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EP-4739688-A2 - TRIAZOLO WRN INHIBITORS

EP4739688A2EP 4739688 A2EP4739688 A2EP 4739688A2EP-4739688-A2

Abstract

The present disclosure is directed to triazolo based compounds, including compounds of Formula I: and pharmaceutically acceptable salts thereof, and compositions thereof, as well as methods of treatment of cancers such as those involving WRN protein.

Inventors

  • LI, DERUN
  • WEST, ANGELA V.
  • CARAVELLA, JUSTIN
  • GENUNG, Nathan E.
  • BARTELS, FLORIAN
  • DOW, ROBERT LEE
  • LEIT DE MORADEI, Silvana Marcel
  • SITNIKOV, Nikolay

Assignees

  • Nimbus Wadjet, Inc.

Dates

Publication Date
20260513
Application Date
20240708

Claims (20)

  1. CLAIMS We Claim: 1. A compound of Formula I, or a pharmaceutically acceptable salt thereof: wherein Y and Z are independently selected from C and N, denotes a single or double bond and wherein when Y is N then Z is C, or when Y is C then Z is N; to form a subformula selected from Formula I-a and Formula I-b: wherein Ring A represents: i. a 4-7 membered saturated or partially unsaturated bivalent monocyclic ring system selected from carbocyclylene and heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or ii. a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclylene or heterocyclylene (having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein Ring A is substituted with 0-4 independently selected R A substituents; L is a linker selected from -C(O)-, -S(O)-, -S(O) 2 -, and R 1 is selected from groups a) to e): a) a 5-6-membered monocyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1-3 groups independently selected from halogen, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, and C 3 - C 6 cycloalkoxy, wherein said 5-6-membered monocyclic heteroaryl is further substituted with 0-3 independently selected R A ; b) a 9-10-membered bicyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1 or 2 groups independently selected from C 1 -C 6 aliphatic, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, and C 3 -C 6 cycloalkoxy, wherein said 9-10 membered bicyclic heteroaryl is further substituted with 0-3 independently selected R A ; c) a 4-7-membered saturated or partially unsaturated monocyclic heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkoxy, and -OR, wherein said 4-7-membered saturated or partially unsaturated monocyclic heterocyclyl is further substituted with 0-3 independently selected R A ; d) a 4-12 membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclyl and heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0-3 independently selected R A ; and e) H, C 1 -C 6 aliphatic, C 3 -C 7 cycloalkyl, C 1 -C 6 alkylene-O-C 1 -C 6 alkyl, -C(O)NR 10 R 11 , - CH 2 NR 10 R 11 , -SO 2 R 12 , wherein the C 1 -C 6 aliphatic, C 3 -C 7 cycloalkyl, or C 1 -C 6 alkylene-O- C 1 -C 6 alkyl is substituted with 0-5 independently selected R A ; R 10 is H, C 1 -C 6 aliphatic, haloC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, haloC 3 -C 6 cycloalkyl, –C(O)C 3 - C 6 cycloalkyl, –C(O)C 1 -C 6 alkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1 or 2 groups independently selected from R A ; R 11 is H, C 1 -C 6 aliphatic, or C 3 -C 6 cycloalkyl, or R 10 and R 11 may combine to form a 5-6 membered ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, -OH, -CN, C 1 -C 4 alkoxy, and haloC 1 -C 4 alkoxy; R 12 is C 1 -C 6 aliphatic, C 3 -C 6 cycloalkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1 or 2 groups independently selected from halogen, C 1 -C 6 aliphatic, haloC 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 - C 6 cycloalkyl, and C 3 -C 6 cycloalkoxy; R A is independently selected at each occurrence from the group consisting of optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogen, optionally substituted C 1 -C 6 aliphatic, hydroxy-C 1 -C 6 alkyl, haloC 1 - C 6 alkyl, an optionally substituted C 3 -C 6 cycloalkyl, haloC 3 -C 6 cycloalkyl, an optionally substituted C 1 -C 6 alkoxy, haloC 1 -C 6 alkoxy, an optionally substituted C 3 -C 6 cycloalkoxy, haloC 3 - C 6 cycloalkoxy, C 1 -C 6 alkylene-O-C 1 -C 6 alkyl, –CN, –NO 2 , oxo, –OR, – SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, – C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -N(R)S(O) 2 NR 2 , and – N(R)S(O) 2 R; R 2 is selected from C(R B ) 2 C(O)N(R)R 2A , C(R B ) 2 C(R B ) 2 C(O)N(R)R 2A , C(R B ) 2 C(R B ) 2 N(R)C(O) N(R)R 2A , and C(R B ) 2 C(R B ) 2 N(R)C(O)R 2A ; R B is independently selected at each occurrence from hydrogen, -CH 3 , or -CH 2 CH 3 , or two R B taken together with the carbon to which they are attached form a cyclopropyl ring; R 2A is phenyl, pyridyl, cubanyl, a saturated or partially unsaturated 4-8 membered monocyclic ring, a saturated or partially unsaturated bridged, fused, or spirocyclic 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, wherein said saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused, or spirocyclic ring contains 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein said phenyl, pyridyl, cubanyl, saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused, or spirocyclic ring are each optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C 1 -C 4 aliphatic, haloC 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, haloC 3 - C 6 cycloalkyl, -OH, -CN, C 1 -C 4 alkoxy, haloC 1 -C 4 alkoxy, C 3 -C 6 cycloalkoxy, haloC 3 -C 6 cyclalkoxy and –SF 5 ; or two substituents on adjacent atoms of the phenyl or pyridyl together with said adjacent atoms form a 4-7 membered carbocyclyl fused to the phenyl or pyridyl; or two substituents on adjacent atoms of the phenyl or pyridyl together with said adjacent atoms form a 4-7 membered heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused to the phenyl or pyridyl, wherein said 4-7 membered carbocyclyl or 4-7 membered heterocyclyl is substituted with 0-5 independently selected halogen, and wherein 2 substituents on the same atom of said saturated or partially unsaturated monocyclic ring, or saturated or partially unsaturated bridged, fused, or spirocyclic ring form a cyclic group selected from: ● an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl, and ● an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or R 2A is 2-benzimidazolyl, 2-naphthyl, or 3-quinolinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C 1 -C 4 aliphatic, haloC 1 -C 4 alkyl and - OH; R 3 is hydrogen, C 1 -C 4 aliphatic, C 3 -C 5 cycloalkyl, C 1 -C 4 alkoxy, -NHR 3A , -N(R 3A ) 2 , or C 1 - C 4 alkylthio, each of which, besides hydrogen, is optionally substituted with -OH, 1-5 independently selected halogen, -OR, -C(O)NR 10 R 11 , or N(R)C(O)R; each R 3A is independently selected at each occurrence from C 1 -C 4 alkyl; R 4 is phenyl or a first 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) wherein said phenyl or first 5-6 membered heteroaryl are substituted with 0-5 R A or two substituents on adjacent atoms of said phenyl or first 5-6 membered heteroaryl together with said adjacent atoms form a 4-7 membered saturated or partially unsaturated fused carbocyclyl, a 4-7 membered saturated or partially unsaturated fused heterocyclyl, or a second 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to the phenyl or first 5-6 membered heteroaryl wherein said 4-7 membered saturated or partially unsaturated fused carbocyclyl , 4-7 membered saturated or partially unsaturated fused heterocyclyl, and second 5-6 membered heteroaryl are substituted with 0-3 R A ; or R 4 is a C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or C 3 -C 6 cycloalkyl, each of which is substituted with 0-3 groups independently selected from halogen, -CN, -OH, oxo, NH 2 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, optionally substituted 5-6 membered heterocyclyl, and optionally substituted 5-6 membered heterocyclyloxy; each R is independently hydrogen, or an optionally substituted C 1–6 aliphatic group, an optionally substituted phenyl, an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or two R groups on the same atom are taken together with the same atom to form an optionally substituted 4-7 membered saturated ring, 4-7 membered partially unsaturated ring, or 5-6 membered heteroaryl ring (wherein said 4-7 membered saturated ring and 4-7 membered partially unsaturated ring has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and wherein said 5-6 membered heteroaryl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 2. A compound of Formula I, or a pharmaceutically acceptable salt thereof: wherein Y and Z are independently selected from C and N, denotes a single or double bond and wherein when Y is N then Z is C, or when Y is C then Z is N; to form a subformula selected from Formula I-a and Formula I-b: wherein Ring A represents: a) a 4-7 membered saturated or partially unsaturated bivalent monocyclic ring system selected from carbocyclylene and heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or b) a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclylene or heterocyclylene (having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); wherein Ring A is substituted with 0-4 independently selected R A substituents; -L- is a linker selected from -C(O)-, -S(O)-, -S(O) 2 -, and R 1 is selected from groups a) to e): a) a 5-6-membered monocyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1-3 groups independently selected from halogen, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, and C 3 - C 6 cycloalkoxy, wherein said 5-6-membered monocyclic heteroaryl is further substituted with 0-3 independently selected R A ; b) a 9-10-membered bicyclic heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1 or 2 groups independently selected from C 1 -C 6 aliphatic, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, and C 3 -C 6 cycloalkoxy, wherein said 9-10 membered bicyclic heteroaryl is further substituted with 0-3 independently selected R A ; c) a 4-7-membered saturated or partially unsaturated monocyclic heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkoxy, and -OR, wherein said 4-7-membered saturated or partially unsaturated monocyclic heterocyclyl is further substituted with 0-3 independently selected R A ; d) a 4-12 membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclyl and heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0-3 independently selected R A ; and e) H, C 1 -C 6 aliphatic, C 3 -C 7 cycloalkyl, C 1 -C 6 alkylene-O-C 1 -C 6 alkyl, -C(O)NR 10 R 11 , - CH 2 NR 10 R 11 , -SO 2 R 12 , wherein the C 1 -C 6 aliphatic, C 3 -C 7 cycloalkyl, or C 1 -C 6 alkylene-O- C 1 -C 6 alkyl is substituted with 0-5 independently selected R A ; R 10 is H, C 1 -C 6 aliphatic, haloC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, haloC 3 -C 6 cycloalkyl, –C(O)C 3 - C 6 cycloalkyl, –C(O)C 1 -C 6 alkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1 or 2 groups independently selected from R A ; R 11 is H, C 1 -C 6 aliphatic, or C 3 -C 6 cycloalkyl, or R 10 and R 11 may combine to form a 5-6 membered ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, -OH, -CN, C 1 -C 4 alkoxy, and haloC 1 -C 4 alkoxy; R 12 is C 1 -C 6 aliphatic, C 3 -C 6 cycloalkyl, or a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1 or 2 groups independently selected from halogen, C 1 -C 6 aliphatic, haloC 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 - C 6 cycloalkyl, and C 3 -C 6 cycloalkoxy; R A is independently selected at each occurrence from the group consisting of optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogen, optionally substituted C 1 -C 6 aliphatic, hydroxy-C 1 -C 6 alkyl, haloC 1 - C 6 alkyl, an optionally substituted C 3 -C 6 cycloalkyl, haloC 3 -C 6 cycloalkyl, an optionally substituted C 1 -C 6 alkoxy, haloC 1 -C 6 alkoxy, an optionally substituted C 3 -C 6 cycloalkoxy, haloC 3 - C 6 cycloalkoxy, C 1 -C 6 alkylene-O-C 1 -C 6 alkyl, –CN, –NO 2 , oxo, –OR, – SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, – C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -N(R)S(O) 2 NR 2 , and – N(R)S(O) 2 R; R 2 is C(R B ) 2 C(O)N(R)R 2A ; R B is independently selected at each occurrence from hydrogen, -CH 3 , or -CH 2 CH 3 , or two R B taken together with the carbon to which they are attached form a cyclopropyl ring; R 2A is phenyl or pyridyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C 1 -C 4 aliphatic, haloC 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, haloC 3 - C 6 cycloalkyl, -OH, -CN, C 1 -C 4 alkoxy, haloC 1 -C 4 alkoxy, and –SF 5 ; or two substituents on adjacent atoms of the phenyl or pyridyl together with said adjacent atoms form a 4-7 membered carbocyclyl fused to the phenyl or pyridyl; or two substituents on adjacent atoms of the phenyl or pyridyl together with said adjacent atoms form a 4-7 membered heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused to the phenyl or pyridyl, wherein said 4-7 membered carbocyclyl or 4-7 membered heterocyclyl is substituted with 0-5 independently selected halogen; or R 2A is 2-benzimidazolyl, 2-naphthyl, or 3-quinolinyl, each of which is optionally substituted with 1,
  2. 2, or 3 substituents independently selected from halogen, C 1 -C 4 aliphatic, haloC 1 -C 4 alkyl and - OH; R 3 is hydrogen, C 1 -C 4 aliphatic, C 3 -C 5 cycloalkyl, C 1 -C 4 alkoxy, -NHR 3A , -N(R 3A ) 2 , or C 1 - C 4 alkylthio, each of which, besides hydrogen, is optionally substituted with -OH, 1-5 independently selected halogen, -OR, -C(O)NR 10 R 11 , or N(R)C(O)R; each R 3A is independently selected at each occurrence from C 1 -C 4 alkyl; R 4 is phenyl or a first 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) wherein said phenyl or first 5-6 membered heteroaryl are substituted with 0-5 R A or two substituents on adjacent atoms of said phenyl or first 5-6 membered heteroaryl together with said adjacent atoms form a 4-7 membered saturated or partially unsaturated fused carbocyclyl, a 4-7 membered saturated or partially unsaturated fused heterocyclyl, or a second 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to the phenyl or first 5-6 membered heteroaryl wherein said 4-7 membered saturated or partially unsaturated fused carbocyclyl , 4-7 membered saturated or partially unsaturated fused heterocyclyl, and second 5-6 membered heteroaryl are substituted with 0-3 R A ; or R 4 is a C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or C 3 -C 6 cycloalkyl, each of which is substituted with 0-3 groups independently selected from halogen, -CN, -OH, oxo, NH 2 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, optionally substituted 5-6 membered heterocyclyl, and optionally substituted 5-6 membered heterocyclyloxy; each R is independently hydrogen, or an optionally substituted C 1–6 aliphatic group, an optionally substituted phenyl, an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or two R groups on the same atom are taken together with the same atom to form an optionally substituted 4-7 membered saturated ring, 4-7 membered partially unsaturated ring, or 5-6 membered heteroaryl ring (wherein said 4-7 membered saturated ring and 4-7 membered partially unsaturated ring has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and wherein said 5-6 membered heteroaryl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  3. 3. A compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, of Formula II- a or Formula II-b: wherein: R 4 is selected from one of a), b), and c): a) R 4 is a Ring B that is selected from the group consisting of wherein * is a point of attachment -L- that is bonded to Ring A in Formula I, wherein -L- is -C(O)- in Formula II-a and Formula II-b; and wherein: any substituents that are present on Ring B selected from R 4A , R 4B , R 4C , R 4D , R 4E , and R 4F are each independently selected from hydrogen; halogen; -OH; -CN; C 1 -C 4 alkyl; C 2 - C 4 alkenyl; C 2 -C 4 alkynyl; C 1 -C 4 alkoxy; haloC 1 -C 4 alkyl; C 1 -C 3 alkyl substituted with -OH, -OCH 3 , or -OCH 2 CH 3 ; haloC 1 -C 4 alkoxy; C 3 -C 6 cycloalkyl; C 3 -C 6 cycloalkoxy; and NR 13 R 14 ; or R 4A and R 4B , along with their intervening atoms, join to form 4-7 membered optionally substituted carbocyclyl, 4-7 membered optionally substituted heterocyclyl, or 5-6 membered optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring B; and any substituents that are present on Ring B selected from R 4C , R 4D , R 4E , and R 4F are each independently selected from hydrogen; halogen; -OH; -CN; C 1 -C 4 alkyl; C 2 -C 4 alkenyl; C 2 -C 4 alkynyl; haloC 1 -C 4 alkyl; C 1 -C 3 alkyl substituted with -OH, -OCH 3 , or -OCH 2 CH 3 ; haloC 1 -C 4 alkoxy; C 3 -C 6 cycloalkyl; C 3 -C 6 cycloalkoxy; and NR 13 R 14 ; or R 4B and R 4C , along with their intervening atoms, join to form 4-7 membered optionally substituted carbocyclyl, 4-7 membered optionally substituted heterocyclyl, or 5-6 membered optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring B; and any substituents that are present on Ring B selected from R 4A , R 4D , R 4E , and R 4F are each independently selected from hydrogen; halogen; -OH; -CN; C 1 -C 4 alkyl; C 2 -C 4 alkenyl; C 2 -C 4 alkynyl; haloC 1 -C 4 alkyl; C 1 -C 3 alkyl substituted with -OH, -OCH 3 , or -OCH 2 CH 3 ; haloC 1 -C 4 alkoxy; C 3 -C 6 cycloalkyl; C 3 -C 6 cycloalkoxy; and NR 13 R 14 ; or R 4C and R 4D , along with their intervening atoms, join to form 4-7 membered optionally substituted carbocyclyl, 4-7 membered optionally substituted heterocyclyl, or 5-6 membered optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring B; and any substituents that are present on Ring B selected from R 4A , R 4B , R 4E and R 4F are each independently selected from hydrogen; halogen; -OH; -CN; C 1 -C 4 alkyl; C 2 -C 4 alkenyl; C 2 -C 4 alkynyl; haloC 1 -C 4 alkyl; C 1 -C 3 alkyl substituted with -OH, -OCH 3 , or -OCH 2 CH 3 ; haloC 1 -C 4 alkoxy; C 3 -C 6 cycloalkyl; C 3 -C 6 cycloalkoxy; and NR 13 R 14 ; or R 4E is halogen or -OH, and R 4A , R 4B , R 4C , and R 4D are each independently selected from hydrogen; halogen; -CN; C 1 -C 4 alkyl; C 2 -C 4 alkenyl; C 2 -C 4 alkynyl; haloC 1 -C 4 alkyl; C 1 - C 3 alkyl substituted with -OH, -OCH 3 , or -OCH 2 CH 3 ; haloC 1 -C 4 alkoxy; C 3 -C 6 cycloalkyl; C 3 -C 6 cycloalkoxy; and NR 13 R 14 ; or R 4E and R 4A , along with their intervening atoms, join to form 4-7 membered optionally substituted carbocyclyl, 4-7 membered optionally substituted heterocyclyl, or 5-6 membered optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring B; and R 4B , R 4C , and R 4D are each independently selected from hydrogen; halogen; -OH; -CN; C 1 -C 4 alkyl; C 2 - C 4 alkenyl; C 2 -C 4 alkynyl; haloC 1 -C 4 alkyl; C 1 -C 3 alkyl substituted with -OH, -OCH 3 , or - OCH 2 CH 3 ; haloC 1 -C 4 alkoxy; C 3 -C 6 cycloalkyl; C 3 -C 6 cycloalkoxy; and NR 13 R 14 ; or R 4F and R 4A , along with their intervening atoms, join to form 4-7 membered optionally substituted carbocyclyl, 4-7 membered optionally substituted heterocyclyl, or 5-6 membered optionally substituted heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) that is fused to Ring B; and any substituents that are present on Ring B selected from R 4B , R 4C , and R 4D are each independently selected from hydrogen; halogen; -OH; -CN; C 1 -C 4 alkyl; C 2 -C 4 alkenyl; C 2 -C 4 alkynyl; haloC 1 - C 4 alkyl; C 1 -C 3 alkyl substituted with -OH, -OCH 3 , or -OCH 2 CH 3 ; haloC 1 -C 4 alkoxy; C 3 - C 6 cycloalkyl; C 3 -C 6 cycloalkoxy; and NR 13 R 14 ; and R 13 is independently selected at each occurrence from hydrogen and C 1 -C 4 alkyl optionally substituted with -OH, -OCH 3 , or -OCH 2 CH 3 ; and R 14 is hydrogen or NR 13 R 14 forms a heterocyclic ring selected from azetidinyl, pyrrolidinyl, and piperidinyl, said heterocyclic ring optionally substituted with -CH 3 ; or b) R 4 is a 5-membered heteroaryl (having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur and 0, 1, 2, or 3 additional ring nitrogen atoms), wherein said heteroaryl is substituted with 0-4 groups independently selected from halogen, -OH, -CN, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and C 1 -C 4 alkoxy; or c) R 4 is a C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or C 3 -C 6 cycloalkyl, each of which is substituted with 0-3 groups independently selected from halogen, -CN, -OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, optionally substituted 5-6 membered heterocyclyl, and optionally substituted 5-6 membered heterocyclyloxy.
  4. 4. The compound of any one of claims 1-3, wherein the compound is of Formula IX or Formula IX-a: or a pharmaceutically acceptable salt thereof.
  5. 5. The compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from wherein Ring A is substituted with 0-4 independently selected R A substituents.
  6. 6. The compound of any one of claims 1-5, wherein R 1 is C 1 -C 6 alkyl, C 2 -C 4 alkene, C 2 -C 4 alkyne, –C(O)NR 10 R 11 , –CH 2 NR 10 R 11 , –SO 2 R 12 , or a 3-7 membered carbocyclyl, wherein C 1 -C 6 alkyl, C 2 -C 4 alkene, C 2 -C 4 alkyne, and 3-7 membered carbocyclyl are substituted with 0-3 substituents independently selected from halogen, C 3 -C 6 cycloalkyl, haloC 3 -C 6 cycloalkyl, -OH, - CN, C 1 -C 4 alkoxy, and haloC 1 -C 4 alkoxy.
  7. 7. The compound of any one of claims 1-5, wherein R 1 is a 5-6 membered heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1-3 groups independently selected from halogen, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkoxy, and C 3 -C 6 cycloalkyl, wherein said 5-6 membered heteroaryl is further substituted with 0-3 independently selected R A .
  8. 8. The compound of any one of claims 1-5, wherein R 1 is pyridyl substituted with C 1 - C 4 alkoxy and further substituted with 0-2 R A .
  9. 9. The compound of any one of claims 1-5, wherein R 1 is 5-membered heteroaryl (having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur, and 0 or 1 additional ring nitrogen atoms), wherein said 5-membered heteroaryl is substituted with a halogen, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 6 cycloalkyl, and further substituted with 0-2 independently selected R A .
  10. 10. The compound of any one of claims 1-5, wherein R 1 is c) a 5-6 membered saturated or partially unsaturated monocyclic heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), said monocyclic heterocyclyl substituted with 0-2 groups independently selected from halogen, oxo, -NR 2 , optionally substituted C 1 -C 4 aliphatic, -OR, azetidinyl optionally substituted with 1 or 2 independently selected halogen, and pyrrolidinyl optionally substituted with 1 or 2 independently selected halogen; or d) a 6-8 membered saturated or partially unsaturated bridged bicyclic heterocyclyl (having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), said heterocyclyl substituted with 0-2 groups independently selected from halogen, oxo, -NR 2 , optionally substituted C 1 -C 4 aliphatic, -OR, azetidinyl optionally substituted with 1 or 2 independently selected halogen, and pyrrolidinyl optionally substituted with 1 or 2 independently selected halogen.
  11. 11. The compound of any one of claims 1-5, wherein R 1 is a 5-6 membered saturated or partially unsaturated heterocyclyl (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), said heterocyclyl substituted with 0-2 groups independently selected from halogen, oxo, -NR 2 , optionally substituted C 1 -C 4 aliphatic, -OR, azetidinyl optionally substituted with 1 or 2 independently selected halogen, and pyrrolidinyl optionally substituted with 1 or 2 independently selected halogen.
  12. 12. The compound of any one of claims 1-5, wherein R 1 is selected from the group consisting of:
  13. 13. The compound of any one of claims 1-12, wherein R 4 is Ring B of the following structure: wherein * is a point of attachment to -L- in Formula I; R 4A is hydrogen, halogen, -CH 3 , -CH 2 CH 3 , -F, -CF 2 H, -CF 3 , -OCH 3 , -OCF 3 , -OCH 2 CH 3 , or - OCHF 2 ; R 4B , R 4C , and R 4D are each independently selected from hydrogen; halogen; -CN; C 1 -C 4 alkyl; C 2 - C 4 alkenyl; C 2 -C 4 alkynyl; haloC 1 -C 4 alkyl; C 1 -C 3 alkyl substituted with -OH, -OCH 3 , or -OCH 2 CH 3 ; haloC 1 -C 4 alkoxy; C 3 -C 6 cycloalkyl; C 3 -C 6 cycloalkoxy; and NR 13 R 14 ; and R 13 is independently selected at each occurrence from hydrogen and C 1 -C 4 alkyl optionally substituted with -OH, -OCH 3 , or -OCH 2 CH 3 ; and R 14 is hydrogen; or R 13 and R 14 are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, and piperidinyl; wherein the heterocyclic ring is optionally substituted with -CH 3 ; or R 4 is a 5-membered heteroaryl (having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur and 0, 1, 2, or 3 additional ring nitrogen atoms), wherein said heteroaryl is substituted with 0-4 groups independently selected from halogen, -OH, -CN, C 1 -C 4 alkyl, haloC 1 - C 4 alkyl, C 3 -C 6 cycloalkyl, and C 1 -C 4 alkoxy.
  14. 14. The compound of any one of claims 1-12, wherein R 4 is: wherein * is a point of attachment to -L- in Formula I; wherein: R 4A is hydrogen, halogen, -CH 3 , -CH 2 CH 3 , -F, -CF 2 H, -CF 3 , -OCH 3 , -OCF 3 , -OCH 2 CH 3 , or - OCHF 2 ; R 4B and R 4C are each independently selected from hydrogen; -CN; C 1 -C 4 alkyl; C 2 -C 4 alkenyl; C 2 - C 4 alkynyl; haloC 1 -C 4 alkyl; C 1 -C 3 alkyl substituted with -OH, -OCH 3 , or -OCH 2 CH 3 ; haloC 1 - C 4 alkoxy; C 3 -C 6 cycloalkyl; C 3 -C 6 cycloalkoxy; and NR 13 R 14 ; and R 13 is independently selected at each occurrence from hydrogen and C 1 -C 4 alkyl optionally substituted with -OH, -OCH 3 , or -OCH 2 CH 3 ; and R 14 is hydrogen; or R 13 and R 14 are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring selected from azetidinyl, pyrrolidinyl, and piperidinyl; wherein the heterocyclic ring is optionally substituted with -CH 3 .
  15. 15. The compound of any one of claims 1-12, wherein R 4 is a 5-membered heteroaryl (having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur and 0, 1, 2, or 3 additional ring nitrogen atoms), wherein said heteroaryl is substituted with 0-4 groups independently selected from halogen, -OH, -CN, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and C 1 -C 4 alkoxy.
  16. 16. The compound of any one of claims 1-12, wherein R 4 is a 5-membered heteroaryl (having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur and 0, 1, 2, or 3 additional ring nitrogen atoms) selected from the group consisting of imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, oxazolyl, isoxazolyl, 1,2,4- oxadiazolyl, 1,2,3-triazolyl, and 1,2,4-triazolyl, wherein said heteroaryl is substituted with 0-4 groups independently selected from halogen, -OH, -CN, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, C 3 - C 6 cycloalkyl, and C 1 -C 4 alkoxy.
  17. 17. The compound of claim 16, wherein R 4 is an isoxazolyl substituted with -OH or C 1 - C 4 alkoxy.
  18. 18. The compound of any one of claims 1-12, wherein R 4 is
  19. 19. The compound of any one of claims 1-18, wherein R 2A is phenyl comprising a -CF 3 substituent or pyridyl comprising a -CF 3 substituent.
  20. 20. The compound of any one of claims 1-18, wherein R 2 is .

Description

TRIAZOLO WRN INHIBITORS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to and the benefit of U.S. Provisional Application No. 63/512,493, filed July 7, 2023; U.S. Provisional Application No.63/613,652, filed December 21, 2023; and U.S. Provisional Application No.63/660,947, filed June 17, 2024; the contents of each of which are hereby incorporated by reference. FIELD OF INVENTION [0002] The invention provides bicyclic compounds and compositions, the use thereof and methods using the compounds, for inhibiting Werner Syndrome RecQ DNA helicase (WRN) and methods of treating disease using said compounds, in particular the use in treating cancer, and in particular the treatment of cancer characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), including colorectal, gastric and endometrial cancer. The invention also provides the use of said compounds as research chemicals, intermediate compounds, combinations, processes and formulations. SEQUENCE LISTING [0003] This application contains a Sequence Listing which has been submitted in .xml format via EFS and is hereby incorporated by reference. The ST.26 copy, created on March 30, 2023, is named 407274-81WRP2_ST26.xml and is 8,751 bytes in size. BACKGROUND [0004] Loss of DNA mismatch repair is a common initiating event in cancer development occurring in 10-30% of colorectal, endometrial, ovarian and gastric cancers (Aaltonen, L. A. et al. Clues to the pathogenesis of familial colorectal cancer, Science 260, 812-816 (1993), Bonneville R et al., Landscape of Microsatellite Instability Across 39 Cancer Types. JCO Precis Oncol. 1: PO.17.00073 (2017)). Cancers that are deficient in mismatch repair (dMMR) have a high mutational burden, and frequent deletion and insertion events in repetitive DNA tracts, a phenotype known as microsatellite instability (MSI). While progress has been made in the treatment of microsatellite instability high (MSI-H) cancers, and the demonstration that pembrolizumab (anti- PD1) treatment led to significantly longer progression-free survival than chemotherapy when received as first-line therapy for MSI-H-dMMR metastatic colorectal cancer (CRC) which resulted in the recent approval of pembrolizumab as first-line treatment of these cancers, there is still a significant unmet medical need in CRC and other MSI-H indications (André T., et al. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med 383(23):22072218 (2020)). Several large-scale functional genomics screens across large panels of cell lines, including Novartis with 398 cell lines from the Cancer Cell Line Encyclopedia (CCLE) (McDonald E.R. et al., Project DRIVE: A Compendium of Cancer Dependencies and Synthetic Lethal Relationships Uncovered by Large-Scale, Deep RNAi Screening. Cell 170(3):577-592 (2017)), have identified the Werner Syndrome RecQ helicase (WRN) as being selectively required for the survival of cell lines with defective mismatch repair that have become MSI-H (Behan, F. M. et al. Prioritization of cancer therapeutic targets using CRISPR—Cas9 screens. Nature 568, 511-516 (2019), Chan, E. M. et al. WRN helicase is a synthetic lethal target in microsatellite unstable cancers. Nature 568, 551-556 (2019). Kategaya, L., Perumal, S. K., Hager, J. H. & Belmont, L. D. Werner syndrome helicase is required for the survival of cancer cells with microsatellite instability. iScience 13, 488-497 (2019), Lieb, S. et al. Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells. eLife 8, e43333 (2019)). WRN is synthetically lethal with MSI cancers. Depletion of WRN leads to anti-proliferative effects and results in activation of multiple DNA damage signaling markers, induction of cell cycle arrest and apoptosis in MSI-H cancer models but not cancer cells with an intact MMR pathway (otherwise known as microsatellite stable or MSS). The anti-proliferative effects of WRN depletion could not be rescued with a helicase deficient WRN construct, demonstrating that helicase activity of WRN is required for MSI-H viability. These findings indicate that WRN helicase provides a DNA repair and maintenance function that is essential for cell survival in MSI cancers. Recently, the mechanism of WRN dependence has been elucidated. It has been shown that dinucleotide TA repeats are selectively unstable in MSI cells and undergo large scale expansions. These expanded TA repeats form secondary DNA structures that require the WRN helicase for unwinding (van Wietmarschen, N. et al. Repeat expansions confer WRN dependence in microsatellite-unstable cancers. Nature 586, 292-298, 2020). In the absence of WRN (or upon WRN helicase inhibition), expanded TA repeats in MSI cells are subject to nuclease cleavage and chromosome breakage. Thus, inhibiting the WRN helicase is an attractive strategy for the treatment of MSI-H cancers. SUMMARY [0005] There remains a need for