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BR-112019011044-B1 - PYRAZOLE SUBSTITUTED COMPOUNDS, THEIR USE, AND PHARMACEUTICAL COMPOSITION

BR112019011044B1BR 112019011044 B1BR112019011044 B1BR 112019011044B1BR-112019011044-B1

Abstract

The present invention discloses compounds useful, for example, in methods of treating hyperproliferative disorders such as cancer, methods of cell cycle arrest in cancer cells, methods of inhibiting glutathione synthesis in cancer cells, and associated compounds for use in medicines. In certain embodiments, the methods, uses and compounds are provided with reference to compounds with structural formulas (Ia), (Ib), (Ic), (Id) and (Ie), characterized in that R1, L1, L2, Q, G3, R3, L4, R4, G5, and R5s are as described herein. In certain embodiments, the compounds described herein are especially active against cancers that have a mutant KRAS gene.

Inventors

  • M. Arshad Siddiqui
  • MATTHEW W. KOSTURA
  • Michael Luther
  • Jedd Levine
  • Stephane Ciblat
  • Martin Dery
  • Lea Constantineau-Forget
  • Chantal Grand-Maitre
  • Nicolas Bruneau-Latour
  • GERALD W. SHIPPS
  • ALAN B. COOPER
  • Vibha Oza

Assignees

  • BANTAM PHARMACEUTICAL, LLC

Dates

Publication Date
20260310
Application Date
20171129
Priority Date
20161130

Claims (20)

  1. 1. Compound, characterized by the fact that it has the Structural Formula (Ia): optionally in the form of a pharmaceutically acceptable salt, wherein L1 is selected from the group consisting of a single linkage, -S-, -S(O)1-2- and -O-, and R1 is selected from C1-C8 alkyl and C1-C8 alkenyl, each unsubstituted or fluorinated; or L1 is a single linkage and R1 is selected from the group consisting of phenyl and monocyclic heteroaryl, each optionally substituted by 1 to 5 R1E, wherein each R1E is independently selected from oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R1F, -SR1F, -S(O)1-2R1F, -OR1F, -(OCH2CH2O)n-R1G where n is 1 to 4, -N(R1G)C(O)CH2-O- (CH2CH2O)nR1G where n is 0 to 3, -C(O)NR1G(CH2CH2O)nR1G, -NR1GR1F and -C(O)R1F; each R1F is independently selected from H, C1-C3 alkyl and C1-C3 fluoroalkyl and each R1G is independently selected from H and C1-C3 alkyl; L2 is selected from the group consisting of a linkage, -CH2-, -CH(CH3)- and -CH2CH2-; Q is selected from the group consisting of -CH2OH, -C(O)OH and -C(O)OR2A, wherein each R2A is independently selected from H and C1-C3 alkyl; L3 is a linkage; R3 is a monocyclic phenyl or heteroaryl, each optionally substituted by 1 to 5 R3E, wherein each R3E is independently selected from oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R3F, -SR3F, -S(O)1-2R3F, -OR3F, -NR3GR3F, -C(O)R3F, -C(O)NR3GR3F, -NR3GC(O)R3F, -C(S)NR3GR3F, -NR3GC(S)R3F, -C(O)OR3 F, -OC(O)R3F, -C(O)SR3F, -SC(O)R3F, -C(S)OR3F, -OC(S)R3F, -C(S)SR3F, -SC(S)R3F, -S(O)1-2OR3F, -OS(O)1-2R3F, -S(O)1-2NR3GR3F, -NR3GS(O)1-2R3F; Each R3F is independently selected from H, C1-C3 alkyl and C1-C3 fluoroalkyl; each R3G is independently selected from H and C1-C3 alkyl, C1-C3 fluoroalkyl; L4 is a linkage; R4 is selected from the group consisting of hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkenyl and optionally substituted C1-C8 alkynyl; L5 is a linkage; eR5 is aryl, heteroaryl, cycloalkyl or heterocycloalkyl monocyclic, each being (i) optionally substituted by a single substituent selected from -L5C- (monocyclic cycloalkyl optionally substituted by 1 to 5 R5D) and -L5C- (monocyclic heterocycloalkyl optionally substituted by 1 to 5 R5D), and (ii) optionally substituted by 1 to 5 R5E, wherein each L5C is a methylene, ethylene, -C(O)-, -S-, -S(O)1-2-, -O- or -NR3G- linkage; each R5D is independently selected from oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R5F, -SR5F, -S(O)1-2R5F, -OR5F, -NR5GR5F, -C(O)R5F, -C(O)NR5GR5F, -NR5GC(O)R5F, -C(S)NR5GR5F, -NR5GC(S)R5F, -C(O)OR5F, -OC(O)R5F, -C(O)SR5F, -SC(O)R5F, -C(S)OR5F, -OC(S)R5F, -C(S)SR5F, -SC(S)R5F, -S(O)1-2OR5F, -OS(O)1-2R5F, -S(O)1-2NR5GR5F and -NR5GS(O)1-2R5F; each R5E is independently selected from oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, -SF5, -N3, -C(O)R5F, -SR5F, -S(O)1-2R5F, -OR5F, -NR5GR5F, -C(O)R5F, -C(O)NR5GR5F, -NR5GC(O)R5F, -C(S)NR5GR5F, -NR1GC(S)R5F, -C(O)OR5F, -OC(O)R5F, -C(O)SR5F, -SC(O)R5F, -C(S)OR5F, -OC(S)R5F, -C(S)SR5F, -SC(S)R5F, -S(O)1-2OR5F, -OS(O)1-2R5F, -S(O)1-2NR5GR5F and -NR5GS(O)1-2R5F; each R5F is independently selected from H, C1-C3 alkyl and C1-C3 fluoroalkyl and each R5G is independently selected from H and C1-C3 alkyl; provided that R5 is cycloalkyl or heterocycloalkyl, each (i) optionally substituted by a single substituent selected from L5C-(monocyclic cycloalkyl optionally substituted by 1-5 R5D) and L5C-(monocyclic heterocycloalkyl optionally substituted by 1-5 R5D), and (ii) optionally substituted by 1-5 R5E, where L1 is selected from the group consisting of a linkage, -S-, -S(O)1-2 and O, and R1 is selected from C1-C8 alkyl and unsubstituted or fluorinated C1C8 alkenyl; wherein each optionally substituted alkyl, alkenyl, and alkynyl group is unsubstituted, fluorinated, or substituted with one or two hydroxyl groups; each cycloalkyl group has 3 to 10 ring carbons and is unsaturated or partially unsaturated, and optionally includes one or two fused cycloalkyl rings, each fused ring having 3 to 8 ring members; each heterocycloalkyl group has 3 to 10 ring members and 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and is unsaturated or partially unsaturated, and optionally includes one or two fused cycloalkyl rings, each having 3 to 8 ring members; each monocyclic heteroaryl group is a 5 to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally includes one or two fused cycloalkyl or heterocycloalkyl rings, each ring having 3 to 8 ring members. fused cycloalkyl or heterocycloalkyl has 4 to 8 ring members; wherein the compound is different from 1-(4-(cyclohex-1-en-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazol-5-carboxylic acid or 1-(4-(cyclopent-1-en-1-yl)-5-(isopropylthio)thiazol-2-yl)- 4-(3-fluorophenyl)-3-methyl-1H-pyrazol-5-carboxylic acid.
  2. 2. Compound according to claim 1, characterized in that (a) L1 is selected from the group consisting of an S, S(O)1-2 and -O- linkage, and R1 is selected from C1-C8 alkyl and C1-C8 alkenyl, each unsubstituted or fluorinated.
  3. 3. Compound according to claim 2, characterized in that R1 is C1-C8 alkyl or unsubstituted or fluorinated C1-C8 alkyl.
  4. 4. Compound according to claim 2, characterized in that R1 is either unsubstituted C1-C8 alkenyl or fluorinated C1-C8 alkenyl.
  5. 5. Compound according to any one of claims 2 to 4, characterized in that L1 is -S-.
  6. 6. A compound according to any one of claims 2 to 4, characterized in that L1 is a bond.
  7. 7. Compound according to claim 1, characterized in that (b) L1 is a linkage, and R1 is selected from the group consisting of monocyclic phenyl and heteroaryl, each optionally substituted by 15 R1E.
  8. 8. Compound according to claim 1 or 7, characterized in that: R1 is phenyl and optionally substituted with 1 to 5 R1E.
  9. 9. Compound according to any one of claims 1 to 8, characterized in that: L2 is a bond, and Q is -C(O)OH.
  10. 10. Compound according to any one of claims 1 to 9, characterized in that R3 is an aryl (e.g., a phenyl) optionally substituted with 1 to 5 R3E.
  11. 11. Compound, according to any one of claims 1 to 9, characterized in that R3 is a monocyclic heteroaryl optionally substituted with 1 to 5 R3E.
  12. 12. Compound according to claim 11, characterized in that the monocyclic heteroaryl is an isothiazole, a pyridone, a thiadiazole, a pyrazine, an imidazole, a pyridine, a pyrazole, an isoxazole, a thiophene, a benzothiophene, a furan or a pyrimidine.
  13. 13. Compound according to any one of claims 1 to 12, characterized in that: R4 is hydrogen or optionally substituted C1-C6 alkyl.
  14. 14. Compound according to any one of claims 1 to 12, characterized in that R4 is an unsubstituted C1-C6 alkyl.
  15. 15. A compound, according to any one of claims 1 to 14, characterized in that R5 is a monocyclic phenyl or heteroaryl group, each optionally substituted with 1 to 5 R5E.
  16. 16. Compound according to any one of claims 1 to 14, characterized in that R5 is a heterocycloalkyl group optionally substituted with 1 to 5 R5E.
  17. 17. Compound according to any one of claims 1 to 14, characterized in that (i) R5 is a heterocycloalkyl substituted with a single -L5C- substituent (monocyclic cycloalkyl optionally substituted with 1 to 5 R5D) and (ii) optionally substituted with 1 to 5 R5E.
  18. 18. Compound according to claim 16 or 17, characterized in that the heterocycloalkyl is a nitrogen-containing heterocycloalkyl linked to -L5- through a nitrogen atom.
  19. 19. Compound, of any one of claims 1 to 14, characterized in that R5 is cycloalkyl optionally substituted by 1 to 5 R5E.
  20. 20. Compound, of any one of claims 1 to 14, characterized in that R5 is a cycloalkyl substituted with a single substituent -L5C- (monocyclic cycloalkyl optionally substituted with 1 to 5 R5D), and (ii) optionally substituted with 1 to 5 R5E.

Description

CROSS-REFERENCE TO RELATED REQUESTS [0001] This application claims the benefit of priority of U.S. Provisional Patent Application 62/428,271, filed November 30, 2016, which is incorporated herein by reference in its entirety. BACKGROUND OF THE DESCRIPTION FIELD [0002] This description refers to the field of compounds, pharmaceutical compositions comprising them, and methods of use of the compounds and compositions. This description refers more particularly to methods of using certain compounds for the treatment of hyperproliferative disorders such as cancer. TECHNICAL CONTEXT [0003] Cancer, an uncontrolled proliferation of cells, is a multifactorial disease characterized by tumor formation, growth, and, in some cases, metastasis. In the United States, this year, more than 1.5 million people will be diagnosed with cancer, and more than 500,000 people will die from cancer. Overall, it is estimated that at least one in three people will develop some type of cancer during their lifetime. There are more than 200 different histopathological types of cancer, with breast, lung, colorectal, and prostate cancer accounting for more than half of all new cases in the U.S. Current cancer therapies vary depending on the location and stage of the cancer, but generally include a combination of surgery, systemic therapy, radiation therapy, and chemotherapy. Despite the effort that has been dedicated to developing anticancer strategies, many remain ineffective for specific cancers. [0004] The uncontrolled cell proliferation that represents the essence of cancer involves not only the dysregulated control of cell proliferation, but also the corresponding adjustments of energy metabolism in order to stimulate cell growth and division. The reprogramming of cellular metabolism is emerging as an important molecular hallmark of cancer cells. Under aerobic conditions, normal cells process glucose, first to pyruvate through glycolysis in the cytosol and then to carbon dioxide in the mitochondria; under anaerobic conditions, glycolysis is favored and relatively little pyruvate is dispatched to the oxygen-consuming mitochondria. When growth factors and nutrients are abundant, oncogenic signaling pathways direct increased metabolism, leading to increased synthesis of macromolecules such as lipids, proteins, and nucleic acids. The net effect is the support of cell growth and proliferation. During tumor formation, however, an aggressive, anoxic, and nutrient-deprived environment challenges the cell and its ability to maintain metabolic homeostasis. Cancer cells can reprogram their glucose metabolism, and thus their energy production, limiting their energy metabolism largely to glycolysis, which was seen by early biochemists as primitive and inefficient. Despite these initial beliefs, the metabolic signatures of cancer cells are not passive responses to damaged mitochondria, but result from oncogenic-directed metabolic reprogramming necessary to support anabolic growth. Oncogenic mutations that allow for increased and more efficient use of scarce nutrients present unique targets in cancer treatment. SUMMARY OF DESCRIPTION [0005] In one aspect, the invention provides compounds with one of the Structural Formulas (Ia) to (Ie): [0006] optionally in the form of a pharmaceutically acceptable salt or N-oxide, and/or a solvate or hydrate, wherein [0007] L1 is selected from a group consisting of a link, -C(O)-, -S-, -S(O)1-2-, -O-, -NR6-, -C(O)NR6-, -NR6C(O)-, -C(S)NR6-, -NR6C(S)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -S(O)1-2O-, -OS(O)1-2-, -S(O)1-2NR6- and -NR6S(O)1-2-; [0008] R1 is selected from a group consisting of [0009] hydrogen, [0010] C1-C8 alkyl, C1-C8 alkenyl and C1-C8 alkynyl, each unsubstituted or fluorinated, [0011] cycloalkyl and heterocycloalkyl, each optionally substituted with 1 to 2 R1E, and [0012] monocyclic phenyl and heteroaryl, each optionally substituted with 1 to 5 R1E, [0013] in which [0014] each R1E is independently selected from oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R1F, -SR1F, -S(O)1-2R1F, -OR1F, -(OCH2CH2O)n-R1G where n is 1-4, -N(R1G)C(O)CH2-O-(CH2CH2O)nR1G where n is 0-3, -C(O)NR1G(CH2CH2O)n R1G, -NR1GR1Fe -C(O)R1F; [0015] each R1F is independently selected from H, C1-C3 alkyl and C1-C3 fluoroalkyl and [0016] each R1G is independently selected from H and C1C3 alkyl; [0017] L2 is selected from the group consisting of a linkage, -CH2-, -CH(CH3)- or -CH2CH2-; [0018] Q is selected from the group consisting of H, -CH2OH, -C(O)OH, -C(O)OR2A, -C(O)NR2BR2A, -C(O)NR2BS(O)2R2A, -C(O)NR2BS(O)2NR2BR2A, -C(O)R2A, -S(O)2OH, -P(O)(OH)2, -C(OH)(CF3)2, S(O)2R2A, -N(R2B)S(O)2R2A, -S(O)2NR2BR2A, -C(O)NHOH, -C(O)NH-O(C1-C3 alkyl), and -CO(NH)CN, wherein [0019] each R2A is independently selected from H and C1C3 alkyl and [0020] each R2B is independently selected from H and C1C3 alkyl; [0021] L3 is a linkage, -C(O)-, -S-, -S(O)1-2-, -O-, -NR6-, -CH2-, -C