IP Library › Granted Patent US 7,148,219

Granted Patent B2

US 7,148,219 · App. 11/118,808 · Granted Dec 12, 2006

Biaryl heterocyclic compounds and methods of making and using the same

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Quick Facts

Patent No.: US 7,148,219
App. No.: 11/118,808
Granted: Dec 12, 2006
Kind: B2

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Abstract

The present invention relates generally to the field of anti-infective, anti-proliferative, anti-inflammatory, and prokinetic agents. More particularly, the invention relates to a family of compounds having both a biaryl moiety and at least one heterocylic moiety that are useful as such agents.

Claims (654)

1. A compound having the formula:

or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein:

A is phenyl;

B is phenyl;

Het-CH 2 —R 3 is

M is selected from the group consisting of:

a) saturated, unsaturated, or aromatic C 3-14 carbocycle, and b) saturated, unsaturated, or aromatic 3–14 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,

wherein a) or b) optionally is substituted with one or more R 5 groups;

M-L is selected from the group consisting of:

a) M-L 1 -X-L 2 and b) M-X-L 1 -X-L 2 , wherein

X, at each occurrence, independently is selected from the group consisting of:

a) —O—, b) —NR 4 —, c) —N(O)—, d) —N(OR 4 )—, e) —S(O) p —, f) —SO 2 NR 4 —, g) —NR 4 SO 2 —, h) —NR 4 —N═, i) ═N—NR 4 —, j) —O—N═, k) ═N—O—, l) —N═, m) ═N—, n) —NR 4 —NR 4 —, o) —NR 4 C(O)O—, p) —OC(O)NR 4 —, q) —NR 4 C(O)NR 4 —, r) —NR 4 C(NR 4 )NR 4 —, and s)

L 1 is selected from the group consisting of:

a) C 1-6 alkyl, b) C 2-6 alkenyl, and c) C 2-6 alkynyl,

wherein any of a)–c) optionally is substituted with one or more R 5 groups; and

L 2 is selected from the group consisting of:

a) C 1-6 alkyl, b) C 2-6 alkenyl, and c) C 2-6 alkynyl,

wherein any of a)–c) optionally is substituted with one or more R 5 groups;

R 1 , at each occurrence, independently is selected from the group consisting of:

a) F, b) Cl, c) Br, d) I, e) —CF 3 , f) —OR 4 , g) —CN, h) —NO 2 , i) —NR 4 R 4 , j) —C(O)R 4 , k) —C(O)OR 4 , l) —OC(O)R 4 , m) —C(O)NR 4 R 4 , n) —NR 4 C(O)R 4 , o) —OC(O)NR 4 R 4 , p) —NR 4 C(O)OR 4 , q) —NR 4 C(O)NR 4 R 4 , r) —C(S)R 4 , s) —C(S)OR 4 , t) —OC(S)R 4 , u) —C(S)NR 4 R 4 , v) —NR 4 C(S)R 4 , w) —OC(S)NR 4 R 4 , x) —NR 4 C(S)OR 4 , y) —NR 4 C(S)NR 4 R 4 , z) —NR 4 C(NR 4 )NR 4 R 4 , aa) —S(O) p R 4 , bb) —SO 2 NR 4 R 4 , and cc) R 4 ;

R 2 , at each occurrence, independently is selected from the group consisting of:

R 3 is —NR 4 C(O)R 4 ;

R 4 , at each occurrence, independently is selected from the group consisting of:

a) H, b) C 1-6 alkyl, c) C 2-6 alkenyl, d) C 2-6 alkynyl, e) C 3-14 saturated, unsaturated, or aromatic carbocycle, f) 3–14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, g) —C(O)—C 1-6 alkyl, h) —C(O)—C 2-6 alkenyl, i) —C(O)—C 2-6 alkynyl, j) —C(O)—C 3-14 saturated, unsaturated, or aromatic carbocycle, k) —C(O)-3–14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, l) —C(O)O—C 1-6 alkyl, m) —C(O)O—C 2-6 alkenyl, n) —C(O)O—C 2-6 alkynyl, o) —C(O)O—C 3-14 saturated, unsaturated, or aromatic carbocycle, and p) —C(O)O-3–14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,

wherein any of b)–p) optionally is substituted with one or more R 5 groups;

R 5 , at each occurrence, is independently selected from the group consisting of:

a) F, b) Cl, c) Br, d) I, e) ═O, f) ═S, g) ═NR 6 , h) ═NOR 6 , i) ═N—NR 6 R 6 , j) —CF 3 , k) —OR 6 , l) —CN, m) —NO 2 , n) —NR 6 R 6 , o) —C(O)R 6 , p) —C(O)OR 6 , q) —OC(O)R 6 , r) —C(O)NR 6 R 6 , s) —NR 6 C(O)R 6 , t) —OC(O)NR 6 R 6 , u) —NR 6 C(O)OR 6 , v) —NR 6 C(O)NR 6 R 6 , w) —C(S)R 6 , x) —C(S)OR 6 , y) —OC(S)R 6 , z) —C(S)NR 6 R 6 , aa) —NR 6 C(S)R 6 , bb) —OC(S)NR 6 R 6 , cc) —NR 6 C(S)OR 6 , dd) —NR 6 C(S)NR 6 R 6 , ee) —NR 6 C(NR 6 )NR 6 R 6 , ff) —S(O) p R 6 , gg) —SO 2 NR 6 R 6 , and hh) R 6 ;

R 6 , at each occurrence, independently is selected from the group consisting of:

wherein any of b)–p) optionally is substituted with one or more R 5 groups;

R 7 , at each occurrence, independently is selected from the group consisting of:

a) F, b) Cl, c) Br, d) I, e) ═O, f) ═S, g) ═NR 8 , h) ═NOR 8 , i) ═N—NR 8 R 8 , j) —CF 3 , k) —OR 8 , l) —CN, m) —NO 2 , n) —NR 8 R 8 , o) —C(O)R 8 , p) —C(O)OR 8 , q) —OC(O)R 8 , r) —C(O)NR 8 R 8 , s) —NR 8 C(O)R 8 , t) —OC(O)NR 8 R 8 , u) —NR 8 C(O)OR 8 , v) —NR 8 C(O)NR 8 R 8 , w) —C(S)R 8 , x) —C(S)OR 8 , y) —OC(S)R 8 , z) —C(S)NR 8 R 8 , aa) —NR 8 C(S)R 8 , bb) —OC(S)NR 8 R 8 , cc) —NR 8 C(S)OR 8 , dd) —NR 8 C(S)NR 8 R 8 , ee) —NR 8 C(NR 8 )NR 8 R 8 , ff) —S(O) p R 8 , gg) —SO 2 NR 8 R 8 , hh) C 1-6 alkyl, ii) C 2-6 alkenyl, jj) C 2-6 alkynyl, kk) C 3-14 saturated, unsaturated, or aromatic carbocycle, and ll) 3–14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,

wherein any of hh)–ll) optionally is substituted with one or more moieties selected from the group consisting of R 8 , F, Cl, Br, I, —CF 3 , —OR 8 , —SR 8 , —CN, —NO 2 , —NR 8 R 8 , —C(O)R 8 , —C(O)OR 8 , —OC(O)R 8 , —C(O)NR 8 R 8 , —NR 8 C(O)R 8 , —OC(O)NR 8 R 8 , —NR 8 C(O)OR 8 , —NR 8 C(O)NR 8 R 8 , —C(S)R 8 , —C(S)OR 8 , —OC(S)R 8 , —C(S)NR 8 R 8 , —NR 8 C(S)R 8 , —OC(S)NR 8 R 8 , —NR 8 C(S)OR 8 , —NR 8 C(S)NR 8 R 8 , —NR 8 C(NR 8 )NR 8 R 8 , —SO 2 NR 8 R 8 , and —S(O) p R 8 ;

R 8 , at each occurrence, independently is selected from the group consisting of:

wherein any of b)–p) optionally is substituted with one or more moieties selected from the group consisting of F, Cl, Br, I, —CF 3 , —OH, —OCH 3 , —SH, —SCH 3 , —CN, —NO 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C(O)CH 3 , —C(O)OCH 3 , —C(O)NH 2 , —NHC(O)CH 3 , —SO 2 NH 2 , —SO 2 NHCH 3 , —SO 2 N(CH 3 ) 2 , and —S(O) p CH 3 ;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4; and

p, at each occurrence, independently is 0, 1, or 2.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein

M-L is M-L 1 -X-L 2 .

3. The compound according to claim 1 , having the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein A, B, L, M, R 1 , R 2 , R 3 , m, and n are defined as described in claim 1 .

4. The compound according to claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein

A is phenyl;

B is phenyl;

m is 0, 1, or 2; and

n is 0, 1, or 2.

5. The compound according to claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein A-B is:

wherein A, R 2 , and n are defined as described in claim 1 .

6. The compound according to claim 5 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein A-B is:

wherein A is phenyl.

7. The compound according to claim 5 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein A-B is:

wherein A is phenyl.

8. The compound according to claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein A-B is:

wherein B is defined as described in claim 1 .

9. The compound according to claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 3 is —NHC(O)R 4 .

10. The compound according to claim 9 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 4 is —CH 3 .

11. The compound according to claim 1 , having the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein A, B, L, M, R 1 , R 2 , m, and n are defined as described in claim 1 .

12. The compound according to claim 1 , having the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein A, L, M, R 1 , R 3 , and m are defined as described in claim 1 .

13. The compound according to claim 1 , having the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein A, L, M, R 1 , and m are defined as described in claim 1 .

14. The compound according to claim 1 , having the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein L, M, and R 3 are defined as described in claim 1 .

15. The compound according to claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 3 is —NHC(O)CH 3 .

16. The compound according to claim 1 , having the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein A, L, M, R 1 , R 3 , and m are defined as described in claim 1 .

17. The compound according to claim 1 , having the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein A, L, M, R 1 , and m are defined as described in claim 1 .

18. The compound according to claim 1 , having the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein L, M, and R 3 are defined as described in claim 1 .

19. The compound according to claim 18 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 3 is —NHC(O)CH 3 .

20. The compound according to claim 2 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein X is —NR 4 —.

21. The compound according to claim 20 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein X is —NH—.

22. The compound according to claim 20 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein X is:

23. The compound according to claim 20 , or a pharmaceutically acceptable salt, ester or prodrug thereof wherein X is —N(O)—.

24. The compound according to claim 20 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein X is —N(OR 4 )—.

25. The compound according to claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein

M-L is M-X-L 1 -X-L 2 .

26. The compound according to claim 24 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 4 is H.

27. The compound according to claim 24 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 4 is C 1-6 alkyl.

28. The compound according to claim 2 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein

L 1 is C 1-6 alkyl, and

L 2 is C 1-6 alkyl.

29. The compound according to claim 28 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein

L 1 is —CH 2 —, and

L 2 is —CH 2 —.

30. The compound according to claim 20 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein M-L is:

M-CH 2 —NH—CH 2 —.

31. The compound according to claim 20 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein M-L is:

32. The compound according to claim 25 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein M-X-L 1 -X-L 2 is M-S(O) p -L 1 -NR 4 -L 2 , where p is 0, L 1 is C 1-6 alkyl, and L 7 is C 1-6 alkyl.

33. The compound according to claim 32 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein M-L is:

M-S—CH 2 CH 2 —NH—CH 2 —.

34. The compound according to claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein M is selected from the group consisting of:

a) phenyl, b) pyridyl, c) pyrazinyl, d) pyrimidinyl, e) pyridazinyl, f) oxiranyl, g) aziridinyl, h) furanyl, i) thiophenyl, j) pyrrolyl, k) oxazolyl, l) isoxazolyl, m) imidazolyl, n) pyrazolyl, o) isothiazolyl, p) thiazolyl, q) triazolyl, r) tetrazolyl, s) indolyl, t) purinyl, u) benzofuranyl, v) benzoxazolyl, w) benzisoxazolyl, x) quinolinyl, y) isoquinolinyl, z) quinoxalinyl, aa) quinazolinyl, bb) cinnolinyl, cc) cyclopropyl, dd) cyclobutyl, ee) cyclopentyl, ff) cyclohexyl, gg) cycloheptyl, hh) oxetanyl, ii) tetrahydrofuranyl, jj) tetrahydropyranyl, kk) azetidinyl, ll) pyrrolidinyl, mm) piperidinyl, nn) thietanyl, oo) tetrahydrothiophenyl, pp) tetrahydrothiopyranyl, qq) piperazinyl, rr) quinuclidinyl, ss) 1-azabicyclo[2.2.1]hyeptanyl, tt) morpholinyl, uu) thiomorpholinyl, vv) thiooxomorpholinyl, ww) thiodioxomorpholinyl, and xx) benzothiophenyl

wherein any of a)–xx) optionally is substituted with one or more R 5 groups.

35. The compound according to claim 34 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein M is [1,2,3]triazol-1-yl.

36. The compound according to claim 34 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein M is 3H-[1,2,3]triazol-4-yl.

37. The compound according to claim 34 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein M is 1H-tetrazol-5-yl.

38. The compound according to claim 34 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein M is piperidin-1-yl.

39. The compound according to claim 34 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein M is pyrrolidin-1-yl.

40. A compound having the structure corresponding to any one of the structures listed below,

Compound

Number

Structure

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

2017

2018

2019

2020

2021

2022

2023

2024

2025

2026

2027

2028

2029

2030

2031

2032

2033

2034

2035

2036

2037

2038

2039

2040

2041

2042

2043

2044

2045

2046

2047

2048

2049

2050

2051

2052

2053

2054

2055

2056

2057

2058

2059

4001

4002

4003

4004

4005

4006

4007

4008

4009

4010

4011

4012

4013

4014

4015

4016

4017

4018

4019

4020

4021

4022

4023

4024

4025

4026

4027

4028

4029

4030

4031

4032

4033

4034

4035

4036

4037

4038

4039

4040

4041

4042

4043

4044

4045

4046

4047

4048

4049

4050

4051

4054

4055

4056

4057

4058

4059

4060

4061

4062

4063

4064

4065

4066

4067

4068

4069

4070

4071

4072

4074

4075

4076

4077

4078

4079

4080

4081

4082

4083

4084

4085

4086

4087

4088

4089

4090

4091

4092

4093

4094

4095

4096

4097

4098

4099

4100

4101

4102

4103

4104

4105

4108

4109

4110

4111

4112

4113

4114

4115

4116

4117

4118

4119

4120

4121

4122

4123

4124

4125

4126

4127

4128

4129

4130

4131

4132

4135

N-[3-(4′-{[(4-Amino-pyridin-3-ylmethyl)-amino]-methyl}-2-fluoro-

biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide

4136

4137

4138

4139

4140

4141

4142

4143

4144

4145

4146

4147

4148

4149

4150

4151

4152

4153

4154

4155

4156

4157

4158

4159

4160

4161

4162

4163

4164

4165

4166

4167

4168

4169

4170

4171

4172

4173

4174

4175

4176

4177

4178

4179

4180

4181

4182

4183

4184

4185

4186

4190

4191

4192

4193

4194

4196

4198

4199

4200

4201

4202

4203

4204

4205

4206

4207

4208

4209

4210

4211

4212

4213

4214

4215

4216

4217

4218

4219

4220

4221

4222

4224

4225

4226

4227

4228

4229

4232

4233

4234

4236

4237

4238

4239

4240

4241

4242

4243

4244

4245

4246

4247

4248

4249

4250

4251

4253

4254

4255

4256

4257

4258

4259

4260

4261

4262

4264

4266

4267

4269

4270

4271

4272

4273

4274

4275

4276

4278

4279

4280

4281

4282

4283

4284

4285

4286

4287

4288

4289

4290

4291

4292

4293

4294

4295

4296

4297

4298

4299

4300

4301

4302

4303

4304

4305

4306

4307

4308

4309

4310

4311

4312

4313

4314

4315

4316

4317

4318

4319

4320

4321

4322

5001

5002

5003

5004

5005

5006

5008

5009

5010

5011

5012

5013

5014

5015

or a pharmaceutically acceptable salt, ester, or prodrug thereof.

41. A pharmaceutical composition comprising one or more compounds according to claim 1 and a pharmaceutically acceptable carrier.

42. The compound according to claim 2 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein M is selected from the group consisting of:

wherein any of a)–xx) optionally is substituted with one or more R 5 groups.

43. The compound according to claim 42 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein M is triazolyl.

44. The compound according to claim 30 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein M is selected from the group consisting of:

wherein any of a)–xx) optionally is substituted with one or more R 5 groups.

45. The compound according to claim 44 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein M is triazolyl.

46. The compound according to claim 14 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 3 is —NHC(O)CH 3 .

47. The compound according to claim 46 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein

M-L is M-L 1 -X-L 2 .

48. The compound according to claim 47 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein M-L is:

M-CH 2 —NH—CH 2 —.

49. The compound according to claim 48 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein M is selected from the group consisting of:

wherein any of a)–xx) optionally is substituted with one or more R 5 groups.

50. The compound according to claim 49 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein M is triazolyl.

51. The compound according to claim 25 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein M is selected from the group consisting of:

wherein any of a)–xx) optionally is substituted with one or more R 5 groups.

52. The compound according to claim 51 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein M is triazolyl.

53. A compound having the formula:

or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein:

A is phenyl,

B is phenyl,

Het-CH 2 —R 3 is

M is selected from the group consisting of:

wherein a) or b) optionally is substituted with one or more R 5 groups;

M-L is selected from the group consisting of a) M-X-L 2 , b) M-L 1 -X-L 2 , and c) M-X-L 1 -X-L 2 , wherein

X is selected from the group consisting of

L 2 is selected from the group consisting of

a) C 1-6 alkyl, b) C 2-6 alkenyl, and c) C 2-6 alkynyl,

wherein any of a)–c) optionally is substituted with one or more R 5 groups;

R 1 , at each occurrence, independently is selected from the group consisting of:

R 2 , at each occurrence, independently is selected from the group consisting of:

R 3 is —NR 4 C(O)R 4 ;

R 4 , at each occurrence, independently is selected from the group consisting of:

wherein any of b)–p) optionally is substituted with one or more R 5 groups;

R 5 , at each occurrence, is independently selected from the group consisting of:

R 6 , at each occurrence, independently is selected from the group consisting of:

wherein any of b)–p) optionally is substituted with one or more R 5 groups;

R 7 , at each occurrence, independently is selected from the group consisting of:

a) F, b) Cl, c) Br, d) I, e) ═O, t) ═S, g) ═NR 8 , h) ═NOR 8 , i) ═N—NR 8 R 8 , j) —CF 3 , k) —OR 8 , l) —CN, m) —NO 2 , n) —NR 8 R 8 , o) —C(O)R 8 , p) —C(O)OR 8 , q) —OC(O)R 8 , r) —C(O)NR 8 R 8 , s) —NR 8 C(O)R 8 , t) —OC(O)NR 8 R 8 , u) —NR 8 C(O)OR 8 , v) —NR 8 C(O)NR 8 R 8 , w) —C(S)R 8 , x) —C(S)OR 8 , y) —OC(S)R 8 , z) —C(S)NR 8 R 8 , aa) —NR 8 C(S)R 8 , bb) —OC(S)NR 8 R 8 , cc) —NR 8 C(S)OR 8 , dd) —NR 8 C(S)NR 8 R 8 , ee) —NR 8 C(NR 8 )NR 8 R 8 , ff) —S(O) p R 8 , gg) —SO 2 NR 8 R 8 , hh) C 1-6 alkyl, ii) C 2-6 alkenyl, jj) C 2-6 alkynyl, kk) C 3-14 saturated, unsaturated, or aromatic carbocycle, and ll) 3–14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,

R 8 , at each occurrence, independently is selected from the group consisting of:

a) H, b) C 1-6 alkyl, c) C 2-6 alkenyl, d) C 2-6 alkynyl, e) C 3-14 saturated, unsaturated, or aromatic carbocycle, t) 3–14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, g) —C(O)—C 1-6 alkyl, h) —C(O)—C 2-6 alkenyl, i) —C(O)—C 2-6 alkynyl, j) —C(O)—C 3-14 saturated, unsaturated, or aromatic carbocycle, k) —C(O)-3–14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, l) —C(O)O—C 1-6 alkyl, m) —C(O)O—C 2-6 alkenyl, n) —C(O)O—C 2-6 alkynyl, o) —C(O)O—C 3-14 saturated, unsaturated, or aromatic carbocycle, and p) —C(O)O-3–14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,

m is 0, 1, 2, 3, or 4;

n is 1, 2, 3, or 4; and

p, at each occurrence, independently is 0, 1, or 2.

54. The compound according to claim 53 , having the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein L, M, and R 3 are defined as described in claim 53 .

55. The compound according to claim 54 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 3 is —NHC(O)CH 3 .

56. The compound according to claim 55 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein X is selected from the group consisting of a) —O—, b) —NR 4 —, and e) —S(O) p —.

57. The compound according to claim 56 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein X is —NH—.

58. The compound according to claim 57 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein M is selected from the group consisting of:

wherein any of a)–xx) optionally is substituted with one or more R 5 groups.

59. The compound according to claim 58 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein M is triazolyl.

60. A compound having the formula:

or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein:

A is phenyl,

B is phenyl,

Het-CH 2 —R 3 is

M is selected from the group consisting of

a) saturated, unsaturated, or aromatic C 3-14 carbocycle, and b) unsaturated or aromatic 3–14 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,

wherein a) or b) optionally is substituted with one or more R 5 groups;

M-L is selected from the group consisting of a) M-X-L 2 , b) M-L 1 -X-L 2 , and c) M-X-L 1 -X-L 2 , wherein

X is selected from the group consisting of:

a) —O—, b) —NR 4 —, c) —N(O)—, d) —N(OR 4 )—, e) —S(O) p —, f) —SO 2 NR 4 —, g) —NR 4 SO 2 —, h) —NR 4 —N, i) ═N—NR 4 —, j) —O—N, k) ═N—O—, l) —N═, m) ═N—, n) —NR 4 —NR 4 —, o) —NR 4 C(O)O—, p) —OC(O)NR 4 —, q) —NR 4 C(O)NR 4 —, r) —NR 4 C(NR 4 )NR 4 —, and s)

L 1 is selected from the group consisting of:

a) C 1-6 alkyl, b) C 2-6 alkenyl, and c) C 2-6 alkynyl,

wherein any of a)–c) optionally is substituted with one or more R 5 groups; and

L 2 is selected from the group consisting of:

a) C 1-6 alkyl, b) C 2-6 alkenyl, and c) C 2-6 alkynyl,

wherein any of a)–c) optionally is substituted with one or more R 5 groups;

R 1 , at each occurrence, independently is selected from the group consisting of:

R 2 , at each occurrence, independently is selected from the group consisting of:

R 3 is —NR 4 C(O)R 4 ;

R 4 , at each occurrence, independently is selected from the group consisting of:

wherein any of b)–p) optionally is substituted with one or more R 5 groups;

R 5 , at each occurrence, is independently selected from the group consisting of:

a) F, b) Cl, c) Br, d) I, e) ═O, f) ═S, g) ═NR 6 , h) ═NOR 6 , i) ═N—NR 6 R 6 j) —CF 3 , k) —OR 6 , l) —CN, m) —NO 2 , n) —NR 6 R 6 , o) —C(O)R 6 , p) —C(O)OR 6 , q) —OC(O)R 6 , r) —C(O)NR 6 R 6 , s) —NR 6 C(O)R 6 , t) —OC(O)NR 6 R 6 , u) —NR 6 C(O)OR 6 , v) —NR 6 C(O)NR 6 R 6 , w) —C(S)R 6 , x) —C(S)OR 6 , y) —OC(S)R 6 , z) —C(S)NR 6 R 6 , aa) —NR 6 C(S)R 6 , bb) —OC(S)NR 6 R 6 , cc) —NR 6 C(S)OR 6 , dd) —NR 6 C(S)NR 6 R 6 , ee) —NR 6 C(NR 6 )NR 6 R 6 , ff) —S(O) p R 6 , gg) —SO 2 NR 6 R 6 , and hh) R 6 ;

R 6 , at each occurrence, independently is selected from the group consisting of:

wherein any of b)–p) optionally is substituted with one or more R 5 groups;

R 7 , at each occurrence, independently is selected from the group consisting of:

R 8 , at each occurrence, independently is selected from the group consisting of:

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4; and

p, at each occurrence, independently is 0, 1, or 2.

61. The compound according to claim 60 , having the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein L, M, and R 3 are defined as described in claim 60 .

62. The compound according to claim 61 , or a pharmaceutically acceptable salt, ester or prodrug thereof wherein R 3 is —NHC(O)CH 3 .

63. The compound according to claim 62 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein X is selected from the group consisting of a) —O—, b) —NR 4 —, and e) —S(O) p —.

64. The compound according to claim 63 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein X is —NH—.

65. The compound according to claim 64 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein M is selected from the group consisting of:

a) pyridyl, b) pyrazinyl, c) pyrimidinyl, d) pyridazinyl, e) aziridinyl, f) pyrrolyl, g) imidazolyl, h) pyrazolyl, i) triazolyl, j) tetrazolyl, k) indolyl, l) purinyl, m) isoquinolinyl, n) quinoxalinyl, o) azetidinyl, p) pyrrolidinyl, q) piperidinyl, and r) quinuclidinyl,

wherein any of a)–r) optionally is substituted with one or more R 5 groups.

66. The compound according to claim 65 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein M is triazolyl.

67. A compound having the formula:

or a pharmaceutically acceptable salt, ester, or prodrug thereof wherein:

A is phenyl;

B is phenyl;

Het-CH 2 —R 3 is

M is selected from the group consisting of

a) saturated, unsaturated, or aromatic C 3-14 carbocycle, and b) saturated, unsaturated, or aromatic 3–14 membered hetero cycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,

wherein a) or b) optionally is substituted with one or more R 5 groups;

M-L is selected from the group consisting of a) M-X-L 2 , b) M-L 1 -X-L 2 , and c) M-X-L 1 -X-L 2 , wherein

X is selected from the group consisting of:

a) —O—, b) —N(O)—, c) —N(OR 4 )—, d) —S(O) p —, e) —SO 2 NR 4 —, f) —NR 4 SO 2 —, g) —NR 4 —N═, h) ═N—NR 4 —, i) —O—N═, j) ═N—O—, k) —N═, l) —NR 4 —NR 4 —, m) —NR 4 C(O)O—, n) —OC(O)NR 4 —, o) —NR 4 C(O)NR 4 —, p) —NR 4 C(NR 4 )NR 4 —, and q)

L 2 is selected from the group consisting of:

a) C 1-6 alkyl, b) C 2-6 alkenyl, and c) C 2-6 alkynyl,

wherein any of a)–c) optionally is substituted with one or more R 5 groups;

R 1 , at each occurrence, independently is selected from the group consisting of:

R 2 , at each occurrence, independently is selected from the group consisting of:

R 3 is —NR 4 C(O)R 4 ;

R 4 , at each occurrence, independently is selected from the group consisting of:

wherein any of b)–p) optionally is substituted with one or more R 5 groups;

R 5 , at each occurrence, is independently selected from the group consisting of:

a) F, b) Cl, c) Br, d) I, e) ═O, t) ═S, g) ═NR 6 , h) ═NOR 6 , i) ═N—NR 6 R 6 , j) —CF 3 , k) —OR 6 , l) —CN, m) —NO 2 , n) —NR 6 R 6 , o) —C(O)R 6 , p) —C(O)OR 6 q) —OC(O)R 6 , r) —C(O)NR 6 R 6 , s) —NR 6 C(O)R 6 , t) —OC(O)NR 6 R 6 , u) —NR 6 C(O)OR 6 , v) —NR 6 C(O)NR 6 R 6 , w) —C(S)R 6 , x) —C(S)OR 6 , y) —OC(S)R 6 , z) —C(S)NR 6 R 6 , aa) —NR 6 C(S)R 6 , bb) —OC(S)NR 6 R 6 , cc) —NR 6 C(S)OR 6 , dd) —NR 6 C(S)NR 6 R 6 , ee) —NR 6 C(NR 6 )NR 6 R 6 , ff) —S(O) p R 6 , gg) —SO 2 NR 6 R 6 , and hh) R 6 ;

R 6 , at each occurrence, independently is selected from the group consisting of:

wherein any of b)–p) optionally is substituted with one or more R 5 groups;

R 7 , at each occurrence, independently is selected from the group consisting of:

R 8 , at each occurrence, independently is selected from the group consisting of:

m is 0, 1, 2, 3, or 4;

n is 1, 2, 3, or 4; and

p, at each occurrence, independently is 0, 1, or 2.

68. The compound according to claim 67 , having the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein L, M, and R 3 are defined as described in claim 67 .

69. The compound according to claim 68 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 3 is —NHC(O)CH 3 .

70. The compound according to claim 69 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein M is selected from the group consisting of:

wherein any of a)–xx) optionally is substituted with one or more R 5 groups.

71. The compound according to claim 70 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein M is triazolyl.

Assignments (6)

AMENDED AND RESTATED INTELLECTUAL PROPERTY SECURITY AGREEMENT Recorded Aug 25, 2022

From: MELINTA SUBSIDIARY CORP.

To: SILICON VALLEY BANK

Reel/Frame 061314/0572 →

INTELLECTUAL PROPERTY SECURITY AGREEMENT Recorded Dec 22, 2020

From: MELINTA SUBSIDIARY CORP.

To: SILICON VALLEY BANK

Reel/Frame 054836/0824 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 16, 2019

From: MELINTA THERAPEUTICS, INC.

To: MELINTA SUBSIDIARY CORP.

Reel/Frame 048030/0489 →

SECURITY INTEREST Recorded Jan 8, 2018

From: MELINTA THERAPEUTICS, INC.; REMPEX PHARMACEUTICALS, INC.; CEMPRA PHARMACEUTICALS, INC.; CEM-102 PHARMACEUTICALS, INC.

To: CORTLAND CAPITAL MARKET SERVICES LLC, AS AGENT

Reel/Frame 045019/0552 →

CHANGE OF NAME Recorded Sep 24, 2014

From: RIB-X PHARMACEUTICALS, INC.

To: MELINTA THERAPEUTICS, INC.

Reel/Frame 033813/0633 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 22, 2005

From: ZHOU, JIACHENG; BHATTACHARJEE, ASHOKE; CHEN, SHILI; CHEN, YI; FARMER, JAY J.; HANSELMANN, ROGER; LOU, RONGLIANG; ORBIN, ALIA; OYELERE, ADEGBOYEGA K.; SALVINO, JOSEPH M.; TRAN, JENNIFER; WANG, DEPING; WU, YUSHENG; SPRINGER, DANE M.; GOLDBERG, JOEL A.

To: RIB-X PHARMACEUTICALS, INC.

Reel/Frame 016935/0766 →