprofen, Indomethacin, Ketoprofen, Ketorolac, Mefenamic acid, Meloxicam, Nabumetone, Naproxen, Nepafenac, Piroxicam, Sulindac, Tenoxicam, Tiaprofenic acid, Diflunisal, Etoricoxib, Fenoprofen, Floctafenine, Lumiracoxib, Oxaprozin, Parecoxib, Rofecoxib, Tolmetin, Valdecoxib, Meclofenamic acid, Dexketoprofen, Licofelone, Lornoxicam, Loxoprofen, Nimesulide, Tolfenamic acid, Phenylbutazone, Firocoxib, Salsalate, Choline Magnesium Trisalicylate, Acetylsalicylic acid, any pharmaceutically acceptable salt thereof, and any combination thereof.
In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is an NSAID selected from Naproxen, Celecoxib, Diclofenac, Ibuprofen, a pharmaceutically acceptable salt thereof, or any combination thereof.
In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Bromfenac or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Etodolac or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Flurbiprofen or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Indomethacin or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Ketoprofen or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Ketorolac or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Mefenamic acid or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Meloxicam or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Nabumetone or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Nepafenac or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Piroxicam or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Sulindac or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Tenoxicam or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Tiaprofenic acid or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Diflunisal or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Etoricoxib or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Fenoprofen or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Floctafenine or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Lumiracoxib or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Oxaprozin or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Parecoxib or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Rofecoxib or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Tolmetin or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Valdecoxib or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Meclofenamic acid or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Dexketoprofen or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Licofelone or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Lornoxicam or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Loxoprofen or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Nimesulide or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Tolfenamic acid or an pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Phenylbutazone or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Firocoxib or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Salsalate or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Choline Magnesium Trisalicylate or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Acetylsalicylic acid or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Naproxen or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Celecoxib or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Diclofenac or a pharmaceutically acceptable salt thereof. In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is Ibuprofen or a pharmaceutically acceptable salt thereof.
In some embodiments, a synergistic pharmaceutical combination can comprise a compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, and a COX inhibitor which is acetaminophen.
In some embodiments, the pharmaceutical combination of the present disclosure can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in a single dosage form. Single dosage form refers to a mixture of the therapeutically active ingredients, namely the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, that are packaged in a single dosage form. For example, and without being limiting to, a dosage form can include a pill, a tablet, a capsule, a drink or a syrup.
In other embodiments, the pharmaceutical combination of the present disclosure can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, each being in an individual dosage form.
In some embodiments, the pharmaceutical combination can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, each in an amount ranging from about 1 mg to about 1000 mg. In other words, the pharmaceutical combination can comprise from about 1 mg to about 1000 mg of the COX inhibitor and from about 1 mg to about 1000 mg of the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof.
In some embodiments, the pharmaceutical combination can comprise the COX inhibitor in an amount of from about 1 mg to about 900 mg, or from about 1 mg to about 800 mg, or from about 1 mg to about 700 mg, or from about 1 mg to about 600 mg, or from about 1 mg to about 500 mg, or from about 1 mg to about 400 mg, or from about 1 mg to about 300 mg, or from about 1 mg to about 200 mg, or from about 1 mg to about 100 mg, or from about 1 mg to about 50 mg, or any range value in between these ranges. In some embodiments, the pharmaceutical combination can comprise the COX inhibitor in an amount of about 1 mg, 1 .5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg,
4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg, 275 mg, 300 mg, 350 mg, 375 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, or any value in between these values.
In some embodiments, the pharmaceutical combination can comprise the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in an amount of from about 1 mg to about 900 mg, or from about 1 mg to about 800 mg, or from about 1 mg to about 700 mg, or from about 1 mg to about 600 mg, or from about 1 mg to about 500 mg, or from about 1 mg to about 400 mg, or from about 1 mg to about 300 mg, or from about 1 mg to about 200 mg, or from about 1 mg to about 100 mg, or from about 1 mg to about 50 mg, or any range value in between these ranges. In some embodiments, the pharmaceutical combination can comprise the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in an amount of about 1 mg, 1 .5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg,
7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg, 275 mg, 300 mg, 350 mg, 375 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, or any value in between these values.
In some embodiments, the pharmaceutical combination can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, of from 1:0.1 to 1:10 by weight. In some embodiments, the ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be from 1:0.1 to 1:9 by weight, or from 1:0.1 to 1:8 by weight, or from 1:0.1 to 1:7 by weight, or from 1 :0.1 to 1 :6 by weight, or from 1 :0.1 to 1 :5 by weight, or from 1:0.1 to 1 :4 by weight, or from 1:0.1 to 1:3 by weight, or from 1:0.1 to 1:2 by weight, or from 1:0.1 to 1:1 by weight. In some embodiments, the ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be from 1:0.1 to 1:1 by weight, or from 1:0.1 to 1:0.9 by weight, or from 1:0.1 to 1 :0.8 by weight, or from 1:0.1 to 1 :0.7 by weight, or from 1:0.1 to 1:0.6 by weight, or from 1:0.1 to 1:0.5 by weight, or from 1:0.1 to 1:0.4 by weight, or from 1:0.1 to 1:0.3 by weight, or from 1:0.1 to 1:0.2 by weight. In some embodiments, the ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be from 1:0.1 to 1:1 by weight, or from 1:0.2 to 1:1 by weight, or from 1:0.3 to 1:1 by weight, or from 1:0.4 to 1:1 by weight, or from 1:0.5 to 1:1 by weight, or from 1:0.6 to 1:1 by weight, or from 1:0.7 to 1:1 by weight, or from 1:0.8 to 1:1 by weight, or from 1:0.9 to 1:1 by weight. In some embodiments, the ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be from 1:1 to 1:2 by weight, or from 1:1 to 1:1.9 by weight, or from 1:1 to 1:1.8 by weight, or from 1:1 to 1:1.7 by weight, or from 1:1 to 1:1.6 by weight, or from 1:1 to 1:1.5 by weight, or from 1:1 to 1:1.4 by weight, or from 1:1 to 1:1.3 by weight, or from 1:1 to 1:1.2 by weight, or from 1:1 to 1:1.1 by weight.
In some embodiments, the pharmaceutical combination can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, of from 1:0.1 to 1:2 by weight. In some embodiments, the pharmaceutical combination can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, of from 1:0.1 to 1:1 by weight.
In some embodiments, the pharmaceutical combination can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, of from about 1 :0.2 to about 1 : 1 by weight, or from about 1 :0.18 to about 1 : 1 by weight, or from about 1:0.2 to about 1:0.83 by weight, or from about 1:0.18 to about 1:0.83 by weight.
In some embodiments, the pharmaceutical combination can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof in a ratio by weight of COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof that results in a synergistic pharmaceutical combination. In some embodiments, the pharmaceutical combination can be synergistic and can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, of from 1 :0.1 to 1 :10 by weight. In some embodiments, the synergistic pharmaceutical combination can have a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, ranging from 1 :0.1 to 1 :9 by weight, or from 1 :0.1 to 1 :8 by weight, or from 1 :0.1 to 1 :7 by weight, or from 1 :0.1 to 1 :6 by weight, or from 1 :0.1 to 1 :5 by weight, or from 1 :0.1 to 1 :4 by weight, or from 1 :0.1 to 1 :3 by weight, or from 1 :0.1 to 1 :2 by weight, or from 1 :0.1 to 1 :1 by weight. In some embodiments, the synergistic pharmaceutical combination can have a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, ranging from 1 :0.1 to 1 :1 by weight, or from 1 :0.1 to 1 :0.9 by weight, or from 1 :0.1 to 1 :0.8 by weight, or from 1 :0.1 to 1 :0.7 by weight, or from 1 :0.1 to 1 :0.6 by weight, or from 1 :0.1 to 1 :0.5 by weight, or from 1 :0.1 to 1 :0.4 by weight, or from 1 :0.1 to 1 :0.3 by weight, or from 1 :0.1 to 1 :0.2 by weight. In some embodiments, the synergistic pharmaceutical combination can have a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, ranging from 1 :0.1 to 1 : 1 by weight, or from 1 :0.2 to 1 :1 by weight, or from 1 :0.3 to 1 :1 by weight, or from 1 :0.4 to 1 :1 by weight, or from 1 :0.5 to 1 :1 by weight, or from 1 :0.6 to 1 :1 by weight, or from 1:0.7 to 1 :1 by weight , or from 1 :0.8 to 1 :1 by weight, or from 1 :0.9 to 1 :1 by weight. In some embodiments, the synergistic pharmaceutical combination can have a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, ranging from 1 :1 to 1 :2 by weight, or from 1 :1 to 1:1.9 by weight, or from 1 :1 to 1 :1.8 by weight, or from 1 :1 to 1 :1.7 by weight, or from 1 :1 to 1 :1.6 by weight, or from 1 :1 to 1 :1.5 by weight, or from 1 :1 to 1 :1.4 by weight, or from 1 :1 to 1 :1.3 by weight, or from 1 :1 to 1 :1.2 by weight, or from 1 :1 to 1 :1.1 by weight.
In some embodiments, the pharmaceutical combination can be synergistic and can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, of from 1 :0.1 to 1 :2 by weight. In some embodiments, the pharmaceutical combination can be synergistic and can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, of from 1:0.1 to 1:1 by weight.
In some embodiments, the pharmaceutical combination can be synergistic and can comprise the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in a ratio COX inhibitor to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, of from about 1 :0.2 to about 1 : 1 by weight, or from about 1:0.18 to about 1:1 by weight, or from about 1:0.2 to about 1:0.83 by weight, or from about 1:0.18 to about 1:0.83 by weight.
In some embodiments, the pharmaceutical combination can comprise an NSAID as the COX inhibitor, and a ratio of the NSAID to the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be of from 1:0.1 to 1:10 by weight. In some embodiments, the ratio NSAID to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be from 1:0.1 to 1:9 by weight, or from 1:0.1 to 1:8 by weight, or from 1:0.1 to 1:7 by weight, or from 1:0.1 to 1:6 by weight, or from 1:0.1 to 1:5 by weight, or from 1:0.1 to 1:4 by weight, orfrom 1:0.1 to 1:3 by weight, or from 1:0.1 to 1:2 by weight, or from 1:0.1 to 1:1 by weight. In some embodiments, the ratio NSAID to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be from 1:0.1 to 1:1 by weight, orfrom 1:0.1 to 1:0.9 by weight, or from 1:0.1 to 1:0.8 by weight, orfrom 1:0.1 to 1:0.7 by weight, orfrom 1:0.1 to 1:0.6 by weight, or from 1:0.1 to 1:0.5 by weight, orfrom 1:0.1 to 1:0.4 by weight, orfrom 1:0.1 to 1:0.3 by weight, or from 1:0.1 to 1:0.2 by weight. In some embodiments, the ratio NSAIDto compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be from 1:0.1 to 1:1 by weight, or from 1:0.2 to 1:1 by weight, orfrom 1:0.3 to 1:1 by weight, orfrom 1:0.4 to 1:1 by weight, orfrom 1:0.5 to 1:1 by weight, orfrom 1:0.6 to 1:1 by weight, orfrom 1:0.7 to 1:1 by weight, orfrom 1:0.8 to 1:1 by weight, orfrom 1:0.9 to 1:1 by weight. In some embodiments, the ratio NSAIDto compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be from 1:1 to 1:2 by weight, orfrom 1:1 to 1:1.9 by weight, orfrom 1:1 to 1:1.8 by weight, orfrom 1:1 to 1:1.7 by weight, orfrom 1:1 to 1:1.6 by weight, orfrom 1:1 to 1:1.5 by weight, orfrom 1:1 to 1:1.4 by weight, orfrom 1:1 to 1:1.3 by weight, orfrom 1:1 to 1:1.2 by weight, orfrom 1:1 to 1:1.1 by weight.
In some embodiments, the pharmaceutical combination can comprise an NSAID as the COX inhibitor, and a ratio of the NSAID to the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be of from 1:0.1 to 1:2 by weight. In some embodiments, the pharmaceutical combination can comprise an NSAID as the COX inhibitor, and a ratio of the NSAID to the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be of from 1:0.1 to 1:1 by weight.
In some embodiments, the pharmaceutical combination can comprise an NSAID as the COX inhibitor, and a ratio of the NSAID to the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be of from about 1 :0.2 to about 1 :1 by weight, or from about 1 :0.18 to about 1:1 by weight, or from about 1:0.2 to about 1:0.83 by weight, or from about 1:0.18 to about 1 :0.83 by weight.
In some embodiments, the pharmaceutical combination can comprise an NSAID as the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof are provided in a ratio by weight of NSAID to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof that results in a synergistic pharmaceutical combination. In some embodiments, the pharmaceutical combination can be synergistic and comprise an NSAID as the COX inhibitor, and a ratio of the NSAID to the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be of from 1 :0.1 to 1:10 by weight. In some embodiments, the synergistic pharmaceutical combination can have a ratio NSAID to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, ranging from 1:0.1 to 1:9 by weight, or from 1:0.1 to 1:8 by weight, or from 1:0.1 to 1:7 by weight, or from 1:0.1 to 1:6 by weight, or from 1:0.1 to 1:5 by weight, or from 1:0.1 to 1:4 by weight, orfrom 1:0.1 to 1:3 by weight, or from 1:0.1 to 1:2 by weight, or from 1:0.1 to 1:1 by weight. In some embodiments, the synergistic pharmaceutical combination can have a ratio NSAID to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, ranging from 1:0.1 to 1:1 by weight, orfrom 1:0.1 to 1:0.9 by weight, orfrom 1:0.1 to 1:0.8 by weight, orfrom 1:0.1 to 1:0.7 by weight, orfrom 1:0.1 to 1:0.6 by weight, orfrom 1:0.1 to 1:0.5 by weight, orfrom 1:0.1 to 1:0.4 by weight, or from 1:0.1 to 1:0.3 by weight, or from 1:0.1 to 1:0.2 by weight. In some embodiments, the synergistic pharmaceutical combination can have a ratio NSAID to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, ranging from 1:0.1 to 1:1 by weight, orfrom 1:0.2 to 1:1 by weight, orfrom 1:0.3 to 1:1 by weight, orfrom 1:0.4 to 1:1 by weight, orfrom 1:0.5 to 1:1 by weight, orfrom 1:0.6 to 1:1 by weight, orfrom 1:0.7 to 1:1 by weight , orfrom 1:0.8 to 1:1 by weight, orfrom 1:0.9 to 1:1 by weight. In some embodiments, the synergistic pharmaceutical combination can have a ratio NSAID to compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, ranging from 1:1 to 1:2 by weight, or from 1:1 to 1:1.9 by weight, orfrom 1:1 to 1:1.8 by weight, orfrom 1:1 to 1:1.7 by weight, orfrom 1:1 to 1:1.6 by weight, orfrom 1:1 to 1:1.5 by weight, orfrom 1:1 to 1:1.4 by weight, orfrom 1:1 to 1:1.3 by weight, orfrom 1:1 to 1:1.2 by weight, orfrom 1:1 to 1:1.1 by weight.
In some embodiments, the pharmaceutical combination can be synergistic and comprise an NSAID as the COX inhibitor, and a ratio of the NSAID to the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be of from 1:0.1 to 1:2 by weight. In some embodiments, the pharmaceutical combination can be synergistic and comprise an NSAID as the COX inhibitor, and a ratio of the NSAID to the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be of from 1:0.1 to 1:1 by weight.
In some embodiments, the pharmaceutical combination can be synergistic and comprise an NSAID as the COX inhibitor, and a ratio of the NSAID to the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be of from about 1 :0.2 to about 1 :1 by weight, or from about 1 :0.18 to about 1 :1 by weight, or from about 1 :0.2 to about 1 :0.83 by weight, or from about 1 :0.18 to about 1 :0.83 by weight.
The above-mentioned dosages and ratios are provided as examples, and one could adapt the dosages and/or ratios of the COX inhibitor and compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, for achieving a suitable treatment such as proper pain relief.
Methods, uses, formulations, kits and administration
The pharmaceutical combinations of the present disclosure, comprising a COX inhibitor and a thiophene fused cyclohexanone derivative, i.e., a compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, can be useful for the treatment of disorders or conditions including pain. In some embodiments, the treatment can involve using, or can be potentiated by using, a pharmaceutical combination of the present disclosure which can be synergistic.
In certain embodiments, the present description thus provides a method for treating pain, comprising administering to a patient or subject identified as in need thereof, a COX inhibitor and a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, as disclosed herein. In some embodiments, the method for treating pain can comprise administering to a patient or subject identified as in need thereof, an effective amount of the COX inhibitor and of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the administration results in a synergistic effect thereof.
The identification of those patients who are in need of treatment for the disorders described herein is well within the ability and knowledge of one skilled in the art. Certain of the methods for identification of patients which are at risk of developing the above disorders which can be treated by the subject method are appreciated in the medical arts, such as family history, and the presence of risk factors associated with the development of that disorder state in the subject patient. A clinician skilled in the art can readily identify such candidate patients, by the use of, for example, clinical tests, physical examination and medical/family history.
As used herein, the term “effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, one can also refer to “therapeutically effective amount” which means any amount which, as compared to a corresponding subject who has not received such amount, results in treatment, healing, prevention, or amelioration of a disorder, disorder, or side effect, or a decrease in the rate of advancement of a disorder or disorder. The term also includes within its scope amounts that are effective to enhance normal physiological function.
As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disorder or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
The terms "patient” or “subject" as used herein generally refer to a mammal. A subject therefore refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, and the like. Preferably the subject is a human. When the subject is a human, the subject may be either a patient or a healthy human.
The expression “pharmaceutically acceptable carrier, diluent, or excipient” and equivalent expressions, refer to a non-toxic carrier, diluent, or excipient that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, diluents or excipients that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
In certain embodiments, as mentioned above, the disorders or conditions that can be treated using the pharmaceutical combination comprising the COX inhibitor and the thiophene fused cyclohexanone derivative, i.e., the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, can include pain.
In some embodiments, the pain can include acute pain or chronic pain. In some embodiments, the pain can include inflammatory pain, neuropathic pain or cancer pain. In some embodiments, the pain can include nociceptive pain, inflammatory pain, neuropathic pain, cancer pain, idiopathic pain, musculoskeletal pain, visceral pain, or abdominal pain. In some embodiments, the pain can include inflammatory pain. In another embodiment, the pain can include neuropathic pain. In yet another embodiment, the pain can include cancer pain. In some embodiments, the pain can include arthritis pain, pain associated with musculoskeletal trauma or soft tissue trauma, post-operative pain, dental pain, dysmenorrhea pain, episiotomy pain, endometriosis pain, post-partum pain, headache pain, ocular pain, bursitis pain, tendinitis pain, tenosynovitis pain, or polymyalgia rheumatica pain. In some embodiments, the pain can include arthritis pain, pain associated with musculoskeletal trauma or soft tissue trauma, post-operative pain, dental pain, dysmenorrhea pain, episiotomy pain, endometriosis pain, post-partum pain, headache pain, ocular pain, bursitis pain, or tendinitis pain.
In some embodiments, the pain can include a rheumatic disorder-related pain.
In certain embodiments, the pain can include arthritis pain. In some embodiments, the pain can include adult arthritis pain or juvenile arthritis pain. In certain embodiments, the pain can include adult arthritis pain. In some embodiments, the pain can include juvenile arthritis pain.
In some embodiments, the pain can include osteoarthritis pain, rheumatoid arthritis pain, ankylosing spondylitis pain, gout pain, psoriatic arthritis pain, or periarthritis pain. In certain embodiments, the pain can include osteoarthritis pain, rheumatoid arthritis pain, ankylosing spondylitis pain, gout pain, or periarthritis pain.
In some embodiments, the pain can include osteoarthritis pain. In certain embodiments, the pain can include osteoarthritis inflammatory pain. In some embodiments, the pain can include osteoarthritis pain of the hip, osteoarthritis pain of the knee, osteoarthritis pain of the spine, osteoarthritis pain of the shoulder, osteoarthritis pain of the hand, osteoarthritis pain of the finger, osteoarthritis pain of the thumb, osteoarthritis pain of the foot, or osteoarthritis pain of the toe.
In some embodiments, the pain can include rheumatoid arthritis pain. In certain embodiments, the pain can include adult rheumatoid arthritis pain or juvenile rheumatoid arthritis pain. In some embodiments, the pain can include adult rheumatoid arthritis pain. In certain embodiments, the pain can include juvenile rheumatoid arthritis pain. In certain embodiments, the pain can include rheumatoid arthritis inflammatory pain. In some embodiments, the pain can include rheumatoid arthritis pain of the hand, rheumatoid arthritis pain of the finger, rheumatoid arthritis pain of the thumb, rheumatoid arthritis pain of the foot, rheumatoid arthritis pain of the toe, rheumatoid arthritis pain of the wrist, rheumatoid arthritis pain of the knee, rheumatoid arthritis pain of the ankle, rheumatoid arthritis pain of the elbow, rheumatoid arthritis pain of the hip, or rheumatoid arthritis pain of the shoulder.
In certain embodiments, the pain can include ankylosing spondylitis pain.
In some embodiments, the pain can include gout pain. In some embodiments, the pain can include gout pain of the foot, gout pain of the toe, gout pain of the ankle, gout pain of the knee, or gout pain of the elbow. In certain embodiments, the pain can include gouty arthritis pain. In certain embodiments, the pain can include psoriatic arthritis pain.
In certain embodiments, the pain can include bursitis pain. In some embodiments, the pain can include bursitis pain of the shoulder or bursitis pain of the hip.
In certain embodiment, the pain can include tendinitis pain. In some embodiments, the pain can include tendinitis pain of the shoulder, tendinitis pain of the elbow, tendinitis pain of the hip, tendinitis pain of the wrist, tendinitis pain of the knee, or tendinitis pain of the heel.
In some embodiments, the pain can include periarthritis pain. In certain embodiments, the pain can include periarthritis pain of the shoulder or periarthritis pain of the hip.
In some embodiments, the pain can include pain associated with musculoskeletal trauma or soft tissue trauma including pain associated with a sprain, a strain, swelling or stiffness. In certain embodiments, the pain can include pain associated with musculoskeletal trauma or soft tissue trauma including pain associated with a sprain or a strain. In certain embodiments, the pain can include pain associated with musculoskeletal trauma or soft tissue trauma of the back, shoulder, or ankle. In certain embodiments, the pain can include myofascial pain syndrome. In other embodiments, the pain can include exercise-induced pain, repetitive motion injury pain, or pain due to a bone fracture. In other embodiments, the pain can include temporomandibular joint disorder pain.
In certain embodiments, the pain can include ocular pain. In certain embodiments, the ocular pain can include post-operative pain after cataract surgery, post-operative pain after refractive surgery, ocular pain from a non-penetrating wound, foreign body sensation ocular pain, burning or stinging of the eye, uveitis pain, iritis pain, retinopathy pain or optic neuritis pain.
In some embodiments, the pain can include dental pain. In certain embodiments, the dental pain can include toothache or post-operative pain after dental surgery. In some embodiments, the dental pain can include pain after dental extraction.
In certain embodiments, the pain can include post-operative pain. In some embodiments, the pain can include post-operative pain following minor surgery, post-operative pain following general surgery, post-operative pain following orthopaedic surgery, post-operative pain following bunionectomy, post-operative pain following hernioplasty, post-operative pain following herniorrhaphy, post-operative pain following arthroplasty including pain following knee arthroplasty or pain following hip arthroplasty, post-operative pain following gynecological surgery, postoperative pain following caesarean section, post-mastectomy pain syndrome (PMPS), postoperative pain following abdominoplasty, post-operative pain following laminectomy, post-operative pain following hemorrhoid removal, or post-operative pain following thoracotomy.
In certain embodiments, the pain can include dysmenorrhea pain, episiotomy pain, endometriosis pain, or post-partum pain. In certain embodiments, the pain can include dysmenorrhea pain, episiotomy pain, endometriosis pain, or post-partum cramping pain.
In some embodiments, the pain can include headache pain. In certain embodiments, the pain can include migraine pain, tension headache pain, or cluster headache pain. In some embodiments, the pain can include migraine pain including migraine with aura pain or migraine without aura pain.
In certain embodiments, the pain can include pain due to the common cold, pain due to the flu, sore throat pain, sinus pain including sinusitis pain, pain due to immunization, earache pain, fever pain, body pain, muscle pain, bone pain, joint pain, back pain, neck pain, or nighttime pain.
In some embodiments, the pain can include mucositis pain or stomatitis pain. In certain embodiments, the pain can include pain associated with lupus including lupus-related inflammatory pain.
In certain embodiments, the pain can include osteoarthritis neuropathic pain. In certain embodiments, the pain can include rheumatoid arthritis neuropathic pain.
In certain embodiments, the pain can include neuralgia. In some embodiments, that pain can include trigeminal neuralgia, postherpetic neuralgia, occipital neuralgia, post-surgical neuralgia, pudendal neuralgia, diabetic neuralgia, glossopharyngeal neuralgia, intercostal neuralgia, or drug therapy-induced neuralgia including cancer chemotherapy-induced neuralgia or anti-retroviral therapy-induced neuralgia.
In certain embodiments, the pain can include nerve injury pain, peripheral nerve injury pain, nerve compression pain, nerve avulsion injury pain, nerve entrapment injury pain, radiculopathy pain, brachial plexus injury pain, burning mouth syndrome pain, complex regional pain syndrome type 1 , complex regional pain syndrome type 2, neuroma pain, Morton’s neuroma pain, spinal cord injury pain, spinal cord compression pain, radicular pain, sciatica pain, spinal stenosis pain, cervical spine injury pain, brain injury pain, or post-stroke pain.
In some embodiments, the pain can include neuropathy pain. In certain embodiments, the pain can include peripheral neuropathy pain, polyneuropathy pain, mononeuropathy pain, multiple mononeuropathy pain, proximal neuropathy pain, sensory neuropathy pain, small fiber sensory neuropathy pain, idiopathic neuropathy pain, or distal sensory polyneuropathy pain. In certain embodiments, the pain can include diabetic neuropathy pain. In some embodiments, the pain can include diabetic peripheral neuropathy pain, diabetic polyneuropathy pain, diabetic proximal neuropathy pain, or diabetic mononeuropathy pain. In certain embodiments, the pain can include autoimmune disease neuropathy pain. In some embodiments, the pain can include Sjogren's syndrome neuropathy pain, Guillain-Barre syndrome neuropathy pain, chronic inflammatory demyelinating polyneuropathy pain, or vasculitis neuropathy pain. In some embodiments, the pain can include multiple sclerosis neuropathic pain. In certain embodiments, the pain can include carpal tunnel syndrome pain. In certain embodiments, the pain can include neuropathy pain associated with a bacterial infection or neuropathy pain associated with a viral infection. In some embodiments, the pain can include Lyme disease neuropathy pain, Epstein-Barr virus neuropathy pain, hepatitis B virus neuropathy pain, hepatitis C virus neuropathy pain, leprosy neuropathy pain, diphtheria neuropathy pain, or human immunodeficiency virus (HIV) neuropathy pain including HIV distal symmetric polyneuropathy pain. In certain embodiments, the pain can include hereditary neuropathy pain. In some embodiments, the pain can include Charcot-Marie-Tooth disease neuropathy pain or hereditary neuropathy with pressure palsies (HNPP) pain. In certain embodiments, the pain can include neuropathy pain caused by a malignant tumor, neuropathy pain caused by a benign tumor, or paraneoplastic neuropathy pain. In some embodiments, the pain can include myeloma neuropathy pain, lymphoma neuropathy pain, or amyloid neuropathy pain. In certain embodiments, the pain can include liver disease neuropathy pain, uremic neuropathy pain, connective tissue disorder neuropathic pain, hypothyroidism neuropathy pain, alcohol use neuropathy pain, or vitamin deficiency neuropathy pain. In some embodiments, the pain can include vitamin B deficiency neuropathy pain including vitamin B1 , niacin, vitamin B6, or vitamin B12 deficiency neuropathy pain, or vitamin E deficiency neuropathy pain. In certain embodiments, the pain can include toxic substance exposure neuropathy pain including neuropathy pain following lead exposure or neuropathy pain following mercury exposure. In certain embodiments, the pain can include anti-retroviral therapy-induced neuropathy pain or neurotoxic drug-induced neuropathic pain. In certain embodiments, the pain can include chemotherapy-induced neuropathy pain including platinum-based antineoplastic drug-induced neuropathic pain or chemotherapy-induced peripheral neuropathy (CIPN) pain, radiation therapy- induced pain including radiation therapy-induced neuropathy pain, cancer targeted therapy- induced neuropathy pain, or immunotherapy-induced neuropathy pain. In some embodiments, that pain can include central neuropathic pain. In certain embodiments, the pain can include central post-stroke pain, spinal cord injury- related central neuropathic pain, brain injury-related central neuropathic pain, or multiple sclerosis-related central neuropathic pain.
In certain embodiments, the pain can include cancer pain. In some embodiments, the pain can include bone cancer pain, breakthrough pain, cancer nociceptive pain, cancer neuropathy pain including neuropathy caused by a tumor pressing on a nerve.
In certain embodiments, the pain can include post-amputation pain. In some embodiments, the pain can include phantom pain, phantom limb pain, or residual limb pain.
In certain embodiments, the pain can include Paget’s disease pain. In other embodiments, the pain can include pain associated with fibromyalgia. In certain embodiments, the pain can include pain associated with lupus including lupus-related inflammatory pain and lupus-related neuropathy pain. In some embodiments, the pain can include gastrointestinal motility disorder pain, irritable bowel syndrome pain, Crohn’s disease pain, ulcer-related pain, or ulcerative colitis pain. In other embodiments, the pain can include incontinence pain or interstitial cystitis pain. In certain embodiments, the pain can include herpes zoster pain. In certain embodiments, the pain can include angina-induced pain. In certain embodiments, the pain can include animal bite or sting pain, or pain caused by a burn including pain caused by a first-degree, second-degree or third-degree burn.
In some embodiments, the pharmaceutical combination disclosed herein which comprises a therapeutically effective amount of at least one COX inhibitor and a therapeutically effective amount of at least one compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein, can be administered to a patient or subject, alone, or admixed with a pharmaceutically acceptable carrier, diluent, or excipient.
In some embodiments, the pharmaceutical combinations described herein are such that the COX inhibitor and the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, are administered each in an individual dosage form. In other embodiments, the pharmaceutical combinations described herein are such that the COX inhibitor and the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, are administered together in a single dosage form.
In some embodiments, when the pharmaceutical combinations comprise separate individual dosage forms (or “single dosage form” or “single dose form” or “unit dose”) of the COX inhibitor and of the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, each separate individual dosage form can be administered either simultaneously or sequentially. When administered sequentially, the individual dosage forms can be administered in any order.
Pharmaceutical combinations described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, ophthalmically, intravaginally, or via an implanted reservoir. Hence, in the present disclosure, the term “oral treatment” means a treatment that occurs by oral administration. In other words, an “oral treatment” refers to a treatment where the pharmaceutical combinations of the present disclosure are administered orally for the indicated treatment. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Other modes of administration also include intradermal ortransdermal administration.
In some embodiments, the pharmaceutical combinations described herein are administered orally, i.e., via the oral cavity, including buccally.
Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetra hydrofurfury I alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include excipients such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3- butanediol. Among the acceptable carriers and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
In order to prolong the effect of a provided compound, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil carrier. Injectable depot forms are made by forming matrices of the compound microencapsulated in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled.
Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the therapeutically active compound in liposomes or microemulsions that are compatible with body tissues.
Formulations for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the therapeutically active compounds of the present description with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone (PVP), sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid formulations of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The therapeutically active compounds can also be in micro- encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
Dosage forms for topical or transdermal administration of a compound of the present description include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of the present description. Additionally, the description contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
Pharmaceutical combinations provided herein may also be formulated for administration by nasal aerosol or inhalation using inhalants. Such formulations are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promotors to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
Pharmaceutical combinations provided herein may be formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutical combinations of this disclosure can be administered without food. In other embodiments, pharmaceutical combinations of this disclosure can be administered with food.
The amount of therapeutically active compounds that may be combined with carrier materials to produce a formulation in a single dosage form can vary depending upon the patient to be treated and the particular mode of administration. The amount of individual therapeutically active compound that may be combined with carrier materials to produce individual dosage forms can vary depending upon the patient to be treated and the particular mode of administration.
It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disorder being treated.
The pharmaceutical combinations described herein may be administered using any amount and any route of administration effective for treating or lessening the severity of the disorders or disorders as contemplated herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disorder or condition, the particular agent, its mode of administration, and the like. In some embodiments, the COX inhibitor and the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof, can be formulated in unit dose for ease of administration and uniformity of dosage. The expression "unit dose" or “single dose form” as used herein refers to a physically discrete unit of therapeutically active agent(s) in an amount appropriate for the patient to be treated. In some embodiments, each unit dose form can include both the required amount of COX inhibitor and of the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof. In other embodiments, separate unit doses can be prepared, a first unit dose including the required amount of COX inhibitor and a second unit dose including the required amount of the compound of Formula (I) or pharmaceutically acceptable salt, solvate, or prodrug thereof. It will be understood, however, that the total daily dosage of the therapeutically active compounds and/or combination thereof will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
In certain embodiments, each one of the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, can be administered at dosage levels of from about 0.01 mg/kg to about 50 mg/kg, or from about 0.01 mg/kg to about 40 mg/kg, or from about 0.01 mg/kg to about 30 mg/kg, or from about 0.1 mg/kg to about 50 mg/kg, or from about 0.1 mg/kg to about 40 mg/kg, or from about 0.1 mg/kg to about 30 mg/kg, or from about 0.1 mg/kg to about 20 mg/kg, or from about 0.1 mg/kg to about 10 mg/kg of subject body weight, one or more times a day, to obtain the desired therapeutic effect.
In certain embodiments, the COX inhibitor can be administered at dosage levels of from about 0.1 mg/kg to about 50 mg/kg, or from about 0.1 mg/kg to about 40 mg/kg, or from about 0.1 mg/kg to about 30 mg/kg, or from about 0.1 mg/kg to about 20 mg/kg, or from about 0.1 mg/kg to about 10 mg/kg of subject body weight, one or more times a day. In some preferred embodiments, the COX inhibitor can be administered at dosage levels of from about 0.1 to about 20 mg/kg.
In certain embodiments, the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, can be administered at dosage levels of from about 0.1 mg/kg to about 50 mg/kg, or from about 0.1 mg/kg to about 40 mg/kg, or from about 0.1 mg/kg to about 30 mg/kg, or from about 0.1 mg/kg to about 20 mg/kg, or from about 0.1 mg/kg to about 10 mg/kg of subject body weight, one or more times a day. In some preferred embodiments, the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, can be administered at dosage levels of from about 0.1 to about 30 mg/kg, or from about 0.1 mg/kg to about 20 mg/kg, or from about 0.1 mg/kg to about 15 mg/kg.
In certain embodiments, the COX inhibitor can be administered at dosage levels of from about 0.1 to about 20 mg/kg and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, can be administered at dosage levels of from about 0.1 to about 30 mg/kg.
In certain embodiments, the COX inhibitor can be administered at dosage levels of from about 0.1 to about 20 mg/kg and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, can be administered at dosage levels of from about 0.1 mg/kg to about 20 mg/kg.
In certain embodiments, the COX inhibitor can be administered at dosage levels of from about 0.1 to about 20 mg/kg and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, can be administered at dosage levels of from about 0.1 mg/kg to about 15 mg/kg.
In some embodiments, the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, are administered in a single dosage form. In other embodiments, the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, are administered each in an individual dosage form. In some embodiments, the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, are administered simultaneously or sequentially. In some embodiments, the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, are administered simultaneously. In some embodiments, the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, are administered sequentially. It is to be noted that when the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, are administered sequentially, they can be administered in any order. Hence, the COX inhibitor can be administered first and then the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered. Alternatively, the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered first and the COX inhibitor in second.
Upon improvement of a subject's condition, a maintenance dose of the pharmaceutical combination of the present description may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, treatment should cease. The subject may, however, require intermittent treatment on a longterm basis upon any recurrence of disorder symptoms.
The total daily inhibitory dose of the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof as defined herein, administered to a subject in single or in divided doses, can be in amounts, for example, from 0.01 to 50 mg/kg body weight, or more usually from 0.1 to 30 mg/kg body weight. Single dose formulations may contain such amounts or submultiples thereof to make up the daily dose. In some embodiments, treatment regimens according to the present description can comprise administration to a patient in need of such treatment of from about 1 mg to about 1000 mg per day in single or multiple doses, of the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof.
The pharmaceutical combinations described herein may be commercialized in the form of a kit. The kit can comprise at least one single dose form of the COX inhibitor (also referred to as “first single dose form of the COX inhibitor”) and at least one single dose form of the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined herein (also referred to as “second single dose form of the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof’). It should be noted that the terms “first” and “second” with reference to the single dose forms of each active ingredient, are used to differentiate the single dose forms and do not relate to any order for using/administering these dose forms. In fact, each of the first and second single dose forms can be administered in any order or even simultaneously.
The kit can thus comprise separate dose forms (dose units) of the COX inhibitor and of the compound having the Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof. Each separate dose can include the same amount of the therapeutically active ingredients or different amounts thereof. In some embodiments, the kit can be tailored for a specific patient by selecting suitable amounts of each therapeutically active ingredient. The kit generally also includes instructions for its proper use by a patient.
In some embodiments, the kit is such that the first single dose form can include the COX inhibitor in any amount as described above with respect to the pharmaceutical combinations. In some embodiments, the kit is such that the second single dose form can include the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof in any amount as described above with respect to the pharmaceutical combinations.
In some embodiments, the kit is such that the amount of the COX inhibitor in the first single dose form and the amount of the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof in the second single dose form, provide a ratio of the COX inhibitor to the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as described above with respect to the pharmaceutical combinations.
In some embodiments, the kit can include a first single dose form of the COX inhibitor and a second single dose form of the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, and is useful for the treatment of a patient suffering from pain, such as any of the pain disclosed in the present disclosure. In some embodiments, the use of the kit, can result in a synergistic effect of the COX inhibitor and of the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, in alleviating pain.
EXAMPLES
General Methods
Preparation of the thiophene fused cyclohexanone derivative compounds
Reagent grade chemicals and anhydrous solvents were purchased from commercial sources and, unless otherwise mentioned, were used without further purification. The names of the products were determined using the naming software included in ChemDraw (PerkinElmer). Where it is stated that compounds were prepared analogously to earlier examples or intermediates, reaction time, number of equivalents of reagents, temperature, work-up and purification techniques may differ slightly from the described example.
Purifications
Chromatographic separations were performed on:
- Teledyne ISCO CombiFlash flash chromatography systems, using pre-packaged SiC>2 or Cis columns.
- Teledyne ISCO ACCQPrep high pressure preparative liquid chromatography system; Column: Gemini 5 urn C18 110 A, 150 x 30 mm.
- Biotage Isolera flash chromatography systems, using pre-packaged SiO2 or Ci8 columns.
- Waters Mass Trigger Semi-Prep HPLC; Column: Gemini 5 urn NX-C18 110 A, 100 x 30 mm.
Chiral separations were performed on:
- Mettler Toledo Berger Minigram supercritical fluid chromatography; Column: ChiralPak IG, 20 x 250 mm or ChiralPak IG, 10 x 250 mm.
- Waters ACQUITY UPC2 supercritical fluid chromatography; Column: ChiralPak IG, 10 x 250 mm.
Analytical Methods
LC-MS were performed on:
- Waters UPLC-MS; Column: Acquity UPLC, CSH C18, 1.7 urn, 2.1 x 30 mm; Methods: from 5% to 95% of CH3CN in H2O with 0.1% (v/v) formic acid in 2 min or from 5% to 95% of CH3CN in 10 mM ammonium bicarbonate in 2 min.
- Agilent HPLC-MS; Column: Kinetex EVO C18 100 A 2.6 urn, 50 x 3 mm; Method: from 10% to 95% of CH3CN with 0.1% (v/v) formic acid in H2O with 0.1% (v/v) formic acid in 4.5 min.
- Agilent UPLC-MS; Column: Kinetex EVO C18 100 A 1.7 urn, 50 x 3 mm; Method: from 5% to 95% of CH3CN with 0.1% (v/v) formic acid in H2O with 0.1% (v/v) formic acid in 3 min.
Analytical SFC were performed on Waters ACQUITY UPC2; Column: ChiralPak IG 4.6 x 250 mm or ChiralPak IC 4.6 x 150 mm. NMR spectroscopy was carried out using a Varian NMR (AS 400) 400 MHz Spectrometer with Inova interface. In all cases, NMR data were consistent with the proposed structures. Characteristic chemical shifts (0) are given in parts-per-million using conventional abbreviations for designation of peaks: e.g. s, singlet; d, doublet; t; triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; etc. Abbreviations 9-BBN 9-Borabicyclo[3.3.1]nonane δ Chemical shift
A Angstrom
Ac Acetyl
Bn Benzyl
Boc fert-Butoxycarbonyl bs “Broad singlet”
Bu Butyl
Calcd Calculated d Doublet
DAST Diethylaminosulfur trifluoride dd Doublet of doublets dt Doublet of triplets
DCM Dichloromethane
DDQ 2,3-Dichloro-5,6-dicyano-1 ,4-benzoquinone DIBALH Diisobutylaluminium hydride
DIPEA N,N-Diisopropylethylamine
DMAP 4-Dimethylaminopyridine
DMF N,N-Dimethylformamide
DMP Dess-Martin periodinane
DMPU N,N'-Dimethylpropyleneurea
DMSO Dimethylsulfoxyde
Dppf 1 , 1 ’-Bis(diphenylphosphino)ferrocene
EA Ethyl acetate ee Enantiomeric excess
Et Ethyl
EtOH Ethanol eq Equivalents g Gram
HATU Hexafluorophosphate Azabenzotriazole Tetramethyl Uranium
Hz Hertz HPLC High performance liquid chromatography i-Pr Isopropyl
J Coupling constant
L Liter
LC-MS Liquid chromatography-mass spectrometry
LDA Lithium diisopropylamide
LHMDS Lithium bis(trimethylsilyl)amide
M Molar m Multiplet mCPBA meta-chloroperoxybenzoic acid
Me Methyl
MeOH Methanol mg Milligram
MHz Megahertz min Minutes mL Milliliter mm Milimeter mmol Millimole mol Mole
MS Mass spectrometry
N Normal
NBS /V-bromosuccinimide
PCC Pyridinium chlorochromate pH Potential of hydrogen
Ph Phenyl
PPh3 Triphenylphosphine ppm Parts per million
PyBOP Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate q Quadruplet
RT Room temperature rt Retention time
NMR Nuclear magnetic resonance s Singulet sat Saturated
SFC Supercritical fluid chromatography sxt sextuplet t tert t Triplet tt Triplet of triplet t-Bu tert-Butyl
TMS Trimethylsilyl
TFA Trifluoroacetic acid THF Tetrahydrofuran
Ts Tosyl uL Microliter umol Micromole v/v Volume/volume
° Degree
% Percentage
Example 1 2-Amino-7-oxo-5-(2-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (4) Scheme 1
Figure imgf000102_0001
Step 1. 2-(3-Oxo-5-(2-(trifluoromethyl)phenyl)cyclohexylidene)malononitrile (2)
A solution of malononitrile (100 mg, 1.51 mmol, recrystallized from EtOH), triethylamine (253 uL, 1.82 mmol) and 5-(2-(trifluoromethyl)phenyl)cyclohexane- 1 ,3-dione (1 , 396 mg, 1.51 mmol) in EtOH (1.30 mL) was stirred at 80 °C for 2 hours. Then, another 62 mg of malononitrile (0.94 mmol) and 250 uL of triethylamine (1.82 mmol) were added and the mixture was stirred at 80 °C for 16 hours. The mixture was then allowed to cool to RT, concentrated to dryness, and the crude product 2 was used in Step 2 without purification. LC-MS: rt = 1 .94 min, MS: 304.1 (calcd), 305.1 (M+H+, found).
Step 2. 2-Amino-7-oxo-5-(2-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carbonitrile (3)
A mixture of sulfur (50.9 mg, 198 umol), diethylamine (157 uL, 1.52 mmol) and 2 (461 mg, 1.52 mmol, assuming the quantitative yield in Step 1) in EtOH (2.00 mL) was stirred at 80 °C for 16 hours. The mixture was then allowed to cool to RT and concentrated by rotary evaporation and the residue was purified by flash column chromatography (eluent gradient from 40% to 100% of EA in hexane) to afford title compound 3 as a light-brown solid (220 mg, 43% yield over two steps). LC-MS: rt = 1.73 min, MS: 336.1 (calcd), 337.0 (M+H+, found). Step 3. 2-Amino-7-oxo-5-(2-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (4)
30% Aqueous hydrogen peroxide solution (0.33 mL) was added to a suspension of 3 (41.1 mg, 122 umol) and potassium carbonate (33.8 mg, 244 umol) in DMSO (1.64 mL). The mixture was stirred at RT for 2 hours, then partitioned between EA and water (20 mL each). The layers were separated and the aqueous phase was extracted with another 20 mL of EA. The combined organics were washed with brine (20 mL), dried over Na2SO4, filtered, concentrated and dried in vacuo to afford title compound 4 as a light-yellow solid (36.7 mg, 85% yield).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.06 (s, 2H), 7.90 (d, J = 8.0 Hz, 1 H), 7.76-7.68 (m, 2H), 7.49 (t, J = 7.7 Hz, 1 H), 6.96 (bs, 2H), 3.73-3.58 (m, 1 H), 3.40-3.29 (m, 1 H), 3.07-2.90 (m, 2H), 2.36 (dd, J = 16.3, 3.8 Hz, 1 H). 19F NMR: 376 MHz, DMSO-d6, δ (ppm): -57.5 (s). LC- MS: rt = 1.40 min, MS: 354.1 (calcd), 355.1 (M+H+, found).
Example 2 2-Amino-N-cyclopropyl-6-ethyl-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (9)
Scheme 2
Figure imgf000103_0001
Step 1 . Ethyl 2-cyano-2-(4-ethyl-3-oxocyclohexylidene)acetate (6)
A mixture of 4-ethylcyclohexane-1 , 3-dione (5, 150 mg, 910 umol) (Synlett. 2012, 1 199- 1204), triethylamine (380 uL, 2.73 mmol) and ethyl 2-cyanoacetate (145 uL, 1.36 mmol) in EtOH (784 uL) was stirred at 80 °C for 16 hours. Then, another 100 uL of ethyl 2-cyanoacetate (0.94 mmol) and 130 uL of triethylamine (0.93 mmol) were added and the resulting mixture was stirred at 80 °C for another 24 hours. The mixture was then allowed to cool to RT, concentrated to dryness, and the crude product 6 was used in Step 2 without purification. LC-MS: rt = 1.73 min, MS: 235.1 (calcd), 236.1 (M+H+, found).
Step 2. Ethyl 2-amino-6-ethyl-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (7)
A mixture of crude 6 (214 mg, 910 umol; assuming the quantitative yield in Step 1), sulfur (30.6 mg, 1 19 umol) and diethylamine (94.1 uL, 910 umol) in EtOH (910 uL) was stirred at 80 °C for 2 hours. The mixture was then allowed to cool to RT, concentrated to dryness, and the residue was purified by flash column chromatography (eluent gradient from 5% to 50% of EA in hexane) to afford title compound 7 as a yellow solid (135.2 mg, 52% yield over two steps). LC-MS: rt = 1.77 min, MS: 267.1 (calcd), 268.1 (M+H+, found).
Step 3. 2-Amino-6-ethyl-7-oxo-4,5,6,7-tetrahydrobenzo[b]1thiophene-3-carboxylic acid (8)
Lithium hydroxide monohydrate (68.0 mg, 1.62 mmol) was added to 7 (86.6 mg, 324 umol) suspended in a mixture of MeOH (4.86 mL) and H2O (1 .62 mL). The resulting mixture was stirred under reflux for 2 hours, then allowed to cool to RT, diluted with water (20 mL) and washed with EA (20 mL). The organic phase was discarded and the aqueous phase was then acidified to pH 2-3 using 3 N HCI and extracted using EA (3 x 20 mL). The combined organics were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to afford title compound 8 as an off- white solid (60.5 mg, 78% yield). The crude product was used in Step 4 with no additional purification. (See table 6 for characterization)
Step 4. 2-Amino-/V-cyclopropyl-6-ethyl-7-oxo-4,5,6,7-tetrahydroben N,N1thiophene-3- carboxamide (9)
To a solution of 8 (60.5 mg, 253 umol) in DMF (3.16 mL) were added N,N- diisopropylethylamine (132 uL, 758 umol), cyclopropylamine (19.3 uL, 278 umol) and HATU (115 mg, 303 umol). The resulting mixture was stirred at RT for 16 hours. The mixture was then diluted with saturated aqueous NH4CI (30 mL) and extracted with EA (3 x 20 mL). The combined organics were washed with ice-cold brine (40 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was first purified by flash column chromatography (eluent gradient from 1% to 10% of MeOH in DCM) and then recrystallized from hot EA to afford title compound 9 as a white solid (16.4 mg, 23% yield).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.68 (d, J = 5.7 Hz, 2H), 7.34 (d, J = 3.8 Hz, 1 H), 2.86 (dt, J = 17.3, 5.2 Hz, 1 H), 2.76 (ddt, J = 19.0, 7.1 , 4.2 Hz, 2H), 2.20 (ddt, J = 9.4, 7.8, 4.7 Hz, 1 H), 2.06 (dq, J = 13.2, 5.0 Hz, 1 H), 1.82-1.67 (m, 2H), 1.50-1.33 (m, 1 H), 0.90 (t, J = 7.4 Hz, 3H), 0.66 (td, J = 7.0, 4.6 Hz, 2H), 0.57-0.47 (m, 2H). LC-MS: rt = 1.26 min, MS: 278.1 (calcd), 279.1 (M+H+, found).
Example 3 2-Amino-6-(2-chlorophenyl)-6-cyano-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (15)
Scheme 3
Figure imgf000105_0001
15: Example 3
Step 1. Ethyl 2-((di-tert-butoxycarbonyl)amino)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate (11)
To a suspension of ethyl 2-amino-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate (10, 2.26 g, 9.25 mmol) in DCM (58.2 mL) were added triethylamine (2.85 mL, 20.4 mmol), 4-dimethylaminopyridine (228 mg, 1.85 mmol) and di-tert-butyldicarbonate (4.44 g, 20.4 mmol). The resulting solution was stirred under reflux for 4 hours. The mixture was then allowed to cool to RT, diluted with DCM (50 mL) and washed successively with 1 N HCI, water and brine (70 mL each). The organic phase was dried over Na2SO4, filtered and concentrated and the residue was purified by flash column chromatography (eluent gradient from 10% to 60% of EA in hexane) to afford title compound 11 as a light-orange solid (3.42 g, 84% yield). LC-MS: rt = 1.78 min, MS: 439.2 (calcd), 462.2 (M+Na+, found).
Step 2. Ethyl 2-((di-tert-butoxycarbonyl)amino)-6-cyano-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (12)
To a solution of LDA (10.4 mL, 1 M in THF/hexane, 10.4 mmol) cooled to -78 °C under Ar was added a solution of 11 (2.29 g, 5.22 mmol) in anhydrous THF (16 mL). The resulting mixture was stirred at -78 °C for 15 min, then a solution of TsCN (975 mg, 5.22 mmol) in anhydrous THF (16 mL) was added dropwise. The mixture was stirred at -78 °C for 20 min, then from -78 °C to RT for 4 hours. Subsequently, the mixture was quenched with saturated aqueous NH4CI (200 mL) and extracted with DCM (2 x 200 mL). The combined organics were dried over Na2SO4, filtered and concentrated, and the residue was purified by flash column chromatography (eluent gradient from 5% to 50% of EA in hexane) to afford title compound 12 as a light-yellow solid (1.13 g, 46% yield). LC-MS: rt = 1.73 min, MS: 464.2 (calcd), 487.2 (M+Na+, found).
Step 3. Ethyl 2-((tert-butoxycarbonyl)amino)-6-(2-chlorophenyl)-6-cyano-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (13)
To a flame-dried microwave vial charged with f-BuOK (57.5 mg, 512 umol) and anhydrous DMF (860 uL) under Ar was added 12 (200 mg, 431 umol) in anhydrous DMF (1.3 mL). The resulting mixture was stirred at 0 °C for 35 min, then bis(2-chlorophenyl)iodonium tetrafluoroborate (188 mg, 431 umol) (J. Am. Chem. Soc. 2016, 13183-13186.) in anhydrous DMF (430 uL) was added dropwise and the mixture was stirred at RT for 2.5 hours. Then, more bis(2- chlorophenyl)iodonium tetrafluoroborate (40 mg, 92 umol dissolved in 500 uL of anhydrous DMF) was added and the mixture was stirred at RT for 16 hours. The mixture was then diluted with water (2 mL) and acidified with 1 N HCI to pH 6-7. Another 10 mL of water was added and the product was extracted with EA (3 x 20 mL). The combined organics were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was taken up in heptanes and concentrated by rotary evaporation several times to get rid of residual DMF. The resulting solid was purified by flash column chromatography (eluent gradient from 0% to 50% of EA in hexane) to afford title compound 13 as a light-yellow solid (40 mg, 20% yield). LC-MS: rt = 2.06 min, MS: 474.1 (calcd), 475.1 (M+H+, found).
Step 4. 2-Amino-6-(2-chlorophenyl)-6-cyano-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylic acid (14)
TFA (2.26 mL, 29.6 mmol) was added dropwise to a solution of 13 (40.0 mg, 84.2 umol) in DCM (4.6 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 1 hour, then concentrated to dryness to afford a crude intermediate as a brown solid (33 mg), which was dissolved in MeOH (10 mL). A solution of lithium hydroxide monohydrate (17.4 mg, 414 umol) in water (10 mL) was added to the solution, which was stirred under reflux for 1 hour. The mixture was then allowed to cool to RT and concentrated to dryness. The residue was washed with EA (10 mL), then acidified to pH 1-2 using 1 N HCI and extracted with EA (3 x 10 mL). The combined organics were dried over Na2SO4, filtered and concentrated to afford title compound 14 as a brown solid (26.9 mg, 94% yield). The crude product was used in Step 5 with no additional purification. (See table 6 for characterization)
Step 5. 2-Amino-6-(2-chlorophenyl)-6-cyano-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (15)
To a suspension of 14 (19.9 mg, 57.4 umol) in CHCl3 (398 uL) were added N,N- diisopropylethylamine (30.0 uL, 172 umol), saturated NH3 solution in CHCl3 (0.3 mL) (prepared in-house) and HATU (24.0 mg, 63.1 umol). The mixture was stirred at RT. After stirring for 5 hours, another 24 mg of HATU (63.1 umol) and 0.5 mL of saturated NH3 solution in CHCI3 were added. The mixture was stirred for 16 hours, then another 25 mg of HATU (65.7 umol) and 0.6 mL of saturated NH3 solution in CHCI3 were added and stirring continued for another 4.5 hours. The mixture was then diluted with 5 mL of water and 5 mL CHCl3. The layers were separated and the aqueous phase was extracted with CHCI3 (2 x 5 mL). The combined organics were dried over Na2SO4, filtered and concentrated, and the residue was purified by reverse-phase flash column chromatography (eluent gradient from 0% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid) to afford title compound 15 as a white solid (6.2 mg, 31% yield).
1H NMR: 400 MHz, CD3OD, δ (ppm): 7.73-7.68 (m, 1 H), 7.50-7.45 (m, 1 H), 7.45-7.40 (m, 2H), 3.29-3.11 (m, 3H), 2.48-2.41 (m, 1 H). LC-MS: rt = 1.15 min, MS: 345.0 (calcd), 346.0 (M+H+, found). Examples 4-27
Compounds 16-34 (examples 4-22) were synthesized starting from appropriately substituted diketones by following the procedures described above for the synthesis of compound 4 (example 1 , scheme 1). Compounds 35 and 36 (examples 23 and 24) were synthesized in a similar fashion by following the procedures described above for the synthesis of compound 8 (scheme 2). Compounds 37-39 (examples 25-27) were synthesized in a similar fashion by following the procedures described above for the synthesis of compound 9 (scheme 2). Characterization of compounds 16-39 (examples 4-27) is provided in the table 2.
Table 2. Characterization of compounds 16-39 (examples 4-27).
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Example 28 -Amino-6-cyano-6-(cyclobutylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylic acid (47) and
Example 29 2-Amino-6-cyano-6-(cyclobutylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-
3-carboxamide (48)
Scheme 4
Figure imgf000113_0001
Step 1. 8-(Cyclobutylmethyl)-1 ,4-dioxaspiro[4.51decane-8-carbonitrile (41)
A flame-dried round bottom flask was charged with a solution of LDA (2.69 mL, 1 M in THF/hexane, 2.69 mmol) in anhydrous THF (3.60 mL) under Ar. The solution was cooled to -78 °C and 1 ,4-dioxaspiro[4.5]decane-8-carbonitrile (40, 265 uL, 1.79 mmol) was added. The mixture was stirred at -78 °C for 30 min, then (bromomethyl)cyclobutane (202 uL, 1 .79 mmol) was added. The reaction vessel was removed from the acetone/dry ice bath and the solution was stirred at RT for 64 hours. The mixture was then partitioned between EA and water (15 mL each), the layers were separated and the aqueous phase was extracted with EA (2 x 15 mL). The combined organics were dried over Na2SO4, filtered and concentrated to afford the crude title compound 41 as an orange oil, which was used in Step 2 without purification and without characterization.
Step 2. 1-(Cyclobutylmethyl)-4-oxocyclohexane-1-carbonitrile (42)
A solution of 41 (422 mg, 1.79 mmol, assuming the quantitative yield in Step 1) in acetone (25.3 mL) was treated with 2 N HCI (4.59 mL, 9.19 mmol) and the resulting mixture was stirred at 40 °C for 64 hours. The mixture was then allowed to cool to RT, concentrated by rotary evaporation to remove acetone, and the aqueous residue was extracted with EA (3 x 30 mL). The combined organics were dried over Na2SO4, filtered and concentrated to afford the crude title compound 42 as a brown solid, which was used in Step 3 without purification and without characterization.
Step 3. Ethyl 2-amino-6-cyano-6-(Cyclobutylmethy-l)4,5,6,7-tetrahydrobenzo[b]thiophene-3-
Figure imgf000113_0002
A suspension of ethyl 2-cyanoacetate (210 uL, 1.97 mmol), morpholine (172 uL, 1.97 mmol), sulfur (63 mg, 247 umol) and 42 (342 mg, 1.79 mmol, assuming the quantitative yield in Step 2) in EtOH (1.8 mL) was stirred at 60 °C for 16 hours. The mixture was allowed to cool to RT, then concentrated by rotary evaporation and the residue was partitioned between EA and water (20 mL each). The organic phase was dried over Na2SO4, filtered and concentrated and the residue was purified by flash column chromatography (eluent gradient from 0% to 50% of EA in hexane) to afford title compound 43 as a light-yellow solid (353 mg, 62% yield over three steps). LC-MS: rt = 1.74 min, MS: 318.1 (calcd), 319.1 (M+H+, found).
Step 4. Ethyl 2-acetamido-6-cyano-6-(Cyclobutylmethy-l)4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate (44)
A suspension of 43 (227 mg, 713 umol) in acetic acid (4.09 mL) was treated with acetic anhydride (80.9 uL, 856 umol) and the resulting mixture was stirred at 70 °C for 3 hours. The mixture was then allowed to cool to RT and concentrated to dryness. The residue was diluted with DCM (10 mL) and washed successively with saturated aqueous NaHCO3, water and brine (10 mL each), then dried over Na2SO4, filtered and concentrated to afford title compound 44 as a yellow solid (227 mg, 88% yield). LC-MS: rt = 1.79 min, MS: 360.2 (calcd), 361.1 (M+H+, found).
Step 5. Ethyl 2-acetamido-6-cyano-6-(cyclobutylmethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (45)
To a suspension of 44 (227 mg, 630 umol) in acetic acid (2.1 mL) and water (6.3 mL) was added ceric sulfate (1 .81 g, 5.44 mmol). The mixture was sonicated for 1 min, then stirred at RT for 88 hours. Subsequently, the mixture was diluted with water and EA (30 mL each), sonicated for 3 minutes and transferred into a separatory funnel. The layers were separated and the organic phase was washed successively with 1 N NaOH and brine (30 mL each), then dried over Na2SO4, filtered and concentrated to afford title compound 45 as a yellow gum (175.1 mg, 74% yield), which was used in Step 6 without purification. LC-MS: rt = 1.71 min, MS: 374.1 (calcd), 375.2 (M+H+, found).
Step 6. Ethyl 2-amino-6-cyano-6-(cyclo butylmethyl)-7-oxo-4, 5,6,7- tetrahydro benzo[b]thiophene-3-carboxylate (46)
A solution of 45 (170 mg, 454 umol) in toluene (744 uL) was treated with pyrrolidine (559 uL, 6.81 mmol) and stirred at RT for 1 hour. The mixture was then concentrated by rotary evaporation and the residue was purified by flash column chromatography (eluent gradient from 0% to 50% of EA in hexane) to afford title compound 46 as an off-white solid (1 18.1 mg, 78% yield). LC-MS: rt = 1.63 min, MS: 332.1 (calcd), 333.1 (M+H+, found).
Step 7. 2-Amino-6-cyano-6-(cyclobutylmethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (47)
A solution of lithium hydroxide monohydrate (66.9 mg, 1 .59 mmol) in water (38.4 mL) was added to a solution of 46 (100 mg, 261 umol) in MeOH (38.4 mL). The mixture was stirred under reflux for 16 hours, then allowed to cool to RT and concentrated by rotary evaporation to remove most of MeOH. The aqueous residue was washed with EA (2 x 25 mL), then acidified to pH 1-2 using 3 N HCI and extracted with EA (3 x 25 mL). The organics were dried over Na2SO4, filtered and concentrated to afford title compound 47 as an off-white solid (78.2 mg, 81 % yield). 1H NMR: 400 MHz, DMSO-d6, δ (ppm): 12.75 (bs, 1 H), 8.48 (bs, 2H), 3.08-3.02 (m, 2H), 2.55-2.42 (m, 1 H), 2.43-2.29 (m, 1 H), 2.27-2.16 (m, 1 H), 2.13-1.96 (m, 3H), 1.93-1.61 (m, 5H). LC-MS: rt = 1.32 min, MS: 304.1 (calcd), 305.1 (M+H+, found).
Step 8. 2-Amino-6-cyano-6-(cyclobutylmethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (48)
To a suspension of 47 (38.3 mg, 126 umol), saturated NH3 solution in chloroform (780 uL) (prepared in-house), ammonium chloride (135 mg, 2.52 mmol) and N,N-diisopropylethylamine (43.8 uL, 252 umol) in DMF (1.39 mL) was added HATU (73.2 mg, 189 umol). The resulting mixture was stirred at RT for 16 hours, then diluted with saturated aqueous NH4CI (20 mL) and extracted with EA (3 x 10 mL). The combined organics were washed with ice-cold brine (2 x 15 mL), dried over Na2SO4, filtered and concentrated. The residue was first purified by reverse-phase flash column chromatography (eluent gradient from 0% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid) and then Semi-Prep HPLC-MS (eluent gradient from 25% to 100% of CH3CN in 10 mM ammonium bicarbonate) to afford title compound 48 as a white solid (14.5 mg, 38%).
1H NMR (400 MHz, CD3OD): δ 3.16-3.08 (m, 2H), 2.65-2.57 (m, 1 H), 2.47 (ddd, J = 13.3, 7.7, 5.4 Hz, 1 H), 2.30 (ddd, J = 13.7, 6.0, 5.0 Hz, 1 H), 2.20-2.10 (m, 3H), 2.00-1.90 (m, 2H), 1.87- 1.74 (m, 3H). LC-MS: rt = 1.15 min, MS: 303.1 (calcd), 304.1 (M+H+, found).
Example 30 2-Amino-6-cyano-6-(cyclopentylmethyl)-7 -oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (49) and Example 31 2-Amino-6-cyano-6-(cyclopentylmethyl)-7 -oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (50)
Scheme 5
Figure imgf000115_0001
2-Amino-6-cyano-6-(Cyclobutylmethyl) -7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylic acid (49)
Compound 49 (example 30) was synthesized similarly to compound 47 (example 28, scheme 4) starting from 1 ,4-dioxaspiro[4.5]decane-8-carbonitrile (40) and using in the first step (bromomethyl)cyclopentane instead of (bromomethyl)cyclobutane.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 12.75 (bs, 1 H), 8.48 (bs, 2H), 3.13-3.00 (m, 2H), 2.48-2.38 (m, 1 H), 2.29 (dt, J = 13.5, 5.2 Hz, 1 H), 2.04-1.76 (m, 5H), 1.63-1.37 (m, 4H), 1.25-1.05 (m, 2H). LC-MS: rt = 1.41 min, MS: 318.1 (calcd), 319.1 (M+H+, found). 2-Amino-6-cyano-6-(cyclopentylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide
To a suspension of 49 (40.0 mg, 126 umol), saturated NH3 solution in chloroform (741 uL) (prepared in-house), ammonium chloride (134 mg, 2.51 mmol) and N,N-diisopropylethylamine (43.8 uL, 252 umol) in DMF (1.39 mL) was added HATU (73.1 mg, 188 umol). The resulting mixture was stirred at RT for 16 hours, then another 40 uL of N,N-diisopropylethylamine (230 umol), 550 uL of saturated NH3 solution in chloroform and 65 mg of HATU (167 umol) were added and the mixture was stirred at 40 °C for 24 hours. Subsequently, the mixture was partitioned between saturated aqueous NH4CI and EA (20 mL each), the layers were separated and the organic phase was washed with ice-cold brine (2 x 15 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by reverse-phase flash column chromatography (eluent gradient from 0% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid) to afford title compound 50 as an off-white solid (14.5 mg, 36%).
1H NMR: 400 MHz, CD3OD, δ (ppm): 3.25-3.05 (m, 2H), 2.54 (ddd, J = 13.4, 7.9, 5.4 Hz, 1H), 2.38 (ddd, J = 13.7, 5.9, 5.0 Hz, 1 H), 2.12 (dd, J = 13.5, 6.7 Hz, 1 H), 2.07-1.85 (m, 4H), 1.73- 1.51 (m, 4H), 1.26-1.18 (m, 2H). LC-MS: rt = 1.25 min, MS: 317.1 (calcd), 318.0 (M+H+, found).
Example 32 2-Amino-6-cyano-6-(cyclohexylmethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (51) and Example 33 2-Amino-6-cyano-6-(cyclohexylmethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (52)
Scheme 6
Figure imgf000116_0001
2-Amino-6-cyano-6-(cyclohexylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3- ic acid
Compound 51 (example 32) was synthesized similarly to compound 47 (example 28, scheme 4) starting from 1 ,4-dioxaspiro[4.5]decane-8-carbonitrile (40) and using in the first step (bromomethyl)cyclohexane instead of (bromomethyl)cyclobutane.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 12.69 (bs, 1 H), 8.48 (bs, 2H), 3.12-2.97 (m, 2H), 2.47-2.36 (m, 1 H), 2.27 (dt, J = 13.7, 5.5 Hz, 1 H), 1.84-1.54 (m, 6H), 1.53-1.46 (m, 1 H), 1.28-1.07 (m, 4H), 1.03-0.90 (m, 2H). LC-MS: rt = 1.49 min, MS: 332.1 (calcd), 333.0 (M+H+, found). 2-Amino-6-cyano-6-(cyclohexylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (52)
To a solution of 51 (24.0 mg, 72.2 umol) in DMF (798 uL) were added PyBOP (56.5 mg, 108 umol), N,N-diisopropylethylamine (40.0 uL, 230 umol) and ammonium chloride (38.6 mg, 722 umol). The resulting mixture was stirred at RT for 80 minutes, then diluted with saturated aqueous NH4CI (5 mL) and extracted with EA (3 x 5 mL). The combined organics were washed with ice- cold brine (2 x 10 mL), dried over Na2SO4, filtered and concentrated and the residue was purified by flash column chromatography (eluent gradient from 10% to 100% of EA in hexane) to afford title compound 52 as an orange solid (13.6 mg, 57% yield).
1H NMR: 400 MHz, CD3OD, δ (ppm): 3.18-3.09 (m, 2H), 2.51 (ddd, J = 13.3, 7.5, 5.6 Hz, 1H), 2.36 (dt, J= 13.6, 5.5 Hz, 1 H), 1.98-1.80 (m, 3H), 1.79-1.59 (m, 5H), 1.38-1.16 (m, 4H), 1.13- 0.97 (m, 2H). LC-MS: rt = 1 .34 min, MS: 331 .1 (calcd), 332.2 (M+H+, found).
Example 34 2-Amino-6-cyano-6-(cyclopropylmethyl)-7 -oxo-4, 5,6, 7-tetrahydrobenzo[b]thiophene-3- carboxylic acid (53) and
Example 35 2-Amino-6-cyano-6-(cyclopropylmethyl)-7 -oxo-4, 5,6, 7-tetrahydrobenzo[b]thiophene-3- carboxamide (54)
Figure imgf000117_0001
53: Example 34 54: Example 35
2-Amino-6-cyano-6-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-
✓lic acid (53).
Compound 53 (example 34) was synthesized similarly to compound 47 (example 28, scheme 4) starting from 1 ,4-dioxaspiro[4.5]decane-8-carbonitrile (40) and using in the first step (bromomethyl)cyclopropane instead of (bromomethyl)cyclobutane.
1H NMR: 400 MHz, CD3OD, δ (ppm): 3.23-3.19 (m, 2H), 2.54-2.50 (m, 1 H), 2.42-2.39 (m, 1 H), 1.89 (dd, J = 14.27, 7.15 Hz, 1 H), 1.78 (dd, J = 14.26, 6.72 Hz, 1 H), 0.91-0.87 (m, 1 H), 0.57- 0.53 (m, 2H), 0.22-0.19 (m, 2H). LC-MS: rt = 1.18 min, MS: 290.1 (calcd), 291.0 (M+H+, found).
2-Amino-6-cyano-6-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (54).
To a suspension of 53 (36.4 mg, 0.125 mmol) in CHCl3 (871 uL) was added HATU (52.4 mg, 0.138 mmol) and N,N-diisopropylethylamine (65.5 uL, 0.376 mmol). The mixture was stirred 20 min at RT and to it was added saturated NH3 solution in CHCI3 (0.8 mL) (prepared in-house) and NH4CI (6.71 mg, 0.125 mmol). The reaction mixture was stirred for 16 hours and partitioned between EA and a saturated aqueous solution of NaHCO3. The layers were separated and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 20% to 100% of EA in hexane) to afford title compound 54 as a white solid (20.0 mg, 55% yield).
1H NMR: 400 MHz, CD3OD, δ (ppm): 3.13 (t, J = 6.03 Hz, 2H), 2.60-2.53 (m, 1 H), 2.48- 2.42 (m, 1 H), 1.93 (dd, J = 14.28, 7.11 Hz, 1 H), 1.80 (dd, J = 14.28, 6.79 Hz, 1 H), 0.94-0.84 (m, 1 H), 0.58-0.55 (m, 2H), 0.24-0.20 (m, 2H). LC-MS: rt = 1 .02 min, MS: 289.1 (calcd), 290.1 (M+H+, found).
Example 36 2-Amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid
Figure imgf000118_0001
Step 1 . Ethyl 2-amino-6-cyano-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate (56).
To a solution of 4-oxo-1-phenylcyclohexane-1 -carbonitrile (55) (6.00 g, 30.1 mmol) and ethyl 2-cyanoacetate (2.91 mL, 27.4 mmol) in EtOH (48.0 mL) were added morpholine (2.60 mL, 30.1 mmol) and sulfur (969 mg, 3.78 mmol). The reaction mixture was stirred at 60 °C for 16 hours. The mixture was allowed to cool to RT and a white precipitate appeared. This solid was collected by filtration, washed with EtOH and dried in vacuo to afford title compound 56 as a white solid (8.15 g, 91% yield). LC-MS: rt = 1.55 min, MS: 326.1 (calcd), 327.0 (M+H+, found).
Step 2. Ethyl 2-acetamido-6-cyano-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate (57).
To a solution of 56 (8.15 g, 25.0 mmol) in acetic acid (143 mL) was added acetic anhydride (2.83 mL, 30.0 mmol). The mixture was stirred at 60 °C for 1 day, then allowed to cool to RT and concentrated to dryness. The residue was partitioned between DCM and water. The layers were separated and the organic phase was washed with a saturated aqueous solution of NaHCO3, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated to afford title compound 57 as a white solid (9.0 g, 98% yield). LC-MS: rt = 1 .61 min, MS: 368.1 (calcd), 369.1 (M+H+, found).
Step 3. Ethyl 2-acetamido-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate (58).
To a solution of 57 (9.00 g, 24.4 mmol) in acetic acid (66 mL) and water (66 mL) was added ceric sulfate (70.1 g, 211 mmol). The mixture was sonicated until it became homogenous, and stirred at RT for 24 hours. The suspension was partitioned between EA and water. The layers were separated and the organic phase was washed with NaOH 1 N, water and brine. The organic layer was then dried over Na2SO4, filtered and concentrated to afford title compound 58 as an off- white solid (9.10 g, 97% yield). LC-MS: rt = 1.56 min, MS: 382.1 (calcd), 383.1 (M+H+, found).
Step 4. 2-Amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylic acid (59).
To a suspension of 58 (4.00 g, 10.44 mmol) in MeOH (1.26 L) was added a solution of lithium hydroxide monohydrate (2.20 g, 52.4 mmol) in water (1.26 L). The reaction mixture was stirred under reflux for 2 hours, then allowed to cool to RT. The mixture was diluted with water and concentrated to remove most of the organic solvent, then washed with EA. The aqueous layer was acidified by slow addition of HCI 3 N and extracted with EA. This organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by trituration with a DCM/pentane mixture to afford title compound 59 as a greyish solid (2.54 g, 78% yield).
1H NMR: 400 MHz, CD3OD, δ (ppm): 7.43-7.31 (m, 5H), 3.27-3.23 (m, 1 H), 2.88-2.73 (m, 2H), 2.71-2.61 (m, 1 H). LC-MS: rt = 1.23 min, MS: 312.1 (calcd), 313.1 (M+H+, found).
Example 37
(R)-2-Amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (60a)
(S)-2-Amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (60b)
Figure imgf000119_0001
Racemic compound 59 (86.0 mg) was submitted to SFC chiral separation (isocratic 35% MeOH in CO2) to afford enantioenriched compound 60a as a light-pink solid (33.1 mg, 38% separation yield) and 60b as a white solid (35.4 mg, 41% separation yield) (the absolute configurations were assigned based on resolved crystal structure of enantiomer 60a). 60a: 1H NMR: same as racemic mixture (59). LC-MS: rt = 1.23 min, MS: 312.1 (calcd),
313.1 (M+H+, found). Analytical SFC (IG column with 5-60% MeOH in water (95-40% CO2) gradient): rt = 3.84 min, ee. = 99.9%.
60b: 1H NMR: same as racemic mixture (59). LC-MS: rt = 1.23 min, MS: 312.1 (calcd), 313.1 (M+H+, found). Analytical SFC (IG column with 5-60% MeOH in water (95-40% CO2) gradient): rt = 4.76 min, ee. = 97.6%.
Example 38 2-Amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (61) and
Example 39 2-Amino-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3,6-dicarboxamide (62) Scheme 10
Figure imgf000120_0001
Step 1 . 2-Amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (61).
To a solution of 59 (2.54 g, 8.13 mmol) in DMF (90.0 mL) were added HATU (4.73 g, 12.2 mmol) and N,N-diisopropylethylamine (2.83 mL, 16.4 mmol) and the mixture was stirred at RT for 20 min. Then, ammonium chloride (8.74 g, 163 mmol), NH3 solution in THF (45.0 mL, 18.0 mmol, 0.4 M) and saturated NH3 solution in chloroform (45.0 mL) (prepared in-house) were added to the mixture. The reaction mixture was stirred at RT for 16 hours and partitioned between EA and a saturated aqueous solution of NaHCO3. The layers were separated, and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 20% to 100% of EA in hexane) and then by reverse-phase flash column chromatography (eluent gradient from 0% to 100% CH3CN in H2O with 0.1% (v/v) formic acid) to afford title compound 61 as a white solid (1 .20 g, 47% yield).
1H NMR: 400 MHz, CD3OD, δ (ppm): 7.41-7.36 (m, 5H), 3.17-3.11 (m, 1 H), 2.87-2.77 (m, 2H), 2.74-2.66 (m, 1 H). LC-MS: rt = 1.04 min, MS: 311.1 (calcd), 312.0 (M+H+, found).
Step 2. 2-Amino-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3,6-dicarboxamide (62)
30% Aqueous hydrogen peroxide solution (170 uL) was added to a suspension of 61 (13.2 mg, 42.4 umol) and potassium carbonate (11.7 mg, 84.8 umol) in DMSO (569 uL). The mixture was stirred at RT for 3 hours, then partitioned between EA and water (5 mL each). The layers were separated, the organic phase was washed with 5 mL of water and the combined aqueous phase was extracted with EA (2 x 3 mL). The combined organics were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by reverse-phase flash column chromatography (eluent gradient from 0% to 70% of CH3CN in H2O with 0.1 % (v/v) formic acid) to afford title compound 62 as a white solid (3.6 mg, 28% yield).
1H NMR: 400 MHz, CD3OD, δ (ppm): 7.41-7.25 (m, 5H), 3.05 (dt, J = 16.8, 4.2 Hz, 1 H), 2.78-2.59 (m, 3H). LC-MS: rt = 0.86 min, MS: 329.1 (calcd), 329.9 (M+H+, found).
Example 40 (S)-2-Amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (63) and
Example 41 (R)-2-Amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (64)
Scheme 11
Figure imgf000121_0001
Racemic compound 61 (96.5 mg) was submitted to SFC chiral separation (isocratic: 45% of CH3CN/EtOH 1 :1 in CO2) to yield enantioenriched compound 63 as a white solid (29.0 mg, 30% separation yield) and enantioenriched compound 64 as a white s olid (29.0 mg, 30% separation yield) (the absolute configurations were assigned based on resolved crystal structure of enantiomer 64).
63: 1H NMR: same as racemic mixture (61). LC-MS: rt = 1.04 min, MS: 311.1 (calcd), 312.0 (M+H+, found). Analytical SFC (IG column with 5-60% ACN/EtOH (95-40% CO2) gradient): rt = 4.71 min, ee. = >99.9%.
64: 1H NMR: same as racemic mixture (61). LC-MS: rt = 1.04 min, MS: 311.1 (calcd), 312.0 (M+H+, found). Analytical SCF (IG column with 5-60% ACN/EtOH (95-40% CO2) gradient): rt = 4.09 min, ee. = >99.9%.
Examples 42-49
Compounds 65-71 (examples 42-48) were synthesized by following a procedure similar to the one described above for the synthesis of compound 9 (example 2, scheme 2), starting from compound 59 (example 36, scheme 8) instead of compound 8, and using cyclobutylamine, cyclopentylamine, 3-aminoxetane, 3-aminotetrahydrofurane, 4-aminotetrahydropyrane, 2,2,2- trifluoroethylamine and 2,2-difluoroethan-1-amine respectively, instead of cyclopropylamine. Compound 72 (example 49) was obtained in the same fashion starting from compound 53 (example 34, scheme 7). Characterization of compounds 65-72 (examples 42-49) is provided in the table 3.
Table 3. Characterization of compounds 65-72 (examples 42-49).
Figure imgf000122_0001
Figure imgf000123_0001
Example 50 2-Amino-6-cyano-6-isobutyl-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (75)
Scheme 12
Figure imgf000124_0001
Step 1. 1-lsobutyl-4-oxocyclohexane-1-carbonitrile (73).
To a solution of 1 ,4-dioxaspiro[4.5]decane-8-carbonitrile (40, 221 uL, 1.50 mmol, scheme 4) in THF (3.0 mL) at -78 °C was added dropwise LDA (2.39 ml, 1 M in THF/hexane, 2.39 mmol). After 30 min, 1-bromo-2-methylpropane (164 uL, 1.50 mmol) was added dropwise and the reaction mixture was stirred at RT for 72 hours. The reaction mixture was then partitioned between hexane and water. The layers were separated and the aqueous phase was extracted with EA. The combined organic layers were combined, dried over Na2SO4, filtered and concentrated. The dry residue was dissolved in acetone (19.7 mL) and HCI 3 N (4.98 mL, 15.0 mmol) was added slowly. The mixture was stirred for 16 hours, then neutralized by slowly adding saturated NaHCO3 solution and concentrated to remove the organic solvent. The remaining aqueous solution was extracted with EA and the organic layer was dried over Na2SO4, filtered and concentrated to dryness to afford title compound 73 (141 mg, 52% yield over two steps). LC-MS: rt = 1.45 min, MS: 179.1 (calcd), 180.0 (M+H+, found).
Step 2. 2-Amino-6-cyano-6-isobutyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (74).
To a solution of 73 (141 mg, 0.784 mmol) and cyanoacetamide (59.9 mg, 0.713 mmol) in EtOH (713 uL) were added morpholine (67.6 uL, 0.784 mmol) and sulfur (25.2 mg, 98.3 umol). The reaction mixture was stirred at 60 °C for 19 hours, allowed to cool to RT and concentrated to dryness. The residue was partitioned between EA and water. The layers were separated and the organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 100% of EA in hexane) to afford title compound 74 as a beige solid (115 mg, 58% yield). LC-MS: rt = 1.49 min, MS: 277.1 (calcd), 277.9 (M+H+, found). Step 3. 2-Amino-6-cyano-6-isobutyl-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (75).
To a solution of 74 (30 mg, 0.108 mmol) in DMSO (643 uL) was added selenium dioxide (12.0 mg, 0.108 mmol). The reaction mixture was stirred at RT for 12 hours, then partitioned between brine and EA. The layers were separated and the organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 10% of MeOH in DCM) then by Semi-Prep HPLC-MS (35% to 100% MeOH in 10 mM ammonium formate pH = 3.8) to afford title compound 75 as a white solid (3.20 mg, 10% yield).
1H NMR: 400 MHz, CD3OD, δ (ppm): 3.19-3.09 (m, 2H), 2.51 (ddd, J = 13.71 , 7.59, 5.42 Hz, 1 H), 2.36 (dt, J = 13.65, 5.45 Hz, 1 H), 1.97-1.85 (m, 2H), 1.80-1.75 (m, 1 H), 1.03 (d, J = 6.05 Hz, 6 H). LC-MS: rt = 1.11 min, MS: 291.1 (calcd), 292.1 (M+H+, found).
Example 51 2-Amino-6-(cyanomethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylic acid (81) and
Example 52 2-Amino-6-(cyanomethyl)- N-cyclopropyl-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (82)
Scheme 13
Figure imgf000125_0001
Step 1 . Ethyl 2-amino-6-(cyanomethyl)-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-
Figure imgf000125_0002
To a solution of 2-(4-oxo-1-phenylcyclohexyl)acetonitrile (76) (Bioorg. Med. Chem. Lett.,
21 , p. 405, 2011) (705 mg, 3.31 mmol) and ethyl 2-cyanoacetate (351 uL, 3.01 mmol) in EtOH (3.01 mL) were added morpholine (285 uL, 3.31 mmol) and sulfur (106 mg, 0.415 mmol). The mixture was stirred at 60 °C for 16 hours, then allowed to cool to RT and a white precipitate formed. This solid was collected by filtration, washed with EtOH and dried in vacuo to afford title compound 77 as a white solid (682 mg, 67% yield). LC-MS: rt = 1.55 min, MS: 340.1 (calcd),
341.1 (M+H+, found).
Step 2. Ethyl 2-acetamido-6-(cyanomethyl)-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate (78).
To a solution of 77 (682 mg, 2.00 mmol) in acetic acid (1 1.5 mL) was added acetic anhydride (227 uL, 2.40 mmol). The mixture was stirred at 60 °C for 24 hours, then allowed to cool to RT and concentrated to dryness. The residue was partitioned between DCM and water. The layers were separated and the organic phase was washed with a saturated aqueous solution of NaHCO3, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated to afford title compound 78 as a white solid (766 mg, >99% yield). LC-MS: rt = 1.61 min, MS:
382.1 (calcd), 383.1 (M+H+, found).
Step 3. Ethyl 2-acetamido-6-(cyanomethyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (79).
To a solution of 78 (766 mg, 2.00 mmol) in acetic acid (6.73 mL) and water (6.73 mL) was added ceric sulfate (5.75 g, 17.3 mmol). The suspension was sonicated until it became homogenous, and stirred at RT for 1 day, then it was partitioned between EA and water. The layers were separated and the organic phase was washed with NaOH 1 N, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated to afford title compound 79 as an off-white solid (794 mg, >99% yield). LC-MS: rt = 1.47 min, MS: 396.1 (calcd), 397.1 (M+H+, found).
Step 4. Ethyl 2-amino-6-(cyanomethyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (80).
To a suspension of 79 (793 mg, 2.00 mmol) in toluene (3.28 mL) was added pyrrolidine (2.46 mL, 30.0 mmol). The suspension turned into a solution after a few minutes of stirring and the reaction mixture was stirred at 80 °C for 1 hour, then allowed to cool to RT and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 100% of EA in hexane) to afford title compound 80 as a white solid (408 mg, 57% yield). LC-MS: rt = 1 .43 min, MS: 354.1 (calcd), 355.0 (M+H+, found).
Step 5. 2-Amino-6-(cyanomethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene- 3-carboxylic acid (81).
To a suspension of 80 (408 mg, 1.15 mmol) in MeOH (139 mL) was added a solution of lithium hydroxide monohydrate (242 mg, 5.76 mmol) in water (139 mL). The reaction mixture was stirred under reflux for 16 hours, then allowed to cool to RT. The mixture was diluted with water and concentrated to remove most of the organic solvent, then washed with EA. The aqueous layer was collected, acidified by slow addition of HCI 2N and extracted with EA. This organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 10% of MeOH in DCM) to afford title compound 81 as a white solid (376 mg, >99% yield).
1H NMR: 400 MHz, CD3OD, δ (ppm): 7.34-7.27 (m, 5H), 3.35-3.30 (m, 1 H), 3.01 (d, J = 16.71 Hz, 1 H), 2.89 (d, J = 16.71 Hz, 1 H), 2.77-2.74 (m, 1 H), 2.49-2.45 (m, 2H). LC-MS: rt = 1.16 min, MS: 326.1 (calcd), 327.0 (M+H+, found).
Step 6. 2-Amino-6-(cyanomethyl)- /V-cyclopropyl-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (82).
To a suspension of 81 (154 mg, 0.472 mmol) in THF (5.90 mL) were added HATU (359 mg, 0.944 mmol) and N,N-diisopropylethylamine (164 uL, 0.944 mmol). The mixture was stirred at RT for 20 min and then cyclopropylamine (327 uL, 4.72 mmol) was added. The reaction mixture was stirred for an additional 16 hours, then partitioned between EA and a saturated aqueous solution of NH4CI. The layers were separated and the organic phase was collected, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 20% to 100% of EA in hexane) and then by reverse-phase flash column chromatography (eluent gradient from 0% to 100% CH3CN in H2O with 0.1% (v/v) formic acid) to afford title compound 82 as a white solid (46.5 mg, 27% yield).
1H NMR: 400 MHz, CD3OD, δ (ppm): 7.35-7.27 (m, 5H), 3.00 (d, J = 16.70 Hz, 1 H), 2.89 (d, J = 16.71 Hz, 1 H), 2.82-2.78 (m, 1 H), 2.77-2.74 (m, 1 H), 2.69-2.64 (m, 2H), 2.49-2.42 (m, 1 H), 0.72-0.67 (m, 2H), 0.54-0.48 (m, 2H). LC-MS: rt = 1.20 min, MS: 365.1 (calcd), 366.1 (M+H+, found).
Example 53 2-Amino-6-(cyanomethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (83) and
Example 54 2-Amino-6-(2-amino-2-oxoethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (84)
Scheme 14
Figure imgf000127_0001
Step 1 . 2-Amino-6-(cyanomethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene- 3-carboxamide (83). A suspension of 81 (50.0 mg, 0.153 mmol) in anhydrous DMF (1.69 mL) was saturated with gaseous NH3. Then, PyBOP (120 mg, 0.230 mmol) and N,N-diisopropylethylamine (53.4 uL, 0.306 mmol) were added and the reaction mixture was stirred at RT for 16 hours. Afterwards, the mixture was partitioned between EA and a saturated aqueous solution of NH4CI. The layers were separated and the aqueous phase was extracted with EA. The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 20% to 100% of EA in hexane) then by reverse-phase flash column chromatography (eluent gradient from 0% to 100% CH3CN in H2O with 0.1% (v/v) formic acid) to afford title compound 83 as a white solid (47.0 mg, 94% yield).
1H NMR: 400 MHz, CD3OD, δ (ppm): 7.39-7.29 (m, 5H), 3.02-2.95 (m, 2H), 2.90 (d, J = 16.72 Hz, 1 H), 2.80 (ddd, J = 13.55, 4.09, 2.50 Hz, 1 H), 2.67 (ddd, J = 17.32, 11.78, 4.10 Hz, 1 H), 2.49 (ddd, J = 13.53, 11.79, 4.45 Hz, 1 H). LC-MS: rt = 1.01 min, MS: 325.1 (calcd), 326.0 (M+H+, found).
Step 2. 2-Amino-6-(2-amino-2-oxoethyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (84).
A suspension of 83 (47.0 mg, 0.144 mmol) in concentrated sulfuric acid (470 uL) was stirred at RT for 72 hours, then poured on crushed ice and the resulting mixture was basified using a 4 N NaOH solution. The solution was extracted with DCM. The organic extract was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 10% of MeOH in DCM, then 100% isopropanol) to afford title compound 84 as a white solid (17.5 mg, 35% yield).
1H NMR: 400 MHz, CD3OD, δ (ppm): 7.32-7.27 (m, 4H), 7.23-7.19 (m, 1 H), 2.99 (d, J = 14.78 Hz, 1 H), 2.92-2.87 (m, 1H), 2.78-2.71 (m, 1 H), 2.65 (d, J = 14.76 Hz, 2H), 2.60-5.50 (m, 1 H). LC-MS: rt = 0.84 min, MS: 343.1 (calcd), 344.1 (M+H+, found).
Example 55 2-Amino-6-(2-hydroxyethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylic acid (89).
Scheme 15
Figure imgf000129_0001
Step 1. Ethyl 2-amino-6-(2-hydroxyethyl)-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-
Figure imgf000129_0002
To a solution of 4-(2-hydroxyethyl)-4-phenylcyclohexan-1-one (85) (Bioorg. Med. Chem. Lett., 21 , p. 405, 2011) (7.95 g, 36.4 mmol) and ethyl 2-cyanoacetate (4.26 mL, 40.1 mmol) in EtOH (36.4 mL) were added morpholine (3.50 mL, 40.1 mmol) and sulfur (1.29 g, 5.03 mmol). The reaction mixture was stirred at 60 °C for 16 hours, then allowed to cool to RT and a white precipitate formed. This solid was collected by filtration, washed with EtOH and dried in vacuo to afford title compound 86 as a white solid (9.40 g, 72% yield). LC-MS: rt = 1.41 min, MS: 345.1 (calcd), 346.1 (M+H+, found).
Step 2. Ethyl 2-acetamido-6-(2-hydroxyethyl)-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (87).
To a solution of 86 (8.30 g, 24.0 mmol) in acetic acid (138 mL) was added acetic anhydride (2.73 mL, 28.8 mmol). The mixture was stirred at 60 °C for 2 hours, then allowed to cool to RT and concentrated to dryness to afford title compound 87 as a brown oil which was used directly for the next step. LC-MS: rt = 1.78 min, MS: 387.2 (calcd), 388.2 (M+H+, found).
Step 3. Ethyl 2-acetamido-6-(2-hydroxyethyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (88).
To a solution of 87 (24.0 mmol) in acetic acid (160 mL), water (160 mL) and dioxane (160 mL) was added ceric sulfate (69.0 g, 208 mmol). The mixture was sonicated until it became homogenous, stirred at RT for 24 hours and partitioned between EA and water. The layers were separated and the organic phase was washed with NaOH 1 N, water and brine. The organic layer was then dried over Na2SO4, filtered and concentrated to afford title compound 88 as an orange solid (9.60 g, 91% yield). LC-MS: rt = 1.56 min, MS: 401.1 (calcd), 402.1 (M+H+, found).
Step 4. 2-Amino-6-(2-hydroxyethyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (89).
To a suspension of 88 (9.60 g, 24.1 mmol) in MeOH (1.11 L) was added a solution of lithium hydroxide monohydrate (6.86 g, 163.4 mmol) in water (1.11 L). The reaction mixture was stirred at 55 °C for 24 hours, then allowed to cool to RT. The cooled mixture was diluted with water and concentrated to remove most of the organic solvent, then washed with EA. The aqueous layer was collected, acidified by slow addition of HCI 2 N and extracted with EA. This organic extract was dried over Na2SO4, filtered and concentrated to afford title compound 89 as an orange solid (7.0 g, 88% yield).
1H NMR: 400 MHz, CD3OD, δ (ppm): 7.29-7.16 (m, 5H), 3.53-3.38 (m, 2H), 3.20-3.12 (m, 1 H), 2.61-2.53 (dt, J = 13.63, 3.48 Hz, 1 H), 2.44 (ddd, J = 18.55, 11.61 , 4.01 Hz, 1 H), 2.34-2.23 (m, 1 H), 2.15-2.03 (m, 2H). LC-MS: rt = 1.04 min, MS: 331.1 (calcd), 332.0 (M+H+, found).
Example 56 2-Amino-7-oxo-5-propyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (91)
Scheme 16
Figure imgf000130_0001
Compound 90 (277 mg, 1.18 mmol, synthesized similarly to compound 3 in scheme 1 starting from 5-propyl-1 ,3-cyclohexanedione instead of 5-(2-(trifluoromethyl)phenyl)cyclohexane- 1 ,3-dione) was dissolved in H2SO4 98% (2.5 mL) and the mixture was stirred at RT for 24 hours. Then, the reaction mixture was slowly poured into ice-cold aqueous K2CO3, diluted with water and extracted with EA (Part of the product precipitated. It was collected by filtration and combined with the rest of the crude). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 50% to 100% of EA in hexane) to afford title compound 91 as an off-white solid (144 mg, 48% yield).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.97 (s, 2H), 6.96 (bs, 2H), 2.99-2.95 (m, 1 H), 2.67-2.57 (m, 1 H), 2.38-2.32 (m, 1 H), 2.19-2.07 (2H, m), 1.36 (bs, 4H), 0.88 (bs, 3H). LC-MS: rt = 2.30 min, MS: 252.1 (calcd), 253.1 (M+H+, found).
Example 57 2-Amino-6-(2,2-difluoroethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (97)
Scheme 17
Figure imgf000131_0001
97: Example 57
Step 1. 2-(8-Phenyl-1 ,4-dioxaspiro[4.51decan-8-yl)acetaldehvde (93)
To a solution of 2-(8-phenyl-1 ,4-dioxaspiro[4.5]decan-8-yl)acetonitrile (92) (1.0 g, 3.89 mmol) (Bioorg Med. Chem Lett. 21 , p. 405, 2011) in anhydrous toluene (24.5 mL) at -78 °C was added dropwise DIBALH (3.92 mL, 25% in toluene, 5.83 mmol). The reaction mixture was stirred at -78 °C for 2 hours, before being carefully quenched with MeOH and saturated NH4CI solution. Afterwards, the mixture was allowed to reach RT and diluted with Et2O, then filtered through a celite pad. The layers were separated and the organic phase was concentrated. The residue was dissolved in THF (15.0 mL) and HC1 1 N (3.89 mL 3.89 mmol) was added. The mixture was stirred at RT for 15 min, before being quenched with saturated NaHCO3 solution and extracted with Et2O. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 5% to 100% of EA in hexane) to afford title compound 93 (605 mg, 60% yield) as a colorless oil, which was not characterized and used directly for the next step.
Step 2. 8-(2,2-Difluoroethyl)-8-phenyl-1 ,4-dioxaspiro[4.51decane (94)
To a solution of 93 (200 mg, 0.77 mmol) in anhydrous DCM (9.5 mL) at 0 °C was added DAST (0.19 mL, 1.54 mmol). The reaction mixture was stirred at RT for 1 hour, then it was quenched with saturated NaHCO3 solution and extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated to afford title compound 94 (213 mg, 98% yield) as a colorless oil, which was not characterized and used directly for the next step.
Step 3. 4-(2,2-Difluoroethyl)-4-phenylcyclohexan-1-one (95) To a solution of 94 (213 mg, 0.75 mmol) in acetone (10.5 mL) was added HCI 2 N (1.89 mL, 3.77 mmol) and the reaction mixture was stirred at RT for 16 hours. Then, the mixture was neutralized by slowly adding saturated NaHCO3 solution and concentrated to remove the organic solvent. The residue was extracted with EA and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to dryness to afford title compound 95 (169 mg, 94% yield) as a colorless oil, which was not characterized and used directly for the next step.
Step 4. 2-Amino-6-(2,2-difluoroethyl)-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (96)
To a solution of 95 (169 mg, 0.709 mmol) and cyanoacetamide (66 mg, 0.78 mmol) in EtOH (0.7 mL) were added morpholine (0.068 mL, 0.78 mmol) and sulfur (25 mg, 0.098 mmol). The reaction mixture was stirred at 60 °C for 16 hours, then allowed to cool to RT and concentrated to dryness. The residue was partitioned between water and EA. The layers were separated and the organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 50% to 100% of EA in hexane) to afford title compound 96 (93 mg, 39% yield). LC-MS: rt = 1.39 min, MS: 336.1 (calcd), 337.1 (M+H+, found).
Step 5. 2-Amino-6-(2,2-difluoroethyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (97)
To a mixture of 96 (40 mg, 0.119 mmol) in THF (0.4 mL) and water (0.08 mL) at 0 °C was added dropwise a solution of DDQ (82 mg, 0.36 mmol) in THF (0.4 mL). The reaction mixture was stirred at 0 °C for 30 min, then the mixture was quenched with saturated NaHCO3 solution and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 50% to 100% of EA in hexane) to afford title compound 97 as a pale-yellow solid (3 mg, 7% yield).
1H NMR: 400 MHz, CDCI3, δ (ppm): 7.37-7.27 (m, 5H), 7.04 (s, 2H), 5.80 (tt, J = 56.4, 4.6, 1 H), 5.32 (s, 2H), 2.97-2.92 (m, 1 H), 2.83-2.78 (m, 1 H), 2.65-2.57 (m, 1 H), 2.53-2.42 (m, 3H). 19F NMR: 376 MHz, CDCI3, δ (ppm): -110.4 (ddt, J = 287.8, 56.1 , 18.0 Hz, 1 F), -111.5 (ddt, J = 287.8, 56.5, 16.3 Hz, 1 F). LC-MS: rt = 1.25 min, MS: 350.1 (calcd), 351.0 (M+H+, found).
Example 58 2-Amino-6-cyano-6-isopropyl-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (101)
Scheme 18
Figure imgf000133_0001
100 101 : Example 58
Step 1. 8-lsopropyl-1 ,4-dioxaspiro[4.51decane-8-carbonitrile (98)
To a solution of 1 ,4-dioxaspiro[4.5]decane-8-carbonitrile (40, scheme 4) (1.0 g, 5.98 mmol) in anhydrous THF (12.0 mL) at 0 °C was added dropwise LHMDS (6.88 mL, 1 M in THF, 6.88 mmol). The reaction mixture was stirred at 0 °C for 1 hour, before adding dropwise 2- iodopropane (0.597 mL, 5.98 mmol). Then, the reaction mixture was allowed to slowly reach RT and stirred for 16 hours. Afterwards, the reaction mixture was quenched with water and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated to dryness to afford title compound 98 as a brown solid, which was used directly for the next step. LC-MS: rt = 3.05 min, MS: 209.1 (calcd), 210.1 (M+H+, found).
Step 2. 1-lsopropyl-4-oxocyclohexane-1-carbonitrile (99)
To a solution of 98 (5.98 mmol) in acetone (80 mL) was added HCI 2 N (23.9 mL, 47.8 mmol) and the reaction mixture was stirred at RT for 2 days. Then, the mixture was neutralized by slowly adding saturated NaHCO3 solution and concentrated to remove the organic solvent. The residue was extracted with EA and the organic layer was dried over Na2SO4, filtered and concentrated to dryness to afford title compound 99 (445 mg, 45% yield over two steps). LC-MS: rt = 2.35 min, MS: 165.2 (calcd), 166.1 (M+H+, found).
Step 3. 2-Amino-6-cyano-6-isopropyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (100)
To a solution of 99 (445 mg, 2.69 mmol) and cyanoacetamide (206 mg, 2.45 mmol) in EtOH (4.9 mL) were added morpholine (0.24 mL, 2.69 mmol) and sulfur (87 mg, 0.338 mmol). The reaction mixture was stirred at 60 °C for 16 hours and an abundant precipitate appeared. This solid was collected by filtration to afford title compound 100 (477 mg, 74% yield) as a white solid. LC-MS: rt = 2.60 min, MS: 263.1 (calcd), 264.1 (M+H+, found).
Step 4. 2-Amino-6-cyano-6-isopropyl-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (101)
To a solution of 100 (100 mg, 0.38 mmol) in DMSO (2.25 mL) was added selenium dioxide (42 mg, 0.38 mmol). The reaction mixture was stirred at RT for 16 hours, then it was partitioned between brine and EA and the organic layer was concentrated. The residue was purified by flash column chromatography (eluent gradient from 0.5% to 10% of MeOH in DCM), then it was purified again by Semi-Prep HPLC-MS (eluent gradient from 30% to 100% of MeOH in 10 mM ammonium bicarbonate) to afford title compound 101 as a white solid (5.0 mg, 5% yield).
1H NMR: 400 MHz, CD3OD, δ (ppm): 3.18 (ddd, J = 17.9, 8.2, 5.1 Hz, 1 H), 3.06 (dt, J = 17.9, 5.4 Hz, 1 H), 2.50-2.39 (m, 3H), 1.12-1.08 (m, 6H). LC-MS: rt = 0.97 min, MS: 277.1 (calcd), 278.1 (M+H+, found).
Example 59
2-Amino-6-(hydroxymethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (109)
Scheme 19
Figure imgf000134_0001
Step 1. 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-Dhenylcyclohexan-1-one (103)
To a solution of 4-(hydroxymethyl)-4-phenylcyclohexan-1-one (102) (Bioorg. Med. Chem. Lett., 21 , p. 405, 2011) (890 mg, 4.36 mmol) in anhydrous DMF (40 mL) were added tert- butyldimethylsilyl chloride (737 mg, 4.79 mmol) and imidazole (653 mg, 9.59 mmol). The resulting mixture was stirred at RT for 16 hours, then diluted with water (30 mL) and extracted with EA (70 mL). The organic phase was dried over Na2SO4, filtered and concentrated, and the residue was purified by flash column chromatography (eluent gradient from 0% to 20% of EA in hexane) to afford title compound 103 as a white solid (1.20 g, 86% yield), which was not characterized and used directly for the next step.
Step 2. Ethyl 2-amino-6-(((tert-butyldimethylsilyl)oxy)methyl)-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (104) A suspension of 103 (1.20 g, 3.77 mmol), morpholine (330 uL, 3.77 mmol), sulfur (121 mg, 473 umol) and ethyl 2-cyanoacetate (364 uL, 3.42 mmol) in EtOH (6.01 mL) was stirred at 60 °C for 16 hours. The mixture was then allowed to cool to RT and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 100% of EA in hexane) to afford title compound 104 as an off-white solid (1.49 g, 97% yield). LC-MS: rt = 2.34 min, MS: 445.2 (calcd), 446.2 (M+H+, found).
Step 3. Ethyl 2-((tert-butoxycarbonyl)amino)-6-(((ferf-butyldimethylsilyl)oxy)methyl)-6- phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (105)
To a solution of 104 (1.49 g, 3.34 mmol), DMAP (41.7 mg, 334 umol) and triethylamine (699 uL, 5.01 mmol) in DCM (66.8 mL) at 0 °C was added dropwise a solution of di-tert- butyldicarbonate (802 mg, 3.68 mmol) in DCM. The resulting mixture was stirred at RT for 16 hours, then quenched with saturated aqueous NH4CI solution. The layers were separated and the aqueous phase was extracted with DCM. The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 100% of EA in hexane) to afford title compound 105 as an off-white solid (1.66 g, 91% yield). LC-MS: rt = 2.63 min, MS: 545.3 (calcd), 546.0 (M+H+, found).
Step 4. Ethyl 2-((terf-butoxycarbonyl)amino)-6-(((tert-butyldimethylsilyl)oxy)methyl)-7- oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (106)
A suspension of pyridinium chlorochromate (4.50 g, 20.9 mmol), celite (1.50 g) and 105 (1 .50 g, 2.75 mmol) in anhydrous benzene (40.7 mL) was stirred at 80 °C for 4 hours. The mixture was then allowed to cool to RT, filtered through a pad of celite and the solid residue was washed with CHCl3. The filtrate was concentrated, and the residue was purified by flash column chromatography (eluent gradient from 0% to 30% of EA in hexane) to afford title compound 106 as a white solid (395 mg, 26% yield). LC-MS: rt = 2.52 min, MS: 559.2 (calcd), 560.2 (M+H+, found).
Step 5. 2-((tert-Butoxycarbonyl)amino)-6-(((tert-butyldimethylsilyl)oxy)methyl)-7-oxo-6- phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (107)
To a solution of 106 (380 mg, 679 umol) in EtOH (20.0 mL) was added a solution of NaOH (136 mg, 3.39 mmol) in water (20.0 mL). The resulting mixture was sonicated for 1 min and then vigorously stirred at RT for 68 hours. Subsequently, the mixture was diluted with water (15 mL) and extracted with EA (3 x 30 mL). The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 50% of EA in hexane, then from 0% to 30% of MeOH in DCM) to afford title compound 107 as a white solid (264 mg, 73% yield). LC-MS: rt = 1.60 min, MS: 531.2 (calcd), 532.1 (M+H+, found).
Step 6. 2-Amino-6-(hydroxymethyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (108) Trifluoroacetic acid (5.99 mL, 78.2 mmol) was added dropwise to a solution of 107 (260 mg, 489 umol) in DCM (30.0 mL) at 0 °C. The mixture was stirred at 0 °C for 2 hours, then the reaction vessel was removed from the ice bath and stirring continued at RT for another 2 hours.
The mixture was then concentrated, the residue was taken up in DCM and concentrated 3 times, then purified by flash column chromatography (eluent gradient from 0% to 13% of MeOH in DCM) to afford title compound 108 as a light-yellow solid (80 mg, 52% yield). (See table 6 for characterization)
Step 7. 2-Amino-6-(hydroxymethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (109)
To a suspension of 108 (54.0 mg, 170 umol), ammonium chloride (182 mg, 3.40 mmol) and HATU (97.0 mg, 255 umol) in DMF (4.00 mL) was added dropwise N,N-diisopropylethylamine (59.3 uL, 340 umol). The mixture was stirred at RT for 16 hours, then another 97 mg of HATU (255 umol) were added and stirring continued for 1 hour. The mixture was diluted with saturated aqueous NH4CI solution and extracted with EA (3 x 20 mL). The combined organics were washed successively with brine (3 x 20 mL) and 0.05 N aqueous HCI, then concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 15% of MeOH in DCM), then it was purified again by reverse-phase flash column chromatography (eluent gradient from 10% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid) to afford title compound 109 as an off-white solid (17.2 mg, 32% yield).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.06 (s, 2H) 7.32-7.27 (m, 4H), 7.23-7.20 (m 1 H), 6.88 (bs, 2H), 4.77 (t, J = 5.5 Hz, 1 H), 3.92 (dd, J = 10.4, 5.6 Hz, 1 H), 3.35-3.32 (m, 1 H), 2.89- 2.84 (m, 1H), 2.73-2.67 (m, 1 H), 2.50-2.48 (m, 1H, partially overlapping with the solvent signal). LC-MS: rt = 0.88 min, MS: 316.1 (calcd), 317.0 (M+H+, found).
Examples 60-67 Intermediate compound 111
1 -Benzyl-4-oxocyclohexane-1 -carbonitrile (111)
Scheme 20
Figure imgf000136_0001
Scheme 4
Step 1. 8-Benzyl-1 ,4-dioxaspiro[4.51decane-8-carbonitrile (110). To a solution of 40 (scheme 4) (1.0 g, 5.98 mmol) in anhydrous THF (24.0 mL) at -78 °C was added dropwise LDA (6.58 mL, 1 M in THF/hexane, 6.58 mmol). The reaction mixture was stirred at -78 °C for 45 min then benzyl bromide (0.870 mL, 7.18 mmol) was added dropwise. The reaction mixture was allowed to reach RT and stirred for 2.5 hours. Afterwards, the reaction mixture was quenched with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 30% of EA in hexane) to afford title compound 110 (1.22 g, 79% yield) as a white solid, which was not characterized and used directly for the next step.
Step 2. 1-Benzyl-4-oxocyclohexane-1-carbonitrile (111).
To a solution of 110 (1.21 g, 4.70 mmol) in acetone (63 mL) was added HCI 2 N (11.8 mL, 23.5 mmol) and the reaction mixture was stirred at RT for 16 hours. Then, the mixture was neutralized by slowly adding saturated NaHCO3 solution and concentrated to remove the organic solvent. The residue was extracted with EA and the organic layer was dried over Na2SO4, filtered and concentrated to dryness to afford title compound 111 (1 .00 g, >99% yield). LC-MS: rt = 2.93 min, MS: 213.1 (calcd), 214.1 (M+H+, found).
Intermediate compound 115 2-(8-(Cyclopropylmethyl)-1,4-dioxaspiro[4.5]decan-8-yl)ethan-1-ol (115) Scheme 21
Figure imgf000137_0001
Step 1. 8-(Cyclopropylmethyl)-1 ,4-dioxaspiro[4.51decane-8-carbaldehvde (113)
Diisobutylaluminum hydride (25% solution in toluene; 121 mL, 180.0 mmol) was added dropwise to a solution of 8-(cyclopropylmethyl)-1 ,4-dioxaspiro[4.5]decane-8-carbonitrile (112) (24.3 g, 110 mmol) (ACS Med. Chem. Lett. 2010, 350-354) in anhydrous toluene (600 mL) at -78 °C and the resulting mixture was stirred at -78 °C for 2 hours. The reaction mixture was then quenched with methanol (15 mL) at -78 °C and partitioned between saturated aqueous NH4CI solution (200 mL) and diethyl ether (300 mL). The mixture was allowed to slowly reach RT and a saturated aqueous solution of Rochelle’s salt (1 L) was added. The layers were separated and the organic phase was washed with brine (2 x 200 mL), dried over Na2SO4, filtered and concentrated. The residue was dissolved in THF (400 mL) and treated with 2 N aqueous HCI (27.5 mL, 54.9 mmol). The mixture was stirred at RT for 1 hour, then quenched with saturated aqueous NaHCO3 and concentrated to remove the organic solvent. The aqueous residue was extracted with diethyl ether and the organics were dried over Na2SO4, filtered and concentrated to afford title compound 113 as a colorless oil (24.6 g, >99% yield), which was not characterized and used directly for the next step.
Step 2. 8-(Cyclopropylmethyl)-8-vinyl-1 ,4-dioxaspiro[4.5]decane (114)
To a 1 M solution of LHMDS in THF (10 mL, 10.0 mmol) diluted with anhydrous THF (55.0 mL) at 60 °C was added methyltriphenylphosphonium bromide (2.23 g, 6.24 mmol) in 4 portions over 30 minutes. The reaction mixture was stirred at 60 °C for 1 hour after the last addition. Then,
113 (700 mg, 3.12 mmol) in anhydrous THF (10.0 mL) was added dropwise and the reaction mixture was stirred at 60 °C for another 30 minutes. The mixture was then allowed to cool to RT, quenched with a saturated solution of NH4CI (40 mL) and extracted 2 times with EA (2 x 50 mL). The combined organics were dried over Na2SO4, filtered and concentrated and the residue was purified by flash column chromatography (eluent gradient from 0% to 30% of Et2O in hexane) to afford title compound 114 as a colorless oil (527 mg, 76% yield), which was not characterized and used directly for the next step.
Step 3. 2-(8-(Cyclopropylmethyl)-1 ,4-dioxaspiro[4.51decan-8-yl)ethan-1-ol (115)
To a solution of 114 (520 mg, 2.34 mmol) in anhydrous THF (12 mL) at 0 °C was added dropwise 9-BBN (9.35 mL, 0.5 M in THF, 4.68 mmol). The reaction mixture was stirred at RT for 2.5 hours, then it was cooled to 0 °C again and water (42 uL, 2.34 mmol), NaOH 1 N (7.0 mL, 7.0 mmol) and H2O2 30% (12 mL) were added. The reaction mixture was stirred at 0 °C for 10 min, then it was stirred at RT for 16 hours. Afterwards, the mixture was diluted with EA and water. The layers were separated, and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 30% to 100% of EA in hexane) to afford title compound 115 as a colorless oil (479 mg, 85% yield), which was not characterized and used directly for the synthesis of relevant examples.
Intermediate compound 118
2-(8-(Cyclopropylmethyl)-1,4-dioxaspiro[4.5]decan-8-yl)acetonitrile (118)
Scheme 22
Figure imgf000138_0001
Step 1. (8-(Cyclopropylmethyl)-1 ,4-dioxaspiro[4.51decan-8-yl)methanol (116)
Sodium borohydride (816 mg, 21.1 mmol) was added to a solution of 113 (scheme 21) (3.16 g, 14.1 mmol) in MeOH (86.8 mL) at 0 °C. The resulting solution was stirred at RT for 1 hour, then the reaction mixture was quenched with saturated aqueous NH4CI solution (30 mL). The mixture was diluted with EA (30 mL), the layers were separated, and the aqueous layer was extracted with EA (30 mL). The combined organics were washed with 0.2 N HCI (50 mL) and brine, then dried over Na2SO4, filtered and concentrated to afford title compound 116 (2.95 g, 93% yield) as a colorless oil, which was not characterized and used directly for the next step.
Step 2. (8-(Cyclopropylmethyl)-1 ,4-dioxaspiro[4.51decan-8-yl)methyl 4- methylbenzenesulfonate (117)
To a solution of 116 (2.70 g, 11.9 mmol) in pyridine (51.9 mL) was added p- toluenesulfonyl chloride (7.96 g, 41.8 mmol) and the resulting mixture was stirred at RT for 16 hours. The mixture was then diluted with EA and water (30 mL each) and the layers were separated. The aqueous phase was extracted with EA (30 mL) and the combined organics were washed with water (30 mL) and brine (2 x 30 mL), then dried over Na2SO4, filtered and concentrated. The residue was diluted with heptanes and concentrated to dryness, then purified by flash column chromatography (eluent gradient from 0% to 40% of EA in hexane) to afford title compound 117 (3.65 g, 80% yield) as a colorless oil. LC-MS: rt = 1.78 min. MS: 380.2 (calcd), 381.3 (M+H+, found).
Step 3. 2-(8-(Cyclopropylmethyl)-1 ,4-dioxaspiro[4.5]decan-8-yl)acetonitrile (118)
To a solution of 117 (3.65 g, 9.59 mmol) in DMSO (57.1 mL) was added sodium cyanide (1 .41 g, 28.8 mmol) and the resulting mixture was stirred at 60 °C for 96 hours. The mixture was allowed to cool to RT and diluted with saturated aqueous NaHCO3 solution (50 mL). The mixture was then diluted with EA (50 mL) and water (40 mL), the layers were separated and the aqueous phase was extracted with EA (2 x 50 mL). The combined organics were washed with water (2 x 30 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated to afford title compound 118 (2.5 g, 72% yield) as a yellow oil, which was not characterized and used directly for the synthesis of relevant examples.
Compounds 119-126
Compounds 119-123 (examples 60-64) were synthesized similarly to compound 81 (example 51 , scheme 13) starting from 4-methyl-4-phenylcyclohexan-1-one, compound 111 (scheme 20), compound 73 (scheme 12), compound 95 (scheme 17), and compound 99 (scheme 18), respectively, instead of 2-(4-oxo-1-phenylcyclohexyl)acetonitrile (76). Compounds 124-126 (examples 65-67) were synthesized similarly to compound 47 (example 28, scheme 4) starting from compound 115 (scheme 21), compound 116 (scheme 22), and compound 118 (scheme 22), respectively, instead of compound 41. Characterization of compounds 119-126 (examples 60-67) is provided in the table 4. Table 4. Characterization of compounds 119-126 (examples 60-67).
Figure imgf000140_0001
Figure imgf000141_0001
Examples 68-77
Compounds 127-133 (examples 68-74) were synthesized similarly to compound 82 (example 52, scheme 13) starting from compounds 119-125 (examples 60-66, table 4), respectively, instead of compound 81. Compounds 134-135 (examples 75-76) were synthesized similarly to compound 9 (example 2, scheme 2) starting from compound 126 (example 67, table 4) and compound 89 (example 55, scheme 15), respectively, instead of compound 8. Compound 136 (example 77) was synthesized similarly to compound 82 (example 52, scheme 13) starting from compound 108 (scheme 19) instead of compound 81. Characterization of compounds 127-
136 (examples 68-77) is provided in the table 5.
Table 5. Characterization of compounds 127-136 (examples 68-77).
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Example 78 2-Amino-6-(2-cyanoethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylic acid (138) and
Example 79 2-Amino-6-(3-amino-3-oxopropyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylic acid (139)
Scheme 23
Figure imgf000145_0001
To a solution of 137 (1 .0 g, 2.71 mmol, synthesized similarly to compound 80 in scheme 13 starting from 3-(4-oxo-1-phenylcyclohexyl)propanenitrile (Bioorg Med. Chem Lett. 21 , p. 405, 2011) instead of 2-(4-oxo-1-phenylcyclohexyl)acetonitrile (76)) in MeOH (330 mL) was added a solution of lithium hydroxide monohydrate (569 mg, 13.6 mmol) in water (330 mL). The reaction mixture was stirred at 80 °C for 16 hours, then allowed to cool to RT. The mixture was concentrated to remove most of the organic solvent. The aqueous layer was acidified by slowly adding HCI 1 N and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 30% of MeOH in DCM) to afford title compound 138 as a yellow solid (648 mg, 70% yield) and title compound 139. The latter was purified again by Semi-Prep HPLC-MS (eluent gradient from 15% to 100% of MeOH in 10 mM ammonium bicarbonate) to afford a white solid (142 mg, 15% yield).
138: 1H NMR: 400 MHz, DMSO-d6, δ (ppm): 12.51 (bs, 1 H), 8.28 (s, 2H), 7.36-7.32 (m, 2H), 7.27-7.24 (m, 3H), 3.15-3.09 (m, 1 H), 2.60-2.55 (m, 1 H), 2.48-2.42 (m, 1 H), 2.38-2.30 (m, 1 H), 2.26-2.18 (m, 2H), 2.12-2.07 (m, 2H). LC-MS: rt = 1.23 min, MS: 340.1 (calcd), 341 .1 (M+H+, found).
139: 1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.30 (bs, 2H), 7.33-7.26 (m, 4H), 7.23-7.19 (m, 1H), 7.18 (s, 1H), 6.62 (s, 1 H), 3.20-3.15 (m, 2H), 2.45-2.37 (m, 1 H), 2.16-2.07 (m, 1 H), 2.00- 1.91 (m, 4H). LC-MS: rt = 0.98 min, MS: 358.1 (calcd), 359.1 (M+H+, found).
Example 80 2-Amino-6-(2-cyanoethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (140)
Scheme 24
Figure imgf000145_0002
To a suspension of 138 (500 mg, 1.47 mmol) and ammonium chloride (1.57 g, 29.4 mmol) in anhydrous DMF (16.2 mL) were added HATU (855 mg, 2.20 mmol) and N,N- diisopropylethylamine (0.512 mL, 2.94 mmol). Then, saturated NH3 solution in CHCl3 (8.7 mL) (prepared in-house) and NH3 0.4 M solution in THF (9.2 mL) were added dropwise and the reaction mixture was stirred at RT for 16 hours. Afterwards, the reaction mixture was quenched with a saturated NH4CI solution and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by reverse-phase flash column chromatography (eluent gradient from 0% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid) to afford title compound 140 as a white solid (419 mg, 84% yield).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.13 (s, 2H), 7.37-7.24 (m, 5H), 6.88 (bs, 2H), 2.91-2.84 (m, 1 H), 2.68-2.56 (m, 2H), 2.46-2.42 (m, 1 H), 2.25-2.17 (m, 2H), 2.13-2.07 (m, 2H). LC-MS: rt = 1.10 min, MS: 339.1 (calcd), 340.1 (M+H+, found).
Example 81 2-Amino-6-(2-cyanoethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (141)
Figure imgf000146_0001
Compound 141 (example 81) was synthesized similarly to compound 62 (example 39, scheme 10) starting from compound 140 (example 80, scheme 24) instead of compound 61. 1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.08 (s, 2H), 7.35-7.21 (m, 5H), 7.17 (s, 1 H), 6.87 (bs, 2H), 6.63 (s, 1 H), 2.91-2.84 (m, 1 H), 2.73-2.65 (m, 1 H), 2.55-2.53 (m, 1 H), 2.20-2.12 (m, 1 H), 2.02-1.90 (m, 4H). LC-MS: rt = 0.88 min, MS: 357.1 (calcd), 358.2 (M+H+, found).
Example 82 (S)-2-Amino-6-(3-amino-3-oxopropyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (142) and Example 83 (R)-2-Amino-6-(3-amino-3-oxopropyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (143)
Scheme 25
Figure imgf000146_0002
100.3 mg of racemic compound 141 were submitted to SFC Chiral Separation to afford enantioenriched title compound 142 as a white solid (29.9 mg, 30% separation yield) and enantioenriched title compound 143 as a white solid (26.2 mg, 26% separation yield). Absolute configurations of compounds 142 and 143 were assigned based on analogy with the assignment of the absolute configuration of a crystallized compound within the same or similar series.
142: 1H NMR: same as racemic mixture (141). LC-MS: rt = 0.88 min, MS: 357.1 (calcd), 358.2 (M+H+, found). Analytical SFC (IC column with 5-60% MeOH + 10mM AmFor (95-40% CO2) gradient): rt = 5.80 min, ee. = 99.76%.
143: 1H NMR: same as racemic mixture (141). LC-MS: rt = 0.88 min, MS: 357.1 (calcd), 358.2 (M+H+, found). Analytical SFC (IC column with 5-60% MeOH + 10mM AmFor (95-40% CO2) gradient): rt = 6.45 min, ee. = 97.82%.
Example 84 2-Amino-6-(2-cyanoethyl)-N-cyclopropyl-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (144) and Example 85 2-Amino-6-(3-amino-3-oxopropyl)-N-cyclopropyl-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (145)
Scheme 26
Figure imgf000147_0001
Compound 144 (example 84) was synthesized similarly to compound 82 (example 52, scheme 13) starting from compound 138 (example 78, scheme 23) instead of compound 81.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.87 (s, 2H), 7.37-7.25 (m, 6H), 2.74-2.52 (m, 4H), 2.48-2.41 (m, 1 H), 2.24-2.07 (m, 4H), 0.64-0.57 (m, 2H), 0.50-0.43 (m, 2H). LC-MS: rt = 1 .27 min, MS: 379.1 (calcd), 380.2 (M+H+, found).
To a suspension of 144 (35 mg, 0.092 mmol) and K2CO3 (26 mg, 0.18 mmol) in MeOH (1 .8 mL) and water (0.6 mL) was added H2O230% (0.09 mL). The reaction mixture was vigorously stirred at RT for 2 days. Then, more H2O2 30% (0.19 mL) was added and the reaction mixture was vigorously stirred at RT for another 24 hours. Afterwards, the mixture was concentrated to remove the organic solvent and the residue was extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated to afford title compound 145 as an off-white solid (17 mg, 46% yield). 1H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.81 (s, 2H), 7.35-7.21 (m, 6H), 7.17 (bs, 1 H), 6.63 (bs, 1 H), 2.77-2.59 (m, 3H), 2.50-2.48 (m, 1 H), 2.16-2.08 (m, 1 H), 2.01-1.90 (m, 4H), 0.64-0.58 (m, 2H), 0.50-0.45 (m, 2H). LC-MS: rt = 1.05 min, MS: 397.2 (calcd), 398.3 (M+H+, found).
Example 86
2-Amino-6-methyl-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (146)
Scheme 27
Figure imgf000148_0001
Table 4
Compound 119 (table 4) (50 mg, 0.17 mmol) was dissolved in a NH30.4 M solution in THF (17 mL) and HATU (126 mg, 0.33 mmol) and N,N-diisopropylethylamine (0.058 mL, 0.33 mmol) were added to the mixture. Then, the reaction mixture was stirred at RT for 16 hours. Afterwards, the reaction mixture was quenched with a saturated NH4CI solution and extracted with EA. The organic layer was washed with water and brine, then dried over Na3SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 40% to 100% of EA in hexane), then it was purified again by Semi-Prep HPLC-MS (eluent gradient from 35% to 100% of CH3CN in 10 mM ammonium bicarbonate) to afford title compound 146 as a white solid (22 mg, 44% yield).
1H NMR: 400 MHz, CD3OD, δ (ppm): 7.32-7.28 (m, 4H), 7.24-7.19 (m, 1 H), 2.95-2.89 (m, 1 H), 2.68-2.58 (m, 2H), 2.28-2.21 (m, 1H), 1.48 (s, 3H). LC-MS: rt = 1.13, MS: 300.1 (calcd), 301.1 (M+H+, found).
Example 87
2-Amino-6-benzyl-6-cyano-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide
Figure imgf000148_0002
To a suspension of 120 (table 4) (50 mg, 0.153 mmol) and ammonium chloride (164 mg, 3.06 mmol) in anhydrous THF (2.0 mL) were added HATU (87 mg, 0.230 mmol) and N,N- diisopropylethylamine (0.053 mL, 0.306 mmol). Then, saturated NH3 solution in CHCI3 (0.25 mL) (prepared in-house) was added dropwise and the reaction mixture was stirred at RT for 16 hours. Afterwards, the reaction mixture was quenched with a saturated NH4CI solution and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by reverse-phase flash column chromatography (eluent gradient from 0% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid) to afford title compound 147 as a white solid (35 mg, 70% yield).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.34 (bs, 2H), 7.40-7.30 (m, 5H), 7.13 (bs, 2H), 3.25-3.16 (m, 2H), 3.10-2.98 (m, 2H), 2.23-2.16 (m, 1 H), 2.11-2.04 (m, 1 H). LC-MS: rt = 1.15 min, MS: 325.1 (calcd), 326.1 (M+H+, found).
Example 88 2-Amino-6-(cyclopropylmethyl)-6-(2-hydroxyethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (148)
Figure imgf000149_0001
148: Example 88
Compound 148 (example 88) was synthesized similarly to compound 140 (example 80, scheme 24) starting from compound 124 (table 4) instead of compound 138.
1H NMR: 400 MHz, CD3OD, δ (ppm): 3.67-3.56 (m, 2H), 3.03 (t, J = 6.1 Hz, 2H), 2.28 (dt, J = 13.8, 5.9 Hz, 1 H), 2.17-2.10 (m, 1 H), 2.05 (ddd, J = 13.7, 8.9, 6.1 Hz, 1 H), 1.85 (ddd, J = 13.7, 8.9, 6.2 Hz, 1 H), 1.74 (dd, J = 14.1 , 6.1 Hz, 1 H), 1.41 (dd, J = 14.2, 7.2 Hz, 1H), 0.74-0.64 (m, 1 H), 0.50-0.42 (m, 2H), 0.11-0.00 (m, 2H). LC-MS: rt = 0.92 min, MS: 308.1 (calcd), 309.2 (M+H+, found).
Example 89 2-Amino-6-(cyclopropylmethyl)-6-(hydroxymethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (149)
Figure imgf000149_0002
149: Example 89
Compound 149 (example 89) was synthesized similarly to compound 140 (example 80, scheme 24) starting from compound 125 (table 4) instead of compound 138. 1H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.97 (s, 2H), 6.92 (bs, 2H), 4.54 (t, J = 5.4 Hz, 1 H), 3.71 (dd, J = 10.5, 5.5 Hz, 1 H), 3.39 (dd, J = 10.5, 5.3 Hz, 1 H), 3.03-2.87 (m, 2H), 2.17-
2.10 (m, 1 H), 2.07-2.01 (m, 1 H), 1.54 (dd, J = 14.0, 6.5 Hz, 1 H), 1.32 (dd, J = 14.0, 7.0 Hz, 1 H), 0.64-0.55 (m, 1 H), 0.40-0.32 (m, 2H), 0.07-0.01 (m, 1 H), -0.05 - -0.09 (m, 1 H). LC-MS: rt = 0.88 min, MS: 294.1 (calcd), 295.0 (M+H+, found).
Example 90 2-Amino-6-(cyanomethyl)-6-(cyclopropylmethyl)-7 -oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (150)
Figure imgf000150_0001
150: Example 90
Compound 150 (example 90) was synthesized similarly to compound 109 (example 59, scheme 19) starting from compound 126 (table 4) instead of compound 108.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.06 (s, 2H), 6.97 (bs, 2H), 3.16-3.03 (m, 1 H), 2.99-2.81 (m, 3H), 2.16-2.02 (m, 2H), 1.60-1.44 (m, 2H), 0.66-0.57 (m, 1 H), 0.47-0.35 (m, 2H), 0.13-0.07 (m, 1H), -0.01 - -0.07 (m, 1 H). LC-MS: rt = 0.94 min. MS: 303.1 (calcd), 304.0 (M+H+, found).
Example 91 2-Amino-7-oxo-4,7-dihydro-5H-spiro[benzo[b]thiophene-6,1'-cyclopentane]-3- carboxamide (155)
Scheme 29
Figure imgf000150_0002
Step 1. Ethyl 2-amino-4,7-dihydro-5H-spiro[benzo[b]thiophene-6,1'-cyclopentanel-3- carboxylate (152)
To a solution of spiro[4.5]decan-8-one (151) (199 mg, 1.31 mmol) and ethyl 2- cyanoacetate (0.139 mL, 1.31 mmol) in EtOH (1.3 mL) were added morpholine (0.126 mL, 1.44 mmol) and sulfur (46 mg, 0.18 mmol). The reaction mixture was stirred at 60 °C for 16 hours, then allowed to cool to RT and concentrated to dryness. The residue was purified by flash column chromatography to afford title compound 152 (270 mg, 74% yield). LC-MS: rt = 1.98 min, MS:
279.1 (calcd), 280.1 (M+H+, found).
Step 2. Ethyl 2-amino-7-oxo-4,7-dihydro-5H-spiro[benzo[b]thiophene-6, 1'-cyclopentane1- 3-carboxylate (153)
To a mixture of 152 (100 mg, 0.358 mmol) in THF (1.2 mL) and water (0.2 mL) at 0 °C was added dropwise a solution of DDQ (81 mg, 0.358 mmol) in THF (1.0 mL) and the reaction mixture was stirred at 0 °C for 30 min. Then, the reaction mixture was quenched with saturated NaHCO3 solution and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography to afford title compound 153 (15 mg, 14% yield). LC-MS: rt = 1.63 min, MS: 293.1 (calcd), 294.1 (M+H+, found).
Step 3. 2-Amino-7-oxo-4,7-dihydro-5H-spiro[benzo[b]thiophene-6, 1 '-cyclopentanel-3- carboxylic acid (154)
To a solution of 153 (15 mg, 0.051 mmol) in MeOH (1.1 mL) was added a solution of lithium hydroxide monohydrate (7 mg, 0.283 mmol) in water (1.1 mL). The reaction mixture was stirred under reflux for 16 hours, then allowed to cool to RT. The mixture was diluted with water and concentrated to remove most of the organic solvent. The aqueous layer was acidified by slowly adding HCI 1 N and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated to afford title compound 154 as a white solid (6 mg, 44% yield). (See table 6 for characterization)
Step 4. 2-Amino-7-oxo-4,7-dihydro-5H-spiro[benzo[b]thiophene-6, 1 '-cyclopentanel-3- carboxamide (155)
Compound 154 (6 mg, 0.023 mmol) was dissolved in a NH3 0.4 M solution in THF (1.5 mL) and HATU (17 mg, 0.045 mmol) and N,N-diisopropylethylamine (0.008 mL, 0.045 mmol) were added to the mixture. Then, the reaction mixture was stirred at RT for 16 hours. Afterwards, the reaction mixture was quenched with a saturated NH4CI solution and extracted with EA. The organic layer was washed with water and brine, then dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography to afford title compound 155 as a white solid (3.7 mg, 62% yield).
1H NMR: 400 MHz, CD3OD, δ (ppm): 2.99 (t, J = 6.0 Hz, 2H), 2.06 (t, J = 6.0 Hz, 2H), 2.03-1 .97 (m, 2H), 1 .79-1.68 (m, 4H), 1 .62-1 .56 (m, 2H). LC-MS: rt = 1 .07 min, MS: 264.1 (calcd),
265.1 (M-H+, found).
Example 92 2-Amino-6-(3-hydroxypropyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (163)
Scheme 30
Figure imgf000152_0001
Step 1. 3-(8-Phenyl-1 ,4-dioxaspiro[4.5]decan-8-yl)propanoic acid (157)
To a solution of 3-(8-phenyl-1 ,4-dioxaspiro[4.5]decan-8-yl)propanenitrile (156) (2.30 g, 8.48 mmol) (Bioorg Med. Chem Lett. 21 , p. 405, 2011) in ethylene glycol (40.0 mL) were added potassium hydroxide (3.80 g, 67.8 mmol) and water (0.030 mL, 1.70 mmol). The reaction mixture was stirred at 170 °C for 16 hours, then allowed to cool to RT and diluted with water and DCM. The layers were separated and the aqueous phase was acidified by slowly adding HCI 2 N and extracted with DCM. This organic layer was dried over MgSO4, filtered and concentrated to afford title compound 157 (2.03 g, 82% yield) as a brown solid. LC-MS: rt = 0.84 min, MS: 290.2 (calcd), 289.2 ([M-H] , found).
Step 2. Methyl 3-(8-phenyl-1 ,4-dioxaspiro[4.51decan-8-yl)propanoate (158)
To a solution of 157 (1.30 g, 4.48 mmol) in anhydrous DMF (10.0 mL) at 0 °C were added potassium carbonate (1.86 g, 13.4 mmol) and iodomethane (0.418 mL, 6.72 mmol). The reaction mixture was stirred at RT for 16 hours, then diluted with water and extracted with Et2O. This organic layer was washed with brine and dried over MgSO4, filtered and concentrated to afford title compound 158 (1.35 g, 99% yield) as an oil. LC-MS: rt = 1.53 min, MS: 304.2 (calcd), 305.2 (M+H+, found).
Step 3. 3-(8-Phenyl-1 ,4-dioxaspiro[4.5]decan-8-yl)propan-1-ol (159)
To a solution of lithium aluminum hydride (6.25 mL, 1 M in THF, 6.25 mmol) in anhydrous THF (7.0 mL) at 0 °C was added dropwise a solution of 158 (865 mg, 2.84 mmol) in anhydrous THF (10.0 mL). The reaction mixture was stirred at 0 °C for 1 hour, before being carefully quenched with MeOH and water at 0 °C. Then, the mixture was diluted with EA and saturated Rochelle’s salt solution and stirred at RT for 30 min. The layers were separated and the aqueous phase was extracted with EA. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 70% of EA in hexane) to afford title compound 159 (760 mg, 97% yield) as a yellow oil. LC- MS: rt = 1.28 min, MS: 276.2 (calcd), 277.2 (M+H+, found).
Step 4. 4-(3-Hydroxypropyl)-4-phenylcyclohexan-1-one (160)
To a solution of 159 (368 mg, 1.33 mmol) in acetone (18.0 mL) was added HCI 2 N (3.33 mL, 6.66 mmol) and the reaction mixture was stirred at RT for 16 hours. Then, the mixture was neutralized by slowly adding saturated aqueous NaHCO3 solution and concentrated to remove the organic solvent. The residue was extracted with EA and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to dryness to afford title compound 160 (289 mg, 94% yield) as a yellow oil, which was not characterized and used directly for the next step.
Step 5. 4-(3-((tert-Butyldimethylsilyl)oxy)propyl)-4-phenylcyclohexan-1-one (161)
To a solution of 160 (196 mg, 0.84 mmol) in anhydrous DMF (4.2 mL) were added tert- butyldimethylsilyl chloride (162 mg, 1.08 mmol) and imidazole (144 mg, 2.11 mmol). The reaction mixture was stirred at RT for 16 hours, then it was diluted with water and EA. The layers were separated and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 30% of EA in hexane) to afford title compound 161 (259 mg, 89% yield) as a pale-yellow oil which was not characterized and used directly for the next step.
Step 6. 2-Amino-6-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (162)
To a solution of 161 (259 mg, 0.747 mmol) and cyanoacetamide (57 mg, 0.679 mmol) in EtOH (1 .4 mL) were added morpholine (0.065 mL, 0.747 mmol) and sulfur (24 mg, 0.093 mmol). The reaction mixture was stirred at 60 °C for 16 hours, allowed to cool to RT and concentrated to dryness. The residue was purified by flash column chromatography (eluent gradient from 0% to 10% of MeOH in DCM) to afford title compound 162 (200 mg, 60% yield). LC-MS: rt = 2.07 min, MS: 444.2 (calcd), 445.3 (M+H+, found).
Step 7. 2-Amino-6-(3-hydroxypropyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (163)
To a mixture of 162 (200 mg, 0.450 mmol) in THF (1.5 mL) and water (0.25 mL) at 0 °C was added dropwise a solution of DDQ (306 mg, 1.35 mmol) in THF (1.25 mL). The reaction mixture was allowed to slowly reach RT and stirred for 16 hours. Then, the mixture was quenched with saturated NaHCO3 solution and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 2% to 10% of MeOH in DCM), then it was purified again by Semi-Prep HPLC-MS (eluent gradient from 30% to 100% of MeOH in 10 mM ammonium bicarbonate) to afford title compound 163 as a white solid (10 mg, 6% yield).
1H NMR: 400 MHz, CD3OD, δ (ppm): 7.34-7.28 (m, 4H), 7.23-7.19 (m, 1 H), 3.54-3.43 (m, 2H), 2.96 (ddd, J = 17.1 , 4.4, 3.1 Hz, 1 H), 2.75-2.69 (m, 1 H), 2.67-2.60 (m, 1 H), 2.41-2.33 (m, 1 H), 2.00-1 .83 (m, 2H), 1 .58-1 .44 (m, 2H). LC-MS: rt = 0.96 min, MS: 344.1 (calcd), 345.1 (M+H+, found).
Example 93 2-Amino-6-(3-hydroxypropyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylic acid (168) and
Example 94 2-Amino-N-cyclopropyl-6-(3-hydroxypropyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (169)
Scheme 31
Figure imgf000154_0001
169: Example 94
Step 1. Ethyl 2-amino-6-(3-hydroxypropyl)-6-phenyl-4,5,6,7-
Figure imgf000154_0002
To a solution of 160 (scheme 30) (289 mg, 1.24 mmol) and ethyl 2-cyanoacetate (0.149 mL, 1.37 mmol) in EtOH (10.0 mL) were added morpholine (0.120 mL, 1.37 mmol) and sulfur (44 mg, 0.172 mmol). The reaction mixture was stirred at 60 °C for 24 hours, then allowed to cool to RT and concentrated to dryness. The residue was partitioned between EA and water. The layers were separated and the aqueous phase was extracted with EA. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 50% of EA in hexane) to afford title compound 164 as a white solid (336 mg, 75% yield). LC-MS: rt = 1.53 min, MS: 359.2 (calcd), 360.2 (M+H+, found).
Step 2. Ethyl 2-acetamido-6-(3-acetoxypropyl)-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (165)
To a suspension of 164 (336 mg, 0.935 mmol) in anhydrous DCM (3.0 mL) were added acetic anhydride (0.265 mL, 2.80 mmol) and acetic acid (0.054 mL, 0.935 mmol). The reaction mixture was stirred at RT for 4 days, then it was diluted with DCM and washed with saturated NaHCO3 solution, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 50% of EA in hexane) to afford title compound 165 as a white solid (208 mg, 50% yield). LC-MS: rt = 1.86 min, MS: 443.2 (calcd), 444.3 (M+H+, found).
Step 3. Ethyl 2-acetamido-6-(3-acetoxypropyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (166)
Intermediate 165 (208 mg, 0.469 mmol) and ceric sulfate (1 .35 g, 4.05 mmol) were added to a 1 :1 :1 acetic acid/water/dioxane mixture (15 mL). The flask was sonicated to make the suspension homogeneous and the reaction mixture was vigourously stirred at RT for 16 hours. Afterwards, the mixture was diluted with water and extracted with EA. The organic layer was washed with NaOH 1 N, water and brine, then dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 45% of EA in hexane) to afford title compound 166 as a white solid (122 mg, 57% yield). LC-MS: rt = 1 .73 min, MS: 457.2 (calcd), 458.3 (M+H+, found).
Step 4. Ethyl 6-(3-acetoxypropyl)-2-amino-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (167)
To a solution of 166 (122 mg, 0.267 mmol) in toluene (0.5 mL) was added pyrrolidine (0.35 mL, 4.26 mmol) and the reaction mixture was stirred at RT for 1 hour. Afterwards, the mixture was diluted with brine and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated to afford title compound 167 as a dark orange oil, which was used directly for the next step. LC-MS: rt = 1.64 min, MS: 415.2 (calcd), 416.3 (M+H+, found).
Step 5. 2-Amino-6-(3-hydroxypropyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (168) To a solution of 167 (0.267 mmol) in MeOH (4.0 mL) was added a solution of lithium hydroxide monohydrate (162 mg, 3.86 mmol) in water (2.0 mL). The reaction mixture was stirred at 60 °C for 3 days, then allowed to cool to RT. The mixture was concentrated to remove most of the organic solvent. The aqueous layer was acidified by slowly adding HC1 1 N and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 50% to 100% of EA in hexane) to afford title compound 168 as a yellow solid (70 mg, 76% yield over two steps).
1H NMR: 400 MHz, CD3OD, δ (ppm): 7.32-7.28 (m, 4H), 7.23-7.18 (m, 1 H), 3.53-3.43 (m, 2H), 3.26-3.19 (m, 1H), 2.60-2.51 (m, 2H), 2.35-2.27 (m, 1 H), 1.98-1.83 (m, 2H), 1.55-1.44 (m, 2H). LC-MS: rt = 1.09 min, MS: 345.1 (calcd), 346.0 (M+H+, found).
Step 6. 2-Amino-/V-cyclopropyl-6-(3-hydroxypropyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (169)
To a solution of 168 (54 mg, 0.156 mmol) in anhydrous DMF (1 .95 mL) were added HATU (119 mg, 0.313 mmol), N,N-diisopropylethylamine (0.082 mL, 0.469 mmol) and cyclopropylamine (0.012 mL, 0.172 mmol). Then, the reaction mixture was stirred at RT for 16 hours. Afterwards, the reaction mixture was diluted with EA and washed with saturated NaHCO3 solution and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 30% to 100% of EA in hexane) to afford title compound 169 as an off-white solid (46 mg, 77% yield).
1H NMR: 400 MHz, CD3OD, δ (ppm): 7.33-7.26 (m, 4H), 7.21-7.17 (m, 1 H), 3.52-3.42 (m, 2H), 2.81 (ddd, J = 17.3, 4.4, 3.3 Hz, 1 H), 2.70-2.62 (m, 2H), 2.58 (dt, J = 13.9, 3.7 Hz, 1 H), 2.31 (ddd, J = 13.8, 11.2, 4.6 Hz, 1 H), 1.98-1.81 (m, 2H), 1.56-1.41 (m, 2H), 0.76-0.68 (m, 2H), 0.57- 0.50 (m, 2H). LC-MS: rt = 1.13 min, MS: 384.1 (calcd), 385.1 (M+H+, found).
Example 95 2-Amino-6-cyano-N-cyclopropyl-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (170)
Scheme 32
Figure imgf000156_0001
Scheme 8
To a solution of 59 (example 36, scheme 8) (2.03 g, 6.50 mmol) in anhydrous DMF (72 mL) at 0 °C were added PyBOP (3.73 g, 7.15 mmol), N,N-diisopropylethylamine (2.26 mL, 13.0 mmol) and cyclopropylamine (2.25 mL, 32.5 mmol). Then, the reaction mixture was stirred at RT for 16 hours. Afterwards, the reaction mixture was quenched with saturated NH4CI solution and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 40% to 100% of EA in hexane), then it was purified again by reverse-phase flash column chromatography (eluent gradient from 10% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid) to afford title compound 170 as an off-white solid (1.48 g, 65% yield).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.16 (s, 2H), 7.61-7.59 (m, 1 H), 7.47-7.38 (m, 5H), 3.04-2.97 (m, 1 H), 2.80-2.70 (m, 3H), 2.64-2.57 (m, 1 H), 0.68-0.60 (m, 2H), 0.54-0.48 (m, 2H). LC-MS: rt = 1.25 min, MS: 351.1 (calcd), 352.2 (M+H+, found).
Example 96 2-Amino-6-cyano-6-((1-methylcyclopropyl)methyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (174)
Intermediate compound 172 8-((1-Methylcyclopropyl)methyl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (172) Scheme 33
Figure imgf000157_0001
Scheme 4
Step 1. 8-(2-Methylallyl)-1 ,4-dioxaspiro[4.51decane-8-carbonitrile (171)
To a solution of 1 ,4-dioxaspiro[4.5]decane-8-carbonitrile (40, scheme 4) (0.696 mL, 4.44 mmol) in anhydrous THF (10 mL) at -78 °C was added dropwise LDA (6.67 mL, 1 M in THF/hexane, 6.67 mmol). The reaction mixture was stirred at -78 °C for 30 min, before adding dropwise a solution of 3-bromo-2-methylpropene (0.448 mL, 4.44 mmol) in anhydrous THF (10 mL). Then, the reaction mixture was allowed to reach RT and stirred for 3 days. Afterwards, the reaction mixture was quenched with saturated NH4CI solution and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 50% of EA in hexane) to afford title compound 171 (753 mg, 77% yield) as a colorless oil, which was not characterized and used directly for the next step.
Step 2. 8-((1-Methylcyclopropyl)methyl)-1 ,4-dioxaspiro[4.51decane-8-carbonitrile (172)
To a solution of 171 (650 mg, 2.94 mmol) in anhydrous DCM (29 mL) at -10 °C were added diethylzinc (5.87 mL, 1 M in hexane, 5.87 mmol) and diiodomethane (0.946 mL, 11.7 mmol). The reaction mixture was stirred at -10 °C for 30 min, then it was allowed to reach RT and stirred for 3 days. Afterwards, the reaction mixture was quenched with saturated NH4CI solution and the layers were separated. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 50% of EA in hexane) to afford title compound 172 (233 mg, 34% yield) as a colorless oil, which was not characterized and used directly for the synthesis of relevant examples.
2-Amino-6-cyano-6-((1-methylcyclopropyl)methyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (174)
Scheme 34
Figure imgf000158_0001
To a suspension of 173 (See table 6 for characterization) (synthesized similarly to compound 47 (scheme 4) starting from compound 172 (scheme 33) instead of compound 41) (46 mg, 0.151 mmol) and ammonium chloride (162 mg, 3.02 mmol) in anhydrous DMF (2.0 mL) were added HATU (88 mg, 0.227 mmol) and N,N-diisopropylethylamine (0.053 mL, 0.302 mmol). Then, saturated NH3 solution in CHCI3 (0.9 mL) (prepared in-house) and NH3 0.4 M in THF (0.9 mL) were added dropwise and the reaction mixture was stirred at RT for 16 hours. Afterwards, the reaction mixture was quenched with a saturated NH4CI solution and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by reverse-phase flash column chromatography (eluent gradient from 0% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid) to afford title compound 174 as a white solid (26 mg, 57% yield).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.24 (s, 2H), 7.09 (bs, 2H), 3.15-3.01 (m, 2H), 2.46-2.43 (m, 1 H), 2.39-2.32 (m, 1 H), 1.88 (s, 2H), 1.12 (s, 3H), 0.46-0.38 (m, 1 H), 0.32-0.24 (m, 3H). LC-MS: rt = 1.12 min, MS: 303.1 (calcd), 304.1 (M+H+, found).
Example 97 2-Amino-N3-cyclopropyl-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3,6- dicarboxamide (175)
Figure imgf000158_0002
175: Example 97
Compound 175 (example 97) was synthesized similarly to compound 145 (example 85, scheme 26) starting from compound 170 (example 95, scheme 32) instead of compound 144. 1H NMR: 400 MHz, CD3OD, δ (ppm): 7.35-7.33 (m, 4H), 7.32-7.28 (m, 1H), 2.92 (dt, J = 17.1 , 4.8 Hz, 1H), 2.73-2.68 (m, 3H), 2.58 (ddd, J = 17.1 , 7.9, 5.5 Hz, 1 H), 0.76-0.71 (m, 2H), 0.57-0.53 (m, 2H). LC-MS: rt = 1.02 min, MS: 369.1 (calcd), 370.2 (M+H+, found).
Example 98 2-Amino-6-(but-3-yn-1-yl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (179)
Intermediate compound 177
8-(But-3-yn-1 -yl)-8-phenyl-1 ,4-dioxaspiro[4.5]decane (177)
Scheme 35
Figure imgf000159_0001
Scheme 30
Step 1. 3-(8-Phenyl-1 ,4-dioxaspiro[4.51decan-8-yl)propanal (176)
To a solution of 3-(8-phenyl-1 ,4-dioxaspiro[4.5]decan-8-yl)propanenitrile (156, scheme 30) (1 .40 g, 5.16 mmol) (Bioorg Med. Chem Lett. 21 , p. 405, 2011) in anhydrous toluene (33 mL) at -78 °C was added dropwise DIBALH (4.16 mL, 25% in toluene, 6.19 mmol). The reaction mixture was stirred at -78 °C for 5 min, then it was quenched with saturated NH4CI solution. Afterwards, the mixture was allowed to reach RT and HCI 2 N (2.58 mL, 5.16 mmol) was added. The mixture was extracted with Et20 and this organic layer was washed with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated to afford title compound 176 as a colorless oil, which was used directly for the next step without characterization.
Step 2. 8-(But-3-yn-1-yl)-8-phenyl-1 ,4-dioxaspiro[4.51decane (177)
To a solution of triphenylphosphine (3.59 g, 13.4 mmol) in anhydrous DCM (32 mL) at 0 °C was added carbon tetrabromide (2.22 g, 6.71 mmol). The reaction mixture was stirred at RT for 30 min, then it was cooled to 0 °C again and a solution of 176 (5.16 mmol) in anhydrous DCM (8 mL) was added and the reaction mixture was stirred at 0 °C for 30 min. Afterwards, the reaction mixture was diluted with hexane, filtered through a celite pad and concentrated. The residue was diluted with hexane, filtered through a celite pad and concentrated again. This residue was dissolved in anhydrous THF (23 mL) and the solution was cooled to -78 °C. Then, n-butyl lithium (4.13 mL, 2.5 M in hexane, 10.3 mmol) was added dropwise and the reaction mixture was stirred at -78 °C for 1 hour. Afterwards, the reaction mixture was quenched with saturated NH4CI solution and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 50% of EA in hexane) to afford title compound 177 as a white solid (734 mg, 53% yield over two steps), which was not characterized and used directly for the synthesis of relevant examples.
2-Amino-6-(but-3-yn-1-yl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (179)
Scheme 36
Figure imgf000160_0001
A solution of 178 (See table 6 for characterization) (synthesized similarly to compound 47 (scheme 4) starting from compound 177 (scheme 35) instead of compound 41) (83 mg, 0.25 mmol) in anhydrous DMF (2.7 mL) was saturated with bubbling NH3from a balloon. Then PyBOP (191 mg, 0.37 mmol) and N,N-diisopropylethylamine (0.085 mL, 0.49 mmol) were added and the reaction mixture was stirred at RT for 16 hours. Afterwards, the reaction mixture was quenched with saturated NH4CI solution and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 40% to 100% of EA in hexane) to afford title compound 179 as an off-white solid (50 mg, 60% yield).
1H NMR: 400 MHz, CDCI3, δ (ppm): 7.34-7.23 (m, 5H), 6.99 (s, 2H), 5.29 (s, 2H), 2.96- 2.88 (m, 1 H), 2.68-2.56 (m, 2H), 2.47-2.40 (m, 1 H), 2.35-2.26 (m, 1 H), 2.23-2.11 (m, 2H), 2.09- 2.01 (m, 1 H), 1.91 (t, J = 2.5 Hz, 1 H). LC-MS: rt = 1.24 min, MS: 338.1 (calcd), 339.1 (M+H+, found).
Example 99
6-(2-(1 H-1 ,2,3-T riazol-5-yl)ethyl)-2-amino-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (180)
Scheme 37
Figure imgf000160_0002
To a suspension of 178 (scheme 36) (20 mg, 0.059 mmol) in DMF (0.6 mL) and water (0.3 mL) were added copper(ll) sulfate pentahydrate (30 mg, 0.12 mmol) and sodium ascorbate (24 mg, 0.12 mmol). The flask was evacuated and backfilled with nitrogen, then trimethylsilyl azide (0.06 mL, 0.47 mmol) was added and the reaction mixture was stirred at RT for 10 min. Afterwards, the mixture was purified by reverse-phase flash column chromatography (eluent gradient from 10% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid) to afford title compound 180 as a white solid (16 mg, 71 % yield).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.26 (s, 2H), 7.49 (bs, 1 H), 7.35-7.31 (m, 4H), 7.26-7.21 (m, 1 H), 3.17-3.12 (m, 1 H), 2.67-2.63 (m, 1 H), 2.50-2.41 (m, 3H), 2.33-2.23 (m, 1 H), 2.11-2.07 (m, 2H). LC-MS: rt = 1 .11 min, MS: 382.1 (calcd), 383.2 (M+H+, found).
Example 100
6-(2-(1 H-1 ,2,3-T riazol-5-yl)ethyl)-2-amino-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (181)
Scheme 38
Figure imgf000161_0001
179 181 : Example 100
Scheme 36
To a suspension of 179 (scheme 36) (25 mg, 0.074 mmol) in DMF (0.8 mL) and water (0.4 mL) were added copper(ll) sulfate pentahydrate (37 mg, 0.148 mmol) and sodium ascorbate (29 mg, 0.148 mmol). The flask was evacuated and backfilled with nitrogen, then trimethylsilyl azide (0.078 mL, 0.591 mmol) was added and the reaction mixture was stirred at RT for 10 min. Then, the reaction mixture was quenched with saturated NH4CI solution and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 20% of MeOH in DCM) to afford title compound 181 as a white solid (13 mg, 46% yield).
1H NMR: 400 MHz, CD3OD, δ (ppm): 7.52 (bs, 1 H), 7.37-7.31 (m, 4H), 7.26-7.22 (m, 1 H), 3.02-2.98 (m, 1 H), 2.85-2.57 (m, 4H), 2.48-2.41 (m, 1 H), 2.30-2.16 (m, 2H). LC-MS: rt = 0.98 min, MS: 381.1 (calcd), 382.2 (M+H+, found).
Example 101 2-Amino-6-(2-(3-bromoisoxazol-5-yl)ethyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (183) Scheme 39
Figure imgf000162_0001
Scheme 36
Step 1. (4-(2-Amino-3-carbamoyl-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b1]thiophen-6- yl)but-1-yn-1-yl)copper (182)
To a solution of cupric sulfate pentahydrate (88.5 mg, 355 umol) and aqueous ammonium hydroxide 28% (177 uL, 1.32 mmol) in water (1 mL) cooled to 0 °C was added hydroxylamine hydrochloride (24.6 mg, 355 umol) under N2. The mixture was stirred for 10 minutes and then a solution of 179 (scheme 36) (30.0 mg, 88.6 umol) in ethanol (3 mL) was added in one portion. The resulting mixture was stirred for 5 minutes, then stirring was stopped and the mixture was allowed to stand for an additional 5 minutes. The precipitate was filtered off and washed successively with water (5 x 5 mL), EtOH (5 x 5 mL) and Et2O (5 x 5 mL). The precipitate was then dried in vacuo overnight to afford title compound 182 as a dark yellow solid (30 mg, 84% yield), which was used directly for the next step without characterization.
Step 2. 2-Amino-6-(2-(3-bromoisoxazol-5-yl)ethyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (183)
To a suspension of 182 (30.0 mg, 74.8 umol) in DCE (1 mL) was added 1 ,1- dibromoformaldoxime (18.2 mg, 89.8 umol) and the resulting mixture was stirred at 45 °C for 4 hours. The mixture was then allowed to cool to RT and purified by flash column chromatography (eluent gradient from 0% to 100% of EA in hexane) and then reverse-phase flash column chromatography (eluent gradient from 5% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid) to afford title compound 183 a pale-yellow solid (2.6 mg, 7.5%).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.10 (s, 2H), 7.35-7.30 (m, 4H), 7.27-7.21 (m, 1 H), 6.85 (bs, 2H); 6.53 (s, 1 H), 2.91-2.81 (m, 1 H), 2.78-2.63 (m, 2H), 2.63-2.54 (m, 2H), 2.33-2.19 (m, 1 H), 2.16-2.09 (m, 2H). LC-MS: rt = 1.39 min, MS: 459.0 and 461.0 (calcd), 460.0 and 462.0 (M+H+, found).
Example 102 2-Amino-6-(2-cyanoethyl)-6-(cyclopropylmethyl)-7 -oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (189)
Example 103 2-Amino-6-(3-amino-3-oxopropyl)-6-(cyclopropylmethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (191)
Example 104 2-Amino-6-(2-cyanoethyl)-N-cyclopropyl-6-(cyclopropylmethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (192)
Scheme 40
Figure imgf000163_0001
Step 1. 3-(8-(Cyclopropylmethyl)-1 ,4-dioxaspiro[4.51decan-8-yl)acrylonitrile (184)
To a mixture of sodium hydride (2.14 g, 53.5 mmol) and DMPU (11.3 mL, 93.6 mmol) in anhydrous THF (40 mL) at 0 °C was slowly added diethylcyanomethylphosphonate (8.65 mL, 53.5 mmol). The mixture was stirred at 0 °C for 1 hour, then a solution of 113 (scheme 21) (10.0 g, 44.6 mmol) in anhydrous THF (65 mL) was added dropwise and the reaction mixture was stirred at RT for 24 hours. The mixture was partitioned between water and EA (200 mL each). The layers were separated and the organic phase was washed with brine (150 mL), dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (eluent mixture 50% of Et2O in hexane) to afford title compound 184 as a colorless oil (10.0 g, 91% yield), which was not characterized and used directly for the next step. Step 2. 3-(8-(Cyclopropylmethyl)-1 ,4-dioxaspiro[4.5]decan-8-yl)propanenitrile (185)
A suspension of 184 (10.0 g, 40.4 mmol) and Pd/C 10% (215 mg) in EA (189 mL) and EtOH (246 mL) was stirred under hydrogen atmosphere (balloon) at RT for 24 hours. The mixture was then filtered and the filtrate was concentrated to afford title compound 185 as a colorless oil (9.90 g, 98% yield), which was used in Step 4 without purification and without characterization.
Step 3. 3-(1-(Cyclopropylmethyl)-4-oxocyclohexyl)propanenitrile (186)
2 N aqueous HCI (186 mL, 372 mmol) was added to a solution of 185 (9.30 g, 37.3 mmol) in acetone (460 mL) and the resulting mixture was stirred at 40 °C for 24 hours, then quenched with saturated aqueous NaHCO3 (200 mL) and concentrated to remove the organic solvent. The residue was extracted with EA (2 x 250 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to afford title compound 186 as a colorless oil (6.90 g, 90% yield), which was used in Step 5 without purification and without characterization.
Step 4. Ethyl 2-amino-6-(2-cyanoethyl)-6-(cyclopropylmethyl)-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (187)
A suspension of 186 (6.10 g, 29.7 mmol), morpholine (2.82 mL, 32.7 mmol), sulfur (1 .05 g, 4.10 mmol) and ethyl 2-cyanoacetate (3.16 mL, 29.7 mmol) in EtOH (52 mL) was stirred at 60 °C for 16 hours. The mixture was then allowed to cool to RT, diluted with brine (100 mL) and extracted with EA (3 x 100 mL). The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 70% of EA in hexane) to afford title compound 187 as a dark yellow oil (4.10 g, 42% yield). LC-MS: rt = 1.71 min, MS: 332.2 (calcd), 333.1 (M+H+, found).
Step 5. Ethyl 2-acetamido-6-(2-cyanoethyl)-6-(cyclopropylmethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (188)
A mixture of 187 (4.10 g, 12.3 mmol) and acetic anhydride (1.40 mL, 14.8 mmol) in acetic acid (71 mL) was stirred at 70 °C for 2 hours. The mixture was allowed to cool to RT and concentrated to around 50 mL. Then, the mixture was diluted with water (50 mL) and dioxane (50 mL) and ceric sulfate (37.3 g, 107 mmol) was added. The reaction mixture was stirred at RT for 24 hours. Then, the yellow solid was filtered off, rinsed with EA (150 mL) and the filtrate was diluted with brine. The layers were separated, and the aqueous phase was extracted with EA (150 mL). The combined organics were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to afford title compound 188 as an orange oil (4.20 g, 88% yield). LC-MS: rt = 1.63 min, MS: 388.2 (calcd), 389.3 (M+H+, found).
Step 6a. 2-Amino-6-(2-cyanoethyl)-6-(cyclopropylmethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (189) and 2-Amino-6-(3-amino-3-oxopropyl)-6- (cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (190)
A solution of lithium hydroxide monohydrate (109 mg, 2.60 mmol) in water (63 mL) was added to a solution of 188 (202 mg, 0.52 mmol) in MeOH (63 mL). The mixture was stirred at 80 °C for 16 hours, then allowed to cool to RT and concentrated by rotary evaporation to remove most of the organic solvent. The aqueous residue was washed with EA and the layers were separated. The aqueous layer was acidified by slowly adding 1 N HCI and extracted with EA (3 x 40 mL). These organics were dried over Na2SO4, filtered and concentrated to afford a mixture of title compounds 189 and 190. This crude was purified by flash column chromatography (eluent gradient from 0% to 35% of MeOH in DCM) to afford 189 (111 mg, 67% yield) and 190 (40.0 mg, 23% yield). 24 mg of 189 were further purified by Semi-Prep HPLC-MS (eluent gradient from 20% to 100% of MeOH in 10 mM ammonium bicarbonate) to afford 14.8 mg of highly pure material as an off-white solid.
1H NMR of 189: 400 MHz, DMSO-d6, δ (ppm): 8.32 (bs, 2H), 3.09-3.03 (m, 1 H), 2.94-2.87 (m, 1 H), 2.43-2.31 (m, 2H), 2.07-1.93 (m, 3H), 1.84-1.74 (m, 1 H), 1.54 (dd, J = 14.2, 6.3 Hz, 1H), 1 .30 (dd, J = 14.2, 7.0 Hz, 1 H), 0.60-0.55 (m, 1 H), 0.39-0.37 (m, 2H), 0.03 - -0.01 (m, 1 H), -0.04 - -0.08 (m, 1 H). LC-MS of 189: rt = 1.22 min, MS: 318.1 (calcd), 319.1 (M+H+, found).
(See table 6 for characterization of 190)
Step 7. 2-Amino-6-(3-amino-3-oxopropyl)-6-(cyclopropylmethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (191)
To a solution of 190 (40.0 mg, 119 umol) in anhydrous DMF (1.26 mL) were added ammonium chloride (127 mg, 2.38 mmol), HATU (69.2 mg, 178 umol) and N,N- diisopropylethylamine (41 .4 uL, 238 umol). The resulting mixture was stirred at RT for 16 hours, then it was concentrated. The residue was purified by reverse-phase column chromatography (eluent gradient from 0% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid) to afford title compound 191 as an off-white solid (15.8 mg, 40% yield).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.97 (s, 2H), 7.20 (s, 1 H), 6.92 (bs, 2H), 6.64 (s, 1 H), 2.98-2.90 (m, 2H), 2.12-2.04 (m, 1 H), 2.00-1.87 (m, 3H), 1.84-1.71 (m, 2H), 1.57 (dd, J = 14.1 , 6.3 Hz, 1 H), 1.27 (dd, J = 14.1 , 6.8 Hz, 1 H), 0.61-0.54 (m, 1 H), 0.40-0.36 (m, 2H), 0.06- 0.01 (m, 1 H), -0.02 - -0.08 (m, 1 H). LC-MS: rt = 0.88 min, MS: 335.1 (calcd), 336.0 (M+H+, found).
Step 6b. 2-Amino-6-(2-cyanoethyl)-/V-cyclopropyl-6-(cyclopropylmethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (192)
A solution of lithium hydroxide monohydrate (3.10 g, 73.8 mmol) in water (500 mL) was added to a solution of 188 (4.20 g, 10.8 mmol) in MeOH (500 mL). The mixture was stirred at 55 °C for 16 hours, then allowed to cool to RT and concentrated by rotary evaporation to remove most of the organic solvent. The aqueous residue was washed with DCM and the layers were separated. The aqueous layer was acidified by slowly adding 1 N HCI and extracted with EA (3 x 100 mL). These organics were dried over Na2SO4, filtered and concentrated. The residue was dissoved in anhydrous THF (90 mL) and HATU (7.17 g, 18.8 mmol), N,N-diisopropylethylamine (3.28 mL, 18.8 mmol) and cyclopropylamine (6.53 mL, 94.2 mmol) were added. The reaction mixture was stirred at RT for 3 hours, then it was diluted with brine (50 mL) and extracted with EA (3 x 100 mL). The combined organics were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 100% of EA in hexane) to afford title compound 192 (1 .86 g, 45% yield over two steps) as a yellow solid.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.73 (s, 2H), 7.31 (d, J = 3.8 Hz, 1 H), 2.93-2.82 (m, 1 H), 2.81-2.77 (m, 1H), 2.77-2.67 (m, 1 H), 2.38-2.32 (m, 2H), 2.02-1.98 (m, 2H), 1.94-1.86 (m, 1 H), 1.84-1.76 (m, 1 H), 1.54 (dd, J = 14.2, 6.3 Hz, 1 H), 1.29 (dd, J = 14.1 , 7.0 Hz, 1 H), 0.66- 0.60 (m, 2H), 0.60-0.52 (m, 1 H), 0.51-0.46 (m, 2H), 0.37-0.35 (m, 2H), 0.04 - -0.01 (m, 1 H), - 0.04 - -0.1 (m, 1 H). LC-MS: rt = 1.25 min, MS: 357.2 (calcd), 358.1 (M+H+, found).
Example 105 (S)-2-Amino-6-(2-cyanoethyl)-N-cyclopropyl-6-(cyclopropylmethyl)-7 -oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (193) and
Example 106 (R)-2-Amino-6-(2-cyanoethyl)-N-cyclopropyl-6-(cyclopropylmethyl)-7 -oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (194)
Scheme 41
Figure imgf000166_0001
192 193: Example 105 194: Example 106
Racemic compound 192 (scheme 40) (1.14 g) was submitted to SFC chiral separation (isocratic: 50% of MeOH 1 :1 in CO2) to yield enantioenriched compound 193 as a orange solid (468.9 mg, 41% separation yield) and enantioenriched compound 194 as an off-white solid (424.5 mg, 37% separation yield) (the absolute configurations were assigned based on resolved crystal structure of enantiomer 194).
193: 1H NMR: same as racemic mixture (192). LC-MS: rt = 1.27 min, MS: 357.2 (calcd), 358.2 (M+H+, found). Analytical SFC (IG column with 5-60% MeOH in water (95-40% CO2) gradient): rt = 5.44 min, ee. = >99.9%.
194: 1H NMR: same as racemic mixture (192). LC-MS: rt = 1.27 min, MS: 357.2 (calcd), 358.2 (M+H+, found). Analytical SFC (IG column with 5-60% MeOH in water (95-40% CO2) gradient): rt = 6.49 min, ee. = 99.4%.
Example 107 2-Amino-6-(2-cyanoethyl)-6-(cyclopropylmethyl)-7 -oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (195)
Figure imgf000167_0001
195: Example 107
Compound 195 (example 107) was synthesized similarly to compound 109 (example 59, scheme 19) starting from compound 189 (scheme 40) instead of compound 108.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.01 (s, 2H), 6.94 (bs, 2H), 3.05-2.89 (m, 2H), 2.44-2.32 (m, 2H), 2.08-2.02 (m, 2H), 1.99-1.92 (m, 1 H), 1.86-1.79 (m, 1H), 1.55 (dd, J = 14.2, 6.4 Hz, 1 H), 1.35 (dd, J = 14.2, 6.8 Hz, 1 H), 0.63-0.54 (m, 1 H), 0.40-0.35 (m, 2H), 0.08-0.04 (m, 1 H), -0.03 - -0.07 (m, 1 H). LC-MS: rt = 1.07 min. MS: 317.1 (calcd), 318.2 (M+H+, found).
Example 108 2-Amino-6-(2-amino-2-oxoethyl)-N-cyclopropyl-6-(cyclopropylmethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (198)
Intermediate compound 196
2-(8-(Cyclopropylmethyl)-1 ,4-dioxaspiro[4.5]decan-8-yl)acetamide (196)
Scheme 42
Figure imgf000167_0002
To a solution of 118 (scheme 22) (814 mg, 3.46 mmol) in ethylene glycol (18.3 mL) were added potassium hydroxide (1.55 g, 27.7 mmol) and water (1 mL). The resulting mixture was stirred at 170 °C for 24 hours, then more potassium hydroxide (1.55 g, 27.7 mmol) and water (1 mL) were added and the reaction mixture was stirred at 170 °C for additional 24 hours. The mixture was allowed to cool to RT, diluted with water (50 mL) and extracted with EA (2 x 50 mL). The aqueous layer was acidified by adding HCI 2 N and extracted with EA (3 x 50 mL). The combined organics were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 100% of EA in hexane, then from 0% to 20% of MeOH in DCM) to afford title compound 196 as a white solid (320 mg, 37% yield), which was not characterized and used directly for the synthesis of relevant examples.
2-Amino-6-(2-amino-2-oxoethyl)-N-cyclopropyl-6-(cyclopropylmethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (198) Scheme 43
Figure imgf000168_0001
Compound 197 (See table 6 for characterization) (synthesized similarly to compound 47 (example 28, scheme 4) starting from compound 196 (scheme 42) instead of compound 41) (70.0 mg, 217 umol) was dissolved in DMF (1 mL). HATU (248 mg, 651 umol), cyclopropylamine (150 uL, 2.17 mmol) and N,N-diisopropylethylamine (113 uL, 651 umol) were added and the resulting mixture was stirred at RT for 1 hour. The crude mixture was directly purified by reverse-phase column chromatography (eluent gradient from 5% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid) to afford title compound 198 (19.2 mg, 24% yield) as a pale-yellow solid.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.68 (s, 2H), 7.29 (s, 1 H), 7.15 (s, 1 H), 6.67 (s, 1 H), 2.96-2.85 (m, 1 H), 2.75-2.70 (m, 2H), 2.56 (d, J = 14.81 Hz, 1 H), 2.36-2.28 (m, 1 H), 2.24 (d, J = 14.80 Hz, 1 H), 2.06-2.00 (m, 1 H), 1.65 (dd, J = 14.02, 6.34 Hz, 1 H), 1.30 (dd, J = 14.00, 7.00 Hz, 1 H), 0.68-0.61 (m, 3H), 0.53-0.49 (m, 2H), 0.38-0.36 (m, 2H), 0.08-0.02 (m, 1 H), -0.06 - - 0.13 (m, 1 H). LC-MS: rt = 1.00 min. MS: 361.1 (calcd), 362.2 (M+H+, found).
Example 109 2-Amino-6-(2-amino-2-oxoethyl)-6-(cyclopropylmethyl)-7 -oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (199)
Figure imgf000168_0002
Compound 199 (example 109) was synthesized similarly to compound 109 (example 59, scheme 19) starting from compound 197 instead of compound 108.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.92 (s, 2H), 7.13 (s, 1 H), 6.88 (bs, 1 H), 6.65 (s, 1 H), 3.00-2.90 (m, 1 H), 2.88-2.81 (m, 1 H), 2.53 (d, J = 14.81 Hz, 1 H), 2.35-2.27 (m, 1 H), 2.24 (d, J = 14.81 Hz, 1 H), 2.06-2.00 (m, 1 H), 1.62-1.56 (m, 1 H), 1.33-1.28 (m, 1 H), 0.62-0.55 (m, 1 H), 0.38-0.30 (m, 2H), 0.07-0.02 (m, 1 H), -0.08 - -0.14 (m, 1 H). LC-MS: rt = 0.83 min. MS: 321.1 (calcd), 322.2 (M+H+, found).
Example 110 2-Amino-6-carbamoyl-6-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene- 3-carboxylic acid (200)
Scheme 44
Figure imgf000169_0001
Scheme 7
To a mixture of 53 (scheme 7) (100 mg, 344 umol) in methanol (4.39 mL) and water (1.41 mL) were added 30% aqueous hydrogen peroxide (352 uL, 3.44 mmol) and potassium hydroxide (199 mg, 3.55 mmol) and the reaction mixture was stirred at RT for 24 hours. The mixture was diluted with water (5 mL) and concentrated to remove the organic solvent. The aqueous residue was washed with EA (10 mL), then it was acidified to pH 1 and extracted with EA (3 x 10 mL). These organics were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 30% of MeOH in DCM), then it was purified again by reverse-phase column chromatography (eluent gradient from 5% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid) to afford title compound 200 (7 mg, 6% yield) as a yellow solid.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 2.50 (bs, 1 H), 8.29 (bs, 2H), 7.05 (s, 1 H), 6.77 (s, 1 H), 3.08-3.01 (m, 1 H), 2.92-2.83 (m, 1 H), 2.47-2.44 (m, 1 H), 2.14-2.06 (m, 1 H), 1.76 (dd, J = 13.99, 6.23 Hz, 1 H), 1.65 (dd, J = 13.99, 6.23 Hz, 1 H), 0.63-0.56 (m, 1 H), 0.39-0.35 (m, 2H), 0.05 - -0.01 (m, 2H). LC-MS: rt = 0.99 min. MS: 308.1 (calcd), 309.0 (M+H+, found).
Example 111 2-Amino-6-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3,6- dicarboxamide (201)
Figure imgf000169_0002
Compound 201 (example 111) was synthesized similarly to compound 109 (example 59, scheme 19) starting from compound 200 instead of compound 108.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.12 (s, 2H), 7.06 (s, 1 H), 6.94 (bs, 1 H), 6.77 (s, 1 H), 3.07-2.97 (m, 1H), 2.90-2.83 (m, 1 H), 2.49-2.44 (m, 1 H), 2.16-2.08 (m, 1 H), 1.79-1.66 (m, 2H), 0.64-0.57 (m, 1 H), 0.38-0.34 (m, 2H), 0.08-0.03 (m, 2H). LC-MS: rt = 0.89 min. MS: 307.1 (calcd), 308.0 (M+H+, found).
Example 112 2-Amino-N3-cyclopropyl-6-(cyclopropylmethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3,6-dicarboxamide (202) Scheme 45
Figure imgf000170_0001
To a solution of compound 72 (Table 3) (77.0 mg, 234 umol) in a mixture of MeOH (10.1 mL) and water (10.1 mL) was added lithium hydroxide monohydrate (19.6 mg, 467 umol) at RT. The reaction mixture was cooled to 0 °C and 30% H2O2 (145 uL) was added. The mixture was stirred at 0 °C for 1 hour, then more 30% H2O2 (145 uL) was added, and the reaction mixture was stirred at RT for an additional 2.5 hours, then at 40 °C for 45 min. Afterwards, the mixture was cooled to 0 °C and diluted with brine (10 mL) and EA (10 mL). The layers were separated and the aqueous phase was extracted with EA (3 x 10 mL). The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 100% of EA in hexane) to afford title compound 202 (13.2 mg, 16% yield) as a white solid.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.84 (s, 2H), 7.40 (d, J = 3.86 Hz, 1 H), 7.05 (s, 1 H), 6.74 (s, 1 H), 2.98-2.90 (m, 1 H), 2.75-2.68 (m, 2H), 2.46-2.41 (m, 1H), 2.12-2.04 (m, 1 H), 1.78-1.73 (m, 1 H), 1.68-1.63 (m, 1 H), 0.66-0.55 (m, 3H), 0.53-0.48 (m, 2H), 0.37-0.34 (m, 2H), 0.05-0.02 (m, 2H). LC-MS: rt = 1 .05 min. MS: 347.1 (calcd), 348.1 (M+H+, found).
Example 113 2-Amino-6-(cyclopropylmethyl)-6-(3-hydroxypropyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (211)
Scheme 46
Figure imgf000171_0001
Step 1. 3-(8-(Cyclopropylmethyl)-1 ,4-dioxaspiro[4.5]decan-8-yl)propanoic acid (203)
To a solution of 185 (scheme 40) (2.14 g, 8.58 mmol) in ethylene glycol (45.5 mL) were added potassium hydroxide (3.85 g, 68.7 mmol) and water (31.0 uL, 1.72 mmol). The resulting mixture was stirred at 170 °C for 24 hours. The mixture was allowed to cool to RT, diluted with water (50 mL) and washed with DCM (2 x 50 mL). The aqueous phase was acidified to pH 2 by adding 2 N HCI and extracted with DCM (3 x 10 mL). These organics were dried over MgSO4, filtered and concentrated to afford title compound 203 as a red oil, which was used directly in Step 2 without purification and characterization. Step 2. 3-(8-(Cyclopropylmethyl)-1 ,4-dioxaspiro[4.51decan-8-yl)propan-1-ol (204)
To a solution of 203 (8.58 mmol) in anhydrous THF (54 mL) at 0 °C was added dropwise lithium aluminum hydride (9.55 mL, 2 M in THF, 19.1 mmol). The resulting mixture was stirred at 0 °C for 1 hour, allowed to reach RT and it stirred for 16 hours. A saturated aqueous solution of Rochelle's salt (30 mL) was added dropwise, then the mixture was diluted with EA (50 mL), stirred at RT for 30 min and filtered through a celite pad. The layers were separated and the aqueous phase was extracted with EA (2 x 50 mL). The combined organics were dried over MgSO4, filtered and concentrated to afford title compound 204 as a yellow oil (2.07 g, 95% yield over two steps), which was used in Step 3 without purification and characterization.
Step 3. 4-(Cyclopropylmethyl)-4-(3-hydroxypropyl)cyclohexan-1-one (205) To a solution of 204 (2.07 g, 8.14 mmol) in acetone (125 mL) was added 2 N aqueous HCI (22.9 mL, 45.7 mmol) and the resulting mixture was stirred at RT for 70 hours. Then, the mixture was neutralized with a saturated aqueous NaHCO3 solution (50 mL) and concentrated to remove the organic solvent. The residue was then partitioned between EA (50 mL) and water (40 mL), the layers were separated and the organic phase was dried over Na2SO4, filtered and concentrated. The residue was taken up in DCM (30 mL) and the insoluble impurity was filtered off and washed with DCM (50 mL). The filtrate and washings were combined and concentrated to afford title compound 205 as a thick pale-yellow oil (1 .53 g, 89% yield), which was used in Step 4 without purification and characterization.
Step 4. 3-(1-(Cyclopropylmethyl)-4-oxocyclohexyl)propyl acetate (206)
To a solution of 205 (1.53 g, 7.27 mmol) in anhydrous DCM (15.9 mL) at 0 °C were added acetic anhydride (1.65 mL, 17.5 mmol) and pyridine (1.77 mL, 21.8 mmol). The reaction mixture was allowed to reach RT and stirred for 19 hours. Then, the mixture was diluted with DCM (40 mL) and washed with 1 N HCI (40 mL). The organic phase was dried over Na2SO4, filtered and concentrated to give title compound 206 as a yellow oil (1.80 g, 98% yield), which was used in Step 5 without purification and characterization.
Step 5. Ethyl 6-(3-acetoxypropyl)-2-amino-6-(cyclopropylmethyl)-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (207)
A suspension of sulfur (253 mg, 984 umol), 206 (1.80 g, 7.13 mmol), morpholine (677 uL, 7.85 mmol) and ethyl 2-cyanoacetate (759 uL, 7.13 mmol) in EtOH (12.5 mL) was stirred at 60 °C for 16 hours. The mixture was allowed to cool to RT, then diluted with brine (20 mL) and extracted with EA (3 x 20 mL). The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 35% of EA in hexane) to afford title compound 207 as a yellow oil (2.25 g, 83% yield). LC- MS: rt = 1.90 min, MS: 379.2 (calcd), 380.2 (M+H+, found).
Step 6. Ethyl 2-acetamido-6-(3-acetoxypropyl)-6-(cyclopropylmethyl)-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (208)
To a solution of 207 (2.25 g, 5.93 mmol) in anhydrous DCM (12.9 mL) at 0 °C were added acetic anhydride (1.34 mL, 14.2 mmol) and pyridine (1.44 mL, 17.8 mmol). The reaction mixture was allowed to reach RT and stirred for 16 hours. Then, the mixture was diluted with DCM (20 mL) and washed with 1 N HCI (40 mL). The organic phase was dried over Na2SO4, filtered and concentrated to give title compound 208 as a yellow oil (2.50 g, >99% yield), which was used in Step 7 without purification. LC-MS: rt = 1.96 min, MS: 421.2 (calcd), 422.2 (M+H+, found).
Step 7. Ethyl 2-acetamido-6-(3-acetoxypropyl)-6-(cyclopropylmethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (209)
To a solution of 208 (2.50 g, 5.93 mmol) in dioxane (27.1 mL) were added acetic acid
(27.1 mL), ceric sulfate (17.0 g, 51.2 mmol) and water (12.9 mL). The resulting mixture was stirred at RT for 16 hours, then the solid was filtered off and washed with EA (100 mL). The filtrate and washings were combined, diluted with water (50 mL), the layers were separated, and the aqueous phase was extracted with EA (2 x 50 mL). The combined organics were dried over Na2SO4, filtered and concentrated to afford title compound 209 as a solid (2.50 g, 97% yield), which was used in Step 8 without purification. LC-MS: rt = 1.76 min, MS: 435.2 (calcd), 436.3 (M+H+, found).
Step 8. Ethyl 6-(3-acetoxypropyl)-2-amino-6-(cyclopropylmethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (210)
To a solution of 209 (2.50 g, 5.74 mmol) in toluene (9.71 mL) was added pyrrolidine (7.30 mL, 88.9 mmol). The resulting mixture was stirred at RT for 1 hour, then diluted with EA (40 mL) and brine (40 mL). The layers were separated and the aqueous phase was extracted with EA (2 x 40 mL). The combined organics were dried over Na2SO4, filtered and concentrated to afford title compound 210 as a dark oil (2.26 g, >99% yield), which was used in Step 9 without purification. LC-MS: rt = 1.68 min, MS: 393.2 (calcd), 394.3 (M+H+, found).
Step 9. 2-Amino-6-(cyclopropylmethyl)-6-(3-hydroxypropyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (211)
To a solution of 210 (2.26 g, 5.74 mmol) in MeOH (100 mL) was added a solution of lithium hydroxide monohydrate (1.24 g, 29.6 mmol) in water (100 mL). The resulting mixture was stirred at 80 °C for 4 hours, then concentrated to remove most of the organic solvent. The aqueous residue was washed with EA (40 mL), then acidified to pH 4 by slowly adding 1 N aqueous HCI and extracted with EA (2 x 70 mL). The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 15% of MeOH in DCM) to afford title compound 211 as a light-brown solid (1.07 g, 58% yield).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 12.44 (s, 1 H), 8.17 (s, 2H), 4.32 (t, J = 5.1 Hz, 1 H), 3.34-3.29 (m, 2H, partially overlapping with the water signal), 3.01-2.83 (m, 2H), 2.14-2.04 (m, 1 H), 1.98-1.88 (m, 1H), 1.65-1.52 (m, 2H), 1.52-1.41 (m, 1 H), 1.38-1.27 (m, 2H), 1.22 (dd, J = 14.1 , 7.4 Hz, 1 H), 0.61-0.50 (m, 1 H), 0.40-0.30 (m, 2H), 0.02 - -0.01 (m, 2H). LC-MS: rt = 1.11 min. MS: 323.1 (calcd), 324.1 (M+H+, found).
Example 114 2-Amino-6-(cyclopropylmethyl)-6-(3-hydroxypropyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (212)
Figure imgf000173_0001
Compound 212 (example 114) was synthesized similarly to compound 109 (example 59, scheme 19) starting from compound 211 (scheme 46) instead of compound 108.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.96 (s, 2H), 6.90 (bs, 1 H), 4.33 (t, J = 5.2 Hz, 1 H), 3.36-3.30 (m, 2H, partially overlapping with the water signal), 2.93 (t, J = 6.0 Hz, 2H), 2.12- 2.06 (m, 1 H), 1.98-1.91 (m, 1 H), 1.62-1.46 (m, 3H), 1.39-1.23 (m, 3H), 0.61-0.54 (m, 1 H), 0.38- 0.33 (m, 2H), 0.06-0.00 (m, 1 H), -0.02 - -0.08 (m, 1 H). LC-MS: rt = 0.97 min. MS: 322.1 (calcd), 323.2 (M+H+, found).
Example 115 2-Amino-N-cyclopropyl-6-(cyclopropylmethyl)-6-(3-hydroxypropyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (213)
Figure imgf000174_0001
Compound 213 (example 115) was synthesized similarly to compound 82 (example 52, scheme 13) starting from compound 211 (scheme 46) instead of compound 81.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.68 (bs, 2H), 7.31 (d, J = 3.8 Hz, 1 H), 4.33 (t, J = 5.2 Hz, 1 H), 3.35-3.27 (m, 2H, partially overlapping with the water signal), 2.83 (t, J = 6.0 Hz, 2H), 2.75-2.70 (m, 1H), 2.07-2.02 (m, 1 H), 1.93-1.88 (m, 1 H), 1.63-1.50 (m, 3H), 1.35-1.23 (m, 3H), 0.67-0.62 (m, 2H), 0.59-0.54 (m, 1 H), 0.52-0.49 (m, 2H), 0.38-0.33 (m, 2H), 0.03 - -0.02 (m, 1 H), -0.02 - -0.09 (m, 1 H). LC-MS: rt = 1.15 min. MS: 362.2 (calcd), 363.2 (M+H+, found).
Example 116 2-Amino-6-cyano-N-isopropyl-7-oxo-6-phenyl-4, 5, 6, 7-tetrahydrobenzo[b]th iophene-3- carboxamide (214)
Scheme 47
Figure imgf000174_0002
Scheme 8
To a solution of compound 59 (example 36, scheme 8) (50.0 mg, 160 umol) in anhydrous DMF (1.58 mL) were added isopropylamine (55.0 uL, 640 umol), HATU (124 mg, 320 umol) and N,N-diisopropylethylamine (55.8 uL, 320 umol). The resulting mixture was stirred at RT for 30 min, then it was diluted with EA (5 mL) and water (5 mL). The layers were separated, and the aqueous phase was extracted with EA (5 mL). The combined organics were washed with brine (2 x 10 mL) and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 100% of EA in hexane), then it was purified again by reverse-phase column chromatography (eluent gradient from 0% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid) to afford title compound 214 (16.2 mg, 29% yield) as an off-white solid.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.11 (bs, 1 H), 7.47-7.36 (m, 6H), 4.03-3.95 (m, 1 H), 3.10-3.02 (m, 1 H), 2.81-2.70 (m, 2H), 2.67-2.59 (m, 1 H), 1.11 (dd, J = 6.58, 3.79 Hz, 6H). LC-MS: rt = 1.33 min. MS: 353.1 (calcd), 354.1 (M+H+, found).
Example 117 2-Amino-6-(2-hydroxyethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (215)
Figure imgf000175_0001
215: Example 117
Compound 215 (example 117) was synthesized similarly to compound 61 (example 38, scheme 10) starting from compound 89 (scheme 15) instead of compound 59.
1H NMR: 400 MHz, CD3OD, δ (ppm): 7.30-7.25 (m, 4H), 7.21-7.17 (m, 1 H), 3.51-3.38 (m, 2H), 2.95-2.87 (m, 1 H), 2.63-2.60 (m, 2H), 2.38-2.29 (m, 1 H), 2.15-2.06 (m, 2H). LC-MS: rt = 0.90 min, MS: 330.1 (calcd), 331.2 (M+H+, found).
Example 118
2-Amino-6-cyano-N-hydroxy-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (216)
Scheme 48
Figure imgf000175_0002
N,N-Diisopropylethylamine (26.8 uL, 154 umol) was added to a solution of 2-amino-6- cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (59, scheme 8) (40.0 mg, 128 umol) and HATU (49.7 mg, 128 umol) in anhydrous DMF (4.20 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. In a separate reaction vessel, to a solution of hydroxylamine (5.23 mg, 154 umol) in anhydrous DMF (1.00 mL) was added N,N- diisopropylethylamine (68.3 uL, 384 umol) and the resulting mixture was stirred for 5 minutes or until complete dissolution of hydroxylamine. The resulting solution was then added to the reaction mixture, which was stirred at RT for 2.5 hours, then diluted with brine (5 mL) and EA (5 mL). The layers were separated, and the aqueous phase was extracted with EA (2 x 10 mL). The combined organics were washed with brine (10 mL), HCI 1 N (2 x 10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by reverse-phase flash column chromatography (eluent gradient from 5% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid), then it was purified a second time by reverse-phase flash column chromatography (eluent gradient from 5% to 100% of CH3CN in 10 mM ammonium bicarbonate), then it was purified a third time by reverse-phase flash column chromatography (eluent gradient from 5% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid) to afford title compound 216 as an off-white solid (8.1 mg, 19% yield).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 9.21 (bs, 1 H), 8.29-8.05 (m, 2H), 7.48-7.31 (m, 5H), 3.05-2.94 (m, 1 H), 2.80-2.71 (m, 2H), 2.68-2.56 (m, 1H). LC-MS: rt = 0.78 min. MS: 327.1 (calcd), 328.1 (M+H+, found).
Example 119 2-Amino-6-ethyl-4-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (219) Scheme 49
Figure imgf000176_0001
217 218 219: Example 119
Step 1. 2-Amino-6-ethyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (218)
To a solution of 4-ethylcyclohexan-1-one (217) (0.776 mL, 5.50 mmol) and cyanoacetamide (420 mg, 5.00 mmol) in EtOH (5 mL) were added morpholine (0.474 mL, 5.50 mmol) and sulfur (177 mg, 0.69 mmol). The reaction mixture was stirred at 60 °C for 19 hours, then allowed to cool to RT and concentrated to dryness. The residue was purified by flash column chromatography (eluent gradient from 0 to 10% of MeOH in DCM) to afford title compound 218 as a light-orange solid (658 mg, 59% yield). LC-MS: rt = 1 .43 min, MS: 224.1 (calcd), 225.1 (M+H+, found).
Step 2. 2-Amino-6-ethyl-4-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (219) Compound 218 (50.0 mg, 0.223 mmol) was dissolved in DMSO (5 mL) and O2 was bubbled through the mixture for 4 days. The mixture was then directly purified by flash column chromatography (eluent gradient from 0% to 100% of EA in hexane with a 90:10 DCM/MeOH wash). The fractions containing the desired compound were combined and diluted with EA and water. The aqueous layer was extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. A subsequent recrystallization from EA yielded title compound 219 as a yellow solid (16.0 mg, 30% yield).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 9.47 (s, 1H), 7.88 (s, 2H), 6.83 (s, 1 H), 2.95 (dd, J = 16.85, 4.44 Hz, 1 H), 2.56-2.50 (m, 2H), 2.35 (dd, J = 16.26, 11.90 Hz, 1 H), 2.12-1.98 (m, 1 H), 1.38 (p, J= 7.23 Hz, 2H), 0.88 (t, J = 7.41 Hz, 3H). LC-MS: rt = 1.31 min, MS: 238.1 (calcd), 239.1 (M+H+, found).
Example 120
2-Amino-4-oxo-4,7-dihydro-5H-spiro[benzo[b]thiophene-6, -cyclopentane]-3- carboxamide (221)
Scheme 50
Figure imgf000177_0001
Step 1. 2-Amino-4,7-dihydro-5H-spiro[benzo[b]thiophene-6,1'-cyclopentane1-3- carboxamide (220)
To a solution of spiro[4.5]decan-8-one (151 , scheme 29) (99.6 mg, 0.654 mmol) and cyanoacetamide (50.0 mg, 0.595 mmol) in EtOH (0.595 mL) were added morpholine (0.056 mL, 0.654 mmol) and sulfur (21.1 mg, 0.082 mmol). The reaction mixture was stirred at 60 °C for 19 hours, then allowed to cool to RT and concentrated to dryness. The residue was first purified by flash column chromatography (eluent gradient from 0 to 10% of MeOH in DCM), then by reversephase flash column chromatography (eluent gradient from 10 to 100% CH3CN in H2O with 0.1% (v/v) formic acid) to afford title compound 220 as a white solid (77.0 mg, 50% yield). LC-MS: rt = 1.73 min, MS: 250.1 (calcd), 251.1 (M+H+, found).
Step 2. 2-Amino-4-oxo-4,7-dihydro-5H-spiro[benzo[b]thiophene-6, 1 '-cyclopentanel-3- carboxamide (221)
A mixture of 220 (10.0 mg, 0.040 mmol) and Oxone® (6.72 mg, 0.040 mmol) in DMSO (0.896 mL) was stirred at RT for 72 hours. The mixture was then diluted with EA and water and the aqueous layer was extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was first purified by flash column chromatography (eluent gradient from 0% to 10% of MeOH in DCM), then by Semi-Prep HPLC- MS (eluent gradient from 30% to 100% of ACN in 10 mM ammonium formate) to afford title compound 221 as a white solid (1.10 mg, 10% yield).
1H NMR: 400 MHz, CD3OD, δ (ppm): 2.86 (s, 2H), 2.59 (s, 2H), 1.74-1.67 (m, 4H), 1.63- 1 .47 (m, 4H). LC-MS: rt = 1 .55 min, MS: 264.1 (calcd), 265.1 (M+H+, found).
Example 121
2-Amino-6-(2-amino-2-oxoethyl)-N-cyclopropyl-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (228) Scheme 51
Figure imgf000178_0001
Step 1. 2-(8-Phenyl-1 ,4-dioxaspiro[4.51decan-8-yl)acetic acid (222)
Powdered potassium hydroxide (48.8 g, 799.0 mmol) was added to a solution of 2-(8- phenyl- 1 ,4-dioxaspiro[4.5]decan-8-yl)acetonitrile (92, scheme 17) (25.7 g, 99.9 mmol) (Bioorg Med. Chem Lett. 21 , p. 405, 2011) in ethylene glycol (524 mL) and water (12.9 mL). The resulting mixture was stirred at 170°C for 16 hours. The mixture was then allowed to cool to RT, diluted with water (250 mL) and washed with DCM (250 mL). This organic layer was discarded. The aqueous layer was acidified with 2 N HCI and extracted with DCM (2 x 250 mL). These organic phases were combined and dried over Na2SO4, then filtered and concentrated to afford title compound 222 as a light-orange solid (24.8 g, 90% yield) which was not characterized and used directly for the next step.
Step 2. 2-(4-Oxo-1-phenylcyclohexyl)acetic acid (223)
To a solution of 222 (2.83 g, 10.2 mmol) in acetone (127 mL) was added 2 N HCI (51.2 mL, 102 mmol) and the reaction mixture was stirred at RT for 16 hours. Then, the mixture was neutralized by slowly adding saturated aqueous NaHCO3 solution and concentrated to remove the organic solvent. The residue was extracted with EA and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to dryness to afford title compound 223 as a yellow oil (2.38 g, 96% yield), which was not characterized and used directly for the next step.
Step 3. 2-(2-Amino-3-(ethoxycarbonyl)-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophen-6- yl)acetic acid (224)
To a solution of 223 (2.38 g, 10.2 mmol) and ethyl 2-cyanoacetate (1.20 mL, 11.3 mmol) in EtOH (10.2 mL) were added morpholine (1 .97 mL, 22.5 mmol) and sulfur (363 mg, 1 .41 mmol). The reaction mixture was stirred at 60 °C for 16 hours, then allowed to cool to RT and concentrated to dryness. The residue was partitioned between water and EA. The layers were separated and the organic phase was dried over Na2SO4, filtered and concentrated. The residue was triturated in MeOH to afford title compound 224 as a beige solid (2.44 g, 66% yield). LC-MS: rt = 1.42 min, MS: 359.1 (calcd), 360.0 (M+H+, found).
Step 4. Ethyl 2-amino-6-(2-amino-2-oxoethyl)-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (225)
Compound 224 (400 mg, 1.11 mmol) was dissolved in anhydrous DMF (11.0 mL). Then, ammonium chloride (1.19 g, 22.3 mmol), HATU (648 mg, 1.67 mmol) and DIPEA (0.388 mL, 2.23 mmol) were added and the reaction mixture was stirred at RT for 16 hours. The mixture was partitioned between aqueous NH4CI, brine and EA. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by reverse-phase flash column chromatography (eluent gradient from 5 to 100% CH3CN in H2O with 0.1% (v/v) formic acid) to afford title compound 225 as a white powder (320 mg, 80% yield). LC-MS: rt = 1 .21 min, MS: 358.1 (calcd), 359.2 (M+H+, found).
Step 5. Ethyl 2-acetamido-6-(2-amino-2-oxoethyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (226)
Acetic anhydride (0.101 mL, 1 .07 mmol) was added to a suspension of 225 (320 mg, 893 umol) in acetic acid (5.12 mL). The resulting mixture was stirred at 60°C for 1.5 hours, then at RT for 16 hours. After completion of the acylation, dioxane (2.59 mL), water (2.59 mL) and ceric sulfate (2.57 g, 7.72 mmol) were added to the mixture. The resulting suspension was stirred for 16 hours at RT. Afterwards, the mixture was diluted with water and extracted with EA. The organic layer was washed successively with NaOH 1 N, water and brine, then dried over Na2SO4, filtered and concentrated to afford title compound 226 as a an off-white solid (189 mg, 51% yield). LC- MS: rt = 1.25 min, MS: 414.1 (calcd), 415.2 (M+H+, found).
Step 6. 2-Amino-6-(2-amino-2-oxoethyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (227)
To a solution of 226 (189 mg, 0.456 mmol) in MeOH (55 mL) was added a solution of lithium hydroxide monohydrate (95.7 mg, 2.28 mmol) in water (55 mL). The reaction mixture was stirred at 80 °C for 2 hours, then allowed to cool to RT. The mixture was concentrated to remove most of the organic solvent. The aqueous residue was acidified by slowly adding HCI 1 N and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated to afford title compound 227 as an orange solid (143 mg, 91% yield). LC-MS: rt = 0.92 min, MS: 344.1 (calcd), 345.1 (M+H+, found).
Step 7. 2-Amino-6-(2-amino-2-oxoethyl)-/V-cyclopropyl-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (228)
To a solution of 227 (143 mg, 0.415 mmol) in anhydrous DMF (4.59 mL) at 0 °C were added PyBOP (238.0 mg, 0.457 mmol), N,N-diisopropylethylamine (0.145 mL, 0.83 mmol) and cyclopropylamine (0.144 mL, 2.08 mmol). Then, the reaction mixture was allowed to warm up to RT and stirred for 16 hours. Subsequently, the mixture was diluted with a saturated aqueous solution of NH4CI and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was first purified by flash column chromatography (eluent gradient from 20% to 100% of EA in hexane), then by Semi-Prep HPLC-MS (eluent gradient from 30% to 100% of MeOH in 10 mM ammonium formate) to afford title compound 228 as a white solid (31 .5 mg, 20% yield).
1H NMR: 400 MHz, CD3OD, δ (ppm): 7.32-7.28 (m, 4H), 7.23-7.20 (m, 1 H), 2.98 (d, J = 14.80 Hz, 1 H), 2.78-2.74 (m, 1 H), 2.73-2.70 (m, 1 H), 2.69-2.66 (m, 1 H), 2.65-2.59 (m, 2H), 2.55- 2.47 (m, 1 H), 0.71-0.67 (m, 2H), 0.51-0.48 (m, 2H). LC-MS: rt = 0.99 min, MS: 383.1 (calcd), 384.3 (M+H+, found).
Example 122 (S)-2-Amino-6-(2-hydroxyethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (229) and
Example 123 (R)-2-Amino-6-(2-hydroxyethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (230)
Scheme 52
Figure imgf000181_0001
Racemic compound 215 (example 117) (917 mg) was submitted to SFC chiral separation (isocratic: 50% of MeOH 1 : 1 in CO2) to yield enantioenriched compound 229 as a white solid (177 mg, 19% separation yield) and enantioenriched compound 230 as a white solid (176 mg, 19% separation yield). Absolute configurations of compounds 229 and 230 were assigned based on analogy with the assignment of the absolute configuration of a crystallized compound within the same or similar series.
229: 1H NMR: same as racemic mixture (215). LC-MS: rt = 0.94 min, MS: 330.1 (calcd), 331.0 (M+H+, found). Analytical SFC (from 5% to 60% of MeOH 1 :1 in water): rt = 3.55 min, ee. = 98.3%.
230: 1H NMR: same as racemic mixture (215). LC-MS: rt = 0.94 min, MS: 330.1 (calcd), 331.0 (M+H+, found). Analytical SFC (from 5% to 60% of MeOH 1 :1 in water): rt = 3.83 min, ee. = 98.6%.
Example 124
2-Amino-6-(2-(1-methyl-1H-1,2,3-triazol-4-yl)ethyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (231) and
Example 125
2-Amino-6-(2-(5-iodo-1-methyl-1H-1,2,3-triazol-4-yl)ethyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (232)
Scheme 53
Figure imgf000181_0002
179: Example 98 231: Example 124 232: Example 125
Scheme 36
Copper(ll) sulfate pentahydrate (60 mg, 0.24 mmol) and sodium ascorbate (47 mg, 0.24 mmol) were added to a solution of 2-amino-6-(but-3-yn-1-yl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (179, scheme 36, example 98) (40 mg, 0.12 mmol) in DMF/H2O 1 :1 (2.6 mL). The flaskwas evacuated and backfilled with nitrogen, then iodomethane (0.06 mL, 0.95 mmol) and sodium azide (61 mg, 0.95 mmol) were added and the reaction mixture was stirred for 5 days at 50 °C. The mixture was then quenched with a saturated aqueous solution of NaHCO3 and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 20% of MeOH in DCM) to afford title compound 231 as an off-white solid (10 mg, 21% yield) and title compound 232 as a pale-yellow solid (12 mg, 19% yield).
231 : 1H NMR: 400 MHz, CD3OD, δ (ppm): 7.60 (s, 1 H), 7.36-7.29 (m, 4H), 7.25-7.21 (m, 1 H), 4.01 (s, 3H), 3.01-2.94 (m, 1 H), 2.77-2.67 (m, 3H), 2.61-2.53 (m, 1H), 2.46-2.39 (m, 1 H), 2.27-2.14 (m, 2H). LC-MS: rt = 1 .00 min, MS: 395.1 (calcd), 396.3 (M+H+, found).
232: 1H NMR: 400 MHz, CD3OD, δ (ppm): 7.38-7.31 (m, 4H), 7.25-7.20 (m, 1 H), 4.01 (s, 3H), 3.02-2.95 (m, 1H), 2.78-2.61 (m, 3H), 2.58-2.50 (m, 1 H), 2.46-2.38 (m, 1 H), 2.21-2.16 (m, 2H). LC-MS: rt = 1.17 min, MS: 521.0 (calcd), 522.1 (M+H+, found).
Example 126 6-(2-(2H-Tetrazol-5-yl)ethyl)-2-amino-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene- 3-carboxylic acid (237)
Figure imgf000182_0001
Step 1. 5-(2-(8-Phenyl-1 ,4-dioxaspiro[4.51decan-8-yl)ethyl)-2H-tetrazole (233)
Triethylamine hydrochloride (1.27 g, 9.21 mmol) and sodium azide (719 mg, 11.1 mmol) were added to a solution of 3-(8-phenyl-1 ,4-dioxaspiro[4.5]decan-8-yl)propanenitrile (156, scheme 30) (500 mg, 1.84 mmol) in DMF (15 mL). The reaction was stirred at 120 °C for 18 hours, then it was diluted with water and neutralized by slow addition of 1 N HCI. The product was extracted with EA and the organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography (eluent gradient from 0% to 20% of MeOH in DCM). The collected fractions were concentrated, suspended in heptane and concentrated again to afford title compound 233 as a pale-yellow solid, which was used directly for the following step.
Step 2. 4-(2-(2H-Tetrazol-5-yl)ethyl)-4-phenylcyclohexan-1-one (234)
To a solution of 233 in acetone (15 mL) was added HCI 2 N (6.15 mL, 12.3 mmol) and the reaction was stirred at 40 °C for 16 hours. Then, the mixture was concentrated to remove the organic solvent. The residue was extracted with EA and the organic layer was dried over Na2SO4, filtered and concentrated to afford title compound 234 as a yellow oil (350 mg, 70% yield over two steps). LC-MS: rt = 0.98 min, MS: 270.3 (calcd), 271 .2 (M+H+, found).
Step 3. Ethyl 6-(2-(2H-tetrazol-5-yl)ethyl)-2-amino-6-phenyl-4, 5,6,7- tetrahydrobenzo[b1]thiophene-3-carboxylate (235)
To a solution of 234 (350 mg, 1.29 mmol) and ethyl 2-cyanoacetate (0.155 mL, 1.42 mmol) in EtOH (1.3 mL) were added morpholine (0.24 mL, 2.10 mmol) and sulfur (46 mg, 0.179 mmol). The reaction mixture was stirred at 60 °C for 16 hours, then allowed to cool to RT and concentrated to dryness. The residue was partitioned between EA and water. The layers were separated and the aqueous phase was acidified by adding 1 N HCI and extracted again with EA. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 20% to 100% of EA in hexane) to afford title compound 235 as a pale-yellow solid (119 mg, 23% yield). LC-MS: rt = 1.40 min, MS: 397.2 (calcd), 398.3 (M+H+, found).
Step 4. Ethyl 6-(2-(2H-tetrazol-5-yl)ethyl)-2-acetamido-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (236)
To a solution of 235 (119 mg, 0.30 mmol) in acetic acid (1.7 mL) was added acetic anhydride (0.034 mL, 0.36 mmol). The reaction was stirred at 80 °C for 2 hours. Then, the mixture was allowed to cool to RT and diluted with acetic acid (0.3 mL), water (2.0 mL) and dioxane (2.0 mL). Ceric sulfate (798 mg, 2.40 mL) was added to the mixture and the flask was sonicated to make the suspension homogeneous. Then, the reaction was vigourously stirred at RT for 24 hours. Afterwards, the mixture was diluted with water and extracted with EA. The organic layer was washed with brine, then dried over Na2SO4, filtered and concentrated to afford title compound 236 as a yellow paste (91 mg, 67% yield). LC-MS: rt = 1.37 min, MS: 453.2 (calcd), 454.3 (M+H+, found).
Step 5. 6-(2-(2H-Tetrazol-5-yl)ethyl)-2-amino-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (237)
To a solution of 236 (91 mg, 0.20 mmol) in MeOH (25 mL) was added a solution of lithium hydroxide monohydrate (42 mg, 1 .0 mmol) in water (25 mL). The reaction was stirred at 60 °C for 16 hours, then more lithium hydroxide monohydrate (42 mg, 1.0 mmol) was added and the reaction was stirred at 60 °C for additional 8 hours. The mixture was allowed to cool to RT and concentrated to remove most of the organic solvent. Then, it was acidified by slowly adding 1 N HCI and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated to afford title compound 237 as a pale-yellow solid (77 mg, >99% yield).
1H NMR: 400 MHz, CD3OD, δ (ppm): 7.38-7.30 (m, 4H), 7.26-7.22 (m, 1 H), 3.28-3.21 (m, 1 H), 3.12-3.04 (m, 1H), 2.84-2.76 (m, 1 H), 2.66-2.61 (m, 1 H), 2.54-2.45 (m, 1 H), 2.40-2.34 (m, 1 H), 2.33-2.29 (m, 2H). LC-MS: rt = 1.03 min, MS: 383.1 (calcd), 384.2 (M+H+, found).
Example 127 6-(2-(2H-Tetrazol-5-yl)ethyl)-2-amino-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (238)
Scheme 55
Figure imgf000184_0001
Scheme 54
To a mixture of 237 (scheme 54, example 126) (40 mg, 0.10 mmol) and ammonium chloride (56 mg, 1.04 mmol) in anhydrous DMF (1.3 mL) were added HATU (79 mg, 0.21 mmol) and N,N-diisopropylethylamine (0.073 mL, 0.417 mmol). The reaction was stirred for 10 minutes, before bubbling gaseous NH3 through the mixture for additional 30 minutes. Afterwards, the reaction was quenched with a saturated aqueous solution of NH4CI and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase flash column chromatography (eluent gradient from 0% to 100% of CH3CN in 0.1 % formic acid (v/v) in water) to afford title compound 238 as a pale-yellow solid (18 mg, 45% yield).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.11 (s, 2H), 7.36-7.31 (m, 4H), 7.27-7.23 (m, 1 H), 6.89 (bs, 2H), 2.91-2.86 (m, 1H), 2.84-2.78 (m, 1 H), 2.74-2.61 (m, 3H), 2.31-2.22 (m, 1 H), 2.21- 2.17 (m, 2H). LC-MS: rt = 0.94 min, MS: 382.1 (calcd), 383.2 (M+H+, found).
Example 128
6-(2-(2H-Tetrazol-5-yl)ethyl )-2-amino-N-cyclopropyl-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (239)
Scheme 56
Figure imgf000185_0001
Scheme 54
To a solution of 237 (scheme 4, example 126) (30 mg, 0.078 mmol) in anhydrous DMF (1.0 mL) were added PyBOP (82 mg, 0.156 mmol), N,N-diisopropylethylamine (0.041 mL, 0.235 mmol) and cyclopropylamine (0.054 mL, 0.782 mmol) and the reaction mixture was stirred at RT for 3 hours. Then, the reaction was quenched with a saturated aqueous solution of NH4CI, the mixture was acidified with 1 N HCI and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was first purified by reverse-phase flash column chromatography (eluent gradient from 0% to 100% of CH3CN in 0.1 % formic acid (v/v) in water) and then Semi-Prep HPLC-MS (eluent gradient from 5% to 100% of CH3CN in 10 mM ammonium bicarbonate) to afford title compound 239 as a white solid (8 mg, 24% yield).
1H NMR: 400 MHz, CD3OD, δ (ppm): 7.36-7.30 (m, 4H), 7.26-7.21 (m, 1 H), 3.08-3.00 (m, 1 H), 2.84-2.73 (m, 2H), 2.70-2.60 (m, 3H), 2.41-2.36 (m, 1 H), 2.33-2.28 (m, 2H), 0.76-0.67 (m, 2H), 0.56-0.48 (m, 2H). LC-MS: rt = 1.11 min, MS: 422.2 (calcd), 423.4 (M+H+, found).
Example 211
2-Amino-6-(2-(1 ,5-dimethyl-1 H-1 ,2,3-triazol-4-yl)ethyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (245) and
Example 129
2-Amino-6-(2-(1 ,5-dimethyl-1 H-1 ,2,3-triazol-4-yl)ethyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (246)
Scheme 57
Figure imgf000186_0001
Step 1 . 1-Methyl-4-(2-(8-phenyl-1 ,4-dioxaspiro[4.5ldecan-8-yl)ethyl)-1 H-1 ,2,3-triazole
Sodium ascorbate (15 mg, 0.074 mmol) and copper(l) iodide (141 mg, 0.74 mmol) were added to a solution of 8-(but-3-yn-1-yl)-8-phenyl-1 ,4-dioxaspiro[4.5]decane (177, scheme 35) (100 mg, 0.37 mmol) in a DMF/H2O 1 :1 mixture (8 mL). The flask was evacuated and backfilled with nitrogen. Then, iodomethane (0.186 mL, 2.96 mmol) and sodium azide (192 mg, 2.96 mmol) were added and the reaction mixture was stirred at 50 °C for 30 minutes. The mixture was then diluted with a saturated aqueous solution of NH4CI and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was suspended in heptane and concentrated again to afford title compound 240 as a white solid (113 mg, 93% yield). LC-MS: rt = 1.30 min, MS: 327.2 (calcd), 328.2 (M+H+, found).
Step 2. 1 ,5-Dimethyl-4-(2-(8-phenyl-1 ,4-dioxaspiro[4.51decan-8-yl)ethyl)-1H-1 ,2,3- triazole (241) n-Butyl lithium (0.21 mL, 2.5 M in hexane, 0.52 mmol) was added to a solution of 240 (113 mg, 0.35 mmol) in anhydrous THF (2.6 mL) at -78 °C and the reaction mixture was stirred at the same temperature for 1 hour. Then, iodomethane (0.043 mL, 0.69 mmol) was added and the reaction mixture was allowed to slowly reach RT and stirred for 24 hours. The reaction was quenched with a saturated aqueous solution of NH4CI and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated to afford title compound 241 as a yellow oil (116 mg, 98% yield). LC-MS: rt = 1.26 min, MS: 341.2 (calcd), 342.2 (M+H+, found).
Step 3. 4-(2-(1 ,5-Dimethyl-1H-1 ,2,3-triazol-4-yl)ethyl)-4-phenylcyclohexan-1-one (242) To a solution of 241 (116 mg, 0.34 mmol) in acetone (4 mL) was added 2 N HCI (1.70 mL, 3.40 mmol) and the reaction was stirred at 40 °C for 16 hours. Then, the mixture was neutralized with a saturated aqueous solution of NaHCO3 and concentrated to remove the organic solvent. The residue was extracted with EA and the organic layer was dried over Na2SO4, filtered and concentrated to afford title compound 242 as an off-white solid (91 mg, 90% yield). LC-MS: rt = 1.18 min, MS: 297.2 (calcd), 298.2 (M+H+, found).
Step 4. Ethyl 2-amino-6-(2-(1 ,5-dimethyl-1 H-1 ,2,3-triazol-4-yl)ethyl)-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (243)
To a solution of 242 (91 mg, 0.306 mmol) and ethyl 2-cyanoacetate (0.036 mL, 0.337 mmol) in EtOH (0.3 mL) were added morpholine (0.029 mL, 0.337 mmol) and sulfur (11 mg, 0.042 mmol). The reaction was heated at 60 °C for 16 hours, then allowed to cool to RT and concentrated to dryness. The residue was partitioned between EA and water. The layers were separated and the organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 40% to 100% of EA in hexane) to afford title compound 243 as a pale-orange solid (89 mg, 69% yield). LC-MS: rt = 1.51 min, MS: 424.2 (calcd), 425.3 (M+H+, found).
Step 5. Ethyl 2-acetamido-6-(2-(1 ,5-dimethyl-1 H-1 ,2,3-triazol-4-yl)ethyl)-7-oxo-6-phenyl- 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (244)
To a solution of 243 (89 mg, 0.21 mmol) in acetic acid (1.2 mL) was added acetic anhydride (0.024 mL, 0.25 mmol). The reaction was stirred at 80 °C for 3 hours. Then, the mixture was allowed to cool to RT and diluted with acetic acid (0.2 mL), water (1 .4 mL) and dioxane (1 .4 mL). Ceric sulfate (558 mg, 1.68 mL) was added to the mixture and the flask was sonicated to make the suspension homogeneous. Then, the reaction was vigourously stirred at RT for 24 hours. Afterwards, the mixture was diluted with water and extracted with EA. The organic layers were washed successively with 1 N NaOH, water and brine, then dried over Na2SO4, filtered and concentrated to afford title compound 244 as an off-white solid (71 mg, 70% yield). LC-MS: rt = 1.46 min, MS: 480.2 (calcd), 481.3 (M+H+, found).
Step 6. 2-Amino-6-(2-(1 ,5-dimethyl-1 H-1 ,2,3-triazol-4-yl)ethyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (245)
To a solution of 244 (71 mg, 0.148 mmol) in MeOH (19 mL) was added a solution of lithium hydroxide monohydrate (31 mg, 0.74 mmol) in water (19 mL). The reaction mixture was stirred at 60 °C for 16 hours, then more lithium hydroxide monohydrate (31 mg, 0.74 mmol) was added and the mixture was stirred at 60 °C for another 8 hours. The mixture was then allowed to cool to RT and concentrated to remove most of the organic solvent. Then, it was acidified by slowly adding 1 N HCI and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated to afford title compound 245 as a yellow solid (69 mg, >99% yield). 1H NMR: 400 MHz, CD3OD, δ (ppm): 7.33-7.28 (m, 4H), 7.24-7.19 (m, 1 H), 3.88 (s, 3H), 3.27-3.21 (m, 1 H), 2.71-2.60 (m, 2H), 2.57-2.44 (m, 2H), 2.43-2.36 (m, 1 H), 2.18 (s, 3H), 2.17- 2.08 (m, 2H). LC-MS: rt = 1.06 min, MS: 410.1 (calcd), 411 .2 (M+H+, found).
Step 7. 2-Amino-6-(2-(1 ,5-dimethyl-1 H-1 ,2,3-triazol-4-yl)ethyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (246)
To a mixture of 245 (59 mg, 0.144 mmol) and ammonium chloride (77 mg, 1.44 mmol) in anhydrous DMF (1.8 mL) were added HATU (109 mg, 0.287 mmol) and N,N- diisopropylethylamine (0.075 mL, 0.431 mmol). The resulting mixture was stirred for 10 minutes, before bubbling gaseous NH3 through the mixture for additional 30 minutes. Afterwards, the reaction was quenched with a saturated aqueous solution of NH4CI and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was first purified by reverse-phase flash column chromatography (eluent gradient from 0% to 100% of CH3CN in 0.1% formic acid (v/v) in water) and then Semi-Prep HPLC-MS (eluent gradient from 20% to 100% of CH3CN in 10 mM ammonium bicarbonate) to afford title compound 246 as a white solid (3.7 mg, 6% yield over two steps).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.08 (s, 2H), 7.33-7.30 (m, 4H), 7.26-7.20 (m, 1 H), 6.84 (bs, 2H), 3.81 (s, 3H), 2.92-2.86 (m, 1 H), 2.76-2.61 (m, 2H), 2.46-2.41 (m, 1 H), 2.37-2.26 (m, 2H), 2.10 (s, 3H), 2.05-1.93 (m, 2H). LC-MS: rt = 1.00 min, MS: 409.2 (calcd), 410.2 (M+H+, found).
Example 130 (R)-2-Amino-6-cyano-N-cyclopropyl-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-
3-carboxamide (247) and Example 131 (S)-2-Amino-6-cyano-N-cyclopropyl-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene- 3-carboxamide (248)
Scheme 58
Figure imgf000188_0001
Scheme 32
1 .05 g of racemic compound 170 (scheme 32, example 95) were submitted to SFC Chiral Separation to afford enantioenriched title compound 247 as a white solid (302 mg, 29% separation yield) and enantioenriched title compound 248 as a white solid (258 mg, 25% separation yield). Absolute configurations of compounds 247 and 248 were assigned based on analogy with the assignment of the absolute configuration of a crystallized compound within the same or similar series.
247: 1H NMR: same as racemic mixture (170). LC-MS: rt = 1.25 min, MS: 351.1 (calcd),
352.2 (M+H+, found). Analytical SFC (IG column with 5-60% MeOH in water (95-40% CO2) gradient): rt = 4.50 min, ee. = 99.98%.
248: 1H NMR: same as racemic mixture (170). LC-MS: rt = 1.25 min, MS: 351.1 (calcd),
352.2 (M+H+, found). Analytical SFC (IG column with 5-60% MeOH in water (95-40% CO2) gradient): rt = 5.93 min, ee. = 98.88%.
Example 132
(R)-2-Amino-6-cyano-N-cyclopropyl-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene- 3-carboxamide (249) and Example 133
(S)-2-Amino-6-cyano-N-cyclopropyl-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene- 3-carboxamide (250)
Scheme 59
Figure imgf000189_0001
146: Example 86 249: Example 132 250: Example 133
Scheme 27
2.18 g of racemic compound 146 (scheme 27, example 86) were submitted to SFC Chiral Separation to afford enantioenriched title compound 249 as an off-white solid (932 mg, 43% separation yield) and enantioenriched title compound 250 as an off-white solid (903 mg, 41% separation yield). Absolute configurations of compounds 249 and 250 were assigned based on analogy with the assignment of the absolute configuration of a crystallized compound within the same or similar series.
249: 1H NMR: same as racemic mixture (146). LC-MS: rt = 1.09 min, MS: 300.1 (calcd),
301.1 (M+H+, found). Analytical SFC (IG column with 5-60% MeOH in water (95-40% CO2) gradient): rt = 4.67 min, ee. = 99.94%.
250: 1H NMR: same as racemic mixture (146). LC-MS: rt = 1.09 min, MS: 300.1 (calcd),
301.1 (M+H+, found). Analytical SFC (IG column with 5-60% MeOH in water (95-40% CO2) gradient): rt = 6.17 min, ee. = 97.60%.
Example 134 2-Amino-6-cyano-N-cyclopropyl-6-((1-methylcyclopropyl)methyl)-7 -oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (251)
Figure imgf000190_0001
251 : Example 134
Compound 251 (example 134) was synthesized similarly to compound 82 (scheme 13) starting from compound 173 (scheme 34) instead of compound 81.
1H NMR (400 MHz, CDCI3) δ 7.06 (bs, 2H), 5.69 (bs, 1 H), 3.16-2.95 (m, 2H), 2.87-2.78 (m, 1H), 2.66 (dt, J = 13.6, 4.3 Hz, 1 H), 2.34 (ddd, J = 14.0, 9.6, 4.7 Hz, 1 H), 2.13 (d, J = 14.7 Hz, 1 H), 1.91 (d, J = 14.7 Hz, 1 H), 1.17 (s, 3H), 0.93-0.87 (m, 2H), 0.65-0.57 (m, 2H), 0.42-0.35 (m, 4H). LC-MS: rt = 1.28 min, MS: 343.1 (calcd), 344.2 (M+H+, found).
Example 135
2-Amino-6-(2-(3-methylisoxazol-4-yl)ethyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (253)
Intermediate compound 252
3-Methyl-4-(2-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)ethyl)isoxazole (252)
Scheme 60
Figure imgf000190_0002
Scheme 35
A solution of /V-hydroxyacetimidoyl chloride (Angew. Chem. Int. Ed. 2017, 12586-12589.) (174 mg, 1.86 mmol) in DCE (9.86 mL) was purged with argon for 2 min, then 8-(but-3-yn-1-yl)- 8-phenyl-1 ,4-dioxaspiro[4.5]decane (177, scheme 35) (504 mg, 1.86 mmol), chloro(pentamethylcyclopentadienyl)(cyclooctadiene)ruthenium(ll) (36.1 mg, 93.2 umol) and triethylamine (0.326 mL, 2.33 mmol) were added and the resulting mixture was stirred at RT for 16 hours. The mixture was then filtered, the filtrate was concentrated to dryness, and the residue was purified by flash column chromatography (eluent gradient from 5% to 80% of EA in hexane) to afford title compound 252 as a light-yellow gum (442 mg, 72% yield). LC-MS: rt = 1.61 min, MS: 327.2 (calcd), 328.2 (M+H+, found). 2-Amino-6-(2-(3-methylisoxazol-4-yl)ethyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (253)
Figure imgf000191_0001
253: Example 135
Compound 253 was synthesized similarly to compound 189 (scheme 40) starting from compound 252 instead of compound 185.
1H NMR (400 MHz, CDCI3) δ 8.02 (s, 1 H), 7.36-7.29 (m, 4H), 7.29-7.21 (m, 1 H, partially overlapping with the solvent signal), 6.65 (bs, 2H), 3.28-3.19 (m, 1 H), 2.78-2.54 (m, 2H), 2.49- 2.33 (m, 2H), 2.26-2.20 (m, 1 H), 2.19 (s, 3H), 2.12 (dd, J = 12.9, 4.0 Hz, 1 H), 2.08-1.99 (m, 1 H). LC-MS: rt = 1.36 min, MS: 396.1 (calcd), 397.3 (M+H+, found).
Example 136
2-Amino-N-cyclopropyl-6-(2-(3-methylisoxazol-4-yl)ethyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (254)
Scheme 61
Figure imgf000191_0002
253 254: Example 136
To a solution of 253 (34.8 mg, 87.8 umol) in DMF (0.97 mL) were added N,N- diisopropylethylamine (49 uL, 281 umol), PyBOP (68.7 mg, 132 umol) and cyclopropylamine (62.7 uL). The resulting mixture was stirred at RT for 2.5 hours. The mixture was then diluted with saturated aqueous NH4CI (5 mL) and extracted with EA (3 x 5 mL). The combined organics were washed with ice-cold brine (10 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was first purified by reverse-phase flash column chromatography (eluent gradient from 0% to 100% CH3CN in 10 mM aqueous ammonium bicarbonate) and then by flash column chromatography (eluent gradient from 0% to 100% of EA in hexane) to afford title compound 254 as an off-white solid (15.5 mg, 41% yield). 1H NMR (400 MHz, CDCI3) δ 8.01 (s, 1 H), 7.38-7.26 (m, 5H), 7.01 (bs, 2H), 5.53 (bs, 1 H), 2.89-2.78 (m, 1 H), 2.76-2.68 (m, 1 H), 2.65-2.57 (m, 1 H), 2.56-2.40 (m, 3H), 2.29-2.09 (m, 5H), 2.03-1 .94 (m, 1 H), 0.91-0.74 (m, 2H), 0.58-0.47 (m, 2H). LC-MS: rt = 1 .33 min, MS: 435.2 (calcd), 436.3 (M+H+, found).
Example 137 2-Amino-6-(2-(3-methylisoxazol-4-yl)ethyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (255)
Figure imgf000192_0001
Compound 255 was synthesized similarly to compound 52 (scheme 6) starting from compound 253 instead of compound 51.
1H NMR (400 MHz, CDCI3) δ 8.02 (s, 1 H), 7.40-7.22 (m, 5H), 7.06 (bs, 2H), 5.36 (bs, 2H), 2.96 (d, J = 15.6 Hz, 1 H), 2.71-2.56 (m, 2H), 2.53-2.42 (m, 2H), 2.27-2.10 (m, 5H), 2.07-1.96 (m, 1 H). LC-MS: rt = 1.16 min, MS: 395.1 (calcd), 396.2 (M+H+, found).
Example 138
2-Amino-6-(2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (258)
Intermediate compound 256
3-Methyl-5-(2-(8-phenyl-1 ,4-dioxaspiro[4.5]decan-8-yl)ethyl)-1 ,2,4-oxadiazole (256)
Scheme 62
Figure imgf000192_0002
To a mixture of 3-(8-phenyl-1 ,4-dioxaspiro[4.5]decan-8-yl)propanenitrile (156, scheme 30) (300 mg, 1.11 mmol) (Bioorg Med. Chem Lett. 21 , p. 405, 2011) and /V-hydroxyacetimidamide (93.8 mg, 1.22 mmol) in DMF (0.91 mL) were added 4-toluenesulfonicacid monohydrate (63.1 mg, 332 umol) and zinc chloride (45.2 mg, 332 umol). The resulting mixture was stirred under nitrogen at 80 °C for 8 days, then allowed to cool to RT, diluted with EA (10 mL), washed with saturated aqueous sodium bicarbonate (3 x 10 mL) and ice-cold brine (2 x 15 mL), then dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash column chromatography (eluent gradient from 0% to 60% of EA in hexane) to afford title compound 256 as a colorless oil (39.8 mg, 11% yield). LC-MS: rt = 1.42 min, MS: 328.2 (calcd), 329.2 (M+H+, found).
2-Amino-6-(2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (258)
Scheme 63
Figure imgf000193_0001
To a solution of 257 (synthesized similarly to compound 189 (scheme 40) starting from compound 256 instead of compound 185) (22 mg, 55.4 umol) in DMF (0.7 mL) were added ammonium chloride (29.6 mg, 554 umol), HATU (42.1 mg, 111 umol) and N,N- diisopropylethylamine (40 uL, 230 umol). The resulting solution was stirred at RT for 10 minutes, then excess of gaseous NH3 was bubbled through the mixture from a balloon. Stirring continued at RT for 30 minutes, then the mixture was diluted with saturated aqueous NH4CI (10 mL) and extracted with EA (3 x 10 mL). The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase flash column chromatography (eluent gradient from 0% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid) to afford title compound 258 as a light-yellow solid (7 mg, 32% yield).
1H NMR (400 MHz, CDCI3) δ 7.36-7.26 (m, 5H), 7.03 (bs, 2H), 5.34 (bs, 2H), 3.11 (ddd, J = 16.3, 10.9, 5.8 Hz, 1 H), 3.00-2.90 (m, 1 H), 2.74-2.62 (m, 1 H), 2.62-2.53 (m, 2H), 2.47-2.34 (m, 3H), 2.33 (s, 3H). LC-MS: rt = 1 .11 min, MS: 396.1 (calcd), 397.2 (M+H+, found).
Example 139 2-Amino-6-(2-(3-bromoisoxazol-5-yl)ethyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (263) Scheme 64
Figure imgf000194_0001
Step 1. 3-Bromo-5-(2-(8-phenyl-1 ,4-dioxaspiro[4.51decan-8-yl)ethyl)isoxazole (259)
A solution of dibromoformaldoxime (2.21 g, 10.9 mmol) in 13 mL of EA was added dropwise to a solution of 177 (scheme 35) (737 mg, 2.73 mmol) and potassium carbonate (755 mg, 5.5 mmol) in EA (60 mL) and water (7.3 mL). The reaction mixture was heated at 40 °C for 20 hours. The mixture was then allowed to cool to RT, additional potassium carbonate (755 mg, 5.5 mmol) and dibromoformaldoxime (1.1 g, 5.5 mmol) were added and stirring at 40 °C was continued for another 72 hours. EA (20 mL) and water (20 mL) were then added, the organic layer was separated and the desired product was extracted with an additional 40 mL of EA. The organic layers were combined, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (eluent gradient from 0% to 25% of EA in hexane) to afford title compound 259 as a pale-yellow sticky solid (885 mg, 83% yield).
Step 2. 4-(2-(3-Bromoisoxazol-5-yl)ethyl)-4-phenylcyclohexan-1-one (260)
To a solution of 259 (680 mg, 1.73 mmol) in acetone (24 mL) was added 2 N HCI (8.7 mL, 17.3 mmol) and the reaction mixture was stirred at 40 °C for 16 hours. Then, the mixture was neutralized by slowly adding a saturated aqueous solution of NaHCO3 and concentrated to remove the organic solvent. The residue was extracted with EA and the organic layer was dried over Na2SO4, filtered and concentrated to dryness to afford title compound 260 as a white solid (589 mg, 98% yield). LC-MS: rt = 1.60 min, MS: 347.1 and 349.1 (calcd), 348.1 and 350.2 (M+H+, found).
Step 3. Ethyl 2-amino-6-(2-(3-bromoisoxazol-5-yl)ethyl)-6-phenyl-4,5,6,7- tetrahydrobenzo[bl]thiophene-3-carboxylate (261)
To a solution of 260 (604 mg, 1.73 mmol) and ethyl 2-cyanoacetate (0.185 mL, 1.73 mmol) in EtOH (3 mL) were added morpholine (0.165 mL, 1 .91 mmol) and sulfur (61 .4 mg, 0.239 mmol). The reaction mixture was stirred at 60 °C for 16 hours, then allowed to cool to RT and concentrated to dryness. The residue was purified by flash column chromatography (eluant gradient from 0% to 60% of EA in hexane) to afford title compound 261 as a yellow oil (547 mg, 66% yield). LC-MS: rt = 1.94 min, MS: 474.1 and 476.1 (calcd), 475.2 and 477.2 (M+H+, found).
Step 4. Ethyl 2-acetamido-6-(2-(3-bromoisoxazol-5-yl)ethyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (262)
A mixture of 261 (545 mg, 1.15 mmol) and acetic anhydride (0.130 mL, 1.38 mmol) in acetic acid (6.6 mL) was stirred at 70 °C for 1 .5 hours. The mixture was then allowed to cool to RT, diluted with water (5 mL) and dioxane (5 mL) and ceric sulfate (3.5 g, 9.9 mmol) was added. The reaction mixture was stirred at RT for 3.5 hours. Then, the solid was filtered off, rinsed with EA (150 mL) and the filtrate was diluted with brine. The layers were separated, and the aqueous phase was extracted with EA (150 mL). The combined organics were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to afford title compound 262 as a yellow solid (400 mg, 66% yield). LC-MS: rt = 1.89 min, MS: 530.1 and 532.1 (calcd), 531 .1 and 533.1 (M+H+, found).
Step 5. 2-Amino-6-(2-(3-bromoisoxazol-5-yl)ethyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (263)
To a suspension of 262 (400 mg, 0.753 mmol) in MeOH (35 mL) was added a solution of lithium hydroxide monohydrate (537 mg, 12.8 mmol) in water (35 mL). The reaction mixture was stirred at 55 °C for 20 hours at which point additional lithium hydroxide monohydrate (316 mg, 7.5 mmol) was added. The mixture was stirred for another 20 hours at 55 °C, then allowed to cool to RT. The mixture was diluted with water and concentrated to remove most of the organic solvent and the aqueous residue was extracted with EA. This organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by reverse-phase flash column chromatography (eluent gradient from 0% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid) to afford title compound 263 as a pale-yellow solid (342 mg, 98% yield).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 12.50 (s, 1 H), 8.26 (s, 2H), 7.33-7.27 (m, 4H), 7.25-7.21 (m, 1 H), 6.55 (s, 1H), 3.14-3.09 (m, 1 H), 2.78-2.70 (m, 1H), 2.63-2.53 (m, 2H), 2.43- 2.35 (m, 1H), 2.28-2.21 (m, 1 H), 2.15-2.02 (m, 2H). LC-MS: rt = 1.54 min, MS: 460.0 and 462.0 (calcd), 461.1 and 463.1 (M+H+, found).
Example 140 2-Amino-6-(2-(3-bromoisoxazol-5-yl)ethyl)-N-cyclopropyl-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (264)
Scheme 65
Figure imgf000196_0001
To a suspension of 263 (100 mg, 0.217 mmol) in DMF (2 mL) were added HATU (165 mg, 0.434 mmol) and N,N-diisopropylethylamine (75.5 uL, 0.434 mmol). The mixture was stirred at RT for 20 minutes and then cyclopropylamine (150 uL, 2.17 mmol) was added. The reaction mixture was then stirred at RT for 72 hours at which point additional HATU (165 mg, 0.434 mmol) and N,N-diisopropylethylamine (75.5 uL, 0.434 mmol) were added and stirring continued at RT for another 2 hours. The mixture was then partitioned between EA and a saturated aqueous solution of NH4CI. The layers were separated and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 15% to 100% of EA in hexane) to afford title compound 264 as a pale-yellow solid (46.0 mg, 42% yield).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.83 (s, 2H), 7.30-7.27 (m, 5H), 7.24-7.20 (m, 1 H), 6.52 (s, 1 H), 2.75-2.51 (m, 6H), 2.22-2.12 (m, 1 H), 2.12-2.05 (m, 2H), 0.61-0.53 (m, 2H), 0.49- 0.38 (m, 2H). LC-MS: rt = 1.58 min, MS: 499.1 and 501.1 (calcd), 500.3 and 502.2 (M+H+, found). Example 141
6-(2-(1 H-1 ,2,4-T riazol-1 -yl)ethyl)-2-amino-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (271)
Scheme 66
Figure imgf000197_0001
Step 1. 2-(8-Phenyl-1 ,4-dioxaspiro[4.51decan-8-yl)ethyl methanesulfonate (266)
To a solution of 2-(8-phenyl-1 ,4-dioxaspiro[4.5]decan-8-yl)ethan-1-ol (265) (Bioorg. Med. Chem. Lett., 21 , p. 405, 2011) (5.64 g, 21.5 mmol) in anhydrous DCM (160 mL) at 0 °C were added methanesulfonyl chloride (1.83 mL, 23.6 mmol) and triethylamine (5.99 mL, 43.0 mmol). The reaction mixture was stirred at RT for 1 hour, then diluted with water and extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 70% of EA in hexane) to afford title compound 266 as a white solid (5.10 g, 70% yield).
Step 2. 1-(2-(8-Phenyl-1 ,4-dioxaspiro[4.51decan-8-yl)ethyl)-1H-1 ,2,4-triazole (267)
To a solution of 266 (1.20 g, 3.52 mmol) in anhydrous DMF (35 mL) was added 1 ,2,4- triazole sodium salt (1.60 g, 17.6 mmol). The reaction mixture was stirred at 110 °C for 20 hours, then allowed to cool to RT and quenched with saturated aqueous NH4CI solution (30 mL) diluted with water (15 mL). Then, the desired product was extracted with EA (2 x 40 mL). The organic layers were combined, washed with brine (2 x 50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 15% to 100% of EA in hexane) to afford title compound 267 as a colorless oil (970 mg, 88% yield). LC-MS: rt = 1.19 min, MS: 313.2 (calcd), 314.2 (M+H+, found).
Step 3. 4-(2-(1 H-1 ,2,4-Triazol-1-yl)ethyl)-4-phenylcyclohexan-1-one (268)
To a solution of 267 (965 mg, 3.08 mmol) in acetone (42 mL) was added 2 N HCI (15.4 mL, 30.8 mmol) and the reaction mixture was stirred at 40 °C for 16 hours. Then, the mixture was neutralized by slowly adding a saturated aqueous solution of NaHCO3 (20 mL). The residue was extracted with EA (3 x 20 mL) and the organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated to dryness to afford title compound 268 as a colorless oil (803 mg, 73% yield). LC-MS: rt = 1.04 min, MS: 269.2 (calcd), 270.3 (M+H+, found).
Step 4. Ethyl 6-(2-(1 H-1 ,2,4-Triazol-1-yl)ethyl)-2-amino-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (269)
To a solution of 268 (603 mg, 2.24 mmol) and ethyl 2-cyanoacetate (0.238 mL, 2.24 mmol) in EtOH (4 mL) were added morpholine (0.212 mL, 2.46 mmol) and sulfur (79 mg, 0.309 mmol). The reaction mixture was stirred at 60 °C for 16 hours, then allowed to cool to RT and concentrated to dryness. The residue was purified by flash column chromatography (eluant gradient from 0% to 100% of EA in hexane) to afford title compound 269 as a yellow oil (701 mg, 79% yield). LC-MS: rt = 1.46 min, MS: 396.2 (calcd), 397.3 (M+H+, found).
Step 5. Ethyl 6-(2-(1 H-1 ,2,4-Triazol-1-yl)ethyl)-2-acetamido-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (270)
A mixture of 269 (701 mg, 1.77 mmol) and acetic anhydride (0.334 mL, 3.54 mmol) in acetic acid (10 mL) was stirred at 60 °C for 1 hour. The mixture was allowed to cool to RT, then diluted with water (25 mL) and acetic acid (15 mL) and ceric sulfate (4.95 g, 14.1 mmol) was added. The reaction mixture was stirred at RT for 72 hours. EA (150 mL) and brine (100 mL) were then added and the organic layer was separated, washed successively with brine (100 mL) and saturated NaHCO3 solution (3 x 100 mL), dried over Na2SO4, filtered and concentrated to afford title compound 270 as an orange solid (560 mg, 70% yield). LC-MS: rt = 1.41 min, MS: 452.2 (calcd), 453.2 (M+H+, found).
Step 6. 6-(2-(1 H-1 ,2,4-Triazol-1-yl)ethyl)-2-amino-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (271)
To a suspension of 270 (560 mg, 1.24 mmol) in MeOH (57 mL) was added a solution of lithium hydroxide monohydrate (883 mg, 21.0 mmol) in water (57 mL). The reaction mixture was stirred at 50 °C for 16 hours, then allowed to cool to RT. The mixture was concentrated to remove most of the organic solvent. The aqueous layer was washed with EA. Then, the aqueous layer was acidified by slowly adding 1 N HCI and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by reverse-phase flash column chromatography (eluent gradient from 5% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid) to afford the title compound 271 as a pale-yellow solid (260 mg, 55% yield).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.58 (bs, 1H), 8.48 (s, 2H), 8.37 (s, 1 H), 7.85 (s, 1 H), 7.30-7.25 (m, 4H), 7.21-7.16 (m, 1 H), 4.24-4.17 (m, 1 H), 3.97-3.90 (m, 1 H), 3.42-3.35 (m, 2H), 2.27-2.21 (m, 3H), 2.16-2.09 (m, 1 H). LC-MS: rt = 1.03 min, MS: 382.1 (calcd), 383.2 (M+H+, found).
Example 142 6-(2-(1H-1,2,4-Triazol-1-yl)ethyl)-2-amino-N-cyclopropyl-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (272)
Scheme 67
Figure imgf000199_0001
271 272: Example 142
To a suspension of 271 (80 mg, 0.209 mmol) in DMF (2 mL) were added HATU (159 mg, 0.418 mmol) and N,N-diisopropylethylamine (72.9 uL, 0.418 mmol). The mixture was stirred at RT for 20 minutes and then cyclopropylamine (145 uL, 2.09 mmol) was added and stirring continued for another 20 hours. The crude mixture was then directly purified first by reverse-phase flash column chromatography (eluent gradient from 5% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid) and then by Semi-Prep HPLC-MS (eluent gradient from 40% to 100% of MeOH in 10 mM ammonium bicarbonate) to afford title compound 272 as an off-white solid (18.5 mg, 21% yield).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.37 (s, 1H), 7.86-7.81 (m, 3H), 7.34-7.28 (m, 4H), 7.25-7.21 (m, 1 H), 4.20-4.13 (m, 1 H), 3.94-3.87 (m, 1 H), 2.71-2.61 (m, 2H), 2.61-2.51 (m, 2H), 2.28-2.10 (m, 3H), 0.60-052 (m, 2H), 0.45-0.41 (m, 2H). LC-MS: rt = 1.08 min, MS: 421.2 (calcd), 422.3 (M+H+, found).
Example 143
6-(2-(1 H-1 ,2,4-T riazol-1 -yl)ethyl)-2-amino-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (273)
Scheme 68
Figure imgf000199_0002
271 273: Example 143
To a solution of 271 (70.0 mg, 183.0 umol) in DMF (2.3 mL) were added PyBOP (143 mg, 275 umol), N,N-diisopropylethylamine (128 uL, 732 umol) and ammonium chloride (97.9 mg, 1.83 mmol). The resulting mixture was stirred at RT for 20 hours. The crude mixture was directly purified by reverse-phase flash column chromatography (eluent gradient from 5% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid) to afford title compound 273 as a yellow solid (26.5 mg, 38% yield).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.37 (s, 1 H), 8.10 (s, 2H), 7.86 (s, 1 H), 7.34-7.30 (m, 4H), 7.26-7.20 (m, 1 H), 6.85 (bs, 1 H), 4.21-4.13 (m, 1 H), 3.95-3.88 (m, 1 H), 2.87-2.79 (m, 1 H), 2.68-2.55 (m, 2H), 2.29-2.19 (m, 3H). LC-MS: rt = 0.95 min, MS: 381.1 (calcd), 382.2 (M+H+, found).
Example 144
2-Amino-6-(2-((4-hydroxypyrimidin-5-yl)oxy)ethyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (278)
Scheme 69
Figure imgf000200_0001
277 278: Example 144
Step 1. 5-(2-(8-Phenyl-1 ,4-dioxaspiro[4.5ldecan-8-yl)ethoxy)pyrimidine (274)
To a solution of 266 (scheme 66) (1.20 g, 3.52 mmol) in anhydrous DMF (24 mL) was added potassium carbonate (1.46 g, 10.6 mmol) and pyrimidin-5-ol (406 mg, 4.23 mmol). The reaction mixture was stirred at 1 10 °C for 20 hours. The reaction mixture was then quenched with a saturated aqueous solution of NH4CI (30 mL) and diluted with water (15 mL). Then, the desired product was extracted with EA (2 x 40 mL). The organic layers were combined, washed with brine (2 x 50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 15% to 100% of EA in hexane) to afford title compound 274 as a yellow oil (927 mg, 77% yield). LC-MS: rt = 1.37 min, MS: 340.2 (calcd), 341.2 (M+H+, found).
Step 2. 4-Phenyl-4-(2-(pyrimidin-5-yloxy)ethyl)cyclohexan-1-one (275) To a solution of 274 (925 mg, 2.72 mmol) in acetone (37 mL) was added 2 N HCI (13.6 mL, 27.2 mmol) and the reaction mixture was stirred at 40 °C for 16 hours. Then, the mixture was neutralized by slowly adding a saturated aqueous solution of NaHCO3 (20 mL). The residue was extracted with EA (3 x 20 mL) and the organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated to dryness to afford title compound 275 as a yellow oil (805 mg, 99% yield). LC-MS: rt = 1.22 min, MS: 296.2 (calcd), 297.3 (M+H+, found).
Step 3. Ethyl 2-amino-6-phenyl-6-(2-(pyrimidin-5-yloxy)ethyl)-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (276)
To a solution of 275 (805 mg, 2.72 mmol) and ethyl 2-cyanoacetate (0.289 mL, 2.72 mmol) in EtOH (4.8 mL) were added morpholine (0.258 mL, 2.99 mmol) and sulfur (96.2 mg, 0.375 mmol). The reaction mixture was stirred at 60 °C for 16 hours, then allowed to cool to RT and concentrated to dryness. The residue was purified by flash column chromatography (eluent gradient from 0% to 55% of EA in hexane) to afford title compound 276 as a yellow oil (1 .0 g, 87% yield). LC-MS: rt = 1.64 min, MS: 423.2 (calcd), 424.3 (M+H+, found).
Step 4. Ethyl 2-acetamido-7-oxo-6-phenyl-6-(2-(pyrimidin-5-yloxy)ethyl)-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (277)
A mixture of 276 (1.0 g, 2.36 mmol) and acetic anhydride (0.446 mL, 4.72 mmol) in acetic acid (14 mL) was stirred at 60 °C for 1 hour. The mixture was then allowed to cool to RT and diluted with water (33 mL) and acetic acid (20 mL) and ceric sulfate (6.61 g, 18.9 mmol) was added. The reaction mixture was stirred at RT for 72 hours. EA (150 mL) and brine (100 mL) were then added and the organic layer was separated, washed successively with brine (100 mL) and a saturated aqueous solution of NaHCO3 (3 x 100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 10% to 100% of EA in hexane, then 15% MeOH in DCM) to afford title compound 277 as an orange solid (510 mg, 44% yield). LC-MS: rt = 1.33 min, MS: 495.2 (calcd), 496.3 (M+H+, found).
Step 5. 2-Amino-6-(2-((4-hydroxypyrimidin-5-yl)oxy)ethyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (278)
To a suspension of 277 (510 mg, 1.03 mmol) in MeOH (48 mL) was added a solution of lithium hydroxide monohydrate (650 mg, 15.5 mmol) in water (48 mL). The reaction mixture was stirred at 50 °C for 16 hours, then allowed to cool to RT. The mixture was concentrated to remove most of the organic solvent. The aqueous layer was washed with EA. Then, the aqueous layer was acidified by slowly adding 1 N HCI and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by reverse-phase flash column chromatography (eluent gradient from 5% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid) to afford the title compound 278 as a yellow solid (105 mg, 24% yield).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 12.48 (bs, 1 H), 8.23 (bs, 2H), 7.75 (s, 1H), 7.38 (s, 1 H), 7.33-7.25 (m, 4H), 7.23-7.16 (m, 2H), 3.96-3.89 (m, 1 H), 3.71-3.64 (m, 1 H), 3.10-3.03 (m, 1 H), 2.72-2.66 (m, 1 H), 2.36-2.12 (m, 4H). LC-MS: rt = 0.96 min, MS: 425.1 (calcd), 426.2 (M+H+, found).
Example 145 2-Amino-N-cyclopropyl-6-(2-((4-hydroxypyrimidin-5-yl)oxy)ethyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (279) and Example 146 2-Amino-N-cyclopropyl-6-(2-((4-(cyclopropylamino)pyrimidin-5-yl)oxy)ethyl)-7-oxo-6- phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (280)
Scheme 70
Figure imgf000202_0001
To a suspension of 278 (60 mg, 0.188 mmol) in DMF (1.35 mL) were added PyBOP (112 mg, 0.212 mmol) and N,N-diisopropylethylamine (98.3 uL, 0.564 mmol). The mixture was stirred at RT for 1.5 hours. The crude mixture was directly purified first by reverse-phase flash column chromatography (eluent gradient from 5% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid), then by flash column chromatography (eluent gradient from 0% to 15% of MeOH in DCM) and finally by Semi-Prep HPLC-MS (eluent gradient from 40% to 100% of MeOH in 10 mM ammonium formate) to afford title compound 279 as an off-white solid (13.4 mg, 20% yield) and 280 as an off-white solid (12.2 mg, 21% yield).
279: 1H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.83 (s, 2H), 7.75 (s, 1 H), 7.37 (s, 1 H), 7.30- 7.29 (m, 5H), 7.22-7.19 (m, 1 H), 3.92-3.89 (m, 1 H), 3.68-3.63 (m, 1 H), 2.70-2.58 (m, 4H), 2.25- 2.09 (m, 4H), 0.59-0.54 (m, 2H), 0.46-0.42 (m, 2H). LC-MS: rt = 1.05 min, MS: 464.2 (calcd), 465.3 (M+H+, found).
280: 1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.23 (s, 1 H), 8.08 (s, 1 H), 7.85 (s, 2H), 7.65 (s, 1 H), 7.37-7.34 (m, 4H), 7.26-7.21 (m, 1 H), 6.66-6.65 (m, 1 H), 4.01-3.95 (m, 1 H), 3.94-3.88 (m, 1 H), 2.78-2.71 (m, 1H), 2.69-2.59 (m, 4H), 2.41-2.31 (m, 1 H), 2.27-2.21 (m, 1 H), 2.17-2.10 (m, 1 H), 0.71-0.67 (m, 2H), 0.63-0.57 (m, 2H), 0.55-0.51 (m, 2H), 0.47-0.43 (m, 2H). LC-MS: rt = 0.98 min, MS: 503.2 (calcd), 504.3 (M+H+, found).
Example 147 2-Amino-6-(2-((4-hydroxypyrimidin-5-yl)oxy)ethyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (281)
Scheme 71
Figure imgf000203_0001
To a solution of 278 (80.0 mg, 188.0 umol) in DMF (2.35 mL) were added PyBOP (147 mg, 282 umol), N,N-diisopropylethylamine (131 uL, 752 umol) and ammonium chloride (101 mg, 1 .88 mmol). The resulting mixture was stirred at RT for 20 hours. The crude mixture was directly purified first by reverse-phase flash column chromatography (eluent gradient from 5% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid), then by Semi-Prep HPLC-MS (eluent gradient from 5% to 100% of MeOH in 10 mM ammonium formate) to afford title compound 281 as a white solid (6.9 mg, 9% yield).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.09 (bs, 2H), 7.73 (s, 1 H), 7.36 (s, 1 H), 7.31-7.26 (m, 4H), 7.25-7.18 (m, 1 H), 6.83 (bs, 2H), 3.93-3.86 (m, 1 H), 3.69-3.62 (m, 1 H), 2.86-2.78 (m, 1 H), 2.73-2.61 (m, 2H), 2.30-2.14 (m, 3H). LC-MS: rt = 0.87 min, MS: 424.1 (calcd), 425.2 (M+H+, found).
Example 148 2-Amino-6-((3-bromoisoxazol-5-yl)methyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (287) Scheme 72
Figure imgf000204_0001
Step 1. 8-Phenyl-8-(prop-2-yn-1-yl)-1 ,4-dioxaspiro[4.5]decane (282)
To a solution of 93 (scheme 17) (4.96 g, 19.1 mmol) in MeOH (235 mL) were added K2CO3 (6.58 g, 47.6 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (4.71 mL, 28.6 mmol). The mixture was stirred at RT for 1 hour, then water (200 mL) and EA (200 mL) were added. The organic layer was separated, washed with brine (3 x 100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 40% of EA in hexane) to afford title compound 282 as a white solid (2.65 g, 54% yield).
Step 2. 4-Phenyl-4-(prop-2-yn-1-yl)cyclohexan-1-one (283)
To a solution of 282 (800 mg, 3.12 mmol) in acetone (47 mL) was added 2 N HCI (15.6 mL, 31 .2 mmol) and the reaction mixture was stirred at 40 °C for 16 hours. Then, the mixture was neutralized by slowly adding a saturated aqueous solution of NaHCO3 (25 mL). The residue was extracted with EA (3 x 20 mL) and the organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated to dryness to afford title compound 283 as a white solid (640 mg, 97% yield).
Step 3. Ethyl 2-amino-6-phenyl-6-(prop-2-yn-1-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene- 3-carboxylate (284)
To a solution of 283 (640 mg, 3.01 mmol) and ethyl 2-cyanoacetate (0.292 mL, 2.74 mmol) in EtOH (4.81 mL) were added morpholine (0.26 mL, 3.01 mmol) and sulfur (97.0 mg, 0.378 mmol). The reaction mixture was stirred at 60 °C for 16 hours, then allowed to cool to RT and concentrated to dryness. The residue was purified by flash column chromatography (eluent gradient from 0% to 55% of EA in hexane) to afford title compound 284 as a white solid (890 mg, 96% yield). LC-MS: rt = 1.67 min, MS: 339.1 (calcd), 340.1 (M+H+, found).
Step 4. Ethyl 2-acetamido-7-oxo-6-phenyl-6-(prop-2-yn-1-yl)-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (285)
Acetic anhydride (0.297 mL, 3.15 mmol) was added to a suspension of 284 (890 mg, 2.62 mmol) in acetic acid (15 mL). The resulting mixture was heated up to 60 °C for 2 hours. After completion of the acylation step, dioxane (18.4 mL), water (18.4 mL) and ceric sulfate (5.35 g,
13.1 mmol) were added to the mixture. The resulting suspension was stirred at RT for 16 hours. The mixture was then diluted with water and extracted with EA. The organic layer was washed successively with NaOH 1 N, water and brine, then dried over Na2SO4, filtered and concentrated to afford title compound 285 as a an off-white solid (1.02 g, 98% yield over two steps). LC-MS: rt = 1.59 min, MS: 395.1 (calcd), 396.2 (M+H+, found).
Step 5. Ethyl 2-acetamido-6-((3-bromoisoxazol-5-yl)methyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (286)
To a solution of 285 (50 mg, 0.126 mmol) in EA (3.4 mL) and water (0.34 mL) was added K2CO3 (70 mg, 0.506 mmol). Then, 1 ,1 -dibromoformaldoxime (154 mg, 0.759 mmol) in EA (2 mL) was added dropwise and the reaction mixture was stirred at 40 °C for 16 hours. The mixture was then allowed to cool to RT and additional 1 ,1-dibromoformaldoxime (308 mg, 1.52 mmol) and K2CO3 (192 mg, 1.39 mmol) were added. Stirring continued at 40 °C for another 1 hour. Brine (10 mL) and EA (10 mL) were then added, the organic layer was separated, washed with brine (15 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 50% of EA in hexane) to afford title compound 286 as a white solid (49 mg, 75% yield). LC-MS: rt = 1.75 min, MS: 516.0 and 518.0 (calcd), 517.1 and 519.0 (M+H+, found).
Step 6. 2-Amino-6-((3-bromoisoxazol-5-yl)methyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (287)
To a suspension of 286 (58 mg, 0.112 mmol) in EtOH (5 mL) was added a solution of lithium hydroxide monohydrate (80 mg, 1.91 mmol) in water (5 mL). The reaction mixture was stirred at 55 °C for 16 hours, then allowed to cool to RT. The mixture was concentrated to remove most of the organic solvent. The residue was purified by reverse-phase flash column chromatography (eluent gradient from 5% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid) to afford the title compound 287 as an off-white solid (21 mg, 42% yield).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 12.49 (bs, 1 H), 8.27 (bs, 2H), 7.31-7.20 (m, 5H), 6.16 (s, 1 H), 3.35-3.30 (m, 1H), 3.26-3.22 (m, 1 H), 3.13-3.06 (m, 1H), 2.65-2.59 (m, 1 H), 2.36- 2.27 (m, 1 H), 2.13-2.05 (m, 1 H). LC-MS: rt = 1.48 min, MS: 446.0 and 448.0 (calcd), 447.1 and
449.1 (M+H+, found). Example 149 2-Amino-6-((3-bromoisoxazol-5-yl)methyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (288)
Scheme 73
Figure imgf000206_0001
287 288: Example 149
To a solution of 287 (20 mg, 44.7 umol) in DMF (0.6 mL) were added PyBOP (35 mg, 67.1 umol), /V,/V-diisopropylethylamine (31.2 uL, 179 umol) and ammonium chloride (23.9 mg, 0.447 mmol). The resulting mixture was stirred at RT for 30 minutes. The crude mixture was directly purified first by reverse-phase flash column chromatography (eluent gradient from 5% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid), then by Semi-Prep HPLC-MS (eluent gradient from 30% to 100% of MeOH in 10 mM ammonium bicarbonate) to afford title compound 288 as a white solid (11 .5 mg, 58% yield).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.09 (s, 2H), 7.32-7.21 (m, 5H), 6.86 (bs, 2H), 6.15 (s, 1 H), 3.36 (d, J = 14.77 Hz, 1 H), 3.23 (d, J = 14.77 Hz, 1 H), 2.85-2.78 (m, 1 H), 2.66-2.56 (m, 2H), 2.13-2.05 (m, 1 H). LC-MS: rt = 1.34 min, MS: 445.0 and 447.0 (calcd), 446.2 and 448.1 (M+H+, found).
Example 150 2-Amino-6-((3-methylisoxazol-5-yl)methyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (291)
Scheme 74
Figure imgf000207_0001
Step 1. Ethyl 2-acetamido-6-((3-methylisoxazol-5-yl)methyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (289)
To a solution of 285 (scheme 72) (50 mg, 0.126 mmol) in DCM (1 mL) were added triethylamine (53 pL, 0.379 mmol) and /V-hydroxyacetimidoyl chloride (Angew. Chem. Int. Ed, 56(41), p. 12589, 2017) (35 mg, 0.379 mmol). The reaction mixture was stirred at RT for 16 hours. Then, additional triethylamine (0.106 mL, 0.758 mmol) and /V-hydroxyacetimidoyl chloride (70 mg, 0.758 mmol) were added and stirring continued at RT for another 16 hours. The mixture was then diluted with brine (15 mL) and DCM (10 mL). The organic layer was separated, washed with brine (15 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 45% of EA in hexane) to afford title compound 289 as a pale-yellow solid (27.5 mg, 48% yield). LC-MS: rt = 1 .61 min, MS: 452.1 (calcd), 453.2 (M+H+, found).
Step 2. 2-Amino-6-((3-methylisoxazol-5-yl)methyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (290)
To a suspension of 289 (40 mg, 88.4 umol) in EtOH (4 mL) was added a solution of lithium hydroxide monohydrate (63 mg, 1.50 mmol) in water (4 mL). The reaction mixture was stirred at 55 °C for 16 hours, then allowed to cool to RT. The mixture was concentrated to remove most of the organic solvent. The aqueous layer was washed with EA. Then, the aqueous layer was acidified by slowly adding HCI 1 N and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated to afford title compound 290 as a red solid (36 mg, >99% yield), which was used directly for the next step without purification. LC-MS: rt = 1.32 min, MS: 382.1 (calcd), 383.2 (M+H+, found).
Step 3. 2-Amino-6-((3-methylisoxazol-5-yl)methyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (291) To a solution of 290 (33 mg, 86.3 umol) in DMF (1.1 mL) were added PyBOP (68 mg, 129 umol), /V,/V-diisopropylethylamine (60 uL, 345 umol) and ammonium chloride (46 mg, 0.863 mmol). The resulting mixture was stirred at RT for 30 minutes. The crude mixture was directly purified first by reverse-phase flash column chromatography (eluent gradient from 5% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid) and then by Semi-Prep HPLC-MS (eluent gradient from 35% to 100% of MeOH in 10 mM ammonium bicarbonate) to afford title compound 291 as a white solid (11 .9 mg, 36% yield).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.09 (bs, 2H), 7.31-7.28 (m, 4H), 7.27-7.22 (m, 1 H), 6.86 (bs, 1 H), 5.80 (s, 1 H), 3.35 (d, J = 14.65 Hz, 1 H), 3.09 (d, J = 14.65 Hz, 1 H), 2.87-2.81 (m, 1H), 2.67-2.57 (m, 2H), 2.11 (s, 3H), 2.08-2.02 (m, 1 H). LC-MS: rt = 1.18 min, MS: 381.1 (calcd), 382.2 (M+H+, found).
Example 151
2-amino-6-cyano-6-cyclopropyl-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3- carboxylic acid (297) and
Example 152
2-amino-6-cyano-6-cyclopropyl-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3- carboxamide (298)
Scheme 75
Figure imgf000208_0001
Figure imgf000208_0002
l-4,5,6,7-tetrahydro-1-
Figure imgf000208_0003
(293).
A 20 ml vial equipped with a stir bar was charged with 1-cyclopropyl-4-oxocyclohexane-1- carbonitrile (292) (700 mg, 4.29 mmol, 1 equiv.), ethyl 2-cyanoacetate (485 mg, 4.29 mmol, 1 equiv.), elemental sulfur (152 mg, 592 pmol, 0.138 equiv.), morpholine (411 mg, 4.72 mmol, 1.1 equiv.) and ethanol (6.84 ml, 0.627 M). The vial was sealed with a lid with a pressure relief septum and the reaction was stirred at 60 °C for 18 hours. The reaction was cooled to room temperature and vacuum filtered. The solids were washed with diethyl ether (2 x 5 ml) to yield the title compound as a pale-yellow solid (658 mg, 2.27 mmol, 53% yield). LC-MS: calc. 290.4, found (M+H) 291.3, retention time 0.44 min.
Step 2 Ethyl 6-cyano-6-cyclopropyl-2-acetamido-4,5,6,7-tetrahydro-1-benzothiophene-3- carboxylate (294).
A 20 ml vial equipped with a stir bar was charged with ethyl 2-amino-6-cyano-6- cyclopropyl-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (293) (658 mg, 2.27 mmol, 1 equiv.) and suspended in acetic acid (13 ml, 0.174 M). Acetic anhydride (257 pl, 2.72 mmol, 1.2 equiv.) was added in a single portion. The vial was sealed with a lid with a pressure relief septum and the reaction was stirred at 60 °C for 18 hours. The reaction was cooled to room temperature and the volatiles were removed in vacuo. The residue was dissolved in DCM (20 ml), consecutively washed with sat. sodium bicarbonate, water and brine. The organic fraction was dried over sodium sulfate, filtered and the volatiles were removed in vacuo to yield the title compound (618 mg, 1.86 mmol, 82% yield). 1H NMR (400 MHz, CDCI3): δ 11.27 (s, 1 H), 4.34 (q, J = 7.1 Hz, 2H), 3.16 - 2.78 (m, 3H), 2.26 (s, 3H), 2.26 - 2.20 (m, 1 H), 1.85 (ddd, J = 13.3, 10.1 , 5.9 Hz, 1 H), 1.40 (t, J = 7.1 Hz, 3H), 1.07 - 0.92 (m, 1 H), 0.66 - 0.60 (m, 4H).
Step 3 Ethyl 6-cyano-6-cyclopropyl-2-acetamido-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3- carboxylate (295).
A 20 ml vial equipped with an egg shaped stir bar was charged with ethyl 6-cyano-6- cyclopropyl-2-acetamido-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (294) (618 mg, 1.86 mmol, 1 equiv.), ceric sulfate (5.33 g, 16.1 mmol, 8.64 equiv.), glacial acetic acid (6.14 ml, 0.303 M) and water (6.14 ml, 0.303 M). The vial was sealed with a lid with a pressure relief septum and sonicated for 15 minutes to form a fine yellow suspension. The reaction was stirred vigorously at room temperature for 18 hours. The reaction mixture was diluted with water (10 ml) and ethyl acetate (10 ml). The aqueous phase was extracted with ethyl acetate (3x10 ml) and the organic fractions were combined and consecutively washed with 1 N NaOH (10 ml), water (10ml) and brine (10 ml). The organic phase was dried over sodium sulfate, filtered and the volatiles were removed in vacuo to yield the title compound (587 mg, 1.69 mmol, 91% yield). LC- MS: calc. 346.4, found (M+H) 347.2, retention time 0.2 min.
Step 4 Ethyl 2-amino-6-cyano-6-cyclopropyl-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3- carboxylate (296).
A 20 ml vial equipped with a stir bar was charged with ethyl 6-cyano-6-cyclopropyl-2- acetamido-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (295) (587 mg, 1.69 mmol, 1 equiv.) and toluene (2.78 ml, 0.61 M). Pyrrolidine (2.09 ml, 25.4 mmol, 15 equiv.) was added in a single portion with a syringe. The vial was sealed with a lid with a pressure relief septum and the reaction was stirred at 80 °C for 2 hours. The reaction was cooled to room temperature, diluted with ethyl acetate (20 ml) and washed with brine. The organic fraction was dried over sodium sulfate, filtered and the volatiles were removed in vacuo. The crude material was purified by automated column chromatography using silica gel and a gradient of 0 - 100% ethyl acetate in hexane as eluent to obtain the title compound as a yellow solid (420 mg, 1.38 mmol, 81% yield). LC-MS: calc. 304.4, found (M+H) 305.4, retention time 3.357 min.
Step 5 2-amino-6-cyano-6-cyclopropyl-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylic acid (297).
A 500 ml round bottom flask equipped with a stir bar was charged with ethyl 2-amino-6- cyano-6-cyclopropyl-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (296) (420 mg, 1.38 mmol, 1 equiv.), lithium hydroxide monohydrate (290 mg, 6.9 mmol, 5 equiv.), water (167 ml, 8.27 mM) and methanol (167 ml, 8.27 mM). A reflux condenser was affixed to the flask and the reaction was stirred at 80 °C for 18 hours. The reaction was cooled to room temperature, acidified by addition of 6 M HCI solution and extracted to ethyl acetate. The organic fractions were combined, dried over sodium sulfate, filtered and the volatiles were removed in vacuo to yield the title compound (312 mg, 1.13 mmol, 82% yield). The title compound was purified by reverse phase chromatography using a C18 column and a gradient of 0 - 100% ACN in water and dried by lyophilization. 1H NMR (400 MHz, CDCI3): δ 12.74 (s, 1 H), 8.49 (s, 2H), 3.25 - 2.99 (m, 2H), 2.44 (td, J = 8.7, 4.4 Hz, 1 H), 2.38 - 2.29 (m, 1 H), 1.40 (tt, J = 8.2, 5.1 Hz, 1H), 0.69 - 0.30 (m, 5H). LC-MS: calc. 276.3, found (M+H) 277.2, retention time 0.26 min.
Step 6 2-amino-6-cyano-6-cyclopropyl-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3- carboxamide (298).
A 20 ml vial equipped with a stir bar was charged with 2-amino-6-cyano-6-cyclopropyl-7- oxo-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylic acid (297) (200 mg, 0.724 mmol, 1 equiv.), DIPEA (252 pl, 1 .45 mmol, 2 equiv.), ammonium chloride (774 mg, 14.5 mmol, 20 equiv.), HATU (413 mg, 1.09 mmol, 1.5 equiv.) and DMF (8 ml, 90.5 mM). The vial was sealed with a pressure relief septum and the reaction was sparged with argon for 5 min. Ammonia 0.4 M in THF solution (18.1 ml, 7.24 mmol, 10 equiv.) was added dropwise via syringe while stirring resulting in the formation of a beige precipitate and the reaction was subsequently stirred at room temperature overnight. The reaction was quenched by addition of 10 ml of saturated ammonium chloride solution and extracted into ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and the volatiles were removed in vacuo. The product was purified by preparative HPLC and subsequently dried by lyophilization to yield the title compound as a white solid (32 mg, 0.116 mmol, 16% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.25 (s, 2H), 7.09 (br s, 2H), 3.20 (ddd, J = 17.9, 8.9, 4.8 Hz, 1 H), 3.03 (dt, J = 17.8, 5.1 Hz, 1 H), 2.43 (ddd, J = 13.5, 8.9, 4.9 Hz, 1 H), 2.32 (dt, J = 13.3, 5.0 Hz, 1 H), 1 .39 (tt, J = 8.2, 5.1 Hz, 1 H), 0.69 - 0.37 (m, 4H). LC-MS: calc. 275.3, found (M+H) 276.3 m/z, retention time 0.26 min.
Example 153 2-amino-6-cyano-6-cyclobutyl-7 -oxo-4, 5, 6, 7-tetrahydro-1 -benzothiophene-3- carboxylic acid (305) and Example 154
2-amino-6-cyano-6-cyclobutyl-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3- carboxamide (306)
Scheme 76
Figure imgf000211_0001
Step 1 8-cyclobutyl-1 ,4-dioxaspiro[4.51decane-8-carbonitrile (299).
A dry 100 ml round bottom flask equipped with a stir bar was charged with 1 ,4- dioxaspiro[4.5]decane-8-carbonitrile (40) (500 mg, 2.99 mmol, 1 equiv.) and 15 ml of dry THF. The solution was sparged with argon for 10 minutes with an argon balloon and cooled to -78 °C with a dry ice acetone bath under positive argon atmosphere. Lithium diisopropylamide 1 M solution in THF/heptanes (3.29 ml, 3.29 mmol, 1.1 equiv.) was added dropwise to the flask and the reaction was stirred at -78 °C for 1.5 hours. A degassed solution of cyclobutylbromide (444 mg, 3.29 mmol, 1.1 equiv.) in 5 ml dry THF was added to the flask by syringe and the reaction was stirred at room temperature overnight. The reaction was quenched with 15 ml saturated ammonium chloride solution and extracted to diethyl ether. The organic fractions were combined, dried over sodium sulfate, filtered and the volatiles were removed in vacuo to yield the title compound as a pale-yellow oil (622 mg, 2.81 mmol, 94% yield). 1H NMR (400 MHz, CDCI3): δ 4.05 - 3.75 (m, 4H), 2.30 (p, J = 8.6 Hz, 1 H), 2.08 - 1.69 (m, 12H), 1.55 - 1.38 (m, 2H). Step 2 1-cyclobutyl-4-oxocyclohexane-1 -carbonitrile (300).
A 20 ml vial equipped with a stir bar was charged with 8-cyclobutyl-1 ,4- dioxaspiro[4.5]decane-8-carbonitrile (299) (622 mg, 2.81 mmol, 1 equiv.) and acetone (5.62 ml, 0.5 M). 12 M HCI (4.68 ml, 56.2 mmol, 20 equiv.) was added to the flask slowly while stirring. The reaction was stirred at room temperature for 48 hours, quenched with saturated sodium bicarbonate solution and extracted to diethyl ether. The organic layers were combined, dried over sodium sulfate, filtered and the volatiles were removed in vacuo to yield the title compound (538 mg, 3.04 mmol, quant, yield. 1H NMR (400 MHz, CDCI3): δ 2.75 - 2.57 (m, 1 H), 2.44 - 1.80 (m, 10H), 1.68 (s, 2H), 1.55 (td, J = 13.8, 4.4 Hz, 1 H), 1.23 (s, 1H).
Step 3 Ethyl 2-amino-6-cyano-6-cyclobutyl-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (301).
A 20 ml vial equipped with a stir bar was charged with 1-cyclobutyl-4-oxocyclohexane-1- carbonitrile (300) (538 mg, 3.04 mmol, 1 equiv.), ethyl 2-cyanoacetate (343 mg, 3.04 mmol, 1 equiv.), elemental sulfur (107 mg, 419 pmol, 0.138 equiv.), morpholine (291 mg, 3.34 mmol, 1.1 equiv.) and ethanol (4.82 ml, 0.63 M). The vial was sealed with a lid with a pressure relief septum and the reaction was stirred at 60 °C for 18 hours. The reaction was cooled to room temperature and cooled to 5 °C for 1 hour to induce precipitation of product. The product was isolated by vacuum filtration and the solids were washed diethyl ether (2 x 5 ml) to yield the title compound as a pale-yellow solid (337 mg, 1 .11 mmol, 37% yield). 1H NMR (400 MHz, CDCI3): δ 4.25 (q, J = 7.1 Hz, 2H), 2.98 - 2.82 (m, 2H), 2.46 - 2.38 (m, 2H), 2.11 - 1.96 (m, 6H), 1.94 - 1.81 (m, 2 H), 1.53 (ddd, J = 13.4, 9.6, 6.2 Hz, 1 H), 1.32 (t, J = 7.1 Hz, 3H).
Step 4 Ethyl 6-cyano-6-cyclobutyl-2-acetamido-4,5,6,7-tetrahydro-1-benzothiophene-3- carboxylate (302).
A 20 ml vial equipped with a stir bar was charged with ethyl 2-amino-6-cyano-6-cyclobutyl- 4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (301) (337 mg, 1.11 mmol, 1 equiv.) and acetic acid (6.36 ml, 174 mM). The reaction was stirred to form an even suspension and acetic anhydride (126 pl, 1 .33 mmol, 1 .2 equiv.) was added in a single portion. The vial was sealed with a lid with a pressure relief septum and the reaction was stirred at 60 °C for 18 hours. The reaction was cooled to room temperature and the volatiles were removed in vacuo. The residue was dissolved in DCM (10 ml), consecutively washed with sat. sodium bicarbonate, water and brine. The organic fraction was dried over sodium sulfate, filtered and the volatiles were removed in vacuo to yield the title compound (360 mg, 1 .04 mmol, 94% yield). 1H NMR (400 MHz, CDCI3): δ 11.27 (s, 1 H), 4.33 (q, J = 7.1 Hz, 3H), 3.03 - 2.92 (m, 2H), 2.63 - 2.36 (m, 2H), 2.26 (s, 3H), 2.15 - 2.03 (m, 6H), 1.97 - 1.84 (m, 2H), 1.65 - 1.52 (m, 1 H), 1.39 (t, J = 7.1 Hz, 3H).
Step 5 Ethyl 6-cyano-6-cyclobutyl-2-acetamido-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3- carboxylate (303). A 20 ml vial equipped with an egg shaped stir bar was charged with ethyl 6-cyano-6- cyclobutyl-2-acetamido-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (302) (360 mg, 1.04 mmol, 1 equiv.), ceric sulfate (2.98 g, 8.64 mmol, 8.64 equiv.), glacial acetic acid (460 pl, 2.26 M) and water (460 pl, 2.26 M). The vial was sealed with a lid with a pressure relief septum and sonicated for 15 minutes to form a fine yellow suspension. The reaction was stirred vigorously at room temperature for 18 hours. The reaction mixture was diluted with water (10 ml) and ethyl acetate (10 ml). The aqueous phase was extracted with ethyl acetate (3x10 ml) and the organic fractions were combined and consecutively washed with 1 N NaOH (10 ml), water (10ml) and brine (10 ml). The organic phase was dried over sodium sulfate, filtered and the volatiles were removed in vacuo to yield the title compound (84.9 mg, 0.236 mmol, 23% yield). LC-MS: calc. 360.4, found 361.1 (M+H), retention time 0.28 min.
Step 6 Ethyl 2-amino-6-cyano-6-cyclobutyl-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3- carboxylate (304).
A 20 ml vial equipped with a stir bar was charged with ethyl 6-cyano-6-cyclobutyl-2- acetamido-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (303) (85 mg, 236 pmol, 1 equiv.) and toluene (387 pl, 0.61 M). Pyrrolidine (252 mg, 3.54 mmol, 15 equiv.) was added in a single portion with a syringe. The vial was sealed with a lid with a pressure relief septum and the reaction was stirred at 80 °C for 2 hours. The reaction was cooled to room temperature, diluted with ethyl acetate (10 ml) and washed with brine. The organic fraction was dried over sodium sulfate, filtered and the volatiles were removed in vacuo to yield the title compound as an orange oil (76.4 mg, 240 pmol, quant yield). LC-MS: calc. 318.4, found (M+H), retention time 0.21 min. Step 7 2-amino-6-cyano-6-cyclobutyl-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylic acid (305).
A 100 ml round bottom flask equipped with a stir bar was charged with ethyl 2-amino-6- cyano-6-cyclobutyl-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (304) (76.4 mg, 240 pmol, 1 equiv.), lithium hydroxide monohydrate (50.3 mg, 1.2 mmol, 5 equiv.), water (29 ml, 8.27 mM) and methanol (29 ml, 8.27 mM). A reflux condenser was affixed to the flask and the reaction was stirred at 80 °C for 18 hours. The reaction was cooled to room temperature, acidified by addition of 6 M HCI solution and extracted to ethyl acetate. The organic fractions were combined, dried over sodium sulfate, filtered and the volatiles were removed in vacuo to yield the title compound (57 mg, 196 pmol, 82% yield). The title compound was purified by reverse phase chromatography using a C18 column and a gradient of 0 - 100% ACN in water and dried by lyophilization. LC-MS: calc. 290.3, found (M+H) 291.3, retention time 3.169 min. 1H NMR (400 MHz, DMSO-c/6): δ 12.68 (br. s, 1 H), 8.42 (br. s, 2H), 3.10 - 3.00 (m, 1 H), 2.96 - 2.86 (m, 1 H), 2.81 (t, J = 8.3 Hz, 1 H), 2.34 - 2.25 (m, 1 H), 2.14 - 2.07 (m, 1 H), 2.03 - 1.97 (m, 2H), 1.92 - 1.77 (m, 3H), 1.75 - 1.68 (m, 1 H). Step 82-amino-6-cyano-6-cyclobutyl-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide (306).
A 5 ml vial equipped with a stir bar was charged with 2-amino-6-cyano-6-cyclobutyl-7-oxo- 4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylic acid (305) (40 mg, 0.138 mmol, 1 equiv.), DIPEA (48 pl, 0.276 mmol, 2 equiv.), ammonium chloride (147 mg, 2.76 mmol, 20 equiv.), HATU (78.6 mg, 0.207 mmol, 1.5 equiv.) and DMF (1.52 ml, 90.5 mM). The vial was sealed with a pressure relief septum and the reaction was sparged with argon for 5 min. Ammonia 0.4 M in THF solution (6.89 ml, 2.76 mmol, 20 equiv.) was added dropwise via syringe while stirring resulting in the formation of a beige precipitate and the reaction was subsequently stirred at room temperature overnight. The reaction was quenched by addition of 10 ml of saturated ammonium chloride solution and extracted into ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and the volatiles were removed in vacuo. The product was purified by preparative HPLC and subsequently dried by lyophilization to yield the title compound as a white solid (8.2 mg, 0.0283 mmol, 21% yield). 1H NMR (400 MHz, CDCI3): δ 5.50 (br. s, 2H), 3.52 (s, 2H), 3.15 - 2.98 (m, 2H), 2.85 (t, J = 8.0, 1 H), 2.53 - 2.45 (m, 1H), 2.37 (t, J = 12.0 1 H), 2.26 - 2.07 (m, 6H), 2.01 - 1.89 (m, 2H). LC-MS: calc. 289.4, found (M+H) 290.2, retention time 0.26 min.
Example 155 2-amino-6-cyano-6-cyclopentyl-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3- carboxylic acid (313) and
Example 156 2-amino-6-cyano-6-cyclopentyl-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3- carboxamide (314)
Scheme 77
Figure imgf000215_0001
1 8-cvclopentvl-1 ,4-dioxaspiro[4.5]decane-8-carbonitrile (307).
A dry 250 ml round bottom flask equipped with a stir bar was charged with 1 ,4- dioxaspiro[4.5]decane-8-carbonitrile (40) (2 g, 12 mmol, 1 equiv.) and 40 ml of dry THF. The solution was sparged with argon for 10 minutes with an argon balloon and cooled to -78 °C with a dry ice acetone bath under positive argon atmosphere. Lithium diisopropylamide 1 M solution in THF/heptanes (13.2 ml, 13.2 mmol, 1.1 equiv.) was added dropwise to the flask and the reaction was stirred at -78 °C for 1 .5 hours. A degassed solution of cyclopentylbromide (1 .96 mg, 13.2 mmol, 1.1 equiv.) in 10 ml dry THF was added to the flask by syringe and the reaction was stirred at room temperature overnight. The reaction was quenched with 50 ml saturated ammonium chloride solution and extracted to diethyl ether. The organic fractions were combined, dried over sodium sulfate, filtered and the volatiles were removed in vacuo to yield the title compound as a pale-yellow oil (2.87 g, 12.2 mmol, quant, yield). 1H NMR (400 MHz, CDCI3): δ 3.99 - 3.89 (m, 4H), 2.04 - 1 .97 (m, 2H), 1 .94 - 1 .85 (m, 3H), 1.85 - 1 .69 (m, 8H), 1 .66 - 1 .54 (m, 4H).
Step 2 1-cyclopentyl-4-oxocyclohexane-1 -carbonitrile (308).
A 20 ml vial equipped with a stir bar was charged with 8-cyclopentyl-1 ,4- dioxaspiro[4.5]decane-8-carbonitrile (307) (937 mg, 3.98 mmol, 1 equiv.) and acetone (2 ml, 2.0 M). 12 M HCI (6.64 ml, 79.6 mmol, 20 equiv.) was added to the vial slowly while stirring. The reaction was stirred at room temperature for 48 hours, quenched with saturated sodium bicarbonate solution and extracted to diethyl ether. The organic layers were combined, dried over sodium sulfate, filtered and the volatiles were removed in vacuo to yield the title compound (638 mg, 3.33 mmol, 84%). 1H NMR (400 MHz, CDCI3): δ 2.70 (td, J = 12, 6 Hz, 2H), 2.45 (p, J = 2.4 Hz, 1 H), 2.41 (p, J = 2.4 Hz, 1 H), 2.38 - 2.31 (m, 2H), 1 .90 - 1.83 (m, 3H), 1 .80 - 1 .68 (m, 4H), 1.65 - 1.49 (m, 4H).
Step 3 Ethyl 2-amino-6-cyano-6-cyclopentyl-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (309).
A 20 ml vial equipped with a stir bar was charged with 1-cyclopentyl-4-oxocyclohexane-1- carbonitrile (308) (638 mg, 3.34 mmol, 1 equiv.), ethyl 2-cyanoacetate (377 mg, 3.34 mmol, 1 equiv.), elemental sulfur (118 mg, 460 pmol, 0.138 equiv.), morpholine (320 mg, 3.67 mmol, 1.1 equiv.) and ethanol (5.32 ml, 0.63 M). The vial was sealed with a lid with a pressure relief septum and the reaction was stirred at 60 °C for 18 hours. The reaction was cooled to room temperature the product was isolated by vacuum filtration. The solids were washed diethyl ether (2 x 5 ml) to yield the title compound as a pale-yellow solid (522 mg, 1.64 mmol, 49% yield). 1H NMR (500 MHz, DMSO-c/6): δ 7.00 (s, 2H), 6.61 (s, 2H), 2.89 - 2.73 (m, 3H), 2.71 - 2.57 (m, 1 H), 2.14 - 1 .97 (m, 2H), 1 .93 - 1 .79 (m, 2H), 1 .73 - 1 .62 (m, 3H), 1 .60 - 1 .50 (m, 2H), 1 .44 - 1 .34 (m, 2H). Step 4 Ethyl 6-cyano-6-cyclopentyl-2-acetamido-4,5,6,7-tetrahydro-1-benzothiophene-3- carboxylate (310).
A 20 ml vial equipped with a stir bar was charged with ethyl 2-amino-6-cyano-6- cyclopentyl-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (309) (522 mg, 1 mmol, 1 equiv.) and acetic acid (9.41 ml, 174 mM). The reaction was stirred to form an even suspension and acetic anhydride (201 mg, 1.97 mmol, 1.2 equiv.) was added in a single portion. The vial was sealed with a lid with a pressure relief septum and the reaction was stirred at 60 °C for 18 hours. The reaction was cooled to room temperature and the volatiles were removed in vacuo. The residue was dissolved in DCM (10 ml), consecutively washed with sat. sodium bicarbonate, water and brine. The organic fraction was dried over sodium sulfate, filtered and the volatiles were removed in vacuo to yield the title compound (497 mg, 1.38 mmol, 84% yield). LC-MS: calc. 360.5, found (M+H) 361 , retention time 0.63 min.
Step 5 Ethyl 6-cyano-6-cyclopentyl-2-acetamido-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3- carboxylate (311).
A 20 ml vial equipped with an egg shaped stir bar was charged with ethyl 6-cyano-6- cyclopentyl-2-acetamido-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (310) (200 mg, 555 pmol, 1 equiv.), ceric sulfate (1.59 g, 4.79 mmol, 8.64 equiv.), glacial acetic acid (1.83 ml, 0.303 M) and water (1.83 ml, 0.303 M). The vial was sealed with a lid with a pressure relief septum and sonicated for 15 minutes to form a fine yellow suspension. The reaction was stirred vigorously at room temperature for 18 hours. The reaction mixture was diluted with water (10 ml) and ethyl acetate (10 ml). The aqueous phase was extracted with ethyl acetate (3x10 ml) and the organic fractions were combined and consecutively washed with 1 N NaOH (10 ml), water (10ml) and brine (10 ml). The organic phase was dried over sodium sulfate, filtered and the volatiles were removed in vacuo to yield the title compound (191 mg, 0.51 mmol, 92% yield). LC-MS: calc. 374.5, found (M+H) 375, retention time 0.20 min.
Step 6 Ethyl 2-amino-6-cyano-6-cyclopentyl-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3- carboxylate (312).
A 5 ml vial equipped with a stir bar was charged with ethyl 6-cyano-6-cyclopentyl-2- acetamido-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (311) (191 mg, 510 pmol, 1 equiv.) and toluene (836 pl, 0.61 M). Pyrrolidine (544 mg, 7.65 mmol, 15 equiv.) was added in a single portion with a syringe. The vial was sealed with a lid with a pressure relief septum and the reaction was stirred at 80 °C for 2 hours. The reaction was cooled to room temperature, diluted with ethyl acetate (30 ml) and washed with 30 ml brine. The organic fraction was dried over sodium sulfate, filtered and the volatiles were removed in vacuo to yield the title compound (176 mg, 530 pmol, quant yield). LC-MS: calc. 332.4, found (M+H) 333.4, retention time 3.008 min. Step 7 2-amino-6-cyano-6-cyclopentyl-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylic acid (313).
A 250 ml round bottom flask equipped with a stir bar was charged with ethyl 2-amino-6- cyano-6-cyclopentyl-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (312) (176 mg, 529 pmol, 1 equiv.), lithium hydroxide monohydrate (111 mg, 2.65 mmol, 5 equiv.), water (64 ml, 8.27 mM) and methanol (64 ml, 8.27 mM). A reflux condenser was affixed to the flask and the reaction was stirred at 80 °C for 18 hours. The reaction was cooled to room temperature, acidified by addition of 6 M HCI solution and extracted to ethyl acetate. The organic fractions were combined, dried over sodium sulfate, filtered and the volatiles were removed in vacuo to yield the title compound (69.9 mg, 230 pmol, 43% yield). The title compound was purified by reverse phase chromatography using a C18 column and a gradient of 0 - 100% ACN in water and dried by lyophilization. LC-MS: calc. 304.4, found (M+H) 305.2, retention time 0.28 min. 1H NMR (400 MHz, DMSO-c/6): δ 12.69 (br. s, 1 H), 8.43 (s, 2H), 3.18 - 3.09 (m, 1 H), 3.01 - 2.88 (m, 1 H), 2.42 - 2.28 (m, 4H), 1 .94 - 1.84 (m, 1 H), 1 .63 - 1.58 (m, 1 H), 1.53 - 1 .46 (m, 3H), 1.40 - 1 .31 (m 1 H). Step 8 2-amino-6-cyano-6-cyclopentyl-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3- carboxamide (314).
A 20 ml vial equipped with a stir bar was charged with 2-amino-6-cyano-6-cyclopentyl-7- oxo-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylic acid (313) (30 mg, 0.138 mmol, 1 equiv.), DIPEA (25.5 mg, 0.197 mmol, 2 equiv.), ammonium chloride (105 mg, 1.97 mmol, 20 equiv.), HATU (56.2 mg, 0.148 mmol, 1.5 equiv.) and DMF (1.09 ml, 90.5 mM). The vial was sealed with a pressure relief septum and the reaction was sparged with argon for 5 min. Ammonia 0.4 M in THF solution (4.93 ml, 1.97 mmol, 20 equiv.) was added dropwise via syringe while stirring resulting in the formation of an orange precipitate and the reaction was subsequently stirred at room temperature overnight. The reaction was quenched by addition of 10 ml of saturated ammonium chloride solution and extracted into ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and the volatiles were removed in vacuo. The product was purified by preparative HPLC and subsequently dried by lyophilization to yield the title compound as a white solid (4.8 mg, 0.0158 mmol, 16% yield). 1H NMR (500 MHz, DMSO-c/6): δ 8.19 (s,
2H), 7.04 (br. s, 2H), 3.19 (ddd, J = 18.0, 10.1 , 4.8 Hz, 1H), 2.93 (dt, J = 18.0, 4.5 Hz, 1 H), 2.47 - 2.23 (m, 3H), 1.95 - 1.81 (m, 1 H), 1.70 - 1.59 (m, 1H), 1.58 - 1.47 (m, 6H), 1.38 (dt, J = 17.9, 8.1 Hz, 1 H). LC-MS: calc. 303.4, found (M+H) 304.3, retention time 1.14 min. Example 157
2-amino-6-cyano-6-cyclohexyl-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylic acid (321) and
Example 158
2-amino-6-cyano-6-cyclohexyl-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide (322)
Scheme 78
Figure imgf000218_0001
Step 1 8-cyclohexyl-1 ,4-dioxaspiro[4.51decane-8-carbonitrile (315). A dry 250 ml round bottom flask equipped with a stir bar was charged with 1 ,4- dioxaspiro[4.5]decane-8-carbonitrile (40) (3 g, 17.9 mmol, 1 equiv.) and 70 ml of dry THF. The solution was sparged with argon for 10 minutes with an argon balloon and cooled to -78 °C with a dry ice acetone bath under positive argon atmosphere. Lithium diisopropylamide 1 M solution in THF/heptanes (19.7 ml, 19.7 mmol, 1.1 equiv.) was added dropwise to the flask and the reaction was stirred at -78 °C for 1 hour. A degassed solution of cyclohexylbromide (4.39 g, 26.9 mmol, 1 .5 equiv.) in 20 ml dry THF was added to the flask by syringe and the reaction was heated to 60 °C while stirring for 36 hours. Note: Reaction does not exceed 50% completion. The reaction cooled to room temperature, quenched with 50 ml saturated ammonium chloride solution and extracted to diethyl ether (2x50 ml). The organic fractions were combined, dried over sodium sulfate, filtered and the volatiles were removed in vacuo. The crude material was purified by automated column chromatography using silica gel and a gradient of 0 - 100% ethyl acetate in hexane as eluent to yield the title compound as a pale-yellow oil (783 mg, 3.14 mmol, 18% yield). 1H NMR (400 MHz, CDCI3): δ 4.11 - 3.67 (m, 4H), 2.16 - 1.47 (m, 15H), 1.3.0 - 1.09 (m, 5H). Step 2 1-cyclohexyl-4-oxocyclohexane-1 -carbonitrile (316).
A 20 ml vial equipped with a stir bar was charged with 8-cyclohexyl-1 ,4- dioxaspiro[4.5]decane-8-carbonitrile (315) (787 mg, 3.16 mmol, 1 equiv.) and acetone (5.3 ml, 0.6 M). 12 M HCI (5.26 ml, 63.1 mmol, 20 equiv.) was added to the vial slowly while stirring. The reaction was stirred at room temperature for 18 hours, quenched with saturated sodium bicarbonate solution and extracted to diethyl ether. The organic layers were combined, dried over sodium sulfate, filtered and the volatiles were removed in vacuo to yield the title compound (728 mg, 3.55 mmol, quant, yield). 1H NMR (400 MHz, CDCI3): δ 2.70 (td, J = 15.4 Hz, 5.9 Hz, 1 H), 2.44 (d, J = 20.0 Hz, 1 H) 2.25 - 2.11 (m, 2H), 2.00 - 1 .80 (m, 4H), 1.78 - 1 .65 (m, 4H), 1 .34 - 1.14 (m, 5H).
Step 3 Ethyl 2-amino-6-cyano-6-cyclohexyl-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (317).
A 20 ml vial equipped with a stir bar was charged with 1-cyclohexyl-4-oxocyclohexane-1- carbonitrile (316) (900 mg, 4.38 mmol, 1 equiv.), ethyl 2-cyanoacetate (4.96 mg, 4.38 mmol, 1 equiv.), elemental sulfur (155 mg, 605 pmol, 0.138 equiv.), morpholine (420 mg, 4.82 mmol, 1.1 equiv.) and ethanol (7.0 ml, 0.63 M). The vial was sealed with a lid with a pressure relief septum and the reaction was stirred at 60 °C for 18 hours. The reaction was cooled to room temperature the product was isolated by vacuum filtration. The solids were washed diethyl ether (2 x 5 ml) to yield the title compound as a pale-yellow solid (869 mg, 2.61 mmol, 60% yield). LC-MS: calculated 332.5, found (M+H) 333.5, retention time 3.895 min.
Step 4 Ethyl 6-cyano-6-cyclohexyl-2-acetamido-4,5,6,7-tetrahydro-1-benzothiophene-3- carboxylate (318). A 20 ml vial equipped with a stir bar was charged with ethyl 2-amino-6-cyano-6-cyclohexyl- 4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (317) (869 mg, 2.61 mmol, 1 equiv.) and acetic acid (15 ml, 174 mM). The reaction was stirred to form an even suspension and acetic anhydride (320 mg, 3.14 mmol, 1.2 equiv.) was added in a single portion. The vial was sealed with a lid with a pressure relief septum and the reaction was stirred at 60 °C for 18 hours. The reaction was cooled to room temperature and the volatiles were removed in vacuo. The residue was dissolved in DCM (10 ml), consecutively washed with sat. sodium bicarbonate, water and brine. The organic fraction was dried over sodium sulfate, filtered and the volatiles were removed in vacuo to yield the title compound (409 mg, 1.09 mmol, 42% yield). LC-MS: Calculated 374.5, found (M+H) 375.5, retention time 3.971 min.
Step 5 Ethyl 6-cyano-6-cyclopentyl-2-acetamido-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3- carboxylate (319).
A 20 ml vial equipped with an egg shaped stir bar was charged with ethyl 6-cyano-6- cyclohexyl-2-acetamido-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (318) (409 mg, 1.09 mmol, 1 equiv.), ceric sulfate (3.14 g, 9.46 mmol, 8.64 equiv.), glacial acetic acid (3.61 ml, 0.303 M) and water (3.61 ml, 0.303 M). The vial was sealed with a lid with a pressure relief septum and sonicated for 15 minutes to form a fine yellow suspension. The reaction was stirred vigorously at room temperature for 18 hours. The reaction mixture was diluted with water (10 ml) and ethyl acetate (10 ml). The aqueous phase was extracted with ethyl acetate (3x10 ml) and the organic fractions were combined and consecutively washed with 1 N NaOH (10 ml), water (10ml) and brine (10 ml). The organic phase was dried over sodium sulfate, filtered and the volatiles were removed in vacuo to yield the title compound (352 mg, 0.91 mmol, 83% yield). LC-MS: Calculated 388.5, found (M+H) 389.1 , retention time 0.44 min.
Step 6 Ethyl 2-amino-6-cyano-6-cyclohexyl-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3- carboxylate (320).
A 20 ml vial equipped with a stir bar was charged with ethyl 6-cyano-6-cyclohexyl-2- acetamido-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (319) (352 mg, 510 pmol, 1 equiv.) and toluene (1.48, 0.61 M). Pyrrolidine (965 mg, 13.6 mmol, 15 equiv.) was added in a single portion with a syringe. The vial was sealed with a lid with a pressure relief septum and the reaction was stirred at 80 °C for 2 hours. The reaction was cooled to room temperature, diluted with ethyl acetate (30 ml) and washed with 30 ml brine. The organic fraction was dried over sodium sulfate, filtered and the volatiles were removed in vacuo. The crude material was purified by automated column chromatography using silica gel and a gradient of 0 - 100% ethyl acetate in hexane to yield the title compound (194 mg, 559 pmol, 62% yield). 1H NMR (400 MHz, CDCI3): 5 4.31 (qq, J = 7.2, 3.7 Hz, 2H), 3.25 - 2.94 (m, 2H), 2.46 - 2.27 (m, 2H), 2.11 - 1.98 (m, 1 H), 1 .88 - 1 .58 (m, 4H), 1 .36 (t, J = 7.1 Hz, 3H), 1 .33 - 1 .04 (m, 5H). Step 7 2-amino-6-cyano-6-cyclohexyl-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylic acid (321).
A 250 ml round bottom flask equipped with a stir bar was charged with ethyl 2-amino-6- cyano-6-cyclohexyl-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (320) (194 mg, 560 mol, 1 equiv.), lithium hydroxide monohydrate (117 mg, 2.8 mmol, 5 equiv.), water (68 ml, 8.27 mM) and methanol (68 ml, 8.27 mM). A reflux condenser was affixed to the flask and the reaction was stirred at 80 °C for 18 hours. The reaction was cooled to room temperature, acidified by addition of 6 M HCI solution and extracted to ethyl acetate. The organic fractions were combined, dried over sodium sulfate, filtered and the volatiles were removed in vacuo to yield the title compound (150 mg, 471 pmol, 84% yield). 1H NMR (400 MHz, DMSO-c/6): δ 12.8 (br. s, 1 H), 8.46 (s, 2H), 3.10 - 2.94 (m, 2H), 2.46 - 2.27 (m, 2H), 1.99 - 1.90 (m, 1 H), 1.83 - 1.55 (m, 6H), 1 .34 - 1 .03 (m, 6H). LC-MS: Calculated 318.4, found (M+H) 319.3, retention time 0.26 min.
Step 8 2-amino-6-cyano-6-cyclohexyl-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3- carboxamide (322).
A 20 ml vial equipped with a stir bar was charged with 2-amino-6-cyano-6-cyclohexyl-7- oxo-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylic acid (321) (150 mg, 0.47 mmol, 1 equiv.), DIPEA (122 mg, 0.94 mmol, 2 equiv.), ammonium chloride (503 mg, 9.41 mmol, 20 equiv.), HATU (166 mg, 0.706 mmol, 1.5 equiv.) and DMF (5.2 ml, 90.5 mM). The vial was sealed with a pressure relief septum and the reaction was sparged with argon for 5 min. Ammonia 0.4 M in THF solution (23.5 ml, 9.41 mmol, 20 equiv.) was added dropwise via syringe while stirring resulting in the formation of an orange precipitate and the reaction was subsequently stirred at room temperature overnight. The reaction was quenched by addition of 10 ml of saturated ammonium chloride solution and extracted into ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and the volatiles were removed in vacuo. The product was purified by preparative HPLC and subsequently dried by lyophilization to yield the title compound as a white solid (84 mg, 0.265 mmol, 56% yield). 1H NMR (500 MHz, DMSO-c/6): δ 8.22 (s, 2H), 7.07 (s, 2H), 3.14 (ddd, J = 18.0, 9.1 , 4.6 Hz, 1 H), 2.92 (dt, J = 18.0, 5.0 Hz, 1 H), 2.40 (dt, J = 13.7, 4.8 Hz, 1H), 2.30 (ddd, J = 13.8, 9.1 , 4.8 Hz, 1 H), 1.96 (d, J = 11.8 Hz, 1 H), 1.77 (d, J = 14.2 Hz, 3H), 1.64 (d, J = 12.3 Hz, 2H), 1.36 - 1.01 (m, 5H). LC-MS: Calculated 317.4, found (M+H) 318.2 m/z, retention time 0.28 min.
Example 159 2-amino-6-(cyclopropylmethyl)-7-oxo-6-[(2,2,2-trifluoroethoxy)methyl]-4,5,6,7-tetrahydro- 1-benzothiophene-3-carboxamide (331)
Scheme 79
Figure imgf000222_0001
Compound 331 (example 159) was synthesized starting from intermediate 116 which was prepared according to scheme 22.
Step 1 [8-(cyclopropylmethyl)-1 ,4-dioxaspiro[4.5]decan-8-ynmethyl 4-methylbenzene-1 -sulfonate
A 50 ml round bottom flask equipped with a stirbar was charged with [8-(cyclopropylmethyl)- 1 ,4-dioxaspiro[4.5]decan-8-yl]methanol (116) (600 mg, 2.65 mmol, 1 equiv.) and pyridine (11.5 ml). 4-methylbenzene-1-sulfonyl chloride was added and the reaction was stirred at room temperature for 22 hours. Water (10 mL) and the product was extracted to ethyl acetate (2x 10 mL). The organic layers were combined, washed with water and brine. The orrganic layer was dried over sodium sulfate, filtered and the volatiles were removed in vacuo. The material was purified by silica gel column chromatography (0-40% EtOAc in hexane) to yield the title compound as a colourless oil (617 mg, 1.62 mmol, 61% yield). 1H NMR (CDCI3, 400 MHz): δ 7.82 - 7.68 (m, 2H), 7.37 - 7.26 (m, 2H), 3.91 (s, 2H), 3.87 (s, 4H), 2.42 (s, 3H), 1 .54 - 1.42 (m, 8H), 1.27 (d, J = 6.8 Hz, 2H), 0.48 - 0.40 (m, 1 H), 0.35 - 0.30 (m, 2H), -0.02 - -0.06 (m, 2H).
Step 2 8-(cvclopropylmethvl)-8-(iodomethyl)-1 ,4-dioxaspiro[4.5]decane (324).
A 50 ml pear shaped flask equipped with a stirbar was charged with [8- (cyclopropylmethyl)-l ,4-dioxaspiro[4.5]decan-8-yl]methyl 4-methylbenzene-1 -sulfonate (323) (424 mg, 1.11 mmol, 1 equiv.) DMF (2.78 ml) and potassium iodide (924 mg, 5.57 mmol, 5 equiv.). A reflux condenser was affixed to the flask and the reaction was stirred at 100 °C for 18 hours. The reaction was cooled to room temperature, filtered and the filtrate was diluted with ethyl acetate. The organic layer was washed with brine (5x10 ml), dried over sodium sulfate, filtered and the volatiles were removed in vacuo io yield the title compound (289 mg, 0.861 mmol, 77.3% yield). LC-MS: Calculated 336.2, found (M+H) 337.3 m/z, retention time 0.75 min.
Step 3 8-(cyclopropylmethyl)-8-[(2,2,2-trifluoroethoxy)methyl1-1 ,4-dioxaspiro[4.51decane (325).
A dry 2 necked round bottom flask equipped with a stirbar was charged with sodium hydride 60 wt% (71.4 mg, 1.78 mmol, 3 equiv.) and evacuated and refilled with dinitrogen gas. Anhydrous DMF (1.13 ml, 0.526 M) was added and the flask was cooled to 0 °C with an icebath. Degassed trifluoroethanol (179 mg, 1.78 mmol, 3 equiv.) was added dropwise via syringe. The reaction was stirred at room temperature for 30 min. A degassed solution of 8- (cyclopropylmethyl)-8-(iodomethyl)-1 ,4-dioxaspiro[4.5]decane (324) (200 mg, 0.595 mmol, 1 equiv.) in degassed DMF (0.2 ml) was added dropwise via syringe. A reflux condenser was affixed to the flask and the reaction was heated to 100 °C for 18 hours under positive dinitrogen atmosphere. The reaction was cooled to 0 °C with an icebath and water (5 ml) was slowly added via syringe. The product was extracted to ethyl acetate (3x10 ml), washed with brine, dried with sodium sulfate, filtered and the volatiles were removed in vacuo to yield the title compound (173 mg, 0.561 mmol, 94% yield). 1H NMR (CDCI3, 400 MHz): δ 3.94 (s, 4H), 3.79 (q, J = 8.8 Hz, 2H), 3.52 (s, 2H), 1 .70 - 1 .52 (m, 8H), 1.32 (d, J = 6.8 Hz, 2H), 0.64 - 0.56 (m, 1 H), 0.49 - 0.35 (m, 2H), 0.11 - -0.04 (m, 2H).
Step 44-(cyclopropylmethyl)-4-[(2,2,2-trifluoroethoxy)methyl1cyclohexan-1-one (326).
A 50 ml round bottom flask equipped with a stirbar was charged with 8- (cyclopropylmethyl)-8-[(2,2,2-trifluoroethoxy)methyl]-1 ,4-dioxaspiro[4.5]decane (325) (248 mg, 0.804 mmol, 1 equiv.) and acetone (4.02 ml, 0.2 M). Aqueous HCI (12 M, 670 ul, 10 equiv.) was added via syringe and the reaction was stirred at room temperature for 7.5 hours. Saturated sodium bicarbonate solution was added until pH 7 was recorded. The product was extracted with ethyl acetate (3x10 ml), washed with brine, dried over sodium sulfate and the volatiles were removed in vacuo to yield the title compound (192 mg, 0.726 mmol, 90% yield). 1H NMR (500 MHz, CDCI3) δ 3.84 (q, J = 8.7 Hz, 2H), 3.63 (s, 2H), 2.35 (t, J = 6.9 Hz, 4H), 1 .91 - 1 .74 (m, 4H), 1 .45 (d, J = 6.8 Hz, 2H), 0.68 - 0.60 (m, 1 H), 0.52 - 0.46 (m, 2H), 0.10 - 0.06 (m, 2H).
Step 5 ethyl 2-amino-6-(cyclopropylmethyl)-6-[(2,2,2-trifluoroethoxy)methyl1-4,5,6,7-tetrahydro-1- benzothiophene-3-carboxylate (327).
To a 2 dram vial equipped with a stirbar was added 4-(cyclopropylmethyl)-4-[(2,2,2- trifluoroethoxy)methyl]cyclohexan-1-one (326) (182 mg, 0.689 mmol, 1 equiv.), ethyl 2- cyanoacetate (73.3 ul, 0.689 mmol, 1 equiv.), elemental sulfur (24.4 mg, 0.689 mmol, 1 equiv.), morpholine (65.3 ul, 0.758 mmol, 1.1 equiv.) and ethanol (1.1 ml, 0.627 M). The vial was sealed with a pressure relief cap and heated to 60 °C while stirring for 18 hours. The vial was cooled to room temperature and the mixture was filtered. The filtrate was collected and the solvent was removed in vacuo to yield the title compound as an orange oil (231 mg, 0.591 mmol, 86% yield). LC-MS: Calculated 391.4, found (M+H) 392 m/z, retention time 1.19 min.
Step 6 ethyl 6-(cyclopropylmethyl)-2-acetamido-6-[(2,2,2-trifluoroethoxy)methyl1-4,5,6,7- tetrahydro-1-benzothiophene-3-carboxylate (328).
=A 2 dram vial equipped with a stir bar was charged with ethyl 2-amino-6- (cyclopropylmethyl)-6-[(2, 2, 2-trifluoroethoxy)methyl]-4, 5, 6, 7-tetrahydro-1 -benzothiophene-3- carboxylate (327) (231 mg, 0.59 mmol, 1 equiv.) and acetic acid (3.39 ml, 174 mM). The vial was stirred at room temperature and acetic anhydride (68.9 ul. 0.708 mmol, 1.2 equiv.) was added in a single portion. The reaction was stirred at 60 °C for 2 hours and cooled to room temperature. Acetic acid was removed by rotary evaporation and the residue was dissolved in 5 ml DCM, washed with saturated sodium bicarbonate solution (5 ml), water (5 ml) and brine (5 ml). The organic fraction was dried with sodium sulfate, filtered and the volatiles were removed in vacuo to yield the title compound as an orange residue (209 mg, 0.483 mmol, 82% yield). LC-MS: Calculated 433.5, found (M+H) 434.3, retention time 1.42.
Step 7 ethyl 6-(cyclopropylmethyl)-2-acetamido-7-oxo-6-[(2,2,2-trifluoroethoxy)methyl1-4,5,6,7- tetrahydro-1-benzothiophene-3-carboxylate (329).
A 2 dram vial equipped with an egg shaped stir bar was charged with ethyl 6- (cyclopropylmethyl)-2-acetamido-6-[(2,2,2-trifluoroethoxy)methyl]-4,5,6,7-tetrahydro-1- benzothiophene-3-carboxylate (328) (209 mg, 0.483 mmol, 1 equiv.), ceric sulfate (1.38 g, 4.17 mmol, 8.64 equiv.), acetic acid (1.59 ml, 0.303 M) and deionized water (1.59 ml, 0.303 M). The mixture was sonicated to form a yellow slurry. The reaction was stirred vigorously at room temperature for 18 hours. The mixture was diluted with deionized water (2 ml) and ethyl acetate (2 ml). The aqueous phase was extracted with ethyl acetate (3x 5 ml). The organic fractions were combined and washed consecutively with 1 N NaOH (5 ml), water (5 ml) and brine (5 ml). The organic fraction was dried with sodium sulfate, filtered and the volatiles were removed in vacuo to yield the title compound as a pale yellow oil (176 mg, 0.394 mmol, 82% yield). LC-MS: Calculated 447.5, found (M+H) 448.2, retention time 0.80.
Step 8 2-amino-6-(cyclopropylmethyl)-7-oxo-6-[(2,2,2-trifluoroethoxy)methyl1-4,5,6,7-tetrahydro- 1-benzothiophene-3-carboxylic acid (330).
A 250 ml round bottom flask equipped with a stir bar was charged with ethyl 6- (cyclopropylmethyl)-2-acetamido-7-oxo-6-[(2,2,2-trifluoroethoxy)methyl]-4,5,6,7-tetrahydro-1- benzothiophene-3-carboxylate (329) (166 mg, 0.371 mmol, 1 equiv.), deionized water (44.9 ml, 8.27 mM), and methanol (44.9 ml, 8.27 mM). Lithium hydroxide monohydrate (77.8 mg, 1.85 mmol, 5 equiv.) was added in a single portion. A reflux condenser was affixed to the flask and the reaction was heated at 80 °C for 18 hours. The reaction was cooled to room temperature and methanol was removed in vacuo. The mixture was acidified by addition of 1 M HCI solution and extracted to ethyl acetate (3 x 50 ml). The organic fractions were combined, dried with sodium sulfate and filtered. The volatiles were removed from the filtrate in vacuo to yield the title compound as a yellow oil (114 mg, 0.302 mmol, 82% yield). LC-MS: Calculated 377.4, found 378.2 (M+H), retention time 0.28.
Step 92-amino-6-(cyclopropylmethyl)-7-oxo-6-[(2,2,2-trifluoroethoxy)methyl1-4,5,6,7-tetrahydro- 1-benzothiophene-3-carboxamide (331).
To a 25 ml pear shaped round bottom flask equipped with a stir bar was added 2-amino- 6-(cyclopropylmethyl)-7-oxo-6-[(2,2,2-trifluoroethoxy)methyl]-4,5,6,7-tetrahydro-1- benzothiophene-3-carboxylic acid (330) (60 mg, 0.159 mmol, 1 equiv.), DMF (1.76 ml, 90.5 mM), HATU (90.7 mg, 0.238 mmol, 1.5 equiv.), DIPEA (55 ul, 0.318 mmol, 2 equiv.)and ammonium chloride (170 mg, 3.17 mmol, 20 equiv.). The flask was sealed with a septum and sparged with a balloon of argon for 10 mins. Ammonium in THF (0.4 M solution, 8 ml, 3.18 mmol, 20 equiv.) was added to the reaction by syringe resulting the formation of a beige precipitate. The reaction was stirred at room temperature for 18 hours under argon atmosphere. The reaction was quenched by addition of 10 ml of saturated ammonium chloride solution and extracted to ethyl acetate (3x10 ml). The ethyl acetate fractions were combined and washed with brine (7 x 10 ml) to remove DMF, dried with sodium sulfate, filtered and the volatiles were removed in vacuo. The crude material was dissolved in 1 ml DMSO and purified with a Prep C18 column 20 x 150 mm 100 A 5 pm (gradient 0 - 100% acetonitrile in water) and dried by lyophilization to yield the title compound as a white solid (3.4 mg, 9.03 umol, 6% yield). 1H NMR (CDCI3): δ 7.03 (br s, 2H), 5.48 (s, 2H), 3.99 - 3.95 (m, 1 H), 3.89 - 3.77 (m, 3H), 3.05 - 2.90 (m, 2H), 2.46 - 2.39 (m, 1 H), 2.29 - 2.22 (m, 1 H), 1 .65 - 1 .59 (m, 1 H), 1 .53 - 1 .47 (1 H), 0.70 - 0.63 (m, 1 H), 0.50 - 0.42 (m, 2H), 0.08 - -0.06 (m, 2H). 19 F{1H} NMR (CDCI3): δ -74.1 (s). LC-MS: Calculated 376.4, found m/z 377.2 (M+H), retention time 0.86 min.
Examples 160-169
Example 160 2-amino-6-(cyclopropylmethyl)-6-[(difluoromethoxy)methyl]-7-oxo-4,5,6,7-tetrahydro-1- benzothiophene-3-carboxamide (338)
Example 169 2-amino-6-(cyclopropylmethyl)-6-[(difluoromethoxy)methyl]-7-oxo-4,5,6,7-tetrahydro-1- benzothiophene-3-carboxylic acid (337)
Scheme 80
Figure imgf000226_0001
Compound 338 (example 160) was synthesized starting from intermediate 116 which was prepared according to scheme 22.
Figure imgf000226_0002
To a 10 ml vial was added [8-(cyclopropylmethyl)-1 ,4-dioxaspiro[4.5]decan-8-yl]methanol
(116) (602 mg, 2.66 mmol, 1 equiv.), KOAc (1.57 g, 16 mmol, 6 equiv.), DCM (1.6 ml, 1.67 M) and water (1.6 ml, 1.67 M). The reaction was stirred at room temperature and (bromodifluoromethyl)trimethylsilane (1.24 ml, 7.98 mmol, 3 equiv.) was added in a single portion by syringe. The reaction was stirred at room temperature for 18 hours. The reaction was diluted with DCM (10 ml), washed with brine, dried over sodium sulfate, filtered and the volatiles were removed in vacuo to yield the title compound as a clear oil (624 mg, 2.26 mmol, 85% yield). 1H NMR (400 MHz, CDCI3): δ 6.20 (t, J = 76 Hz, 1 H), 3.93 (s, 4H), 3.78 (s, 2H), 1 .64 - 1.57 (m, 8H), 1 .32 (d, J = 6.8 Hz, 2H), 0.65 - 0.56 (m, 1 H), 0.46 - 0.40 (m, 2H), 0.09 - -0.01 (m, 2H).
Step 24-(cyclopropylmethyl)-4-[(difluoromethoxy)methyl1cyclohexan-1-one (333).
A 50 ml pear shaped flask equipped with a stir bar was charged with 8- (cyclopropylmethyl)-8-[(difluoromethoxy)methyl]-1 ,4-dioxaspiro[4.5]decane (332) (624 mg, 2.26 mmol, 1 equiv.) and acetone (11.3 ml, 0.2 M). HCI (12 M, 1.88 ml, 10 equiv.) was added in a single portion with a syringe. The reaction was stirred at room temperature for 5 hours, then quenched with sat. sodium bicarb solution until pH 7 and extracted to ethyl acetate (3 x 15 ml). The organic fractions were combined, washed with brine, dried over sodium sulfate, filtered and the volatiles were removed in vacuo to yield the title compound as a yellow oil (476 mg, 66% yield). 1H NMR (400 MHz, CDCI3): δ 6.24 ( 3.93 (s, 2H), 2.36 (t, J = 12 Hz, 4H),
Figure imgf000226_0003
1 .84 (t, J = 7 Hz, 4H), 1 .46 (d, J = 8 Hz, 2H), 0.70 - 0.59 (m, 1 H), 0.53 - 0.48 (m, 2H), 0.13 - 0.068 (m, 2H).
Step 3 ethyl 2-amino-6-(cyclopropylmethyl)-6-[(difluoromethoxy)methyl1-4,5,6,7-tetrahydro-1- benzothiophene-3-carboxylate (334).
A 1 dram vial equipped with a stir bar was charged with 4-(cyclopropylmethyl)-4- [(difluoromethoxy)methyl]cyclohexan-1-one (333) (476 mg, 1.44 mmol, 1 equiv.), ethyl 2- cyanoacetate (218 ul, 2.05 mmol, 1 equiv.), morpholine (194 ul, 2.25 mmol, 1.1 equiv.), sulfur (72.4 mg, 2.05 mmol, 1 equiv.) and ethanol (3.27 ml, 0.627 M). The vial was sealed with a pressure relief cap and heated at 60 °C for 18 hours, resulting in the formation of an orange solution. The volatiles were removed in vacuo and the crude material was purified by automated column chromatography with silica gel and 0 - 40% EA in hexane as the eluent to yield the title compound an orange oil (150.7 mg, 0.42 mmol, 21 % yield). 1H NMR (400 MHz, CDCh): 56.17 (t, J = 75.3 Hz, 1 H), 4.24 (q, J = 7.1 Hz, 2H), 3.78 (t, J = 8.0 Hz, 2H), 2.76 - 2.61 (m, 2H), 2.45 - 2.41 (m, 2H), 1.74 - 1.59 (m, 2H), 1.47 - 1.41 ( 1 H), 1.31 (t, J = 7.1 Hz, 3H), 1.24 - 1.17 (m, 1 H), 0.67 - 0.57 (m, 1 H), 0.45 - 0.39 (m, 2H), 0.03 - -0.01 (m, 2H).
Step 4 ethyl 6-(cyclopropylmethyl)-6-[(difluoromethoxy)methyl1-2-acetamido-4,5,6,7-tetrahydro- 1-benzothiophene-3-carboxylate (335).
A 2 dram vial equipped with a stir bar was charged with ethyl 2-amino-6- (cyclopropylmethyl)-6-[(difluoromethoxy)methyl]-4,5,6,7-tetrahydro-1 -benzothiophene-3- carboxylate (334) (151 mg, 0.42 mmol, 1 equiv.) and acetic acid (2.4 ml, 174 mM). The vial was stirred at room temperature and acetic anhydride (48.7 ul. 0.501 mmol, 1.2 equiv.) was added in a single portion. The reaction was stirred at 60 °C for 1.5 hours and cooled to room temperature resulting in a pink solution. Acetic acid was removed in vacuo and the residue was dissolved in 5 ml DCM, washed with saturated sodium bicarbonate solution (5 ml), water (5 ml) and brine (5 ml). The organic fraction was dried with sodium sulfate, filtered and the volatiles were removed in vacuo to yield the title compound as a dark red oil (138 mg, 0.344 mmol. 82% yield). 1H NMR (400 MHz, CDCI3): δ 11.25 (s, 1 H), 6.21 (t, J = 75.2 Hz, 1 H), 4.33 (q, J = 8 Hz, 2H), 3.84 - 3.77 (m, 2H), 2.81 - 2.72 (m, 2H), 2.67 - 2.52 (m, 2H), 2.25 (s, 3H), 1.84 - 1.65 (m, 2H), 1 .52 - 1.44 (m, 1 H), 1.39 (t, J = 8 Hz, 3H), 1.31 - 1.19 (m, 2H), 0.73 - 0.61 (m, 1 H), 0.52 - 0.41 (m, 2H), 0.07 - 0.00 (m, 2H).
Step 5 ethyl 6-(cyclopropylmethyl)-6-[(difluoromethoxy)methyl1-2-acetamido-7-oxo-4, 5,6,7- tetrahydro-1-benzothiophene-3-carboxylate (336).
A 2 dram vial equipped with an egg shaped stir bar was charged with ethyl 6- (cyclopropylmethyl)-2-acetamido-6-[(2,2,2-trifluoroethoxy)methyl]-4,5,6,7-tetrahydro-1- benzothiophene-3-carboxylate (335) (69 mg, 0.172 mmol, 1 equiv.), ceric sulfate (493 mg, 1.48 mmol, 8.64 equiv.), acetic acid (567 ul, 0.303 M) and deionized water (567 ml, 0.303 M). The mixture was sonicated to form a yellow slurry. The reaction was stirred vigorously at room temperature for 18 hours. The mixture was diluted with deionized water (2 ml) and ethyl acetate (2 ml). The aqueous phase was extracted with ethyl acetate (3x 5 ml). The organic fractions were combined and washed consecutively with 1N NaOH (5 ml), water (5 ml) and brine (5 ml). The organic fraction was dried with sodium sulfate, filtered and the volatiles were removed in vacuo to yield the title compound as a pale yellow oil (60 mg, 0.144 mmol, 84% yield). LC-MS: retention time 0.28, 416.2 m/z (M+H).
Step 6 2-amino-6-(cyclopropylmethyl)-6-[(difluoromethoxy)methyl1-7-oxo-4,5,6,7-tetrahydro-1- benzothiophene-3-carboxylic acid (337).
A 20 ml vial equipped with a stir bar was charged with ethyl 6-(cyclopropylmethyl)-6- [(difluoromethoxy)methyl]-2-acetamido-7-oxo-4, 5, 6, 7-tetrahydro-1 -benzothiophene-3- carboxylate (336) (60 mg, 0.144 mmol, 1 equiv.), deionized water (17.5 ml, 8.27 mM), and methanol (17.5 ml, 8.27 mM). Lithium hydroxide monohydrate (30.3 mg, 0.722 mmol, 5 equiv.) was added in a single portion. The vial was sealed with a pressure relief cap and the reaction was heated at 80 °C for 18 hours. The reaction was cooled to room temperature and methanol was removed by rotary evaporation. The mixture was acidified by addition of 1 M HCI solution and extracted to ethyl acetate (3 x 50 ml). The organic fractions were combined, dried with sodium sulfate and filtered. The volatiles were removed from the filtrate in vacuo to yield the title compound as a yellow oil (56 mg, 0.162 mmol). The crude material was dissolved in 1 ml DMSO and purified with a Prep C18 column 20 x 150 mm 100 A 5 pm (gradient 0 - 100% acetonitrile in water) and dried by lyophilization to yield the title compound as a white solid. 1H NMR (DMSO- d6, 400 MHz): δ 12.54 (br. s, 1 H), 8.27 (s, 2H), 6.64 (t, J = 76.4 Hz, 1 H), 4.19 (d, J = 9.4 Hz, 1 H), 3.88 (d, J = 9.4 Hz, 1 H), 3.19 - 3.08 (m, 1 H), 2.95 - 2.79 (m, 1 H), 2.23 - 2.00 (m, 2H), 1.55 - 1.38 (m, 2H), 0.68 - 0.56 (m, 1 H), 0.45 - 0.31 (m, 2H), 0.07 - -0.11 (m, 2H). LC-MS: Calculated 345.36, found 346.1 (M+H), retention time 0.27.
Step 7 2-amino-6-(cyclopropylmethyl)-6-[(difluoromethoxy)methyl1-7-oxo-4,5,6,7-tetrahydro-1- benzothiophene-3-carboxamide (338).
To a 25 ml pear shaped round bottom flask equipped with a stir bar was added 2-amino- 6-(cyclopropylmethyl)-6-[(difluoromethoxy)methyl]-7-oxo-4, 5, 6, 7-tetrahydro-1 -benzothiophene- 3-carboxylic acid (337) (30 mg, 0.0869 mmol, 1 equiv.), DMF (960 ul, 90.5 mM), HATU (49.5 mg, 0.130 mmol, 1.5 equiv.), DIPEA (22.5 mg, 0.174 mmol, 2 equiv.) and ammonium chloride (92.9 mg, 1.74 mmol, 20 equiv.). The flask was sealed with a septum and sparged with a balloon of argon for 10 mins. Ammonium in THF (0.4 M solution, 4.34 ml, 1.74 mmol, 20 equiv.) was added to the reaction by syringe resulting the formation of a beige precipitate. The reaction was stirred at room temperature for 18 hours with an argon balloon. The reaction was quenched by addition of 10 ml of saturated NH4CI solution and extracted to ethyl acetate (3x10 ml). The ethyl acetate fractions were combined and washed with brine (7 x 10 ml) to remove DMF, dried with sodium sulfate, filtered and rotovapped to yield the crude material as a brown residue. The crude material was dissolved in 1 ml DMSO and purified with a Prep C18 column 20 x 150 mm 100 A 5 pm (gradient 0 - 100% acetonitrile in water) and dried by lyophilization to yield the title compound as a pale yellow solid (2.6 mg, 7.55 umol, 9% yield). 1H NMR (DMSO-c/6, 400 MHz): 0 8.03 (s, 2H), 6.64 (t, J = 80 Hz, 1 H), 4.20 (d, J = 10 Hz, 1 H), 3.88 (d, J = 10 Hz, 1 H), 3.29 (s, 2H), 3.12 - 2.86 (m, 2H), 2.22 - 2.00 (m, 2H), 1.53 - 1.39 (m, 2H), 0.69 - 0.57 (m, 1 H), 0.47 - 0.33 (m, 2H), 0.1 1 -
-0.12 (m, 2H). 19F NMR (CDCI3, 400 MHz): 0 -84.06 (dd, J = 81 .2 Hz, J = 24.0 Hz, 2F). LC-MS: Calculate 344.4, found 345.2 (M+H), retention time 0.28 min.
Table 6. Characterization of compounds 8, 14, 108, 154, 173, 178, 190, 197 (examples 161-
168).
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0002
Example 172 2-Amino-6-((3-methylisoxazol-4-yl)methyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (339)
Scheme 81
Figure imgf000231_0001
360 339: Example 172
Step 1. Ethyl 2-acetamido-6-((3-methylisoxazol-4-yl)methyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]]thiophene-3-carboxylate (359)
A solution of /V-hydroxyacetimidoyl chloride (236 mg, 379 umol) (Angew. Chem. Int. Ed. 2017, 12586-12589.) in DCE (2.01 mL) was purged with argon for 2 minutes, then 285 (scheme 72) (150 mg, 379 umol) and chloro(1 ,5-cyclooctadiene)Cp*Ru(ll) (7.35 mg, 19.0 umol) were added, followed by triethylamine (66.4 uL, 474 umol). The mixture was stirred at RT under argon for 16 hours. The mixture was then filtered, the solvent removed under reduced pressure and the residue was purified by flash column chromatography (eluent gradient from 5% to 80% of EA in hexane) to afford title compound 359 as a clear oil (102 mg, 59% yield). LC-MS: rt = 1.60 min, MS: 452.1 (calcd), 453.2 (M+H+, found).
Step _ 2. _ 2-Amino-6-((3-methylisoxazol-4-yl)methyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b1]thiophene-3-carboxylic acid (360)
To a suspension of 359 (102 mg, 225 umol) in MeOH (13.8 mL) was added a solution of lithium hydroxide monohydrate (64.6 mg, 1.54 mmol) in water (13.8 mL). The reaction mixture was stirred at 55 °C for 48 hours, then allowed to cool to RT. The mixture was concentrated to remove most of the organic solvent. Then, the aqueous layer was acidified by slowly adding a 2 N aqueous solution of HCI and the product was extracted with EA. The organic layers were combined then washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 15% of MeOH in DCM) to afford title compound 360 (68.8 mg, 80% yield). LC-MS: rt = 1.33 min, MS: 382.1 (calcd), 383.2 (M+H+, found).
Step 3. 2-Amino-6-((3-methylisoxazol-4-yl)methyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (339)
To a solution of 360 (68.8 mg, 183.0 umol) in DMF (2.3 mL) were added PyBOP (141 mg, 270 umol), N,N-diisopropylethylamine (125 uL, 720 umol) and ammonium chloride (96.2 mg, 1.80 mmol). The resulting mixture was stirred at RT for 45 minutes. The crude mixture was directly purified by reverse-phase flash column chromatography (eluent gradient from 5% to 100% of CH3CN in H2O with 0.1 % (v/v) formic acid), then by Semi-Prep HPLC-MS (eluent gradient from 40% to 100% of MeOH in 10 mM ammonium formate) to afford title compound 339 as an off-white solid (29.6 mg, 43% yield).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.18 (s, 1 H), 8.06 (bs, 2H), 7.31-7.27 (m, 2H), 7.24- 7.21 (m, 3H), 6.82 (bs, 2H), 2.89-2.75 (m, 3H), 2.69-2.61 (m, 1 H), 2.57-2.50 (m, 1 H), 2.12-2.03 (m, 1 H), 1.76 (s, 3H). LC-MS: rt = 1.19 min, MS: 381.1 (calcd), 382.2 (M+H+, found).
Example 173 2-Amino-6-((1-methyl-1 H-1 ,2,3-triazol-4-yl)methyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (341)
Scheme 82
Figure imgf000232_0001
Step 1. Ethyl 2-acetamido-6-((1-methyl-1 H-1 ,2,3-triazol-4-yl)methyl)-7-oxo-6-phenyl-
4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (361) Sodium ascorbate (10.1 mg, 50.6 umol) and copper iodide (96.3 mg, 0.506 mmol) were added to a solution of 285 (scheme 72) (100 mg, 0.253 mmol) in DMF (2.8 mL) and water (2.8 mL). The flask was evacuated and backfilled with nitrogen. Then, iodomethane (127 uL, 2.02 mL) and sodium azide (132 mg, 2.02 mmol) were added and the reaction mixture was stirred at 50 °C for 20 hours. The mixture was then diluted with brine (10 mL) and extracted with EA (2 x 15 mL). Saturated sodium bicarbonate solution was added to the aqueous layer and the product was extracted with EA (3 x 15 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 15% to 100% of EA in hexane) to afford title compound 361 as a black oil (65.0 mg, 57% yield). LC-MS: rt = 1.36 min, MS: 452.2 (calcd), 453.4 (M+H+, found).
Step 2. 2-Amino-6-((1-methyl-1 H-1 ,2,3-triazol-4-yl)methyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (362)
To a suspension of 361 (65.0 mg, 144 umol) in EtOH (8.8 mL) was added a solution of lithium hydroxide monohydrate (90.4 mg, 2.15 mmol) in water (8.8 mL). The reaction mixture was stirred at 55 °C for 20 hours, then allowed to cool to RT. The mixture was concentrated to remove most of the organic solvent. The aqueous layer was purified by reverse-phase flash column chromatography (eluent gradient from 5% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid) to afford title compound 362 (31.0 mg, 56% yield). LC-MS: rt = 0.97 min, MS: 382.1 (calcd), 383.1 (M+H+, found).
Step 3. 2-Amino-6-((1-methyl-1 H-1 ,2,3-triazol-4-yl)methyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (341)
To a solution of 362 (31 mg, 81.1 umol) in DMF (0.7 mL) were added PyBOP (63.4 mg, 122 umol), N,N-diisopropylethylamine (56.5 uL, 324 umol) and ammonium chloride (43.4 mg, 0.811 mmol). The resulting mixture was stirred at RT for 1 hour. The crude mixture was directly purified by reverse-phase flash column chromatography (eluent gradient from 5% to 100% of CH3CN in H2O with 10 mM ammonium bicarbonate aqueous solution) to afford title compound 341 as a beige solid (14.6 mg, 47% yield).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.04 (s, 2H), 7.36 (s, 1H), 7.29-7.26 (m, 4H), 7.23- 7.18 (m, 1 H), 6.81 (m, 1H), 3.89 (s, 3H), 3.24 (d, 1 H, J = 14.2 Hz), 2.93 (d, 1 H, J = 14.2 Hz), 2.82- 2.76 (m, 1 H), 2.65-2.49 (m, 2H), 2.13-2.05 (m, 1H). LC-MS: rt = 0.97 min, MS: 381.1 (calcd), 382.2 (M+H+, found).
Example 174 2-Amino-6-(cyclopropylmethyl)-6-(2-(isoxazol-3-yl)ethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (343)
Scheme 83
Figure imgf000234_0001
Step 1 . 3-(8-(Cyclopropylmethyl)-1 ,4-dioxaspiro[4.51decan-8-yl)-/V-methoxy-/V- methylpropanamide (363)
Compound 203 (scheme 46) (1.19 g, 4.43 mmol) was dissolved in dry DMF (28 mL). N,O- Dimethylhydroxylamine hydrochloride (865 mg, 8.87 mmol), HATU (2.58 g, 6.65 mmol) and DIPEA (3.1 mL, 17.7 mmol) were added and the reaction mixture was stirred at RT for 20 hours. EA (40 mL) and brine (40 mL) were then added and the layers were separated. The aqueous phase was extracted with EA (2 x 40 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 30% to 100% of EA in hexane) to afford title compound 363 as a colorless oil (1.2 g, 86% yield), which was not characterized and used directly for the next step.
Step 2. 5-(8-(Cyclopropylmethyl)-1 ,4-dioxaspiro[4.5]decan-8-yl)pent-1-yn-3-one (364)
To a solution of 363 (1 g, 3.21 mmol) in dry toluene (30 mL) was added dropwise ethynylmagnesium chloride (9.6 mL, 0.5 M in THF, 4.82 mmol) and the resulting mixture was stirred at RT for 45 minutes. A saturated solution of ammonium chloride (30 mL) and EA (40 mL) were then added. The layers were separated and the aqueous phase was extracted with EA (2 x 40 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 50% of EA in hexane) to afford title compound 364 as a colorless oil (366 mg, 41% yield), which was not characterized and used directly for the next step.
Step 3. 5-(8-(Cyclopropylmethyl)-1 ,4-dioxaspiro[4.51decan-8-yl)pent-1-yn-3-one oxime (365)
To a solution of 364 (575 mg, 2.08 mmol) in ethanol (30 mL) was added a 50% aqueous solution of hydroxylamine (1 .27 mL, 20.8 mmol). The reaction mixture was stirred at RT for 1 hour. Brine (50 mL) and EA (30 mL) were then added and the layers were separated. The aqueous phase was extracted with EA (2 x 40 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to afford title compound 365 as a white gum (606 mg, 100% yield), which was not characterized and used directly for the next step.
Step 4. 3-(2-(8-(Cyclopropylmethyl)-1 ,4-dioxaspiro[4.51decan-8-yl)ethyl)isoxazole (366)
To a solution of 365 (380 mg, 1.30 mmol) in DCM (20 mL) was added gold (III) chloride (4.0 mg, 13 umol). The reaction mixture was stirred at 40 °C for 20 hours, then concentrated to afford title compound 366 as a brown oil (328 mg, 86% yield), which was not characterized and used directly for the next step.
Step 5. 4-(Cyclopropylmethyl)-4-(2-(isoxazol-3-yl)ethyl)cyclohexan-1-one (367)
To a solution of 366 (328 mg, 1.13 mmol) in acetone (16.8 mL) was added HCI 3 N (3.75 mL, 11 .3 mmol) and the reaction mixture was stirred at 40 °C for 20 hours. EA (15 mL) and brine (10 mL) were then added, the layers were separated and the organic phase was dried over Na2SC>4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 55% of EA in hexane) to afford title compound 367 as a colorless oil (226 mg, 81% yield), which was not characterized and used directly for the next step.
Step 6. tert-Butyl 2-amino-6-(cyclopropylmethyl)-6-(2-(isoxazol-3-yl)ethyl)-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (368)
A suspension of sulfur (32.2 mg, 126 umol), 367 (225 mg, 0.910 mmol), morpholine (86.3 uL, 1.00 mmol) and tert-butyl cyanoacetate (133 uL, 0.910 mmol) in EtOH (5 mL) was stirred at 60 °C for 72 hours. The mixture was allowed to cool to RT, then diluted with brine (20 mL) and extracted with EA (3 x 20 mL). The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 50% of EA in hexane) to afford title compound 368 as a yellow oil (288 mg, 79% yield). LC- MS: rt = 2.01 min, MS: 402.2 (calcd), 403.4 (M+H+, found).
Step 7. tert-Butyl 2-acetamido-6-(cyclopropylmethyl)-6-(2-(isoxazol-3-yl)ethyl)-7-oxo- 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (369) To a solution of 368 (288 mg, 0.715 mmol) in acetic acid (4.1 mL) was added acetic anhydride (135 uL, 1 .43 mmol). The reaction mixture was stirred at 60 °C for 1 hour, then allowed to cool to RT and diluted with acetic acid (5.9 mL), water (10.1 mL) and dioxane (8.5 mL). Ceric sulfate (1.25 g, 3.58 mmol) was added to the mixture and the flask was sonicated to make the suspension homogeneous. Then, the reaction was vigourously stirred at RT for 20 hours. Afterwards, the mixture was diluted with water (50 mL) and extracted with EA (70 mL). The organic layer was washed with saturated solution of ammonium bicarbonate (3 x 100 mL), then dried over Na2SC>4, filtered and concentrated to afford title compound 369 as a yellow oil (349 mg, >99% yield). LC-MS: rt = 1.76 min, MS: 458.2 (calcd), 459.3 (M+H+, found).
Step 8. tert- Butyl 2-amino-6-(cyclopropylmethyl)-6-(2-(isoxazol-3-yl)ethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (370)
A solution of 369 (259 mg, 565 umol) in toluene (6.9 mL) was treated with pyrrolidine (696 uL, 8.47 mmol) and stirred at RT for 2 hours. Water (15 ml) and EA (10 mL) were then added, the layers were separated and the aqueous phase was extracted with another 10 mL of EA. The combined organics were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated to afford title compound 370 as a brown oil (188 mg, 80% yield). LC-MS: rt = 1.70 min, MS: 416.2 (calcd), 417.3 (M+H+, found).
Step 9. 2-Amino-6-(cyclopropylmethyl)-6-(2-(isoxazol-3-yl)ethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (371)
To a solution of 370 (188 mg, 451 umol) in DCM (4.3 mL) cooled to 0 °C was added TFA (1 .9 mL) and the resulting mixture was stirred at 0 °C for 3 hours. The solvent was then removed under reduced pressure and the residue was purified by reverse-phase flash column chromatography (eluent gradient from 5% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid) to afford title compound 371 as a yellow solid (92 mg, 45% yield). LC-MS: rt = 1.34 min, MS: 360.1 (calcd), 361.2 (M+H+, found).
Step 10. 2-Amino-6-(cyclopropylmethyl)-6-(2-(isoxazol-3-yl)ethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (343)
To a solution of 371 (90 mg, 250 umol) in DMF (1.2 mL) were added PyBOP (195 mg, 375 umol), N,N-diisopropylethylamine (174 uL, 999 umol) and ammonium chloride (134 mg, 2.50 mmol). The resulting mixture was stirred at RT for 45 minutes. The crude mixture was directly purified first by reverse-phase flash column chromatography (eluent gradient from 5% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid), then by Semi-Prep HPLC-MS (eluent gradient from 40% to 100% of MeOH in 10 mM ammonium formate) to afford title compound 343 as a paleyellow solid (40.5 mg, 45% yield).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.40 (s, 1H), 7.99 (s, 2H), 6.91 (bs, 2H), 6.24 (s, 1 H), 3.01-2.91 (m, 2H), 2.72-2.62 (m, 2H), 2.15-2.09 (m, 1 H), 2.05-1.98 (m, 2H), 1.89-1.81 (m, 1 H), 1.62 (dd, 1 H, J = 14.1 , 6.3 Hz), 1.38 (dd, 1 H, J = 14.1 , 6.9 Hz), 0.66-0.57 (m, 1 H), 0.43-0.35 (m, 2H), 0.07-0.04 (m, 1H), 0.01- -0.06 (m, 1 H). LC-MS: rt = 1.18 min, MS: 359.1 (calcd), 360.2 (M+H+, found).
Example 175 6-((1H-1,2,3-Triazol-4-yl)methyl)-2-amino-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (344) Intermediate compound 372
Ethyl 6-((1 H-1 ,2,3-triazol-4-yl)methyl)-2-acetamido-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (372)
Scheme 84
Figure imgf000237_0001
285 372
Scheme 72
Sodium ascorbate (201 mg, 1.01 mmol) and copper iodide (193 mg, 1.01 mmol) were added to a solution of ethyl 2-acetamido-7-oxo-6-phenyl-6-(prop-2-yn-1-yl)-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (285, scheme 72) (200 mg, 506 umol) in DMF (5.47 mL) and water (2.73 mL). The flask was evacuated and backfilled with nitrogen. Then, azidotrimethylsilane (537 uL, 4.05 mmol) was added and the reaction mixture was stirred at RT for 16 hours. The mixture was then diluted with EA, a saturated solution of NH4CI and brine and then extracted twice with EA. Saturated aqueous sodium bicarbonate solution was added to the aqueous layer and the product was extracted three times with EA. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by reverse-phase flash column chromatography (eluent gradient from 10% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid) to afford title compound 372 as a white solid (120 mg, 54% yield). LC-MS: rt = 1.32 min, MS: 438.1 (calcd), 439.2 (M+H+, found).
6-((1H-1,2,3-Triazol-4-yl)methyl)-2-amino-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (344)
Figure imgf000237_0002
344: Example 175 Compound 344 (example 175) was synthesized similarly to compound 341 (example 173, scheme 82) starting from compound 372 (scheme 84) instead of compound 361.
1H NMR: 400 MHz, CD3OD, δ (ppm): 7.33-7.27 (m, 4H), 7.25-7.23 (m, 1 H), 7.21 (s, 1 H), 3.40 (d, J = 14.4 Hz, 1H), 3.17 (d, J = 14.4 Hz, 1H), 2.91-2.87 (m, 1 H), 2.66-2.60 (m, 2H), 2.21- 2.14 (m, 1 H). LC-MS: rt = 0.85 min, MS: 367.1 (calcd), 368.1 (M+H+, found).
Example 176
2-Amino-6-(2-(3-methylisoxazol-5-yl)ethyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (345)
Scheme 85
Figure imgf000238_0001
Step 1. 4-(But-3-yn-1-yl)-4-phenylcyclohexan-1-one (373)
To a solution of compound 177 (scheme 35) (734 mg, 2.71 mmol) in acetone (33.6 mL) was added HCI 2 N (13.6 mL, 27.1 mmol) and the reaction mixture was stirred at RT for 20 hours. The mixture was neutralized with saturated solution of ammonium bicarbonate and concentrated to remove the organic solvent. The product was extracted with EA and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to afford title compound 373 as a white solid (599 mg, 97% yield), which was not characterized and used directly for the next step.
Step 2. Ethyl 2-amino-6-(but-3-yn-1-yl)-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate (374)
A suspension of sulfur (94 mg, 365 umol), 373 (599 mg, 2.65 mmol), morpholine (255 uL, 2.91 mmol) and ethyl 2-cyanoacetate (310 uL, 2.91 mmol) in EtOH (2.7 mL) was stirred at 60 °C for 20 hours. The mixture was concentrated and the residue was partitioned between water and EA. The layers were separated and the organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 50% of EA in hexane) to afford title compound 374 as a white solid (870 mg, 93% yield). LC-MS: rt = 1.84 min, MS: 353.1 (calcd), 354.1 (M+H+, found).
Step 3. Ethyl 2-acetamido-6-(but-3-yn-1-yl)-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (375)
To a solution of 374 (841 mg, 2.38 mmol) in acetic acid (13.6 mL) was added acetic anhydride (0.41 mL, 4.28 mmol). The mixture was stirred at 80 °C for 24 hours. The mixture was then concentrated, the residue was dissolved in DCM and washed with saturated aqueous solution of sodium bicarbonate, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated to afford title compound 375 as a light-orange powder (1 .01 g, >99% yield). LC- MS: rt = 1.93 min, MS: 395.2 (calcd), 396.3 (M+H+, found).
Step 4. Ethyl 2-acetamido-6-(but-3-yn-1-yl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (376)
To a solution of 375 (941 mg, 2.38 mmol) in acetic acid (16 mL), water (16 mL) and dioxane (16 mL) was added ceric sulfate (6.83 g, 20.6 mmol). The mixture was sonicated until it became homogenous, and then stirred at RT for 72 hours. The suspension was partitioned between EA and water, the layers were separated and the organic phase was washed with NaOH 1 N, water and brine, then dried over Na2SO4, filtered and concentrated to afford title compound 376 as a light-orange solid (713 mg, 73% yield). LC-MS: rt = 1.76 min, MS: 409.1 (calcd), 410.2 (M+H+, found).
Step 5. Ethyl 2-acetamido-6-(2-(3-methylisoxazol-5-yl)ethyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (377)
To a solution of 376 (150 mg, 366 umol) in DCM (3.0 mL) was added /V- hydroxyacetimidoyl chloride (103 mg, 1.10 mmol) (Angew. Chem. Int. Ed. 2017, 12586-12589.) and triethylamine (154 uL, 1.10 mmol). The reaction mixture was stirred at RT for 4 days. Brine (15 mL) and DCM (10 mL) were then added, the layers were separated and the aqueous phase was extracted with another 15 mL of EA. Organic layers were combined and washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 45% of EA in hexane) to afford title compound 377 as a light-yellow solid (99 mg, 58% yield). LC-MS: rt = 1.64 min, MS: 466.2 (calcd), 467.2 (M+H+, found).
Step 6. 2-Amino-6-(2-(3-methylisoxazol-5-yl)ethyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (378)
To a suspension of 377 (99.0 mg, 212 umol) in EtOH (13 mL) was added a solution of lithium hydroxide monohydrate (89 mg, 2.12 mmol) in water (13 mL). The reaction mixture was stirred at 55 °C for 24 hours, then allowed to cool to RT. The mixture was concentrated to remove most of the organic solvent. The aqueous layer was acidified with 1 M HCI to pH 4, which induced precipitation of a light-yellow solid. This solid was filtered, rinsed with water (25 mL) and dried to afford title compound 378 (75 mg, 89% yield). LC-MS: rt = 1.29 min, MS: 396.1 (calcd), 397.2 (M+H+, found).
Step 7. 2-Amino-6-(2-(3-methylisoxazol-5-yl)ethyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (345)
To a solution of 378 (70 mg, 177 umol) in DMF (3.8 mL) were added PyBOP (138 mg, 265 umol), N,N-diisopropylethylamine (123 uL, 706 umol) and ammonium chloride (94.4 mg, 1.77 mmol). The resulting mixture was stirred at RT for 45 minutes. The crude mixture was directly purified by reverse-phase flash column chromatography (eluent gradient from 5% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid), then by Semi-Prep HPLC-MS (eluent gradient from 30% to 100% of acetonitrile in 10 mM ammonium formate) to afford title compound 345 as a lightyellow solid (32.8 mg, 47% yield).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.08 (bs, 2H), 7.31-7.26 (m, 4H), 7.24-7.20 (m, 1 H), 6.84 (bs, 2H), 6.01 (s, 1 H), 2.89-2.81 (m, 1 H), 2.71-2.53 (m, 2H), 2.43-2.35 (m, 1 H), 2.32- 2.15 (m, 2H), 2.09 (s, 3H), 2.09-2.02 (m, 2H). LC-MS: rt = 1.15 min, MS: 395.1 (calcd), 396.2 (M+H+, found).
Example 177
2-Amino-6-(1 -benzyl-1 H-1 ,2,3-triazol-4-yl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (348) Intermediate compound 381
1 -Benzyl-4-(8-phenyl-1 ,4-dioxaspiro[4.5]decan-8-yl)-1 H-1 ,2,3-triazole (381 )
Scheme 86
Figure imgf000240_0001
Step 1. 8-Ethvnyl-8-phenyl-1 ,4-dioxaspiro[4.51decane (380) To a solution of 8-phenyl-1 ,4-dioxaspiro[4.5]decane-8-carbaldehyde (379) (Bioorg Med. Chem Lett. 21 , p. 405, 2011) (500 mg, 2.03 mmol) in MeOH (25 mL) were added K2CO3 (700 mg, 5.08 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (0.50 mL, 3.05 mmol). The mixture was stirred at RT for 1 hour, then it was diluted with water (25 mL) and concentrated to remove most of the organic solvent. The residue was extracted with EA (50 mL) and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 50% of EA in hexane) to afford title compound 380 as a white solid (395 mg, 80% yield), which was used directly for the next step without characterization.
Step 2. 1-Benzyl-4-(8-phenyl-1 ,4-dioxaspiro[4.51decan-8-yl)-1 H-1 ,2,3-triazole (381)
A solution of 380 (370 mg, 1.53 mmol) and benzyl azide (3.7 mL, 0.5 M in DCM, 1.85 mmol) in DCM (10 mL) was added to a solution of Cui (29 mg, 0.15 mmol) and 2-2’-dipyridyl (24 mg, 0.15 mmol) in DCM (10 mL). The reaction mixture was stirred at 40 °C for 24 hours. Then, the mixture was filtered though a celite pad and the filtrate was concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 100% of EA in hexane) to afford title compound 381 as a white solid (490 mg, 85% yield), which was not characterized and used directly for the synthesis of relevant examples.
2-Amino-6-(1 -benzyl-1 H-1 ,2,3-triazol-4-yl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (348)
Figure imgf000241_0001
Compound 348 (example 177) was synthesized similarly to compound 189 (example 102, scheme 40) starting from compound 381 (scheme 86) instead of compound 185.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 12.51 (bs, 1 H), 8.31 (s, 2H), 7.69 (s, 1 H), 7.36- 7.20 (m, 8H), 7.15-7.12 (m, 2H), 5.52 (s, 2H), 2.99 (dt, J = 18.5, 4.9 Hz, 1H), 2.91-2.78 (m, 2H), 2.61 (ddd, J = 18.5, 8.6, 4.6 Hz, 1 H). LC-MS: rt = 1.25 min, MS: 444.1 (calcd), 445.2 (M+H+, found).
Example 178
2-Amino-6-(1 -benzyl-1 H-1 ,2,3-triazol-4-yl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (346)
Figure imgf000242_0001
Compound 346 (example 178) was synthesized similarly to compound 258 (example 138, scheme 63) starting from compound 348 (example 177) instead of compound 257.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.15 (s, 2H), 7.68 (s, 1H), 7.36-7.20 (m, 8H), 7.15- 7.12 (m, 2H), 6.90 (bs, 2H), 5.52 (s, 2H), 2.94-2.86 (m, 2H), 2.82-2.69 (m, 2H). LC-MS: rt = 1.25 min, MS: 443.1 (calcd), 444.3 (M+H+, found).
Example 179
2-Amino-6-(1-benzyl-1H-1,2,3-triazol-4-yl)-N-cyclopropyl-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (352)
Figure imgf000242_0002
352: Example 179
Compound 352 (example 179) was synthesized similarly to compound 170 (example 95, scheme 32) starting from compound 348 (example 177) instead of compound 59.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.90 (s, 2H), 7.66 (s, 1H), 7.38-7.20 (m, 9H), 7.14- 7.11 (m, 2H), 5.52 (s, 2H), 2.93-2.85 (m, 1 H), 2.82-2.73 (m, 2H), 2.71-2.62 (m, 2H), 0.63-0.58 (m, 2H), 0.50-0.46 (m, 2H). LC-MS: rt = 1.32 min, MS: 483.2 (calcd), 484.2 (M+H+, found).
Example 180 (S)-2-Amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (353) and Example 181 (R)-2-Amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (354)
Scheme 87
Figure imgf000242_0003
Racemic compound 150 (1.71 g) was submitted to SFC chiral separation (isocratic: 40% of MeOH in CO2) to yield enantioenriched compound 353 as an off-white solid (493 mg, 29% separation yield) and enantioenriched compound 354 as a pale-yellow solid (534 mg, 31% separation yield). Absolute configurations of compounds 353 and 354 were assigned based on analogy with the assignment of the absolute configuration of a crystallized compound within the same or similar series.
353: 1H NMR: same as racemic mixture (150). LC-MS: rt = 1.03 min, MS: 303.1 (calcd), 304.1 (M+H+, found). Analytical SFC (isocratic 30% iPrOH in CO2): rt = 3.56 min, ee. = 92.5%.
354: 1H NMR: same as racemic mixture (150). LC-MS: rt = 1.03 min, MS: 303.1 (calcd), 304.1 (M+H+, found). Analytical SFC (isocratic 30% iPrOH in CO2):. rt = 2.71 min, ee. = 98.2%.
Example 182 2-Amino-7-oxo-6-phenyl-6-(1H-1,2,3-triazol-4-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-
Figure imgf000243_0001
1 N aqueous HCI (0.8 mL, 0.8 mmol) was added to a suspension of 346 (72 mg, 0.16 mmol) and Pd/C 10% (wet) (60 mg) in a 5:1 MeOH/EA mixture (24 mL). Then, the reaction mixture was vigorously stirred under a hydrogen atmosphere (balloon) at RT for 16 hours. The mixture was filtered through a celite pad and the filtrate was concentrated. The residue was purified by reverse-phase flash column chromatography (eluent gradient from 0% to 100% CH3CN in H2O with 0.1% (v/v) formic acid) to afford title compound 355 as a white solid (24 mg, 42% yield).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.15 (s, 2H), 7.39 (bs, 1 H), 7.31-7.28 (m, 2H), 7.25-7.21 (m, 1 H), 7.11-7.09 (m, 2H), 6.90 (bs, 2H), 2.92-2.82 (m, 2H), 2.80-2.71 (m, 2H). LC- MS: rt = 0.93 min, MS: 353.1 (calcd), 354.2 (M+H+, found).
Example 183
2-Amino-N-cyclopropyl-7-oxo-6-phenyl-6-(1H-1,2,3-triazol-4-yl)-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (356)
Figure imgf000244_0001
Compound 356 (example 183) was synthesized similarly to compound 355 (example 182, scheme 88) starting from compound 352 (example 179) instead of compound 346.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.89 (s, 2H), 7.39-7.36 (m, 2H), 7.31-7.27 (m, 2H), 7.25-7.21 (m, 1 H), 7.10-7.08 (m, 2H), 2.85-2.63 (m, 5H), 0.63-0.58 (m, 2H), 0.49-0.46 (m, 2H). LC-MS: rt = 1.09 min, MS: 393.1 (calcd), 394.3 (M+H+, found).
Example 184
(R)-2-Amino-7-oxo-5-(2-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (357) and Example 185
(S)-2-Amino-7-oxo-5-(2-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (358)
Figure imgf000244_0002
4: Example 1 357: Example 184 358: Example 185
Scheme 1
718 mg of racemic compound 4 (scheme 1 , example 1) were submitted to SFC chiral separation (isocratic 30% /-PrOH in CO2) to afford enantioenriched title compound 357 as a brown solid (234 mg, 33% separation yield) and enantioenriched title compound 358 as a brown solid (287 mg, 40% separation yield) (the absolute configurations were assigned based on resolved crystal structure of enantiomer 357).
357: 1H NMR: same as racemic mixture (4). LC-MS: rt = 1.13 min, MS: 354.1 (calcd), 355.1 (M+H+, found). Analytical chiral SFC (30% of /-PrOH in CO2): rt = 3.20 min, ee. = 99.29%.
358: 1H NMR: same as racemic mixture (4). LC-MS: rt = 1 .13 min, MS: 354.1 (calcd), 355.1 (M+H+, found). Analytical chiral SFC (30% of /-PrOH in CO2): rt = 2.35 min, ee. = 99.85%.
Examples 186-192 Intermediate compound 384 4-(2-(8-(Cyclopropylmethyl)-1,4-dioxaspiro[4.5]decan-8-yl)ethyl)-3-methylisoxazole (384) Scheme 90
Figure imgf000245_0001
Step 1. 3-(8-(Cyclopropylmethyl)-1 ,4-dioxaspiro[4.51decan-8-yl)propanal (382)
To a solution of compound 185 (scheme 40) (2.50 g, 10 mmol) in anhydrous toluene (63 mL) at -78 °C was added dropwise DIBALH (8.09 mL, 25% in toluene, 12 mmol). The reaction mixture was stirred at -78 °C for 2 hours, before being carefully quenched with MeOH and saturated NH4CI solution. Afterwards, the mixture was allowed to reach RT and diluted with Et2O, then filtered through a celite pad. The layers were separated, and the organic phase was concentrated. The residue was dissolved in THF (134 mL) and HCI 1 N (10 mL, 10 mmol) was added. The mixture was stirred at RT for 15 min, before being quenched with saturated NaHCO3 solution and extracted with Et2O. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (eluent gradient from 5% to 100% of EA in hexane) to afford title compound 382 (2.4 g, 95% yield) as a colorless oil, which was not characterized and used directly for the next step.
Step 2. 8-(But-3-yn-1-yl)-8-(cyclopropylmethyl)-1 ,4-dioxaspiro[4.51decane (383)
To a solution of compound 382 (2.40 g, 9.51 mmol) in MeOH (117 mL) were added K2CO3 (3.29 g, 23.8 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (2.35 mL, 14.3 mmol). The mixture was stirred at RT for 1 hour, then it was diluted with water (25 mL) and concentrated to remove most of the organic solvent. The residue was extracted with EA (50 mL) and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 50% of EA in hexane) to afford title compound 383 as a white solid (1.55 g, 66% yield), which was used directly for the next step without characterization.
Step _ 3. _ 4-(2-(8-(Cyclopropylmethyl)-1 ,4-dioxaspiro[4.51decan-8-yl)ethyl)-3- methylisoxazole (384)
A solution of /V-hydroxyacetimidoyl chloride (Angew. Chem. Int. Ed. 2017, 12586-12589.) (56.5 mg, 604 umol) in DCE (3.20 mL) was purged with argon for 2 min, then compound 383 (150 mg, 604 umol) and chloro(pentamethylcyclopentadienyl)(cyclooctadiene)ruthenium(ll) (11.7 mg, 30.2 umol) were added followed by triethylamine (106 uL, 755 umol). The mixture was stirred under Ar at RT for 48 hours. The reaction mixture was then directly purified by flash column chromatography (eluent gradient from 5% to 80% of EA in hexane) to afford a colorless oil (93.0 mg, 50% yield) which was not characterized and used directly for the next step. Intermediate compound 386
1 -(2-(8-(Cyclopropylmethyl)-1 ,4-dioxaspiro[4.5]decan-8-yl)ethyl)-1 H-1 ,2,4-triazole (386) Scheme 91
Figure imgf000246_0001
Scheme 21
Step 1. 2-(8-(Cyclopropylmethyl)-1 ,4-dioxaspiro[4.51decan-8-yl)ethyl methanesulfonate (385)
To a solution of compound 115 (scheme 21) (5.0 g, 19.1 mmol) in anhydrous DCM (95 mL) at 0 °C were added methanesulfonyl chloride (2.4 g, 21 .0 mmol) and triethylamine (5.31 mL, 38.1 mmol). The reaction mixture was stirred at RT for 1 hour, then diluted with water and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 40% of EA in hexane) to afford title compound 385 as a white solid (5.2 g, 80% yield) which was not characterized and used directly for the next step.
Step 2. 1-(2-(8-(Cyclopropylmethyl)-1 ,4-dioxaspiro[4.51decan-8-yl)ethyl)-1H-1 ,2,4- triazole (386)
To a solution of 385 (50 mg, 157 umol) in anhydrous DMF (1.57 mL) was added 1 ,2,4- triazole sodium salt (71.5 mg, 785 umol). The reaction mixture was stirred at 110 °C for 20 hours, then allowed to cool to RT and quenched with saturated aqueous NH4CI solution (10 mL) diluted with water (10 mL). Then, the desired product was extracted with EA (2 x 20 mL). The organic layers were combined, washed with brine (2 x 20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (eluent gradient from 15% to 100% of EA in hexane) to afford title compound 386 as a colorless oil (45 mg, 99%). which was not characterized and used directly for the next step.
Intermediate compound 387
1-(2-(8-(Cyclopropylmethyl)-1,4-dioxaspiro[4.5]decan-8-yl)ethyl)-3-methyl-1 H-1 ,2,4- triazole (387) and
Intermediate compound 388
1-(2-(8-(Cyclopropylmethyl)-1,4-dioxaspiro[4.5]decan-8-yl)ethyl)-5-methyl-1 H-1 ,2,4- triazole (388)
Scheme 92
Figure imgf000247_0001
Scheme 91
To a suspension of sodium hydride (117 mg, 2.94 mmol) in DMF (7 mL) at 0 °C was added 3-methyl-1 H-1 ,2,4-triazole (125 mg, 1.47 mmol). The resulting mixture was stirred at 0 °C for 15 minutes and then compound 385 (scheme 91) (500 mg, 1.47 mmol) was added dropwise as a solution in DMF (7 mL). The reaction mixture was stirred at RT for 18 hours, then quenched with saturated aqueous NH4CI solution (30 mL) and diluted with water (15 mL). Then, the desired product was extracted with EA (2 x 40 mL) and purified by flash column chromatography (eluent gradient from 15% to 100% of EA in hexane) to afford a 1 :1 regioisomeric mixture of title compounds 387 and 388 as a colorless oil (274 mg, 57%), which was not characterized and used directly for the next step.
Intermediate compound 389
3-Methyl-4-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)isoxazole (389)
Figure imgf000247_0002
389
Intermediate 389 was synthesized similarly to compound 384 (scheme 90) starting from compound 380 (scheme 86) instead of compound 383. The product was not characterized and used directly for the next step.
Intermediate compound 390 3-Methyl-5-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)isoxazole (390) Scheme 93
Figure imgf000247_0003
To a solution of compound 380 (scheme 86) (700 mg, 2.89 mmol) in DCM (23 mL) was added /V-hydroxyacetimidoyl chloride (810 mg, 8.66 mmol) (Angew. Chem. Int. Ed. 2017, 12586- 12589.) and triethylamine (1.2 mL, 8.66 mmol). The reaction mixture was stirred at RT for 4 days. Subsequently, brine (15 mL) and DCM (10 mL) were added, the layers were separated, and the aqueous phase was extracted with another 15 mL of EA. The organic layers were combined, washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (eluent gradient from 10% to 50% of EA in hexane) to afford title compound 390 as a colorless oil (174 mg, 20% yield), which was not characterized and used directly for the next step.
Compounds 391-397
Compounds 391, 393 and 396-397 (examples 186, 188 and 191-192) were synthesized similarly to compound 246 (example 129, scheme 57) starting from compounds 384 (scheme 90), 386 (scheme 91), 389 and 390 (scheme 93), respectively, instead of compound 241. Compound 392 (example 187) was synthesized similarly to compound 192 (example 104, scheme 40) starting from compound 384 (scheme 90) instead of compound 185. 394 (example 189) refers to a 1 :1 mixture of regioisomers 394a and 394b that were synthesized similarly to compound 192 (example 104, scheme 40) starting from the 1 :1 mixture of regioisomers 387and 388 instead of compound 185. 395 (example 190) refers to a 1 :1 mixture of regioisomers 395a and 395b that were synthesized similarly to compound 246 (example 129, scheme 57) starting from the 1 :1 mixture of regioisomers 387and 388 instead of compound 241. Characterization of compounds 391-397 (examples 186-192) is provided in the table 7.
Table 7. Characterization of compounds 391-397 (examples 186-192).
Figure imgf000248_0001
Figure imgf000249_0001
Figure imgf000250_0001
Figure imgf000251_0002
Example 193
2-Amino-6-(cyclopropylmethyl)-6-(2-(isoxazol-5-yl)ethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (401) Intermediate compound 400 5-(2-(8-(Cyclopropylmethyl)-1,4-dioxaspiro[4.5]decan-8-yl)ethyl)isoxazole (400)
Scheme 94
Figure imgf000251_0001
Step 1. 5-(8-(Cyclopropylmethyl)-1 ,4-dioxaspiro[4.51decan-8-yl)pent-2-vnal (398)
To a solution of 383 (scheme 90) in dry THF (8.2 mL) cooled to 0 °C was added dropwise n-butyl lithium (676 pL, 2.5 M in hexane, 1 .69 mmol). The reaction mixture was stirred at 0 °C for
15 minutes, then dry DMF (103 pL, 1.33 mmol) was added. The resulting mixture was allowed to warm to RT over 2 hours. In another flask, sodium dihydrogenphosphate (580 mg, 4.83 mmol) was dissolved in deionized water (6 mL). Diethyl ether (30 mL) was added and the mixture was stirred vigorously. The contents of the first flask were then added dropwise at 0 °C and the mixture was allowed to stir for 30 minutes at RT. The layers were separated and the ether layer was washed with water (2 x 30 mL), brine (2 x 20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 35% of EA in hexane) to afford title compound 398 as a colorless oil (226 mg, 68% yield), which was not characterized and used directly for the next step.
Step 2. 5-(8-(Cyclopropylmethyl)-1 ,4-dioxaspiro[4.51decan-8-yl)pent-2-vnal oxime (399) To a solution of 398 (358 mg, 1.30 mmol) in ethanol (21.1 mL) was added a 50% aqueous solution of hydroxylamine (794 uL, 13.0 mmol). The reaction mixture was stirred at RT for 2 hours. Brine (50 mL) and EA (30 mL) were then added and the layers were separated. The aqueous phase was extracted with EA (2 x 40 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to afford title compound 399 as a yellow oil (362 mg, 96% yield), which was not characterized and used directly for the next step.
Step 3. 5-(2-(8-(Cyclopropylmethyl)-1 ,4-dioxaspiro[4.51decan-8-yl)ethyl)isoxazole (400) To a solution of 399 (377 mg, 1.29 mmol) in DCM (20 mL) was added gold (III) chloride (4.0 mg, 13 umol). The reaction mixture was stirred at 40 °C for 20 hours, then concentrated to afford a colorless oil (275 mg, 73% yield), which was not characterized and used directly for the next step.
2-Amino-6-(cyclopropylmethyl)-6-(2-(isoxazol-5-yl)ethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (401)
Figure imgf000252_0001
401 : Example 193
Compound 401 (example 193) was synthesized similarly to compound 189 (example 102, scheme 40) starting from compound 400 (scheme 94) instead of compound 185.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 12.52 (s, 1H), 8.43 (s, 1 H), 8.25 (s, 2H), 6.28 (s, 1 H), 3.04-2.99 (m, 2H) 2.73-2.67 (m, 2H), 2.15-2.08 (m, 3H), 1.91-1.82 (m, 1 H), 1.68-1.61 (m, 1 H), 1.41-1.34 (m, 1 H), 0.66-0.60 (m, 1H), 0.43-0.36 (m, 2H), 0.07- -0.01 (m, 2H). LC-MS: rt = 1.34 min, MS: 360.1 (calcd), 361.2 (M+H+, found).
Example 194
2-Amino-6-(cyclopropylmethyl)-6-(2-(isoxazol-5-yl)ethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (402)
Figure imgf000253_0001
402: Example 194
Compound 402 (example 194) was synthesized similarly to compound 52 (example 33, scheme 6) starting from compound 401 (example 193) instead of compound 51.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.38 (s, 1 H), 7.97 (s, 2H), 6.91 (bs, 1 H), 6.22 (s, 1 H), 2.98-2.93 (m, 2H), 2.69-2.63 (m, 2H), 2.13-2.06 (m, 1 H), 2.03-1.96 (m, 2H), 1.88-1.80 (m, 1 H), 1.57-1.63 (m, 1H), 1.33-1.39 (m, 1 H), 0.56-0.62 (m, 1 H), 0.35-0.39 (m, 2H), 0.01-0.06 (m, 1 H), -0.01- -0.06. LC-MS: rt = 1.17 min, MS: 359.1 (calcd), 360.1 (M+H+, found).
Example 195 2-Amino-N-cyclopropyl-6-((3-methylisoxazol-5-yl)methyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (403)
Scheme 95
Figure imgf000253_0002
290 403: Example 195
Scheme 74
To a solution of 290 (scheme 74) (65.0 mg, 0.170 mmol) in anhydrous DMF (1.6 mL) were added PyBOP (133 mg, 0.255 mmol), N,N-diisopropylethylamine (118 pL, 0.680 mmol) and cyclopropylamine (121 pL, 1.70 mmol) and the reaction mixture was stirred at RT for 20 hours. The crude was purified by reverse-phase flash column chromatography (eluent gradient from 0% to 100% of CH3CN in 0.1% formic acid (v/v) in water) and then Semi-Prep HPLC-MS (eluent gradient from 30% to 50% of CH3CN in 10 mM ammonium formate) to afford title compound 403 as an off-white solid (19.6 mg, 27% yield).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.80 (s, 2H), 7.32-7.27 (m, 5H), 7.24-7.21 (m, 1 H), 5.78 (s, 1 H), 3.34 (d, J = 14.7 Hz, 1 H), 3.04 (d, J = 14.6 Hz, 1 H), 2.65-2.60 (m, 2H), 2.58-2.50 (m, 2H), 2.09 (s, 3H), 2.05-1 .95 (m, 1 H), 0.60-0.51 (m, 2H), 0.43-0.40 (m, 2H). LC-MS: rt = 1 .35 min, MS: 421 .2 (calcd), 422.3 (M+H+, found).
Example 196 2-Amino-6-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (406) Intermediate compound 405 3-Methyl-5-((8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)methyl)-1,2,4-oxadiazole (405) Scheme 96
Figure imgf000254_0001
Scheme 51
Step 1. Methyl 2-(8-phenyl-1 ,4-dioxaspiro[4.51decan-8-yl)acetate (404)
To a solution of compound 222 (scheme 51) (936 mg, 3.39 mmol) in DMF (18.7 mL) were added potassium carbonate (936 mg, 6.77 mmol) and iodomethane (426 pL, 6.77 mmol). The resulting solution was stirred at RT for 20 hours, then the reaction mixture was quenched with water (20 mL). The mixture was diluted with EA (15 mL), the layers were separated, and the aqueous layer was extracted with EA (30 mL). The combined organics were washed with brine (2 x 50 mL), then dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 60% of EA in hexane) to afford title compound 404 (718 mg, 73% yield) as a yellow oil, which was not characterized and used directly for the next step.
Step 2. 3-Methyl-5-((8-phenyl-1 ,4-dioxaspiro[4.51decan-8-yl)methyl)-1 ,2,4-oxadiazole (405)
To a solution of 404 (100 mg, 0.373 mmol) and /V-hydroxyacetimidamide (31.6 mg, 0.410 mmol) in DMSO (3.0 mL) was added ground sodium hydroxide (22.4 mg, 0.559 mmol). The reaction mixture was stirred at RT for 5 days, then quenched with brine (30 mL) and extracted with EA (40 mL). The organic layer was separated and the aqueous phase was extracted with EA (3 x 30 mL). All the organic phases were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 70% of EA in hexane) to afford title compound 405 as a colorless oil (26.0 mg, 25% yield), which was not characterized and used directly for the next step.
2-Amino-6-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (406)
Figure imgf000254_0002
406: Example 196 Compound 406 (example 196) was synthesized similarly to compound 189 (example 102, scheme 40) starting from compound 405 (scheme 96) instead of compound 185.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 12.52 (s, 1 H), 8.29 (s, 2H), 7.32-7.22 (m, 5H), 3.37 (s, 2H), 3.15 (d, J = 18.5 Hz, 1H), 2.74 (d, J = 13.9 Hz, 1 H), 2.55-2.48 (m, 1 H), 2.37-2.28 (m, 1 H), 2.23 (s, 3H). LC-MS: rt = 1.17 min, MS: 383.1 (calcd), 384.1 (M+H+, found).
Example 197
2-Amino-6-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (407)
Figure imgf000255_0001
407: Example 197
Compound 407 (example 197) was synthesized similarly to compound 52 (example 33, scheme 6) starting from compound 406 (example 196) instead of compound 51.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.11 (s, 2H), 7.33-7.22 (m, 5H), 6.90 (bs, 2H), 3.38 (s, 2H), 2.90-2.85 (m, 1 H), 2.76-2.69 (m, 1 H), 2.68-2.63 (m, 1 H), 2.60-2.52 (m, 1 H), 2.23 (s, 3H). LC-MS: rt = 1.10 min, MS: 382.1 (calcd), 383.2 (M+H+, found).
Example 198 2-Amino-N-cyclopropyl-6-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (408)
Figure imgf000255_0002
408: Example 198
Compound 408 (example 198) was synthesized similarly to compound 170 (example 95, scheme 32) starting from compound 406 (example 196) instead of compound 59.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.33-7.30 (m, 4H), 7.28-7.23 (m, 1 H), 3.50-3.40 (m, 2H), 2.83-2.78 (m, 2H), 2.70-2.66 (m, 1 H), 2.64-2.55 (m, 2H), 2.28 (s, 3H), 0.73-0.66 (m, 2H), 0.56-0.47 (m, 2H). LC-MS: rt = 1.21 min, MS: 422.1 (calcd), 423.2 (M+H+, found).
Example 199 2-Amino-6-(cyclopropylmethyl)-6-(3-methyl-1,2,4-oxadiazol-5-yl)-7-oxo-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (412) Intermediate compound 411
5-(8-(Cyclopropylmethyl)-1,4-dioxaspiro[4.5]decan-8-yl)-3-methyl-1,2,4-oxadiazole (411) Scheme 97
Figure imgf000256_0001
Step 1. Ethyl 8-(cyclopropylmethyl)-1 ,4-dioxaspiro[4.51decane-8-carboxylate (410)
A flame-dried round bottom flask was charged with a solution of LDA (33.6 mL, 1 M in THF/hexane, 2.69 mmol) in anhydrous THF (4.02 mL) under argon. The solution was cooled to - 78 °C and ethyl 1 ,4-dioxaspiro[4.5]decane-8-carboxylate (409, 6 g, 26.9 mmol) was added. The mixture was stirred at -78 °C for 35 min, then (bromomethyl)cyclopropane (2.96 mL, 29.6 mmol) was added. The reaction vessel was removed from the acetone/dry ice bath and the solution was stirred at RT for 20 hours. The mixture was then partitioned between EA and water, the layers were separated and the aqueous phase was extracted with EA. The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 5% to 50% of EA in hexane) to afford title compound 410 (5.33 g, 74% yield) as a yellow oil, which was not characterized and used directly for the next step.
Step 2. 5-(8-(Cyclopropylmethyl)-1 ,4-dioxaspiro[4.51decan-8-yl)-3-methyl-1 ,2,4- oxadiazole (411)
To a solution of 410 (1 g, 3.73 mmol) and /V-hydroxyacetimidamide (316 mg, 4.10 mmol) in DMSO (30 mL) was added ground sodium hydroxide (224 mg, 5.59 mmol). The reaction mixture was stirred at 50 °C for 5 days, then quenched with brine (30 mL) and extracted with EA (40 mL). The organic layer was separated and the aqueous phase was extracted with EA (3 x 30 mL). All the organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 50% of EA in hexane) to afford title compound 411 as a colorless oil (454 mg, 44% yield), which was not characterized and used directly for the next step.
2-Amino-6-(cyclopropylmethyl)-6-(3-methyl-1,2,4-oxadiazol-5-yl)-7-oxo-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (412)
Figure imgf000256_0002
412: Example 199 Compound 412 (example 199) was synthesized similarly to compound 189 (example 102, scheme 40) starting from compound 411 (scheme 97) instead of compound 185.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 12.62 (bs, 1 H), 8.38 (s, 2H), 3.17-3.08 (m, 1 H), 3.05-2.97 (m, 1 H), 2.72-2.66 (m, 1 H), 2.47-2.38 (m, 1 H), 2.30 (s, 3H), 1.98-1.87 (m, 2H), 0.70- 0.59 (m, 1 H), 0.42-0.33 (m, 1H), 0.33-0.26 (m, 1 H), 0.10-0.04 (m, 1 H), -0.10- -0.19 (m, 1 H). LC- MS: rt = 1 .25 min, MS: 347.1 (calcd), 348.2 (M+H+, found).
Example 200
2-Amino-6-(cyclopropylmethyl)-6-(3-methyl-1,2,4-oxadiazol-5-yl)-7-oxo-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (413)
Figure imgf000257_0001
413: Example 200
Compound 413 (example 200) was synthesized similarly to compound 52 (example 33, scheme 6) starting from compound 412 (example 199) instead of compound 51.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.15 (s, 2H), 7.01 (bs, 2H), 3.03-3.00 (m, 2H), 2.72-2.66 (m, 1 H), 2.45-2.40 (m, 1 H), 2.31 (s, 3H), 2.00 (dd, J = 14.2, 6.9 Hz, 1 H), 1.86 (dd, J = 14.2, 6.7 Hz, 1 H), 0.70-0.60 (m, 1 H), 0.42-0.26 (m, 2H), 0.18-0.09 (m, 1 H), -0.08- -0.17 (m, 1 H). LC-MS: rt = 1.10 min, MS: 346.1 (calcd), 347.1 (M+H+, found).
Example 201 2-Amino-N-cyclopropyl-6-(cyclopropylmethyl)-6-(3-methyl-1,2,4-oxadiazol-5-yl)-7-oxo- 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (414)
Figure imgf000257_0002
Compound 414 (example 201) was synthesized similarly to compound 170 (example 95, scheme 32) starting from compound 412 (example 199) instead of compound 59.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.91 (s, 2H), 7.46 (d, J = 3.71 Hz, 1 H), 2.95-2.88 (m, 2H), 2.74-2.63 (m, 2H), 2.45-2.35 (m, 1 H), 2.31 (s, 3H), 1.98-1.85 (m, 2H), 0.67-0.63 (m, 3H), 0.53-0.49 (m, 2H), 0.39-0.29 (m, 2H), 0.15-0.08 (m, 1 H), -0.09- -0.19 (m, 1 H). LC-MS: rt = 1.30 min, MS: 386.1 (calcd), 387.3 (M+H+, found). Example 202
2-Amino-6-cyano-6-(methoxymethyl)-7 -oxo-4, 5,6, 7-tetrahydrobenzo[b]thiophene-3- carboxamide (416) Intermediate compound 415 8-(Methoxymethyl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (415)
Figure imgf000258_0001
415
Intermediate 415 was synthesized similarly to compound 41 (scheme 4) starting from 1 ,4- dioxaspiro[4.5]decane-8-carbonitrile (40) and using chloromethyl methyl ether instead of (bromomethyl) cyclobutane.
2-Amino-6-cyano-6-(methoxymethyl)-7 -oxo-4, 5,6, 7-tetrahydrobenzo[b]thiophene-3- carboxamide (416)
Figure imgf000258_0002
416: Example 202
Compound 416 (example 202) was synthesized similarly to compound 246 (example 129, scheme 57) starting from compound 415 instead of compound 241.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 7.11 (bs, 2H), 3.73 (d, J = 9.5 Hz, 1H), 3.67 (d, J = 9.5 Hz, 1 H), 3.33 (s, 3H), 3.06 (t, J = 6.0 Hz, 2H), 2.41-2.35 (m, 1 H), 2.32-2.25 (m, 1 H). LC-MS: rt = 0.88 min, MS: 279.1 (calcd), 280.1 (M+H+, found).
Example 203 2-Amino-6-cyano-6-(isopropoxymethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (418)
Intermediate compound 417
8-(lsopropoxymethyl)-1 ,4-dioxaspiro[4.5]decane-8-carbonitrile (417)
Figure imgf000259_0001
Intermediate 417 was synthesized similarly to compound 41 (scheme 4) starting from 1 ,4- dioxaspiro[4.5]decane-8-carbonitrile (40) and using 2-(chloromethoxy)propane instead of (bromomethyl) cyclobutane.
2-Amino-6-cyano-6-(isopropoxymethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (418)
Figure imgf000259_0002
418: Example 203
Compound 418 (example 203) was synthesized similarly to compound 246 (example 129, scheme 57) starting from compound 417 instead of compound 241.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.26 (s, 2H), 7.08 (s, 2H), 3.74-3.66 (m, 2H), 3.64- 3.59 (m, 1 H), 3.04 (t, J = 6.0 Hz, 2H), 2.37-2.24 (m, 2H), 1.10-1.06 (m, 6H). LC-MS: rt = 1.04 min, MS: 307.1 (calcd), 308.2 (M+H+, found).
Example 204
2-Amino-6-cyano-6-((cyclopropylmethoxy)methyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (422) Intermediate compound 421 8-((Cyclopropylmethoxy)methyl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile
Scheme 98
Figure imgf000259_0003
Scheme 4
Step 1. 8-(Hvdroxymethyl)-1 ,4-dioxaspiro[4.51decane-8-carbonitrile (419)
Aflame-dried round-bottom flask was evacuated, filled with Ar and charged with LDA (2.63 mL, 1 M in THF/hexane, 2.63 mmol) and dry THF (2 mL). The resulting solution was cooled to - 78 °C and 1 ,4-dioxaspiro[4.5]decane-8-carbonitrile (40, scheme 4) (412 mg, 2.39 mmol) dissolved in 1 mL THF was added. The mixture was stirred at -78 °C for 1 hour and then paraformaldehyde (108 mg, 3.59 mmol) suspended in 2.78 mL THF was slowly added. The reaction vessel was taken out of the acetone/dry ice bath and the mixture was allowed to warm to RT overnight. The mixture was then quenched with saturated aqueous NH4CI solution (30 mL) and extracted with EA (3 x 30 mL). The combined organics were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to afford title compound 419 as a yellow solid (480.3 mg, >99% yield), which was not characterized and used directly for the next step.
Step 2. 8-((Allyloxy)methyl)-1 ,4-dioxaspiro[4.51decane-8-carbonitrile (420)
To a solution of 419 (150 mg, 0.761 mmol) in DMF (6 mL) was added sodium hydride (36.5 mg, 0.913 mmol). The reaction mixture was stirred at RT for 30 minutes, then allyl bromide (78.9 pL, 0.913 mmol) was added. The resulting mixture was stirred at RT for 4 hours, then diluted with water (10 mL) and EA (15 mL). The layers were separated and the aqueous phase was extracted with another 10 mL of EA. The combined organics were washed with water (2 x 15 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 70% of EA in hexane) to afford title compound 420 as a colorless oil (72 mg, 40% yield), which was not characterized and used directly for the next step.
Step 3. 8-((Cyclopropylmethoxy)methyl)-1 ,4-dioxaspiro[4.51decane-8-carbonitrile (421)
Diethylzinc (0.61 mL, 1 M in hexane, 0.61 mmol) and diiodomethane (97.8 pL, 1 .21 mmol) were added to a solution of 420 (72 mg, 0.303 mmol) in dry DCM (3 mL) under argon at -10 °C. The resulting solution was stirred at -10 °C for 15 minutes, then allowed to reach room temperature and stirred at RT for 20 hours. The reaction mixture was quenched with saturated aqueous NH4CI solution (10 mL) and the layers were separated. The organic phase was dried over Na2SO4, filtered and concentrated to afford title compound 421 as a colorless oil (98 mg, >99% yield), which was not characterized and used directly for the next step.
2-Amino-6-cyano-6-((cyclopropylmethoxy)methyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (422)
Figure imgf000260_0001
Compound 422 (example 204) was synthesized similarly to compound 246 (example 129, scheme 57) starting from compound 421 (scheme 98) instead of compound 241.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.27 (s, 2H), 7.10 (bs, 2H), 3.80-3.77 (m, 1 H), 3.74-3.70 (m, 1 H), 3.37-3.32 (m, 2H), 3.07-3.02 (m, 2H), 2.41-2.27 (m, 2H), 1.02-0.95 (m, 1 H), 0.49-0.41 (m, 2H), 0.20-0.13 (m, 2H). LC-MS: rt = 0.99 min, MS: 319.1 (calcd), 320.1 (M+H+, found).
Example 205
2-Amino-3',7-dioxo-2,,3,,4,7-tetrahydro-5H-spiro[benzo[b]thiophene-6,1'-indene]-3- carboxylic acid (427)
Figure imgf000261_0001
Step 1 . 2-(2-Acetamido-3-(ethoxycarbonyl)-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophen- 6-yl)acetic acid (423)
A suspension of 224 (scheme 51) (1.0 g, 2.78 mmol) in acetic acid (15.9 mL) was treated with acetic anhydride (526 uL, 5.56 mmol) and the resulting mixture was stirred at 60 °C for 45 minutes. The mixture was then allowed to cool to RT, diluted with EA and washed successively with saturated aqueous NaHCO3, water and brine (10 mL each), then dried over Na2SO4, filtered and concentrated to afford title compound 423 as an off-white solid (1.04 g, 93% yield). LC-MS: rt = 1 .45 min, MS: 401 .1 (calcd), 402.3 (M+H+, found).
Step 2. Ethyl 2-acetamido-6-(2-chloro-2-oxoethyl)-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (424)
To a suspension of 423 (1 .04 g, 2.59 mmol) in DCM (20.8 mL) at 0 °C was added dropwise oxalyl chloride (438 uL, 5.18 mmol) and 1 drop of DMF. The mixture was stirred at RT for 3 hours. The reaction progress was followed by LCMS by quenching an aliquot with MeOH. The solvent was removed in vacuo to afford title compound 424 as an orange solid that was used for the next step without further purification or characterization. LC-MS: rt = 1.64 min, MS: 415.1 (calcd for M- CI+OMe), 416.2 (M-CI+OMe+H+, found).
Step 3. Ethyl 2-acetamido-3'-oxo-2',3',4,7-tetrahydro-5H-spiro[benzo[b1]thiophene-6,1'- indenel-3-carboxylate (425)
A suspension of aluminium chloride (839 mg, 6.23 mmol) in DCM (2.18 mL) was cooled to 0 °C and a solution of 424 (1.09 g, 2.60 mmol) in DCE (3.27 mL) was added dropwise. The reaction was heated at reflux for 1.5 hours, then poured onto ice-water. The layers were separated, the aqueous layer was extracted with DCM and the combined organics were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford title compound 425 as an off-white solid (924 mg, 93% yield). LC-MS: rt = 1 .55 min, MS: 383.1 (calcd), 384.2 (M+H+, found).
Step 4. Ethyl 2-acetamido-3',7-dioxo-2',3',4,7-tetrahydro-5H-spiro[benzo[b]thiophene- 6,1'-indene]-3-carboxylate (426)
To a suspension of 425 (600 mg, 1 .56 mmol) in acetic acid (11 .0 mL), dioxane (11 .0 mL) and water (11.0 mL) was added ceric sulfate (3.19 g, 7.82 mmol). The mixture was sonicated for 1 min, then stirred at RT for 16 hours. Subsequently, the mixture was diluted with water and EA, sonicated for 3 minutes, filtered, and the filtrate was transferred into a separatory funnel. The layers were separated and the organic phase was washed successively with a 1 N aqueous solution of NaOH and brine, then dried over Na2SO4, filtered and concentrated to afford title compound 426 as an off-white powder (554 mg, 89% yield). LC-MS: rt = 1.40 min, MS: 397.1 (calcd), 398.1 (M+H+, found).
Step 5. 2-Amino-3',7-dioxo-2',3',4,7-tetrahydro-5H-spiro[benzo[b]thiophene-6, 1 '-indenel- 3-carboxylic acid (427)
To a suspension of 426 (377 mg, 949 umol) in MeOH (58.1 mL) was added a solution of lithium hydroxide monohydrate (272 mg, 6.48 mmol) in water (58.1 mL). The reaction mixture was stirred at 55 °C for 24 hours, then allowed to cool to RT. The mixture was concentrated to remove most of the organic solvent. Then, the aqueous layer was acidified by slowly adding a 2 N aqueous solution of HCI and the product was extracted with EA. The organic layers were combined then washed with brine, dried over Na2SO4, filtered and concentrated to afford title compound 427 (326 mg, >99% yield).
1H NMR: 400 MHz, CD3OD, δ (ppm): 7.74 (d, J = 7.7 Hz, 1 H), 7.66 (t, J = 7.5 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1 H), 7.45 (d, J = 7.80 Hz, 1 H), 3.37-3.34 (m, 1 H), 3.28-3.20 (m, 1 H), 3.13 (d, J = 18.67 Hz, 1 H), 2.70 (d, J = 18.70 Hz, 1H), 2.49-2.34 (m, 2H). LC-MS: rt = 1.01 min, MS: 327.1 (calcd), 328.0 (M+H+, found).
Example 206 2-Amino-3',7-dioxo-2,,3,,4,7-tetrahydro-5H-spiro[benzo[b]thiophene-6,1'-indene]-3- carboxamide (428)
Figure imgf000263_0001
428: Example 206
Compound 428 (example 206) was synthesized similarly to compound 238 (example 127, scheme 55) starting from compound 427 (scheme 99) instead of compound 237.
1H NMR: 400 MHz, CD3OD, δ (ppm): 7.75 (d, J = 7.7 Hz, 1 H), 7.67 (t, J = 7.5 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 3.26 (t, J = 6.4 Hz, 1 H), 3.20-3.11 (m, 2H), 2.72 (d, J = 18.7 Hz, 1 H), 2.53-2.47 (m, 1 H), 2.43-2.36 (m, 1 H). LC-MS: rt = 0.93 min, MS: 326.1 (calcd), 327.1 (M+H+, found).
Example 207 2-Amino-N-cyclopropyl-3',7-dioxo-2,,3,,4,7-tetrahydro-5H-spiro[benzo[b]thiophene-6,1'- indene]-3-carboxamide (429)
Figure imgf000263_0002
429: Example 207
Compound 429 (example 207) was synthesized similarly to compound 170 (example 95, scheme 32) starting from compound 427 (scheme 99) instead of compound 59.
1H NMR: 400 MHz, CD3OD, δ (ppm): 7.74 (d, J = 7.7 Hz, 1 H), 7.66 (t, J = 7.5 Hz, 1H), 7.52-7.47 (m, 2H), 3.21-3.03 (m, 3H), 2.82-2.78 (m, 1 H), 2.74-2.66 (m, 1 H), 2.47-2.42 (m, 1 H), 2.38-2.33 (m, 1 H), 0.84-0.76 (m, 2H), 0.65-0.59 (m, 2H). LC-MS: rt = 1.03 min, MS: 366.1 (calcd), 367.2 (M+H+, found).
Example 208 2-Amino-3'-(hydroxyimino)-7-oxo-2,,3,,4,7-tetrahydro-5H-spiro[benzo[b]thiophene-6,1'- indene]-3-carboxamide (430)
Scheme 100
Figure imgf000263_0003
To a solution of 428 (70.0 mg, 214 umol) in EtOH (2.47 mL) was added hydroxylamine hydrochloride (44.7 mg, 643 umol) and sodium acetate trihydrate (135 mg, 991 umol). The mixture was stirred at RT for 16 hours. The reaction mixture was then diluted with water and EA, the layers were separated and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by Semi-Prep HPLC-MS (eluent gradient from 25% to 100% of MeOH in 10 mM ammonium bicarbonate) to afford title compound 430 as a white solid (50.9 mg, 70 % yield; single product, E/Z stereochemistry not established).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 10.98 (s, 1 H), 8.12 (s, 2H), 7.56-7.53 (m, 1 H), 7.32-7.28 (m, 2H), 7.09-6.94 (m, 1 H), 3.17-3.12 (m, 1 H), 3.10-3.00 (m, 2H), 2.72 (d, J = 18.41 Hz, 1 H), 2.27-2.15 (m, 2H). LC-MS: rt = 0.92 min, MS: 341.1 (calcd), 342.1 (M+H+, found).
Example 209 2-Amino-N-cyclopropyl-3'-(hydroxyimino)-7-oxo-2,,3',4,7-tetrahydro-5H- spiro[benzo[b]thiophene-6,1'-indene]-3-carboxamide (431)
Figure imgf000264_0001
Compound 431 (example 209; single product, E/Z stereochemistry not established) was synthesized similarly to compound 430 (example 208, scheme 100) starting from compound 429 (example 207) instead of compound 428.
1H NMR: 400 MHz, CD3OD, δ (ppm): 7.69-7.67 (m, 1 H), 7.34-7.31 (m, 2H), 7.26-7.24 (m, 1 H), 3.33 (d, J = 12.9 Hz, 1 H), 3.06-3.03 (m, 2H), 2.95 (d, J = 18.5 Hz, 1 H), 2.82-2.73 (m, 1 H), 2.35-2.20 (m, 2H), 0.81-0.76 (m, 2H), 0.64-0.60 (m, 2H). LC-MS: rt = 1.10 min, MS: 381.1 (calcd), 382.3 (M+H+, found).
Example 210
2-Amino-7-oxo-2',3,,4,7-tetrahydro-5H-spiro[benzo[b]thiophene-6,1'-indene]-3- carboxamide (434)
Scheme 101
Figure imgf000265_0001
Step 1. Ethyl 2-acetamido-7-oxo-2',3',4,7-tetrahydro-5H-spiro[benzo[b]thiophene-6,1'- indenel-3-carboxylate (432)
A solution of trifluoromethanesulfonic acid (71.2 uL. 788 umol) in dry DCM (300 uL) was added dropwise to a stirred solution of 425 (scheme 99) (78.3 mg, 197 umol) in dry DCM (300 uL) at 0 °C under nitrogen. Then, a solution of triethylsilane (95.4 uL, 591 umol) in dry DCM (300 uL) was added dropwise. After 5 minutes of stirring, additional trifluoromethanesulfonic acid (71 .2 uL, 788 umol) was added, followed by the addition of triethylsilane (95.4 uL, 591 umol). The mixture was stirred at RT for 1 hour, then poured into cold saturated aqueous NaHCO3 solution and extracted with DCM. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 100% of EA in hexane) to afford title compound 432 as a brown solid (44.8 mg, 59 % yield). LC-MS: rt = 1.77 min, MS: 383.1 (calcd), 384.2 (M+H+, found).
Step 2. 2-Amino-7-oxo-2',3',4,7-tetrahydro-5H-spiro[benzo[b]thiophene-6,1'-indene1-3- carboxylic acid (433)
To a suspension of 432 (44.8 mg, 117 umol) in MeOH (7.15 mL) was added a solution of lithium hydroxide monohydrate (33.5 mg, 798 umol) in water (7.15 mL). The reaction mixture was stirred at 55 °C for 48 hours, then allowed to cool to RT and concentrated to remove most of the organic solvent. The aqueous residue was acidified by slowly adding a 2 N aqueous solution of HCI and the product was extracted with EA. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by reverse-phase flash column chromatography (eluent gradient from 10% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid) to afford title compound 433 as a white solid (20.0 mg, 55% yield). LC-MS: rt = 1.37 min, MS: 313.1 (calcd), 314.1 (M+H+, found).
Step 3. 2-Amino-7-oxo-2',3',4,7-tetrahydro-5H-spiro[benzo[b]thiophene-6,1'-indene1-3- carboxamide (434) To a mixture of 433 (20.0 mg, 63.8 umol) and ammonium chloride (34.3 mg, 638 umol) in anhydrous DMF (798 uL) were added HATU (49.5 mg, 128 umol) and N,N-diisopropylethylamine (33.3 uL, 191 umol). The reaction mixture was stirred at RT for 10 minutes, then gaseous NH3 was bubbled through the mixture for additional 40 minutes. Afterwards, the reaction was quenched with a saturated aqueous NH4CI solution and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase flash column chromatography (eluent gradient from 10% to 100% of CH3CN in 0.1% formic acid (v/v) in water) to afford title compound 434 as an off-white solid (14.7 mg, 74% yield).
1H NMR: 400 MHz, CD3OD, δ (ppm): 7.25 (d, J = 7.5 Hz, 1 H), 7.20-7.16 (m, 1 H), 7.12 (t, J = 7.4 Hz, 1 H), 7.03 (d, J = 7.5 Hz, 1 H), 3.09-3.04 (m, 2H), 3.04-2.98 (m, 2H), 2.63-2.58 (m, 1 H), 2.36-2.31 (m, 1 H), 2.21-2.16 (m, 1 H), 2.14-2.06 (m, 1 H). LC-MS: rt = 1 .16 min, MS: 312.1 (calcd), 313.2 (M+H+, found).
Examples 212-221 Intermediate compound 435 1 -(2-(8-Phenyl-1 ,4-dioxaspiro[4.5]decan-8-yl)ethyl)-1 H-pyrazole (435) Scheme 102
Figure imgf000266_0001
Scheme 66
To a solution of pyrazole (40 mg, 0.59 mmol) in anhydrous DMF (2 mL) at 0 °C was added sodium hydride (24 mg, 60% in mineral oil, 0.59 mmol) and the mixture was stirred for 15 minutes at the same temperature. Then, a solution of 266 (scheme 66) (100 mg, 0.294 mmol) in anhydrous DMF (1 mL) was added and the reaction mixture was allowed to reach RT and stirred for 16 hours. Then, the mixture was quenched with saturated aqueous NH4CI solution, diluted with water and extracted with EA. The organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 40% to 100% of EA in hexane) to afford title compound 435 as a colorless oil (78 mg, 85% yield). LC-MS: rt = 1.37 min, MS: 312.2 (calcd), 313.2 (M+H+, found).
Intermediate compound 436
1 -(2-(8-Phenyl-1 ,4-dioxaspiro[4.5]decan-8-yl)ethyl)-1 H-imidazole (436)
Figure imgf000267_0001
Intermediate 436 was synthesized similarly to intermediate 435 (scheme 102), but using imidazole instead of pyrazole. LC-MS: rt = 0.77 min, MS: 312.2 (calcd), 313.2 (M+H+, found).
Intermediate compound 439 4-Phenyl-4-(2H-tetrazol-5-yl)cyclohexan-1-one (439) Scheme 103
Figure imgf000267_0002
Step 1. Methyl 4-hydroxy-1-(2-trityl-2H-tetrazol-5-yl)-1 ,2,5,6-tetrahydro-[1 ,1 '-biphenyl1-3-
Figure imgf000267_0003
To a stirred suspension of 5-benzyl-2-trityl-2H-tetrazole 437 (N. Choi et al. W02007124544) (1.06 g, 2.63 mmol) and methyl acrylate (0.48 mL, 5.26 mmol) in anhydrous DMF (10 mL) at 0 °C was added sodium hydride (211 mg, 60% in mineral oil, 5.26 mmol) and the resulting mixture was vigorously stirred at RT for 2.5 hours. Afterwards, the mixture was cooled down to 0 °C, acidified with 1 N aqueous HCI and extracted with DCM. The combined organics were washed with brine and dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 50% of EA in hexane) to afford title compound 438 as a colorless oil (350 mg, 24% yield). LC-MS: rt = 2.15 min, MS: 542.2 (calcd), 559.3 ([M+H2O-H]-, found).
Step 2. 4-Phenyl-4-(2H-tetrazol-5-yl)cyclohexan-1-one (439)
To a solution of 438 (350 mg, 0.645 mmol) in DMSO (1.3 mL) were added H2O (0.013 mL) and NaCI (11 mg, 0.19 mmol) and the resulting mixture was stirred at 160 °C for 1 hour. Then, the mixture was diluted with H2O and extracted with EA. The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 20% of MeOH in DCM) to afford title compound 439 as a light-orange oil (69 mg, 44% yield). LC-MS: rt = 1.71 min, MS: 242.1 (calcd), 243.3 (M+H+, found).
Intermediate compound 441 8-((1-Methoxycyclopropyl)methyl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (441) Scheme 104
Figure imgf000268_0001
Scheme 4
Step 1. 8-(2-Methoxyallyl)-1 ,4-dioxaspiro[4.51decane-8-carbonitrile (440)
To a solution of 1 ,4-dioxaspiro[4.5]decane-8-carbonitrile (40, scheme 4) (959 mg, 5.56 mmol) in anhydrous THF (13 mL) at -78 °C was added dropwise LDA (8.34 mL, 1 M in THF/hexane, 8.34 mmol). The reaction mixture was stirred at -78 °C for 30 min, then a solution of 3-bromo-2-methoxyprop-1-ene (J. Org. Chem. 42, 15, p. 2545, 1977) (840 mg, 5.56 mmol) in anhydrous THF (13 mL) was added dropwise. The reaction mixture was allowed to reach RT and stirred for 16 hours. Afterwards, the reaction mixture was quenched with saturated NH4CI solution and extracted with EA. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 50% of EA in hexane) to afford title compound 440 as a colorless oil (756 mg, 57% yield), which was not characterized and used directly for the next step.
Step 2. 8-((1-Methoxycyclopropyl)methyl)-1 ,4-dioxaspiro[4.51decane-8-carbonitrile (441)
To a solution of 440 (688 mg, 2.90 mmol) in anhydrous DCM (29 mL) at -10 °C were added diethylzinc (5.80 mL, 1 M in hexane, 5.80 mmol) and diiodomethane (0.934 mL, 11.6 mmol). The reaction mixture was stirred at -10 °C for 30 min, then it was allowed to reach RT and stirred for 16 hours. Afterwards, the reaction mixture was quenched with saturated NH4CI solution and the layers were separated. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 50% of EA in hexane) to afford title compound 441 as a colorless oil (340 mg, 47% yield) as a colorless oil, which was not characterized and used directly for the synthesis of relevant examples.
Intermediate compound 444 8-(2-(Difluoromethoxy)ethyl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (444) Scheme 105
Figure imgf000268_0002
Step 1 . 8-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1 ,4-dioxaspiro[4.5]decane-8-carbonitrile
To a solution of 1 ,4-dioxaspiro[4.5]decane-8-carbonitrile (40, scheme 4) (1.0 g, 5.80 mmol) in anhydrous THF (12 mL) at -78 °C was added dropwise LDA (6.38 mL, 1 M in THF/hexane, 6.38 mmol). The reaction mixture was stirred at -78 °C for 1 hour, then (2- bromoethoxy)(tert-butyl)dimethylsilane (1.56 g, 6.38 mmol) was added. The reaction mixture was allowed to reach RT and stirred for 16 hours. Afterwards, the reaction mixture was quenched with saturated NH4CI solution and extracted with EA. The organic phase was dried over Na2SO4, filtered and concentrated to afford title compound 442 (1.89 g, >99% yield) as a light-yellow oil, which was not characterized and used directly for the next step without further purification.
Step 2. 8-(2-Hvdroxyethyl)-1 ,4-dioxaspiro[4.51decane-8-carbonitrile (443)
To a solution of 442 (1.79 g, 5.50 mmol) in anhydrous THF (55 mL) at 0 °C was added TBAF (8.25 mL, 1 M in THF, 8.25 mmol). The reaction mixture was stirred at RT for 30 minutes, then it was quenched with saturated NH4CI solution and extracted with EA. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 100% of EA in hexane) to afford title compound 443 as a colorless oil (1.09 g, 94% yield), which was not characterized and used directly for the next step.
Step 3. 8-(2-(Difluoromethoxy)ethyl)-1 ,4-dioxaspiro[4.51decane-8-carbonitrile (444)
A plastic vial was charged with 443 (54 mg, 0.256 mmol) and potassium acetate (101 mg, 1.02 mmol), then, DCM (0.16 mL) and water (0.16 mL) were added. The mixture was stirred at RT and (bromodifluoromethyl)trimethylsilane (0.081 mL, 0.511 mmol) was added. The resulting mixture was stirred for 48 hours. Afterwards, the mixture was diluted with water and extracted with DCM. The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 50% of EA in hexane) to afford title compound 444 as a colorless oil (19 mg, 28% yield), which was not characterized and used directly for the synthesis of relevant examples.
Compounds 445-454
Compound 445 (example 212) was synthesized similarly to compound 170 (example 95, scheme 32) starting from compound 245 (example 211 , scheme 57) instead of compound 59. Compounds 446-447 and 453-454 (examples 213-214 and 220-221) were synthesized starting from intermediates 435 (scheme 102), 436, 441 (scheme 104) and 444 (scheme 105), respectively, following the procedure reported for the synthesis of compound 246 (example 129, scheme 57) from intermediate 241. Compound 452 (example 219) was synthesized similarly to compound 246 (example 129, scheme 57) starting from intermediate 439 (scheme 103) instead of intermediate 242. Compounds 448 (example 215) and 450 (example 217) were synthesized starting from intermediates 435 (scheme 102) and 436, respectively, following the procedure reported for the synthesis of compound 192 (example 104, scheme 40) from intermediate 185. Compounds 449 (example 216) and 451 (example 218) were synthesized starting from intermediates 435 (scheme 102) and 436, respectively, following the procedure reported for the synthesis of compound 189 (example 102, scheme 40) from intermediate 185. Characterization of compounds 445-454 (examples 212-221) is provided in table 8.
Table 8. Characterization of compounds 445-454 (examples 212-221).
Figure imgf000270_0001
Figure imgf000271_0001
Figure imgf000272_0001
Example 222 -Amino-6-(oxazol-5-yl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (462) and Example 223
2-Amino-6-(oxazol-5-yl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (463)
Intermediate compound 455 5-(8-Phenyl-1 ,4-dioxaspiro[4.5]decan-8-yl)oxazole (455) Scheme 106
Figure imgf000273_0001
379 455
To a solution of 8-phenyl-1 ,4-dioxaspiro[4.5]decane-8-carbaldehyde (379) (Bioorg Med. Chem Lett. 21 , p. 405, 2011) (2.99 g, 12.2 mmol) in MeOH (101 mL) were added K2CO3 (5.04 g, 36.5 mmol) and toluenesulfonylmethyl isocyanide (3.56 g, 18.2 mmol). The resulting mixture was stirred under reflux for 16 hours, then allowed to cool to RT and partitioned between EA and water (100 mL each). The layers were separated and the aqueous phase was extracted with another 3 x 50 mL EA. The combined organics were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified twice by flash column chromatography (first eluent gradient from 30% to 100% of EA in hexane; second eluent gradient from 25% to 100% of EA in hexane) to afford the title compound 455 as a yellow solid (592 mg, 17% yield), which was not characterized and used directly for the next step.
2-Amino-6-(oxazol-5-yl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (462) and 2-Amino-6-(oxazol-5-yl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (463)
Scheme 107
Figure imgf000274_0001
462: Example 222 463: Example 223
Step 1. 4-(Oxazol-5-yl)-4-phenylcyclohexan-1-one (458)
2 N aqueous HCI (10.3 mL, 20.6 mmol) was added to a solution of 455 (590 mg, 2.07 mmol) in acetone (25.6 mL) and the resulting mixture was stirred at RT for 16 hours. Then, another 5 mL of 2 N aqueous HCI (10 mmol) was added and the mixture was stirred at 40 °C for 5 hours. Subsequently, the mixture was quenched with saturated aqueous NaHCO3 and concentrated to remove the organic solvent. The residue was extracted with EA (3 x 25 mL). The combined organics were washed with brine (25 mL), dried over Na2SO4, filtered and concentrated to afford title compound 458 as a yellow solid (455 mg, 91% yield), which was not characterized and used directly for the next step.
Step 2. tert-Butyl 2-amino-6-(oxazol-5-yl)-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene- 3-carboxylate (459)
A suspension of 458 (448 mg, 1.86 mmol), morpholine (178 uL, 2.04 mmol), sulfur (65.7 mg, 256 umol) and tert-butyl 2-cya noacetate (298 uL, 2.04 mmol) in EtOH (1.86 mL) was stirred at 60 °C for 4.5 hours. The mixture was then allowed to cool to RT and concentrated. The residue was purified by flash column chromatography (eluent gradient from 10% to 100% of EA in hexane) to afford title compound 459 as a light-yellow solid (538 mg, 64% yield). LC-MS: rt = 1.64 min, MS: 396.2 (calcd), 397.2 (M+H+, found).
Step 3. tert-Butyl 2-acetamido-6-(oxazol-5-yl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[bl]thiophene-3-carboxylate (460) A mixture of 459 (532 mg, 1.34 mmol) and acetic anhydride (152 uL, 1 .61 mmol) in acetic acid (7.7 mL) was stirred at 80 °C for 1 hour. The mixture was then allowed to cool to RT, diluted with water (8.95 mL), dioxane (8.95 mL) and acetic acid (1.23 mL) and treated with ceric sulfate (3.86 g, 11 .6 mmol). The resulting mixture was sonicated for 1 minute, stirred at RT for 2.5 hours, then diluted with water (30 mL) and extracted with EA (3 x 30 mL). The combined organics were successively washed with 1 M aqueous NaOH (30 mL), water (30 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated to afford title compound 460 as a yellow gum (623.3 mg, >99% yield). LC-MS: rt = 1.69 min, MS: 452.1 (calcd), 453.3 (M+H+, found).
Step 4. 2-Acetamido-6-(oxazol-5-yl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (461)
To a solution of 460 (622 mg, 1.37 mmol) in DCM (12.1 mL) was added TFA (5.79 mL, 75.6 mmol) and the mixture was stirred at RT for 16 hours. Then, the mixture was concentrated to afford title compound 461 as a brown gum (938 mg, >99% yield). LC-MS: rt = 1.30 min, MS: 396.1 (calcd), 397.2 (M+H+, found).
Step 5. 2-Amino-6-(oxazol-5-yl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylic acid (462)
To a solution of 461 (938 mg) in MeOH (3.5 mL) and water (3.5 mL) was added lithium hydroxide monohydrate (406 mg, 9.68 mmol) and the resulting mixture was stirred at RT for 1.5 hours. The mixture was then concentrated to remove most of the organic solvent and the residue was diluted with water (15 mL) and EA (15 mL). The layers were separated and the aqueous phase was acidified by slowly adding 1 N HCI and then extracted with EA (3 x 15 mL). These organics were combined, dried over Na2SO4, filtered and concentrated and the residue was purified by reverse-phase column chromatography (eluent gradient from 0% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid) to afford title compound 462 as a beige solid (279 mg, 57% yield).
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 12.61 (bs, 1 H), 8.37 (bs, 2H), 8.30 (s, 1 H), 7.42- 7.28 (m, 3H), 7.21 (d, J = 7.3 Hz, 2H), 6.72 (s, 1H), 3.06 (dt, J = 18.5, 4.5 Hz, 1 H), 2.89-2.68 (m, 2H), 2.65-2.55 (m, 1 H). LC-MS: rt = 1.19 min, MS: 354.1 (calcd), 355.1 (M+H+, found).
Step 6. 2-Amino-6-(oxazol-5-yl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (463)
To a solution of 462 (21.5 mg, 60.7 umol) in DMF (0.76 mL) were added ammonium chloride (32.5 mg, 607 umol), HATU (46.1 mg, 121 umol) and N,N-diisopropylethylamine (44 uL, 252 umol). The resulting solution was stirred at RT for 10 minutes, then excess of gaseous NH3 was bubbled through the mixture from a balloon. Stirring continued at RT for 30 minutes, then the mixture was diluted with saturated aqueous NH4CI (3 mL) and extracted with EA (3 x 3 mL). The combined organics were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase flash column chromatography (eluent gradient from 0% to 100% of CH3CN in H2O with 0.1% (v/v) formic acid), then by Semi-Prep HPLC-MS (eluent gradient from 30% to 100% of MeOH in 10 mM ammonium formate) and then by flash column chromatography (eluent gradient from 0% to 20% of MeOH in DCM) to afford title compound 463 as a white solid (2.7 mg, 13% yield).
1H NMR: 400 MHz, CD3OD, δ (ppm): 8.16 (s, 1 H), 7.41-7.27 (m, 5H), 6.67 (s, 1 H), 3.01 (dt, J = 16.7, 4.3 Hz, 1 H), 2.94-2.84 (m, 2H), 2.82-2.73 (m, 1 H). LC-MS: rt = 0.88 min, MS: 353.1 (calcd), 354.1 (M+H+, found).
Example 224 2-Amino-N-cyclopropyl-6-(oxazol-5-yl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (464)
Figure imgf000276_0001
464: Example 224
Compound 464 (example 224) was synthesized similarly to compound 170 (example 95, scheme 32) starting from compound 462 (scheme 107) instead of compound 59.
1H NMR: 400 MHz, CDCI3, δ (ppm): 7.85 (s, 1 H), 7.40-7.32 (m, 3H), 7.30-7.26 (m, 2H), 7.04 (bs, 2H), 6.69 (s, 1 H), 5.53 (s, 1 H), 3.00-2.88 (m, 1 H), 2.87-2.83 (m, 1 H), 2.82-2.79 (m, 1 H), 2.78-2.71 (m, 1 H), 2.65-2.55 (m, 1 H), 0.94-0.75 (m, 2H), 0.62-0.46 (m, 2H). LC-MS: rt = 1.19 min, MS: 393.1 (calcd), 394.2 (M+H+, found).
Example 225
Intermediate compound 456
5-(8-(Cyclopropylmethyl)-1,4-dioxaspiro[4.5]decan-8-yl)oxazole (456)
Figure imgf000276_0002
456
Intermediate 456 was synthesized similarly to intermediate 455 (scheme 106), starting from compound 113 (scheme 21) instead of compound 379.
2-Amino-6-(cyclopropylmethyl)-6-(oxazol-5-yl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (465)
Figure imgf000277_0001
465: Example 225
Compound 465 (example 225) was synthesized similarly to compound 463 (example 223, scheme 107) starting from intermediate 456 instead of intermediate 455.
1H NMR: 400 MHz, CD3OD, δ (ppm): 8.15 (s, 1 H), 6.98 (s, 1 H), 3.12 (dt, J = 17.6, 5.4 Hz, 1 H), 2.97 (ddd, J = 17.6, 8.5, 4.9 Hz, 1H), 2.64 (ddd, J = 13.8, 5.8, 4.9 Hz, 1H), 2.55 (ddd, J = 13.7, 8.5, 5.0 Hz, 1 H), 1.98 (dd, J = 14.2, 6.3 Hz, 1 H), 1.89 (dd, J = 14.1 , 7.2 Hz, 1 H), 0.74-0.60 (m, 1 H), 0.50-0.35 (m, 2H), 0.16-0.05 (m, 1 H), -0.00 - -0.12 (m, 1 H). LC-MS: rt = 1.02 min, MS: 331.1 (calcd), 332.2 (M+H+, found).
Example 226 2-Amino-6-(oxazol-5-ylmethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (466)
Intermediate compound 457
5-((8-Phenyl-1,4-dioxaspiro[4.5]decan-8-yl)methyl)oxazole (457)
Figure imgf000277_0002
457
Intermediate 457 was synthesized similarly to intermediate 455 (scheme 106), starting from compound 93 (scheme 17) instead of compound 379.
2-Amino-6-(oxazol-5-ylmethyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide (466)
Figure imgf000277_0003
466: Example 226
Compound 466 (example 226) was synthesized similarly to compound 463 (example 223, scheme 107) starting from intermediate 457 instead of intermediate 455. 1H NMR: 400 MHz, CD3OD, δ (ppm): 8.03 (s, 1 H), 7.40-7.19 (m, 5H), 6.68 (s, 1 H), 3.42
(d, J = 15.1 Hz, 1 H), 3.21 (d, J = 15.1 Hz, 1 H), 3.01-2.89 (m, 1 H), 2.81-2.61 (m, 3H). LC-MS: rt = 1.02 min, MS: 367.1 (calcd), 368.1 (M+H+, found).
Example 227 2-Amino-6-cyano-6-((2,2-difluoroethoxy)methyl)-7 -oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (468) Intermediate compound 467 8-((2,2-Difluoroethoxy)methyl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (467) Scheme 108
Figure imgf000278_0001
419 467
Scheme 98
Compound 419 (scheme 98) (119 mg, 602 umol) was dissolved in dry THF (2 mL) under argon and the resulting solution was cooled down to -10 °C. Then, 2,2-difluoroethyl trifluoromethanesulfonate (155 mg, 722 umol) was added followed by sodium hydride (28.9 mg, 60% in mineral oil, 722 umol) suspended in dry THF (3.14 mL). The reaction vessel was taken out of the ice bath and the mixture was allowed to reach RT and stir for 2 hours. The mixture was then diluted with 10 mL saturated aqueous NaHCO3 and extracted with 3 x 10 mL EA. The combined organics were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 0% to 70% of EA in hexane) to afford the title compound 467 as a light-yellow oil (108 mg, 69% yield), which was not characterized and used directly for the next step.
2-Amino-6-cyano-6-((2,2-difluoroethoxy)methyl)-7 -oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (468)
Figure imgf000278_0002
468: Example 227
Compound 468 (example 227) was synthesized similarly to compound 246 (example 129, scheme 57) starting from intermediate 467 instead of intermediate 241.
1H NMR: 400 MHz, CD3OD, δ (ppm): δ.97 (tt, J = 55.2, 3.9 Hz, 1 H), 4.02 (d, J = 9.6 Hz, 1 H), 3.98 (d, J = 9.6 Hz, 1 H), 3.80 (tdd, J = 14.3, 6.0, 3.9 Hz, 2H), 3.18 (dd, J = 6.8, 5.3 Hz, 2H), 2.63-2.38 (m, 2H). 19F NMR: 376 MHz, CD3OD, δ (ppm): -127.4 (dt, J = 55.3, 14.4 Hz). LC-MS: rt = 0.92 min, MS: 329.1 (calcd), 330.1 (M+H+, found).
Examples 228-235
Compounds 469-476 (examples 228-235) were synthesized by following a procedure similar to the one described above for the synthesis of compound 170 (example 95, scheme 32), starting from compound 59 (example 36, scheme 8) and using azetidin-3-ol, 2- methoxyethylamine, 2-amino-1 ,3-propanediol, ethylamine, 3-methylazetidin-3-ol hydrochloride, 1-(aminomethyl)cyclopropanol, propylamine, and methylamine hydrochloride, respectively, instead of cyclopropylamine. Characterization of compounds 469-476 (examples 228-235) is provided in table 9.
Table 9. Characterization of compounds 469-476 (examples 228-235).
Figure imgf000279_0001
Figure imgf000280_0001
Figure imgf000281_0003
Example 236 3-(2-Amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamido)propanoic acid (478) Intermediate compound 477 tert-Butyl 3-(2-amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamido)propanoate (477)
Figure imgf000281_0001
477
Intermediate 477 was synthesized similarly to compound 170 (example 95, scheme 32), starting from compound 59 (example 36, scheme 8) and using p-alanine tert-butyl ester hydrochloride instead of cyclopropylamine.
LC-MS: rt = 1.38 min, MS: 439.2 (calcd), 440.3 (M+H+, found).
3-(2-Amino-6-cyano-7-oxo-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamido)propanoic acid (478)
Figure imgf000281_0002
To a stirred solution of 477 (46.9 mg, 0.107 mmol) in DCM (1.07 mL) was added TFA (449 pL, 5.87 mmol). The reaction mixture was stirred at RT for 3 hours, then concentrated under reduced pressure. The residue was purified by reverse-phase flash column chromatography (eluent gradient from 0% to 100% CH3CN in H2O with 0.1% (v/v) formic acid) to afford title compound 478 as a white solid (30 mg, 74% yield).
1H NMR: 400 MHz, CD3OD, δ (ppm): 7.43-7.38 (m, 5H), 3.59-3.51 (m, 2H), 3.14-3.08 (m, 1 H), 2.85-2.67 (m, 4H), 2.59 (t, J = 6.6 Hz, 2H). LC-MS: rt = 1.00 min, MS: 383.2 (calcd), 384.1 (M+H+, found).
Example 237 2-Amino-6-cyano-N-(2-hydroxyethyl)-7-oxo-6-phenyl-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (479)
Figure imgf000282_0001
479: Example 237
Compound 479 (example 237) was synthesized similarly to compound 170 (example 95, scheme 32), starting from compound 59 (example 36, scheme 8) and using ethanolamine instead of cyclopropylamine.
1H NMR: 400 MHz, CD3OD, δ (ppm): 7.42-7.37 (m, 5H), 3.65 (t, J = 5.6 Hz, 2H), 3.44-3.40 (m, 2H), 3.17-3.11 (m, 1H), 2.86-2.77 (m, 2H), 2.73-2.68 (m, 1 H). LC-MS: rt = 1.03 min, MS: 355.1 (calcd), 356.2 (M+H+, found).
Example 238 2-Amino-6-cyano-N-(1-cyanocyclopropyl)-7-oxo-6-phenyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (480)
Figure imgf000282_0002
480: Example 238
Compound 480 (example 238) was synthesized similarly to compound 170 (example 95, scheme 32), starting from compound 59 (example 36, scheme 8) and using 1-amino- cyclopropanecarbonitrile instead of cyclopropylamine.
1H NMR: 400 MHz, CD3OD, δ (ppm): 7.42-7.37 (m, 5H), 3.06-3.01 (m, 1 H), 2.80-2.65 (m, 3H), 1.51-1.44 (m, 2H), 1.32-1.27 (m, 2H). LC-MS: rt = 1.26 min, MS: 376.1 (calcd), 377.2 (M+H+, found). Example 239 2-Amino-3'-hydroxy-7-oxo-2',3,,4,7-tetrahydro-5H-spiro[benzo[b]thiophene-6,1'-indene]-3- carboxamide (481)
Figure imgf000283_0001
Sodium borohydride (1.17 mg, 36.6 umol) was added to a solution of 2-amino-3',7-dioxo- 2',3',4,7-tetrahydro-5H-spiro[benzo[b]thiophene-6,1 '-indene]-3-carboxamide (428, example 206) (20.0 mg, 61 .3 umol) in EtOH (0.096 mL) at 0 °C. The mixture was stirred at 0 °C for 1 hour, then diluted with water and EA. The layers were separated and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by Semi- Prep HPLC-MS (eluent gradient from 15% to 100% of ACN in 10 mM ammonium formate) to afford title compound 481 as a white solid (2.5 mg, 12 % yield).
1H NMR: 400 MHz, CD3OD, δ (ppm): 7.42 (d, J = 7.5 Hz, 1 H), 7.31-7.26 (m, 1H), 7.24- 7.19 (m, 1 H), 7.08 (d, J = 7.6 Hz, 1H), 5.24 (t, J = 6.8 Hz, 1H), 3.10-3.07 (m, 2H), 2.49 (dd, J = 13.0, 6.7 Hz, 1 H), 2.40 (dd, J =13.0, 6.9 Hz, 1 H), 2.26-2.17 (m, 2H). LC-MS: rt = 0.89 min, MS: 328.1 (calcd), 327.1 (M-H+, found).
Example 240
2-Amino-6-cyano-N-cyclopropyl-6-(2-(difluoromethoxy)ethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (482)
Figure imgf000283_0002
482: Example 240
Compound 482 (example 240) was synthesized similarly to compound 192 (example 104, scheme 40), starting from compound 444 (scheme 105) instead of compound 185.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.04 (s, 2H), 7.57 (d, J = 3.9 Hz, 1 H), 6.67 (t, J = 77.2 Hz, 1 H), 4.01 (t, J = 6.8 Hz, 2H), 2.99-2.92 (m, 2H), 2.75-2.70 (m, 1 H), 2.43-2.35 (m, 1H), 2.34-2.27 (m, 1 H), 2.27-2.18 (m, 1 H), 2.15-2.01 (m, 1 H), 0.66-0.61 (m, 2H), 0.53-0.48 (m, 2H). 19F NMR: 376 MHz, DMSO-d6, δ (ppm): -83.4 (d, J = 75.2 Hz). LC-MS: rt = 1.09 min, MS: 369.1 (calcd), 370.1 (M+H+, found).
Example 241 2-Amino-6-cyano-6-(2-(difluoromethoxy)ethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (483)
Figure imgf000284_0001
483: Example 241
Compound 483 (example 241) was synthesized similarly to compound 189 (example 102, scheme 40), starting from compound 444 (scheme 105) instead of compound 185.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 12.79 (bs, 1 H), 8.52 (bs, 2H), 6.69 (t, J = 75.7 Hz, 1 H), 4.02 (t, J = 6.7 Hz, 2H), 3.15 (dt, J = 19.3, 5.8 Hz, 1 H), 3.02 (ddd, J = 19.3, 7.5, 4.9 Hz, 1 H), 2.47-2.42 (m, 1 H), 2.32-2.26 (m, 2H), 2.15-2.08 (m, 1 H). 19F NMR: 376 MHz, CD3OD, δ (ppm): - 83.4 (d, J = 75.2 Hz). LC-MS: rt = 1.16 min, MS: 330.1 (calcd), 331.1 (M+H+, found).
Example 242 2-Amino-6-((difluoromethoxy)methyl)-6-(3-methylisoxazol-4-yl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (486) Intermediate compound 484 8-((Difluoromethoxy)methyl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (484)
Figure imgf000284_0002
484
Intermediate compound 484 was synthesized similarly to intermediate compound 444 (scheme 105), starting from 8-(hydroxymethyl)-1 ,4-dioxaspiro[4.5]decane-8-carbonitrile (419, scheme 98) instead of 8-(2-hydroxyethyl)-1 ,4-dioxaspiro[4.5]decane-8-carbonitrile (443, scheme 105). The product was not characterized and used directly for the synthesis of relevant examples.
Intermediate compound 485
4-(8-((Difluoromethoxy)methyl)-1 ,4-dioxaspiro[4.5]decan-8-yl)-3-methylisoxazole (485)
Figure imgf000284_0003
Intermediate compound 485 was synthesized similarly to intermediate compound 384 (scheme 90), starting from 8-((difluoromethoxy)methyl)-1 ,4-dioxaspiro[4.5]decane-8-carbonitrile (intermediate compound 484) instead of 3-(8-(cyclopropylmethyl)-1 ,4-dioxaspiro[4.5]decan-8- yl)propanenitrile (185). The product was not characterized and used directly for the synthesis of relevant examples.
2-Amino-6-((difluoromethoxy)methyl)-6-(3-methylisoxazol-4-yl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (486)
Figure imgf000285_0001
486: Example 242
Compound 486 (example 242) was synthesized similarly to compound 246 (example 129, scheme 57) starting from intermediate 485 instead of intermediate 241.
1H NMR: 400 MHz, CD3OD, δ (ppm): 8.46 (s, 1 H), 6.40 (t, J = 75.3 Hz, 1H), 4.29 (d, J = 9.8 Hz, 1 H), 4.09 (d, J = 9.8 Hz, 1H), 3.09 (dt, J = 17.7, 4.8 Hz, 1 H), 2.89 (ddd, J = 17.7, 9.6, 4.8 Hz, 1 H), 2.57 (dt, J = 14.0, 4.8 Hz, 1 H), 2.46 (ddd, J = 14.0, 9.6, 4.8 Hz, 1 H), 2.26 (s, 3H). 19F NMR: 376 MHz, CD3OD, δ (ppm): -85.5 (dd, J = 162.8, 75.3 Hz, 1 F), -86.1 (dd, J = 162.8, 75.3 Hz, 1 F). LC-MS: rt = 0.98 min, MS: 371.1 (calcd), 372.1 (M+H+, found).
Example 243 2-Amino-3'-(methoxyimino)-7-oxo-2',3,,4,7-tetrahydro-5H-spiro[benzo[b]thiophene-6,1'- indene]-3-carboxamide (489) Intermediate compound 488 2-Amino-3'-(methoxyimino)-7-oxo-2',3,,4,7-tetrahydro-5H-spiro[benzo[b]thiophene-6,1'- indene]-3-carboxylic acid (488)
Scheme 111
Figure imgf000285_0002
Step 1. Ethyl 2-acetamido-3'-(methoxyimino)-7-oxo-2',3',4,7-tetrahydro-5H- spiro[benzo[b1]thiophene-6, 1 '-indenel-3-carboxylate (487)
To a solution of ethyl 2-acetamido-3',7-dioxo-2',3',4,7-tetrahydro-5H- spiro[benzo[b]thiophene-6,1'-indene]-3-carboxylate (426, scheme 99) (60 mg, 0.151 mmol) in EtOH (1 .7 mL) were added sodium acetate trihydrate (95 mg, 0.697 mmol) and methoxyamine hydrochloride (38 mg, 0.453 mmol). The reaction mixture was stirred at RT for 72 hours. Then, it was diluted with EA and water. The layers were separated and the organic layer was dried over Na2SO4, filtered and concentrated to give title compound 487 (64 mg, 99% yield) as a white solid. LC-MS: rt = 1.70 min, MS: 426.1 (calcd), 427.3 (M+H+, found).
Step 2. 2-Amino-3'-(methoxyimino)-7-oxo-2',3',4,7-tetrahydro-5H- spiro[benzo[b]thiophene-6,1'-indene1-3-carboxylic acid (488)
To a solution of 487 (64 mg, 0.150 mmol) in MeOH (1.9 mL) was added a solution of lithium hydroxide monohydrate (18 mg, 0.75 mmol) in water (1.9 mL). The reaction mixture was stirred for 16 hours at 55 °C. The mixture was then concentrated to remove most of the organic solvent and the residue was diluted with water (15 mL) and EA (15 mL). The layers were separated and the aqueous phase was acidified by slowly adding 1 N HCI and then extracted with EA (3 x 15 mL). These organics were combined, dried over Na2SO4, filtered and concentrated to give title compound 488 (53 mg, 99% yield) as a yellow solid. LC-MS: rt = 0.88 min, MS: 356.1 (calcd), 357.1 (M+H+, found).
2-Amino-3'-(methoxyimino)-7-oxo-2',3,,4,7-tetrahydro-5H-spiro[benzo[b]thiophene-6,1'- indene]-3-carboxamide (489)
Figure imgf000286_0001
Compound 489 (example 243; single product, E/Z stereochemistry not established) was synthesized similarly to compound 238 (example 127, scheme 55) starting from intermediate compound 488 (scheme 111) instead of compound 237.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.21-8.09 (bs, 2H), 7.60-7.58 (m, 1 H), 7.38-7.31 (m, 2H), 7.28-7.23 (m, 1H), 7.13-6.97 (bs, 2H), 3.90 (s, 3H), 3.22-3.01 (m, 3H), 2.78-2.72 (m, 1 H), 2.27-2.19 (m, 2H). LC-MS: rt = 1.04 min, MS: 355.4 (calcd), 356.1 (M+H+, found).
Example 244 2-Amino-6-cyano-6-(2-(2,2-difluoroethoxy)ethyl)-7 -oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (492) Intermediate compound 491
Ethyl 2-amino-6-cyano-6-(2-(2,2-difluoroethoxy)ethyl)-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (491)
Scheme 112
Figure imgf000287_0001
To a suspension of sodium hydride (24.1 mg, 604 umol) in anhydrous THF (0.5 mL) cooled down to -10 °C was added ethyl 2-amino-6-cyano-6-(2-hydroxyethyl)-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (490, synthesized similarly to compound 43, scheme 4, starting from compound 443, scheme 105, instead of 41) (148 mg, 503 umol) dissolved in anhydrous THF (6 mL). The mixture was allowed to stir at -10 °C for 1 minute, then 2,2- difluoroethyl trifluoromethanesulfonate (79.8 uL, 604 umol) was added dropwise. The reaction vessel was removed from the cold bath and the mixture was allowed to stir for 2 hours at RT, then diluted with saturated aqueous NaHCO3 (10 mL) and EA (10 mL). The layers were separated and the aqueous layer was extracted with additional EA (2 x 20 mL). The combined organics were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient from 10% to 100% of EA in hexane) to afford the title compound 491 as a yellow gum (33 mg, 18% yield). LC-MS: rt = 1.38 min, MS: 358.1 (calcd), 359.1 (M+H+, found).
2-Amino-6-cyano-6-(2-(2,2-difluoroethoxy)ethyl)-7 -oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (492)
Figure imgf000287_0002
492: Example 244
Compound 492 (example 244) was synthesized similarly to compound 246 (example 129, scheme 57), starting from compound 491 (scheme 112) instead of compound 243. 1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.24 (bs, 2H), 7.08 (bs, 2H), 6.09 (tt, J = 55.0, 3.7 Hz, 1 H), 3.73-3.63 (m, 4H), 3.08-3.01 (m, 2H), 2.44-2.36 (m, 1 H), 2.25-2.17 (m, 2H), 2.07-1.99 (m, 1 H). 19F NMR: 376 MHz, DMSO-d6, δ (ppm): -125.2 (dt, J = 55.0, 15.1 Hz, 2F). LC-MS: rt = 0.91 min, MS: 343.1 (calcd), 344.1 (M+H+, found).
Example 245 2-Amino-6-methyl-7-oxo-6-((2,2,2-trifluoroethoxy)methyl)-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (495) Intermediate compound 494 8-Methyl-8-((2,2,2-trifluoroethoxy)methyl)-1,4-dioxaspiro[4.5]decane (494) Scheme 113
Figure imgf000288_0001
To a suspension of sodium hydride (176 mg, 4.41 mmol) in anhydrous DMF (1.5 mL) at 0 °C was added trifluoroethanol (0.317 mL, 4.41 mmol, previously degassed) and the mixture was stirred at RT for 1 hour. Then, a degassed solution of (8-methyl-1 ,4- dioxaspiro[4.5]decan-8-yl)methyl 4-methylbenzenesulfonate (493, WO 2014/053666) (500 mg, 1.47 mmol) in anhydrous DMF (0.79 mL) was added dropwise. The reaction was stirred at 100 °C for 18 hours. Then, it was allowed to reach RT, cooled down to 0 °C and carefully quenched by adding MeOH (0.5 mL) and water (1 mL). The mixture was diluted with EA (25 mL) and washed with brine (5 x 20 mL). The organic layer was dried over MgSO4, filtered and concentrated to give title compound 494 (411 mg, >99% yield) as an orange oil, which was not characterized and used directly for the synthesis of relevant examples.
2-Amino-6-methyl-7-oxo-6-((2,2,2-trifluoroethoxy)methyl)-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (495)
Figure imgf000288_0002
495: Example 245
Compound 495 (example 245) was synthesized similarly to compound 246 (example 129, scheme 57) starting from intermediate compound 494 (scheme 113) instead of intermediate 241.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.02 (s, 2H), 6.96 (bs, 2H), 4.03 (q, J = 9.4 Hz, 2H), 3.83 (d, J = 9.2 Hz, 1 H), 3.43 (d, J = 9.2 Hz, 1 H), 3.03-2.88 (m, 2H), 2.20-2.13 (m, 1 H), 1.79 (dt, J = 13.5, 4.8 Hz, 1H), 1.02 (s, 3H). 19F NMR: 376 MHz, DMSO-d6, δ (ppm): -72.8 (t, J = 9.4 Hz, 3F). LC-MS: rt = 1 .12 min, MS: 336.1 (calcd), 337.2 (M+H+, found).
Example 246
2-Amino-N-cyclopropyl-6-methyl-7-oxo-6-((2,2,2-trifluoroethoxy)methyl)-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (496)
Figure imgf000288_0003
Compound 496 (example 246) was synthesized similarly to compound 192 (example 104, scheme 40), starting from intermediate compound 494 (scheme 113) instead of compound 185.
1H NMR: 400 MHz, CD3OD, δ (ppm): 3.93-3.85 (m, 3H), 3.48 (d, J = 9.1 Hz, 1 H), 2.94- 2.85 (m, 2H), 2.78-2.71 (m, 1 H), 2.35-2.28 (m, 1H), 1.86 (dt, J = 13.6, 4.9 Hz, 1 H), 1.12 (s, 3H), 0.79-0.74 (m, 2H), 0.61-0.57 (m, 2H). 19F NMR: 376 MHz, CD3OD, δ (ppm): -75.96 (t), LC-MS: rt = 1.33 min, MS: 376.1 (calcd), 377.1 (M+H+, found).
Example 247
2-Amino-6-methyl-7-oxo-6-((2,2,2-trifluoroethoxy)methyl)-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (497)
Figure imgf000289_0001
Compound 497 (example 247) was synthesized similarly to compound 189 (example 102, scheme 40), starting from intermediate compound 494 (scheme 113) instead of compound 185.
1H NMR: 400 MHz, DMSO-d6, δ (ppm): 8.23-8.22 (m, 2H), 4.01 (q, J = 9.4 Hz, 2H), 3.80 (d, J = 9.1 Hz, 1 H), 3.40 (d, J = 6.9 Hz, 1 H), 3.13-3.02 (m, 1H), 2.89-2.77 (m, 1 H), 2.16-2.09 (m, 1 H), 1 .80-1 .75 (m, 1 H), 0.99 (s, 3H). 19F NMR: 376 MHz, CD3OD, δ (ppm): -76.0 (t). LC-MS: rt = 1.29 min, MS: 337.1 (calcd), 338.1 (M+H+, found).
Example 248 2-Amino-3'-hydroxy-7-oxo-3,-(trifluoromethyl)-2,,3,,4,7-tetrahydro-5H- spiro[benzo[b]thiophene-6,1'-indene]-3-carboxamide (498)
Scheme 114
Figure imgf000289_0002
To a mixture of 428 (example 206) (50.0 mg, 153 umol) and trifluoromethyltrimethylsilane (116 uL, 766 umol) in anhydrous THF (198 uL) under an argon atmosphere was added tetrabutylammonium fluoride (230 uL, 230 umol) at 0 °C. Then, the reaction was stirred at RT for 16 hours. More trifluoromethyltrimethylsilane (116 uL, 766 umol) and tetrabutylammonium fluoride (230 uL, 230 umol) were added and the mixture was stirred at 40 °C for 24 hours. Afterwards, the mixture was diluted with water and extracted with EA twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude was first purified by flash column chromatography (eluent gradient from 5% to 100% of EA in hexane), then by Semi-Prep HPLC-MS (eluent gradient from 40% to 100% of MeOH in 10 mM ammonium formate) to afford title compound 498 as a white solid (4.8 mg, 8% yield).
1H NMR: 400 MHz, CD3OD, δ (ppm): 7.53 (s, 1 H), 7.38-7.35 (m, 2H), 7.24-7.22 (m, 1 H), 3.26- 3.24 (m, 1 H), 3.15-3.11 (m, 1 H), 2.75 (d, J= 14.9 Hz, 1 H), 2.57 (d, J= 14.8 Hz, 1H), 2.41-2.33 (m, 2H).19F NMR: 376 MHz, CD3OD, δ (ppm): -81 .0 (s). LC-MS: rt = 1 .20 min, MS: 396.1 (calcd), 397.1 (M+H+, found).
Example 249 2-Amino-6-(cyclopropylmethyl)-6-(2-(difluoromethoxy)ethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (347)
Scheme 1 15
Figure imgf000290_0001
Step 1 . 8-(Cyclopropylmethyl)-8-[2-(difluoromethoxy)ethyl1-1 ,4-dioxaspiro[4.51decane (499)
To a 20 mL vial equipped with a stir bar were added 2-[8-(cyclopropylmethyl)-1 ,4- dioxaspiro[4.5]decan-8-yl]ethan-1-ol (115, scheme 21) (690 mg, 2.87 mmol), potassium acetate (1.69 g, 17.2 mmol), DCM (1.72 mL), water (1.72 mL) and (bromodifluoromethyl)trimethylsilane
(1.34 mL, 8.61 mmol). The reaction mixture was stirred at RT for 18 hours, then diluted with 50 mL DCM, dried over Na2SO4, filtered and concentrated to yield title compound 499 as a clear oil (700 mg, 84% yield). 1H NMR: 400 MHz, CDCI3, δ (ppm): 6.18 (t, J = 75.1 Hz, 1 H), 3.93 (s, 4H), 3.90 (t, J = 7.6 Hz, 2H), 1 .81 (t, J = 7.6 Hz, 2H), 1 .66-1 .48 (m, 8H), 1.25 (d, J = 6.6 Hz, 2H), 0.66- 0.57 (m, 1 H), 0.51-0.39 (m, 2H), 0.15-0.04 (m, 2H).
Step 2. 4-(Cyclopropylmethyl)-4-[2-(difluoromethoxy)ethyl1cyclohexan-1-one (500)
To a 20 mL vial equipped with a stir bar were added 499 (690 mg, 2.38 mmol) and acetone (11 .9 mL). 12 N aqueous HCI (1 .98 mL, 23.8 mmol) was then added and the reaction mixture was stirred at RT for 6 hours. The reaction mixture was neutralized by addition of saturated NaHCO3 aqueous solution and extracted with EA (3 x 50 mL). The organic fractions were combined, washed with brine, dried over Na2SO4, filtered and concentrated to yield title compound 500 as a clear oil (592 mg, >99% yield). 1H NMR: 400 MHz, CDCI3, δ (ppm): 6.20 (t, J = 74.6 Hz, 1H), 3.96 (t, J = 7.3 Hz, 2H), 2.35 (q, J = 6.8 Hz, 4H), 1.95 (t, J = 7.3 Hz, 2H), 1.87-1.75 (m, 4H), 1.38 (dd, J = 6.6, 4.9 Hz, 2H), 0.74-0.56 (m, 1 H), 0.55-0.48 (m, 2H), 0.11-0.05 (m, 2H).
Step 3. Ethyl 2-amino-6-(cyclopropylmethyl)-6-[2-(difluoromethoxy)ethyl1-4, 5,6,7- tetrahydro-1-benzothiophene-3-carboxylate (501)
A 20 mL vial equipped with a stir bar was charged with 500 (680 mg, 2.76 mmol), ethyl 2- cyanoacetate (294 uL, 2.76 mmol), morpholine (262 uL, 3.04 mmol), sulfur (97.5 mg, 2.76 mmol) and EtOH (4.4 mL). The vial was sealed with a pressure relief cap and heated at 60 °C overnight, resulting in the formation of a dark red solution. The reaction was cooled to room temperature and concentrated to yield title compound 501 as a red oil (1.03 g, >99% yield), which was not characterized and used directly for the next step.
Step 4. Ethyl 6-(cyclopropylmethyl)-6-[2-(difluoromethoxy)ethyl]-2-acetamido-4, 5,6,7- tetrahydro-1-benzothiophene-3-carboxylate (502)
A 1 dram vial equipped with a stir bar was charged with 501 (1.02 g, 2.73 mmol) and acetic acid (15.7 mL). Acetic anhydride (319 uL, 3.28 mmol) was then added in a single portion and the reaction mixture was stirred at 60 °C for 2.5 hours, then cooled to room temperature and concentrated. The residue was dissolved in DCM (50 mL), washed with saturated NaHCO3 aqueous solution, then brine, dried over Na2SO4 and concentrated to yield title compound 502 as a red oil (880 mg, 76% yield). MS: 416.1 (calcd), 417.1 (M+H+, found).
Step 5. Ethyl 6-(cyclopropylmethyl)-2-acetamido-6-(2-hydroxyethyl)-7-oxo-4, 5,6,7- tetrahydro-1-benzothiophene-3-carboxylate (503)
To a 20 mL vial equipped with a stir bar was added 502 (820 mg, 1.97 mmol), acetic acid (6.51 mL), water (6.51 mL) and ceric sulfate (5.66 g, 17.1 mmol). The resulting slurry was stirred vigorously at RT for 18 hours. The mixture was then diluted with deionized water (6 mL) and EA (6 mL). The aqueous phase was extracted with EA (3 x 10 mL). The organic fractions were combined and washed consecutively with 1 N NaOH (10 mL), water (10 mL) and brine (10 mL). The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (eluent 0-100% EtOAc in heptane) to yield title compound 503 as an orange oil (324 mg, 43% yield). 1H NMR: 400 MHz, CDCI3, δ (ppm): 11.52 (bs, 1 H), 4.38 (q, J = 7.1 Hz, 2H), 4.19-4.12 (m, 2H), 3.18-3.00 (m, 2H), 2.31 (s, 3H), 2.27-2.11 (m, 4H), 1.97-1.90 (m, 1 H), 1.75-1.68 (m, 1H), 1.43 (t, J = 7.0 Hz, 3H), 0.72-0.62 (m, 1 H), 0.49-0.43 (m, 2H), 0.08- 0.05 (m, 2H). MS: 379.1 (calcd), 380.1 (M+H+, found).
Step 6. Ethyl 6-(cyclopropylmethyl)-6-[2-(difluoromethoxy)ethyl1-2-acetamido-7-oxo- 4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (504)
To a 1 dram vial equipped with a stir bar was added 503 (83.6 mg, 229 umol), potassium acetate (135 mg, 1.37 mmol), DCM (137 uL), water (137 uL) and (bromodifluoromethyl)trimethylsilane (139 mg, 686 umol). The reaction mixture was stirred at RT for 18 hours, then diluted with 10 mL EA, dried over Na2SO4, filtered and concentrated to yield title compound 504 as an orange oil (66 mg, 67% yield). 1H NMR: 400 MHz, CDCI3, δ (ppm): 11.52 (bs, 1 H), 4.38 (q, J = 7.1 Hz, 2H), 4.19-4.12 (m, 2H), 3.18-3.00 (m, 2H), 2.31 (s, 3H), 2.27- 2.11 (m, 4H), 1.97-1.90 (m, 1 H), 1.75-1.68 (m, 1H), 1.43 (t, J = 7.0 Hz, 3H), 0.72-0.62 (m, 1 H), 0.49-0.43 (m, 2H), 0.08-0.05 (m, 2H). MS: 429.1 (calcd), 430.1 (M+H+, found).
Step 7. 2-Amino-6-(cyclopropylmethyl)-6-(2-(difluoromethoxy)ethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (347)
A 50 mL round bottom flask equipped with a stir bar was charged with 504 (66.0 mg, 0.154 mmol), water (18.6 mL), and MeOH (18.6 mL). Lithium hydroxide monohydrate (32.2 mg, 0.768 mmol) was added in a single portion. A reflux condenser was attached to the flask and the reaction mixture was stirred at 80 °C for 18 hours. The mixture was then cooled to room temperature and MeOH was removed by rotary evaporation. The aqueous residue was acidified by addition of 1 N HCI solution and extracted with EA (3 x 50 mL). The organic fractions were combined, dried over Na2SO4, filtered and concentrated. The residue was purified with RediSep Prep C18 column 20 x 150 mm 100 A 5 μm; gradient 10% ACN in water 0-1.0 min, 10-100% ACN in water 1.0-12.0 min, 100% ACN 12.0-14.0 min to yield title compound 347 as a white solid (2.11 mg, 3.7% yield).
1H NMR: 500 MHz, DMSO-d6, δ (ppm): 8.27 (bs., 1 H), 6.61 (t, J = 76.4 Hz, 1H), 3.85-3.80 (m, 2H), 3.06-2.90 (m, 2H), 2.53-2.51 (m, 2H), 2.13-1.94 (m, 3H), 1.87-1.79 (m, 1 H), 1.59 (dd, J = 14.2, 6.2 Hz, 1 H), 1.32 (dd, J = 14.2, 7.1 Hz, 1 H), 0.64-0.57 (m, 1 H), 0.39 (dd, J = 8.0, 2.4 Hz, 2H), 0.08-0.10 (m, 2H). MS: 359.1 (calcd), 360.1 (M+H+, found).
Example 250 2-Amino-6-(cyclopropylmethyl)-6-(2-(difluoromethoxy)ethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (340)
Figure imgf000292_0001
To a 50 mL round bottom flask equipped with a stir bar was added 347 (25.5 mg, 71 umol), DMF (784 uL), HATU (40.5 mg, 0.106 mmol), DIPEA (24.7 uL, 0.142 mmol) and ammonium chloride (75.9 mg, 1.42 mmol). The flask was sealed with a septum and sparged with a balloon of argon for 10 mins. Ammonia in THF (0.4 M solution, 3.55 mL, 1.42 mmol) was added to the reaction by syringe. The reaction mixture was stirred at r t for 18 hours under an atmosphere of argon. The reaction was quenched by addition of 50 mL of saturated NH4CI solution and extracted with EA (3 x 50 mL). The EA fractions were combined and washed with brine (10 mL), dried with Na2SO4, filtered and concentrated. The crude material was purified using a RediSep Prep C18 column 20 x 150 mm 100 A 5 pm (gradient 10% ACN in water 0-1.0 min, 10-100% ACN in water 1.0-12.0 min, 100% ACN 12.0-14.0 min) and dried by lyophilization to yield the title compound as a white solid (4.99 mg, 19% yield).
1H NMR: 500 MHz, DMSO-d6, δ (ppm): 8.00 (s, 2H), 6.60 (t, J = 76.4 Hz, 1 H), 3.85-3.79 (m, 2H), 3.28 (s, 2H), 3.03-2.88 (m, 2H), 2.14-1 .93 (m, 3H), 1.88-1.81 (m, 1 H), 1.57 (dd, J = 14.1 , 6.4 Hz, 1 H), 1.35 (dd, J = 14.1 , 6.9 Hz, 1 H), 0.65-0.57 (m, 1 H), 0.42-0.37 (m, 2H), 1.91 (m, 2H). MS: 358.1 (calcd), 359.1 (M+H+, found).
Example 251 2-Amino-6-(cyclopropylmethyl)-6-(methoxymethyl)-7 -oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid
Figure imgf000293_0001
Scheme 116
Figure imgf000293_0002
Step 1 : 8-(Cyclopropvlmethvl)-8-(methoxvmethyl)-1 ,4-dioxaspiro[4 .51decane (505)
A dry 100 mL Schlenk flask equipped with a stir bar under nitrogen was charged with NaH (302 mg, 12.6 mmol). Anhydrous THF (5.4 mL) was added via syringe and the flask was stirred at 0 °C for 15 mins. A degassed solution of [8-(cyclopropylmethyl)-1 ,4-dioxaspiro[4.5]decan-8- yl]methanol (116, scheme 22) (950 mg, 4.2 mmol) in anhydrous THF (3 mL) was added via syringe and the reaction was stirred at RT for 1 hour. The flask was then cooled to 0 °C and degassed methyl iodide (784 uL. 12.6 mmol) was added via syringe in a single portion. The resulting mixture was stirred at 50 °C for 18 hours, then cooled to room temperature and then to 0 °C. The mixture was quenched by dropwise addition of MeOH by syringe (~0.5 mL). 50 mL brine was then added and the product was extracted with EA (3 x 50 mL). The organic fractions were combined, dried over Na2SO4, filtered, and concentrated to yield title compound 505 as a yellow oil (930 mg, 92% yield).
1H NMR: 400 MHz, CDCI3, δ (ppm): 3.93 (s, 4H), 3.32 (s, 3H), 3.29 (s, 2H), 1.67-1.50 (m, 8H), 1.29 (d, J = 6.8 Hz, 2H), 0.67-0.54 (m, 2H), 0.44-0.38 (m, 2H), 0.05-0.00 (m, 2H).
Step 2. 4-(cyclopropylmethyl)-4-(methoxymethyl)cyclohexan-1-one (506)
A 50 mL round bottom flask equipped with a stir bar was charged with 505 (930 mg, 3.87 mmol) and acetone (19.3 mL). HCI (12 M, 3.22 mL) was added in a single portion with a syringe. The reaction was stirred at RT for 5 h. The reaction was quenched with sat. NaHCO3 until pH 7 and extracted with EA (3 x 15 mL). The organic fractions were combined, washed with brine, dried over Na2SO4, filtered, and concentrated to yield title compound 506 as a yellow oil. (638 mg, 84% yield).
1H NMR: 400 MHz, CDCI3, δ (ppm): 3.36 (s, 2H), 3.32 (s, 3H), 2.31 (t, J = 6.9 Hz, 5H), 1.77 (q, J = 6.6 Hz, 5H), 1.38 (d, J = 7.4 Hz, 2H), 0.73-0.54 (m, 1 H), 0.49-0.42 (m, 2H), 0.17-0.15 (m, 2H).
Step 3. ethyl 2-amino-6-(cyclopropylmethyl)-6-(methoxymethyl)-4,5,6,7-tetrahydro-1- benzothiophene-3-carboxylate (507)
A 20 mL vial equipped with a stir bar was charged with 506 (638 mg, 3.25 mmol), ethyl 2- cyanoacetate (346 uL, 3.25 mmol), morpholine (308 uL, 3.58 mmol), sulfur (115 mg, 0.449 mmol) and ethanol (5.18 mL). The vial was sealed and heated at 60 °C overnight. The reaction was cooled to RT and concentrated to yield the crude product 507 as a red oil (1.21 g, quant yield). MS: 323.3 (calcd), 324.3 (M+H+, found).
Step 4. ethyl 6-(cyclopropylmethyl)-2-acetamido-6-(methoxymethyl)-4,5,6,7-tetrahydro-1- benzothiophene-3-carboxylate (508)
A 40 mL vial equipped with a stir bar was charged with 507 (1.2 mg, 3.71 mmol) and acetic acid (21.3 mL). The vial was stirred at room temperature and acetic anhydride (433 uL, 4.45 mmol) was added in a single portion. The reaction was stirred at 60 °C for 2 hours and cooled to RT. The reaction mixture was concentrated, and the residue was dissolved in 50 mL DCM, washed with saturated NaHCO3 solution (25 mL), water (25 mL) and brine (25 mL). The organic fraction was dried with Na2SO4, filtered, and concentrated to yield the title compound 508 as a red oil (1.17 g, 86% yield). MS: 365.2 (calcd), 366.2 (M+H+, found).
Step 5. ethyl 6-(cyclopropylmethyl)-2-acetamido-6-(methoxymethyl)-7-oxo-4, 5,6,7- tetrahydro-1-benzothiophene-3-carboxylate (509)
A 20 mL vial equipped with a stir bar was charged with 508 (500 mg, 1.37 mmol), ceric sulfate (3.92 g, 11.8 mmol), acetic acid (4.51 mL) and deionized water (4.51 mL). The mixture was sonicated then stirred vigorously at RT for 18 hours. The mixture was diluted with deionized water (5 mL) and EA (5 mL). The aqueous phase was extracted with EA (3 x 10 mL). The organic fractions were combined and washed with 1 N NaOH (10 mL), water (10 mL) and brine (10 mL). The organic fraction was dried with Na2SO4, filtered, and concentrated to yield the title compound 509 as a yellow oil (320 mg, 62% yield). MS: 379.1 (calcd), 380.2 (M+H+, found).
Step 6. 2-amino-6-(cyclopropylmethyl)-6-(methoxymethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (349)
A 500 mL round bottom equipped with a stir bar was charged with 509 (320 mg, 0.843 mmol), deionized water (102 mL), and methanol (102 mL). Lithium hydroxide monohydrate (177 mg, 4.22 mmol) was added in a single portion. A reflux condenser was affixed to the flask and the reaction was heated at 80 °C for 18 hours. The reaction was cooled to RT and methanol was removed by rotary evaporation. The mixture was acidified by addition of 1 M HCI solution and extracted with EA (3 x 50 mL). The organic fractions were combined, dried with Na2SO4, filtered, and concentrated to yield the title compound 349 as a yellow oil. The crude material was purified by Waters Prep HPLC-MS. XSELECT CSH C185 pm 30 x 75 mm Column (Eluent A: Acetonitrile, Eluent B: H2O + 0.1% Formic Acid) to yield the title compound as a white solid (3.94 mg, 1% yield).
1H NMR: 500 MHz, DMSO-d6, δ (ppm): 8.24 (s, 2H), 3.61 (d, J = 8.9 Hz, 1 H), 3.36 (d, J = 8.9 Hz, 2H), 3.22 (s, 3H), 3.06 (dt, J = 18.7, 5.3 Hz, 2H), 2.9-2.86 (m, 2H), 2.19-2.00 (m, 2H), 1.50 (dd, J = 14.2, 6.6 Hz, 1 H), 1.44-1.42 (m, 1H), 1.36 (dd, J = 14.2, 6.9 Hz, 1H), 0.65-0.57 (m, 1 H), 0.41-0.35 (m, 2H), 0.04-0.10 (m, 2H). MS: 309.1 (calcd), 310.1 (M+H+, found).
Example 252 2-Amino-6-(cyclopropylmethyl)-6-(methoxymethyl)-7 -oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (342)
Figure imgf000295_0001
342: Example 252
To a 50 mL round bottom flask equipped with a stir bar was added 349 (124 mg, 0.401 mmol), DMF (4.43 mL), HATU (229 mg, 0.601 mmol), DIPEA (140 uL, 0.802 mmol) and NH4CI (429 mg, 8.02 mmol). The flask was sealed with a septum and sparged with a balloon of argon for 10 mins. Ammonia in THF (0.4 M solution, 20.0 mL, 8.02 mmol) was added to the reaction by syringe. The reaction was stirred at RT for 18 hours with an argon balloon. The reaction was quenched by addition of 50 mL of saturated NH4CI solution and extracted with EA (3 X 50 mL). The EA fractions were combined and washed with brine (7 x 10 mL), dried with Na2SO4, filtered, and concentrated to yield title compound as a brown residue. The crude material was purified by Waters Prep HPLC-MS. XSELECT CSH C18 5 μm 30 x 75 mm Column (Eluent A: Acetonitrile, Eluent B: H2O + 0.1% Formic Acid) to yield the title compound 342 as a white solid (2.09 mg, 1% yield).
1H NMR: 500 MHz, DMSO-d6, δ (ppm): 7.99 (s, 2H), 3.61 (d, J = 8.9 Hz, 1 H), 3.36 (d, J = 8.9 Hz, 1 H), 3.22 (s, 3H), 3.12-2.80 (m, 2H), 2.25-1.96 (m, 2H), 1.52-1.35 (m, 2H), 0.64-0.54 (m, 1 H), 0.41-0.34 (m, 2H), 0.07-0.11 (m, 2H). MS: 308.1 (calcd), 309.1 (M+H+, found).
Example 253 2-Amino-6-cyano-6-(2-cyclopropylethyl)-7 -oxo-4, 5,6, 7-tetrahydrobenzo[b]thiophene-3- carboxylic acid (511)
Scheme 117
Figure imgf000296_0001
Step 1. 8-(2-cyclopropylethyl)-1 ,4-dioxa-8-spiro[4.51decanecarbonitrile (510)
A dry 100 mL round bottom flask equipped with a stir bar was charged with 1 ,4- dioxaspiro[4.5]decane-8-carbonitrile (1.80 g, 10.8 mmol) and 50 mL of dry THF. The solution was sparged with argon for 10 minutes with an argon balloon and cooled to -78 °C. Lithium diisopropylamide 1 M solution in THF/heptanes (12.0 mL, 12.0 mmol) was added dropwise to the flask and the reaction was stirred at -78 °C for 1 hour. A degassed solution of 1-(2- bromoethyl)cyclopropane (1.79 g, 12.0 mmol) in 10 mL anhydrous THF was added to the flask by syringe and the reaction was stirred at RT overnight. The reaction was quenched with 20 mL saturated NH4CI solution and extracted with EA (3x20 mL). The organic fractions were combined, dried over Na2SO4, filtered and concentrated to yield the title compound 510 as a yellow solid (2.34 g, 83% yield).
1H NMR: 400 MHz, CDCI3, δ (ppm): 4.00-3.88 (m, 4H), 2.02-1.83 (m, 4H), 1.77-1.62 (m, 4H), 1.58 (t, J = 13.3, 2H), 1.42-1.34 (m, 2H). 0.72-0.61 (m, 1 H), 0.48-0.41 (m, 2H), 0.08-0.02 (m, 2H).
Step 2. 1-(2-cyclopropylethyl)-4-oxocyclohexanecarbonitrile (516) A 250 mL round bottom flask equipped with a stir bar was charged with 510 (2.34 g, 9.94 mmol) and acetone (49.7 mL). Aqueous HCI (16.6 mL, 199 mmol, 12 M) was added in a single portion. The reaction was stirred at RT for 18 hours. Saturated aqueous NaHCO3 (400 mL) was added. The product was extracted with EA (3 x 200 mL), washed with brine, dried with Na2SO4, filtered and concentrated. The crude material was purified by silica gel chromatography (eluent 0-50% ethyl acetate in heptanes) to yield the title compound 516 as a white solid (746 mg, 39% yield).
1H NMR: 400 MHz, CDCI3, δ (ppm): 2.69 (ddd, J = 20.1 , 10.2, 5.5 Hz, 2H), 2.43 (d, J = 15.8 Hz, 2H), 2.38-2.23 (m, 2H), 1.86-1.61 (m, 4H), 1.52-1.38 (m, 2H), 0.78-0.62 (m, 1 H), 0.55- 0.40 (m, 2H), 0.17-0.01 (m, 2H).
Step 3. ethyl 2-amino-6-cyano-6-(2-cyclopropylethyl)-4,5,6,7-tetrahydro-1-thia-3- indenecarboxylate (517)
A 20 mL vial equipped with a stir bar was charged with 516 (746 mg, 3.9 mmol), ethyl 2- cyanoacetate (415 uL, 3.9 mmol), morpholine (370 uL, 4.29 mmol), sulfur (138 mg, 538 umol) and ethanol (6.22 mL). The vial was sealed and heated at 60 °C for 18 hours. The reaction was cooled to RT and concentrated. The crude material was purified by silica gel chromatography (eluent 0-60% ethyl acetate in heptanes) to yield the title compound 517 as a yellow solid (924 mg, 74% yield).
1H NMR: 400 MHz, CDCI3, δ (ppm): 4.26 (q, J = 7.1 , 2H), 2.99-2.82 (m, 2H), 2.54 (d, J = 16.0 Hz, 1H), 2.2-2.07 (m, 1 H), 1.92-1.62 (m, 4H), 1.88-1.64 (m, 4H), 1.53-1.40 (m, 3H), 1.34 (t, J = 7.1 , 3H), 0.79-0.60 (m, 1 H), 0.58-0.33 (m, 2H), 0.08 (d, J = 4.6 Hz, 2H).
Step 4. ethyl 2-acetylamino-6-cyano-6-(2-cyclopropylethyl)-4,5,6,7-tetrahydro-1-thia-3- indenecarboxylate (518)
A 40 mL vial equipped with a stir bar was charged with 517 (924 mg, 2.90 mmol) and acetic acid (16.7 mL). Acetic anhydride (329 uL, 3.48 mmol) was added in a single portion by syringe and the reaction was stirred at 60 °C for 1 hour. The reaction was cooled to RT and concentrated. The crude residue was dissolved in DCM (50 mL), washed with aq. sat. NaHCO3 (10 mL), water (10 mL) and brine (10 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to yield the title compound as an orange residue (963 mg, 92% yield).
1H NMR: 400 MHz, CDCI3, δ (ppm): 11.27 (s, 1 H), 4.34 (q, J = 7.2 Hz, 2H), 3.13-2.96 (m, 3H), 2.65 (d, J = 16.1 Hz, 1 H), 2.26 (s, 3H), 2.21-2.12 (m, 1 H), 1.87-1.67 (m, 3H), 1.51-1.43 (m, 2H), 1.39 (t, J = 7.1 , 3H), 0.70 (d, J = 7.6 Hz, 1 H), 0.47 (d, J = 7.9 Hz, 2H), 0.09 (d, J = 5.0 Hz, 2H). MS: 360.1 (calcd), 361.2 (M+H+, found).
Step 5. ethyl 2-acetylamino-6-cyano-6-(2-cyclopropylethyl)-7-oxo-4,5,6,7-tetrahydro-1- thia-3-indenecarboxylate (525)
To a 50 mL round bottom equipped with a stir bar was added 518 (963 mg, 2.67 umol), acetic acid (8.82 mL) and water (8.82 uL). Cerium (IV) sulfate (7.67 mg, 23.1 mmol) was added in a single portion and the reaction was stirred vigorously at RT for 18 hours. EA (50 mL) and water (50 mL) were added and the product was extracted to EA (3 x 50 mL). The organic fractions were combined and washed with 1 M NaOH (50 mL), water (50 mL) and brine (50 mL) and dried over Na2SC>4, filtered and concentrated to yield the title compound 525 as an orange residue (767 mg, 76% yield).
1H NMR: 400 MHz, CDCI3, δ (ppm): 11.58 (s, 1 H), 4.40 (qd, J = 7.1 , 1.9 Hz, 2H), 3.38- 3.09 (m, 2H), 2.58-2.41 (m, 1H), 2.34 (s, 3H), 2.31-2.13 (m, 2H), 1.94-1.85 (m, 1 H), 1.50-1.36 (m, 5H), 0.81-0.61 (m, 1 H), 0.60-0.31 (m, 2H), 0.19-0.05 (m, 2H). MS: 374.1 (calcd), 375.1 (M+H+, found).
Step 6. 2-amino-6-cyano-6-(2-cyclopropylethyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (511)
A 100 mL round bottom equipped with a stir bar was charged with 525 (100 mg, 267 umol), deionized water (32.3 mL), and methanol (32.3 mL). Lithium hydroxide monohydrate (56 mg, 1.34 mmol) was added in a single portion. A reflux condenser was affixed to the flask and the reaction was heated at 80 °C for 18 hours. The reaction was cooled to RT and aqueous 1 M HCI was added. The product was extracted with EA (3 x 50 mL), washed with brine (20 mL), dried over Na2SC>4, filtered, and concentrated. The crude material was purified by C18 reverse phase chromatography (eluent 0-100% acetonitrile in water) to yield the title compound 511 as an off white solid (1.16 mg, 1% yield).
1H NMR: 500 MHz, DMSO-d6, δ (ppm): 8.49 (br s, 1 H), 3.06 (t, J = 6.1 Hz, 2H), 2.45-2.35 (m, 1 H), 2.30-2.20 (m, 1H), 2.04-1.95 (m, 1 H), 1.89-1.81 (m, 2H), 1.90-1.81 (m, 2H), 1.44-1.24 (m, 3H), 0.77-0.66 (m, 3H), 0.40 (dd, J = 8.0, 1.7 Hz, 2H), 0.19-0.09 (m, 2H). MS: 304.1 (calcd), 305.1 (M+H+, found).
Example 254 2-Amino-6-cyano-6-(2-cyclopropylethyl)-7 -oxo-4, 5,6, 7-tetrahydrobenzo[b]thiophene-3- carboxamide (512)
Figure imgf000298_0001
512: Example 254
To a 50 mL round bottom flask equipped with a stir bar was added 511 (96.2 mg, 316 umol), DMF (3.49 mL), HATU (180 mg, 474 umol), DIPEA (110 uL, 632 umol) and ammonium chloride (338 mg, 6.32 mmol). The flask was sealed with a septum and sparged with a balloon of argon for 10 mins. Ammonia in THF (0.4 M solution, 15.8 mL, 6.32 mmol) was added to the reaction by syringe. The reaction was stirred at RT for 18 hours with an argon balloon. The reaction was quenched by addition of 50 mL of saturated NH4CI solution and extracted with EA (3 x 50 mL). The EA fractions were combined, washed with brine (10 mL), dried with Na2SO4, filtered and concentrated. The crude material was purified with reverse phase C18 chromatography (eluent 0-100% acetonitrile in water) to yield the title compound 512 as a pale yellow solid (1.78 mg, 2% yield).
1H NMR: 500 MHz, DMSO-d6, δ (ppm): 8.24 (s, 2H), 3.20-2.92 (m, 2H), 2.69 (s, 1 H), 2.43- 2.34 (m, 2H), 2.29-2.18 (m, 1 H), 2.05-1.91 (m, 1 H), 1.91-1.81 (m, 1 H), 1.40-1.27 (m, 2H), 0.77- 0.66 (m, 1 H), 0.46-0.35 (m, 2H), 0.14-0.02 (m, 2H). MS: 303.1 (calcd), 304.1 (M+H+, found).
Example 255
2-Amino-6-cyano-6-((difluoromethoxy)methyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (513)
Scheme 118
Figure imgf000299_0001
Step 1. ethyl 8-cyano-1 ,4-dioxa-8-spiro[4.51decanecarboxylate (526)
To a dry 250 mL round bottom flask equipped with a stir bar under argon was charged with ethyl 1 ,4-dioxaspiro[4.5]decane-8-carboxylate (3.00 g, 14.0 mmol) and anhydrous THF (60 mL). The flask was cooled to -78 °C and LDA (15.4 mL, 15.4 mmol, 1 M in THF/hexanes) was added slowly. The reaction mixture was stirred for 1 hour at -78 °C and a degassed suspension of 4-methylbenzene-1 -sulfonyl cyanide (2.79 g, 15.4 mmol) in anhydrous THF (10.0 mL) was added slowly by syringe. The reaction was stirred at RT for 18 hours. The reaction mixture was quenched by addition of saturated NH4CI solution (50 mL) and extracted with EA (3 x 50 mL). The organic fractions were combined, washed with brine, dried over Na3SO4, filtered and concentrated. The crude material was purified by silica gel chromatography with eluent 0-100% ethyl acetate in heptanes to yield the title compound 526 as a white solid (2.31 g, 69% yield).
1H NMR: 400 MHz, CDCI3, δ (ppm): 4.27 (q, J = 7.1 Hz, 2H), 4.09-3.79 (m, 4H), 2.17 (dd, J = 10.8, 4.3 Hz, 4H), 1.98-1.86 (m, 2H), 1.86-1.73 (m, 2H), 1.32 (t, J = 7.2 Hz, 3H).
Step 2. 8-(hydroxymethyl)-1 ,4-dioxa-8-spiro[4.51decanecarbonitrile (419)
To a 250 mL round bottom flask equipped with a stir bar was added 526 (2.31 g, 9.65 mmol) and methanol (48.3 mL). The flask was cooled to 0 °C and sodium borohydride (1.46 mg, 38.6 mmol) was added in a single portion. The reaction was stirred at RT for 2.5 hours then concentrated. DCM (50 mL) was added, and the solution was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to yield the title compound 419 as a white solid (1.61 g, 85% yield).
1H NMR: 400 MHz, CDCI3, δ (ppm): 4.00-3.90 (m, 4H), 3.66 (s, 2H), 2.08-2.01 (m, 2H), 1.97-1.84 (m, 2H), 1.85-1.74 (m, 2H), 1.63 (td, J = 13.4, 3.8 Hz, 2H), 1.55 (s, 1H).
Step 3. 8-(difluoromethoxymethyl)-1 ,4-dioxa-8-spiro[4.51decanecarbonitrile (484)
To a 25 mL round bottom flask equipped with a stir bar was added 419 (1.61 g, 8.16 mmol), potassium acetate (4.81 g, 49 mmol), DCM (4.89 mL), water (4.89 mL) and (bromodifluoromethyl)trimethylsilane (3.81 mL, 24.5 mmol). The reaction was stirred at RT for 22 hours. The reaction was diluted with 20 mL DCM, dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel chromatography (eluent 0-70% ethyl acetate in heptanes) to yield the title compound 484 as a white solid (668 mg, 33% yield).
1H NMR: 400 MHz, CDCI3, δ (ppm): 6.29 (t, J = 73 Hz, 1 H), 4.01-3.90 (m, 4H), 3.86 (s, 2H), 2.08-2.01 (m, 2H), 1.93 (td, J = 13.7, 4.0 Hz, 3H), 1.86-1.75 (m, 2H), 1.69 (td, J = 13.3, 3.8 Hz, 2H).
Step 4. 1-(difluoromethoxymethyl)-4-oxocyclohexanecarbonitrile (527)
To a 1 dram vial equipped with a stir bar was charged with 484 (668 mg, 2.7 mmol) and acetone (13.5 mL). Aqueous HCI (2.25 mL, 12 M) was added in a single portion via syringe. The reaction was stirred at RT for 5 hours. Saturated NaHCO3 (100 mL) was added, and extracted with EA (3x20 mL). The organic fractions were combined, washed with brine, dried over Na2SO4, filtered, and concentrated to yield the title compound 527 (535 mg, 81% yield).
1H NMR: 400 MHz, CDCI3, δ (ppm): δ 6.32 (t, J = 72 Hz, 1 H), 3.95 (s, 2H), 2.72 (td, J = 15.0, 4.0 Hz, 2H), 2.51 (d, J = 15.0 Hz, 2H), 2.38 (d, J = 14.3, 2H), 1.83 (td, J = 13.8, 4.3 Hz, 2H).
Step 5. ethyl 2-amino-6-cyano-6-(difluoromethoxymethyl)-4,5,6,7-tetrahydro-1-thia-3- indenecarboxylate (528)
A 20 mL vial equipped with a stir bar was charged with 527 (170 mg, 837 umol), ethyl 2- cyanoacetate (89 uL, 837 umol), morpholine (79.4 uL, 920 umol), sulfur (29.6 mg, 837 umol) and ethanol (1 .33 mL). The vial was heated at 60 °C for 18 hours. The reaction was cooled to RT and concentrated. The crude material was purified by silica gel chromatography (eluent 0-100% ethyl acetate in heptanes) to yield the title compound 528 as a yellow oil (240 mg, 70% yield).
1H NMR: 400 MHz, CDCI3, δ (ppm): 06.31 (t, J = 73.0, 1 H), 4.28 (q, J = 7.1 Hz, 2H), 4.07- 3.90 (m, 2H), 3.04-2.91 (m, 2H), 2.71 (dt, J = 16.4 Hz, J = 2.0 Hz, 1 H), 2.22-2.14 (m, 1H), 2.09- 2.00 (m, 1 H), 1.97-1.64 (m, 3H), 1.35 (m, J = 7.1 Hz, 3H). LC-MS: 331.1 m/z (M+H), retention time 1.17 min.
Step 6 ethyl 2-acetylamino-6-cyano-6-(difluoromethoxymethyl)-4,5,6,7-tetrahydro-1-thia- 3-indenecarboxylate (529)
A 1 dram vial equipped with a stir bar was charged with ethyl 2-amino-6-cyano-6- (difluoromethoxymethyl)-4,5,6,7-tetrahydro-1-thia-3-indenecarboxylate (240 mg, 726 umol) and acetic acid (4.18 mL). Acetic anhydride (82.4 uL, 872 umol) was added in a single portion by syringe and the reaction was stirred at 60 °C for 2 hours. The reaction was cooled to RT and concentrated. The crude material was dissolved in DCM (5ml) and washed with sat. NaHCO3 solution (3 mL). The organic layer was dried over Na2SO4 and concentrated to yield the title compound 529 as a yellow solid (109 mg, 40% yield).
1H NMR: 400 MHz, CDCI3, δ (ppm): 11.28 (s, 1 H), 6.31 (t, J = 73.0 Hz, 1 H), 4.35 (q, J = 7.1 Hz, 2H), 4.05-3.90 (m, 3H), 3.16-3.10 (m, 1 H), 3.08-3.00 (m, 1 H), 2.85-2.78 (m, 1 H), 2.27 (s, 3H), 1.98-1.65 (m, 2H), 1.40 (t, J = 7.1 Hz, 3H). MS: 372 (calcd), 373 (M+H+, found).
Step 7. ethyl 2-acetylamino-6-cyano-6-(difluoromethoxymethyl)-7-oxo-4,5,6,7-tetrahydro- 1-thia-3-indenecarboxylate (530)
529 (109 mg, 1 equiv.), acetic acid (966 uL) and water (966 uL) were added to a 2 dram vial equipped with a stir bar. Cerium (IV) sulfate (840 mg, 2.53 mmol) was added in a single portion and the reaction was stirred vigorously at RT for 18 hours. EA (2 mL) and water (2 mL) were added, and the product was extracted to EA (3 x 10 mL). The organic fractions were combined and washed with 1 M NaOH (10 mL), water (10 mL) and brine (10 mL) and dried over Na2SO4, filtered and concentrated to yield the title compound 530 as a yellow residue (82.2 mg, 73% yield).
1H NMR: 400 MHz, CDCI3, δ (ppm): 11 .63 (s, 1 H), 6.31 (t, J = 73.3 Hz, 1 H), 4.47-4.37 (m, 4H), 3.43 (dt, J = 18.9, 4.4 Hz, 1 H), 3.32-3.21 (m, 1 H), 2.62 (dt, J = 13.9, 4.3 Hz, 1 H), 2.40-2.32 (m, 1 H), 2.35 (s, 3H), 1.45 (t, J = 7.1 Hz, 4H). MS: 386.1 (calcd), 387.0 (M+H+, found).
Step 8. 2-amino-6-cyano-6-((difluoromethoxy)methyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (513)
530 (82.2 mg, 1 equiv.), methanol (25.7 mL) and water (25.7 mL) were added to a 100 mL round bottom flask equipped with a stir bar. Lithium hydroxide monohydrate (44.6 mg, 1 .06 mmol) was added in a single portion. A reflux condenser was affixed to the flask and the reaction was heated at 80 °C for 18 hours. The reaction was cooled to RT and concentrated. Aqueous 1 M HCI was added. The product was extracted to EA (3x 5 mL), washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified by preparative HPLC to yield the title compound as a white solid (8.56 mg, 13% yield).
1H NMR: 500 MHz, DMSO-d6, δ (ppm): 8.69 (s, 1 H), 6.79 (t, J = 74.7 Hz, 1H), 4.31 (d, J = 10.1 Hz, 1H), 4.22 (d, J = 10.2 Hz, 1 H), 3.36-3.32 (m, 1 H), 3.02-2.94 (m, 1 H), 2.52-2.51 (m, 2H), 2.48-2.42 (m, 1 H), 2.34-2.27 (m, 1 H). LC-MS: retention time 3.47 min, m/z 317.033 (M+H). MS: 316.0 (calcd), 317.0 (M+H+, found).
Example 256 2-Amino-6-cyano-6-((difluoromethoxy)methyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (514)
Figure imgf000302_0001
514: Example 256
To a 50 mL round bottom flask equipped with a stir bar was added 513 (40.6 mg, 128 umol), DMF (1.42 mL), HATU (73.3 mg, 193 umol), DIPEA (44.7 uL, 257 umol) and ammonium chloride (137 mg, 2.57 mmol). The flask was sealed and sparged with a balloon of argon for 10 mins. Ammonia in THF (0.4 M solution, 6.42 mL, 2.57 mmol) was added to the reaction by syringe. The reaction was stirred at RT for 18 hours under an atmosphere of argon. The reaction was quenched by addition of 50 mL of saturated NH4CI solution and extracted with EA (3 x 50 mL), washed with brine (10 mL), dried with Na2SO4, filtered and concentrated. The crude product was purified by RediSep Prep C18 column 20 x 150 mm 100 A 5 pm; gradient 10% ACN in water 0- 1 .0 min, 10-100% ACN in water 1 .0-12.0 min, 100% ACN 12.0-14.0 min and dried by lyophilization to yield the title compound 514 as a yellow solid (2.44 mg, 6% yield).
1H NMR: 500 MHz, DMSO-d6, δ (ppm): 8.35 (s, 2H), 6.80 (t, J = 74.6 Hz, 1H), 4.33 (d, J = 10.1 Hz, 1 H), 4.22 (d, J = 10.1 Hz, 1 H), 3.13 (s, 2H), 2.48-2.42 (m, 3H), 2.34-2.27 (m, 1 H). MS: 315.0 (calcd), 316.0 (M+H+, found).
Example 257 2-Amino-6-cyano-6-(4-fluorophenyl)-7 -oxo-4, 5,6, 7-tetrahydrobenzo[b]thiophene-3- carboxamide (515)
Scheme 119
Figure imgf000303_0001
515: Example 257
Step 1. Ethyl 2-amino-6-cyano-6-(4-fluorophenyl)-4,5,6,7-tetrahydro-1-benzothiophene- 3-carboxylate (532)
A 4 mL dram vial equipped with a stir bar was charged with 1-(p-fluorophenyl)-4- oxocyclohexanecarbonitrile (1 g, 4.6 mmol), ethyl cyanoacetate (0.49 mL, 4.6 mmol), elemental sulfur (163 mg, 0.428 mmol), morpholine (0.438 g, 5.07 mmol) and ethanol (7 mL). The reaction vessel was sealed and heated to 60 °C for 2 h, cooled to RT, filtered and the crystals washed with diethyl ether (2 x 4 mL), to afford the title compound 532 as a white solid (1 .34 g, 85% yield).
1H NMR: 500 MHz, CDCI3, δ (ppm): 7.55-7.45 (m, 2H), 7.17-7.06 (m, 2H), 5.63 (s, 2H), 4.30 (q, J = 7.1 Hz, 2H), 3.22-2.94 (m, 4H), 2.43-2.31 (m, 1 H), 2.31-2.13 (m, 1 H), 1.40 (t, J = 7.1 Hz, 3H). MS: 344.1 (calcd), 345.1 (M+H+, found).
Step 2. Ethyl 6-cyano-6-(4-fluorophenyl)-2-acetamido-7-oxo-4,5,6,7-tetrahydro-1- benzothiophene-3-carboxylate (533)
A 100 mL round bottom flask with stir bar was charged with 532 (1 g, 2.9 mmol) and acetic acid (14.5 mL). Acetic anhydride (329 uL, 3.48 mmol) was added and the reaction mixture heated to 60 °C for 3h. The reaction was cooled to RT, and water (15 mL) and 1 ,4-dioxane (15 mL) were added, followed by Ce(IV) sulfate (8.18 g, 24.5 mmol), and the suspension was stirred at RT overnight. The reaction mixture was filtered, washed with EA, and the filtrate was diluted with water (100 mL), extracted with EA (2 x 100 mL), and the combined organic extracts were washed with 1N NaOH (70 mL), water (70 mL) and brine (70 mL), dried over Na2SO4, filtered, and concentrated to afford the title compound 533 as a white solid (259 mg, 22% yield). 1H NMR: 500 MHz, CDCI3, δ (ppm): 11.62 (s, 1 H), 7.50-7.32 (m, 2H), 7.10 (t, J = 8.6 Hz, 2H), 4.40 (q, J = 7.2 Hz, 2H), 3.38 (ddd, J = 18.8, 7.5, 5.0 Hz, 1 H), 3.21-3.01 (m, 1 H), 2.75 (td, J = 7.2, 4.8 Hz, 2H), 2.35 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H). MS: 400.1 (calcd), 401.0 (M+H+, found).
Step 3. 2-amino-6-cyano-6-(4-fluorophenyl)-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene- 3-carboxylic acid (534)
A 500 mL round bottom flask with stir bar was charged with 533 (259 mg, 0.647 mmol), lithium hydroxide monohydrate (136 mg, 3.23 mmol), methanol (80 mL), and water (80 mL). A reflux condenser was affixed to the flask and the reaction was stirred at 80 °C for 18 hours. The reaction was cooled to RT, concentrated to approximately half-volume, acidified by addition of 6 M HCI solution and extracted with EA. The organic fractions were combined, dried over Na2SO4, filtered and concentrated. The residue was washed with Et20. The washings were concentrated to afford crude title compound as a white solid (30 mg, 14% yield) MS: 330.1 (calcd), 331.0 (M+H+, found).
Step 4. 2-amino-6-cyano-6-(4-fluorophenyl)-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene- 3-carboxamide (515)
A 1-dram vial equipped with a stir bar was charged with 534 (30 mg, 90.8 mmol), ammonium chloride (146 mg, 2.72 mmol) and DMF (0.725 mL). HATU (51.8 mg, 0.136 mmol) was added, followed by N-ethylbis(isopropyl)amine (70.4 mg, 6 eq., 0.545 mmol), and the reaction mixture was stirred at RT for 2 h. The crude reaction was purified by preparative HPLC to yield the title compound 515 as an off-white solid (2.74 mg, 9%).
1H NMR: 500 MHz, DMSO-d6, δ (ppm): 8.38 (s, 2H), 7.53-7.39 (m, 2H), 7.35-7.23 (m, 2H), 7.11 (s, 2H), 3.10 (ddd, J = 18.6, 6.9, 4.6 Hz, 1 H), 2.92-2.75 (m, 2H), 2.71-2.59 (m, 1 H). MS: 329.0 (calcd), 330.1 (M+H+, found).
Example 258 2-Amino-6-(cyanomethyl)-6-((difluoromethoxy)methyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (519)
Scheme 120
Figure imgf000305_0001
Step 1. ethyl 8-(cyanomethyl)-1 ,4-dioxa-8-spiro[4.51decanecarboxylate (535)
LDA (1 M in THF, 25.7 mL) was added to a solution of ethyl 1 ,4-dioxaspiro[4.5]decane-8- carboxylate (5.00 g, 23.3 mmol) in THF (50.0 mL) at -78 °C, and the mixture was stirred at -78°C for 1 h. A solution of 2-bromoacetonitrile (1.95 mL, 28.0 mmol) and DMPU (1 .41 mL, 11 .7 mmol) in THF (10.0 mL) was added, and the resulting mixture was slowly warmed to RT and stirred for 16 h. The mixture was diluted with sat. aq. NH4CI (200 mL), and the aqueous phase was extracted with EA (2 x 400 mL). The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of heptane and EA (5-100%) to provide the title compound 535 as a yellow oil (4.21 g, 71% yield).
1H NMR (400 MHz, CDCI3) δ (ppm): 4.24 (q, J = 7.1 Hz, 2H), 4.00- 3.89 (m, 4H), 2.58 (s, 2H), 2.24 (qd, J = 4.9, 3.6 Hz, 2H), 1.78-1.62 (m, 6H), 1.30 (t, J = 7.1 Hz, 3H).
Step 2. {8-(hydroxymethyl)-1 ,4-dioxa-8-spiro[4.51decyl}acetonitrile (536)
NaBH4 (3.77 g, 99.7 mmol) was added to a solution of 535 (4.21 g, 16.6 mmol) in MeOH (40.0 mL), and the mixture was stirred at 50 °C for 30 min. The mixture was diluted with water
(200 mL), and the aqueous phase was extracted with EA (2 x 200 mL). The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of heptane and EA (5-100%) to provide the title compound
536 as a colorless solid (1 .90 g, 59% yield).
1H NMR (400 MHz, CDCI3) δ (ppm): 3.94 (d, J = 1.4 Hz,4H), 3.62 (s, 2H), 2.48 (s, 2H), 1.75-1.55 (m, 9H).
Step 3. 2-{8-[(difluoromethoxy)methyl1-1 ,4-dioxaspiro[4.51decan-8-yl)acetonitrile (537)
A solution of KOAc (5.30 g, 54.0 mmol) in water (7.60 mL) was added to a solution of (bromodifluoromethyl)trimethylsilane (4.20 mL, 27.0 mmol) and 536 (1.90 g, 8.99 mmol) in DCM (7.60 mL), and the mixture was stirred at RT for 20 h. The mixture was diluted with water (200 mL), and the aqueous phase was extracted with DCM (2 x 200 mL). The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of heptane and EA (5-100%) to provide the title compound
537 as a colorless solid (1.43 g, 61% yield).
1H NMR (400 MHz, CDCI3) δ (ppm): 6.24 (t, J = 74.1 Hz, 1 H), 3.95 (s, 4H), 3.82 (s, 2H), 2.46 (s, 2H), 1.78-1.56 (m, 8H). 19F NMR (376 MHz, CDCI3) δ (ppm): -84.77 (d, J = 73.9 Hz).
Step 4. 2-{1-[(difluoromethoxy)methyl1-4-oxocyclohexyl}acetonitrile (538)
Aq. HCI (37%, 1.66 mL, 54.7 mmol) was added to a solution of 537 (1.43 g, 5.47 mmol) in acetone (25.0 mL), and the mixture was stirred at RT for 16 h. The mixture was diluted with sat. aq. NaHCO3 (200 mL), and the aqueous phase was extracted with EA (2 x 200 mL). The organic phase was washed with brine, dried over Na2SO4 and concentrated to provide the title compound 538 as a colorless oil (80% pure, 5.20 g, 80% yield).
1H NMR (500 MHz, CDCI3) δ (ppm): 6.30 (t, J = 73.5 Hz, 1 H), 3.96 (s, 2H), 2.58 (s, 2H), 2.44-2.32 (m, 4H), 2.02-1.87 (m, 4H).
Step 5. ethyl 2-amino-6-(cyanomethyl)-6-[(difluoromethoxy)methyl1-4,5,6,7-tetrahydro-1- benzothiophene-3-carboxylate (539)
Ethyl 2-cyanoacetate (0.470 mL, 4.42 mmol) was added to a mixture of 538 (80% pure, 1.20 g, 4.42 mmol), sulfur (0.138 g, 0.610 mmol) and morpholine (0.419 mL, 4.86 mmol) in EtOH (8.00 mL), and the mixture was stirred at 60 °C for 4 h. The mixture was concentrated and the residue was purified by silica gel chromatography eluting with a gradient of heptane and EA (5- 100%) to provide the title compound 539 as a yellow solid (810 mg, 53% yield). MS: 344.4 (calcd), 345.1 (M+H+, found).
Step 6. ethyl 6-(cyanomethyl)-6-[(difluoromethoxy)methyl1-2-acetamido-4, 5,6,7- tetrahydro-1-benzothiophene-3-carboxylate (540)
Acetic anhydride (275 uL, 2.82 mmol) was added to a mixture of 539 (810 mg, 2.35 mmol) in AcOH (8.50 mL), and the mixture was stirred at 60 °C for 1 h. The mixture was concentrated in vacuo and the residue was diluted with sat. aq. NaHCO3 (50 mL). The aqueous phase was extracted with EA (2 x 50 mL), and the organic phase was dried over Na2SO4 and concentrated to provide the title compound 540 as a yellow solid (751 mg, 82% yield). MS: 386.4 (calcd), 387.1 (M+H+, found).
Step 7. ethyl 6-(cyanomethyl)-6-[(difluoromethoxy)methyl]-2-acetamido-4,5,6,7- tetrahydro-1-benzothiophene-3-carboxylate (541)
Cerium(IV) sulfate (5.55 g, 16.7 mmol) was added to a mixture of ethyl 6-(cyanomethyl)- 6-[(difluoromethoxy)methyl]-2-acetamido-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (0.751 g, 1 .94 mmol) in water (7.00 mL) and acetic acid (7.00 mL), and the mixture was stirred at RT for 18 h. The mixture was diluted with water (100 mL), and the aqueous phase was extracted with EA (2 x 100 mL). The organic phase was washed with aq. NaOH (1 M, 100 mL), dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of heptane and EA (5-100%) to provide the title compound 541 as a colorless solid (454 mg, 58%).
1H NMR (400 MHz, CDCI3) δ 11.58 (s, 1 H), 6.24 (t, J = 73.3 Hz, 1 H), 4.41 (qd, J = 7.2, 1.3 Hz, 2H), 4.04 (dd, J = 58.8, 10.3 Hz, 2H), 3.35 - 3.25 (m, 1 H), 3.08 (ddd, J = 19.1 , 9.9, 5.2 Hz, 1 H), 2.87 - 2.75 (m, 2H), 2.47 - 2.24 (m, 5H), 1 .44 (t, J = 7.1 Hz, 3H). MS: 400.4 (calcd), 401.0 (M+H+, found).
Step 8. 2-amino-6-(cyanomethyl)-6-(difluoromethoxymethyl)-7-oxo-4,5,6,7-tetrahydro-1- thia-3-indenecarboxylic acid (519)
LiOH.H2O (21.0 mg, 0.499 mmol) was added to a mixture of ethyl 2-acetylamino-6- (cyanomethyl)-6-(difluoromethoxymethyl)-7-oxo-4,5,6,7-tetrahydro-1-thia-3-indenecarboxylate (40.0 mg, 0.0999 mmol) in water (10.0 mL) and methanol (10.0 mL), and the mixture was stirred in a sealed tube at 80°C for 5 h. The mixture was diluted with aq. HCI (1 M, 5 mL), and the aqueous phase was extracted with EA (2 x 10 mL), dried over Na2SO4 and concentrated. The residue was purified by C18 chromatography eluting with a gradient of H2O + 0.1% HCO2H and MeCN + 0.1% HCO2H (5-100%) followed by RediSep Prep C18 column 20 x 150 mm 100 A 5 pm (gradient 10% ACN in water 5-100%) to provide the title compound as a colorless solid (1 .35 mg, 4% yield).
1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.41 (br s, 1 H), 6.68 (t, J = 75.3 Hz, 1 H), 4.16- 3.82 (m, 2H), 3.20- 2.96 (m, 2H), 2.95- 2.75 (m, 2H), 2.24- 2.03 (m, 2H). MS: 330.3 (calcd), 331 .1 (M+H+, found).
Example 259 2-Amino-6-(cyanomethyl)-6-((difluoromethoxy)methyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (520)
Figure imgf000308_0001
520: Example 259
Ammonia (0.4 M in THF, 7.57 mL, 3.03 mmol) was added to a mixture of 2-amino-6-
(cyanomethyl)-6-(difluoromethoxymethyl)-7-oxo-4,5,6,7-tetrahydro-1-thia-3-indenecarboxylic acid (519) (50.0 mg, 0.151 mmol), HATU (86.3 mg, 0.227 mmol), DIPEA (52.7 uL, 0.303 mmol), ammonium chloride (162 mg, 3.03 mmol) in DMF (2.00 mL), and the mixture was stirred at RT for 2 h. The mixture was diluted with sat. aq. NaHCO3 (20 mL), and the aqueous phase was extracted with EA (2 x 30 mL). The organic phase was dried over Na2SO4 and concentrated. The residue was purified by C18 chromatography eluting with a gradient of MeCN in water + 0.1% formic acid
(5-100%), followed by C18 chromatography eluting with a gradient of MeCN in water + 0.1% formic acid (5-50%) to provide title compound (520) a light yellow solid (5.12 mg, 10%).
1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.16 (s, 2H), 7.02 (bs, 2H), 6.70 (t, J = 75.2 Hz, 1 H), 4.00 (dd, J = 59.8, 10.0 Hz, 2H), 3.15-2.88 (m, 2H), 2.96-2.75 (m, 2H), 2.25-2.04 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ (ppm): -82.05 - -83.93 (m). MS: 329.3 (calcd), 328.0 (M+H+, found).
Example 260 2-Amino-6-(cyclobutylmethyl)-6-((difluoromethoxy)methyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (524) Intermediate compound 522 (8-(Cyclobutylmethyl)-1,4-dioxaspiro[4.5]decan-8-yl)methanol (522)
Scheme 121
Figure imgf000308_0002
Step 1. 8-(Cyclobutylmethyl)-1 ,4-dioxa-8-spiro[4.51decanecarbaldehyde (521)
To a dry 100 mL round bottom flask equipped with a stir bar were added 8- (cyclobutylmethyl)-1 ,4-dioxa-8-spiro[4.5]decanecarbonitrile (41 , scheme 4) (558 mg, 2.37 mmol) and anhydrous toluene (13 mL). The reaction mixture was sparged with argon gas and cooled to -78 °C. DIBAL-H (3.89 mL, 3.89 mmol, 1 M in toluene) was then added dropwise and the resulting mixture was stirred at -78 °C for 2 hours. Subsequently, the reaction mixture was quenched with 1 mL of methanol at -78 °C. Saturated Rochelle's salt solution (50 mL) was added and the mixture was allowed to warm up to RT. The product was extracted with diethyl ether (3 x 50 mL). The organic fractions were combined, dried over Na2SO4, filtered and concentrated. The crude material was dissolved in THF (8.99 mL) and 2 N aq. HCI (593 uL, 1.19 mmol, 0.5 equiv.) was added. The mixture was stirred at RT for 20 minutes, then saturated aqueous NaHCO3 (20 mL) was added and the product was extracted with EA (3 x 25 mL), washed with brine (10 mL), dried over Na2SO4 and concentrated to yield title compound 521 as a pale yellow oil (425 mg, 75% yield). 1H NMR (400 MHz, CDCI3) δ (ppm): 9.43 (s, 1 H), 3.92 (s, 4H), 2.28 (sept, J = 8.0 Hz, 1 H), 2.09-1.88 (m, 4H), 1.87-1.43 (m, 12H).
Step 2. (8-(Cyclobutylmethyl)-1 ,4-dioxaspiro[4.51decan-8-yl)methanol (522)
To a 250 mL round bottom flask equipped with a stir bar was added 521 (425 mg, 1.78 mmol) and MeOH (8.9 ml). The resulting solution was cooled to 0 °C and NaBH4 (202 mg, 5.35 mmol) was added in a single portion. The reaction mixture was stirred at RT for 1.5 hours. The volatiles were then removed in vacuo, brine (20 mL) was added and the residue was extracted with EA (3 x 25 mL). The organic fractions were combined, dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel chromatography using eluent 0-100% EA in heptane to yield title compound 522 as a clear oil (134 mg, 31%). 1H NMR (400 MHz, CDCI3) δ (ppm): 4.02-3.86 (m, 4H), 3.45 (s, 2H), 2.41 (ddq, J = 14.4, 9.1 , 7.6 Hz, 1 H), 2.12-1.96 (m, 3H), 1.99-1.56 (m, 8H), 1.56-1.40 (m, 6H).
Intermediate compound 523 2-Amino-6-(cyclobutylmethyl)-6-((difluoromethoxy)methyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid (523)
Figure imgf000309_0001
Compound 523 was synthesized similarly to compound 347 (example 249, scheme 115), starting from intermediate compound 522 (scheme 121) instead of compound 115. MS: 359.2 (calcd), 360.2 (M+H+, found).
2-Amino-6-(cyclobutylmethyl)-6-((difluoromethoxy)methyl)-7-oxo-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (524)
Figure imgf000310_0001
524: Example 260
Compound 524 (example 260) was synthesized similarly to compound 238 (example 127, scheme 55) starting from intermediate compound 523 instead of compound 237.
1H NMR (500 MHz, CD3OD) δ (ppm): 6.35 (dd, J= 76.5, 75.2 Hz, 1 H), 4.14 (d, J = 9.5 Hz, 1 H), 3.79 (d, J = 9.6 Hz, 1 H), 3.23-2.91 (m, 2H), 2.46 (dt, J = 15.5, 8.0 Hz, 1 H), 2.29 (ddd, J = 13.8, 10.3, 5.4 Hz, 1 H), 2.15-1.93 (m, 3H), 1.93-1.81 (m, 1 H), 1.81-1.67 (m, 3H), 1.58 (p, J = 9.6 Hz, 1 H). 19F NMR (470 MHz, CD3OD) δ (ppm): -85.07, -85.41 , -85.61 , -85.96 (two overlapping doublets.). MS: 358.2 (calcd), 359.2 (M+H+, found).
Example 261
Protocol for the human acid-sensing channel 1a (hASICIa) assay
A human acid-sensing channel 1a (hASICIa) assay was developed to evaluate both the potential agonistic and antagonistic activity of compounds on human acid-sensing channel 1a (hASICIa) in a single run. hASICIa is generally activated in acidic conditions and leads to Ca2+ influx into the cell. Therefore, detection and quantification of the change in intracellular Ca2+ may be used as a measure of hASICIa activity or inhibition. In this assay, cells expressing hASICIa containing a Ca2+-specific fluorescent dye are first treated with a compound of interest at a neutral pH to evaluate the agonist effect of solely the compound on hASICI a in the absence of an acidic environment. Then the same cells, without washing, are subsequently treated with an acidic solution to determine the antagonistic effect of the compound on hASICIa activation caused by the acidic environment.
Briefly, black 384-well plates were first coated with 0.005% Polyethylenimine (PEI) (50 pl/well for 24 hours at 37°C) to fix the cells and avoid resuspension during the measurements and washed 4 times ddH2O before use. F9 cells (HEK293S) stably expressing hASICIa were resuspended in extracellular fluid buffer pH 7.4 (ECF 7.4; 140 mM NaCI, 5 mM KCI, 2 mM CaCI2, 2 mM MgCI2, 10 mM HEPES, and 10 mM glucose) and labelled with Fluo-8™ AM dye (4 pM final), which is fluorescent upon binding to Ca2+, according to the manufacturer’s protocol. Cells were then washed and resuspended in ECF 7.4, and plated (40,000 cells/well; 15 pl/well) in the PEI pre-coated black 384-well plate, centrifuged at 400 rpm for 1 minute, and incubated for 60 minutes at room temperature in the dark before addition of the test samples. Extracellular fluid buffer pH 5.85 (ECF 5.85; 140 mM NaCI, 5 mM KCI, 2 mM CaCI2, 2 mM MgCI2, 10 mM HEPES, and 10 mM glucose) is added to some wells (50 pl/well), which is used as a positive control for the agonist mode. 200 pM Benzamil is added to other wells (50 pl/well), which is used as a positive control for the antagonist mode. 100% DMSO is added to other wells, which is used as a baseline level of fluorescence.
Agonist mode ( 1st addition)
The agonist activity of the compound of interest is assessed first. Serial dilutions (e.g., 1 .2.2) prepared of the compounds to be tested are prepared in ECF 7.4 in duplicates at a 4X and are subsequently added to the cells (15pl/well) (effectively diluting the compounds to 2X final concentration) and incubated for 4 minutes inside an FDSS7000™ (Functional Drug Screening System; Hamamatsu) instrument (exposure: 200 ms (normal); excitation filter: 472 nm (+/- 30); emission filter (540 nm (+/- 40)) to measure the fluorescence (i.e., Ca2+ influx). Addition of the compounds is made at photo 11 (at 11 seconds). Data acquisition is performed for 70 seconds (70 photos x 1 sec)
Antagonist mode (2nd addition)
The antagonist activity of the compound of interest is then assessed. 30 pl ECF 5.85 each well is then added to the cells (effectively diluting the compounds to 1X final concentration) and measurements are taken for the next minute inside the FDSS7000. After addition of ECF 5.85, the resulting final pH of the well is roughly 6.5. Addition of ECF 5.85 is made at photo 241 (at 241 seconds). Data acquisition is performed for 60 seconds (60 photos x 1 sec).
After the readings, three sets of data (outputs) are exported as text file format (.TXT) with the FDSS7000 hASICIa assay protocol:
Output 1 (.TXT): Is the Max and Min FU counts for the agonist mode (after the addition of compounds (between 11 and 80 seconds)
Output 2 (_2.TXT): Is the Max and Min FU counts for the antagonist mode (after the addition of ECF pH 5.85 (between 241 and 300 seconds))
Output 3 (_3.TXT): Is the maximum baseline value (maximum FU value just prior the addition of ECF pH 5.85 (between intervals 235-240 seconds))
For the agonist mode, the MAX minus MIN FU values from the Output 1 text file (.TXT) are used for the curve fitting. Max-Min data in Fluorescent Unit (FU) from each well are converted in percent value relative to the pH 6.5 (final pH of the well after addition of ECF 5.85) maximum effect (maximum FU) using the following formula:
[(well FU - mean baseline FU with DMSO)/(mean maximum FU at pH 6.5 - mean baseline FU with DMSO)] *100
A 100% effect corresponds to the control wells containing a final pH of 6.5 and the 0% effect to the control wells with DMSO only (No ECF 5.85). Dose-response relationships are analyzed using the transformed Max-Min data in relative percent value and XLfit™ software (Model 205, 4 parameters logistic equation).
For the antagonist mode, the ratio MAX FU values over MAX baseline FU values are used for the curve fitting. The Max values and the Max baseline values used are respectively from the Output 2 file (_2.TXT) and the Output 3 file (_3.TXT). The ratio MAX over MAX baseline data from each well are converted in percent value relative to the Benzamil maximum effect (maximum FU) at 50 pM final using the formula:
(1-[(well ratio - mean ratio Benzamil)/(mean ratio with DMSO - mean ratio Benzamil)]) *100 A 100% effect corresponds to the control wells containing 50 pM Benzamil and the 0% effect to the control wells with DMSO only (with EOF 5.85). Dose-response relationships are analyzed using the transformed ratio MAX over MAX baseline data in relative percent value and XLfit™ software (Model 205, 4 parameters logistic equation). Average hASICIa antagonist IC50 (nM) values of tested compounds are provided in Table 10. Table 10. Average hASICIa Antagonist IC50 (nM) of Compounds
Figure imgf000312_0001
Figure imgf000313_0001
Figure imgf000314_0001
Figure imgf000315_0001
**395 is mixture of regioisomers 395a and 395b Example 262
Efficacy of combination therapy in inflammatory pain
Material and Methods
Animals
Experiments were conducted in male Sprague-Dawley rats (~250g, Charles River, St. Constant, Canada). Rats were group-housed on autoclaved corncob bedding in individual HEPA ventilated cages (Innocage® IVC, Innovive, San Diego, CA, USA) in a temperature-controlled environment (22±1.5 °C, 30-80 % relative humidity, 12-hr light/dark) and had irradiated food (Harlan Teklad, Montreal, Canada) and filtered water ad libitum. Rats were acclimatized in the animal facility (adMare BioInnovations, Montreal, Canada) for at least 5 days prior to use. Studies were conducted under a protocol that has been approved by the NEOMED Animal Care Committee and performed during the light phase of the cycle. The number of rats used was the minimum necessary to achieve an 80% statistical power to detect a 40% change.
Carrageenan-induced Inflammation Model
The effect of specific compounds, either alone or in combination with a cyclooxygenase (COX) inhibitor, was assessed in the carrageenan-induced inflammation model, as previously described in Ferenbacher, J. C. et al. (2012). Briefly, carrageenan is administered in the paw of rats to induce inflammation and hypersensitivity (e.g., thermal hypersensitivity), prior to administering a test drug. Rat paws are then subjected to a heat source and the withdrawal time of the paw is then evaluated as a measure of heat hyperalgesia.
Carrageenan-lambda (Sigma-Aldrich) was dissolved in sterile saline 0.9% at a concentration of 1% w/v. Rats were placed in a plexiglass chamber with 2% isoflurane at a flow rate of 0.8-1 l/hr with oxygen, for approximately 60-90 seconds, until a light-medium depth of anesthesia was attained. One hundred microliters of carrageenan solution were injected into the subcutaneous space of the dorsal aspect of the left hind paw, in the center of the four pads.
Test compounds and COX inhibitors were dissolved in 40% polyethylene glycol (PEG) 400 (in 0.9% sterile saline) and orally administered 2 hr after carrageenan inoculation, once inflammation was established, at a volume of 5ml/kg, and heat hyperalgesia was assessed 30min later. For the combination studies, the COX inhibitor to compound dose ratio was kept fixed for all dose levels.
Heat hyperalgesia was assessed using the Hargreaves Plantar test. Animals were placed on a glass surface, and a heat-source was focused onto the plantar surface of the affected paw. The time from the initiation of the heat until the animal withdraws the paw was recorded and defined as the Paw Withdrawal Latency (PWL). Statistical significance was determined using one-way ANOVA on raw data followed by a post-hoc Holm-Sidakt-test. The level of statistical significance was set at p < 0.05. Raw data were normalized using the following formula: % Anti-hyperalgesia = (PWL(dose)-PWL(vehicle)) I (PWL(naive)- PWL(vehicle)) X 100. Data are expressed as mean ±SEM.
It is to be noted that the present study involved assessment of hyperalgesia based on thermal response and Paw Withdrawal Latency. Alternatively, one can assess mechanical allodynia using the Dynamic Von Frey test. In the Dynamic Von Frey test, animals are placed on a wire mesh surface, and the Von Frey filament is applied onto the plantar surface of the affected paw at an increasing force in grams. The force required for the animal to withdraw its paw is then recorded. The data can be expressed as mean ±SEM. Statistical significance can be determined using one-way ANOVA on raw data followed by a post-hoc Holm-Sidak t-test. The level of statistical significance can be set at p < 0.05. Raw data can be normalized using the following formula: % efficacy = (Force(dose)-Force(vehicle)) / (Force(naive)-Force(vehicle)) X 100.
Isobolographic Analysis
After generating individual dose-response curves for each compound or COX inhibitor in the carrageenan model and determining their ED50 values (with 95% CL), compound and COX inhibitor combinations were administered at selected dose-ratio derived from their ED50 values. Evaluation of the co-administration effect was performed using a graphical approach visualized by an isobologram to compare experimentally obtained ED50 values (Tallarida, R. J. et al. (1989)). The theoretical additive ED50 was estimated according to the methodology. The criterion for establishing a statistical significance was P<0.05. Graphically, mean ED50 values (with 95% CL) for each compound or COX inhibitor administered either alone or as part of a combination were plotted. In this analysis, the line that connects the ED50 values for each compound or COX inhibitor alone is the theoretical line of additivity. Experimentally obtained ED50 of the combination and its 95% CLs that fall above the line of additivity are suggestive of subadditivity (antagonism), whereas points that fall below are suggestive of supra-additivity (synergism).
Results
Having available efficacy data for both compound 61 (oral ED50 = 6.7 mg/kg with 95% confidence limits (CL) of 3.3 to 19.5 mg/kg) and naproxen (oral ED50 = 8.1 mg/kg with 95% CL of 3.5 to 20 mg/kg), the first step was to determine the potency ratio, in this case the ratio of the ED50 values of naproxen to compound 61 was 1.0 to 0.83. Through isobolographic analysis, the theoretical ED50 value for the combination, assuming additivity, was calculated to be 7.4 mg/kg. Consequently, selected doses for the combination, keeping the ratio fixed, were 0.3, 1.0, 3.0, 10.0, and 30.0 mg/kg. In the carrageenan model, the combination resulted in a maximum effect of 86% at the highest dose tested. The ED50 for the combination was calculated to be 1.4 mg/kg with 95% CL of 1.0 to 2.0 mg/kg (Figure 1A). In comparison to the theoretical ED50, the effect of the combination was 5.3-fold more than expected if the interaction was purely additive. Using the calculated ratio, 1 .4 mg/kg represents an ED50 for compound 61 of 0.63 mg/kg (with 95% CL of 0.45 to 0.91 mg/kg), and for naproxen of 0.77 mg/kg (with 95% CL of 0.55 to 1.1 mg/kg). Comparing the new ED50 values, the combination of compound 61 and naproxen showed a 10.6- fold increase in potency as compared to when given alone. The isobolographic analysis (Figure 1 B) demonstrated that the ED50 of the combination lies below the line of additivity indicating a synergistic interaction. Isobolographic analysis confirms that there exists a ratio-dependent synergy of compound 61 in combination with naproxen, celecoxib, ibuprofen, or diclofenac, as well as compound 63 in combination with naproxen (Table 11 , Figure 2, Figure 3, Figure 4, Figure 5, Figure 6). As noted in Table 11 , the combination of compound 61 and naproxen was tested in duplicate (see Figures 1 and 2).
Table 11. Anti-hyperalgesic response of ASIC1 inhibitors in combination with COX inhibitors
Figure imgf000318_0001
Example 263
Combination therapy in a Neuropathic Pain Model
Material and Methods
Animals
Experiments were conducted in male Sprague-Dawley rats (~250g, Charles River, St. Constant, Canada). Rats were group-housed on autoclaved corncob bedding in individual HEPA ventilated cages (Innocage® IVC, Innovive, San Diego, CA, USA) in a temperature-controlled environment (22±1.5 °C, 30-80 % relative humidity, 12-h light/dark) and had irradiated food (Harlan Teklad, Montreal, Canada) and filtered water ad libitum. Rats were acclimatized in the animal facility (adMare BioInnovations, Montreal, Canada) for at least 5 days prior to use. Studies were conducted under a protocol that has been approved by the Animal Care Committee and performed during the light phase of the cycle. The number of rats used was the minimum necessary to achieve an 80% statistical power
Chronic Constriction Injury (CCI) model of neuropathic pain and testing
CCI was performed under anesthesia. About a 3-cm long blunt dissection was made into the skin overlying the area between the gluteus and biceps femoris muscles, and the common sciatic nerve of the hind paw was exposed at the mid-thigh level. Approximately 7 mm of the nerve was freed, proximal to the sciatic trifurcation, and four or three loose ligatures (about 1 mm spacing) of 4-0 chromic guts (or 4-0 silk) were placed around the sciatic nerve until a brief twitch was observed. The wound was closed with sutures in the muscle and staples in the skin. The animal was then allowed to recover from surgery for 24 h before pain hypersensitivity testing began.
Compound 61 alone or in combination with naproxen or diclofenac was dissolved in 40% polyethylene glycol (PEG) 400 (in 0.9% sterile saline) and orally administered at a volume of 5mL/kg and tested 30min later. The ratio Compound 61 to naproxen in the tested combination was 0.83:1 and the ratio Compound 61 to diclofenac in the tested combination was 0.57:1.
Heat hyperalgesia was assessed using the Hargreaves Plantar test. Animals were placed on a glass surface, and a heat-source was focused onto the plantar surface of the affected paw. The time from the initiation of the heat until the animal withdraws the paw was recorded and defined as the Paw Withdrawal Latency (PWL).
Statistical significance was determined using one-way ANOVA on raw data followed by a post-hoc Holm-Sidak t-test. The level of statistical significance was set at p < 0.05. Raw data were normalized using the following formula: % Anti-hyperalgesia = (Response(dose)- Response(vehicle)) I (Response(naive)-Response(vehicle)) X 100. Data are expressed as mean ±SEM. PWL and % efficacy values of the naproxen:Compound 61 and diclofenac:Compound 61 combinations are provided in Table 12.
Isobolographic analysis: After generating a dose-response curve for compound 61 in the CCI model its ED30 value (with 95% Cl) was determined. Evaluation of the co-administration effect was performed using a graphical approach visualized by an isobologram to compare experimentally obtained ED30. For the CCI model, modified type II isobolographic analysis was used (modified analytical method as described in Matsumura, N. et al. (2014)), with selected dose ratio derived from studies conducted in inflammatory models. Additionally, the theoretical additive ED30 was estimated according to the methodology. The criterion for establishing a statistical significance was P<0.05. Graphically, mean ED30 values (with 95% Cl) for compound 61 administered either alone or as part of a combination were plotted. In this analysis, the line that connects the ED30 values is the theoretical line of additivity. Experimentally obtained ED30 of the combination and its 95% Cis that fall above the area of additivity are suggestive of subadditivity (antagonism), whereas points that fall below are suggestive of supra-additivity (synergism).
Results
Having available efficacy data for each of Compound 61 (oral ED30 = 7.9 mg/kg with 95% confidence limits (CL) of 4.6 to 14.5 mg/kg), naproxen (maximum efficacy of 19%) and diclofenac (maximum efficacy of 21%) in the CCI model, combination studies were performed using selected dose ratios of 1 :0.83 (naproxen:Compound 61) and 1 :0.57 (diclofenac: Compound 61), which were derived from studies conducted in inflammatory pain models. Through isobolographic analysis, the theoretical combination ED30 assuming additivity was calculated to be 17.5 mg/kg for naproxen:Compound 61 and 21.7 mg/kg for diclofenac:Compound 61. Consequently, selected doses for the combination, keeping the ratio fixed, were 2, 5, 10, 20 and 50.0 mg/kg for naproxen:Compound 61 and 3, 6, 15, 30 and 60.0 mg/kg for diclofenac:Compound 61.
In the CCI model, the naproxen:Compound 61 combination dose-dependently increased the withdrawal latency to a heat stimulus, indicating a reduction in heat hyperalgesia with a maximum efficacy of 35 % at the highest dose tested (Table 12). The ED30 for the combination was calculated to be 22.4 mg/kg with 95% CL of 11 to 35 mg/kg. Using the dose ratio, the new ED30 for Compound 61 was calculated to be 10.1 mg/kg (with 95% CL of 5 to 15.8 mg/kg). The isobolographic analysis demonstrated that the ED30 of the naproxen:Compound 61 combination lies within the area of additivity indicating a ratio-dependent additive interaction of Compound 61 in combination with naproxen in the CCI model (Table 13). The diclofenac:Compound 61 combination dose-dependently increased the withdrawal latency to a heat stimulus, indicating a reduction in heat hyperalgesia with a maximum efficacy of 45 % at the highest dose tested (Table 12). The ED30 for the diclofenac:Compound 61 combination was calculated to be 18.4 mg/kg with 95% CL of 3.5 to 37.1 mg/kg, with a new ED30 for Compound 61 of 6.7 mg/kg (with 95% CL of 1.3 to 13.5 mg/kg). The isobolographic analysis demonstrated that the ED30 of the diclofenac:Compound 61 combination lies within the area of additivity indicating a ratio-dependent additive interaction of Compound 61 in combination with diclofenac in the CCI model (Table 13).
Table 12. Anti-hyperalgesic response of ASIC1 inhibitors in combination with COX inhibitors in the CCI model of neuropathic pain
Figure imgf000321_0001
Although the invention has been illustrated and described with respect to one or more implementations, equivalent alterations and modifications will occur to others skilled in the art upon the reading and understanding of this specification. In addition, while a particular feature of the invention may have been disclosed with respect to only one of several implementations, such feature may be combined with one or more other features of the other implementations as may be desired and advantageous for any given or particular application.
Accordingly, it is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. Any publication, document, patent, patent application or publication referred to herein should be construed as incorporated by reference each in their entirety for all purposes.
REFERENCES
Ferenbacher, J. C., Vasko, M. R., and Duarte, D. B.: Models of Inflammation: Carrageenan- or Complete Freund’s Adjuvant-Induced Edema and Hypersensitivity in the Rat. Curr. Protoc. Pharmacol. Chapter s: Unit 5.4, 2012.
Matsumura, N. and Nakaki, T.: Isobolographic analysis of the mechanisms of action of anticonvulsants from a combination effect. European Journal of Pharmacology, 741 :237-246, 2014.
Tallarida, R. J., Porreca, F. and Cowan, A.: Statistical analysis of drug-drug and site-site interactions with isobolograms. Life Sci. 45: 947-961, 1989.

Claims

1 . A pharmaceutical combination comprising:
(a) a cyclooxygenase (COX) inhibitor; and
(b) a compound having the Formula (I)
Figure imgf000323_0001
or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
Ra is -NH2, -NH-OH, -OH, -NHRb or -NRcRd;
Rb is C1-C6 alkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein C1-C6 alkyl is optionally substituted with 1 to 3 halogens, 1 to 3 -OH, -OC1-C3alkyl, -COOH, or cyclopropyl optionally substituted with -OH, and wherein C3-C6cycloalkyl is optionally substituted with -ON;
Rc and Rd form with the nitrogen to which they are attached a 4-membered heterocycloalkyl, wherein the 4-membered heterocycloalkyl is optionally substituted with at least one of -OH and C1-C3alkyl; represents one of the following residues Ao to A12
Figure imgf000323_0002
Figure imgf000323_0003
wherein:
R is H, C1-C6alkyl or phenyl; R1 and R2 are independently -CN, C6-C10aryl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- Cscycloalkyl, 4- to 14-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C(O)NH2, - C(O)NHR5, -C(O)R6, or -C(0)OR5, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R7 substituents, each C6-C10aryl is optionally substituted with 1 to 3 R8 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R22 substituents, with the proviso that when Ra is -OH,
Figure imgf000324_0003
represents Ao,
Figure imgf000324_0001
then R2 in residue Ao is different than
Figure imgf000324_0002
each R5 is independently C1-C6alkyl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R9 substituents; each R6 is independently C3-C6cycloalkyl, 4- to 6-membered heterocycloalkyl, or C6-C10aryl; each R7 is independently -OH, -C(O)R11, C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6alkyl), -N(C1-C4alkyl)(C(O)OC1-C6alkyl), 4- to 6- membered heterocycloalkyl, -NH(C(O)C1-C6alkyl), -OR20, -SC1-C6alkyl, -NH2, -NH(C1-C4alkyl), or -N(C1-C4alkyl)2, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 3 R12 substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R13 substituents, and each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl or oxo; each R8 is independently halogen, C1-C6alkyl, -OC1-C6alkyl, C3-C6cycloakyl, or 5- to 10- membered heteroaryl, wherein each -OC1-C6alkyl is optionally substituted with -OC1-C4alkyl, and each 5- to 10-membered heteroaryl is optionally substituted with C1-C4alkyl; each R22 is independently C1-C6alkyl optionally substituted with phenyl; each R9 is independently -OH, -C(O)R15, C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, -C(O)OH, 4- to 6-membered heterocycloalkyl, -NH(C(O)C1-C6alkyl), -OC1-C6alkyl, -SC1-C6alkyl, -NH2, -NH(C1- C4alkyl), or -N(C1-C4alkyl)2, wherein each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl, and each -OC1-C6alkyl is optionally substituted with -OC1-C4alkyl; each R11 is independently -NH2, -NH(C1-C4alkyl), -N(C1-C4alkyl)2, or 4- to 6-membered heterocycloalkyl; each R20 is independently C1-C6alkyl or 5- to 10-membered heteroaryl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R14 substituents and each 5- to 10-membered heteroaryl is optionally substituted with -OH or -NH(cyclopropyl); each R12 is independently C1-C4alkyl, -SC1-C4alkyl, -Ph, -OC1-C4alkyl, or -SPh, wherein each C1- C4alkyl is optionally substituted with -OH; each R13 is independently halogen, C1-C4alkyl, C3-C6cycloalkyl, -OH, -OC1-C6alkyl, -SC1-C6alkyl, -S(O)2C1-C6alkyl, -NH2, -NH(C1-C4alkyl), or -N(C1-C4alkyl)2, wherein each -OC1-C8alkyl, -SC1- C6alkyl, -S(O)2C1-C6alkyl, -NH(C1-C4alkyl), and -N(C1-C4alkyl)2 is optionally substituted with 1 to 3 R9 substituents; each R14 is independently halogen, -OC1-C4alkyl, or C3-C6cycloalkyl; each R15 is independently -NH2, -NH(C1-C4alkyl), -N(C1-C4alkyl)2, or 4- to 6-membered heterocycloalkyl;
R4 is C1-C6alkyl, C3-C8cycloalkyl, C6-C10aryl, 7- to 10-membered partially unsaturated heterocyclic group, or 5- to 10-membered heteroaryl, wherein C1-C6alkyl and C3-C8cycloalkyl are optionally substituted with 1 to 3 R9 substituents, and C6-C10aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R10 substituents, with the proviso that: (i) when Ra is -OH, -NH2, represents A2, then R4 in residue A2 is different than -CH3; and (ii) when
Figure imgf000325_0001
resents A3, then R4 in residue A3 is different than -C(CH3)3; each R10 is independently C1-C4alkyl, halogen, -OC1-C6alkyl, -NH2, -NH(C1-C4alkyl), or -N(C1- C4alkyl)2, wherein each C1-C4alkyl is optionally substituted with 1 to 3 halogens;
R2a is C1-C6alkyl, C3-C8cycloalkyl, or C6-C10aryl, wherein C1-C6alkyl and C3-C8cycloalkyl are optionally substituted with 1 to 3 R9 substituents, and C6-C10aryl is optionally substituted with 1 to 3 R10 substituents;
R1a and R2b are independently -CN, C6-C10aryl, C1-C6alkyl, C3-C8cycloalkyl, -C(O)NH2, - C(O)NHR5, or -C(0)OC1-C6alkyl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R16 substituents and each C6-C10aryl is optionally substituted with 1 to 3 R17 substituents; each R16 is independently -OH, -C(O)NH2, -C(O)NH(C1-C4alkyl), C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, -C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6alkyl), 4- to 6-membered heterocycloalkyl, -NH(C(O)C1-C6alkyl), or -OC1-C4alkyl(OC1-C4alkyl), wherein each C3- C6cycloalkyl is optionally substituted with 1 to 3 R18 substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R21 substituents, and each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl; each R17 is independently halogen, C1-C6alkyl, -OC1-C6alkyl, or 5- to 10-membered heteroaryl, wherein each 5- to 10-membered heteroaryl is optionally substituted with C1-C4alkyl; each R18 is independently C1-C4alkyl, -SC1-C4alkyl, -Ph, or -OC1-C4alkyl; each R21 is independently halogen or C1-C4alkyl; R4a is C1-C6alkyl or C3-C8cycloalkyl, wherein each C1-C6alkyl and C3-C8cycloalkyl are optionally substituted with 1 to 3 R19 substituents; each R19 is independently halogen, -OH, -OC1-C4alkyl, -SC1-C4alkyl, -NH2, -NH(C1-C4alkyl), or - N(C1-C4alkyl)2;
R1b and R2c form together with the carbon atom to which they are attached a C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, 8- to 14-membered partially unsaturated heterocyclic group, or 8- to 14-membered partially unsaturated carbocyclic group, wherein C3-C8cycloalkyl is optionally substituted with 1 to 3 R9 substituents, and wherein 4- to 14-membered heterocycloalkyl, 8- to 14- membered partially unsaturated heterocyclic group, or 8- to 14-membered partially unsaturated carbocyclic group is optionally substituted with oxo (=0), oxime (=N-OH), C1-C3alkoxyoxime (=N- OC1-C3alkyl), or 1 to 3 substituents independently selected from -OH and -CF3;
R2d and R4b form together with the carbon atoms to which they are attached a C3-C8cycloalkyl or 4- to 14-membered heterocycloalkyl, wherein C3-C8cycloalkyl is optionally substituted with 1 to 3 R19 substituents; and
R1c and R3 form together with the carbon atoms to which they are attached a C3-C8cycloalkyl or 4- to 14-membered heterocycloalkyl, wherein C3-C8cycloalkyl is optionally substituted with 1 to 3 R19 substituents.
2. The pharmaceutical combination of claim 1 , wherein in the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, R is H.
3. The pharmaceutical combination of claim 1 or 2, wherein the compound of Formula (I) is represented by the formula (la) or (la’):
Figure imgf000326_0001
wherein R1, R2, R and Ra are as defined in claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
4. The pharmaceutical combination of claim 3, wherein the compound of Formula (I) is represented by the formula (la):
Figure imgf000327_0001
wherein R1, R2 and Ra are as defined in claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
5. The pharmaceutical combination of any one of claims 1 to 4, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, R1 and R2 are independently -CN, C6-C10aryl, C1-C6alkyl, C2-Cealkynyl, C3-C6cycloalkyl, 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHR5, -C(O)R6, or -C(O)OR5, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R7 substituents, each C6-C10aryl is optionally substituted with 1 to 3 R8 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R22 substituents, and R5, R6, R7, R8 and R22 are as defined in claim 1.
6. The pharmaceutical combination of any one of claims 1 to 5, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof:
R1 and R2 are independently -CN, C6-C10aryl, C1-C6alkyl, C2-Cealkynyl, C3-C6cycloalkyl, 5- to 10- membered heteroaryl, -C(O)NH2, -C(O)NHR5, -C(O)R6, or -C(0)OR5, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R7 substituents, each C6-C10aryl is optionally substituted with 1 to 3 R8 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R22 substituents, and wherein: each R5 is independently C1-C6alkyl; each R6 is independently a 4- to 6-membered heterocycloalkyl; each R7 is independently -OH, -C(O)R11, C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, - C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6alkyl), -N(C1-C4alkyl)(C(O)OC1- C6alkyl), 4- to 6-membered heterocycloalkyl, -NH(C(O)C1-C6alkyl), -OR20, -SC1-C6alkyl, - NH2, or -N(C1-C4alkyl)2, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 3 R12 substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R13 substituents, and each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl or oxo; each R8 is independently halogen, C1-C6alkyl, or -OC1-C6alkyl, wherein each -OC1-C6alkyl is optionally substituted with -OC1-C4alkyl; each R22 is independently C1-C6alkyl optionally substituted with phenyl; each R11 is independently -NH2, -NH(C1-C4alkyl), or 4- to 6-membered heterocycloalkyl; each R20 is independently C1-C8alkyl or 5- to 10-membered heteroaryl, wherein each C1- C6alkyl is optionally substituted with 1 to 3 R14 substituents and each 5- to 10-membered heteroaryl is optionally substituted with -OH or -NH(cyclopropyl); each R12 is independently C1-C4alkyl, -SC1-C4alkyl, -Ph, -OC1-C4alkyl, or -SPh, wherein each C1-C4alkyl is optionally substituted with -OH; each R13 is independently halogen, C1-C4alkyl, or C3-C6cycloalkyl; and each R14 is independently halogen, -OC1-C4alkyl, or C3-C6cycloalkyl.
7. The pharmaceutical combination of any one of claims 1 to 5, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, R1 and R2 are independently -ON, C6-C10aryl, C1-C6alkyl, C2-C6alkynyl, C3-C8cycloalkyl, 5- to 10-membered heteroaryl, or -C(O)NH2, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R7 substituents, each C6-C10aryl is optionally substituted with 1 to 3 R8 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R22 substituents, and R7, R8, and R22 are as defined in claim 1 .
8. The pharmaceutical combination of any one of claims 1 to 5, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof:
R1 and R2 are independently -CN, C6-C10aryl, C1-C6alkyl, C2-C6alkynyl, C3-C8cycloalkyl, 5- to 10- membered heteroaryl, or -C(O)NH2, wherein each C1-C8alkyl is optionally substituted with 1 to 3 R7 substituents, each C6-C10aryl is optionally substituted with 1 to 3 R8 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R22 substituents, and wherein: each R7 is independently -OH, -C(O)R11, C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, - C(O)OH, 5- to 10-membered heteroaryl, -NH(C(O)OC1-C6alkyl), -N(C1-C4alkyl)(C(O)OC1- C6alkyl), -NH(C(O)C1-C6alkyl), 4- to 6-membered heterocycloalkyl, -OR20, -SC1-C6alkyl, - NH2, or -N(C1-C4alkyl)2, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 3 R12 substituents, each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R13 substituents, and each 4- to 6-membered heterocycloalkyl is optionally substituted with C1-C4alkyl or oxo; each R8 is independently halogen, C1-C6alkyl, or -OC1-C6alkyl, wherein each -OC1-C6alkyl is optionally substituted with -OC1-C4alkyl; each R11 is independently -NH2, -NH(C1-C4alkyl), or 4- to 6-membered heterocycloalkyl; each R20 is independently C1-C6alkyl or 5- to 10-membered heteroaryl, wherein each C1- Cealkyl is optionally substituted with 1 to 3 R14 substituents and each 5- to 10-membered heteroaryl is optionally substituted with -OH or -NH(cyclopropyl); each R12 is independently C1-C4alkyl, -SC1-C4alkyl, -Ph, -OC1-C4alkyl, or -SPh, wherein each C1-C4alkyl is optionally substituted with -OH; each R13 is independently halogen, C1-C4alkyl, or C3-C6cycloalkyl; each R14 is independently halogen, -OC1-C4alkyl, or C3-C6cycloalkyl; and each R22 is independently C1-C4alkyl.
9. The pharmaceutical combination of any one of claims 1 to 5, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof:
R1 and R2 are independently -ON, C6-C10aryl, C1-C6alkyl, C2-C6alkynyl, C3-C8cycloalkyl, 5- to 10- membered heteroaryl, or -C(0)NH2, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R7 substituents, each C6-C10aryl is optionally substituted with 1 to 3 R8 substituents, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R22 substituents, and wherein: each R7 is independently -OH, -C(O)R11 , -OR20, C3-C6cycloalkyl, -ON, C6-C10aryl, halogen, -C(O)OH, or 5- to 10-membered heteroaryl, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 3 R12 substituents and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 R13 substituents; each R8 is a halogen; each R11 is -NH2; each R20 is C1-C6alkyl or 5- or 6-membered heteroaryl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 R14 substituents and each 5- or 6-membered heteroaryl is optionally substituted with -OH or -NH(cyclopropyl); each R12 is C1-C4alkyl; each R13 is independently halogen or C1-C4alkyl; each R14 is halogen; and each R22 is independently C1-C4alkyl.
10. The pharmaceutical combination of any one of claims 1 to 5, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof:
R1 and R2 are independently -ON, phenyl, C1-C4alkyl, C2-C4alkynyl, C3-C6cycloalkyl, 5-membered heteroaryl, or -C(O)NH2, wherein each C1-C4alkyl is optionally substituted with 1 or 2 R7 substituents, each phenyl is optionally substituted with 1 or 2 halogens, and each 5-membered heteroaryl is optionally substituted with 1 or 2 -CH3, and wherein: each R7 is independently -OH, -C(O)NH2, -OR20, C3-C6cycloalkyl, -ON, phenyl, halogen, - C(O)OH, or 5-membered heteroaryl, wherein each C3-C6cycloalkyl is optionally substituted with -CH3; and each R20 is C1-C6alkyl or 5- or 6-membered heteroaryl, wherein each C1-C6alkyl is optionally substituted with 1 to 3 halogen and each 5- or 6-membered heteroaryl is optionally substituted with -OH.
11 . The pharmaceutical combination of any one of claims 1 to 5, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, R1 and R2 independently represent:
Figure imgf000330_0001
Figure imgf000331_0001
12. The pharmaceutical combination of any one of claims 1 to 5, wherein in the compound of
Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, R1 and R2 independently represent:
Figure imgf000331_0002
Figure imgf000332_0001
13. The pharmaceutical combination of any one of claims 1 to 5, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, R1 and R2 independently represent:
Figure imgf000332_0002
14. The pharmaceutical combination of any one of claims 1 to 5, wherein in the compound of
Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, R1 and R2 independently represent:
Figure imgf000332_0003
15. The pharmaceutical combination of any one of claims 1 to 5, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof:
R1 and R2are independently -CN, C6-C10aryl, C1-C6alkyl, C3-C8cycloalkyl, 5-membered heteroaryl, or -C(0)NH2, wherein each C1-C6alkyl is optionally substituted with 1 to 2 R7 substituents; each R7 is independently -OH, -C(O)NH2, C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, or 5- to 8- membered heteroaryl, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 2 C1- C4alkyl, and each 5- to 8-membered heteroaryl is optionally substituted with 1 to 2 R13 substituents; and wherein each R13 is independently halogen or C1-C4alkyl.
16. The pharmaceutical combination of any one of claims 1 to 15, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, R1 and R2 are different.
17. The pharmaceutical combination of any one of claims 1 to 16, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, one of R1 and R2 is -CN.
18. The pharmaceutical combination of any one of claims 1 to 17, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, one of R1 and
Figure imgf000333_0001
19. The pharmaceutical combination of claim 1 or 2, wherein the compound of Formula (I) is represented by the formula (lb) or (lb’):
Figure imgf000333_0002
wherein R4, R and Ra are as defined in claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
20. The pharmaceutical combination of claim 19, wherein the compound of Formula (I) is represented by the formula (lb):
Figure imgf000333_0003
wherein R4 and Ra are as defined in claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
21. The pharmaceutical combination of any one of claims 1 , 2, 19 and 20, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, R4 is C1-C6alkyl, C6-C10aryl, 7- to 10-membered partially unsaturated heterocyclic group, or 5- to 10- membered heteroaryl, wherein C1-C6alkyl is optionally substituted with 1 to 3 R9 substituents, and C6-C10aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R10 substituents, and R9 and R10 are as defined in claim 1.
22. The pharmaceutical combination of any one of claims 1 , 2, 19 and 20, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, R4 is C1-C6alkyl, C6-C10aryl, 7- to 10-membered partially unsaturated heterocyclic group, or 5- to 10- membered heteroaryl, wherein C6-C10aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R10 substituents, and wherein: each R10 is independently C1-C4alkyl, halogen, -OC1-C6alkyl, -NH2, -NH(C1-C4alkyl), or - N(C1-C4alkyl)2, wherein each C1-C4alkyl is optionally substituted with 1 to 3 halogens.
23. The pharmaceutical combination of any one of claims 1 , 2, 19 and 20, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, R4 is C1-C6alkyl, C6-C10aryl, 7- to 10-membered partially unsaturated heterocyclic group, or 5- to 10- membered heteroaryl, wherein C6-C10aryl and 5- to 10-membered heteroaryl are optionally substituted with 1 to 3 R10 substituents, and wherein: each R10 is independently C1-C4alkyl, halogen, -OC1-C6alkyl, or -N(C1-C4alkyl)2, wherein each C1-C4alkyl is optionally substituted with 1 to 3 halogens.
24. The pharmaceutical combination of any one of claims 1 , 2, 19 and 20, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, R4 is C1-C4alkyl, phenyl, 9-membered partially unsaturated heterocyclic group, or 5- to 6-membered heteroaryl, wherein phenyl and 5- to 6-membered heteroaryl are optionally substituted with 1 or 2 R10 substituents, and wherein: each R10 is independently -CF3, halogen, -OCH3, or -N(CH3)2.
25. The pharmaceutical combination of any one of claims 1 , 2, 19 and 20, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, R4 represents:
Figure imgf000335_0001
26. The pharmaceutical combination of claim 1 or 2, wherein the compound of Formula (I) is represented by the formula (Ic) or (lc’):
Figure imgf000335_0002
wherein R2a, R and Ra are as defined in claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
27. The pharmaceutical combination of claim 26, wherein the compound of Formula (I) is represented by the formula (Ic):
Figure imgf000335_0003
wherein R2a and Ra are as defined in claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
28. The pharmaceutical combination of any one of claims 1 , 2, 26 and 27, wherein in the compound of Formula (I), orthe pharmaceutically acceptable salt, solvate, or prodrug thereof, R2a is C1-C6alkyl or C6-C10aryl, wherein C1-C6alkyl is optionally substituted with 1 to 3 R9 substituents and C6-C10aryl is optionally substituted with 1 to 3 R10 substituents, and R9 and R10 are as defined in claim 1.
29. The pharmaceutical combination of any one of claims 1 , 2, 26 and 27, wherein in the compound of Formula (I), orthe pharmaceutically acceptable salt, solvate, or prodrug thereof, R2a is C1-C6alkyl or C6-C10aryl, wherein C1-C6alkyl is optionally substituted with 1 to 3 halogens.
30. The pharmaceutical combination of any one of claims 1 , 2, 26 and 27, wherein in the compound of Formula (I), orthe pharmaceutically acceptable salt, solvate, or prodrug thereof, R2a is C1-C6alkyl.
31. The pharmaceutical combination of any one of claims 1 , 2, 26 and 27, wherein in the compound of Formula (I), orthe pharmaceutically acceptable salt, solvate, or prodrug thereof, R2a is C1-C4alkyl.
32. The pharmaceutical combination of any one of claims 1 , 2, 26 and 27, wherein in the compound of Formula (I), orthe pharmaceutically acceptable salt, solvate, or prodrug thereof, R2a is ethyl.
33. The pharmaceutical combination of claim 1 or 2, wherein the compound of Formula (I) is represented by the formula (Id) or (Id’):
Figure imgf000336_0001
wherein R1a, R2b, R4a, R and Ra are as defined in claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
34. The pharmaceutical combination of claim 33, wherein the compound of Formula (I) is represented by the formula (Id):
Figure imgf000336_0002
wherein R1a, R2b, R4a and Ra are as defined in claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
35. The pharmaceutical combination of any one of claims 1 , 2, 33 and 34, wherein in the compound of Formula (I), orthe pharmaceutically acceptable salt, solvate, or prodrug thereof, R1a and R2b are independently -CN, C6-C10aryl, C1-C6alkyl, C3-C8cycloalkyl, or -C(O)NH2, wherein each C1-C6alkyl is optionally substituted with 1 to 2 R16 substituents, and wherein: each R16 is independently -OH, -C(O)NH2, C3-C6cycloalkyl, -CN, C6-C10aryl, halogen, or 5- to 8-membered heteroaryl, wherein each C3-C6cycloalkyl is optionally substituted with 1 to 2 C1-C4alkyl, and each 5- to 10-membered heteroaryl is optionally substituted with 1 to 2 R21 substituents; and each R21 is independently halogen or C1-C4alkyl.
36. The pharmaceutical combination of any one of claims 1 , 2, 33 and 34, wherein in the compound of Formula (I), orthe pharmaceutically acceptable salt, solvate, or prodrug thereof, R1a and R2bare independently -CN or C6-C10aryl.
37. The pharmaceutical combination of any one of claims 1 , 2, 33, 34, 35 and 36, wherein in the compound of Formula (I), orthe pharmaceutically acceptable salt, solvate, or prodrug thereof, R4a is C1-C6alkyl.
38. The pharmaceutical combination of claim 1 or 2, wherein the compound of Formula (I) is represented by the formula (le) or (le’):
Figure imgf000337_0001
wherein R, Ra, R1 band R2c are as defined in claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
39. The pharmaceutical combination of claim 38, wherein the compound of Formula (I) is represented by the formula (le):
Figure imgf000337_0002
wherein Ra, R1b and R2c are as defined in claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
40. The pharmaceutical combination of any one of claims 1 , 2, 38 and 39, wherein in the compound of Formula (I), orthe pharmaceutically acceptable salt, solvate, or prodrug thereof, R1b and R2c form together with the carbon atom to which they are attached a C3-C8cycloalkyl, 4- to 14-membered heterocycloalkyl, 8- to 14-membered partially unsaturated heterocyclic group, or 8- to 14-membered partially unsaturated carbocyclic group, wherein each 4- to 14-membered heterocycloalkyl, 8- to 14-membered partially unsaturated heterocyclic group, or 8- to 14- membered partially unsaturated carbocyclic group is optionally substituted with oxo (=0), oxime (=N-OH), C1-C3alkoxyoxime (=N-OC1-C3alkyl), or 1 to 3 substituents independently selected from -OH and -CF3.
41. The pharmaceutical combination of any one of claims 1 , 2, 38 and 39, wherein in the compound of Formula (I), orthe pharmaceutically acceptable salt, solvate, or prodrug thereof, R1b and R2c form together with the carbon atom to which they are attached a C3-C8cycloalkyl or a 8- to 10-membered partially unsaturated carbocyclic group, wherein 8- to 10-membered partially unsaturated carbocyclic group is optionally substituted with oxo (=0), oxime (=N-OH), methoxyoxime (=N-OCH3), or 1 to 2 substituents independently selected from -OH and -CF3.
42. The pharmaceutical combination of any one of claims 1 , 2, 38 and 39, wherein in the compound of Formula (I), orthe pharmaceutically acceptable salt, solvate, or prodrug thereof, R1b and R2c form together with the carbon atom to which they are attached a C4C6cycloalkyl, or a group selected from
Figure imgf000338_0001
wherein the dashed lines represent the portion of the cyclohexanone moiety of the compound of formula (le) or (le’) bearing R1b and R2c.
43. The pharmaceutical combination of any one of claims 1 , 2, 38 and 39, wherein in the compound of Formula (I), orthe pharmaceutically acceptable salt, solvate, or prodrug thereof, R1b and R2c form together with the carbon atom to which they are attached a cyclopentyl, or a group selected from
Figure imgf000339_0001
wherein the dashed lines represent the portion of the cyclohexanone moiety of the compound of formula (le) or (le’) bearing R1b and R2c.
44. The pharmaceutical combination of any one of claims 1 , 2, 38 and 39, wherein in the compound of Formula (I), orthe pharmaceutically acceptable salt, solvate, or prodrug thereof, R1b and R2c form together with the carbon atom to which they are attached a group selected from
Figure imgf000339_0002
, wherein the dashed lines represent the portion of the cyclohexanone moiety of the compound of formula (le) or (le’) bearing R1b and R2c.
45. The pharmaceutical combination of claim 1 or 2, wherein the compound of Formula (I) is represented by the formula (If) or (If’):
Figure imgf000339_0003
wherein R, Ra, R4band R2d are as defined in claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
46. The pharmaceutical combination of claim 45, wherein the compound of Formula (I) is represented by the formula (If):
Figure imgf000339_0004
wherein Ra, R4b and R2d are as defined in claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
47. The pharmaceutical combination of any one of claims 1 , 2, 45 and 46, wherein in the compound of Formula (I), orthe pharmaceutically acceptable salt, solvate, or prodrug thereof, R2d and R4b form together with the carbon atoms to which they are attached a C3-C8cycloalkyl, wherein each C3-C8cycloalkyl is optionally substituted with 1 to 3 R19 substituents as defined in claim 1.
48. The pharmaceutical combination of any one of claims 1 , 2, 45 and 46, wherein in the compound of Formula (I), orthe pharmaceutically acceptable salt, solvate, or prodrug thereof, R2d and R4b form together with the carbon atoms to which they are attached a C3-C8cycloalkyl.
49. The pharmaceutical combination of claim 1 or 2, wherein the compound of Formula (I) is represented by the formula (Ig):
Figure imgf000340_0001
wherein Ra, R1c and R3 are as defined in claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
50. The pharmaceutical combination of any one of claims 1 , 2 and 49, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, R1c and R3form together with the carbon atoms to which they are attached a C3-C8cycloalkyl, wherein each C3-C8cycloalkyl is optionally substituted with 1 to 3 R19 substituents as defined in claim 1.
51. The pharmaceutical combination of any one of claims 1 , 2 and 49, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, R1c and R3form together with the carbon atoms to which they are attached a C3-C8cycloalkyl.
52. The pharmaceutical combination of any one of claims 1 to 51 , wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, Ra is -NHRb and Rb represents:
Figure imgf000340_0002
Figure imgf000341_0001
53. The pharmaceutical combination of any one of claims 1 to 52, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, Ra is -NHRb and Rb represents:
Figure imgf000341_0002
54. The pharmaceutical combination of any one of claims 1 to 53, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, Ra is -NHRb and Rb represents
Figure imgf000341_0003
55. The pharmaceutical combination of any one of claims 1 to 51 , wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, Ra is
Figure imgf000341_0004
Figure imgf000341_0005
56. The pharmaceutical combination of any one of claims 1 to 51 and 55, wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, Ra
Figure imgf000341_0006
57. The pharmaceutical combination of any one of claims 1 to 51 , wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, Ra is -OH.
58. The pharmaceutical combination of any one of claims 1 to 51 , wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, Ra is -NH2.
59. The pharmaceutical combination of any one of claims 1 to 51 , wherein in the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, Ra is -NH-OH.
60. The pharmaceutical combination of any one of claims 1 to 59, wherein the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, or prodrug thereof, is in the form of a racemate or any enantiomer thereof.
61. The pharmaceutical combination of claim 1, wherein the compound is Compound 4, 8, 9,
14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,
47, 48, 49, 50, 51, 52, 53, 54, 59, 60a, 60b, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 75, 81,
82, 83, 84, 89, 91, 97, 101, 108, 109, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150,
154, 155, 163, 168, 169, 170, 173, 174, 175, 178, 179, 180, 181, 183, 189, 190, 191, 192, 193,
194, 195, 197, 198, 199, 200, 201, 202, 211, 212, 213, 214, 215, 216, 219, 221, 227, 228, 229,
230, 231, 232, 237, 238, 239, 245, 246, 247, 248, 249, 250, 251, 253, 254, 255, 257, 258, 263,
264, 271, 272, 273, 278, 279, 280, 281, 287, 288, 290, 291, 297, 298, 305, 306, 313, 314, 321,
322, 330, 331, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 352, 353, 354,
355, 356, 357, 358, 360, 362, 371, 378, 391, 392, 393, 394a, 394b, 395a, 395b, 396, 397, 401,
402, 403, 406, 407, 408, 412, 413, 414, 416, 418, 422, 427, 428, 429, 430, 431, 433, 434, 445,
446, 447, 448, 449, 450, 451, 452, 453, 454, 462, 463, 464, 465, 466, 468, 469, 470, 471, 472,
473, 474, 475, 476, 478, 479, 480, 481, 482, 483, 486, 488, 489, 492, 495, 496, 497, 498, 511,
512, 513, 514, 515, 520, 523, 524, or 534 of Table 1 of the description, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
62. The pharmaceutical combination of claim 1, wherein the compound is Compound 4, 15,
16, 17, 20, 24, 25, 26, 27, 29, 30, 31, 32, 33, 34, 36, 37, 47, 48, 49, 50, 51, 52, 53, 54, 59, 60b, 61, 62, 63, 64, 65, 66, 67, 71, 72, 75, 81, 82, 83, 84, 89, 91, 97, 101, 109, 119, 120, 121, 122, 123, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141, 143, 144, 145, 146,
147, 148, 149, 150, 155, 163, 168, 169, 170, 173, 174, 175, 179, 180, 181, 183, 191, 192, 194,
195, 198, 199, 201, 202, 212, 213, 214, 215, 216, 228, 230, 231, 232, 237, 238, 239, 246, 248,
250, 251, 253, 254, 255, 258, 263, 264, 271, 272, 273, 278, 279, 280, 281, 287, 288, 291, 298,
305, 306, 313, 314, 321, 322, 331, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 352, 353,
354, 355, 356, 357, 358, 391, 392, 393, 394a, 394b, 395a, 395b, 396, 397, 401, 402, 403, 406, 407, 408, 413, 414, 416, 418, 422, 428, 429, 430, 431, 434, 445, 446, 447, 448, 449, 450, 451,
453, 454, 462, 463, 464, 465, 466, 468, 470, 472, 474, 475, 476, 479, 480, 481, 482, 486, 489,
495, 496, 498, 511, 512, 513, 514, 515, 520, or 524 of Table 1 of the description, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
63. The pharmaceutical combination of claim 1, wherein the compound is Compound 4, 15, 25, 32, 33, 47, 48, 49, 50, 52, 54, 59, 60b, 61, 62, 63, 72, 75, 82, 83, 89, 97, 101, 109, 119, 121, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141, 143, 144, 145, 146, 147, 148, 149, 150, 163, 169, 170, 174, 179, 181 , 183, 191 , 192, 194, 195, 212, 213, 214, 215, 230,
231 , 232, 238, 239, 246, 248, 250, 251 , 253, 254, 255, 258, 263, 264, 272, 273, 278, 279, 280,
281 , 288, 291 , 298, 305, 306, 313, 314, 321 , 322, 331 , 338, 339, 340, 341 , 342, 343, 344, 345,
353, 355, 356, 358, 391 , 392, 393, 394a, 394b, 395a, 395b, 396, 397, 402, 403, 407, 408, 413,
418, 422, 428, 429, 430, 431 , 434, 445, 446, 447, 448, 449, 450, 451 , 454, 463, 464, 465, 466, 472, 475, 476, 479, 481 , 486, 489, 495, 498, 512, 514, 515, 520, or 524 of Table 1 of the description, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
64. The pharmaceutical combination of claim 1 , wherein the compound is Compound 48, 50, 54, 60b, 61 , 63, 72, 75, 83, 97, 101 , 109, 127, 135, 140, 141 , 143, 144, 145, 146, 147, 149, 163, 169, 170, 174, 179, 181 , 191 , 194, 195, 212, 215, 230, 231 , 232, 238, 246, 248, 250, 251 , 255, 258, 272, 273, 279, 281 , 291 , 306, 314, 321 , 322, 331 , 338, 339, 340, 341 , 342, 345, 353, 355, 356, 391 , 393, 395a, 395b, 397, 402, 428, 430, 431 , 434, 446, 447, 448, 450, 463, 464, 465, 466, 489, 512, 514, 515, or 524 of Table 1 of the description, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
65. The pharmaceutical combination of claim 1 , wherein the compound is Compound 54, 61 , 63, 75, 140, 143, 146, 174, 215, 230, 250, 251 , 273, 306, 322, 430, 446, 463, or 512 of Table 1 of the description, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
66. The pharmaceutical combination of any one of claims 1 to 65, wherein the COX inhibitor comprises a Non-Steroidal Anti-Inflammatory Drug (NSAID).
67. The pharmaceutical combination of claim 66, wherein the NSAID is selected from the group consisting of Bromfenac, Celecoxib, Diclofenac, Etodolac, Flurbiprofen, Ibuprofen, Indomethacin, Ketoprofen, Ketorolac, Mefenamic acid, Meloxicam, Nabumetone, Naproxen, Nepafenac, Piroxicam, Sulindac, Tenoxicam, Tiaprofenic acid, Diflunisal, Etoricoxib, Fenoprofen, Floctafenine, Lumiracoxib, Oxaprozin, Parecoxib, Rofecoxib, Tolmetin, Valdecoxib, Meclofenamic acid, Dexketoprofen, Licofelone, Lornoxicam, Loxoprofen, Nimesulide, Tolfenamic acid, Phenylbutazone, Firocoxib, Salsalate, Choline Magnesium Trisalicylate, Acetylsalicylic acid, any pharmaceutically acceptable salt thereof, and any combination thereof.
68. The pharmaceutical combination of claim 66, wherein the NSAID is Naproxen, Celecoxib, Diclofenac, Ibuprofen, a pharmaceutically acceptable salt thereof, or any combination thereof.
69. The pharmaceutical combination of any one of claims 1 to 65, wherein the COX inhibitor is acetaminophen.
70. The pharmaceutical combination of any one of claims 1 to 69, wherein the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof are combined in a single dosage form.
71. The pharmaceutical combination of any one of claims 1 to 69, wherein the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof are each in an individual dosage form.
72. The pharmaceutical combination of any one of claims 1 to 71 , comprising the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof each in an amount ranging from about 1 mg to about 1000 mg.
73. The pharmaceutical combination of any one of claims 1 to 72, comprising the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof in a ratio of 1 :0.1 to 1 : 10 by weight.
74. The pharmaceutical combination of any one of claims 1 to 73, comprising the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof in a ratio of 1 :0.1 to 1 :1 by weight.
75. The pharmaceutical combination of any one of claims 1 to 74, wherein the pharmaceutical combination is a synergistic pharmaceutical combination.
76. The pharmaceutical combination of any one of claims 1 to 75, for use in the treatment of pain in a subject in need thereof.
77. Use of a pharmaceutical combination as defined in any one of claims 1 to 75, for the treatment of pain in a subject in need thereof.
78. A method for the treatment of pain, comprising administering to a subject in need thereof the pharmaceutical combination as defined in any one of claims 1 to 75.
79. The pharmaceutical combination for use of claim 76, the use of claim 77, or the method of claim 78, wherein the pain is inflammatory pain, neuropathic pain or cancer pain.
80. The pharmaceutical combination for use of claim 76, the use of claim 77, or the method of claim 78, wherein the pain is inflammatory pain.
81. The pharmaceutical combination for use of claim 76, the use of claim 77, or the method of claim 78, wherein the pain is neuropathic pain.
82. The pharmaceutical combination for use of claim 76, the use of claim 77, or the method of claim 78, wherein the pain is cancer pain.
83. The pharmaceutical combination for use of claim 76, 79 or 80, the use of claim 77, 79 or 80, or the method of claim 78, 79 or 80, wherein the pain is arthritis pain, pain associated with musculoskeletal trauma or soft tissue trauma, post-operative pain, dental pain, dysmenorrhea pain, episiotomy pain, endometriosis pain, post-partum pain, headache pain, ocular pain, bursitis pain, or tendinitis pain.
84. The pharmaceutical combination for use of claim 83, the use of claim 83, or the method of claim 83, wherein the pain is arthritis pain, and the arthritis pain is osteoarthritis pain, rheumatoid arthritis pain, ankylosing spondylitis pain, gout pain, or periarthritis pain.
85. The pharmaceutical combination for use of claim 83, the use of claim 83, or the method of claim 83, wherein the pain is pain associated with musculoskeletal trauma or soft tissue trauma, and the pain associated with musculoskeletal trauma or soft tissue trauma is pain associated with a sprain or pain associated with a strain.
86. The pharmaceutical combination for use of claim 83, the use of claim 83, or the method of claim 83, wherein the pain is post-operative pain, and the post-operative pain is post-operative pain following minor surgery, post-operative pain following general surgery, post-operative pain following orthopaedic surgery, post-operative pain following bunionectomy, post-operative pain following hernioplasty, post-operative pain following herniorrhaphy, post-operative pain following arthroplasty including pain following knee arthroplasty or pain following hip arthroplasty, postoperative pain following gynecological surgery, post-operative pain following cesarean section, post-mastectomy pain syndrome (PMPS), post-operative pain following abdominoplasty, postoperative pain following laminectomy, post-operative pain following hemorrhoid removal, or postoperative pain following thoracotomy.
87. The pharmaceutical combination for use of claim 83, the use of claim 83, or the method of claim 83, wherein the pain is dental pain, and the dental pain is toothache or post-operative pain after dental surgery.
88. The pharmaceutical combination for use of claim 83, the use of claim 83, or the method of claim 83, wherein the pain is dental pain, and the dental pain is pain after dental extraction.
89. The pharmaceutical combination for use of claim 83, the use of claim 83, or the method of claim 83, wherein the pain is dysmenorrhea pain, episiotomy pain, endometriosis pain, or postpartum cramping pain.
90. The pharmaceutical combination for use of claim 83, the use of claim 83, or the method of claim 83, wherein the pain is headache pain, and the headache pain is migraine pain, tension headache pain, or cluster headache pain.
91. The pharmaceutical combination for use of claim 83, the use of claim 83, or the method of claim 83, wherein the pain is ocular pain, and the ocular pain is post-operative pain after cataract surgery, post-operative pain after refractive surgery, ocular pain from a non-penetrating wound, foreign body sensation ocular pain, burning or stinging of the eye, uveitis pain, iritis pain, retinopathy pain or optic neuritis pain.
92. The pharmaceutical combination for use of any one of claims 76 and 79 to 91 , the use of any one of claims 77 and 79 to 91 , or the method of any one of claims 78 to 91 , wherein the treatment is an oral treatment.
93. The pharmaceutical combination for use of any one of claims 76 and 79 to 92, the use of any one of claims 77 and 79 to 92, or the method of any one of claims 78 to 92, wherein the subject is a mammal.
94. The pharmaceutical combination for use of any one of claims 76 and 79 to 93, the use of any one of claims 77 and 79 to 93, or the method of any one of claims 78 to 93, wherein the subject is a human.
95. A method for the treatment of pain, comprising administering to a subject in need thereof a cyclooxygenase (COX) inhibitor and a compound having the Formula (I) as defined in any one of claims 1 to 65 or the pharmaceutically acceptable salt, solvate, or prodrug thereof.
96. The method of claim 95, wherein the COX inhibitor comprises a Non-Steroidal Anti- Inflammatory Drug (NSAID).
97. The method of claim 96, wherein the NSAID is selected from the group consisting of Bromfenac, Celecoxib, Diclofenac, Etodolac, Flurbiprofen, Ibuprofen, Indomethacin, Ketoprofen, Ketorolac, Mefenamic acid, Meloxicam, Nabumetone, Naproxen, Nepafenac, Piroxicam, Sulindac, Tenoxicam, Tiaprofenic acid, Diflunisal, Etoricoxib, Fenoprofen, Floctafenine, Lumiracoxib, Oxaprozin, Parecoxib, Rofecoxib, Tolmetin, Valdecoxib, Meclofenamic acid, Dexketoprofen, Licofelone, Lornoxicam, Loxoprofen, Nimesulide, Tolfenamic acid, Phenylbutazone, Firocoxib, Salsalate, Choline Magnesium Trisalicylate, Acetylsalicylic acid, any pharmaceutically acceptable salt thereof, and any combination thereof.
98. The method of claim 96, wherein the NSAID is Naproxen, Celecoxib, Diclofenac, Ibuprofen, a pharmaceutically acceptable salt thereof, or any combination thereof.
99. The method of claim 95, wherein the COX inhibitor is acetaminophen.
100. The method of any one of claims 95 to 99, wherein the pain is inflammatory pain, neuropathic pain or cancer pain.
101 . The method of any one of claims 95 to 100, wherein the pain is inflammatory pain.
102. The method of any one of claims 95 to 100, wherein the pain is neuropathic pain.
103. The method of any one of claims 95 to 100, wherein the pain is cancer pain.
104. The method of any one of claims 95 to 101 , wherein the pain is arthritis pain, pain associated with musculoskeletal trauma or soft tissue trauma, post-operative pain, dental pain, dysmenorrhea pain, episiotomy pain, endometriosis pain, post-partum pain, headache pain, ocular pain, bursitis pain, or tendinitis pain.
105. The method of claim 104, wherein the pain is arthritis pain, and the arthritis pain is osteoarthritis pain, rheumatoid arthritis pain, ankylosing spondylitis pain, gout pain, or periarthritis pain.
106. The method of claim 104, wherein the pain is pain associated with musculoskeletal trauma or soft tissue trauma, and the pain associated with musculoskeletal trauma or soft tissue trauma is pain associated with a sprain or pain associated with a strain.
107. The method of claim 104, wherein the pain is post-operative pain, and the post-operative pain is post-operative pain following minor surgery, post-operative pain following general surgery, post-operative pain following orthopaedic surgery, post-operative pain following bunionectomy, post-operative pain following hernioplasty, post-operative pain following herniorrhaphy, postoperative pain following arthroplasty including pain following knee arthroplasty or pain following hip arthroplasty, post-operative pain following gynecological surgery, post-operative pain following caesarean section, post-mastectomy pain syndrome (PMPS), post-operative pain following abdominoplasty, post-operative pain following laminectomy, post-operative pain following hemorrhoid removal, or post-operative pain following thoracotomy.
108. The method of claim 104, wherein the pain is dental pain, and the dental pain is toothache or post-operative pain after dental surgery.
109. The method of claim 104, wherein the pain is dental pain, and the dental pain is pain after dental extraction.
110. The method of claim 104, wherein the pain is dysmenorrhea pain, episiotomy pain, endometriosis pain, or post-partum cramping pain.
111. The method of claim 104, wherein the pain is headache pain, and the headache pain is migraine pain, tension headache pain, or cluster headache pain.
112. The method of claim 104, wherein the pain is ocular pain, and the ocular pain is postoperative pain after cataract surgery, post-operative pain after refractive surgery, ocular pain from a non-penetrating wound, foreign body sensation ocular pain, burning or stinging of the eye, uveitis pain, iritis pain, retinopathy pain or optic neuritis pain.
113. The method of any one of claims 95 to 112, wherein the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof are administered simultaneously or sequentially.
114. The method of any one of claims 95 to 112, wherein the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof are administered simultaneously.
115. The method of any one of claims 95 to 114, wherein the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof are administered each in an individual dosage form.
116. The method of any one of claims 95 to 114, wherein the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof are administered in a single dosage form.
117. The method of any one of claims 95 to 116, wherein the COX inhibitor and the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof are administered orally.
118. The method of any one of claims 95 to 117, wherein the COX inhibitor is administered at a dose of 0.1 to 20 mg/kg.
119. The method of any one of claims 95 to 118, wherein the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof is administered at a dose of 0.1 to 30 mg/kg, preferably 0.1 to 15 mg/kg.
120. The method of any one of claims 95 to 119, wherein the subject is a mammal.
121 . The method of any one of claims 95 to 120, wherein the subject is a human.
122. A kit comprising a first single dose form of a cyclooxygenase (COX) inhibitor and a second single dose form of a compound having the Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined in any one of claims 1 to 65, and instructions for use.
123. The kit of claim 122, wherein the COX inhibitor comprises a Non-Steroidal Anti- Inflammatory Drug (NSAID).
124. The kit of claim 123, wherein the NSAID is selected from the group consisting of Bromfenac, Celecoxib, Diclofenac, Etodolac, Flurbiprofen, Ibuprofen, Indomethacin, Ketoprofen, Ketorolac, Mefenamic acid, Meloxicam, Nabumetone, Naproxen, Nepafenac, Piroxicam, Sulindac, Tenoxicam, Tiaprofenic acid, Diflunisal, Etoricoxib, Fenoprofen, Floctafenine, Lumiracoxib, Oxaprozin, Parecoxib, Rofecoxib, Tolmetin, Valdecoxib, Meclofenamic acid, Dexketoprofen, Licofelone, Lornoxicam, Loxoprofen, Nimesulide, Tolfenamic acid, Phenylbutazone, Firocoxib, Salsalate, Choline Magnesium Trisalicylate, Acetylsalicylic acid, any pharmaceutically acceptable salt thereof, and any combination thereof.
125. The kit of claim 123, wherein the NSAID is Naproxen, Celecoxib, Diclofenac, Ibuprofen, a pharmaceutically acceptable salt thereof, or any combination thereof.
126. The kit of claim 122, wherein the COX inhibitor is acetaminophen.
127. The kit of any one of claims 122 to 126, wherein the first single dose form comprises the COX inhibitor in an amount ranging from about 1 mg to about 1000 mg and the second single dose form comprises the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, or prodrug thereof in an amount ranging from about 1 mg to about 1000 mg.
128. The kit of any one of claims 122 to 127, for use in the treatment of pain.
129. The kit for use of claim 128, wherein the pain is inflammatory pain, neuropathic pain or cancer pain.
130. The kit for use of claim 128 or 129, wherein the pain is inflammatory pain.
131. The kit for use of claim 128 or 129, wherein the pain is neuropathic pain.
132. The kit for use of claim 128 or 129, wherein the pain is cancer pain.
133. The kit for use of any one of claims 128 to 130, wherein the pain is arthritis pain, pain associated with musculoskeletal trauma or soft tissue trauma, post-operative pain, dental pain, dysmenorrhea pain, episiotomy pain, endometriosis pain, post-partum pain, headache pain, ocular pain, bursitis pain, or tendinitis pain.
134. The kit for use of any one of claims 128 to 130, wherein the pain is arthritis pain, and the arthritis pain is osteoarthritis pain, rheumatoid arthritis pain, ankylosing spondylitis pain, gout pain, or periarthritis pain.
135. The kit for use of any one of claims 128 to 130, wherein the pain is pain associated with musculoskeletal trauma or soft tissue trauma, and the pain associated with musculoskeletal trauma or soft tissue trauma is pain associated with a sprain or pain associated with a strain.
136. The kit for use of any one of claims 128 to 130, wherein the pain is post-operative pain, and the post-operative pain is post-operative pain following minor surgery, post-operative pain following general surgery, post-operative pain following orthopaedic surgery, post-operative pain following bunionectomy, post-operative pain following hernioplasty, post-operative pain following herniorrhaphy, post-operative pain following arthroplasty including pain following knee arthroplasty or pain following hip arthroplasty, post-operative pain following gynecological surgery, post-operative pain following cesarean section, post-mastectomy pain syndrome (PMPS), post-operative pain following abdominoplasty, post-operative pain following laminectomy, post-operative pain following hemorrhoid removal, or post-operative pain following thoracotomy.
137. The kit for use of any one of claims 128 to 130, wherein the pain is dental pain, and the dental pain is toothache or post-operative pain after dental surgery.
138. The kit for use of any one of claims 128 to 130, wherein the pain is dental pain, and the dental pain is pain after dental extraction.
139. The kit for use of any one of claims 128 to 130, wherein the pain is dysmenorrhea pain, episiotomy pain, endometriosis pain, or post-partum cramping pain.
140. The kit for use of any one of claims 128 to 130, wherein the pain is headache pain, and the headache pain is migraine pain, tension headache pain, or cluster headache pain.
141. The kit for use of any one of claims 128 to 130, wherein the pain is ocular pain, and the ocular pain is post-operative pain after cataract surgery, post-operative pain after refractive surgery, ocular pain from a non-penetrating wound, foreign body sensation ocular pain, burning or stinging of the eye, uveitis pain, iritis pain, retinopathy pain or optic neuritis pain.
142. The kit for use of any one of claims 128 to 141 , wherein the treatment is an oral treatment.
PCT/CA2024/051045 2023-08-11 2024-08-08 Pharmaceutical combinations comprising a substituted thiophene fused cyclohexanone derivative and a cyclooxygenase (cox) inhibitor, and their use for the treatment of pain Pending WO2025035205A1 (en)

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Citations (3)

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WO2008124496A1 (en) * 2007-04-03 2008-10-16 Parion Sciences, Inc. Method of treating acid-sensing ion channel mediated pain, cough, and central nervous system disorders
WO2024192522A1 (en) * 2023-03-21 2024-09-26 Neurasic Therapeutics Inc. Substituted thiophene fused derivatives, compositions comprising the same and their use as pharmaceuticals
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WO2024192522A1 (en) * 2023-03-21 2024-09-26 Neurasic Therapeutics Inc. Substituted thiophene fused derivatives, compositions comprising the same and their use as pharmaceuticals
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VARRASSI GIUSTINO, YEAM CHENG TENG, REKATSINA MARTINA, PERGOLIZZI JOSEPH V., ZIS PANAGIOTIS, PALADINI ANTONELLA: "The Expanding Role of the COX Inhibitor/Opioid Receptor Agonist Combination in the Management of Pain", DRUGS, ADIS INTERNATIONAL, AUCKLAND, vol. 80, no. 14, 1 September 2020 (2020-09-01), Auckland, pages 1443 - 1453, XP093282393, ISSN: 0012-6667, DOI: 10.1007/s40265-020-01369-x *

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