BORONIC ACID DERIVATIVES AND THERAPEUTIC USES THEREOF

• US 20180051041A1
• Filed: 03/16/2016
• Published: 02/22/2018
• Est. Priority Date: 03/17/2015
• Status: Abandoned Application

• Current Assignee: The Medicines Company (San Diego), LLC. (Novartis Ag)
• Original Assignee: Rempex Pharmaceuticals, Inc (Melinta Therapeutics, Inc.)
• Inventors: Hecker, Scott, Reddy, Raja K.
• Application Number:
  US15/558,544
• Publication Number:
  US 20180051041A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Disclosed herein are antimicrobial compounds compositions, pharmaceutical compositions, the use and preparation thereof. Some embodiments relate to boronic acid derivatives and their use as therapeutic agents.

Claims

1. A compound having the structure of the formula III′

or IV′

;

2. The compound of claim 1, having the structure of the formula Ill or IV:

3. The compound of claim 1 or 2, having the structure of Formula (IIIa)

4. The compound of claim 1 or 2, having the structure of Formula (IIIb)

5. The compound of claim 1 or 2, having the structure of Formula (IIIc)

6. The compound of claim 1, 2, or 5, having the structure of Formula (IIId)

7. The compound of claim 1 or 2, having the structure of Formula (IVa)

8. The compound of claim 1, 2, or 7, having the structure of Formula (IVb)

9. The compound of any one of claims 1 to 8, wherein Y⁷ is CH₂, O, or S.

10. The compound of claim 1 or 2, having the structure of (III-1) or (IV-1):

11. The compound of claim 10, having the structure of (III-2) or (IV-2):

12. The compound of claim 1, wherein n¹ is 1 and Q¹ and Q² are deuterium.

13. The compound of any one of claims 1-2, 4-5, 7, and 12, wherein Y⁷ is O, n¹ is 1, and m is 1.

14. The compound of any one of claims 10 to 13, wherein M is CR⁵.

15. The compound of any one of claims 10 to 13, wherein M is N.

16. The compound of any one of claims 10 to 15, wherein J and L are each independently CR⁵.

17. The compound of claim 16, wherein J and L are CH.

18. The compound of any one of claims 10 to 13, wherein J is N.

19. The compound of any one of claims 10 to 15 and 18, wherein L and M are each independently CR⁵.

20. The compound of claim 19, wherein L and M are CH.

21. The compound of any one of claims 10 to 13, wherein L is N.

22. The compound of any one of claims 10 to 13 and 21, wherein J and M are each independently CR⁵.

23. The compound of claim 22, wherein J and M are CH.

24. The compound of any one of claims 10 to 15 and 21, wherein M is CH.

25. The compound of any one of claims 1 to 24, wherein each R⁵ is independently selected from the group consisting of C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ carbocyclyl, C₁-C₆ heteroalkyl, 5-10 membered heterocyclyl, C₆-C₁₀ aryl, 5-10 membered heteroaryl, cyano, hydroxy, —

OR³, —

SR³, —

S(O)₂M′

, —

P(O)R¹M′

, and halogen.

26. The compound of claim 25, wherein R⁵ is halogen.

27. The compound of claim 26, wherein R⁵ is F.

28. The compound of claim 25, wherein R⁵ is alkoxy.

29. The compound of claim 28, wherein R⁵ is —

OCH₃.

30. The compound of claim 28, wherein R⁵ is —

OCH₂CH₃.

31. The compound of any one of claims 1 to 25, wherein R⁵ is —

OH.

32. The compound of any one of claims 1 to 25, wherein R⁵ is —

SH.

33. The compound of any one of claims 1 to 25, wherein R⁵ is —

SCH₃.

34. The compound of any one of claims 1 to 25, wherein R⁵ is —

S(O)₂M′

.

35. The compound of claim 34, wherein R⁵ is —

S(O)₂CH₃.

36. The compound of any one of claims 1 to 25, wherein R⁵ is —

SOM′

.

37. The compound of claim 36, wherein R⁵ is —

SOCH₃.

38. The compound of any one of claims 1 to 25, wherein R⁵ is cyano.

39. The compound of any one of claims 1 to 25, wherein R⁵ is —

C≡

CH.

40. The compound of any one of claims 1 to 24, wherein R⁵ is —

CHF₂.

41. The compound of any one of claims 1 to 24, wherein R⁵ is —

CF₃.

42. The compound of any one of claims 1 to 24, wherein R⁵ is —

C(O)NR¹R².

43. The compound of claim 42, wherein R⁵ is —

C(O)NH₂.

44. The compound of any one of claims 1 to 24, wherein R⁵ is —

C(═

NR)R².

45. The compound of claim 44, wherein R⁵ is —

CH═

N—

OCH₃.

46. The compound of any one of claims 1 to 24, wherein R⁵ is —

COOR¹.

47. The compound of claim 46, wherein R⁵ is —

COOH.

48. The compound of any one of claims 1 to 24, wherein R⁵ is a C_2-4 alkynyl, triazole, or diazole, optionally substituted with 0-2 substituents selected from —

(CH₂)_0-4OR¹, —

(CH₂)_0-4CN, —

(CH₂)_0-4NR¹R², —

(CH₂)_0-4-heterocyclyl, halogen, —

C(O)NR¹R², and —

NR¹C(O)R².

49. The compound of claim 48, wherein R⁵ is

50. The compound of any one of claims 1 to 24, wherein R⁵ is —

(CH₂)_p—

Y³—

(CH₂)_qM′

.

51. The compound of claim 50, wherein Y³ is —

S—

, —

O—

, or —

NH—

.

52. The compound of claim 50 or 51, wherein M′

is a 5-10 membered heteroaryl or 3-10 membered heterocyclyl, each optionally substituted with 0-2 substituents selected from the group consisting of C_1-4 alkyl, —

(CH₂)_0-4OR¹, —

(CH₂)_0-4CN, —

(CH₂)_0-4NR¹R², —

(CH₂)_0-4-heterocyclyl, halogen, —

C(O)NR¹R², and —

NR¹C(O)R².

53. The compound of claim 52, wherein M′

is azetine, thiadiazole, triazole, dioxolane, pyridine, morpholine, or cyclopropyl, each optionally substituted with 0-2 substituents selected from the group consisting of C_1-4 alkyl, —

(CH₂)_0-4OR¹, —

(CH₂)_0-4CN, —

(CH₂)_0-4NR¹R², —

(CH₂)_0-4-heterocyclyl, halogen, —

C(O)NR¹R², and —

NR¹C(O)R².

54. The compound of claim 53, wherein M′

is

55. The compound of claim 54, wherein M′

is

56. The compound of claim 50 or 51, wherein M′

is cyano.

57. The compound of claim 50 or 51, wherein M′

is —

OH.

58. The compound of claim 50 or 51, wherein M′

is —

S(O)₂R or —

S(O)₂NR¹R².

59. The compound of claim 58, wherein M′

is —

S(O)₂CH₃ or —

S(O)₂NH₂.

60. The compound of claim 50 or 51, wherein M′

is —

C(O)NR¹R².

61. The compound of claim 60, wherein M′

is —

C(O)NH₂.

62. The compound of claim 50, wherein Y³ is —

S(O)—

or —

S(O)₂—

.

63. The compound of any one of claims 50-51 and 62, wherein M′

is C_1-4 alkyl optionally substituted with 0-2 substituents selected from the group consisting of —

OR¹, —

CN, —

NR¹R², -heterocyclyl, halogen, —

C(O)NR¹R², and —

NR¹C(O)R²;

C_2-4 alkenyl optionally substituted with 0-2 substituents selected from the group consisting of C_1-4 alkyl, —

(CH₂)_0-4OR¹, —

(CH₂)_0-4CN, —

(CH₂)_0-4NR¹R², —

(CH₂)_0-4-heterocyclyl, halogen, —

C(O)NR¹R², and —

NR¹C(O)R²;

or C_2-4 alkynyl optionally substituted with 0-2 substituents selected from the group consisting of C_1-4 alkyl, —

(CH₂)_0-4OR¹, —

(CH₂)_0-4CN, —

(CH₂)_0-4NR¹R², —

(CH₂)_0-4-heterocyclyl, halogen, —

C(O)NR¹R², and —

NR¹C(O)R².

64. The compound of claim 63, wherein M′

is —

C≡

CH.

65. The compound of claim 63, wherein M′

is —

C≡

C—

(CH₂)_0-4OR¹, —

C≡

C—

(CH₂)_0-4NR¹R², or —

C≡

C—

(CH₂)_0-4-heterocyclyl.

66. The compound of claim 65, wherein M′

is —

C≡

C—

(CH₂)—

OCH₃, —

C≡

C—

(CH₂)—

OH, —

C≡

C—

(CH₂)—

NH₂, or

67. The compound of claim 63, wherein M′

is —

(CH₂)₃NH₂, CH₂F, CHF₂, CF₃, CH(CH₂OH)₂, or CH₂N(CH₃)₂.

68. The compound of claim 63, wherein M′

is C_1-4 alkyl.

69. The compound of any one of claims 10 to 12, wherein R⁵ is present twice.

70. The compound of any one of claims 10 to 12, wherein:

L and M are each independently CR⁵;

J is CH; and

each R⁵ is independently selected from the group consisting of OH, halogen, CN, —

C(O)OR¹;

—

C(O)NR¹R²;

—

C(O)NR¹OR²;

—

NR¹C(O)R²;

—

NR¹C(O)NR²R³;

—

NR¹C(O)OR²;

—

NR¹S(O)₂R²;

—

NR¹S(O)₂NR²R³;

—

C(═

NR¹)R²;

—

C(═

NR¹)NR²R³;

—

NR¹CR²(═

NR³);

—

NR¹C(═

NR²)NR³R⁴;

—

S(O)(CH₂)_1-3R⁴, —

S(O)₂NR¹R², —

S(O)₂NR¹OR³, —

NR¹S(O)₂NR¹OR³, optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₇ carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted C_6-10aryl, optionally substituted 5-10 membered heteroaryl, cyano, C₁-C₆ alkoxy(C₁-C₆)alkyl, aryloxy, sulfhydryl (mercapto), and —

(CH₂)_p—

Y³—

(CH₂)_qM′

.

71. The compound of any one of claims 69 to 70, wherein each R⁵ is independently halogen or —

OM′

72. The compound of claim 71, wherein each R⁵ is independently F or —

OCH₃.

73. The compound of claim 71, wherein each R⁵ is independently Cl or —

OCH₃.

74. The compound of any one of claims 1 to 73, wherein R⁶ is —

COOR or —

P(O)(OR)₂.

75. The compound of claim 74, wherein R⁶ is —

COOH or —

P(O)(OH)₂.

76. The compound of claim 1, having the structure selected from the group consisting of

77. The compound of claim 1, having the structure selected from the group consisting

101. The compound of claim 18, wherein G is

111. The compound of any one of claims 79-17 and 23-31, wherein:

n is 0 or 1;

Y² is —

NH—

;

G is selected from the group consisting of —

C(O)R⁴, —

C(O)(CH₂)_0-3SR³, —

C(O)(CH₂)_1-3R⁴, —

C(O)OR³, —

C(O)NR¹R², —

S(O)₂R³, —

C(═

NR¹)R⁴, and —

C(═

NR)NR¹R².

112. The compound of claim 111, wherein G is selected from the group consisting of —

C(O)R⁴, —

C(O)(CH₂)_0-3SR³, —

C(O)OR³, —

C(O)NR¹R², —

S(O)₂R³, —

C(═

NR¹)R⁴, and —

C(═

NR¹)NR¹R².

113. The compound of claim 111 or 112, wherein G is —

C(O)R⁴.

114. The compound of claim 111 or 112, wherein G is —

C(O)(CH₂)R⁴.

115. The compound of any one of claims 111 to 114, wherein R⁴ is optionally substituted C_1-4alkyl.

116. The compound of claim 115, wherein R⁴ is C_1-4alkyl substituted with C₁-C₄ alkylthio.

117. The compound of claim 116, wherein R⁴ is —

CH₂SCH₃

118. The compound of claim 115, wherein R⁴ is C_1-4alkyl substituted with 5-10 membered heteroaryl optionally substituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy.

119. The compound of claim 118, wherein R⁴ is

120. The compound of claim any one of claims 111 to 114, wherein R is optionally substituted 5-10 membered heteroaryl.

121. The compound of claim 120, wherein R⁴ is 5-10 membered heteroaryl substituted with amino.

122. The compound of claim 120, wherein R⁴ is

123. The compound of any one of claims 1 to 96, wherein G is —

C(O)CH₂SR³.

124. The compound of claim 123, wherein R³ is C_1-4alkyl.

125. The compound of claim 123, wherein R³ is 5-10 membered heterocyclyl.

126. The compound of any one of claims 79 to 96 and 23-31, wherein G is —

C(O)(CH₂)SCH₃.

127. The compound of any one of claims 79 to 96 and 23-31, wherein G is

128. The compound of any one of claims 79 to 96 and 23-31, wherein G is

135. The compound of any one of claims 1-134, wherein the pharmaceutically acceptable salt is an alkaline metal salt or ammonium salt.

136. The compound of claim 135, wherein the pharmaceutically acceptable salt is a sodium salt.

137. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-136 and a pharmaceutically acceptable excipient.

138. The pharmaceutical composition of claim 137, further comprising an additional medicament.

139. The composition of claim 138, wherein the additional medicament is selected from an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, or an anti-allergic agent.

140. The composition of claim 139, wherein the additional medicament is a β

-lactam antibacterial agent.

141. The composition of claim 140, wherein the β

-lactam antibacterial agent is selected from Amoxicillin, Ampicillin (Pivampicillin, Hetacillin, Bacampicillin, Metampicillin, Talampicillin), Epicillin, Carbenicillin (Carindacillin), Ticarcillin, Temocillin, Azlocillin, Piperacillin, Mezlocillin, Mecillinam (Pivmecillinam), Sulbenicillin, Benzylpenicillin (G), Clometocillin, Benzathine benzylpenicillin, Procaine benzylpenicillin, Azidocillin, Penamecillin, Phenoxymethylpenicillin (V), Propicillin, Benzathine phenoxymethylpenicillin, Pheneticillin, Cloxacillin (Dicloxacillin, Flucloxacillin), Oxacillin, Meticillin, Nafcillin, Faropenem, Tomopenem, Razupenem, Cefazolin, Cefacetrile, Cefadroxil, Cefalexin, Cefaloglycin, Cefalonium, Cefaloridine, Cefalotin, Cefapirin, Cefatrizine, Cefazedone, Cefazaflur, Cefradine, Cefroxadine, Ceftezole, Cefaclor, Cefamandole, Cefininox, Cefonicid, Ceforanide, Cefotiam, Cefprozil, Cefbuperazone, Cefuroxime, Cefuzonam, Cefoxitin, Cefotetan, Cefmetazole, Loracarbef, Cefixime, Ceftriaxone, Cefcapene, Cefdaloxime, Cefdinir, Cefditoren, Cefetamet, Cefinenoxime, Cefodizime, Cefoperazone, Cefotaxime, Cefpimizole, Cefpiramide, Cefpodoxime, Cefsulodin, Cefteram, Ceftibuten, Ceftiolene, Ceftizoxime, Flomoxef, Latamoxef, Cefepime, Cefozopran, Cefpirome, Cefquinome, Ceftobiprole, Ceftaroline, CXA-101, RWJ-54428, MC-04,546, ME 1036, Ceftiofur, Cefquinome, Cefovecin, RWJ-442831, RWJ-333441, or RWJ-333442.

142. The composition of claim 140 wherein the β

-lactam antibacterial agent is selected from Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Tebipenem, Tebipenem pivoxil, Apapenem, or Panipenem.

143. The composition of claim 140, wherein the β

-lactam antibacterial agent is selected from Aztreonam, Tigemonam, BAL30072, SYN 2416, or Carumonam.

144. A method of treating a bacterial infection, comprising administering to a subject in need thereof, a compound according any one of claims 1-136.

145. The method of claim 144, further comprising administering to the subject an additional medicament.

146. The method of claim 145, wherein the additional medicament is selected from an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, or an antiallergic agent.

147. The method of claim 146, wherein the additional medicament is a β

-lactam antibacterial agent.

148. The method of claim 147, wherein the β

-lactam antibacterial agent is selected from Amoxicillin, Ampicillin (Pivampicillin, Hetacillin, Bacampicillin, Metampicillin, Talampicillin), Epicillin, Carbenicillin (Carindacillin), Ticarcillin, Temocillin, Azlocillin, Piperacillin, Mezlocillin, Mecillinam (Pivmecillinam), Sulbenicillin, Benzylpenicillin (G), Clometocillin, Benzathine benzylpenicillin, Procaine benzylpenicillin, Azidocillin, Penamecillin, Phenoxymethylpenicillin (V), Propicillin, Benzathine phenoxymethylpenicillin, Pheneticillin, Cloxacillin (Dicloxacillin, Flucloxacillin), Oxacillin, Meticillin, Nafcillin, Faropenem, Tomopenem, Razupenem, Cefazolin, Cefacetrile, Cefadroxil, Cefalexin, Cefaloglycin, Cefalonium, Cefaloridine, Cefalotin, Cefapirin, Cefatrizine, Cefazedone, Cefazaflur, Cefradine, Cefroxadine, Ceftezole, Cefaclor, Cefamandole, Cefininox, Cefonicid, Ceforanide, Cefotiam, Cefprozil, Cefbuperazone, Cefuroxime, Cefuzonam, Cefoxitin, Cefotetan, Cefmetazole, Loracarbef, Cefixime, Ceftriaxone, Cefcapene, Cefdaloxime, Cefdinir, Cefditoren, Cefetamet, Cefinenoxime, Cefodizime, Cefoperazone, Cefotaxime, Cefpimizole, Cefpiramide, Cefpodoxime, Cefsulodin, Cefteram, Ceftibuten, Ceftiolene, Ceftizoxime, Flomoxef, Latamoxef, Cefepime, Cefozopran, Cefpirome, Cefquinome, Ceftobiprole, Ceftaroline, CXA-101, RWJ-54428, MC-04,546, ME 1036, Ceftiofur, Cefquinome, Cefovecin, RWJ-442831, RWJ-333441, or RWJ-333442.

149. The method of claim 147, wherein the β

-lactam antibacterial agent is selected from Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Tebipenem, Tebipenem pivoxil, Apapenem, or Panipenem.

150. The method of claim 147, wherein the β

-lactam antibacterial agent is selected from Aztreonam, Tigemonam, BAL30072, SYN 2416, or Carumonam.

151. The method of any one of claims 144-150, wherein the subject is a mammal.

152. The method of claim 151, wherein the mammal is a human.

153. The method of any one of claims 144-152, wherein the infection comprises a bacteria selected from Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Burkholderia cepacia, Aeromonas hydrophilia, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter baumannii, Bordetella pertussis, Bordetella para pertussis, Bordetella bronchiseptica, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Borrelia burgdorferi, Kingella, Gardnerella vaginalis, Bacteroides distasonis, Bacteroides 3452A homology group, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis, or Staphylococcus saccharolyticus.

154. The method of any one of claims 144-152, wherein the infection comprises a bacteria selected from Pseudomonas aeruginosa, Pseudomonas fluorescens, Stenotrophomonas maltophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella, Bacteroides fragilis, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, or Bacteroides splanchnicus.

78. A compound having the structure selected from the group consisting of

79. A compound having the structure of the formula I′

or II′

;

80. The compound of claim 79 having the structure of formula I or II:

81. The compound of claim 79 or 80, wherein the compound has the structure of formula I

82. The compound of any one of claims 79 to 81, wherein Q is —

Y²—

(CH₂)_n-G.

83. The compound of any one of claims 79 to 81, wherein the compound has the structure of formula I-1

84. The compound of any one of claims 79-81 and 83, having the structure of formula Ia:

85. The compound of any one of claims 79-81 and 83, having the structure of (Ib):

86. The compound of any one of claims 79-81 and 83, having the structure of (Ic):

87. The compound of claim 79 or 80 having the structure of formula IIa:

88. The compound of claim 87, having the structure of (IIb):

89. The compound of claim 87, having the structure of (IIc):

90. The compound of any one of claims 79-89, wherein Y² is selected from the group consisting of —

S—

, —

SO₂—

, —

O—

, or —

NH—

.

91. The compound of any one of claims 79-90, wherein M is N.

92. The compound of any one of claims 79-90, wherein M is CR⁵.

93. The compound of any one of claims 79-92, wherein J and L are each independently CR⁵.

94. The compound of any one of claims 79-83, wherein Y⁴ is —

O—

.

95. The compound of any one of claims 79-83 wherein R⁷ is —

OH.

96. The compound of any one of claims 79-81 and 83, having the structure of Formula (Id):

97. The compound of any one of claims 79-90, wherein:

Y² is —

O—

or —

S—

;

G is selected from the group consisting of C_1-4alkyl, phenyl, imidazole, pyrazole, triazole, tetrazole, thiazole, thiadiazole, oxazole, oxadiazole, isoxazole, isothiazole, pyridine, pyrazine, pyrimidine, pyridazine, and pyrazine, each optionally substituted by 0-2 substituents selected from the group consisting of hydroxy, C₁-C₆ alkoxy, C₁-C₆ alkoxy(C₁-C₆)alkyl, aryloxy, halo(C₁-C₆)alkoxy, amino, C-amido, and N-amido; and

J, L and M are CR⁵.

98. The compound of claim 97, wherein G is C_1-4alkyl.

99. The compound of claim 98, wherein G is —

CH₃.

100. The compound of claim 97, wherein G is thiadiazole optionally substituted with amino.

102. The compound of any one of claims 79-90, wherein:

M is CR⁵; and

each R⁵ is independently selected from the group consisting of —

H, —

C_1-4alkyl, and halogen, —

CF₃, and —

(CH₂)_p—

Y³—

(CH₂)_qM′

.

103. The compound of claim 102, wherein R⁵ is halogen.

104. The compound of claim 103, wherein R⁵ is F.

105. The compound of any one of claims 79-90, wherein:

R⁵ is —

(CH₂)_p—

Y³—

(CH₂)_qM′

;

m is 0;

p is 0;

Y³ is S or O; and

M′

is hydrogen;

hydroxyl;

C₁-C₄ alkyl optionally substituted with one or more substituents selected from the group consisting of —

O—

C₁-C₆alkyl, —

S—

C₁-C₆alkyl, amino, —

C(O)-amino, —

S(O)₂-amino, hydroxy, cyano, azido, and halogen;

C_3-10 cycloalkyl optionally substituted with one or more substituents selected from the group consisting of C₁-C₆alkyl, —

O—

C₁-C₆alkyl, —

S—

C₁-C₆alkyl, amino, —

C(O)-amino, —

S(O)₂-amino, hydroxy, cyano, azido, and halogen;

C₆-C₁₀ aryl optionally substituted with one or more substituents selected from the group consisting of C₁-C₆alkyl, —

O—

C₁-C₆alkyl, —

S—

C₁-C₆alkyl, amino, —

C(O)-amino, —

S(O)₂-amino, hydroxy, cyano, azido, and halogen;

5 to 10 membered heteroaryl optionally substituted with one or more substituents selected from the group consisting of C₁-C₆alkyl, —

O—

C₁-C₆alkyl, —

S—

C₁-C₆alkyl, amino, —

C(O)-amino, —

S(O)₂-amino, hydroxy, cyano, azido, and halogen; and

4 to 10 membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of C₁-C₆alkyl, —

O—

C₁-C₆alkyl, —

S—

C₁-C₆alkyl, amino, —

C(O)-amino, —

S(O)₂-amino, hydroxy, cyano, azido, and halogen.

106. The compound of claim 105, wherein R⁵ is —

S—

C₁-C₆alkyl, —

S—

C₁-C₆ cycloalkyl, or —

S-4 to 10 membered heterocyclyl.

107. The compound of claim 106, wherein R⁵ is —

S—

CH₃.

108. The compound of claim 105, wherein R⁵ is —

O—

C₁-C₆alkyl, —

O—

C₁-C₆ cycloalkyl, or —

O-4 to 10 membered heterocyclyl.

109. The compound of claim 108, wherein R⁵ is

110. The compound of claim 108, wherein R⁵ is —

OCH₃.

129. The compound of any one of claims 79-96 and 102-110, wherein Y² is —

S(O)₂—

.

130. The compound of claim 129, wherein G is optionally substituted C_6-10aryl.

131. The compound of any one of claims 79-130, wherein Y¹ is CH.

132. The compound of any one of claims 79-130, wherein Y¹ is N.

133. The compound of claim 79-81 and 83-132, wherein Q¹ and Q² are deuterium.

134. The compound of claim 79, having the structure selected from the group consisting of: