AUTOTAXIN INHIBITOR COMPOUNDS

• US 20160214935A1
• Filed: 09/25/2014
• Published: 07/28/2016
• Est. Priority Date: 09/26/2013
• Status: Active Grant

• Current Assignee: DF 2024 IP Acquisition LLC
• Original Assignee: PharmAkea, Inc.
• Inventors: HUANG, Fei, ROWBOTTOM, Martin, HUTCHINSON, John Howard, LONERGAN, David, CALDERON, Imelda
• Granted Patent: US 9,850,203 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/38 Cellulose; Derivatives thereof
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 : for myasthenia gravis
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/30 : for treating abuse or dependence
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 33/14 : Ectoparasiticides, e.g. scabicides
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 209/30 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 401/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 471/10 : Spiro-condensed systems
• CPC Class Codes: C07D 487/10 : Spiro-condensed systems
• CPC Class Codes: C07D 491/10 : Spiro-condensed systems
• CPC Class Codes: C07D 491/107 : with only one oxygen atom as ring hetero atom in the oxygen-containing ring
• CPC Class Codes: C07D 498/10 : Spiro-condensed systems

Abstract

Described herein are compounds that are autotaxin inhibitors, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders associated with autotaxin activity.

Claims

1. A compound of Formula (I), or a pharmaceutically acceptable salt, or solvate thereof:

2. The compound of claim 1, or a pharmaceutically acceptable salt, or solvate thereof, wherein:

R⁶ and R⁷ are taken together with the nitrogen atom to which they are attached to form a ring B as shown in Formula (II);

3. The compound of claim 2, or a pharmaceutically acceptable salt, or solvate thereof, wherein:

4. The compound of claim 3, or a pharmaceutically acceptable salt, or solvate thereof, wherein:

5. The compound of claim 2, or a pharmaceutically acceptable salt, or solvate thereof, wherein the compound has the structure of Formula (II):

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, or solvate thereof, wherein:

Ring A is phenyl, naphthyl, monocyclic heterocycloalkyl containing 1-2 N atoms and 0-1 O or S atoms, monocyclic heteroaryl containing 1-4 N atoms and 0 or 1 O or S atoms, monocyclic heteroaryl containing 0-4 N atoms and 1 O or S atoms, bicyclic heteroaryl containing 1-4 N atoms and 0 or 1 O or S atoms, or bicyclic heteroaryl containing 0-4 N atoms and 1 O or S atoms;

X is —

S—

.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, or solvate thereof, wherein:

Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl.

8. The compound of any one of claims 1-7, wherein the compound has the following structure of Formula (IV):

9. The compound of claim 8, wherein the compound has the following structure of Formula (V):

10. The compound of any one of claims 4-9, wherein

the two R⁸ substituents are joined together to form a substituted or unsubstituted C₃-C₈cycloalkyl or substituted or unsubstituted C₂-C₈ heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from —

NR¹¹—

or —

O—

.

11. The compound of any one of claims 4-9, wherein

each R⁸ substituent is independently H, halogen, OH, —

CN, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, C₃-C₈cycloalkyl, or C₁-C₆alkoxy.

12. The compound of claim 2, or a pharmaceutically acceptable salt, or solvate thereof, wherein:

13. The compound of claim 2, or a pharmaceutically acceptable salt, or solvate thereof, wherein the compound has the following structure of Formula (VI):

14. The compound of claim 12 or claim 13, or a pharmaceutically acceptable salt, or solvate thereof, wherein:

Ring A is phenyl, naphthyl, monocyclic heterocycloalkyl containing 1-2 N atoms and 0-1 O or S atoms, monocyclic heteroaryl containing 1-4 N atoms and 0 or 1 O or S atoms, monocyclic heteroaryl containing 0-4 N atoms and 1 O or S atoms, bicyclic heteroaryl containing 1-4 N atoms and 0 or 1 O or S atoms, or bicyclic heteroaryl containing 0-4 N atoms and 1 O or S atoms;

X is —

S—

.

15. The compound of claim 12 or claim 13, or a pharmaceutically acceptable salt, or solvate thereof, wherein:

Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl;

X is —

S—

.

16. The compound of any one of claims 13-15, wherein the compound has the following structure of Formula (VII):

17. The compound of any one of claims 12-16, or a pharmaceutically acceptable salt, or solvate thereof, wherein:

R¹ is H, halogen, —

CN, —

C(═

O)H, C₁-C₄alkyl, C₃-C₆cycloalkyl, or C₁-C₄fluoroalkyl;

L₂ is absent or C₁-C₄ alkylene.

18. The compound of any one of claims 12-17, or a pharmaceutically acceptable salt, or solvate thereof, wherein:

L₂ is absent, —

CH₂—

, —

CH(CH₃)—

, —

C(CH₃)₂—

, or —

(CH₂)₂—

.

19. The compound of any one of claims 12-18, or a pharmaceutically acceptable salt, or solvate thereof, wherein:

R¹ is halogen, C₁-C₄alkyl, C₃-C₆cycloalkyl, or C₁-C₄fluoroalkyl.

20. The compound of any one of claims 12-19, or a pharmaceutically acceptable salt, or solvate thereof, wherein:

R¹ is Cl, —

CH₃, —

CH₂CH₃, cyclopropyl, or —

CF₃.

21. The compound of claim 20, wherein the compound has the following structure of Formula (VIII):

22. The compound of any one of claims 12-21, wherein:

the two R⁸ substituents are joined together to form a substituted or unsubstituted C₃-C₈cycloalkyl.

23. The compound of any one of claims 12-21, wherein:

each R⁸ substituent is independently H, halogen, OH, —

CN, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, C₃-C₈cycloalkyl, or C₁-C₆alkoxy.

24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt, or solvate thereof, wherein

R² and R⁵ are each independently H, halogen, —

CN, —

OH, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄fluoroalkoxy, or C₁-C₄fluoroalkyl.

25. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt, or solvate thereof, wherein

R² is H, F, Cl, —

CN, —

CH₃, —

OCH₃, —

CF₃, or —

OCF₃;

R⁵ is H, F, Cl, —

CN, —

OH, —

CH₃, —

OCH₃, —

CF₃, or —

OCF₃.

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt, or solvate thereof, wherein

R⁵ is H, F, or Cl.

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt, or solvate thereof, wherein

R³ is —

CO₂H, —

CO₂(C₁-C₆alkyl), —

B(OH)₂, —

C(═

O)NHSO₂R⁹, —

SO₂NHC(═

O)R⁹, tetrazolyl, —

OP(═

O)(OH)₂, —

P(═

O)(OH)₂, or carboxylic acid bioisostere;

L¹ is absent, C₁-C₆alkylene, or C₃-C₆cycloalkylene.

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, or solvate thereof, wherein

L¹ is absent, —

CH₂—

, —

CH(CH₃)—

, —

C(CH₃)₂—

, or —

CH₂CH₂—

.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, or solvate thereof, wherein

L¹ is absent.

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt, or solvate thereof, wherein

R³ is —

CO₂H, —

CO₂(C₁-C₆alkyl), or C(═

O)NHSO₂R⁹.

31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt, or solvate thereof, wherein

R³ is —

CO₂H or —

CO₂(C₁-C₆alkyl).

32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt, or solvate thereof, wherein

R³ is —

CO₂H.

33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt, or solvate thereof, wherein

R⁴ is H, halogen, —

CN, —

OH, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄deuteroalkyl, C₁-C₄alkoxy, C₁-C₄fluoroalkoxy, —

S—

C₁-C₄alkyl, —

S(═

O)—

C₁-C₄alkyl, —

S(═

O)₂—

C₁-C₄alkyl, or C₁-C₄hydroxyalkyl.

34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt, or solvate thereof, wherein

R⁴ is halogen, —

CN, —

OH, C₁-C₄alkyl, C₁-C₄alkoxy, —

S—

C₁-C₄alkyl, C₁-C₄fluoroalkyl, or C₁-C₄fluoroalkoxy.

35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt, or solvate thereof, wherein

R⁴ is F, Cl, Br, I, —

CN, —

OH, —

CH₃, —

CH₂CH₃, —

CH(CH₃)₂, —

OCH₃, —

OCH₂CH₃, —

CF₃, —

OCF₃, or —

S—

CH₃.

36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, or solvate thereof, wherein

R⁴ is F or Cl.

37. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt, or solvate thereof, wherein:

R² is H, F, Cl, —

CN, —

OH, —

CH₃, —

OCH₃, —

CF₃, or —

OCF₃;

L is absent, C₁-C₆alkylene, or C₃-C₆cycloalkylene;

R³ is —

CO₂H, —

CO₂(C₁-C₆alkyl), —

B(OH)₂, or C(═

O)NHSO₂R⁹;

R⁴ is F, Cl, Br, I, —

CN, —

OH, —

CH₃, —

CH₂CH₃, —

CH(CH₃)₂, —

OCH₃, —

OCH₂CH₃, —

CF₃, —

OCF₃, —

S—

CH₃, or —

S(O)₂—

CH₃; and

R⁵ is H, F, Cl, —

CN, —

OH, —

CH₃, —

OCH₃, —

CF₃, or —

OCF₃.

38. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt, or solvate thereof, wherein:

R² is H, F, Cl, —

CN, —

OH, —

CH₃, —

OCH₃, —

CF₃, or —

OCF₃;

L is absent, —

CH₂—

, —

CH(CH₃)—

, or —

CH₂CH₂—

;

R³ is —

CO₂H or —

CO₂(C₁-C₆alkyl);

R⁴ is F, Cl, Br, —

CN, —

OCH₃, or —

CF₃; and

R⁵ is H, F, Cl, —

CN, —

CH₃, —

OCH₃, —

CF₃, or —

OCF₃.

39. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt, or solvate thereof, wherein:

R² is H, F, Cl, —

CH₃, —

OCH₃, —

CF₃, or —

OCF₃;

L¹ is absent;

R³ is —

CO₂H;

R⁴ is F or Cl; and

R⁵ is H, F, or Cl.

41. A pharmaceutical composition comprising a compound of any one of claims 1-40, or a pharmaceutically acceptable salt, or solvate thereof, and at least one pharmaceutically acceptable excipient.

42. The pharmaceutical composition of claim 41, wherein the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration.

43. The pharmaceutical composition of claim 41, wherein the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion.

44. Use of a compound of any one of claims 1-40, or a pharmaceutically acceptable salt, or solvate thereof, in the treatment or prevention of cancer, fibrosis, pruritis, an inflammatory disease or condition, an airway disease or condition, an autoimmune disease or condition, obesity, intraocular pressure, neuropathic pain, or combinations thereof in a mammal.

45. Use of a compound of any one of claims 1-40, or a pharmaceutically acceptable salt, or solvate thereof, in the treatment or prevention of cancer in a mammal.

46. The use of claim 45, wherein the cancer is a solid tumor.

47. The use of claim 45, wherein the cancer is bladder cancer, colon cancer, brain cancer, breast cancer, endometrial cancer, heart cancer, kidney cancer, lung cancer, liver cancer, uterine cancer, blood and lymphatic cancer, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, or skin cancer.

48. The use of claim 45, wherein the cancer is a sarcoma, carcinoma, or lymphoma.

49. Use of a compound of any one of claims 1-40, or a pharmaceutically acceptable salt, or solvate thereof, in the treatment or prevention of fibrosis in a mammal.

50. The use of claim 49, wherein the fibrosis comprises lung fibrosis, liver fibrosis, kidney fibrosis, ocular fibrosis or cutaneous fibrosis.

51. Use of a compound of any one of claims 1-40, or a pharmaceutically acceptable salt, or solvate thereof, in the reduction or inhibition of angiogenesis in a mammal.

52. The use of claim 51, wherein the reduction or inhibition of angiogenesis in the mammal treats atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet-form macular degeneration, choroidal neovascularization, retinal neovascularization, or diabetic retinopathy.

53. Use of a compound of any one of claims 1-40, or a pharmaceutically acceptable salt, or solvate thereof, in the treatment or prevention of an inflammatory disease or condition in a mammal.

54. The use of claim 53, wherein the inflammatory disease or condition is psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, eczema, lupus erythematosus, dermatomyositis, Sjö

gren'"'"'s syndrome, thyroiditis, myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, allergic conjunctivitis or atopic dermatitis.

55. Use of a compound of any one of claims 1-40, or a pharmaceutically acceptable salt, or solvate thereof, in the treatment or prevention of pruritis in a mammal.

56. The use of claim 55, wherein the pruritus is associated with dermatitis herpetiformis, dermatomyositis, pemphigoid, Sjö

gren'"'"'s syndrome, Darier'"'"'s disease, Hailey-Hailey disease, Ichthyoses, Sjö

gren-Larsson syndrome, dermatophytosis, folliculitis, impetigo and other bacterial infections, insect bites, pediculosis, ccabies, viral infection, asteatosis, atopic eczema, contact dermatitis, drug reaction, lichen planus, lichen simplex chronicus, mastocytosis (urticaria pigmentosa), miliaria, psoriasis, scar(s), urticaria, cutaneous T-cell lymphoma or mycosis fungoides, cutaneous B-cell lymphoma, leukemia cutis, pemphigoid gestationis, polymorphic eruption of pregnancy or prurigo gestationis.

57. Use of a compound of any one of claims 1-40, or a pharmaceutically acceptable salt, or solvate thereof, in the treatment or prevention of cholestatic pruritis in a mammal.

40. A compound that is:

3-((6-Chloro-1-(2-((3, 5-dichlorophenyl) amino)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-4);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(phenylamino) ethyl)-1H-indol-3-yl) thio) benzoic acid (Compound 1-3);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-((1-methyl-1H-pyrazol-4-yl) amino)-2-oxoethyl)-1H-indol-3-yl) thio) benzoic acid (Compound 1-6);

3-((6-Chloro-7-fluoro-1-(2-(isoxazol-4-ylamino)-2-oxoethyl)-2-methyl-1H-indol-3-yl) thio) benzoic acid (Compound 1-11);

2-(6-Chloro-7-fluoro-2-methyl-3-((3-propionylphenyl) thio)-1H-indol-1-yl)-N-(2, 2, 2-trifluoroethyl) acetamide (Compound 1-5);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(pyrrolidin-1-yl) ethyl)-1H-indol-3-yl) thio) benzoic acid (Compound 1-9);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-(methyl (phenyl) amino)-2-oxoethyl)-1H-indol-3-yl) thio) benzoic acid (Compound 1-8);

3-((6-Chloro-1-(2-(cyclohexylamino)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl) thio) benzoic acid (Compound 1-2);

3-((6-Chloro-7-fluoro-1-(2-(isopropylamino)-2-oxoethyl)-2-methyl-1H-indol-3-yl) thio) benzoic acid (Compound 1-1);

3-((6-Chloro-1-(2-(dimethylamino)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl) thio) benzoic acid (Compound 1-7);

3-((1-(Benzylcarbamoyl)-6-chloro-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-17);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(piperidin-1-yl) ethyl)-1H-indol-3-yl) thio) benzoic acid (Compound 1-10);

3-((6-Chloro-1-(2-(4-((3, 4-difluorobenzyl) oxy) piperidin-1-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl) thio) benzoic acid (Compound 1-13);

3-((6-Chloro-7-fluoro-1-(2-(3-(4-fluorobenzyl) piperidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl) thio) benzoic acid (Compound 1-15);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-(2-oxo-1-oxa-3, 8-diazaspiro[4.5]decan-8-yl) acetyl)-1H-indol-3-yl) thio) benzoic acid (Compound 1-12);

3-((6-Chloro-7-fluoro-2-methyl-1-(3-oxo-3-(phenylamino)propyl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-16);

3-((6-Chloro-7-fluoro-1-(2-(indolin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl) thio) benzoic acid (Compound 1-14);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(2-oxo-7-azaspiro[3.5]nonan-7-yl) ethyl)-1H-indol-3-yl) thio) benzoic acid (Compound 1-18);

3-((6-Chloro-1-(2-(2-cyano-7-azaspiro[3.5]nonan-7-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl) thio) benzoic acid (Compound 1-19);

3-((6-Chloro-7-fluoro-1-(2-(3-(4-fluorophenyl)pyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-20);

3-((6-Chloro-7-fluoro-1-(2-(3-(4-fluorobenzyl)pyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-21);

3-((6-Chloro-7-fluoro-1-(2-(3-((4-fluorobenzyl)oxy)pyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-22);

3-((6-Chloro-7-fluoro-1-(2-(3-((4-trifluoromethylbenzyl)pyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-23);

3-((6-Chloro-7-fluoro-1-(2-(3-cyanopyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-24);

3-((6-Chloro-7-fluoro-2-methyl-1-(3-oxo-3-(pyrrolidin-1-yl)propyl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-25);

3-((6-Chloro-7-fluoro-1-(3-(indolin-1-yl)-3-oxopropyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-26);

3-((6-Chloro-7-fluoro-2-methyl-1-(3-oxo-3-(spiro[cyclopropane-1,3′

-indolin]-1′

-yl)propyl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-27);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(spiro[cyclopropane-1,3′

-indolin]-1′

-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-31);

3-((6-Chloro-7-fluoro-1-(2-(5′

-fluorospiro[cyclopropane-1,3′

-indolin]-1′

-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-32);

3-((6-Chloro-7-fluoro-1-(2-(4′

-fluorospiro[cyclobutane-1,3′

-indolin]-1′

-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-33);

3-((6-Chloro-7-fluoro-1-(2-(6-fluoro-3,3-dimethylindolin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-34);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(3-oxo-2,7-diazaspiro[4.5]decan-7-yl) ethyl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-35);

3-((6-Chloro-1-(2-(3,4-dihydroquinolin-1(2H)-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-36);

3-((6-Chloro-7-fluoro-1-(2-(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-37);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-(1′

-methylspiro[indoline-3,4′

-piperidin]-1′

-yl)-2-oxoethyl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-38);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(spiro[cyclopentane-1,3′

-indolin]-1-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-39);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(1-(pyrrolidine-1-carbonyl)-6-azaspiro[2.5]octan-6-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-40);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(2-oxo-1,7-diazaspiro[3.5]nonan-7-yl) ethyl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-41);

3-((6-Chloro-1-(2-(3-(3,3-difluoropyrrolidin-1-yl)azetidin-1-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-42);

3-((6-Chloro-1-(2-(2,4-dioxo-1,3,7-triazaspiro[4.4]nonan-7-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-43);

3-((6-Chloro-1-(2-(4,4-dimethylpiperidin-1-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-44);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(3-oxo-2,8-diazaspiro[4.5]decan-8-yl) ethyl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-45);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(8-oxa-2-azaspiro[4.5]decan-2-yl) ethyl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-46);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl) ethyl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-47);

3-((6-Chloro-1-(2-(3-(1,1-dioxidothiomorpholino)azetidin-1-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-48);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(7-oxo-2,6-diazaspiro[3.4]octan-2-yl) ethyl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-49);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(2-oxa-6-azaspiro[3.4]octan-6-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-50);

3-((1-(2-((1R,5S,6R)-6-Carbamoyl-3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)-6-chloro-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-51);

3-((6-Chloro-7-fluoro-1-(2-(3-hydroxy-3-methylazetidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-52);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(10-oxo-3,9-diazaspiro[5.6]dodecan-3-yl) ethyl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-53);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(2-oxopyrrolidin-1-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-59);

3-((6-Chloro-7-fluoro-1-(2-(4-(4-fluorobenzyl)piperidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-60);

3-((1-(2-(4-(2-(1H-Pyrazol-1-yl)ethyl)piperidin-1-yl)-2-oxoethyl)-6-chloro-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-61);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(4-phenethylpiperidin-1-yl) ethyl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-62);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(4-(pyridin-4-ylmethyl)piperidin-1-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-63);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-(4-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl)-2-oxoethyl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-64);

3-((6-Chloro-7-fluoro-1-(2-(3-(4-fluorobenzyl)pyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid Enantiomer A (Compound 1-65);

3-((6-Chloro-7-fluoro-1-(2-(3-(4-fluorobenzyl)pyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid Enantiomer B (Compound 1-66);

3-((1-(2-(8-Benzyl-2,8-diazaspiro[4.5]decan-2-yl)-2-oxoethyl)-6-chloro-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-67);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-2-oxoethyl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-68);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(2-oxo-1-oxa-3,7-diazaspiro[4.5]decan-7-yl) ethyl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-69);

3-((6-Chloro-1-(2-(4,6-difluoroindolin-1-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-70);

3-((6-Chloro-1-(2-(5-chloroindolin-1-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-71);

3-((6-Chloro-1-(2-(6-chloroindolin-1-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-73);

3-((6-Chloro-1-(2-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-72);

3-((6-Chloro-7-fluoro-1-(2-(3-(4-fluorophenyl)pyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid Enantiomer A (Compound 1-74);

3-((6-Chloro-7-fluoro-1-(2-(3-(4-fluorophenyl)pyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid Enantiomer B (Compound 1-75);

6-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-8-yl) ethyl)-1H-indol-3-yl)thio)picolinic acid (Compound 2-1);

Methyl 6-((6-chloro-7-fluoro-1-(2-(indolin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)picolinate (Compound 2-3);

6-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(spiro[cyclopropane-1,3′

-indolin]-1′

-yl) ethyl)-1H-indol-3-yl)thio)picolinic acid (Compound 2-54);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(spiro[cyclopropane-1,3′

-indolin]-1-yl) ethyl)-1H-indol-3-yl)thio)-2-fluorobenzoic acid (Compound 2-55);

3-((6-Chloro-1-(2-(5-methoxyindolin-1-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-58);

3-[6-Chloro-7-fluoro-1-[2-(5′

-fluorospiro[cyclopropane-1,3′

-indoline]-1′

-yl)-2-oxo-ethyl]-2-methyl-indol-3-yl]sulfanyl-2-fluoro-benzoic acid (Compound 3-23);

6-((6-Chloro-7-fluoro-1-(2-(4′

-fluorospiro[cyclobutane-1,3′

-indolin]-1′

-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)picolinic acid (Compound 3-104);

3-((6-Chloro-7-fluoro-1-(2-(4′

-fluorospiro[cyclobutane-1,3′

-indolin]-1′

-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid (Compound 3-96);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(spiro[cyclopentane-1,3′

-indolin]-1′

-yl)ethyl)-1H-indol-3-yl)thio)-2-fluorobenzoic acid (Compound 3-221);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(3-phenethylpyrrolidin-1-yl) ethyl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-76);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(3-propylpyrrolidin-1-yl) ethyl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-77);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(3-(4-(trifluoromethyl) benzyl) pyrrolidin-1-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-78);

3-((6-Chloro-1-(2-(3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-79);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(6-(trifluoromethyl)indolin-1-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-80);

3-((6-Chloro-7-fluoro-1-(2-(4-fluoroindolin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-81);

3-((6-Chloro-1-(2-(3-cyclopropyl-3-hydroxyazetidin-1-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-82);

3-((6-Chloro-7-fluoro-1-(2-(3-hydroxy-3-(trifluoromethyl)piperidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-83);

3-((6-Chloro-7-fluoro-1-(2-(3-hydroxy-3-(trifluoromethyl)azetidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-84);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-(2-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-85);

3-((1-(2-(3-(1H-Pyrazol-1-yl)azetidin-1-yl)-2-oxoethyl)-6-chloro-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-86);

6-((6-Chloro-7-fluoro-1-(2-(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)picolinic acid (Compound 2-56);

3-((6-chloro-7-fluoro-1-(2-(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid (Compound 2-57);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-(7-methyl-1,7-diazaspiro[3.5]nonan-1-yl)-2-oxoethyl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-87);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(3-(pyridin-4-ylmethyl) pyrrolidin-1-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-88);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(3-(pyridin-4-yl)pyrrolidin-1-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-89);

3-((6-Chloro-7-fluoro-1-(2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-90);

3-((6-Chloro-7-fluoro-1-(2-(isoindolin-2-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-91);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-(5-methylindolin-1-yl)-2-oxoethyl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-92);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-(3-((1-methyl-1H-pyrazol-4-yl)methyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-93);

3-((1-(2-(2-(2-(1H-Pyrazol-1-yl)ethyl)piperidin-1-yl)-2-oxoethyl)-6-chloro-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-94);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(5-azaspiro[2.4]heptan-5-yl) ethyl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-95);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-(3-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indol-3-yl)thio)benzoic acid (Compound 1-96);

3-((6-Chloro-1-(2-(2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-97);

3-((6-Chloro-7-fluoro-1-(2-(hexahydro-1H-isoindol-2(3H)-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid (Compound 1-98);

3-((6-chloro-7-fluoro-1-(2-(indolin-1-yl)ethyl)-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid (Compound 2-73);

3-((6-Chloro-1-(2-(2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid (Compound 2-60);

3-((6-Chloro-7-fluoro-1-(2-(3-hydroxy-3-methylpyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid (Compound 2-61);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(spiro[cyclobutane-1,3′

-indolin]-1′

-yl) ethyl)-1H-indol-3-yl)thio)-2-fluorobenzoic acid (Compound 3-220);

3-((6-chloro-7-fluoro-2-methyl-1-(2-(spiro[cyclopropane-1,3′

-indolin]-1-yl)ethyl)-1H-indol-3-yl)thio)-2-fluorobenzoic acid (Compound 2-74);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-(spiro[cyclobutane-1,3′

-indolin]-1-yl) ethyl)-1H-indol-3-yl)thio)-2-fluorobenzoic acid (Compound 2-75);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(spiro[cyclopentane-1,3′

-indolin]-1-yl)ethyl)-1H-indol-3-yl)thio)-2-fluoro-N-(phenylsulfonyl)benzamide;

3-((6-Chloro-7-fluoro-1-(2-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid (Compound 2-62);

3-((6-Chloro-1-(2-(3-cyclopropyl-3-hydroxyazetidin-1-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid (Compound 2-63);

(R)-3-((6-Chloro-7-fluoro-1-(2-(3-(hydroxymethyl)pyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid (Compound 2-64);

3-((6-Chloro-7-fluoro-1-(2-((3S,4S)-3-hydroxy-4-morpholinopyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid (Compound 2-65);

3-((6-Chloro-7-fluoro-1-(2-((3R,4R)-3-fluoro-4-hydroxypyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid (Compound 2-66);

(S)-3-((6-chloro-7-fluoro-1-(2-(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid Enantiomer A(Compound 2-58);

(R)-3-((6-chloro-7-fluoro-1-(2-(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid Enantiomer B (Compound 2-59);

3-((6-Chloro-1-(2-(3-cyanoazetidin-1-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid (Compound 2-67);

3-((6-Chloro-7-fluoro-1-(2-(3-hydroxy-3-phenylpyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid (Compound 2-68);

3-((6-Chloro-1-(2-((3S,4S)-3-(dimethylamino)-4-hydroxypyrrolidin-1-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid (Compound 2-69);

3-((6-Chloro-7-fluoro-1-(2-((3S,4S)-3-hydroxy-4-(4-methylpiperazin-1-yl)pyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid (Compound 2-70);

3-((6-Chloro-1-(2-(3-((dimethylamino)methyl)azetidin-1-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid (Compound 2-71);

3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(1,4-dioxa-7-azaspiro[4.4]nonan-7-yl) ethyl)-1H-indol-3-yl)thio)-2-fluorobenzoic acid (Compound 2-72);

3-((2,6-dichloro-7-fluoro-1-(2-oxo-2-(spiro[cyclobutane-1,3′

-indolin]-1-yl)ethyl)-1H-indol-3-yl)thio)-2-fluorobenzoic acid (Compound 4-121);

3-((2,6-dichloro-7-fluoro-1-(2-oxo-2-(spiro[cyclopropane-1,3′

-indolin]-1-yl) ethyl)-1H-indol-3-yl)thio)-2-fluorobenzoic acid (Compound 2-45);

3-((6-chloro-2-cyclopropyl-7-fluoro-1-(2-(indolin-1-yl)-2-oxoethyl)-1H-indol-3-yl)thio)-2-fluorobenzoic acid (Compound 4-29);

3-((6-chloro-2-cyclopropyl-7-fluoro-1-(2-oxo-2-(spiro[cyclobutane-1,3′

-indolin]-1-yl)ethyl)-1H-indol-3-yl)thio)-2-fluorobenzoic acid (Compound 4-129);

3-((6-chloro-2-cyclopropyl-7-fluoro-1-(2-oxo-2-(spiro[cyclopropane-1,3′

-indolin]-1′

-yl) ethyl)-1H-indol-3-yl)thio)-2-fluorobenzoic acid (Compound 4-85);

3-((2,6-dichloro-7-fluoro-1-(2-(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indol-3-yl)thio)-2-fluorobenzoic acid (Compound 5-5);

3-((6-chloro-2-cyclopropyl-7-fluoro-1-(2-(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indol-3-yl)thio)-2-fluorobenzoic acid (Compound 5-6);

3-((6-chloro-2-cyclopropyl-7-fluoro-1-(2-(methoxy(methyl)amino)-2-oxoethyl)-1H-indol-3-yl)thio)-2-fluorobenzoic acid (Compound 5-7);

or a pharmaceutically acceptable salt, or solvate thereof.