Pyrido-pyrimidinyl compounds and methods of use

1 . A compound having formula (II):

or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

Ring B is C 3-7 cycloalkyl, 3 to 7 membered heterocycloalkyl, C 5-7 aryl, or 5 to 7 membered heteroaryl;

L 1 is —NHSO 2 —, —SO 2 NH—, —NH—, or pyrrolidin-2-one;

X 1 and X 2 are independently —N— or —CR 2 —;

X 3 is —N— or —CR 3 —, wherein one of X 1 , X 2 , and X 3 is —N—;

Ring A is C 3-6 cycloalkyl or 3 to 6 membered heterocycloalkyl;

m is 0, 1, 2, 3, 4, or 5;

each R 2 is independently hydrogen, halogen, —OR 7 , R 10 -substituted or unsubstituted C 1-6 alkyl, R 10 -substituted or unsubstituted C 3-7 cycloalkyl, or R 10 -substituted or unsubstituted 3 to 7 membered heterocycloalkyl,

R 3 is hydrogen, halogen, —CN, —OR 7 , —NO 2 , —C(O)R 7 , —C(O)OR 7 , —C(O)NR 7A R 7B , —OC(O)R 7 , —OC(O)NR 7A R 7B , —SR 7A , —S(O)R 7 , —S(O) 2 R 7 , —S(O)(═NR 7A )R 7B , —S(O) 2 NR 7A R 7B , —NR 7A R 7B , —NR 7A C(O)R 7 , —NR 7A C(O)OR 7 , —N(R 7A )C(O)NR 7A R 7B , —NR 7A S(O) 2 R 7 , —NR 7A S(O) 2 NR 7A R 7B , —P(O)(R 7 ) 2 , R 10 -substituted or unsubstituted C 1-6 alkyl, R 10 -substituted or unsubstituted C 1-6 haloalkyl, R 10 -substituted or unsubstituted C 3-7 cycloalkyl, R 10 -substituted or unsubstituted 3 to 7 membered heterocycloalkyl, R 10 -substituted or unsubstituted C 5-7 aryl, or R 10 -substituted or unsubstituted 5 to 7 membered heteroaryl;

each R 4 is hydrogen, halogen, —OR 7 , —CN, —S(O) 2 R 7 , R 10 -substituted or unsubstituted C 1-6 alkyl, R 10 -substituted or unsubstituted C 1-6 haloalkyl, or R 10 -substituted or unsubstituted C 3-7 cycloalkyl;

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

R 5 is R 10 -substituted or unsubstituted C 1-6 alkyl, R 10 -substituted or unsubstituted C 1-6 haloalkyl, R 10 -substituted or unsubstituted 3 to 7 membered heterocycloalkyl, R 10 -substituted or unsubstituted benzyl, R 10 -substituted or unsubstituted pyrrolidinyl, R 10 -substituted or unsubstituted piperidinyl, or R 10 -substituted or unsubstituted C 3-7 membered cycloalkyl;

or, wherein an atom on R 5 , together with L 1 and an atom on ring B, form a 4 to 7 membered heterocycloalkyl or 5 to 7 membered heteroaryl;

each R 6 is independently hydrogen, halogen, —OR 7 , —NR 6A R 6B , R 10 -substituted or unsubstituted C 1-6 alkyl, or R 10 -substituted or unsubstituted C 1-6 haloalkyl;

R 6A and R 6B are independently hydrogen or R 10 -substituted or unsubstituted C 1-6 alkyl, or R 6A and R 6B are taken together with the nitrogen atom to which they are attached to form a R 10 -substituted or unsubstituted 4 to 7 membered heterocycloalkyl,

each R 7 is independently hydrogen, R 8 -substituted or unsubstituted C 1-6 alkyl, R 8 -substituted or unsubstituted C 1-6 haloalkyl, R 8 -substituted or unsubstituted C 3-7 cycloalkyl, or R 8 -substituted or unsubstituted 3 to 7 membered heterocycloalkyl,

each R 7A and R 7B is independently hydrogen, R 8A -substituted or unsubstituted C 1-6 alkyl, R 8A -substituted or unsubstituted C 1-6 haloalkyl, R 8A -substituted or unsubstituted C 3-7 cycloalkyl, or R 8A -substituted or unsubstituted 3 to 7 membered heterocycloalkyl,

each R 8A is independently hydrogen, halogen, oxo, —CN, —NO 2 , —C(O)H, —C(O)CH 3 , —C(O)OH, —C(O)OCH 3 , —C(O)NH 2 , —OH, —OCH 3 , —OCF 3 , —OC(O)H, —OC(O) CH 3 , —OC(O)NH 2 , —SH, —S(O)H, —S(O) 2 H, —S(O)(=NH)H, —S(O) 2 NH 2 , —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —NHC(O)H, —NHC(O)OH, —N(H)C(O)NH 2 , —NHS(O) 2 H, —NHS(O) 2 NH 2 , or —P(O)(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, —C(CH 3 ) 2 F, —C(CH 3 )F 2 , unsubstituted C 1-6 alkoxy, unsubstituted C 1-6 alkyl, unsubstituted C 1-6 haloalkyl, unsubstituted C 3-7 cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted C 5-7 aryl, or unsubstituted 5 to 7 membered heteroaryl;

each R 8 is independently hydrogen, halogen, oxo, —CN, —OR 8B , —NO 2 , —C(O)R 8B , —C(O)OR 8B , —C(O)NR 8C R 8D , —OC(O)R 8B , —OC(O)NR 8C R 8D , —SR 8C , —S(O)R 8B , —S(O) 2 R 8B , —S(O)(=NR 8C )R 8D , —S(O) 2 NR 8C R 8D , —NR 8C R 8D , —NR 8C C(O)R 8B , —NR 8C C(O)OR 8B , —N(R 8C )C(O)NR 8C R 8D , —NR 8C S(O) 2 R 8B , —NR 8C S(O) 2 NR 8C R 8D , —P(O)(R 8B ) 2 , R 9 -substituted or unsubstituted C 1-6 alkyl, R 9 -substituted or unsubstituted C 1-6 haloalkyl, R 9 -substituted or unsubstituted C 3-7 cycloalkyl, R 9 -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R 9 -substituted or unsubstituted C 5-7 aryl, or R 9 -substituted or unsubstituted 5 to 7 membered heteroaryl;

each R 8B , R 8C , and R 8D is independently hydrogen, R 9A -substituted or unsubstituted C 1-6 alkyl, R 9A -substituted or unsubstituted C 1-6 haloalkyl, R 9A -substituted or unsubstituted C 3-7 cycloalkyl, or R 9A -substituted or unsubstituted 3 to 7 membered heterocycloalkyl,

each R 9A is independently hydrogen, halogen, oxo, —CN, —NO 2 , —C(O)H, —C(O)CH 3 , —C(O)OH, —C(O)OCH 3 , —C(O)NH 2 , —OH, —OCH 3 , —OCF 3 , —OC(O)H, —OC(O) CH 3 , —OC(O)NH 2 , —SH, —S(O)H, —S(O) 2 H, —S(O)(=NH)H, —S(O) 2 NH 2 , —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —NHC(O)H, —NHC(O)OH, —N(H)C(O)NH 2 , —NHS(O) 2 H, —NHS(O) 2 NH 2 , or —P(O)(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, —C(CH 3 ) 2 F, —C(CH 3 )F 2 , unsubstituted C 1-6 alkoxy, unsubstituted C 1-6 alkyl, unsubstituted C 1-6 haloalkyl, unsubstituted C 3-7 cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted C 5-7 aryl, or unsubstituted 5 to 7 membered heteroaryl;

each R 9 is independently hydrogen, halogen, oxo, —CN, —OR 9B , —NO 2 , —C(O)R 9B , C(O)OR 9B , —C(O)NR 9C R 9D , —OC(O)R 9B , —OC(O)NR 9C R 9D , —SR 9C , —S(O)R 9B , —S(O) 2 R 9B , —S(O)(=NR 9C )R 9D , —S(O) 2 NR 9C R 9D , —NR 9C R 9D , —NR 9C C(O)R 9B , —NR 9C C(O)OR 9B , —N(R 9C )C(O)NR 9C R 9D , —NR 9C S(O) 2 R 9B , —NR 9C S(O) 2 NR 9C R 9D , —P(O)(R 9B ) 2 , R 12 -substituted or unsubstituted C 1-6 alkyl, R 12 -substituted or unsubstituted C 1-6 haloalkyl, R 12 -substituted or unsubstituted C 3-7 cycloalkyl, R 12 -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R 12 -substituted or unsubstituted C 5-7 aryl, or R 12 -substituted or unsubstituted 5 to 7 membered heteroaryl;

each R 9B , R 9C , and R 9D is independently hydrogen, R 10A -substituted or unsubstituted C 1-6 alkyl, R 10A -substituted or unsubstituted C 1-6 haloalkyl, R 10A -substituted or unsubstituted C 3-7 cycloalkyl, or R 10A -substituted or unsubstituted 3 to 7 membered heterocycloalkyl,

each R 10A is independently hydrogen, halogen, oxo, —CN, —NO 2 , —C(O)H, —C(O)CH 3 , —C(O)OH, —C(O)OCH 3 , —C(O)NH 2 , —OH, —OCH 3 , —OCF 3 , —OC(O)H, —OC(O) CH 3 , —OC(O)NH 2 , —SH, —S(O)H, —S(O) 2 H, —S(O)(=NH)H, —S(O) 2 NH 2 , —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —NHC(O)H, —NHC(O)OH, —N(H)C(O)NH 2 , —NHS(O) 2 H, —NHS(O) 2 NH 2 , or —P(O)(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, —C(CH 3 ) 2 F, —C(CH 3 )F 2 , unsubstituted C 1-6 alkoxy, unsubstituted C 1-6 alkyl, unsubstituted C 1-6 haloalkyl, unsubstituted C 3-7 cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted C 5-7 aryl, or unsubstituted 5 to 7 membered heteroaryl;

each R 10 is independently hydrogen, halogen, oxo, —CN, —OR 11A , —NO 2 , —C(O)R 11A , —C(O)OR 11A , —C(O)NR 11B R 11C , —OC(O)R 11A , —OC(O)NR 11B R 11C , —SR 11B , —S(O)R 11A , —S(O) 2 R 11A , —S(O)(=NR 11B )R 11C , —S(O) 2 NR 11B R 11C , —NR 11B R 11C , —NR 11B C(O)R 11A , —NR 11B C(O)OR 11A , —N(R 11B )C(O)NR 11B R 11C , —NR 11B S(O) 2 R 11A , —NR 11B S(O) 2 NR 11B R 11C , —P(O)(R 11A ) 2 , R 11 -substituted or unsubstituted C 1-6 alkoxy, R 11 -substituted or unsubstituted C 1-6 alkyl, R 11 -substituted or unsubstituted C 1-6 haloalkyl, R 11 -substituted or unsubstituted C 3 -7 cycloalkyl, R 11 -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R 11 -substituted or unsubstituted C 5-7 aryl, or R 11 -substituted or unsubstituted 5 to 7 membered heteroaryl;

each R 11A , R 11B , and R 11C is independently hydrogen, R 12A -substituted or unsubstituted C 1-6 alkyl, R 12A -substituted or unsubstituted C 1-6 haloalkyl, R 12A -substituted or unsubstituted C 3-7 cycloalkyl, or R 12A -substituted or unsubstituted 3 to 7 membered heterocycloalkyl,

each R 12A is independently hydrogen, halogen, oxo, —CN, —NO 2 , —C(O)H, —C(O)CH 3 , —C(O)OH, —C(O)OCH 3 , —C(O)NH 2 , —OH, —OCH 3 , —OCF 3 , —OC(O)H, —OC(O) CH 3 , —OC(O)NH 2 , —SH, —S(O)H, —S(O) 2 H, —S(O)(=NH)H, —S(O) 2 NH 2 , —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —NHC(O)H, —NHC(O)OH, —N(H)C(O)NH 2 , —NHS(O) 2 H, —NHS(O) 2 NH 2 , or —P(O)(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, —C(CH 3 ) 2 F, —C(CH 3 )F 2 , unsubstituted C 1-6 alkoxy, unsubstituted C 1-6 alkyl, unsubstituted C 1-6 haloalkyl, unsubstituted C 3-7 cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted C 5-7 aryl, or unsubstituted 5 to 7 membered heteroaryl;

each R 11 is independently hydrogen, halogen, oxo, —CN, —OR 12B , —NO 2 , —C(O)R 12B , C(O)OR 12B , —C(O)NR 12C R 12D , —OC(O)R 12B , —OC(O)NR 12C R 12D , —SR 12C , —S(O)R 12B , —S(O) 2 R 12B , —S(O)(=NR 12C )R 12D , —S(O) 2 NR 12C R 12D , —NR 12C R 12D , —NR 12C C(O)R 12B , —NR 12C C(O)OR 12B , —N(R 12C )C(O)NR 12C R 12D , —NR 12C S(O) 2 R 12B , —NR 12C S(O) 2 NR 12C R 12D , —P(O)(R 12B ) 2 , R 12 -substituted or unsubstituted C 1-6 alkyl, R 12 -substituted or unsubstituted C 1-6 haloalkyl, R 12 -substituted or unsubstituted C 3-7 cycloalkyl, R 12 -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R 12 -substituted or unsubstituted C 5-7 aryl, or R 12 -substituted or unsubstituted 5 to 7 membered heteroaryl;

each R 12B , R 12C , and R 12D is independently hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 1-6 haloalkyl, unsubstituted C 3-7 cycloalkyl, or unsubstituted 3 to 7 membered heterocycloalkyl,

each R 12 is independently hydrogen, halogen, oxo, —CN, —NO 2 , —C(O)H, —C(O)CH 3 , —C(O)OH, —C(O)OCH 3 , —C(O)NH 2 , —OH, —OCH 3 , —OCF 3 , —OC(O)H, —OC(O)CH 3 , —OC(O)NH 2 , —SH, —S(O)H, —S(O) 2 H, —S(O)(=NH)H, —S(O) 2 NH 2 , —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —NHC(O)H, —NHC(O)OH, —N(H)C(O)NH 2 , —NHS(O) 2 H, —NHS(O) 2 NH 2 , or —P(O)(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, —C(CH 3 ) 2 F, —C(CH 3 )F 2 , unsubstituted C 1-6 alkoxy, unsubstituted C 1-6 alkyl, unsubstituted C 1-6 alkoxy, unsubstituted C 1-6 haloalkyl, unsubstituted C 1-6 haloalkoxy, unsubstituted C 3-7 cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted C 5-7 aryl, or unsubstituted 5 to 7 membered heteroaryl; and

R 13 is hydrogen, halogen, or R 10 -substituted or unsubstituted C 1-6 alkyl.

2 . The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound has the formula:

3 . The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 1 , wherein R 2 is independently hydrogen, —OR 7 , or R 10 -substituted or unsubstituted C 1-6 alkyl.

4 . The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 3 , wherein R 7 is hydrogen, R 8 -substituted or unsubstituted C 1-6 alkyl, R 8 -substituted or unsubstituted C 1-6 haloalkyl, R 8 -substituted or unsubstituted C 3-7 cycloalkyl, or R 8 -substituted or unsubstituted 3 to 7 membered heterocycloalkyl.

5 . The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 1 , wherein R 3 is hydrogen, halogen, —OR 7 , —NR 7A R 7B , R 10 -substituted or unsubstituted C 1-6 alkyl, R 10 -substituted or unsubstituted C 1-6 haloalkyl, R 10 -substituted or unsubstituted C 3-7 cycloalkyl, or R 10 -substituted or unsubstituted 3 to 7 membered heterocycloalkyl.

6 . The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 5 , wherein R 7 is R 8 -substituted or unsubstituted C 1-6 alkyl, R 8 -substituted or unsubstituted C 1-6 haloalkyl, R 8 -substituted or unsubstituted C 3-7 cycloalkyl, or R 8 -substituted or unsubstituted 3 to 7 membered heterocycloalkyl, and wherein R 7A and R 7B are independently hydrogen or R 8A -substituted or unsubstituted C 1-6 alkyl.

7 . The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 5 , wherein R 3 is methyl, ethyl, propyl isopropyl, —C(CH 3 ) 2 F, —C(CH 3 )F 2 , —CH 2 F, —CHF 2 , or —CF 3 .

8 . The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 1 , wherein R 4 is halogen and n is 1, 2, or 3.

9 . The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 1 , wherein R 4 is F and n is 1, 2, or 3; or, wherein R 4 is —OR 7 and n is 1.

10 . The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 1 , wherein L 1 is —NHSO 2 — or pyrrolidin-2-one.

11 . The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 1 , wherein R 5 is R 10 -substituted or unsubstituted benzyl, R 10 -substituted or unsubstituted pyrrolidinyl, R 10 -substituted or unsubstituted piperidinyl, R 10 -substituted or unsubstituted C 1-6 haloalkyl, or R 10 -substituted or unsubstituted C 1-6 alkyl.

12 . The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 11 , wherein R 10 is hydrogen, halogen —OH, —CN, —CF 3 , —CHF 2 , —CH 2 F, —C(CH 3 ) 2 F, —C(CH 3 )F 2 , methyl, propyl, or ethyl.

13 . The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 1 , wherein R 6 is independently hydrogen, halogen, R 10 -substituted or unsubstituted C 1-6 alkyl, R 10 -substituted or unsubstituted C 1-6 haloalkyl, or —NR 6A R 6B .

14 . The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 13 , wherein at least one R 6 is —NR 6A R 6B , wherein R 6A and R 6B are each R 10 -substituted or unsubstituted C 1-6 alkyl.

15 . The compound, stereoisomer, tautomer, or A pharmaceutically acceptable salt thereof of claim 1 , wherein Ring A is R 6 -substituted cyclohexyl or R 6 -substituted piperidinyl.

16 . The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 1 , wherein Ring A has the formula:

17 . The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 1 , wherein Ring B is R 4 -substituted or unsubstituted C 5-7 aryl.

18 . The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 17 , wherein Ring B has the formula:

wherein R 4A , R 4B , R 4C , and R 4D are each independently hydrogen, halogen, —CN, R 10 -substituted or unsubstituted C 1-6 alkyl, R 10 -substituted or unsubstituted C 1-6 haloalkyl, R 10 -substituted or unsubstituted C 3-6 cycloalkyl, R 10 -substituted or unsubstituted C 1-6 alkoxy, or R 10 -substituted or unsubstituted C 1-6 haloalkoxy.

19 . The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound has the formula:

20 . The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound has the formula:

21 . The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound has the formula:

22 . The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 21 , wherein the compound has the formula:

23 . The compound of claim 1 or pharmaceutically acceptable salt thereof selected from the group consisting of:

Cmpd No.

Structure

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

124

125

126

127

129

130

131

132

137

138

139

140

142

144

151

152

153

154

156

157

158

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

259

260

261

262

263

264

265

266

24 . A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of claim 1 and one or more pharmaceutically acceptable excipients.

25 . A method of treating an IRE1-related disease or disorder, wherein the IRE1-related disease or disorder is cancer, the method comprising administering to a subject having an IRE1-related disease or disorder an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof,

wherein the cancer is squamous cell carcinoma, small-cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, squamous cell lung cancer, peritoneum cancer, hepatocellular cancer, stomach cancer, gastrointestinal cancer, esophageal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland carcinoma, renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatocellular carcinoma (HCC), anal carcinoma, penile carcinoma, head and neck cancer, lymphoma, lymphocytic leukemia, multiple myeloma (MM), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), or triple-negative breast cancer (TNBC).