# US 11,077,101 B1 · Compounds and methods of use

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- Number: US 11,077,101 B1
- Document ID: US11077101B1
- Status: Granted
- Kind: B1
- Application number: 16/515,910
- Filed: 2019-07-18
- Granted: 2021-08-03
- Earliest claimed: 2018-07-18
- Assignees: Tango Therapeutics, Inc.
- Applicants: Tango Therapeutics, Inc.
- Inventors: Kevin M. Cottrell; John P. Maxwell; Douglas A. Whittington
- Web page: https://patentgrep.com/patent/US11077101B1

## CPC

- A61K 31/4725: containing further heterocyclic rings
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/5386: spiro-condensed or forming part of bridged ring systems
- C07D 401/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 498/08: Bridged systems
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Compounds are provided according to Formula (I): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein X1, X2, X3, X4, Y, A, L1, L2, R1, R2, R5, m and n are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.

## Claims

### Claim 1

A compound or a pharmaceutically acceptable salt thereof wherein the compound is of formula (I)
wherein
X1, X2, X3 and X4 are each independently N or CRx;
Y is N, CH or CR5;
L1 is a bond or C1-C4-alkylene substituted with 0-2 instances of R6;
L2 is a bond, —NH— or —O—;
Ring A is a carbocycle, heterocycle, 5-6 member monocyclic heteroaryl or a monocyclic aryl;
R1 is a 3-7 membered carbocycle, a 4-7 membered heterocycle or a 5-6 membered heteroaryl substituted with 0-3 instances of R4;
each R2 is independently selected from ═O, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 carbocyclyl, —C3-C9 heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, —OR3, —N(R3)2, —C(═O)R3, —C(═O)OR3, —CH2C(═O)R3, —NR3C(═O)R3, —NR3C(═O)OR3, —C(═O)N(R3)2, —OC(═O)N(R3)2, —S(═O)R3, —S(═O)2R3, —SR3, —S(═O)(═NR3)R3, —NR3S(═O)2R3 and —S(═O)2N(R3)2;
each R3 is independently selected from H, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C7 carbocyclyl, C3-C7 heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5-6 membered heteroaryl, arylalkyl and heteroarylalkyl wherein each alkyl, carbocyclyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl is optionally substituted;
each R4 is independently selected from ═O, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 carbocyclyl, —C3-C9 heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, —OR3, —N(R3)2, —C(═O)R3, —C(═O)OR3, —NR3C(═O)R3, —NR3C(═O)OR3, —C(═O)N(R3)2, —OC(═O)N(R3)2, —S(═O)R3, —S(═O)2R3, —SR3, —S(═O)(═NR3)R3, —NR3S(═O)2R3 and —S(═O)2N(R3)2;
each Rx is independently selected from hydrogen, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 carbocyclyl, —C3-C9 heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, —OR3, —N(R3)2, —C(═O)R3, —C(═O)OR3, —NR3C(═O)R3, —NR3C(═O)OR3, —C(═O)N(R3)2, —OC(═O)N(R3)2, —S(═O)R3, —S(═O)2R3, —SR3, —S(═O)(═NR3)R3, —NR3S(═O)2R3 and —S(═O)2N(R3)2 wherein each alkyl, carbocyclyl, heterocyclyl, heterocyclylalkyl, cycloalkylalkyl is optionally substituted;
each R5 is independently selected from ═O, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 carbocyclyl, —C3-C9 heterocyclyl, C6-C10 aryl, C5-C10 heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, —OR3, —N(R3)2, —C(═O)R3, —C(═O)OR3, —NR3C(═O)R3, —NR3C(═O)OR3, —C(═O)N(R3)2, —OC(═O)N(R3)2, —S(═O)R3, —S(═O)2R3, —SR3, —S(═O)(═NR3)R3, —NR3S(═O)2R3, —S(═O)2N(R3)2, or two R5 can be taken together with the atoms to which they are attached to form a —C3-C9 carbocyclyl or a —C3-C9 heterocyclyl;
each R6 is independently selected from halo, —C1-C4 alkyl, —C1-C4 haloalkyl, —OC1-C4 alkyl, —OC1-C4 haloalkyl, or two R6 can be taken together with the atoms to which they are attached to form a C3-C7 carbocycle or a C3-C7 heterocycle;
m is 0, 1, 2 or 3; and
n is 0, 1, 2 or 3.

### Claim 2 (depends on 1)

The compound of claim 1 wherein the compound has structure (Ia)

### Claim 3 (depends on 1)

The compound of claim 1 wherein the compound has structure (Ib)

### Claim 4 (depends on 1)

The compound of claim 1 wherein Y is CH or CR5.

### Claim 5 (depends on 4)

The compound of claim 4 wherein the compound has structure (IIa)

### Claim 6 (depends on 4)

The compound of claim 4 wherein the compound has structure (IIIa)

### Claim 7 (depends on 4)

The compound of claim 4 wherein the compound has structure

### Claim 8 (depends on 4)

The compound of claim 4 wherein L1 is a bond.

### Claim 9 (depends on 4)

The compound of claim 4 wherein L1 is —CH2—.

### Claim 10 (depends on 4)

The compound of claim 4 wherein L2 is —NH—.

### Claim 11 (depends on 10)

The compound of claim 10 wherein the compound has structure (Va1′)

### Claim 12 (depends on 11)

The compound of claim 11 wherein Rx is H, N(R3)2, NHR3, N(CH3)R3, OR3, C1-C6 alkyl, optionally substituted —C3-C9 carbocyclyl or optionally substituted —C3-C9 heterocyclyl.

### Claim 13 (depends on 10)

The compound of claim 10 wherein the compound has structure (VIa1′)

### Claim 14 (depends on 13)

The compound of claim 13 wherein Rx is H, N(R3)2, NHR3, N(CH3)R3, OR3, C1-C6 alkyl, optionally substituted —C3-C9 carbocyclyl or optionally substituted —C3-C9 heterocyclyl.

### Claim 15 (depends on 10)

The compound of claim 10 wherein the compound has structure (VIIa1)

### Claim 16 (depends on 4)

The compound of claim 4 wherein L2 is a bond.

### Claim 17 (depends on 4)

The compound of claim 4 wherein L2 is —O—.

### Claim 18

A compound or pharmaceutically acceptable salt thereof according to Formula (XI)
wherein:
R1 is a 3-7 membered carbocycle, a 4-7 membered heterocycle or a 5-6 membered heteroaryl substituted with 0-3 instances of R4;
each R2 is independently selected from ═O, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 carbocyclyl, —C3-C9 heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, —OR3, —N(R3)2, —C(═O)R3, —C(═O)OR3, —NR3C(═O)R3, —NR3C(═O)OR3, —C(═O)N(R3)2, —OC(═O)N(R3)2, —S(═O)R3, —S(═O)2R3, —SR3, —S(═O)(═NR3)R3, —NR3S(═O)2R3 and —S(═O)2N(R3)2;
each R3 is independently selected from H, C1-C6 alkyl, C3-C7 carbocyclyl, C3-C7 heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5-6 membered heteroaryl, arylalkyl and heteroarylalkyl wherein each alkyl, carbocyclyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl is optionally substituted;
each R4 is independently selected from ═O, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 carbocyclyl, —C3-C9 heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, —OR3, —N(R3)2, —C(═O)R3, —C(═O)OR3, —NR3C(═O)R3, —NR3C(═O)OR3, —C(═O)N(R3)2, —OC(═O)N(R3)2, —S(═O)R3, —S(═O)2R3, —SR3, —S(═O)(═NR3)R3, —NR3S(═O)2R3 and —S(═O)2N(R3)2;
each R5 is independently selected from ═O, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 carbocyclyl, —C3-C9 heterocyclyl, C6-C10 aryl, C5-C10 heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, —OR3, —N(R3)2, —C(═O)R3, —C(═O)OR3, —NR3C(═O)R3, —NR3C(═O)OR3, —C(═O)N(R3)2, —OC(═O)N(R3)2, —S(═O)R3, —S(═O)2R3, —SR3, —S(═O)(═NR3)R3, —NR3S(═O)2R3, —S(═O)2N(R3)2, or two R5 can be taken together with the atoms to which they are attached to form a —C3-C9 carbocyclyl or a —C3-C9 heterocyclyl; and
m is 0, 1, 2 or 3.

### Claim 19

A compound or pharmaceutically acceptable safes alt thereof according to Formula (XII)
wherein
Ring A is a carbocycle, heterocycle, 5-6 member monocyclic heteroaryl or a monocyclic aryl;
R1 is a 3-7 membered carbocycle, a 4-7 membered heterocycle or a 5-6 membered heteroaryl substituted with 0-3 instances of R4;
each R2 is independently selected from ═O, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 carbocyclyl, —C3-C9 heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, —OR3, —N(R3)2, —C(═O)R3, —C(═O)OR3, —NR3C(═O)R3, —NR3C(═O)OR3, —C(═O)N(R3)2, —OC(═O)N(R3)2, —S(═O)R3, —S(═O)2R3, —SR3, —S(═O)(═NR3)R3, —NR3S(═O)2R3 and —S(═O)2N(R3)2;
each R3 is independently selected from H, C1-C6 alkyl, C3-C7 carbocyclyl, C3-C7 heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5-6 membered heteroaryl, arylalkyl and heteroarylalkyl wherein each alkyl, carbocyclyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl is optionally substituted;
each R4 is independently selected from ═O, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 carbocyclyl, —C3-C9 heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, —OR3, —N(R3)2, —C(═O)R3, —C(═O)OR3, —NR3C(═O)R3, —NR3C(═O)OR3, —C(═O)N(R3)2, —OC(═O)N(R3)2, —S(═O)R3, —S(═O)2R3, —SR3, —S(═O)(═NR3)R3, —NR3S(═O)2R3 and —S(═O)2N(R3)2;
each R5 is independently selected from ═O, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 carbocyclyl, —C3-C9 heterocyclyl, C6-C10 aryl, C5-C10 heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, —OR3, —N(R3)2, —C(═O)R3, —C(═O)OR3, —NR3C(═O)R3, —NR3C(═O)OR3, —C(═O)N(R3)2, —OC(═O)N(R3)2, —S(═O)R3, —S(═O)2R3, —SR3, —S(═O)(═NR3)R3, —NR3S(═O)2R3, —S(═O)2N(R3)2, or two R5 can be taken together with the atoms to which they are attached to form a —C3-C9 carbocyclyl or a —C3-C9 heterocyclyl; and
m is 0, 1, 2 or 3.

### Claim 20 (depends on 4)

The compound of claim 4 wherein R1 is a 3-7 membered carbocycle substituted with 0-3 instances of R4.

### Claim 21 (depends on 4)

The compound of claim 4 wherein R1 is a 4-7 membered heterocycle substituted with 0-3 instances of R4.

### Claim 22 (depends on 4)

The compound of claim 4 wherein R1 is a 5-6 membered heteroaryl substituted with 0-3 instances of R4.

### Claim 23 (depends on 4)

The compound of claim 4 wherein R1 is selected from:

### Claim 24 (depends on 4)

The compound of claim 4 wherein ring A is a 4-7 membered monocyclic heterocycle.

### Claim 25 (depends on 24)

The compound of claim 24 wherein ring A is piperidinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, azetidinyl, tetrahydropyranyl, 1,4-dioxan-2-yl or morpholinyl.

### Claim 26 (depends on 4)

The compound of claim 4 wherein ring A is a 5-6 membered monocyclic heteroaryl.

### Claim 27 (depends on 4)

The compound of claim 4 wherein ring A is aryl.

### Claim 28 (depends on 4)

The compound of claim 4 wherein ring A is a 3-8 membered carbocycle.

### Claim 29 (depends on 28)

The compound of claim 28 wherein ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, spiro[2.3]hexyl, spiro[3.3]heptyl.

### Claim 30 (depends on 4)

The compound of claim 4 wherein n is 1 and R2 is —C(═O)R3.

### Claim 31 (depends on 30)

The compound of claim 30 wherein R3 is C1-C6 alkyl or C3-C7 carbocyclyl.

### Claim 32 (depends on 19)

The compound of claim 19 wherein n is 1 and R2 is arylalkyl or heteroarylalkyl.

### Claim 33 (depends on 4)

The compound of claim 4 wherein n is 0.

### Claim 34 (depends on 4)

The compound of claim 4 wherein m is 1.

### Claim 35 (depends on 4)

The compound of claim 4 wherein m is 0.

### Claim 36 (depends on 4)

The compound of claim 4 wherein each R5 is independently selected from ═O, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 carbocyclyl, —C3-C9 heterocyclyl, —OR3, —N(R3)2, —CO(R3), —NR3(CO)R3, —(CO)N(R3)2.

### Claim 37 (depends on 36)

The compound of claim 36 wherein each R5 is independently selected from halo, —CN and —C1-C6 alkyl.

### Claim 38 (depends on 1)

The compound of claim 1 wherein Y is N.

### Claim 39 (depends on 1)

The compound of claim 1 wherein the compound is selected from:
Nr.
Structure
14
74
76
96
135
140
161
163
179
194
198
201
203
207
219
233
241
242
249
250
251
252
253
254
255
256
257
258
259
260
261
262
263
264
265
266
267
268
269
270
271
272
273
274
275
276
277
278
279
280
281
282
283
284
285
286
287
288
289
290
292
293
294
295
296
297
298
299
300
302
303
304
305
306
307
308
309
310
311
312
313
314
315
316
317
318
319
320
321
322
323
324
325
326
327
329
331
332
333
334
335
336
337
338
339
340
341
342
343
344
345
346
347
348
349
350
351
352
353
354
355
356
357
358
359
360
361
362
363
364
365
366
367
368
369
370
371
372
373
374
375
376
377
378
379
380
381
382
383
384
385
386
387
388
389
390
391
393
394
395
396
397
398
399
400
401
402
403
404
405
406
407
408
409
410
411
412
413
414
415
417
418
419
420
421
422
423
424
425
426
427
428
429
430
431
432
433
434
435
436
437
438
439
441
442
443
444
445
446
447
448
449
450
451
452
453
454
455
456
457
458
459
460
461
462
463
464
465
466
467
468
469
470
471
472
473
474
476
477
478
479
480
481
483
484
485
486
487
488
489
490
491
492
494
495
496
497
499
500
501
502
503
504
505*
506
507
508
509
510
511
512
513
514
515
516
517
518
519
520
521
522
523
524
525
526
527
528
529
530
531
532
534
535
536
537
538
539
541
542
543
544
545
548
549
550
551
552
553
554
555
556
557
558
559
560
562
563
564
565
566
567
568
569
570
571
572
573
574
575
576
579
580
581
582
583
584
585
586
587
588
589
590
591
592
593
594
595
596
597
598
599
600
601
602
603
604
605
606
607
608
609
610
611
612
613
614
615
616
617
618
619
620
621
622
623
624
625
626
627
628
629
630
631
632
633
634
635
636
637
638
639
640
641
642
643
644
645
646
647
648**
649**
650
651
652
653
654
.

### Claim 40 (depends on 19)

A compound of claim 19 wherein the compound is selected from:
Nr.
Structure
291
301
328
330
392
416
440
475
482
.

### Claim 41 (depends on 18)

A compound of claim 18 wherein the compound is selected from:
Nr.
Structure
493
498
530
533
540
546
547
561
577
578
.

### Claim 42 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim 43 (depends on 42)

The pharmaceutical composition of claim 42, further comprising a second therapeutic agent.