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JP-2026076270-A - Allosteric inhibitor of SHP2 octahydrocyclopenta[c]pyrrole

JP2026076270AJP 2026076270 AJP2026076270 AJP 2026076270AJP-2026076270-A

Abstract

[Problem] Compounds having the ability to inhibit the activity of SHP2, methods for producing the same, pharmaceutical preparations, and the use of such compounds in the management of diseases or disorders associated with abnormal activity of SHP2. [Solution] A compound represented by the following general formula is used. Specifically, for example, the following compounds: [Selection Diagram] None

Inventors

  • ロバート・ボークマン
  • アンソニー・マーファット
  • フレデリック・ネルソン
  • パナヨティス・ザグラス

Assignees

  • クルーゾン・ファーマシューティカルズ・インコーポレイテッド

Dates

Publication Date
20260511
Application Date
20260123
Priority Date
20170911

Claims (20)

  1. Formula A1: [In the formula: L is O, S, or absent; X1 is N or CR X1 ; X2 is N or CR X2 ; Y1 is N or CR Y1 ; Y2 is N or CR Y2 ; Here, X1 , X2 , Y1 , and Y2 are at most three such that N is the same; R1 is a C6-10 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, or 4-14 membered heterocycloalkyl, respectively: Cy1 , halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2 , OR a1 , SR a1 , C ( O)R b1, C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , C (=NR e1 )NR c1 R d1 , NR c1 C(=NR e1 )NR c1 R d1 , NR c1 R d1 , NR c1 The C1-6 alkyl, C2-6 alkenyl , and C2-6 alkynyl are substituted with 1 , 2, 3, 4, or 5 substituents independently selected from C (O)R b1 , NR c1 , C (O) OR a1 , NR c1 , C (O)NR c1 R d1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2 R b1, and S(O) 2 NR c1 R d1, where the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are Cy1 , halo, CN, NO2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , NR c1 C(=NR e1 )NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , may be substituted with one, two, or three substituents independently selected from S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2NR c1 R d1 ; R2a , R2b , R4a , R4b , R5a , R5b , R7a , and R7b are each independently selected from H, C1-4 alkyl, C1-4 alkoxy, amino, hydroxy, C3-8 cycloalkyl, and C1-4 alkylamino; R3 and R6 are each independently selected from H, F, or C1-4 alkyl; R8 and R9 are independently H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, OR a2 , SR a2 , C(O)R b2, C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C (O)R b2 , NR c2 C(O)OR a2 , NR c2 C (O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 , where the alkyl, C2-6 alkenyl, and C2-6 alkynyl are selected from halo, CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , NR c2 C(=NR e2 )NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 may be substituted with one, two, or three substituents independently selected from these; Here, at least one of R8 and R9 is a group other than H; R X1 , R X2 , R Y1 , and R Y2 are each independently H, Cy 2 , halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 , C(O)NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 , where the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are selected from Cy 2 , halo, CN, NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , may be substituted with one , two , or three substituents independently selected from S(O) 2Rb3 and S(O ) 2NRc3Rd3 ; Each Cy1 is independently selected from C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, respectively, and is one of the following: halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl- C1-4 alkyl, C3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl , CN, NO2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 ) may be substituted with one, two , three , or four substituents independently selected from NR c1 R d1 , NR c1 C (= NR e1 ) NR c1 R d1 , NR c1 R d1 , NR c1 C(O) R b1 , NR c1 C (O) OR a1 , NR c1 C(O) NR c1 R d1 , NR c1 S(O) R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , S(O) R b1 , S(O) NR c1 R d1 , S(O) 2 R b1, and S(O) 2 NR c1 R d1; Each Cy2 is independently selected from C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, respectively, and is one of the following: halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl- C1-4 alkyl, C3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl , CN, NO2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , C(=NR e3 ) may be substituted with one, two , three , or four substituents independently selected from NR c3 R d3 , NR c3 C (=NR e3 ) NR c3 R d3 , NR c3 R d3 , NR c3 C(O) R b3 , NR c3 C(O) OR a3 , NR c3 C(O) NR c3 R d3 , NR c3 S(O) R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , S(O) R b3 , S(O) NR c3 R d3 , S(O) 2 R b3, and S(O) 2 NR c3 R d3; Each R a1 , R b1 , R c1 , R d1 , R a3 , R b3 , R c3 , and R d3 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl, where R a1 , R b1 , R c1 , R d1 , R a3 , R b3 , R c3 , and R d3 are C 1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl- C1-4 alkyl, C3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl- C1-4 alkyl, and 4-10 membered heterocycloalkyl- C1-4 alkyl are halo, C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)NR c7 R d4 , NR c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , NR c4 C(=NR e4 )NR c3 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 may be substituted with one, two, or three substituents independently selected from these; Alternatively, R c1 and R d2 , together with the N atom to which they are bonded, form CN, halo, C1-4 alkyl, C1-4 haloalkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 C (O)R b4 , NR c4 C (O)NR c7 R d4 , NR c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , NR c4 Forming a 4-7 member heterocycloalkyl group which may be substituted with 1 , 2, or 3 substituents independently selected from C(=NR e4)NR c3 R d4 , S ( O ) R b4 , S (O)NR c4 R d4 , S(O) 2 R b4, NR c4 S(O) 2 R b4, NR c4 S ( O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4; Alternatively, R c3 and R d3 , together with the N atom to which they are bonded, form CN, halo, C1-4 alkyl, C1-4 haloalkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 , C(O)NR b4 , NR c4 , C(O)NR c7 R d4 , NR c4 , C(O)OR a4 , C(=NR e4 )NR c4 R d4 , NR c4 Forming a 4-7 member heterocycloalkyl group which may be substituted with 1 , 2, or 3 substituents independently selected from C(=NR e4)NR c3 R d4 , S ( O ) R b4 , S (O)NR c4 R d4 , S(O) 2 R b4, NR c4 S(O) 2 R b4, NR c4 S ( O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4; Each R a2 , R b2 , R c2 , and R d2 is independently selected from H and C 1-4 alkyl groups; Each R a4 , R b4 , R c4 , and R d4 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl- C1-4 alkyl, C3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl- C1-4 alkyl, and 4-10 membered heterocycloalkyl- C1-4 alkyl, where C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, and C6-10 aryl-C Each of the 1-4 alkyl, C3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl- C1-4 alkyl, and 4-10 membered heterocycloalkyl- C1-4 alkyl groups may be substituted with one, two, or three substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy groups; and each of Re1 , Re2 , Re3 , and Re4 may be independently selected from H, C1-4 alkyl, and CN; Each of the heteroaryl or heterocycloalkyl groups described herein comprises one, two, three, or four ring-forming heteroatoms independently selected from O, N, and S; and one or more ring-forming C or N atoms of each of the heterocycloalkyl groups described herein may be replaced with an oxo (=O) group. The compound indicated by, or a pharmaceutically acceptable salt thereof.
  2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L is absent.
  3. The compound according to claim 1, wherein L is O, or a pharmaceutically acceptable salt thereof.
  4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L is S.
  5. A compound according to any one of claims 1 to 4, wherein X1 is N, or a pharmaceutically acceptable salt thereof.
  6. A compound according to any one of claims 1 to 4, wherein X1 is CR X1 , or a pharmaceutically acceptable salt thereof.
  7. A compound according to any one of claims 1 to 6, wherein X2 is N, or a pharmaceutically acceptable salt thereof.
  8. A compound according to any one of claims 1 to 6, wherein X2 is CR X2 , or a pharmaceutically acceptable salt thereof.
  9. A compound according to any one of claims 1 to 6, wherein X1 is CR X1 and X2 is N, or a pharmaceutically acceptable salt thereof.
  10. A compound according to any one of claims 1 to 9, wherein Y1 is N, or a pharmaceutically acceptable salt thereof.
  11. A compound according to any one of claims 1 to 9, wherein Y1 is CR Y1 , or a pharmaceutically acceptable salt thereof.
  12. A compound according to any one of claims 1 to 11, wherein Y2 is N, or a pharmaceutically acceptable salt thereof.
  13. A compound according to any one of claims 1 to 11, wherein Y2 is CR Y2 , or a pharmaceutically acceptable salt thereof.
  14. A compound according to any one of claims 1 to 6, wherein X1 is CR X1 , X2 is N, and Y2 is N, or a pharmaceutically acceptable salt thereof.
  15. A compound according to any one of claims 1 to 6, wherein X1 is CR X1 , X2 is N, and Y1 is N, or a pharmaceutically acceptable salt thereof.
  16. A compound according to any one of claims 1 to 6, wherein X1 is CR X1 , X2 is N, Y1 is N, and Y2 is N, or a pharmaceutically acceptable salt thereof.
  17. R1 is a C6-10 aryl or 5-14 member heteroaryl, each being Cy1 , halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , NR c1 C(=NR e1 )NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 may be substituted with 1, 2, 3 , 4 or 5 substituents independently selected from C (O) OR a1, NR c1 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , NR c1 C(=NR e1 )NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof , which may be substituted with one, two, or three substituents independently selected from d1 , S(O) 2R b1 , and S(O) 2NR c1R d1.
  18. R1 is phenyl or a 6-membered heteroaryl, each being Cy1 , halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , NR c1 C(=NR e1 )NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 may be substituted with 1, 2, 3, 4 or 5 substituents independently selected from the alkyl, C2-6 alkenyl, and C2-6 alkynyl, where the alkyl, C2-6 alkenyl, and C2-6 alkynyl are Cy1 , halo, CN, NO2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , NR c1 C(=NR e1 ) NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, which may be substituted with one, two, or three substituents independently selected from b1 and S(O) 2NR c1R d1 .
  19. R1 is phenyl or a 6-membered heteroaryl, each being Cy1 , halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , NR c1 C(=NR e1 )NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 may be substituted with 1, 2, 3, 4 or 5 substituents independently selected from the alkyl, C2-6 alkenyl, and C2-6 alkynyl, where the alkyl, C2-6 alkenyl, and C2-6 alkynyl are Cy1 , halo, CN, NO2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , NR c1 C(=NR e1 ) NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, which may be substituted with one, two, or three substituents independently selected from b1 and S(O) 2NR c1R d1 .
  20. R1 is phenyl or a 6-membered heteroaryl, and each is a halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2R b1 , and S(O) 2NR c1R d1 may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from the alkyl, C2-6 alkenyl, and C2-6 alkynyl, where the alkyl, C1-6 alkyl, C1-6 haloalkyl, CN, NO2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1R d1 , C(O)OR a1 , NR c1R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1R d1 , NR c1 S(O)R b1 , NR c1 A compound according to any one of claims 1 to 16 , or a pharmaceutically acceptable salt thereof , which may be substituted with one, two, or three substituents independently selected from S(O)2R b1 , NR c1 S(O) 2NR c1R d1 , S(O) R b1 , S(O)NR c1R d1 , S(O)2R b1, and S(O)2NR c1R d1.

Description

This invention relates to a compound having the ability to inhibit the activity of SHP2. Furthermore, this invention provides a method for producing the compound, a pharmaceutical formulation containing such compound, and a method for using such compound and composition in the management of diseases or disorders associated with abnormal SHP2 activity. Src homology-2 phosphatase (SHP2) is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene, involved in numerous cellular functions including proliferation, differentiation, cell cycle maintenance, and migration. SHP2 is associated with signaling via the Ras-mitogen-activated protein kinase, JAK-STAT, or phosphoinositol 3-kinase-AKT pathways. SHP2 possesses two N-terminal Src homology 2 domains (N-SH2 and C-SH2), a catalytic domain (PTP), and a C-terminal chain. The two SH2 domains regulate the intracellular localization and functional regulation of SHP2. The molecule exists in an inactive, self-inhibitory form, stabilized by a binding network containing residues from both the N-SH2 and PTP domains. For example, stimulation with cytokines or growth factors exposes the catalytic site, leading to enzymatic activation of SHP2. Mutations in the PTPN11 gene, and subsequently in SHP2, have been identified in several human diseases, including Noonan syndrome, Leopard syndrome, Curzon syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and heart, lung, and colon cancers. Therefore, SHP2 is an extremely attractive target for developing novel therapies to treat various diseases. The compounds of the present invention satisfy the requirement that small molecules inhibit SHP2 activity. In particular, the present invention relates to formula A1: [In the formula, the constituent variable groups are as defined herein.] The present invention provides the compound represented by or a pharmaceutically acceptable salt thereof. This disclosure further provides a pharmaceutical composition comprising a compound of the disclosure or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. The disclosure further provides a method for modulating (e.g., inhibiting) SHP2 activity, comprising administering a compound of the disclosure or a pharmaceutically acceptable salt thereof to an individual. The disclosure further provides a method for treating or preventing a disease in a patient in need of treatment or prevention, comprising administering a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to the patient, wherein the disease is mediated by the activity of SHP2. This disclosure also provides the use of the compounds described herein in the manufacture of pharmaceuticals for therapeutic use. This disclosure also provides the compounds described herein for therapeutic use. This invention relates to a novel octahydrocyclopenta[c]pyrrole compound, comprising a pharmaceutically acceptable salt thereof. The invention also relates to a method for producing a pharmaceutical composition, intermediates used in its production, and the use of such compound in the treatment of SHP2-mediated disorders such as cancer. Compound This disclosure relates to formula A1: [In the formula: L is O, S, or absent; X1 is N or CR X1 ; X2 is N or CR X2 ; Y1 is N or CR Y1 ; Y2 is N or CR Y2 ; Here, X1 , X2 , Y1 , and Y2 are at most three such that N is the same; R1 is a C6-10 aryl, C3-14 cycloalkyl, 5-14 membered heteroaryl, or 4-14 membered heterocycloalkyl, respectively: Cy1 , halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2 , OR a1 , SR a1 , C ( O)R b1, C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , C (=NR e1 )NR c1 R d1 , NR c1 C(=NR e1 )NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 may optionally be substituted with 1, 2, 3, 4 or 5 substituents independently selected from C(O)2 NR c1 R d1, where C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are Cy1 , halo, CN, NO2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , NR c1 C(=NR e1 )NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , may optionally be substituted with one, two, or three substituents independently selected from S(O)R b1 , S(O)NR c1R d1 , S(O) 2R b1 , and S(O) 2NR c1R d1 ; R2a , R2b , R4a , R4b , R5a , R5b , R7a , and R7b are each independently selected from H, C1-4 alkyl, C1-4 alkoxy, amino, hydroxy, C3-8 cycloalkyl, and C1-4 alkylamino; R3 and R6 are independently selected from H, F, or C1-4 alkyl groups; R8 and R9 are H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O