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WO2025241048A1 - Inhibiteurs de lactate déshydrogénase, compositions comprenant l'inhibiteur, et leurs procédés d'utilisation - Google Patents

Inhibiteurs de lactate déshydrogénase, compositions comprenant l'inhibiteur, et leurs procédés d'utilisation

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Publication number
WO2025241048A1
WO2025241048A1 PCT/CN2024/094118 CN2024094118W WO2025241048A1 WO 2025241048 A1 WO2025241048 A1 WO 2025241048A1 CN 2024094118 W CN2024094118 W CN 2024094118W WO 2025241048 A1 WO2025241048 A1 WO 2025241048A1
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Prior art keywords
groups
alkyl
substituted
unsubstituted
independently selected
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PCT/CN2024/094118
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English (en)
Inventor
Ke Xu
Anjin XIANYU
Helmut Haning
Shiqiang ZHOU
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Meta Pharmaceuticals Hk Ltd
Shenzhen Moyuan Pharmaceuticals
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Meta Pharmaceuticals Hk Ltd
Shenzhen Moyuan Pharmaceuticals
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Priority to PCT/CN2024/094118 priority Critical patent/WO2025241048A1/fr
Priority to PCT/CN2025/095852 priority patent/WO2025242055A1/fr
Publication of WO2025241048A1 publication Critical patent/WO2025241048A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present disclosure relates to novel compounds that can serve as inhibitors of lactate dehydrogenase, pharmaceutical compositions, comprising at least one of such compounds, and methods of using at least one of such compounds in treating or preventing diseases associated with lactate dehydrogenase activities, such as autoimmune diseases.
  • Lactate dehydrogenase is an important enzyme of the glucose metabolism. It belongs to the class of oxidoreductases and functions to catalyze the reversible conversion of lactate to pyruvate with the reduction of NAD+ to NADH and vice versa.
  • LDH is a tetrameric protein composed of the products of the LDHA (subunit M) and LDHB (subunit H) genes. The tetrameric combination of these gene products generates 5 LDH isoforms with different combinations of subunits depending on the cell type. All LDH isoforms catalyze the last step in the glycolytic pathway converting pyruvate to lactate while regenerating NAD+from NADH. This reaction is important for the production of ATP through glycolysis.
  • Lactate dehydrogenase inhibition has been considered as a therapeutic option for cancer treatment.
  • Cancer cells exhibit metabolic characteristics that are different from normal cells. Cancer cells prefer glycolysis over mitochondrial oxidative phosphorylation to regenerate NAD+ and produce essential cellular building blocks, such as amino acids, lipids, and nucleotides that are needed to support rapid cell growth. While aerobic glycolysis is an inefficient way to generate ATP in comparison with oxidative phosphorylation, it generates ATP rapidly. Many non-cancer cells use a combination of oxidative phosphorylation and glycolysis to achieve the metabolic plasticity that is needed to serve their biological functions. The preference of cancer cells for aerobic glycolysis and the enzymes in glycolysis have long been recognized as potential targets for the selective killing of cancer cells. Cancer cells overexpress many glycolytic enzymes, including lactate dehydrogenase (LDH) enzymes A (LDHA) and B (LDHB) .
  • LDH lactate dehydrogenase
  • Lactate dehydrogenase A (LDHA) inhibition attracts more attention, since it can help regulate the metabolic activity of cells. Genetic knockdown of LDHA has been shown to elicit cell death or delay cell growth in various cell lines, while knockdown of lactate dehydrogenase B (LDHB) has been reported to be less effective in impacting survival of tumor cells. Inhibition of LDHA can lead to a decrease in lactate production and an increase in oxidative phosphorylation, which can help regulate cellular metabolism. Therefore, LDHA inhibition is not only considered as a potential treatment of cancers, but in general a potential treatment of metabolic disorders and other diseases that are associated with altered cellular functions.
  • LDHA inhibition is not only considered as a potential treatment of cancers, but in general a potential treatment of metabolic disorders and other diseases that are associated with altered cellular functions.
  • thiazolyl-based compounds substituted with a thiazolyl group that is substituted or unsubstituted for use in inhibiting lactase dehydrogenase activity and for the treatment of one or more symptoms of hyperoxaluria, including primary hyperoxaluria and stone formation in the kidney and urinary tract were known. See WO2021234543A1 and WO2021234547A1.
  • thiazole carboxylic acid was considered as a critical substitute, and replacement of the thiazole carboxylic acid with other rings, such as oxazole, pyridine, and other heterocycles, was reported to be markedly detrimental to the activity of compounds. See J. Med. Chem., 60 (22) , pp. 9184-9204 (2017) .
  • substituted pyrazolyl compounds which inhibit lactase dehydrogenase activity and could be used for treating cancer, have also been known. See J. Med. Chem. 63 (19) , pp. 10984-11011 (2020) ; J. Med. Chem., 60 (22) , pp. 9184-9204 (2017) ; Bioorg. Med. Chem. Lett. 41, Article 127974 (2021) ; WO2016109559A2; and WO2018005807A1.
  • the present disclosure relates to compounds that can serve as inhibitors of lactate dehydrogenase A, compositions comprising at least one of such compounds, and methods of uses thereof.
  • One objective of the present disclosure is to provide a compound of formula I, a stereoisomer, a tautomer, an isotope labeled compound, or a pharmaceutically acceptable salt thereof:
  • Z 1 and Z 2 are each independently selected from CH and N;
  • ring A is not a pyrazole ring
  • ring A is a five-membered heterocyclic moiety which is aromatic or partially unsaturated, in which:
  • X 1 , X 2 , X 3 , X 4 , and X 5 are each independently selected from CR 5 and NR 5 ;
  • each R 5 is independently absent or selected from hydrogen, halogen, hydroxyl, carboxyl, cyano, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 cycloalkyl, and substituted or unsubstituted C1-C6 alkoxyl,
  • each substituent group is independently selected from halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COO (C1-C6 alkyl) , - C (O) NH 2 , -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and -SO 2 N (C1-C6 alkyl) (C1-C6 alkyl) ;
  • ring A is a five-membered heterocyclic moiety which is aromatic or partially unsaturated, in which:
  • X 1 , X 2 , X 3 and X 5 are each independently selected from C or N;
  • X 4 is selected from CR 5 and NR 5 ;
  • ring A three or four ring atoms in ring A are carbon atoms
  • each R 5 is independently selected from hydrogen, halogen, hydroxyl, carboxyl, cyano, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 cycloalkyl, and substituted or unsubstituted C1-C6 alkoxyl;
  • each substituent group is independently selected from halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COO (C1-C6 alkyl) , -C (O) NH 2 , -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and -SO 2 N (C1-C6 alkyl) (C1-C6 alkyl) ;
  • ring A comprises a structure selected from:
  • ring A comprises a structure selected from:
  • Ar 1 is a substituted or unsubstituted six-membered aromatic ring, preferably Ar 1 is selected from substituted or unsubstituted phenyl, and substituted or unsubstituted six-membered heteroaryl groups with 1 to 3 hetero atoms, such as nitrogen atom; in which each substituent group is independently selected from halogen, hydroxyl, cyano, carboxyl, deuterium, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COOR c , -CONR d R e , -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl)
  • Ar 1 is a substituted six-membered aromatic ring, preferably Ar 1 is selected from substituted phenyl and substituted six-membered heteroaryl groups with 1 to 3 hetero atoms, such as nitrogen atom; each substituent group is independently selected from halogen, hydroxyl, cyano, carboxyl, deuterium, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COO (C1-C6 alkyl) , -C (O) NH 2 , -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and -SO 2 N (C1-C6
  • Ar 1 has a structure selected from: in which R 6 is selected from halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, -COOR c , -CONR d R e , and -SO 2 NR d R e , wherein R c , R d , and R e are each independently selected from hydrogen, and C1-C6 alkyl groups, and m is 0, 1 or 2;
  • Ar 1 is wherein E 1 , E 2 , E 3 and E 4 are each independently selected from N and CR f , and at least one of E 1 , E 2 , E 3 and E 4 is N; R f is halogen, hydroxyl, cyano, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups; R c is hydrogen or C1-C6 alkyl groups.
  • Ar 1 is wherein E 1 , E 2 , E 3 and E 4 are each independently selected from N and CR f , and at least one of E 1 , E 2 , E 3 and E 4 is N; R f is halogen, hydroxyl, cyano, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups; R c is hydrogen or C1-C6 alkyl groups.
  • R 3 is selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C1-C6 alkoxyl groups, substituted or unsubstituted four-to six-membered heterocyclic groups with one or two hetero atoms each independently selected from N, O, and S, substituted or unsubstituted C6-C10 aryl groups, and substituted or unsubstituted five-to ten-membered heteroaryl groups with one or two or three heteroatoms each independently selected from N, O, and S, substituted or unsubstituted C3-C8 cycloalkoxy groups, substituted or unsubstituted four-to six-membered heterocycloalkoxy groups with one or two hetero atoms each independently selected from N, O, and S, substituted or unsubstituted C6-C10 aryloxy groups, and
  • substituent group is each independently selected from oxo, hydroxyl, halogen, C1-C6 alkyl groups, C6-C10 aryl groups, and C3-C6 cycloalkyl groups;
  • L 1 is selected from -CR 1 R 2 -, -CO-, -O-, -NH-, and -S-;
  • R 1 and R 2 are each independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted C1-C4 alkyl groups, and substituted or unsubstituted C1-C4 alkoxyl groups, and in which the substituent group is each independently selected from halogen, hydroxyl, C1-C6 alkyl groups, and C3-C6 cycloalkyl groups; or wherein R 1 and R 2 , together with the atom to which they are bound, to form a C3-C6 cycloalkyl group;
  • ring B is selected from substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocyclic alkyl, substituted or unsubstituted six-to ten-membered aryl, and substituted or unsubstituted five-to ten-membered heteroaryl comprising one to three heteroatoms each independently selected from N, O, and S;
  • each substituent group is independently selected from halogen, hydroxyl, cyano, oxo, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COO (C1-C6 alkyl) , -C (O) NH 2 , -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and -SO 2 N (C1-C6 alkyl) (C1-C6 alkyl) ;
  • ring B is selected from a substituted or unsubstituted C4-C8 cycloalkyl, a substituted or unsubstituted C4-C8 heterocyclic alkyl comprising one to three heteroatoms each independently selected from N, O, and S, a substituted or unsubstituted six-to ten-membered aryl, and a substituted or unsubstituted five-to eight-membered heteroaryl comprising one to three heteroatoms each independently selected from N, O, and S; in which each substituent group is preferably independently selected from halogen, hydroxyl, cyano, oxo, carboxyl, and C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group,
  • ring B is selected from:
  • ring B is substituted by substituents each independently selected from halogen, hydroxyl, cyano, oxo, carboxyl, and C1-C6 alkyl groups;
  • R 4 is each independently selected from halogen, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, substituted or unsubstituted C6-C10 aryl group, a hydroxyl group, carboxyl, -NH (C1-C6 alkyl) , -SO 2 NR a R b , -CONR a R b , and -N (C1-C6 alkyl) (C1-C6 alkyl) ; in which R a and R b are each independently selected from hydrogen, C1-C6 alkyl groups, C1-C6 haloalkyl groups, and C3-C6 cycloalkyl groups;
  • substituent group is each independently selected from halogen, hydroxyl, cyano, carboxyl, -C (O) NH 2 , -NH-COOH, C1-C6 alkyl groups, and C3-C6 cycloalkyl groups; and n is an integer selected from 0, 1, 2, 3, and 4;
  • R 4 is each independently selected from fluorine, chlorine, and -SO 2 NH 2 ;
  • L 2 is a linker comprising an unsaturated or aromatic moiety, preferably L 2 is selected from C2-C4 alkenylene groups, C2-C4 alkynylene groups, six-membered aromatic groups, and five-to six-membered heteroaromatic groups with one or two or three hetero atoms each independently selected from N, O, and S; in which, each hydrogen in L 2 is independently substituted by substituents selected from halogen, cyano, carboxyl, hydroxyl, -C (O) NH 2 , -C (O) N (CH 3 ) 2 , -NH-COOH, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halocycloalkyl groups, and amino group;
  • L 2 is selected from in which R’ is selected from a halogen, cyano, carboxyl, hydroxyl, -C (O) NH 2 , -C (O) N (CH 3 ) 2 , -NH-COOH, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halocycloalkyl groups, and amino group;
  • hydrogen in L 2 is each independently substituted by substituents selected from halogen, cyano, carboxyl, hydroxyl, -C (O) NH 2 , -C (O) N (CH 3 ) 2 , -NH-COOH, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halocycloalkyl groups, and amino group;
  • Q is selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, -C (O) NH 2 , -C (O) N (C1-C6 alkyl) (C1-C6 alkyl) , -NH-COOH, -NH (C1-C6 alkyl) , C1-C6 alkyl-C (O) -NH-, C1-C6 haloalkoxy group, substituted or unsubstituted C1-C8 alkyl groups, C1-C6 alkylamino groups, amino groups, substituted or unsubstituted C3-C8 monocyclic or bicyclic alkyl groups, substituted or unsubstituted four-to six-membered heterocyclic groups with one to three hetero atoms each independently selected from N, O and S, substituted or unsubstituted six-to ten-membered aryl groups, and substituted or unsubstituted five-to ten-member
  • Q is selected from hydrogen, cyano, halogen, hydroxyl, carboxyl, -C (O) NH 2 , -C (O) N (CH 3 ) 2 , -NH-COOH, -CH 3 , -CF 3 , -CF 2 H, -CH 2 -CF 3 , -O-CH 3 , -O-CF 3 , -O-CF 2 H, -O-CH 2 -CF 3 , -CD 3 , -CN,
  • ring B comprises an aliphatic ring, an aromatic ring, or a partially saturated ring. In some embodiments, ring B is an aliphatic ring, an aromatic ring, or a partially saturated ring.
  • ring B is selected from substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocyclic alkyl, substituted or unsubstituted six-to ten-membered aryl, and substituted or unsubstituted five-to ten-membered heteroaryl comprising one to three heteroatoms each independently selected from N, O, and S; in which each substituent group is independently selected from halogen, hydroxyl, cyano, oxo, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COO (C1-C6 alkyl) , -C (O) NH 2
  • ring B is selected from a substituted or unsubstituted C4-C8 cycloalkyl, a substituted or unsubstituted C4-C8 heterocyclic alkyl comprising one to three heteroatoms each independently selected from N, O, and S, a substituted or unsubstituted six-to ten-membered aryl, and a substituted or unsubstituted five-to eight-membered heteroaryl comprising one to three heteroatoms each independently selected from N, O, and S; in which each substituent group is preferably independently selected from halogen, hydroxyl, cyano, oxo, carboxyl, and C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino
  • ring B is selected from a substituted or unsubstituted C5-C7 cycloalkyl, a substituted or unsubstituted C5-C7 heterocyclic alkyl comprising one to three heteroatoms each independently selected from N, O, and S, a substituted or unsubstituted six-membered aryl, and a substituted or unsubstituted five-to six-membered heteroaryl comprising one to three heteroatoms each independently selected from N, O, and S; in which each substituent group is preferably independently selected from halogen, hydroxyl, cyano, oxo, carboxyl, and C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -
  • ring B is optionally substituted by substituents each independently selected from halogen, hydroxyl, cyano, oxo, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COO (C1-C6 alkyl) , -C (O) NH 2 , -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and -SO 2 N (C1-C6 alkyl) (C1-C6 alkyl) .
  • substituents each independently selected from halogen, hydroxyl, cyano, oxo, carboxyl, C1-
  • ring B is optionally substituted by substituents each independently selected from halogen, hydroxyl, cyano, oxo, carboxyl, and C1-C6 alkyl groups.
  • ring B comprises a structure selected from
  • ring B is substituted by substituents independently selected from halogen, hydroxyl, cyano, oxo, carboxyl, and C1-C6 alkyl groups.
  • ring B comprises a structure selected from
  • ring A is an heteroaromatic ring, or a partially saturated ring, with the proviso that ring A is not a pyrazole ring.
  • ring A is not
  • ring A is a five-membered heteroaromatic ring, or a five-membered partially saturated ring, with the proviso that ring A is not a pyrazole ring.
  • ring A is a five-membered heterocyclic moiety which is aromatic or partially unsaturated, in which:
  • X 1 , X 2 , X 3 , X 4 , and X 5 are each independently selected from CR 5 and NR 5 ;
  • X 1 , X 2 , X 3 , X 4 , and X 5 are CR 5 ;
  • each R 5 is independently absent or selected from hydrogen, halogen, hydroxyl, carboxyl, cyano, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 cycloalkyl, and substituted or unsubstituted C1-C6 alkoxyl, wherein each substituent group is independently selected from halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COO (C1-C6 alkyl) , -C (O) NH 2 , -NH-COOH, -NH
  • ring A comprises a structure selected from:
  • ring A comprises a structure selected from:
  • Ar 1 is a six-membered aromatic or partially saturated ring.
  • Ar 1 is a six-membered aromatic or partially saturated ring, comprising 0 to 3 heteroatoms selected from N, S, and O.
  • Ar 1 is a six-membered aromatic or partially saturated ring which is optionally substituted by halogen, hydroxyl, cyano, carboxyl, -COOR c , -CONR d R e , and -SO 2 NR d R e , wherein R c , R d , and R e are each independently selected from hydrogen, and C1-C6 alkyl groups.
  • Ar 1 is selected from substituted or unsubstituted phenyl, and substituted or unsubstituted six-membered heteroaryl groups with 1 to 3 hetero atoms.
  • Ar 1 is selected from substituted or unsubstituted phenyl, and substituted or unsubstituted six-membered heteroaryl groups with 1 to 3 nitrogen atoms.
  • Ar 1 is selected from substituted or unsubstituted phenyl, and substituted or unsubstituted six-membered heteroaryl groups with 1 to 3 nitrogen atom; in which each substituent group is independently selected from halogen, hydroxyl, cyano, carboxyl, deuterium, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COOR c , -CONR d R e , -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and SO 2 NR d R e ; and wherein R c , R d , and
  • Ar 1 has a structure selected from:
  • R 6 is selected from halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, -COOR c , -CONR d R e , and -SO 2 NR d R e , wherein R c , R d , and R e are each independently selected from hydrogen, and C1-C6 alkyl groups;
  • n 0, 1 or 2.
  • Ar 1 is wherein E 1 , E 2 , E 3 and E 4 are each independently selected from N and CR f , and at least one of E 1 , E 2 , E 3 and E 4 is N; R f is halogen, hydroxyl, cyano, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups; R c is hydrogen or C1-C6 alkyl groups.
  • Ar 1 is wherein E 1 , E 2 , E 3 and E 4 are each independently selected from N and CR f , and at least one of E 1 , E 2 , E 3 and E 4 is N; R f is halogen, hydroxyl, cyano, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups; R c is hydrogen or C1-C6 alkyl groups.
  • L 2 is a linker comprising an unsaturated or aromatic moiety, preferably L 2 is selected from C2-C4 alkenylene groups, C2-C4 alkynylene groups, three-to six-membered aromatic groups, and three-to six-membered heteroaromatic groups with one or two or three hetero atoms each independently selected from N, O, and S.
  • each hydrogen in L 2 is each independently substituted by substituents selected from halogen, cyano, carboxyl, hydroxyl, -C (O) NH 2 , -C (O) N (CH 3 ) 2 , -NH-COOH, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halocycloalkyl groups, and amino group.
  • substituents selected from halogen, cyano, carboxyl, hydroxyl, -C (O) NH 2 , -C (O) N (CH 3 ) 2 , -NH-COOH, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halocycloalkyl groups, and amino group.
  • L 2 is selected from in which R’ is selected from halogen, cyano, carboxyl, hydroxyl, -C (O) NH 2 , -C (O) N (CH 3 ) 2 , -NH-COOH, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halocycloalkyl groups, and amino group.
  • R’ is selected from halogen, cyano, carboxyl, hydroxyl, -C (O) NH 2 , -C (O) N (CH 3 ) 2 , -NH-COOH, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halocycloalkyl groups, and amino group.
  • Q is selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, -C (O) NH 2 , -C (O) N (C1-C6 alkyl) (C1-C6 alkyl) , -NH-COOH, -NH (C1-C6 alkyl) , C1-C6 alkyl-C (O) -NH-, C1-C6 haloalkoxy group, substituted or unsubstituted C1-C8 alkyl groups, C1-C6 alkylamino groups, amino groups, substituted or unsubstituted C3-C8 monocyclic or bicyclic alkyl groups, substituted or unsubstituted four-to six-membered heterocyclic groups with one to three hetero atoms each independently selected from N, O and S, substituted or unsubstituted six-to ten-membered aryl groups, and substituted or unsubstituted five-to
  • Q is selected from hydrogen, cyano, halogen, hydroxyl, carboxyl, -C (O) NH 2 , -C (O) N (CH 3 ) 2 , -NH-COOH, -CH 3 , -CF 3 , -CF 2 H, -CH 2 -CF 3 , -O-CH 3 , -O-CF 3 , -O-CF 2 H, -O-CH 2 -CF 3 , -CD 3 , -CN,
  • R 3 is selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C1-C6 alkoxyl groups, substituted or unsubstituted four-to six-membered heterocyclic groups with one or two hetero atoms each independently selected from N, O, and S, substituted or unsubstituted C6-C10 aryl groups, and substituted or unsubstituted five-to ten-membered heteroaryl groups with one or two or three heteroatoms each independently selected from N, O, and S, substituted or unsubstituted C3-C8 cycloalkoxy groups, substituted or unsubstituted four-to six-membered heterocycloalkoxy groups with one or two hetero atoms each independently selected from N, O, and S, substituted or unsubstituted C6-C10 aryl
  • substituent group is each independently selected from oxo, hydroxyl, halogen, C1-C6 alkyl groups, C6-C10 aryl groups, and C3-C6 cycloalkyl groups.
  • R 3 is a substituted C1-C6 alkyl groups, C6-10 aryloxy, C3-C6 cycloalkoxy and substituted C1-C6 alkoxyl groups, wherein the substituent group is independently selected from hydroxyl, halogen, C1-C6 alkyl groups, and C3-C6 cycloalkyl groups; or R 3 and X 2 together form
  • R 3 is selected from or R 3 and X 2 together form
  • R 4 is each independently selected from halogen, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, substituted or unsubstituted C6-C10 aryl group, a hydroxyl group, carboxyl, -NH (C1-C6 alkyl) , -SO 2 NR a R b , -CONR a R b , and -N (C1-C6 alkyl) (C1-C6 alkyl) ; in which R a and R b are each independently selected from hydrogen, C1-C6 alkyl groups, C1-C6 haloalkyl groups, and C3-C6 cycloalkyl groups; wherein the substituent group is each independently selected from halogen, hydroxyl, cyano, carboxyl, -C (O) NH 2 , -NH-COOH, C1-C6 alkyl
  • R 4 is each independently selected from fluorine, chlorine, and -SO 2 NH 2 .
  • n 0, 1, 2, or 3.
  • L 1 is selected from -CR 1 R 2 -, -CO-, -O-, -NH-, and -S-; in which R 1 and R 2 are each independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted C1-C4 alkyl groups, and substituted or unsubstituted C1-C4 alkoxyl groups, and wherein the substituent group is each independently selected from halogen, hydroxyl, C1-C6 alkyl groups, and C3-C6 cycloalkyl groups; or R 1 and R 2 , together with the atom to which they are bound, to form a C3-C6 cycloalkyl group.
  • L 1 is selected from -CH 2 -, -CHF-, -CHOH-, -CO-, -O-, -NH-, and -S.
  • L 1 can be absent.
  • a compound of the present disclosure has a structure of any one of Formula II
  • Z 1 and Z 2 are each independently selected from CH and N;
  • ring A is not a pyrazole ring
  • ring A is a five-membered heterocyclic moiety which is aromatic or partially unsaturated, in which:
  • X 1 , X 2 , X 3 , X 4 , and X 5 are each independently selected from CR 5 and NR 5 ;
  • each R 5 is independently absent or selected from hydrogen, halogen, hydroxyl, carboxyl, cyano, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 cycloalkyl, and substituted or unsubstituted C1-C6 alkoxyl, wherein each substituent group is independently selected from halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COO (C1-C6 alkyl) , -C (O) NH 2 , -NH-COOH, -
  • ring A is a five-membered heterocyclic moiety which is aromatic or partially unsaturated, in which:
  • X 1 , X 2 , X 3 and X 5 are each independently selected from C or N;
  • X 4 is selected from CR 5 and NR 5 ;
  • ring A three or four ring atoms in ring A are carbon atoms
  • each R 5 is independently selected from hydrogen, halogen, hydroxyl, carboxyl, cyano, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 cycloalkyl, and substituted or unsubstituted C1-C6 alkoxyl;
  • each substituent group is independently selected from halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COO (C1-C6 alkyl) , -C (O) NH 2 , -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and -SO 2 N (C1-C6 alkyl) (C1-C6 alkyl) ;
  • ring A comprises a structure selected from:
  • ring A comprises a structure selected from:
  • Y 1 , Y 2 , Y 3 , and Y 4 of ring B are each independently selected from CR 7 and NR 7 ;
  • Y 5 is absent, CR 7 or NR 7 ;
  • each R 7 is independently absent or selected from hydrogen, halogen, hydroxyl, cyano, oxo, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COO (C1-C6 alkyl) , - C (O) NH 2 , -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and -SO 2 N (C1-C6 alkyl) (C1-C6 alkyl) ;
  • Y 1 , Y 2 , Y 3 , Y 4 and Y 5 of ring B are each independently selected from CR 7 and N;
  • Y 1 , Y 2 , Y 3 and Y 4 of ring B are each independently selected from CR 7 , N, NR 7 , O and S; and only one of Y 1 , Y 2 , Y 3 and Y 4 is NR 7 , O or S;
  • each R 7 is independently selected from hydrogen, halogen, hydroxyl, cyano, oxo, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino, four-to six-membered heterocycloalkyl groups optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano and oxo, -COO (C1-C6 alkyl) , -C (O) NH 2 , -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and -SO 2 N (C1-C6 alkyl) (C1-C6 al
  • each R 7 is independently absent or selected from hydrogen, halogen, hydroxyl, cyano, oxo, carboxyl, and C1-C6 alkyl groups;
  • each R 7 is independently absent or selected from hydrogen, halogen, and oxo;
  • ring B is selected from substituted or unsubstituted six-to ten-membered aryl, and substituted or unsubstituted five-to eight-membered heteroaryl comprising one to three heteroatoms each independently selected from N, O, and S; in which each substituent group is preferably independently selected from halogen, hydroxyl, cyano, oxo, carboxyl, and C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COO (C1-C6 alkyl) , -C (O) NH 2 , -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alky
  • ring B is selected from:
  • ring B is optionally substituted by substituents each independently selected from halogen, hydroxyl, cyano, oxo, carboxyl, and C1-C6 alkyl groups;
  • Ar 1 is a substituted or unsubstituted six-membered aromatic ring, preferably Ar 1 is selected from substituted or unsubstituted phenyl, and substituted or unsubstituted six-membered heteroaryl groups with 1 to 3 hetero atoms, such as nitrogen atoms; in which each substituent group is independently selected from halogen, hydroxyl, cyano, carboxyl, deuterium, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COOR c , -CONR d R e , -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl
  • Ar 1 has a structure selected from: in which R 6 is selected from halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, -COOR c , -CONR d R e , and -SO 2 NR d R e , wherein R c , R d , and R e are each independently selected from hydrogen, and C1-C6 alkyl groups, and m is 0, 1 or 2;
  • Ar 1 is wherein E 1 , E 2 , E 3 and E 4 are each independently selected from N and CR f , and at least one of E 1 , E 2 , E 3 and E 4 is N; R f is halogen, hydroxyl, cyano, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups; R c is hydrogen or C1-C6 alkyl groups.
  • Ar 1 is wherein E 1 , E 2 , E 3 and E 4 are each independently selected from N and CR f , and at least one of E 1 , E 2 , E 3 and E 4 is N;
  • R f is halogen, hydroxyl, cyano, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups;
  • R c is hydrogen or C1-C6 alkyl groups;
  • R 3 is selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C1-C6 alkoxyl groups, substituted or unsubstituted four-to six-membered heterocyclic groups with one or two hetero atoms each independently selected from N, O, and S, substituted or unsubstituted C6-C10 aryl groups, and substituted or unsubstituted five-to ten-membered heteroaryl groups with one or two or three heteroatoms each independently selected from N, O, and S, substituted or unsubstituted C3-C8 cycloalkoxy groups, substituted or unsubstituted four-to six-membered heterocycloalkoxy groups with one or two hetero atoms each independently selected from N, O, and S, substituted or unsubstituted C6-C10 aryloxy groups, and
  • substituent group is each independently selected from oxo, hydroxyl, halogen, C1-C6 alkyl groups, C6-C10 aryl groups, and C3-C6 cycloalkyl groups;
  • L 1 is selected from -CR 1 R 2 -, -CO-, -O-, -NH-, and -S-;
  • R 1 and R 2 are each independently selected from H, hydroxyl, halogen, substituted or unsubstituted C1-C4 alkyl groups, and substituted or unsubstituted C1-C4 alkoxyl groups, and in which the substituent group is each independently selected from halogen, hydroxyl, C1-C6 alkyl groups, and C3-C6 cycloalkyl groups; or wherein R 1 and R 2 , together with the atom to which they are bound, to form a C3-C6 cycloalkyl group;
  • R 4 is each independently selected from halogen, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, substituted or unsubstituted C6-C10 aryl group, a hydroxyl group, carboxyl, -NH (C1-C6 alkyl) , -SO 2 NR a R b , -CONR a R b , and -N (C1-C6 alkyl) (C1-C6 alkyl) ; in which R a and R b are each independently selected from hydrogen, C1-C6 alkyl groups, C1-C6 haloalkyl groups, and C3-C6 cycloalkyl groups; wherein the substituent group is each independently selected from halogen, hydroxyl, cyano, carboxyl, -C (O) NH 2 , -NH-COOH, C1-C6 alkyl groups, and C
  • R 4 is each independently selected from fluorine, chlorine, and -SO 2 NH 2 ;
  • L 2 is a linker comprising an unsaturated or aromatic moiety, preferably L 2 is selected from C2-C4 alkenylene groups, C2-C4 alkynylene groups, six-membered aromatic groups, and five-to six-membered heteroaromatic groups with one or two or three hetero atoms each independently selected from N, O, and S;
  • L 2 is selected from in which R’ is selected from a halogen, cyano, carboxyl, hydroxyl, -C (O) NH 2 , -C (O) N (CH 3 ) 2 , -NH-COOH, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halocycloalkyl groups, and amino group;
  • Q is selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, -C (O) NH 2 , -C (O) N (C1-C6 alkyl) (C1-C6 alkyl) , -NH-COOH, -NH (C1-C6 alkyl) , C1-C6 alkyl-C (O) -NH-, C1-C6 haloalkoxy group, substituted or unsubstituted C1-C8 alkyl groups, C1-C6 alkylamino groups, amino groups, substituted or unsubstituted C3-C8 monocyclic or bicyclic alkyl groups, substituted or unsubstituted four-to six-membered heterocyclic groups with one to three hetero atoms each independently selected from N, O and S, substituted or unsubstituted six-to ten-membered aryl groups, and substituted or unsubstituted five-to ten-member
  • Q is selected from hydrogen, cyano, halogen, hydroxyl, carboxyl, -C (O) NH 2 , -C (O) N (CH 3 ) 2 , -NH-COOH, -CH 3 , -CF 3 , -CF 2 H, -CH 2 -CF 3 , -O-CH 3 , -O-CF 3 , -O-CF 2 H, -O-CH 2 -CF 3 , -CD 3 , -CN,
  • X 1 , X 2 , X 3 , X 4 , X 5 , L 1 , L 2 , Ar 1 , R 3 , R 4 , and Q of Formula II are defined as disclosed above for Formula I.
  • ring A is an heteroaromatic ring, or a partially saturated ring, with the proviso that ring A is not a pyrazole ring.
  • Formula II comprises the following Formula II-1 and II-2:
  • Formula II comprises the following Formula II-3, II-4, and II-5
  • a compound of the present disclosure has a structure of any one of Formulae II-1, II-2, II-3, II-4, and II-5.
  • a compound of the present disclosure has a structure of Formula III
  • Z 1 and Z 2 are each independently selected from CH and N;
  • ring A is not a pyrazole ring
  • ring A is a five-membered heterocyclic moiety which is aromatic or partially unsaturated, in which:
  • X 1 , X 2 , X 3 , X 4 , and X 5 are each independently selected from CR 5 and NR 5 ;
  • each R 5 is independently absent or selected from hydrogen, halogen, hydroxyl, carboxyl, cyano, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 cycloalkyl, and substituted or unsubstituted C1-C6 alkoxyl, wherein each substituent group is independently selected from halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COO (C1-C6 alkyl) , -C (O) NH 2 , -NH-COOH, -
  • ring A is a five-membered heterocyclic moiety which is aromatic or partially unsaturated, in which:
  • X 1 , X 2 , X 3 and X 5 are each independently selected from C or N;
  • X 4 is selected from CR 5 and NR 5 ;
  • ring A three or four ring atoms in ring A are carbon atoms
  • each R 5 is independently selected from hydrogen, halogen, hydroxyl, carboxyl, cyano, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 cycloalkyl, and substituted or unsubstituted C1-C6 alkoxyl;
  • each substituent group is independently selected from halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COO (C1-C6 alkyl) , -C (O) NH 2 , -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and -SO 2 N (C1-C6 alkyl) (C1-C6 alkyl) ;
  • ring A comprises a structure selected from:
  • ring A comprises a structure selected from:
  • Y 1 , Y 2 , Y 3 , and Y 4 of ring B are each independently selected from C (R 7 ) 2 and NR 7 ;
  • Y 5 and Y 6 of ring B are each independently absent, C (R 7 ) 2 or NR 7 ;
  • each R 7 is independently absent or selected from hydrogen, halogen, hydroxyl, cyano, oxo, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COO (C1-C6 alkyl) , -C (O) NH 2 , -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl) , and -SO 2 N (C1-C6 alkyl) (C1-C6 alkyl) ;
  • each R 7 is independently absent or selected from hydrogen, halogen, hydroxyl, cyano, oxo, carboxyl, and C1-C6 alkyl groups;
  • each R 7 is independently absent or selected from hydrogen, halogen, and oxo;
  • ring B is selected from a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted C3-C8 heterocyclic alkyl comprising one to three heteroatoms each independently selected from N, O, and S; in which each substituent group is preferably independently selected from halogen, hydroxyl, cyano, oxo, carboxyl, and C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COO (C1-C6 alkyl) , -C (O) NH 2 , -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C
  • preferably ring B is selected from
  • ring B is optionally substituted by substituents each independently selected from halogen, hydroxyl, cyano, oxo, carboxyl, and C1-C6 alkyl groups;
  • Ar 1 is a substituted or unsubstituted six-membered aromatic ring, preferably Ar 1 is selected from substituted or unsubstituted phenyl, and substituted or unsubstituted six-membered heteroaryl groups with 1 to 3 hetero atoms, such as nitrogen atoms; in which each substituent group is independently selected from halogen, hydroxyl, cyano, carboxyl, deuterium, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, amino group, -COOR c , -CONR d R e , -NH-COOH, -NH (C1-C6 alkyl) , -N (C1-C6 alkyl) (C1-C6 alkyl
  • Ar 1 has a structure selected from: in which R 6 is selected from halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups, -COOR c , -CONR d R e , and -SO 2 NR d R e , wherein R c , R d , and R e are each independently selected from hydrogen, and C1-C6 alkyl groups, and m is 0, 1 or 2;
  • Ar 1 is wherein E 1 , E 2 , E 3 and E 4 are each independently selected from N and CR f , and at least one of E 1 , E 2 , E 3 and E 4 is N; R f is halogen, hydroxyl, cyano, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups; R c is hydrogen or C1-C6 alkyl groups.
  • Ar 1 is wherein E 1 , E 2 , E 3 and E 4 are each independently selected from N and CR f , and at least one of E 1 , E 2 , E 3 and E 4 is N;
  • R f is halogen, hydroxyl, cyano, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halogenated cycloalkyl groups, C1-C6 halogenated alkoxyl groups;
  • R c is hydrogen or C1-C6 alkyl groups;
  • R 3 is selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C1-C6 alkoxyl groups, substituted or unsubstituted four-to six-membered heterocyclic groups with one or two hetero atoms each independently selected from N, O, and S, substituted or unsubstituted C6-C10 aryl groups, and substituted or unsubstituted five-to ten-membered heteroaryl groups with one or two or three heteroatoms each independently selected from N, O, and S, substituted or unsubstituted C3-C8 cycloalkoxy groups, substituted or unsubstituted four-to six-membered heterocycloalkoxy groups with one or two hetero atoms each independently selected from N, O, and S, substituted or unsubstituted C6-C10 aryloxy groups, and
  • substituent group is each independently selected from oxo, hydroxyl, halogen, C1-C6 alkyl groups, C6-C10 aryl groups, and C3-C6 cycloalkyl groups;
  • L 1 is selected from -CR 1 R 2 -, -CO-, -O-, -NH-, and -S-;
  • R 1 and R 2 are each independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted C1-C4 alkyl groups, and substituted or unsubstituted C1-C4 alkoxyl groups, and in which the substituent group is each independently selected from halogen, hydroxyl, C1-C6 alkyl groups, and C3-C6 cycloalkyl groups; or wherein R 1 and R 2 , together with the atom to which they are bound, to form a C3-C6 cycloalkyl group;
  • R 4 is each independently selected from halogen, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, substituted or unsubstituted C6-C10 aryl group, a hydroxyl group, carboxyl, -NH (C1-C6 alkyl) , -SO 2 NR a R b , -CONR a R b , and -N (C1-C6 alkyl) (C1-C6 alkyl) ; in which R a and R b are each independently selected from hydrogen, C1-C6 alkyl groups, C1-C6 haloalkyl groups, and C3-C6 cycloalkyl groups; wherein the substituent group is each independently selected from halogen, hydroxyl, cyano, carboxyl, -C (O) NH 2 , -NH-COOH, C1-C6 alkyl groups, and C
  • R 4 is each independently selected from fluorine, chlorine, and -SO 2 NH 2 ;
  • L 2 is a linker comprising an unsaturated or aromatic moiety, preferably L 2 is selected from C2-C4 alkenylene groups, C2-C4 alkynylene groups, six-membered aromatic groups, and five-to six-membered heteroaromatic groups with one or two or three hetero atoms each independently selected from N, O, and S; in which, each hydrogen in L2 is independently substituted by substituents selected from halogen, cyano, carboxyl, hydroxyl, -C (O) NH2, -C (O) N (CH 3 ) 2 , -NH-COOH, C1-C6 alkyl groups, C1-C6 alkoxyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, C3-C6 halocycloalkyl groups, and amino group preferably, L 2 is selected from in which R’ is selected from a halogen, cyano, carboxyl, hydroxyl, -
  • Q is selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, -C (O) NH 2 , -C (O) N (C1-C6 alkyl) (C1-C6 alkyl) , -NH-COOH, -NH (C1-C6 alkyl) , C1-C6 alkyl-C (O) -NH-, C1-C6 haloalkoxy group, substituted or unsubstituted C1-C8 alkyl groups, C1-C6 alkylamino groups, amino groups, substituted or unsubstituted C3-C8 monocyclic or bicyclic alkyl groups, substituted or unsubstituted four-to six-membered heterocyclic groups with one to three hetero atoms each independently selected from N, O and S, substituted or unsubstituted six-to ten-membered aryl groups, and substituted or unsubstituted five-to ten-member
  • Q is selected from hydrogen, cyano, halogen, hydroxyl, carboxyl, -C (O) NH 2 , -C (O) N (CH 3 ) 2 , -NH-COOH, -CH 3 , -CF 3 , -CF 2 H, -CH 2 -CF 3 , -O-CH 3 , -O-CF 3 , -O-CF 2 H, -O-CH 2 -CF 3 , -CD 3 , -CN,
  • ring A is an heteroaromatic ring, or a partially saturated ring, with the proviso that ring A is not a pyrazole ring.
  • X 1 , X 2 , X 3 , X 4 , X 5 , L 1 , L 2 , Ar 1 , R 3 , R 4 , and Q of Formula III are defined as disclosed above for Formula I or II.
  • Formula III comprises the following Formula III-1 and Formula III-2:
  • Formula III comprises the following Formula III-3, Formula III-4, and Formula III-5:
  • Formula III comprises the following Formula III-6, Formula III-7, and Formula III-8:
  • a compound of the present disclosure has a structure of any one of Formulae III-1, III-2, III-3, III-4, III-5, III-6, III-7, and III-8.
  • a compound of the present disclosure comprises a structure selected from:
  • One objective of the present disclosure is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound as described above, a stereoisomer, a tautomer, an isotope labeled compound, or a pharmaceutically acceptable salt thereof.
  • Another objective of the present disclosure is to provide a method of inhibiting lactate dehydrogenase A activity in a cell, comprising: administering to a subject an effective amount of at least one compound as described above, or a stereoisomer, a tautomer, an isotope labeled compound, or a pharmaceutically acceptable salt thereof.
  • Another objective of the present disclosure is to provide a method of treating or preventing a disease associated with lactate dehydrogenase A activity, comprising administering to a subject an effective amount of at least one compound as described above, or a stereoisomer, a tautomer, an isotope labeled compound, or a pharmaceutically acceptable salt thereof.
  • a disease associated with lactate dehydrogenase A activity is an autoimmune disorder.
  • the autoimmune disorder is selected from: autoimmune disorders of the nervous system, autoimmune disorders of the blood, autoimmune disorders of the blood vessels, autoimmune disorders of the skin, autoimmune disorders of the gastrointestinal system, autoimmune disorders of the endocrine glands, autoimmune disorders of multiple organs including connective tissue and musculoskeletal system diseases, and other immune system mediated diseases including graft-versus-host diseases and allergic disorders.
  • the autoimmune disorders of the nervous system are selected from multiple sclerosis, myasthenia gravis, autoimmune neuropathies such as Guillain-Barré, and autoimmune uveitis.
  • the autoimmune disorders of the blood are selected from autoimmune hemolytic anemia, pernicious anemia, autoimmune thrombocytopenia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia.
  • the autoimmune disorders of the blood vessels are selected from temporal arteritis, anti-phospholipid syndrome, vasculitides such as Wegener’s granulomatosis, and Behcet’s disease.
  • the autoimmune disorders of the skin are selected from cutaneous lupus erythematosus, Steven-Johnson syndrome, psoriasis, dermatitis herpetiformis, pemphigus vulgaris, and vitiligo.
  • the autoimmune disorders of the gastrointestinal system are selected from Crohn’s disease, ulcerative colitis, chronic active hepatitis, idiopathic sprue, autoimmune inflammatory bowel disease, irritable bowel syndrome, alcoholic liver disease, nonalcoholic liver disease, nonalcoholic fatty liver, primary biliary cirrhosis, and autoimmune hepatitis.
  • the autoimmune disorders of the endocrine glands are selected from Type 1 or immune-mediated diabetes mellitus, Grave’s disease, Hashimoto’s thyroiditis, autoimmune oophoritis and orchitis, and autoimmune disorder of the adrenal gland.
  • the autoimmune disorders of multiple organs are selected from rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, spondyloarthropathies selected from ankylosing spondylitis, polychondritis, celiac disease, periodontitis, hyaline membrane disease, glomerular disease, endocrine opthalmopathy, Lupus nephritis, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, and Sjogren’s syndrome.
  • the allergic disorders are selected from allergic rhinitis, sinusitis, rhinosinusitis, chronic or recurrent otitis media, ocular allergy, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis drug reactions, insect sting reactions, latex reactions, conjunctivitis, urticaria, anaphylaxis and anaphylactoid reactions, atopic dermatitis, asthma, and food allergies.
  • the autoimmune disorder is a kidney disease selected from hyperoxaluria, chronic kidney disease, end stage renal disease and kidney stone disease; and wherein the hyperoxaluria is selected from primary hyperoxaluria type 1, primary hyperoxaluria type 2, primary hyperoxaluria type 3, and secondary hyperoxaluria.
  • the method as described above comprises administering once daily, twice daily, or three times daily to a subject an effective amount of the compound as described above, or the stereoisomer, the tautomer, the isotope labeled compound, or the pharmaceutically acceptable salt thereof, or the composition as described above.
  • Another objective of the present disclosure is to provide a use of a compound as described above, or a stereoisomer, a tautomer, an isotope labeled compound, or a pharmaceutically acceptable salt thereof, to manufacture a medicament in treating or preventing a disease associated with lactate dehydrogenase A activity.
  • a further objective of the present disclosure is to provide a compound as described above, or a stereoisomer, a tautomer, an isotope labeled compound, or the pharmaceutically acceptable salt thereof, for use in treating or preventing a disease associated with lactate dehydrogenase A activity.
  • alkyl refers to a hydrocarbon group selected from linear and branched saturated hydrocarbon groups of 1-18, or 1-12, or 1-6, or 1-3 carbon atoms.
  • alkyl group include methyl, ethyl, 1-propyl or n-propyl ( “n-Pr” ) , 2-propyl or isopropyl ( “i-Pr” ) , 1-butyl or n-butyl ( “n-Bu” ) , 2-methyl-1-propyl or isobutyl ( “i-Bu” ) , 1-methylpropyl or s-butyl ( “s-Bu” ) , and 1, 1-dimethylethyl or t-butyl ( “t-Bu” ) .
  • alkyl group examples include 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3- methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2, 3-dimethyl-2-butyl and 3, 3-dimethyl-2-butyl groups.
  • alkenyl group may be selected from ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1, 3-dienyl, 2-methylbuta-1, 3-diene, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1, 3-dienyl groups.
  • alkynyl refers to a hydrocarbon group selected from linear and branched hydrocarbon group, comprising at least one C ⁇ C triple bond and of 2-18, or 2-12, or 2-6 carbon atoms.
  • alkynyl group include ethynyl, 1-propynyl, 2-propynyl (propargyl) , 1-butynyl, 2-butynyl, and 3-butynyl groups.
  • cycloalkyl refers to a hydrocarbon group selected from saturated and partially unsaturated cyclic hydrocarbon groups, comprising monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups.
  • the cycloalkyl group may be of 3-12, or 3-8, or 3-6, or 3-4, or 5-6 carbon atoms.
  • the cycloalkyl group may be a monocyclic group of 3-12, or 3-8, or 3-6 carbon atoms.
  • Examples of the monocyclic cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups.
  • bicyclic cycloalkyl groups include those having 7-12 ring atoms arranged as a bicycle ring selected from [4, 4] , [4, 5] , [5, 5] , [5, 6] and [6, 6] ring systems, or as a bridged bicyclic ring selected from bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, and bicyclo [3.2.2] nonane.
  • the ring may be saturated or have at least one double bond (i.e. partially unsaturated) , but is not fully conjugated, and is not aromatic, as aromatic is defined herein.
  • aryl herein refers to a group selected from: 5-and 6-membered carbocyclic aromatic rings, for example, phenyl; bicyclic ring systems such as 7-12 membered bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, selected, for example, from naphthalene, indane, and 1, 2, 3, 4-tetrahydroquinoline; and tricyclic ring systems such as 10-15 membered tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene.
  • aryloxy group refers to a univalent radical R-O-, or anion R-O-, where R is an aryl group.
  • heteroaryloxy group refers to a univalent radical R-O-, or anion R-O-, where R is a heteroaryl group.
  • saturated, aromatic or partially unsaturated heterocyclic ring containing 1, 2 or 3 heteroatoms or “containing heteroatom groups” , wherein those heteroatom (s) (group (s) ) are selected from N, O, S, NO, SO and SO 2 and are ring members, as used herein refers to monocyclic radicals, the monocyclic radicals being saturated, partially unsaturated or aromatic.
  • the heterocyclic radical may be attached to the remainder of the molecule via a carbon ring member or via a nitrogen ring member.
  • Examples of 3-, 4-, 5-, 6-or 7-membered saturated heterocyclyl or heterocyclic rings include: oxiranyl, aziridinyl, azetidinyl, 2 tetrahydrofuranyl, 3-tetrahydrofuranyl, 2 tetrahydrothienyl, 3 tetrahydrothienyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3 pyrazolidinyl, 4 pyrazolidinyl, 5-pyrazolidinyl, 2 imidazolidinyl, 4 imidazolidinyl, 2-oxazolidinyl, 4-oxazolidinyl, 5 oxazolidinyl, 3-isoxazolidinyl, 4 isoxazolidinyl, 5 isoxazolidinyl, 2 thiazolidinyl, 4-thiazolidinyl, 5-thiazolidinyl, 3 isothiazolidinyl, 4-isothiazolidiny
  • Examples of 3-, 4-, 5-, 6-or 7-membered partially unsaturated heterocyclyl or heterocyclic rings include: 2, 3-dihydrofur-2-yl, 2, 3-dihydrofur-3-yl, 2, 4-dihydrofur-2-yl, 2, 4-dihydrofur-3-yl, 2, 3-dihydrothien-2-yl, 2, 3 dihydrothien-3-yl, 2, 4 dihydrothien-2-yl, 2, 4-dihydrothien-3-yl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3 pyrrolin-2-yl, 3-pyrrolin-3-yl, 2-isoxazolin-3-yl, 3-isoxazolin-3-yl, 4 isoxazolin 3 yl, 2-isoxazolin-4-yl, 3-isoxazolin-4-yl, 4-isoxazolin-4-yl, 2 isoxazolin-5-yl, 3-isoxa
  • Examples of 5-or 6-membered aromatic heterocyclyl (heteroaryl) or heteroaromatic rings are: 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 4-pyrazo-lyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4 thiazolyl, 5-thiazo-lyl, 2-imidazolyl, 4-imidazolyl, 1, 3, 4-triazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl and 2-pyrazinyl.
  • heteroaryl refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ( “5-14 membered heteroaryl” ) , or a group derived therefrom.
  • the point of attachment may be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl polycyclic ring systems may include one or more heteroatoms in one or both rings.
  • “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system.
  • Heteroaryl also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system.
  • Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl) .
  • each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl” ) or substituted (a “substituted heteroaryl” ) with one or more substituents.
  • Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl.
  • Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl.
  • Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5, 6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • Exemplary 6, 6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.
  • C1-C6 is selected from C1, C2, C3, C4, C5, and C6;
  • C3-6 is selected from C3, C4, C5, and C6.
  • halo or “halogen” itself or as a part of another substituent refers to a fluorine, chlorine, bromine or iodine.
  • haloalkyl is intended to include monohaloalkyl and polyhaloalkyl. Examples of haloalkyl include but are not limited to: trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • Cn-Cm-haloalkyl refers to a straight-chain or branched alkyl group having n to m carbon atoms, e.g.
  • C1-C4-haloalkyl such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2, 2-difluoroethyl, 2, 2, 2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2, 2-difluoroethyl, 2, 2-dichloro-2-fluoroethyl, 2, 2, 2-trichloroethyl, pentafluoroethyl and
  • C1-C10-haloalkyl in particular comprises C1-C2-fluoroalkyl, which is synonym with methyl or ethyl, wherein 1, 2, 3, 4 or 5 hydrogen atoms are substituted by fluorine atoms, such as fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2, 2-difluoroethyl, 2, 2, 2-trifluoroethyl and pentafluoromethyl.
  • alkoxy represents an alkyl group as described above with a specific number of carbon atoms which is connected by an oxygen bridge.
  • the C1-6 alkoxy includes C1, C2, C3, C4, C5 and C6 alkoxy.
  • Examples of alkoxy include but not limited to: methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S-pentyloxy.
  • Cycloalkoxy means a cycloalkyl further consisting of a carbon-oxygen single bond, including, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, norbornyloxy, and bicyclo [2.2.2] octyloxy.
  • “Cycloalkenyl” means a monocyclic or polycyclic, unsaturated (at least one carbon-carbon double bond) substituent consisting of carbon and hydrogen, including, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornenyl, bicyclo [2.2.2] octenyl, tetrahydronaphthyl, hexahydronaphthyl, and octahydronaphthyl.
  • Cycloalkenyloxy means a cycloalkenyl further consisting of a carbon-oxygen single bond, including, for example, cyclobutenyloxy, cyclopentenyloxy, norbornenyloxy, and bicyclo [2.2.2] octenyloxy.
  • cycloalkylamino represents a saturated monocyclic hydrocarbon group having an indicated number of carbon atoms linked through amino having a free valence bond from the nitrogen atom.
  • Representative examples include, but are not limited to, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino and the like.
  • a bond can be a covalent bond or an ionic bond. In some embodiments, a bond can be a saturated bond or an unsaturated bond. In some embodiments, a bond refers to a single bond. In some embodiments, a bond refers to a double bond. In other embodiments, a bond refers to a triple bond. The term “unsaturated bond” refers to a double or triple bond.
  • saturated or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.
  • saturated refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.
  • a group is optionally substituted unless expressly provided otherwise.
  • the term “optionally substituted” refers to a group which may be substituted or unsubstituted as defined herein.
  • aliphatic group refers to a straight-chain, branched-chain, or cyclic non-aromatic saturated or unsaturated hydrocarbon group and includes as alkyl groups, alkenyl groups, and alkynyl groups.
  • aryloxy refers to both an -O-aryl group and an -O-heteroaryl group, as defined herein.
  • a “cyano” group refers to a -CN group.
  • oxo refers to a carbonyl moiety such that alkyl substituted by oxo refers to a ketone group.
  • C1-C6 alkyl-C (O) -NH- refers to a moiety containing an amide group connected to a C1-C6 alkyl, where the C1-C6 alkyl group is optionally substituted, and the substituent is each independently selected from an alkyl, a cycloalkyl, aryl, a heteroaryl (bonded through a ring carbon) , a heteroalkyl, and a heterocyclylalkyl.
  • the C1-C6 alkyl group may optionally be taken together with the nitrogen to which it is attached to form a 4-, 5-, 6-, or 7-membered ring.
  • Alkylene refers to a straight or branched divalent hydrocarbon chain linking two groups in a molecule, which may be saturated or unsaturated (i.e., contains one or more double and/or triple bonds) , and have from one to twelve carbon atoms, preferably one to eight carbon atoms (C 1 -C 8 alkylene) or one to six carbon atoms (C 1 -C 6 alkylene) , e.g., methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, n-butynylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single or double bond.
  • the points of attachment of the alkylene chain to the rest of the molecule may be through one carbon, e.g., methylene, or any two carbons within the chain, e.g., -CH 2 CH (CH 3 ) CH 2 CH 2 -.
  • an alkylene chain is optionally substituted.
  • Alkenylene is an unsaturated alkylene, as defined herein, which comprises one or more carbon-carbon double bonds. Unless stated otherwise specifically in the specification, an alkenylene is optionally substituted.
  • Alkynylene is an unsaturated alkylene, as defined herein, which comprises one or more carbon-carbon triple bonds. Unless stated otherwise specifically in the specification, an alkynylene is optionally substituted.
  • the “ring” refers to a substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl.
  • the so-called ring includes a single ring, a joint ring, a spiro ring, a fused ring or a bridged ring.
  • a number of the atoms on the ring is usually defined as the member of the ring, for example, “5-to 7-membered ring” refers to a ring looped with 5 to 7 atoms.
  • the ring optionally contains 1-3 of heteroatoms. Therefore, “5-to 7-membered ring” includes, for example, phenyl, pyridine and piperidinyl; on the other hand, the term “5-to 7-membered heterocycloalkyl” includes pyridyl and piperidinyl, but does not include phenyl.
  • the term “ring” also includes a ring system containing at least one ring, wherein each of the “rings” is independently in line with the above definition.
  • heterocyclic group refers to a stable monocyclic, bicyclic or tricyclic group containing a heteroatom or heteroatom group, which can be saturated, partially unsaturated or unsaturated (aromatic) , and contains carbon atoms and 1, 2, 3 or 4 ring heteroatom (s) independently selected from the group consisting of N, O and S, wherein any of the above heterocycle can be fused to a benzene ring to form a bicyclic ring.
  • Nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S (O) p) .
  • the nitrogen atom can be substituted or unsubstituted (i.e.
  • the heterocycle can be attached to a side group of any heteroatom or carbon atom to form a stable structure. If the formed compound is stable, the heterocyclic group described herein can be substituted on its carbon or nitrogen atom.
  • the nitrogen atom in the heterocycle is optionally quaternized. As a preferred embodiment, when the total number of S and O atoms contained in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. As another preferred embodiment, the total number of S and O atoms in the heterocycle is no more than 1.
  • aromatic heterocyclic group refers to a stable aromatic ring of a 5-, 6-, 7-membered monocyclic or bicyclic or 7-, 8-, 9-or 10-membered bicyclic heterocyclyl, which contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from the group consisting of N, O and S.
  • the nitrogen atom can be substituted or unsubstituted (i.e. N or NR, wherein R is H or other substituent defined herein) .
  • Nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S (O) p) .
  • bridge rings are also included in the definition of the heterocycle.
  • one or more than one atoms i.e. C, O, N, or S
  • a bridged ring is formed.
  • the preferred bridge ring includes but is not limited to: one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms and one carbon-nitrogen group. It is worth noting that a bridge always converts a monocyclic ring into a tricyclic ring. In the bridge ring, the substituent on the ring can also locate on the bridge.
  • heterocyclic group examples include but are not limited to: acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzomercaptofuranyl, benzomercaptophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzoisoxazolyl, benzoisothiazolyl, benzoimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromene, cinnolinyl decahydroquinolyl, 2H, 6H-1, 5, 2-dithiazinyl, dihydrofuro [2, 3-b] tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indoalkeny
  • C1-C6 haloalkoxy group is a C1-C6 haloalkyl group, as defined above, attached via an oxygen atom.
  • C1-C6 haloalkoxy group is, for example, OCH 2 F, OCHF 2 , OCF 3 , OCH 2 Cl, OCHCl 2 , OCCl 3 , chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2, 2-difluoroethoxy, 2, 2, 2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2, 2-difluoroethoxy, 2, 2-dichloro-2-fluoroethoxy, 2, 2, 2-trichloroethoxy, OC 2 F 5 , 2-fluoropropoxy, 3-fluoropropoxy, 2-fluoro
  • halogen will be taken to mean fluorine, chlorine, bromine and iodine.
  • substituted refers to any one or more hydrogen atoms on a specific atom being optionally replaced by a substituent, including a deuterium and a variant of hydrogen, as long as the valence state of the specific atom is normal and the substituted compound is stable.
  • it means that two hydrogen atoms are replaced.
  • a substitution of keto group will not occur on an aryl.
  • optionally substituted means that it may be substituted or not be substituted, unless otherwise specified, the type and number of substituents can be arbitrary under the premise of being chemically feasible.
  • any parameter e.g. R
  • its definition at each occurrence is independent. Therefore, for example, if a group is substituted by 0-2 of R, the group may optionally be substituted by at most two Rs, and R has an independent option at each occurrence.
  • a combination of substituents and/or their variants is allowed only if such a combination will lead to a stable compound.
  • pharmaceutically acceptable as used herein is directed to those compounds, materials, compositions and/or formulations which are within the scope of reliable medical judgment, suitable for use in contact with human and animal tissues but without too much toxicity, irritation, allergic reactions or other problems or complications, and also commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of the compound disclosed herein, which is prepared from the compound with specific substituents disclosed herein and a relatively non-toxic acid or alkali.
  • an alkali-addition salt can be obtained by contacting the compound in a neutral form with a sufficient amount of alkali in a pure solution or suitable inert solvent.
  • the pharmaceutically acceptable alkali-addition salt includes, for example, the salt of sodium, potassium, calcium, ammonium, organic ammine or magnesium or the like.
  • an acid-addition salt can be obtained by contacting the compound in a neutral form with a sufficient amount of acid in a pure solution or suitable inert solvent.
  • the pharmaceutically acceptable acid-addition salt include a salt of an inorganic acid, wherein the inorganic acid includes, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, hydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydriodic acid, phosphorous acid; and a salt of an organic acid, wherein the organic acid includes, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, phenylsulfonic acid, p-toluene sulfonic acid
  • arginine etc. examples include arginine etc. ) , and salts of organic acids such as glucuronic acid and the like (see Berge et al., “Pharmaceutical Salts, ” Journal of Pharmaceutical Science 66: 1-19 (1977) ) .
  • Some specific compounds disclosed herein contain both alkaline and acidic functional groups and thereby may be transformed to any of the alkali-addition or acid-addition salt.
  • the “pharmaceutically acceptable salt” used herein belongs to the derivatives of the compounds disclosed herein, wherein the compound disclosed herein is modified by salifying with an acid or an alkali.
  • the pharmaceutically acceptable salt disclosed herein include but are not limited to: an inorganic acid or organic acid salt of an alkali such as amine, alkali metal or an organic salt of an acid radical such as carboxylic acid.
  • the pharmaceutically acceptable salts disclosed herein include conventional non-toxic salts or quaternary ammonium salts of the compounds disclosed herein, such as a salt formed by a non-toxic inorganic acid or organic acid.
  • the conventional non-toxic salt includes but is not limited to those salts derived from an inorganic acid and an organic acid, the inorganic acid or organic acid is selected, for example, from 2-acetoxybenzoic acid, 2-isethionic acid, acetic acid, ascorbic acid, phenylsulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydriodate, hydroxyl, hydroxynaphthoic, isethionic acid, lactic acid, lactose, dodecanesulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid,
  • the pharmaceutically acceptable salt of the present disclosure can be prepared by a conventional chemical method using the compounds disclosed herein.
  • the compounds disclosed herein and/or the pharmaceutically acceptable salts thereof may be employed alone or in combination with at least one other therapeutic agent for treatment.
  • the compound and/or a pharmaceutically acceptable salt thereof disclosed herein may be administered with the at least one other therapeutic agent in a single dosage form or as a separate dosage form.
  • the at least one other therapeutic agent may be administered prior to, at the same time as, or following administration of the compound and/or a pharmaceutically acceptable salt thereof disclosed herein.
  • compositions comprising the compound disclosed herein and/or a pharmaceutically acceptable salt thereof can be administered in various known manners, such as orally, topically, rectally, parenterally, by inhalation spray, or via an implanted reservoir, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • the compositions disclosed herein may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art.
  • the compound disclosed herein and/or a pharmaceutically acceptable salt thereof can be administered orally in solid dosage forms, such as capsules, tablets, troches, dragées, granules and powders, or in liquid dosage forms, such as elixirs, syrups, emulsions, dispersions, and suspensions.
  • Liquid dosage forms for oral administration can further comprise at least one agent selected from coloring and flavoring agents to increase patient acceptance.
  • at least one agent selected from coloring and flavoring agents to increase patient acceptance.
  • water, a suitable oil, saline, aqueous dextrose (glucose) , and related sugar solutions and glycols such as propylene glycol or polyethylene gycols can be examples of suitable carriers for parenteral solutions.
  • a pharmaceutically acceptable carrier disclosed herein is, for example, selected from carriers that are compatible with active ingredients of the composition (and in some embodiments, capable of stabilizing the active ingredients) and not deleterious to the subject to be treated.
  • solubilizing agents such as cyclodextrins (which can form specific, more soluble complexes with the at least one compound and/or at least one pharmaceutically acceptable salt disclosed herein)
  • examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments such as D&C Yellow # 10. Suitable pharmaceutically acceptable carriers are described in Remington’s Pharmaceutical Sciences, A. Osol, a standard reference text in the art.
  • Some compounds of the present disclosure may contain an asymmetric carbon atom (optical center) or double bond.
  • the racemic isomers, diastereomers, geometric isomers and single isomers are all included within the scope of the present disclosure.
  • the term “stereoisomers” includes enantiomers, diastereomers, racemic isomers, and geometric isomers.
  • the term “effective amount” or “therapeutically effective amount” refers to a quantity of a compound disclosed herein or a composition comprising the compound that is sufficient to achieve desired effects without toxicity.
  • an effective amount” of the compound in the composition disclosed herein refers to the amount that is required to achieve desired effects in combination with another active substance, if any, in the composition.
  • the determination of the therapeutically effective amount varies from person to person, and depends, for example, on the age and the general condition of a recipient. An appropriate therapeutically effective amount can be determined by a person skilled in the art according to conventional tests.
  • the term “treat, ” “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof) .
  • “treat” , “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • “treat” , “treating” or “treatment” refers to modulating the disease or disorder, either physically (e.g., stabilization of a discernible symptom) , physiologically (e.g., stabilization of a physical parameter) , or both.
  • “treat” , “treating” or “treatment” refers to delaying the development or progression of the disease or disorder.
  • a subject is “in need of “a treatment if such subject would be expected to benefit biologically, medically or in quality of life from such treatment.
  • a disease associated with lactate dehydrogenase A activity disclosed herein includes a disease selected, for example, from autoimmune disorders, allergic disorders, inflammatory conditions, cancers, metabolic syndrome, and Syndrome X.
  • immune disorders include those diseases, syndrome, disorders or conditions that have an immune component and those that are substantially or entirely immune system-mediated. Autoimmune disorders are those wherein the animal’s (including humans) own immune system mistakenly attacks itself, thereby targeting the cells, tissues, and/or organs of the animal’s own body.
  • autoimmune disorders of the nervous system e.g., multiple sclerosis, myasthenia gravis, autoimmune neuropathies such as Guillain-Barré, and autoimmune uveitis
  • autoimmune disorders of the blood e.g., autoimmune hemolytic anemia, pernicious anemia, and autoimmune thrombocytopenia
  • autoimmune disorders of the blood vessels e.g., temporal arteritis, anti-phospholipid syndrome, vasculitides such as Wegener’s granulomatosis, and Behcet’s disease
  • autoimmune disorders of the skin e.g., psoriasis, dermatitis herpetiformis, pemphigus vulgaris, and vitiligo
  • autoimmune disorders of the gastrointestinal system e.g., Crohn’s disease, ulcerative colitis, primary biliary cirrhosis, and autoimmune hepatitis
  • immune disorders are also included in the definition of immune disorders herein.
  • immune disorders are caused by inflammation, there is some overlap between disorders that are considered immune disorders and inflammatory disorders.
  • an overlapping disorder it may be considered either an immune disorder or an inflammatory disorder.
  • allergic disorder means a disease, condition or disorder associated with an allergic response against normally innocuous substances. These substances may be found in the environment (such as indoor air pollutants and aeroallergens) or they may be non-environmental (such as those causing dermatological or food allergies) . Allergens can enter the body through a number of routes, including by inhalation, ingestion, contact with the skin or injection (including by insect sting) . Many allergic disorders are linked to atopy, a predisposition to generate the allergic antibody IgE. Because IgE is able to sensitize 49the-cells anywhere in the body, atopic individuals often express disease in more than one organ.
  • allergic disorders include any hypersensitivity that occurs upon re-exposure to the sensitizing allergen, which in turn causes the release of inflammatory mediators.
  • Allergic disorders include without limitation, allergic rhinitis (e.g., hay fever) , sinusitis, rhinosinusitis, chronic or recurrent otitis media, ocular allergy, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis drug reactions, insect sting reactions, latex reactions, conjunctivitis, urticaria, anaphylaxis and anaphylactoid reactions, atopic dermatitis, asthma, and food allergies.
  • fibrosis means the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process, in a pathological situation, as opposed to formation of fibrous tissue as a normal constituent of an organ or tissue. Fibrosis may be the result of chronic inflammatory reactions induced by a variety of stimuli including persistent infections, autoimmune reactions, allergic responses, chemical insults, radiation, and tissue injury. Scarring is confluent fibrosis that obliterates the architecture of the underlying organ or tissue.
  • fibrotic diseases including: Pulmonary fibrosis (lungs) ; Idiopathic pulmonary fibrosis (where the cause is unknown) , Cystic fibrosis (caused by genetic mutation of CFTR gene [cystic fibrosis transmembrane conductance regulator] ) ; Cirrhosis (liver) ; Endomyocardial fibrosis (heart) ; Progressive kidney disease, Mediastinal fibrosis (soft tissue of the mediastinum) ; Myelofibrosis (bone marrow) , Retroperitoneal fibrosis (soft tissue of the retroperitoneum) ; Progressive massive fibrosis (lungs) ; a complication of coal workers’ pneumoconiosis; Nephrogenic systemic fibrosis (skin) , Crohn’s Disease (intestine) ; Keloid (skin) ; Old myocardial infarction (heart) ; Scleroderma/systemic s
  • cancers is not particularly limited, but in certain aspects, the cancer is characterized as hypoxic and/or highly glycolytic relative to normal tissue of the same type.
  • examples of cancer include cancers of the head and neck, eye, skin, mouth, throat, esophagus, chest, bone, lung, colon, sigmoid, rectum, stomach, prostate, breast, ovaries, kidney, liver, pancreas, brain, intestine, heart, or adrenals.
  • cancers include solid tumor, sarcoma, carcinomas, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendothelio sarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,
  • cancer can also be a solid tumor, such as the leukemia, melanoma, liver cancer, pancreatic cancer, lung cancer, colon cancer, brain cancer, ovarian cancer, breast cancer, prostate cancer, and renal cancer.
  • the cancer is liver cancer, pancreatic cancer, non-small cell lung cancer, breast cancer, or renal cancer.
  • references herein to the compounds disclosed herein include salts and solvates thereof, including stereoisomers, tautomers, and isotopically labeled versions thereof.
  • compounds of the present disclosure can be pharmaceutically acceptable salts and/or pharmaceutically acceptable solvates.
  • stereoisomers refers to compounds that have identical chemical constitution but differ with regard to the arrangement of their atoms or groups in space.
  • enantiomers refers to two stereoisomers of a compound that are non-superimposable mirror images of one another. A pure enantiomer can be contaminated with up to 10%of the opposite enantiomer.
  • racemic or “racemic mixture, ” as used herein, refer to a 1: 1 mixture of enantiomers of a particular compound.
  • diastereomers refers to the relationship between a pair of stereoisomers that comprise two or more asymmetric centers and are not mirror images of one another.
  • a compound of the present disclosure contains an alkenyl or alkenylene group
  • geometric cis/trans (or Z/E) isomers are possible.
  • the compound contains, for example, a keto or oxime group or an aromatic moiety
  • tautomeric isomerism ( ‘tautomerism’ ) can occur.
  • tautomerism include keto and enol tautomers.
  • a single compound may exhibit more than one type of isomerism.
  • Disclosed herein are all stereoisomers, geometric isomers and tautomeric forms of the compounds of the present disclosure, including, for example, compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof.
  • Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.
  • the compounds of the present disclosure may be administered as prodrugs.
  • certain derivatives of compounds of Formula I which may have little or no pharmacological activity themselves can, when administered to a mammal, be converted into a compound of Formula I having the desired activity, for example, by hydrolytic cleavage.
  • Such derivatives are referred to as “prodrugs. ”
  • Prodrugs can, for example, be produced by replacing appropriate functionalities present in the compound of Formula I with certain moieties known to those skilled in the art. See, e.g. “Pro-drugs as Novel Delivery Systems” , Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and “Bioreversible Carriers in Drug Design” , Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association) .
  • Salts of the present disclosure can be prepared according to methods known to those of skill in the art.
  • Examples of salts include, but are not limited to, acetate, acrylate, benzenesulfonate, benzoate (such as chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, and methoxybenzoate) , bicarbonate, bisulfate, bisulfite, bitartrate, borate, bromide, butyne-1, 4-dioate, calcium edetate, camsylate, carbonate, chloride, caproate, caprylate, clavulanate, citrate, decanoate, dihydrochloride, dihydrogenphosphate, edetate, edislyate, estolate, esylate, ethylsuccinate, formate, fumarate, gluceptate, gluconate, glutamate, glycollate, glycollylarsanilate, heptanoate, he
  • the compound disclosed herein can be prepared through various synthetic methods, including the specific embodiments listed below and/or its combination with other chemical synthetic methods and equivalent alternatives known to a person skilled in the art.
  • Bottle A To the suspension of 4-amino-3-fluorobenzonitrile (20 g, 146.92 mmol, 1.0 eq) in 12 N HCl (200 mL) was added a solution of sodium nitrite (11.15 g, 161.61 mmol, 1.1 eq) in H 2 O (200 mL) dropwise with the temperature was kept at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour.
  • Bottle B SOCl 2 (100 mL) was added dropwise to H 2 O (200 mL) with the temperature was kept at 0 °C. The resuting mixture was added chlorocopper (I) (4.36 g, 44.08 mmol, 0.3 eq) and stirred at RT for 1 hour.
  • the bottle B was added the reaction mixture in bottle A dropwise with the temperature was kept at 0 °C. After addition, the resulting mixture was stirred at 0 °C for 1 hour.
  • the reaction mixture was diluted with EA (500 mL) and washed with brine (500 mL) , dried over Na 2 SO 4 , filtered and concentrated.
  • Step 2 Preparation of compound 546-d: 4-cyano-2-fluoro-N, N-bis (4-methoxybenzyl) benzenesulfonamide
  • Step 3 Preparation of compound 546-6: 4- (aminomethyl) -2-fluoro-N, N-bis (4-methoxybenzyl) benzenesulfonamide
  • Step 1 Preparation of compound 546-3: methyl (E) -6- (3- (3-iodophenyl) -3-oxoprop-1-en-1-yl) picolinate 4-Methylbenzenesulfonic acid hydrate (5.79 g, 30.4 mmol, 0.1 eq) was added to the solution of methyl 5-formylpyridine-3-carboxylate (50 g, 302.7 mmol, 1.0 eq) and 1- (3-bromophenyl) ethan-1-one (75 g, 304.8 mmol, 1.0 eq) in Toluene (500 mL) at rt. The mixture was stirred at 130 °C to remove water by Dean-Stark trap overnight.
  • Step 2 Preparation of compound 546-5: methyl 6- (5-cyclopropyl-1- (3-iodophenyl) -1, 4-dioxopentan-3-yl) picolinate
  • reaction mixture was stirred at 100 °C for 2 h. After the reaction completion, the mixture was concentrated under vacuum to afford crude product.
  • the mixture was purified by silica gel column (eluent: 10%to 15% (v/v) EA in PE) to afford the title product as a yellow gum (53.7 g, 98.3%) .
  • Step 3 Preparation of compound 546-7: methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) picolinate
  • Step 4 Preparation of compound 546-8: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) picolinate
  • Step 5 Preparation of compound 546-9: methyl 6- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate
  • Step 6 Preparation of compound 546: 6- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid
  • Step 1 Preparation of compound 548-2: methyl 2-vinylpyrimidine-4-carboxylate
  • Step 3 Preparation of compound 548-4: methyl (E) -2- (3- (3-bromophenyl) -3-oxoprop-1-en-1-yl) pyrimidine-4-carboxylate
  • Step 4 Preparation of compound 548-5: methyl 2- (1- (3-bromophenyl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) pyrimidine-4-carboxylate
  • Step 5 Preparation of compound 548-6: methyl 2- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -5- (3-bromophenyl) -2- (cyclopropylmethyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate
  • methyl 2- (1- (3-bromophenyl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) pyrimidine-4-carboxylate 600 mg, 1.39 mmol, 1.0 eq
  • EtOH (2 mL) in AcOH (8 mL) was added 4- (aminomethyl) -2-fluoro-N, N-bis (4-methoxybenzyl) benzenesulfonamide (928 mg, 2.09 mmol, 1.5 eq) and stirred at 110 °C for 18 hours.
  • Step 6 Preparation of compound 548-7: methyl 2- (5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate
  • Step 7 Preparation of compound 548-8: methyl 2- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate
  • methyl 2- (5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate 100 mg, 0.17 mmol, 1.0 eq)
  • 1, 4-diazabicyclo [2.2.2] octane 56 mg, 0.50 mmol, 3.0 eq
  • Tri-tert-butylphosphine tetrafluoroborate 24 mg, 0.08 mmol, 0.5 eq
  • Step 8 Preparation of compound 548: 2- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylic acid
  • Step 1 Preparation of compound 568-1: methyl 5-formylnicotinate
  • Step 2 Preparation of compound 568-2: methyl (E) -5- (3- (3-bromophenyl) -3-oxoprop-1-en-1-yl) nicotinate
  • methyl 5-formylnicotinate 3.4 g, 20.59 mmol, 1.0 eq
  • 1- (3-bromophenyl) ethan-1-one 3.03 mL, 22.65 mmol, 1.1 eq
  • K 3 PO 4 (6.55 g, 30.88 mmol, 1.5 eq)
  • the reaction mixture was stirred at 85°C overnight.
  • the reaction mixture was diluted with DCM (200 mL) .
  • Step 3 Preparation of compound 568-3: methyl 5- (1- (3-bromophenyl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) nicotinate
  • Step 4 Preparation of compound 568-5: methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -2- (cyclopropylmethyl) -5- (p-tolyl) -1H-pyrrol-3-yl) picolinate
  • Step 5 Preparation of compound 568-6: methyl 5- (5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) nicotinate
  • Step 6 Preparation of compound 568-7: methyl 5- (5- (3- (cyclopentylethynyl) phenyl) -2- (Cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) nicotinate
  • reaction mixture was H 2 O (30 mL) , extracted with EA (30 mL ⁇ 3) .
  • the combined organic phase washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 40%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow oil (60 mg, 83%) .
  • Step 7 Preparation of compound 568: 5- (5- (3- (cyclopentylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) nicotinic acid
  • Step 2 Preparation of compound 608-3: methyl 6- (1- (3-bromophenyl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) picolinate
  • Step 3 Preparation of compound 608-4: methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -5- (3-bromophenyl) -2- (cyclopropylmethyl) -1H-pyrrol-3-yl) picolinate
  • Step 4 Preparation of compound 608-5: methyl 6- (5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate
  • reaction mixture was concentrated under vacuum to afford the crude product was purified by column chromatography through silica gel, eluting with 0%to 35%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (190 mg, 78%) .
  • Step 5 Preparation of compound 608-6: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (3-hydroxy-3-methylbut-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) picolinate
  • methyl 6- (5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (120 mg, 0.20 mmol, 1.0 eq)
  • DABCO (112 mg, 1.00 mmol, 5.0 eq)
  • Tri-tert-butylphosphine tetrafluoroborate 29 mg, 0.10 mmol, 0.5 eq)
  • Allylpalladium chloride dimer (15 mg, 0.04 mmol, 0.2 eq) in di
  • Step 6 Preparation of compound 608: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (3-hydroxy-3-methylbut-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) picolinic acid
  • the combined organic phase washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated under vacuum.
  • the mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm ⁇ 25 mm ⁇ 10 um column (eluent: 60%to 95% (v/v) CH 3 CN and H 2 O with 0.025%HCOOH) to afford the title product as a white solid (35 mg, 40%) .
  • Step 1 Preparation of compound 609-2: methyl (E) -6- (3- (3-bromo-4-fluorophenyl) -3-oxoprop-1-en-1-yl) picolinate
  • Step 2 Preparation of compound 609-3: methyl 6- (1- (3-bromo-4-fluorophenyl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) picolinate
  • Step 3 Preparation of compound 609-4: methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -5- (3-bromo-4-fluorophenyl) -2- (cyclopropylmethyl) -1H-pyrrol-3-yl) picolinate
  • methyl 6- (1- (3-bromo-4-fluorophenyl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) picolinate (280 mg, 0.62 mmol, 1.0 eq) in a mixture solvent of AcOH (2 mL) in EtOH (8 mL) was added 4- (aminomethyl) -2-fluoro-N, N-bis [ (4-methoxyphenyl) methyl] benzenesulfonamide (333 mg, 0.75 mmol, 1.2 eq) .
  • reaction mixture was stirred at 100 °C for 12 hours. This mixture was concentrated under reduced vacuum, then the residue was diluted with NaHCO 3 (30 mL) and extracted with EtOAc (50 mL ⁇ 2) . The organic layers were combined, washed with brine, dried over Na 2 SO 4 , filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel (eluting with 5%to 33%EtOAc in petroleum ether as a gradient) to afford the title product as a white solid (480 mg, 89.70%) .
  • Step 4 Preparation of compound 609-5: methyl 6- (5- (3-bromo-4-fluorophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate
  • Step 5 Preparation of compound 609-6: methyl 6- (2- (cyclopropylmethyl) -5- (4-fluoro-3- (3-hydroxy-3-methylbut-1-yn-1-yl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate Under N 2 , to the solution of methyl 6- (5- (3-bromo-4-fluorophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4- sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (150 mg, 0.24 mmol, 1.0 eq) and 2-methylbut-3-yn-2-ol (102 mg, 1.22 mmol, 5.0 eq) in dioxane (2 mL) was added DABCO (82 mg, 0.73 mmol, 3.0 eq) , CuI (9 mg, 0.05 mmol,
  • Step 6 Preparation of compound 609: 6- (2- (cyclopropylmethyl) -5- (4-fluoro-3- (3-hydroxy-3-methylbut-1-yn-1-yl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid
  • Step 1 Preparation of compound 610-2: methyl (E) -3- (3- (3-bromophenyl) -3-oxoprop-1-en-1-yl) benzoate To the solution of methyl 3-formylbenzoate (2 g, 12.18 mmol, 1.0 eq) and 1- (3-bromophenyl) ethan-1-one (2.44 mL, 18.27 mmol, 1.5 eq) in methanol (40 mL) was added sodium hydroxide (970 mg, 24.37 mmol, 2.0 eq) . The reaction mixture was stirred at room temperature for 18 hours.
  • Step 2 Preparation of compound 610-3: methyl 3- (1- (3-bromophenyl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) benzoate
  • Step 3 Preparation of compound 610-4: methyl 3- (5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) benzoate
  • Step 4 Preparation of compound 610-5: methyl 3- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (3-hydroxy-3-methylbut-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) benzoate
  • Step 5 Preparation of compound 610: 3- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (3-hydroxy-3-methylbut-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) benzoic acid
  • the mixture was acidified with 1 M aqueous HCl solution until the pH was ⁇ 6 at 0 °C and extracted with EA (10 mL ⁇ 2) .
  • the organic layers were combined, washed with brine, dried over Na 2 SO 4 , filtered and concentrated under vacuum.
  • the mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm ⁇ 25 mm ⁇ 10 um column (eluent: 60%to 95% (v/v) CH 3 CN and H 2 O with 0.1%HCOOH) to afford the title product as a yellow solid (3 mg, 17%) .
  • Step 1 Preparation of compound 612-1: methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (3-hydroxy-3-methylbut-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate
  • the mixture was stirred at RT for 18 hours under N 2 .
  • the reaction mixture was diluted with H 2 O (15 mL) and extracted with EA (15 mL ⁇ 3) .
  • the combined organic phase washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated under vacuum to afford the crude product and purified by column chromatography through silica gel, eluting with 0%to 50%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow oil (70 mg, 69%) .
  • Step 2 Preparation of compound 612: 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (3-hydroxy-3-methylbut-1-yn-1-yl) phenyl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylic acid
  • the combined organic phase washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated under vacuum.
  • the mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm ⁇ 25 mm ⁇ 10 um column (eluent: 60%to 95% (v/v) CH 3 CN and H 2 O with 0.025%HCOOH) to afford the title product as a white solid (35 mg, 51%) .
  • Step 1 Preparation of compound 616-2: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3’-fluoro- [1, 1’-biphenyl] -3-yl) -1H-pyrrol-3-yl) picolinate
  • reaction mixture was stirred 60 °C for 2 hours under N 2 atmosphere. After completion, the reaction mixture was poured into water (40 mL) and extracted with EA (50 mL ⁇ 3) . The combined organic layer washed with brine, dried over Na 2 SO 4 , filtered, concentrated. The mixture was purified by column chromatography through silica gel (eluting with 0: 100 to 60: 40 petroleum ether: ethyl acetate) to afford the title compound (800 mg, 78 %yield) .
  • Step 2 Preparation of compound 616: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3’-fluoro- [1, 1’-biphenyl] -3-yl) -1H-pyrrol-3-yl) picolinic acid
  • Step 1 Preparation of compound 617-1: methyl 6- (2- (cyclopropylmethyl) -5- (3’, 6-difluoro- [1, 1’-biphenyl] -3-yl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate
  • Step 2 Preparation of compound 617: 6- (2- (cyclopropylmethyl) -5- (3’, 6-difluoro- [1, 1’-biphenyl] -3-yl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid
  • Step 1 Preparation of compound 622-2: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (4’- (2-hydroxypropan-2-yl) - [1, 1’-biphenyl] -3-yl) -1H-pyrrol-3-yl) picolinate
  • Step 2 Preparation of compound 622: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (4’- (2-hydroxypropan-2-yl) - [1, 1’-biphenyl] -3-yl) -1H-pyrrol-3-yl) picolinic acid
  • Step 1 Preparation of compound 623-2: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4- sulfamoylbenzyl) -5- (3’- (2-hydroxypropan-2-yl) - [1, 1’-biphenyl] -3-yl) -1H-pyrrol-3-yl) picolinate
  • Step 2 Preparation of compound 623: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3’- (2-hydroxypropan-2-yl) - [1, 1’-biphenyl] -3-yl) -1H-pyrrol-3-yl) picolinic acid
  • Step 1 Preparation of compound 636-1: methyl 6- (5- (3’-cyano- [1, 1’-biphenyl] -3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate
  • Methyl 6- (5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (100 mg, 167.09 ⁇ mol, 1 eq) was added to a mixture of water (0.5 mL) and THF (3 mL) , and followed by (3-cyanophenyl) boronic acid (36.83 mg, 250.63 ⁇ mol, 1.5 eq) , cesium carbonate (106.40 mg, 501.27 ⁇ mol, 3 eq) and Xphos Pd G 3 (14.14 mg, 16.71 ⁇ mol, 0.1 eq) in turn.
  • Step 1 Preparation of compound 636: 6- (5- (3’-cyano- [1, 1’-biphenyl] -3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid
  • Methyl 6- (5- (3’-cyano- [1, 1’-biphenyl] -3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (100 mg, 161.11 ⁇ mol, 1 eq) was added to a mixture of methanol (2 mL) and THF (2 mL) , and LiOH (2 M, 4.00 mL) was added. The resulting mixture was stirred at 30 °C for 0.5 hour and diluted with 1 N HCl aq (3 mL) , and extracted with EtOAc (5 mL ⁇ 3) .
  • Step 1 Preparation of compound 637-1: methyl 6- (5- (4’-cyano- [1, 1’-biphenyl] -3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate
  • Methyl 6- (5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoyl benzyl) -1H-pyrrol-3-yl) picolinate (100 mg, 167.09 ⁇ mol, 1 eq) was added to a mixture of water (0.5 mL) and THF (3 mL) , and followed by (4-cyanophenyl) boronic acid (36.83 mg, 250.63 ⁇ mol, 1.5 eq) , K 3 PO 4 (106.40 mg, 501.27 ⁇ mol, 3 eq) and Xphos Pd G 3 (14.14 mg, 16.71 ⁇ mol, 0.1 eq) in turn.
  • Step 2 Preparation of compound 637: 6- (5- (4’-cyano- [1, 1’-biphenyl] -3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid
  • Methyl 6- (5- (4’-cyano- [1, 1’-biphenyl] -3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (95 mg, 153.06 ⁇ mol, 1 eq) was added to a mixture of methanol (2 mL) and THF (2 mL) , and LiOH (2 M, 1.00 mL) was added. The resulting mixture was stirred at 30 °C for 0.5 hour and diluted with 1 N HCl aq (3 mL) , and extracted with EA (5 mL ⁇ 3) .
  • Step 1 Preparation of compound 646-1: methyl 6- (2- (cyclopropylmethyl) -5- (3- ( (3, 3-difluorocyclobutyl) ethynyl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate
  • methyl 6- (5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate (150 mg, 0.25 mmol, 1.0 eq) , 3-ethynyl-1, 1-difluorocyclobutane (87 mg, 0.75 mmol, 3.0 eq) , DABCO (84 mg, 0.75 mmol, 3.0 eq) , CuI (5 mg, 0.03 mmol, 0.1 eq) , Pd-162 (50 mg, 0.13 mmol, 0.5 eq) and dioxane (6 mL) .
  • reaction mixture was degassed for 10 minutes and stirred at 25 °C for 18 hours.
  • the reaction mixture was concentrated under reduced pressure.
  • the residue was purified by column chromatography through silica gel (eluting with 100: 0 to 60: 40 petroleum ether: ethyl acetate) to afford the title compound (100 mg, 63 %yield) .
  • Step 2 Preparation of compound 646: 6- (2- (cyclopropylmethyl) -5- (3- ( (3, 3-difluorocyclobutyl) ethynyl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid
  • the mixture was acidified with 1 M aqueous HCl solution until the pH was ⁇ 6 and the mixture were extracted with ethyl acetate (10 mL ⁇ 3) .
  • the organic layers were combined, washed with saturated aqueous NaHCO 3 solution and brine, dried over Na 2 SO 4 , and concentrated under vacuum.
  • the residue was purified by Prep-HPLC (Phenomenex Gemini 150 mm ⁇ 25 mm ⁇ 10 um column (eluent: 70%to 95% (v/v) CH 3 CN and H 2 O with 0.025%HCOOH) to afford the title compound (49 mg, 50%yield) .
  • Step 1 Preparation of compound 647-1: methyl 6- (5- (3- (cyclopentylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate
  • Step 2 Preparation of compound 647: 6- (5- (3- (cyclopentylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid
  • Step 1 Preparation of compound 648-1: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( (5-methylthiophen-2-yl) ethynyl) phenyl) -1H-pyrrol-3-yl) picolinate
  • Step 2 Preparation of compound 648: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- ( (5-methylthiophen-2-yl) ethynyl) phenyl) -1H-pyrrol-3-yl) picolinic acid
  • the mixture was acidified with 1 M aqueous HCl solution until the pH was ⁇ 6 at 0 °C.
  • the resulting was extracted with EA (30 mL ⁇ 3) .
  • the organic layer washed with brine (30 mL) , dried over Na 2 SO 4 , filtered and concentrated.
  • the mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm ⁇ 25 mm ⁇ 10 um column (eluent: 60%to 95% (v/v) CH 3 CN and H 2 O with 0.025%HCOOH) to afford the title compound (220 mg, 0.35 mmol, 40.90%) .
  • Step 1 Preparation of compound 649-2: methyl (E) -6- (3- (3-bromo-4-methylphenyl) -3-oxoprop-1-en-1-yl) picolinate
  • Step 2 Preparation of compound 649-3: methyl 6- (1- (3-bromo-4-methylphenyl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) picolinate
  • Step 3 Preparation of compound 649-4: methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -5- (3-bromo-4-methylphenyl) -2- (cyclopropylmethyl) -1H-pyrrol-3-yl) picolinate
  • Step 4 Preparation of compound 649-5: methyl 6- (5- (3-bromo-4-methylphenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate
  • Step 5 Preparation of compound 649-6: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (4’-fluoro-6-methyl- [1, 1’-biphenyl] -3-yl) -1H-pyrrol-3-yl) picolinate
  • Step 6 Preparation of compound 649: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (4’-fluoro-6-methyl- [1, 1’-biphenyl] -3-yl) -1H-pyrrol-3-yl) picolinic acid
  • Step 1 Preparation of compound 650-a: 4-cyano-2-fluorobenzenesulfonamide
  • Step 2 Preparation of compound 650-4: 4- (aminomethyl) -2-fluorobenzenesulfonamide
  • Step 1 Preparation of compound 650-2: methyl (E) -6- (3- (3-bromo-2-methylphenyl) -3-oxoprop-1-en-1-yl) picolinate
  • Step 2 Preparation of compound 650-3: methyl 6- (1- (3-bromo-2-methylphenyl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) picolinate
  • Step 3 Preparation of compound 650-5: methyl 6- (5- (3-bromo-2-methylphenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate
  • Step 4 Preparation of compound 650-6: methyl 6- (2- (cyclopropylmethyl) -5- (4’-fluoro-2-methyl- [1, 1’-biphenyl] -3-yl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate
  • reaction mixture was stirred 85 °Cfor 2 hours under N 2 atmosphere. After completion, the reaction mixture was poured into water (10 mL) and extracted with EA (10 mL ⁇ 3) . The combined organic layer washed with brine, dried over Na 2 SO 4 , filtered, concentrated. The mixture was purified by column chromatography through silica gel (eluting with 0:100 to 60: 40 petroleum ether: ethyl acetate) to afford the title compound (115 mg, 95.65%) .
  • Step 5 Preparation of compound 650: 6- (2- (cyclopropylmethyl) -5- (4’-fluoro-2-methyl- [1, 1’-biphenyl] -3-yl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid
  • the reaction mixture was extracted with EA (10 mL ⁇ 3) .
  • the organic layer washed with brine (30 mL) , dried over Na 2 SO 4 , filtered and concentrated.
  • the mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm ⁇ 25 mm ⁇ 10 um column (eluent: 60%to 95% (v/v) CH 3 CN and H 2 O with 0.025%HCOOH) to afford the title product as a white solid (66 mg, 58.77%) .
  • Step 1 Preparation of compound 651-2: methyl (E) -6- (3- (3-bromo-2-fluorophenyl) -3-oxoprop-1-en-1-yl) picolinate
  • Step 2 Preparation of compound 651-3: methyl 6- (1- (3-bromo-2-fluorophenyl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) picolinate
  • Step 3 Preparation of compound 651-4: methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3- fluorobenzyl) -5- (3-bromo-2-fluorophenyl) -2- (cyclopropylmethyl) -1H-pyrrol-3-yl) picolinate
  • Step 4 Preparation of compound 651-5: methyl 6- (5- (3-bromo-2-fluorophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate
  • Step 5 Preparation of compound 651-6: methyl 6- (2- (cyclopropylmethyl) -5- (2, 4’-difluoro- [1, 1’-biphenyl] -3-yl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate
  • Step 6 Preparation of compound 651: 6- (2- (cyclopropylmethyl) -5- (2, 4’-difluoro- [1, 1’-biphenyl] -3-yl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid
  • Step 1 Preparation of compound 652-2: methyl 6- (5- (4’-carbamoyl- [1, 1’-biphenyl] -3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate
  • reaction mixture was stirred at 80 °C for 2 hours.
  • the reaction mixture was filtered and concentrated under vacuum.
  • the residue was purified by column chromatography through silica gel (eluting with 0%to 70%EtOAc in petroleum ether) to afford the title product as a yellow solid (60 mg, 0.09 mmol, 70.28 %) .
  • Step 2 Preparation of compound 652: 6- (5- (4’-carbamoyl- [1, 1’-biphenyl] -3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid
  • the mixture was acidified with 1 N aqueous HCl solution until the pH ⁇ 6 at 0 °C and extracted with EA (20 mL ⁇ 2) .
  • the organic layers were combined, washed with brine, dried over Na 2 SO 4 , filtered and concentrated under vacuum.
  • the mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm ⁇ 25 mm ⁇ 10 um column (eluent: 70%to 95% (v/v) CH 3 CN and H 2 O with 0.025%HCOOH) to afford the title product as a white solid (31.65 mg, 0.05 mmol, 53.9%) .
  • Step 1 Preparation of compound 653-1: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1H-pyrrol-3-yl) picolinate
  • Step 2 Preparation of compound 653-3: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (4- (trifluoromethyl) oxazol-2-yl) phenyl) -1H-pyrrol-3-yl) picolinate
  • Step 3 Preparation of compound 653: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (4- (trifluoromethyl) oxazol-2-yl) phenyl) -1H-pyrrol-3-yl) picolinic acid
  • Bottle A To the suspension of 4-amino-3-methylbenzene-1-carbonitrile (5.00 g, 37.83 mmol, 1.0 eq) in 12 N HCl (10 mL) was added a sodium nitrite (2.87 g, 41.61 mmol, 1.1 eq) in H 2 O (10 mL) portion wise with the temperature was kept at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour.
  • Bottle B SOCl 2 (10 mL) was added to the H 2 O (20 mL) portion wise with the temperature was kept at 0 °C. The resuting mixture was added chlorocopper (I) (1.12 g, 11.35 mmol, 0.3 eq) . The reaction mixture was stirred at RT for 1 hour.
  • the bottle B was added the reaction mixture in bottle A portion wise with the temperature was kept at 0 °C.
  • the reaction mixture was stirred at 0 °C for 1 hour.
  • the reaction mixture was extracted with EA (20 mL) .
  • the organic layer washed with brine (20 mL) , dried over Na 2 SO 4 , filtered and concentrated.
  • Step 2 Preparation of compound 654-3: 4-cyano-N, N-bis [ (4-methoxyphenyl) methyl] -2- methylbenzenesulfonamide
  • Step 3 Preparation of compound 654-4: 4- (aminomethyl) -N, N-bis [ (4-methoxyphenyl) methyl] -2-methylbenzenesulfonamide
  • Step 4 Preparation of compound 654-5: methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-methylbenzyl) -2- (cyclopropylmethyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) picolinate
  • Step 5 Preparation of compound 654-6: methyl 6- (2- (cyclopropylmethyl) -5- (3-iodophenyl) -1- (3-methyl-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate
  • Step 6 Preparation of compound 654-7: methyl 6- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-methyl-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate
  • reaction mixture was cooled to room temperature and diluted with water (50 mL) , and then extracted with EtOAc (2 ⁇ 20 mL) .
  • EtOAc 2 ⁇ 20 mL
  • the combined organic layer washed with brine, dried over Na 2 SO 4 , filtered and concentrated under vacuum.
  • the residue was purified by column chromatography through silica gel, eluting with 0%to 35%EtOAc in petroleum ether as a gradient, to afford the title product as a solid (180 mg, 0.30 mmol, 77.79%) .
  • Step 7 Preparation of compound 654: 6- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-methyl-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid
  • the mixture was acidified with 1 M aqueous HCl solution until the pH was ⁇ 6 at 0 °C, and the mixture was extracted with ethyl acetate (10 mL ⁇ 3) .
  • the organic layers were combined, washed with saturated aqueous NaHCO 3 solution and brine, dried over Na 2 SO 4 , and concentrated under vacuum.
  • the residue was purified Prep-HPLC (Phenomenex Gemini 150 mm ⁇ 25 mm ⁇ 10 um column (eluent: 30%to 60% (v/v) CH 3 CN and H 2 O with 0.025%HCOOH) to afford the title compound (30 mg, 0.05 mmol, 30.73%) .
  • Step 1 Preparation of compound 655-2: 4-cyano-2- [ (trifluoromethyl) oxy] benzene sulfonyl chloride
  • Bottle A To the suspension of 4-amino-3- [ (trifluoromethyl) oxy] benzene-1-carbonitrile (2.00 g, 9.89 mmol, 1.0 eq) in 12N HCl (20 mL) was added a sodium nitrite (1.10 g, 15.94 mmol, 1.50 eq) in H 2 O (20 mL) portion wise with the temperature was kept at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour.
  • Step 2 Preparation of compound 655-3: 4-cyano-N, N-bis [ (4-methoxyphenyl) methyl] -2- [ (trifluoromethyl) oxy] benzenesulfonamide
  • Step 3 Preparation of compound 655-4: 4-cyano-2- [ (trifluoromethyl) oxy] benzene-1-sulfonamide
  • Step 4 Preparation of compound 655-5: methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3- (trifluoromethoxy) benzyl) -2- (cyclopropylmethyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) picolinate
  • Step 5 Preparation of compound 655-6: methyl 6- (2- (cyclopropylmethyl) -5- (3-iodophenyl) -1- (4-sulfamoyl-3- (trifluoromethoxy) benzyl) -1H-pyrrol-3-yl) picolinate
  • Step 6 Preparation of compound 655-7: methyl 6- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (4-sulfamoyl-3- (trifluoromethoxy) benzyl) -1H-pyrrol-3-yl) picolinate
  • Step 7 Preparation of compound 655: 6- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (4-sulfamoyl-3- (trifluoromethoxy) benzyl) -1H-pyrrol-3-yl) picolinic acid
  • Bottle A To the suspension of 4-amino-3- (trifluoromethyl) benzene-1-carbonitrile (2.00 g, 10.74 mmol, 1.0 eq) in 12 N HCl (20 mL) was added a sodium nitrite (1.10 g, 15.94 mmol, 1.50 eq) in H 2 O (20 mL) portion wise with the temperature was kept at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour.
  • Bottle B SOCl 2 (10 mL) was added to the H 2 O (20 mL) portion wise with the temperature was kept at 0 °C. The resuting mixture was added chlorocopper (I) (0.43 g, 4.34 mmol, 0.4 eq) . The reaction mixture was stirred at RT for 1 hour.
  • the bottle B was added the reaction mixture in bottle A portion wise with the temperature was kept at 0 °C.
  • the reaction mixture was stirred at 0 °C for 1 hour.
  • the reaction mixture was extracted with EA (20 mL) .
  • the organic layer washed with brine (20 mL) , dried over Na 2 SO 4 , filtered and concentrated.
  • Step 2 Preparation of compound 656-3: 4-cyano-N, N-bis [ (4-methoxyphenyl) methyl] -2- (trifluoromethyl) benzenesulfonamide
  • Step 3 Preparation of compound 656-4: 4- (aminomethyl) -N, N-bis [ (4-methoxyphenyl) methyl] -2- (trifluoromethyl) benzenesulfonamide
  • Step 4 Preparation of compound 656-5: methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3- (trifluoromethyl) benzyl) -2- (cyclopropylmethyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) picolinate
  • Step 5 Preparation of compound 656-6: methyl 6- (2- (cyclopropylmethyl) -5- (3-iodophenyl) -1- (4-sulfamoyl-3- (trifluoromethyl) benzyl) -1H-pyrrol-3-yl) picolinate
  • Step 7 Preparation of compound 656: 6- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (4-sulfamoyl-3- (trifluoromethyl) benzyl) -1H-pyrrol-3-yl) picolinic acid
  • methyl 6- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (4-sulfamoyl-3- (trifluoromethyl) benzyl) -1H-pyrrol-3-yl) picolinatein (65 mg, 0.10 mmol, 1.0 eq) , methanol (5 mL) and H 2 O (1 mL) .
  • Lithium hydroxide (7 mg, 0.30 mmol, 3.0 eq) was added, and the mixture was stirred at 25 °C for 16 h.
  • the mixture was acidified with 1 M aqueous HCl solution until the pH was ⁇ 6 at 0 °C, and the mixture was extracted with ethyl acetate (10 mL ⁇ 3) .
  • the organic layers were combined, washed with saturated aqueous NaHCO 3 solution and brine, dried over Na 2 SO 4 , and concentrated under vacuum.
  • the residue was purified Prep-HPLC (Phenomenex Gemini 150 mm ⁇ 25 mm ⁇ 10 um column (eluent: 60%to 95% (v/v) CH 3 CN and H 2 O with 0.025%HCOOH) to afford to afford the title compound (30 mg, 0.05 mmol, 50%) .
  • Step 1 Preparation of compound 657-1: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (2’-fluoro- [1, 1’-biphenyl] -3-yl) -1H-pyrrol-3-yl) picolinate
  • Step 2 Preparation of compound 657 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (2’-fluoro- [1, 1’-biphenyl] -3-yl) -1H-pyrrol-3-yl) picolinic acid
  • Step 1 Preparation of compound 658-2: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (89thenone-2-yl) phenyl) -1H-pyrrol-3-yl) picolinate
  • Step 2 Preparation of compound 658: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (89thenone-2-yl) phenyl) -1H-pyrrol-3-yl) picolinic acid
  • Step 1 Preparation of compound 659-1: methyl 6- (5- (3- (cyclobutylethynyl) -4-fluorophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate
  • Step 2 Preparation of compound 659: 6- (5- (3- (cyclobutylethynyl) -4-fluorophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid
  • the reaction mixture was extracted with EA (10 mL ⁇ 3) .
  • the organic layer washed with brine (30 mL) , dried over Na 2 SO 4 , filtered and concentrated.
  • the mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm ⁇ 25 mm ⁇ 10 um column (eluent: 60%to 95% (v/v) CH 3 CN and H 2 O with 0.025%HCOOH) to afford the title product as a white solid (87.19 mg, 58.13%) .
  • Step 1 Preparation of compound 660-2: methyl 6- (5- (4’-chloro- [1, 1’-biphenyl] -3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate
  • reaction mixture was stirred at 80 °C for 2 hours.
  • the reaction mixture was filtered and concentrated under vacuum.
  • the residue was purified by column chromatography through silica gel, eluting with 0%to 35%EtOAc in petroleum ether, to afford the title product as a yellow solid (102 mg, 0.16 mmol, 94.99 %) .
  • Step 2 Preparation of compound 660: 6- (5- (4’-chloro- [1, 1’-biphenyl] -3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid
  • the mixture was acidified with 1 N aqueous HCl solution until the pH ⁇ 6 at 0 °C and extracted with EA (20 mL ⁇ 2) .
  • the organic layers were combined, washed with brine, dried over Na 2 SO 4 , filtered and concentrated under vacuum.
  • the mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm ⁇ 25 mm ⁇ 10 um column (eluent: 70%to 95% (v/v) CH 3 CN and H 2 O with 0.025%HCOOH) to afford the title product as a white solid (60.00 mg, 0.10 mmol, 60.16%) .
  • Step 1 Preparation of compound 661-2: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (1-methyl-1H-imidazol-4-yl) phenyl) -1H-pyrrol-3-yl) picolinate
  • Step 2 Preparation of compound 661: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (1-methyl-1H-imidazol-4-yl) phenyl) -1H-pyrrol-3-yl) picolinic acid
  • Step 1 Preparation of compound 662-2: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (thiazol-4-yl) phenyl) -1H-pyrrol-3-yl) picolinate
  • Step 2 Preparation of compound 662: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (thiazol-4-yl) phenyl) -1H-pyrrol-3-yl) picolinic acid
  • Step 1 Preparation of compound 663-1: methyl 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3’-fluoro- [1, 1’-biphenyl] -3-yl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylate
  • the mixture was stirred at 80 °C for 2 hours under N 2 .
  • the reaction mixture was diluted with H 2 O (20 mL) , extracted with EA (20 mL ⁇ 3) .
  • the combined organic phase washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated under vacuum to afford the crude product as a yellow solid (170 mg) .
  • Step 2 Preparation of compound 663: 2- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3’-fluoro- [1, 1’-biphenyl] -3-yl) -1H-pyrrol-3-yl) pyrimidine-4-carboxylic acid
  • Step 1 Preparation of compound 664-2: methyl (E) -6- (3- (4-bromophenyl) -3-oxoprop-1-en-1-yl) picolinate
  • Step 2 Preparation of compound 664-3: methyl 6- (1- (4-bromophenyl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) picolinate
  • Step 3 Preparation of compound 664-4: methyl 6- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3- fluorobenzyl) -5- (4-bromophenyl) -2- (cyclopropylmethyl) -1H-pyrrol-3-yl) picolinate
  • Step 4 Preparation of compound 664-5: methyl 6- (5- (4-bromophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate
  • Step 5 Preparation of compound 664-6: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (4’-fluoro- [1, 1’-biphenyl] -4-yl) -1H-pyrrol-3-yl) picolinate
  • Step 6 Preparation of compound 664: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (4’-fluoro- [1, 1’-biphenyl] -4-yl) -1H-pyrrol-3-yl) picolinic acid
  • Step 1 Preparation of compound 666-2: 1- [1- (4-fluorophenyl) pyrazol-3-yl] ethenone
  • the reaction mixture was filtered and the filtrate was diluted with H 2 O 100 mL and extracted with DCM (50 mL ⁇ 3) .
  • the organic layers were combined, washed with brine, dried over Na 2 SO 4 , filtered and concentrated under vacuum.
  • the residue was purified by column chromatography through silica gel (eluting with 0%to 30%EtOAc in petroleum ether as a gradient) to afford the title product as a white solid (370 mg, 6.65%) .
  • Step 2 Preparation of compound 666-3: methyl methyl 6- [ (E) -3- [1- (4-fluorophenyl) pyrazol-3-yl] -3-oxo-prop-1-enyl] pyridine-2-carboxylate
  • Step 3 Preparation of compound 666-4: methyl 6- [3-cyclopropyl-1- [2- [1- (4-fluorophenyl) pyrazol-3-yl] -2-oxo-ethyl] -2-oxo-propyl] pyridine-2-carboxylate
  • Step 4 Preparation of compound 666-5: methyl 6- [1- [ [4- [bis [ (4-methoxyphenyl) methyl] sulfamoyl] -3-fluoro-phenyl] methyl] -2- (cyclopropylmethyl) -5- [1- (4-fluorophenyl) pyrazol-3-yl] pyrrol-3-yl] pyridine-2-carboxylate
  • Step 5 Preparation of compound 666-6: methyl 6- [2- (cyclopropylmethyl) -5- [1- (4-fluorophenyl) pyrazol-3-yl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylate
  • Step 6 Preparation of compound 666: 6- [2- (cyclopropylmethyl) -5- [1- (4-fluorophenyl) pyrazol-3-yl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylic acid
  • the mixture was acidified with 1 N aqueous HCl solution until the pH was ⁇ 6 at 0 °C and extracted with EtOAc (3 mL ⁇ 3) .
  • the organic layers were combined, washed with brine, dried over Na 2 SO 4 , filtered and concentrated under vacuum.
  • the mixture was purified by prep-HPLC (column: Boston Prime C18 150 ⁇ 30mm ⁇ 5um; mobile phase: [Water (FA) -MeCN] ; gradient: 42%-72%B over 8 min) to afford the title product as a yellow solid (22 mg, 40%) .
  • Step 1 Preparation of compound 667-b: methyl 1- (4-fluorophenyl) piperidine-3-carboxylate
  • Step 3 Preparation of compound 667-d: 1- (4-fluorophenyl) -N-methoxy-N-methyl-piperidine-3-carboxamide
  • Step 4 Preparation of compound 667-1: 1- [1- (4-fluorophenyl) -3-piperidyl] ethenone
  • Step 1 Preparation of compound 667-2: methyl 6- [ (E) -3- [1- (4-fluorophenyl) -3-piperidyl] -3-oxo-prop-1-enyl] pyridine-2-carboxylate
  • Step 2 Preparation of compound 667-3: methyl 6- [3-cyclopropyl-1- [2- [1- (4-fluorophenyl) -3-piperidyl] -2-oxo-ethyl] -2-oxo-propyl] pyridine-2-carboxylate
  • Step 3 Preparation of compound 667-4: methyl 6- [1- [ [4- [bis [ (4-methoxyphenyl) methyl] sulfamoyl] -3-fluoro-phenyl] methyl] -2- (cyclopropylmethyl) -5- [1- (4-fluorophenyl) -3-piperidyl] pyrrol-3-yl] pyridine-2-carboxylate
  • Step 4 Preparation of compound 667-5: methyl 6- [2- (cyclopropylmethyl) -5- [1- (4-fluorophenyl) -3-piperidyl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylate
  • Step 5 Preparation of compound 667: 6- [2- (cyclopropylmethyl) -5- [1- (4-fluorophenyl) -3-piperidyl] -1- [ (3-fluoro-4-sulfamoyl-phenyl) methyl] pyrrol-3-yl] pyridine-2-carboxylic acid
  • the mixture was acidified with 1 N aqueous HCl solution until the pH was ⁇ 6 at 0 °C and extracted with EtOAc (3 mL ⁇ 3) .
  • the organic layers were combined, washed with brine, dried over Na 2 SO 4 , filtered and concentrated under vacuum.
  • the mixture was purified by prep-HPLC (column: Boston Prime C18 150 ⁇ 30mm ⁇ 5um; mobile phase: [Water (FA) -MeCN] ; gradient: 32%-62%B over 8 min) to afford the title product as a yellow solid (54.27 mg, 44.07%) .
  • Step 2 Preparation of compound 668-3: methyl (E) -4- (3- (3-bromophenyl) -3-oxoprop-1-en-1-yl) picolinate
  • methyl 4-formylpicolinate 500 mg, 3.03 mmol, 1.0
  • 1- (3-bromophenyl) ethan-1-one (663 mg, 3.33 mmol, 1.1 eq) in toluene (15 mL) was added PTSA (288 mg, 1.51 mmol, 0.5 eq) .
  • the reaction mixture was stirred at 140 °C with Dean-Stark trap for 2 hours.
  • Step 3 Preparation of compound 668-4: methyl 4- (1- (3-bromophenyl) -5-cyclopropyl-1, 4-dioxopentan-3-yl) picolinate
  • Step 4 Preparation of compound 668-5: methyl 4- (1- (4- (N, N-bis (4-methoxybenzyl) sulfamoyl) -3-fluorobenzyl) -5- (3-bromophenyl) -2- (cyclopropylmethyl) -1H-pyrrol-3-yl) picolinate
  • Step 5 Preparation of compound 668-6: methyl 4- (5- (3-bromophenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate
  • Step 6 Preparation of compound 668-7: methyl 4- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate
  • Step 7 Preparation of compound 668: 4- (5- (3- (cyclobutylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid
  • Step 1 Preparation of compound 671-1: methyl 6- (5- (3- (cyclobutylethynyl) -4-methylphenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate
  • Step 2 Preparation of compound 671: 6- (5- (3- (cyclobutylethynyl) -4-methylphenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid
  • Step 1 Preparation of compound 682-1: methyl 6- (5- (4’-chloro-3’-fluoro- [1, 1’-biphenyl] -3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate
  • Step 2 Preparation of compound 682: 6- (5- (4’-chloro-3’-fluoro- [1, 1’-biphenyl] -3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid
  • Step 1 Preparation of compound 683-1: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3-iodophenyl) -1H-pyrrol-3-yl) picolinic acid
  • Step 2 Preparation of compound 683: 6- (5- (4’-cyclopentyl- [1, 1’-biphenyl] -3-yl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid
  • Step 1 Preparation of compound 688-1: methyl 6- (5- (3- (cyclohexylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate
  • Step 2 Preparation of compound 688: 6- (5- (3- (cyclohexylethynyl) phenyl) -2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid
  • Step 1 Preparation of compound 695-2: methyl 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (4-methyloxazol-2-yl) phenyl) -1H-pyrrol-3-yl) picolinate
  • reaction mixture was stirred at 80 °C for 12 hours. This mixture was concentrated under reduced vacuum, then diluted with H 2 O (10 mL) and extracted with EtOAc (10 mL ⁇ 2) . The organic layers were combined, washed with brine, dried over Na 2 SO 4 , filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel, eluting with 20%to 80%EtOAc in petroleum ether as a gradient, to afford the title product as a yellow oil (120 mg, 64.72%) .
  • Step 2 Preparation of compound 695: 6- (2- (cyclopropylmethyl) -1- (3-fluoro-4-sulfamoylbenzyl) -5- (3- (4-methyloxazol-2-yl) phenyl) -1H-pyrrol-3-yl) picolinic acid
  • the reaction mixture was extracted with EA (10 mL ⁇ 3) .
  • the organic layer washed with brine (20 mL) , dried over Na 2 SO 4 , filtered and concentrated.
  • the mixture was purified by Prep-HPLC (Phenomenex Gemini 150 mm ⁇ 25 mm ⁇ 10 um column) (eluent: 60%to 95% (v/v) CH 3 CN and H 2 O with 0.025%HCOOH) to afford the title product as a white solid (94 mg, 79.89%) .
  • Step 1 Preparation of compound 696-1: methyl 6- (2- (cyclopropylmethyl) -5- (2-fluoro-3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate
  • Step 2 Preparation of compound 696-2: methyl 6- (2- (cyclopropylmethyl) -5- (2-fluoro-3- (4- (trifluoromethyl) oxazol-2-yl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinate
  • Step 3 Preparation of compound 696: 6- (2- (cyclopropylmethyl) -5- (2-fluoro-3- (4- (trifluoromethyl) oxazol-2-yl) phenyl) -1- (3-fluoro-4-sulfamoylbenzyl) -1H-pyrrol-3-yl) picolinic acid
  • Step 1 Preparation of compound 667-b: methyl 1- (4-fluorophenyl) piperidine-3-carboxylate

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Abstract

La présente invention concerne de nouveaux composés à petites molécules ayant des substituants aromatiques à six chaînons qui peuvent servir d'inhibiteurs de lactate déshydrogénase. La présente invention concerne également des compositions pharmaceutiques, comprenant au moins l'un de tels nouveaux composés substitués, et des procédés d'utilisation d'au moins l'un de tels composés ou compositions dans le traitement ou la prévention de maladies associées à des activités de lactate déshydrogénase, telles que des maladies auto-immunes.
PCT/CN2024/094118 2024-05-20 2024-05-20 Inhibiteurs de lactate déshydrogénase, compositions comprenant l'inhibiteur, et leurs procédés d'utilisation Pending WO2025241048A1 (fr)

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PCT/CN2024/094118 WO2025241048A1 (fr) 2024-05-20 2024-05-20 Inhibiteurs de lactate déshydrogénase, compositions comprenant l'inhibiteur, et leurs procédés d'utilisation
PCT/CN2025/095852 WO2025242055A1 (fr) 2024-05-20 2025-05-19 Inhibiteurs de lactate déshydrogénase, compositions comprenant l'inhibiteur, et leurs procédés d'utilisation

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PCT/CN2025/095852 Pending WO2025242055A1 (fr) 2024-05-20 2025-05-19 Inhibiteurs de lactate déshydrogénase, compositions comprenant l'inhibiteur, et leurs procédés d'utilisation

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US10351532B2 (en) * 2014-12-29 2019-07-16 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Small molecule inhibitors of lactate dehydrogenase and methods of use thereof
AU2017290233A1 (en) * 2016-06-29 2019-01-24 The Trustees Of The University Of Pennsylvania 1 H-pyrazol-1 -YL-thiazoles as inhibitors of lactate dehydrogenase and methods of use thereof
US20250205203A1 (en) * 2020-05-18 2025-06-26 Chinook Therapeutics Canada, Inc. Substituted pyrazolyl compounds and methods of use thereof
JP2023528274A (ja) * 2020-05-18 2023-07-04 チヌーク セラピューティクス カナダ， インコーポレイテッド 置換ピラゾリル化合物及びその使用方法
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