Allosteric inhibitors of SHP2 octahydrocyclopenta[c]pyrrole

Abstract

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. JPEG2026076270000064.jpg45150 Specifically, for example, the following compounds: JPEG2026076270000065.jpg2263

Description

[Technical Field]

[0001] The present invention relates to compounds having the ability to inhibit the activity of SHP2. The present invention further provides a method for producing the compounds of the present invention, pharmaceutical formulations containing such compounds, and methods for using such compounds and compositions in the management of diseases or disorders associated with abnormal activity of SHP2. [Background technology]

[0002] 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.

[0003] 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.

[0004] 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 cancers of the heart, lung, and colon. 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 the activity of SHP2. [Overview of the project]

[0005] In particular, the present invention relates to formula A1: [ka] [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.

[0006] 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.

[0007] This 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. [Modes for carrying out the invention]

[0008] The present invention relates to a novel octahydrocyclopenta[c]pyrrole compound comprising a pharmaceutically acceptable salt thereof. The present invention also relates to a method for producing a pharmaceutical composition, intermediates used in the production thereof, and the use of such compound in the treatment of SHP2-mediated disorders such as cancer.

[0009] compound This disclosure is based on formula A1: [ka] [In formula: L is O, S, or absent; X 1 is N or CR X1 ; X 2 is N or CR X2 ; Y 1 is N or CR Y1 ; Y 2 is N or CR Y2 ; where X 1 , X 2 , Y 1 and Y 2 are at most 3 N simultaneously; R 1 is C 6-10 aryl, C 3-14 cycloalkyl, 5 - 14 member heteroaryl, or 4 - 14 member heterocycloalkyl, each, Cy 1 , halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 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(#ID=94]] c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NRc1 S(O)2R b1 、NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 、およびS(O)2NR c1 R d1 may be optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from, where the C 1-6 alkyl, C 2-6 alkenyl, and C<0**********61>alkynyl is Cy 1 、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)2R b1 、NR c1 S(O)2NR c1 R d1 、S(O)R b1 S(O)NR c1 R d1 、S(O)2R b1 、およびS(O)2NR c1 R d1They may be optionally substituted with one, two, or three substituents selected more independently; R 2a , R 2b , R 4a , R 4b , R 5a , R 5b , R 7a , and R 7b H, C 1-4 Alkyl, C 1-4 Alkoxy, amino, hydroxy, C 3-8 Cycloalkyl and C 1-4 Each alkylamino molecule is independently selected; R 3 and R 6 is H, F, or C 1-4 Each alkyl group is independently selected; R 8 and R 9 H, Halo, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-4 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)2R b2 , NR c2 S(O)2NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 S(O)2R b2, and S(O)2NR c2 R d2 Each is selected independently, where the alkyl, C 2-6 Alkenyl and C 2-6 Alkinyl is Halo, CN, NO2, 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)2R b2 , NR c2 S(O)2NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 S(O)2R b2 , and S(O)2NR c2 R d2 They may be optionally substituted with one, two, or three substituents selected more independently; Here R 8 and R 9 At least one of them is a group other than H; R X1 , R X2 , R Y1 , and R Y2 H, Cy 2 Hello, C 1-6 Alkyl, C 2-6Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, 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 )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)2R b3 , NR c3 S(O)2NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 S(O)2R b3 , and S(O)2NR c3 R d3 Each is selected independently, and here C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkinyl is Cy 2 Hello, 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 )NRc3 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)2R b3 , NR c3 S(O)2NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 S(O)2R b3 , and S(O)2NR c3 R d3 They may be optionally substituted with one, two, or three substituents selected more independently; Each Cy 1 C 6-10 Ariel, C 3-7 A cycloalkyl group is independently selected from 5-10 membered heteroaryl groups and 4-10 membered heterocycloalkyl groups, each being a halo, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 member heteroaryl-C 1-4 Alkyl, 4-10 member heterocycloalkyl-C 1-4 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)NRc1 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)2R b1 , NR c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 S(O)2R b1 , and S(O)2NR c1 R d1 They may be optionally substituted with one, two, three, or four substituents selected more independently; Each Cy 2 C 6-10 Ariel, C 3-7 A cycloalkyl group is independently selected from 5-10 membered heteroaryl groups and 4-10 membered heterocycloalkyl groups, each being a halo, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 member heteroaryl-C 1-4 Alkyl, 4-10 member heterocycloalkyl-C 1-4 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 )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)2R b3 , NR c3 S(O)2NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 S(O)2R b3 , and S(O)2NR c3 R d3 They may be optionally substituted with one, two, three, or four substituents selected more independently; Each R a1 , R b1 , R c1 , R d1 , R a3 , R b3 , R c3 , and R d3 H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 6-10 Ariel, 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 member heteroaryl-C1-4 Alkyl and 4-10 member heterocycloalkyl-C 1-4 Selected independently of alkyl, where R a1 , R b1 , R c1 , R d1 , R a3 , R b3 , R c3 , and R d3 of C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 6-10 Ariel, 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 member heteroaryl-C 1-4 Alkyl and 4-10 member heterocycloalkyl-C 1-4 alkyl is halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, 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)2R b4 , NR c4 S(O)2R b4 , NR c4 S(O)2NR c4 R d4 , and S(O)2NR c4 R d4 They may be optionally substituted with one, two, or three substituents selected more independently; Or R c1 and R d2 Together with the N atom to which they bond, they form CN, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, 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)2R b4 , NR c4 S(O)2R b4 , NR c4 S(O)2NR c4 R d4 , and S(O)2NR c4 Rd4 Forming a 4-7 member heterocycloalkyl group which may be optionally substituted with one, two, or three substituents selected more independently; Or R c3 and R d3 Together with the N atom to which they bond, they form CN, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, 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)2R b4 , NR c4 S(O)2R b4 , NR c4 S(O)2NR c4 R d4 , and S(O)2NR c4 R d4 Forms a 4-7 member heterocycloalkyl group which may be optionally substituted with one, two, or three substituents selected more independently; Each R a2 , R b2 , R c2 , and R d2H and C 1-4 Selected independently of alkyl groups; Each R a4 , R b4 , R c4 , and R d4 H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 6-10 Ariel, 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 member heteroaryl-C 1-4 Alkyl and 4-10 member heterocycloalkyl-C 1-4 Selected independently of alkyl, where C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 6-10 Ariel, 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 member heteroaryl-C 1-4 Alkyl and 4-10 member heterocycloalkyl-C 1-4 Alkyl is represented by OH, CN, amino, halo, and C respectively. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 It may optionally be substituted with one, two, or three substituents independently selected from the haloalkoxy; and Each R e1 , R e2 , R e3 , and R e4 H, C 1-4 Selected independently of alkyl and CN; Herein, each of the heteroaryl or heterocycloalkyl groups comprises one, two, three, or four ring-forming heteroatoms independently selected from O, N, and S; and Here, one or more ring-forming C or N atoms of any of the heterocycloalkyl groups described above may be optionally replaced with an oxo (=O) group. The present invention provides an inhibitor of SHP2, which is a compound represented by or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, L is absent. In some embodiments, L is O. In some embodiments, L is S. In some embodiments, X 1 It is N. In some embodiments, X 1 CR X1 That is the case.

[0011] In some embodiments, X 2 It is N. In some embodiments, X 2 CR X2 That is the case. In some embodiments, X 1 CR X1 X 2 It is N. In some embodiments, Y 1 It is N. In some embodiments, Y 1 CR Y1 That is the case.

[0012] In some embodiments, Y 2 It is N. In some embodiments, Y 2 CR Y2 That is the case. In some embodiments, X 1 CR X1 X 2is N, Y 2 It is N. In some embodiments, X 1 CR X1 X 2 is N, Y 1 It is N. In some embodiments, X 1 CR X1 X 2 is N, and Y 1 is N, Y 2 It is N.

[0013] In some embodiments, R 1 is C 6-10 It is an aryl or 5-14 member heteroaryl, each being Cy 1 Hello, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 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)2R b1 , NR c1 S(O)2NR c1 Rd1 , S(O)R b1 , S(O)NR c1 R d1 S(O)2R b1 , and S(O)2NR c1 R d1 The alkyl, C may optionally be substituted with 1, 2, 3, 4, or 5 substituents selected more independently, where C is the alkyl. 2-6 Alkenyl and C 2-6 Alkinyl is Cy 1 Hello, 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)2R b1 , NR c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 S(O)2R b1 , and S(O)2NR c1 R d1 The substituents may be optionally substituted with one, two, or three substituents selected more independently.

[0014] In some embodiments, R 1is a phenyl or 6-membered heteroaryl, each being Cy 1 Hello, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 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)2R b1 , NR c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 S(O)2R b1 , and S(O)2NR c1 R d1 The alkyl, C may optionally be substituted with 1, 2, 3, 4, or 5 substituents selected more independently, where C is the alkyl. 2-6 Alkenyl and C 2-6 Alkinyl is Cy 1 Hello, CN, NO2, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)ORa1 ,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)2R b1 , NR c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 S(O)2R b1 , and S(O)2NR c1 R d1 The substituents may be optionally substituted with one, two, or three substituents selected more independently.

[0015] In some embodiments, R 1 is a phenyl or 6-membered heteroaryl, each being Cy 1 Hello, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 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)2R b1 , NR c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 S(O)2R b1 , and S(O)2NR c1 R d1 The alkyl, C may optionally be substituted with 1, 2, 3, 4, or 5 substituents selected more independently, where C is the alkyl. 2-6 Alkenyl and C 2-6 Alkinyl is Cy 1 Hello, 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 c1S(O)R b1 、NR c1 S(O)2R b1 、NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 、およびS(O)2NR c1 R d1 may be optionally substituted with 1, 2 or 3 substituents independently selected from

[0016] In some embodiments, R 1 is phenyl or 6-membered heteroaryl, each independently optionally substituted with 1, 2, 3, 4 or 5 substituents selected from halo, C 1-6 alkyl, C 1-6 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)2R b1 、NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 、およびS(O)2NR c1 R d1 wherein the alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each independently optionally substituted with halo, C 1-6 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)2R b1 , NR c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 S(O)2R b1 , and S(O)2NR c1 R d1 The substituents may be optionally substituted with one, two, or three substituents selected more independently.

[0017] In some embodiments, R 1 This is a phenyl molecule that may be optionally substituted with one, two, or three substituents independently selected from F, Cl, methyl, and CF3. In some embodiments, R 1 This is a pyridyl which may be optionally substituted with one, two, or three substituents independently selected from F, Cl, methyl, and CF3.

[0018] In some embodiments, R 1 These are 2-chloro-3-methylphenyl, 2,3-dichlorophenyl, 2-chloro-3-fluorophenyl, 2-chloropyridine-3-yl, 3-chloro-2-fluorophenyl, or 2-chloro-3-(trifluoromethyl)phenyl. In some embodiments, R 3and R 6 are both H.

[0019] In some embodiments, R 2a , R 2b , R 4a , R 4b , R 5a , R 5b , R 7a , and R 7b are all H. In some embodiments, R 8 and R 9 are each independently selected from H, halo, C 1-6 alkyl, C 1-4 ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​, 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)2R b3 , NR c3 S(O)2NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 S(O)2R b3 , and S(O)2NR c3 R d3 The substituents may be optionally substituted with one, two, or three substituents selected more independently.

[0022] In some embodiments, R X1 H, C 1-6 Alkyl and NR c3 R d3 Selected from, where C 1-6 Alkyl is Cy 2 Hello, 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 )NRc3 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)2R b3 , NR c3 S(O)2NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 S(O)2R b3 , and S(O)2NR c3 R d3 The substituents may be optionally substituted with one, two, or three substituents selected more independently.

[0023] In some embodiments, R X1 The methyl group is selected from NH2. In some embodiments, R X1 It is NH2. In some embodiments, R X2 H is H. In some embodiments, R Y1 H is H. In some embodiments, R Y2 H is H.

[0024] In some embodiments, the compound of formula A1 is formula A2: [ka] It is indicated by or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula A1 is formula A2a or A2b: [ka] It is indicated by or a pharmaceutically acceptable salt thereof.

[0025] In some embodiments, the compound of formula A1 is formula A3a, A3b, or A3c: [ka] It is indicated by or a pharmaceutically acceptable salt thereof.

[0026] In some embodiments, compounds of formula A1 are: (3aR,5r,6aS)-2-(6-amino-5-(2-chloro-3-methylphenyl)pyrazine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-amine; (3aR,5r,6aS)-2-(6-amino-5-(2,3-dichlorophenyl)pyrazine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-amine; (3aR,5r,6aS)-2-(6-amino-5-(2-chloro-3-fluorophenyl)pyrazine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-amine; (3aR,5r,6aS)-2-(6-amino-5-(2-chloropyridine-3-yl)pyrazine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-amine; (3aR,5r,6aS)-2-(6-amino-5-(3-chloro-2-fluorophenyl)pyrazine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-amine; 3aR,5r,6aS)-2-(6-amino-5-(2-chloro-3-(trifluoromethyl)phenyl)pyrazine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-amine; (3aR,5s,6aS)-2-(6-amino-5-(2,3-dichlorophenyl)pyrazine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-amine; (3aR,5s,6aS)-2-(6-amino-5-(2-chloro-3-methylphenyl)pyrazine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-amine; 6-((3aR,5r,6aS)-5-(aminomethyl)-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-yl)-3-(2,3-dichlorophenyl)pyrazine-2-amine; 6-((3aR,5s,6aS)-5-(aminomethyl)-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-yl)-3-(2,3-dichlorophenyl)pyrazine-2-amine; (3aR,5r,6aS)-2-(4-amino-5-(2-chloro-3-methylphenyl)pyrimidine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-amine; (3aR,5r,6aS)-2-(4-amino-5-(2,3-dichlorophenyl)pyrimidine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-amine; (3aR,5r,6aS)-2-(4-amino-5-(2-chloro-3-fluorophenyl)pyrimidine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-amine; and (3aR,5r,6aS)-2-(4-amino-5-(2-chloropyridine-3-yl)pyrimidine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-amine; or a pharmaceutically acceptable salt thereof More likely to be selected.

[0027] Formula B1: [ka] [In the formula: R 1 , L, Y 1 , Y 2 , R 8 , and R 9 [This is defined according to any embodiment described herein.] Compounds shown in are also provided. In some embodiments, R8 and R 9 One of the compounds is methyl, and the other is amino. Compounds of formula B1 can be prepared by a method similar to the synthetic route shown in the scheme described herein.

[0028] Formula C1: [ka] [In the formula: R 1 L, X 1 , X 2 , Y 1 , R 8 , and R 9 [This is defined according to any embodiment described herein.] Compounds shown in are also provided. In some embodiments, R 8 and R 9 One of the compounds is methyl, and the other is amino. Compounds of formula C1 can be prepared by a method similar to the synthetic route shown in the scheme described herein.

[0029] Formula D1: [ka] [In the formula: R 1 L, X 1 , Y 1 , Y 2 , R 8 , and R 9 [This is defined according to any embodiment described herein.] Compounds shown in are also provided. In some embodiments, R 8 and R 9 One of the compounds is methyl, and the other is amino. Compounds of formula D1 can be prepared by a method similar to the synthetic route shown in the scheme described herein.

[0030] In one embodiment, the present invention relates to formula I: [ka] [In formula: Y 1 It is selected from CH and N; Y 2 CR 12 and selected from N; Y 3 NH and CR 8 R 9 More selected; R 1 The group is selected from (C6-C10)aryl, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl, and 5-9 membered heteroaryl groups containing 1 to 4 heteroatoms selected from N, O, and S; where the aryl or heteroaryl is 1 to 5 R 10 The base may be substituted as desired; R 2a and R 2b Each of these is independently selected from hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, amino, hydroxy, (C3-C8)cycloalkyl, (C1-C4)alkyl-amino, and di(C1-C4)alkyl-amino; R 3 These are hydrogen, fluoro, or (C1-C4) alkyl; R 4a and R 4b Each of these is independently selected from hydrogen, halo, carbonyl, (C1-C4)alkyl, (C1-C4)alkoxy, amino, hydroxy, (C3-C8)cycloalkyl, (C1-C4)alkylamino, and di(C1-C4)alkylamino; R 5a and R 5b Each of these is independently selected from hydrogen, halo, carbonyl, (C1-C4)alkyl, (C1-C4)alkoxy, amino, hydroxy, (C3-C8)cycloalkyl, (C1-C4)alkylamino, and di(C1-C4)alkylamino; R 6 This is selected from hydrogen, fluoro, or (C1-C4) alkyl; R 7a and R 7bEach of these is independently selected from hydrogen, carbonyl, (C1-C4)alkyl, (C1-C4)alkoxy, amino, hydroxy, (C3-C8)cycloalkyl, (C1-C4)alkylamino, and di(C1-C4)alkylamino; R 8 This is selected from a 5-9 membered heteroaryl group containing hydrogen, (C1-C4) alkyl, (C3-C6) cycloalkyl, (C6-10) aryl, and 1-4 heteroatoms selected from N, O, and S; R 9 These are selected from NH2, (C1-C4)alkylamino, di(C1-C4)alkylamino, NH2-(CH2)-, (C1-C4)alkyl-NH-(CH2)-, and di[(C1-C4)alkyl]N-(CH2)-; Each R 10 This includes halo, amino, hydroxy, N3, (C1-C4) alkyl, hydroxy-substituted (C1-C4) alkyl, halo-substituted (C1-C4) alkyl, amino-substituted (C1-C4) alkyl, and -C(O)OR. 11 and -NHC(O)R 11 Selected more independently; Each R 11 is independently selected from hydrogen, phenyl, and naphthyl; where phenyl may optionally be substituted with methoxy; R 12 This includes hydrogen, halo, cyano, (C1-C4) alkyl, (C1-C4) alkoxy, amino-carbonyl, halo-substituted (C1-C4) alkyl, halo-substituted (C1-C4) alkoxy, hydroxy-substituted (C1-C4) alkyl, amino-substituted (C1-C4) alkyl, and -S(=O)R 12a , -SO2R 12a -C(=S)R 12a -C(=O)NR 12a R 12b -C(NH)NR 12a R 12b and -NR 12a C(=O)R 12b Selected from; here each R 12a and R 12b [The element is independently selected from hydrogen and (C1-C4) alkyl groups.] Compounds represented by or pharmaceutically acceptable salts thereof are provided herein.

[0031] One aspect of the present invention is Y 1 N is Y 2 CR 12 And R 12 is hydrogen; Y 3 CR 8 R 9 And; R 1 R has 1 or 2 10 This relates to a compound of formula I, which is a (C6-C10) aryl group that may be optionally substituted at the base. Another aspect of the present invention is that each R 10 This relates to the compound of formula I, in which the group is independently a halo.

[0032] Another aspect of the present invention is that each R 10 This relates to compounds of formula I, where the group is independently chloro or fluoro. Another aspect of the present invention is Y 3 CR 8 R 9 And; R 8 This relates to compounds of formula I in which is hydrogen or (C1-C4) alkyl. Another aspect of the present invention is Y 3 CR 8 R 9 And; R 9 This relates to compounds of formula I, where is selected from amino, amino-methyl, and methyl-amino.

[0033] One aspect of the present invention is [ka] This relates to the compound indicated by or its pharmaceutically acceptable salts. Another embodiment of the present invention is, [ka] This relates to the compound indicated by or its pharmaceutically acceptable salts. Another embodiment of the present invention is, [ka] This relates to the compound indicated by or its pharmaceutically acceptable salts.

[0034] Another embodiment of the present invention is, [ka] This relates to the compound indicated by or its pharmaceutically acceptable salts. Another embodiment of the present invention is, [ka] This relates to the compound indicated by or its pharmaceutically acceptable salts. Another embodiment of the present invention is, [ka] This relates to the compound indicated by or its pharmaceutically acceptable salts.

[0035] In yet another embodiment, the present invention provides a method for producing the compounds of the present invention, their prodrug derivatives, protective derivatives, individual isomers and mixtures of isomers, and pharmaceutically acceptable salts thereof.

[0036] Furthermore, to clarify, certain features of the present invention, described in the form of separate embodiments, can also be provided in combination in a single embodiment (although these embodiments are described as being combined, they are described as if they were complexly dependent). In contrast, for the sake of brevity, various features of the present invention, described in the form of a single embodiment, can be provided separately or in any appropriate subcombination. Thus, it is thought that the features described as embodiments of the compounds of the present invention can be combined in any appropriate combination.

[0037] In various parts of this specification, certain characteristics of compounds are disclosed in the form of groups or ranges. Specifically, such disclosures shall encompass all individual subcombinations of members within such groups or ranges. For example, "C 1-6 The term "alkyl" specifically refers to (without limitation) methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl, respectively.

[0038] The general terms used above and below will be well understood by those skilled in the art and, unless otherwise specified, preferably within the context of this disclosure. More general terms used anywhere may be used independently, replaced with more specific definitions, or used in more detailed embodiments of the present invention:

[0039] The term "n-membered" (where n is an integer) typically describes the number of ring-forming atoms in a part of the ring where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydronaphthalene is an example of a 10-membered cycloalkyl group.

[0040] Variable groups defining divalent linking groups may be described in various places in this specification. Each linking substituent is specifically intended to encompass both the forward and backward forms of the linking substituent. For example, -NR(CR'R'') n - is -NR(CR'R'') n -and-(CR'R'') n Both NR- forms are included, and each form is disclosed individually. If a structure requires a linking group, the Markush variable groups listed for that group are understood to be linking groups. For example, if a structure requires a linking group and the definition of a Markush group for that variable group includes "alkyl" or "aryl", then the "alkyl" or "aryl" is understood to indicate the linking alkylene group or arylene group, respectively.

[0041] The term "substituted" means that an atom or group of atoms formally replaces a hydrogen atom as a "substituent" bonded to another group. Unless otherwise specified, "substituted" can refer to any level of substitution where such substitution is permissible, such as mono, di, tri, tetra, or penta substitutions. Substituents are independently selected, and substitutions may occur at any chemically available position. It should be recognized that substitutions at a given atom are limited by their valence. It should be recognized that substitutions at a given atom result in a chemically stable molecule. The phrase "may be substituted as desired" means either unsubstituted or substituted. The phrase "substituted" means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, such as an oxo substituent, can replace two hydrogen atoms.

[0042] "C n-m The phrase "n" suggests a range of carbon atoms, where n and m are integers, including the endpoint. For example, C 1-4 , C 1-6 These are some examples.

[0043] The term "alkyl," used alone or in combination with other terms, refers to a saturated hydrocarbon group, which may be straight-chain or branched. n-mThe term "alkyl" refers to an alkyl group having n to m carbon atoms. Formally, an alkyl group corresponds to an alkane in which one CH bond is replaced by an attachment site with the remainder of the alkyl compound. Formally, an alkyl group corresponds to an alkane in which one CH bond is replaced at the attachment site with the residue of the alkyl compound. In some embodiments, the alkyl group contains 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; and higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, etc.

[0044] The term "alkenyl," used alone or in combination with other terms, refers to a linear or branched hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon double bonds. Formally, an alkenyl group corresponds to an alkene, where one CH bond is replaced by an attachment site with the remainder of the compound. n-m The term "alkenyl" refers to an alkenyl group having n to m carbon atoms. In some embodiments, the alkenyl portion contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, and sec-butenyl.

[0045] The term "alkynyl," used alone or in combination with other terms, refers to a linear or branched hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon triple bonds. Formally, an alkynyl group corresponds to an alkyne, where one CH bond is replaced by an attachment site with the remainder of the compound of the alkynyl group. n-mThe term "alkynyl" refers to an alkynyl group having n to m carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propyne-1-yl, propyne-2-yl, etc. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0046] The term "alkylene," used alone or in combination with other terms, refers to a divalent alkyl linking group. Formally, an alkylene group corresponds to an alkane, where two CH bonds are replaced by bonding sites with the remainder of the alkylene compound. n-m The term "alkylene" refers to an alkylene group having n to m carbon atoms. Examples of alkylene groups include, but are not limited to, ethane-1,2-diyl, ethane-1,1-diyl, propane-1,3-diyl, propane-1,2-diyl, propane-1,1-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, and 2-methylpropane-1,3-diyl.

[0047] The term "alkoxy," used alone or in combination with other terms, refers to a group represented by the formula:-O-alkyl, where the alkyl group is as defined above. n-m The term "alkoxy" refers to an alkoxy group in which the alkyl group has n to m carbon atoms. Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, etc. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. n-m The term "dialkoxy" is derived from the formula: -O-(C n-m A linking group represented by alkyl)-O-, where the alkyl group has n to m carbon atoms. Examples of dialkoxy groups include -OCH2CH2O- and -OCH2CH2CH2O-. In some embodiments, C n-m The two oxygen atoms of the dialkoxy group may bond to the same carbon atom to form a 5- or 6-membered heterocycloalkyl group.

[0048] The term "amino" refers to the group represented by the formula -NH2. The term "carbonyl," used alone or in combination with other terms, refers to a -C(=O)- group, which can also be written as C(O). The terms "cyano" or "nitrile" refer to the group represented by the formula -C≡N, which can also be written as -CN.

[0049] The terms “halo” or “halogen,” used alone or in combination with other terms, refer to fluoro, chloro, bromo, and iodine. In some embodiments, “halo” refers to a halogen atom selected from F, Cl, or Br. In some embodiments, the halo atom is F.

[0050] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are substituted with halogen atoms. n-m The term "haloalkyl" refers to a C11 alkyl group that has n to m carbon atoms and at least 1 to {2(n to m) + 1} halogen atoms (which may be the same or different). n-m This refers to an alkyl group. In some embodiments, the halogen atom is a fluoro atom. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms. Examples of haloalkyl groups include CF3, C2F5, CHF2, CH2F, CCl3, CHCl2, C2Cl5, etc. In some embodiments, the haloalkyl group is a fluoroalkyl group.

[0051] The term "haloalkoxy," used alone or in combination with other terms, refers to a group represented by the formula:-O-haloalkyl, where the haloalkyl group is as defined above. n-mThe term "haloalkoxy" refers to a haloalkoxy group in which the haloalkyl group has n to m carbon atoms. Examples of haloalkoxy groups include trifluoromethoxy. In some embodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0052] The term "oxo" refers to a divalent oxygen atom that forms a carbonyl group when bonded to carbon, and a sulfoxide, sulfone, or N-oxide group when bonded to a heteroatom. In some embodiments, the heterocyclic group may be optionally substituted with one or two oxo (=O) substituents.

[0053] The term "sulfide" refers to a sulfur atom as a divalent substituent that, when bonded to carbon, forms a thiocarbonyl group (C=S). In relation to the N atoms that form a ring, the term "oxidized" refers to the N-oxide that forms the ring. In relation to the sulfur atoms forming a ring, the term "oxidized" refers to the sulfonyl or sulfinyl atoms that form the ring.

[0054] The term "aromatic" refers to a carbon ring or heteroring that has one or more polyvalent unsaturated rings that possess aromatic properties (i.e., it has (4n+2) delocalized π electrons, where n is an integer).

[0055] The term "aryl," used alone or in combination with other terms, refers to an aromatic hydrocarbon group that may be monocyclic or polycyclic (for example, a ring having two fused rings). n-m The term "aryl" refers to an aryl group having n to m ring carbon atoms. Examples of aryl groups include phenyl, naphthyl, etc. In some embodiments, the aryl group has 6 to about 10 carbon atoms. In some embodiments, the aryl group has 6 carbon atoms. In some embodiments, the aryl group has 10 carbon atoms. In some embodiments, the aryl group is phenyl.

[0056] The terms “heteroaryl” or “heteroaromatic,” used alone or in combination with other terms, refer to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl ring has one, two, three, or four heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, any of the ring-forming N in the heteroaryl portion may be N-oxide. In some embodiments, the heteroaryl has 5–14 ring atoms, including a carbon atom and one, two, three, or four heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl has 5–10 ring atoms, including a carbon atom and one, two, three, or four heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl has 5–6 ring atoms and one or two heteroatoms independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a six-membered or five-membered heteroaryl ring. In other embodiments, the heteroaryl is an eight-membered, nine-membered, or ten-membered fused bicyclic heteroaryl ring. Examples of heteroaryl groups include, but are not limited to, pyridinyl (pyridyl), pyrimidinyl, pyrazinyl, pyridadinyl, pyrrolyl, pyrazolyl, azolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl, quinolinyl, isoquinolinyl, naphthylidinyl (including 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3- and 2,6-naphthyridines), indolyl, isoindolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, prinyl, and the like.

[0057] A five-membered heteroaryl ring is a heteroaryl group having five ring atoms, where one or more (e.g., one, two, or three) ring atoms are independently selected from N, O, and S. Heteroaryl rings of five members include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.

[0058] A six-membered heteroaryl ring is a heteroaryl group having six ring atoms, where one or more (e.g., one, two, or three) ring atoms are independently selected from N, O, and S. Six-membered heteroaryl rings include pyridyl, pyrazinyl, pyrimidinyl, triazinyl, isoindolyl, and pyridazinyl.

[0059] The term "cycloalkyl," used alone or in combination with other terms, refers to a non-aromatic hydrocarbon ring system (monocyclic, dicyclic, or polycyclic ring system) containing cyclic alkyl and alkenyl groups. n-m The term "cycloalkyl" refers to a cycloalkyl group having n to m ring-member carbon atoms. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spiro rings. Cycloalkyl groups have 3, 4, 5, 6, or 7 ring-forming carbon atoms (C 3-7) may have. In some embodiments, a cycloalkyl group has 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some embodiments, a cycloalkyl group is a monocyclic group. In some embodiments, a cycloalkyl group is a monocyclic or dicyclic group. In some embodiments, a cycloalkyl group is a C3-6 monocyclic cycloalkyl group. The ring-forming carbon atoms of a cycloalkyl group may optionally be oxidized to form oxo or sulfide groups. Cycloalkyl groups also include cycloalkylides. In some embodiments, a cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. A moiety having one or more aromatic rings condensed with (i.e., sharing a common bond with) a cycloalkyl ring, such as benzo or thienyl derivatives like cyclopentane or cyclohexane, is also included in the definition of a cycloalkyl group. A cycloalkyl group containing a condensed aromatic ring may be bonded via any ring-forming atom, including the ring-forming atom of the condensed aromatic ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbonyl, norpinyl, norcarnyl, bicyclo[1.1.1]pentanyl, and bicyclo[2.1.1]hexanyl. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0060] The term “heterocycloalkyl,” used alone or in combination with other terms, refers to a non-aromatic ring or ring system having at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen, and phosphorus, and having 4–10 ring members, 4–7 ring members, or 4–6 ring members, which may optionally contain one or more alkenylene groups as part of the ring structure. Heterocycloalkyl groups can include monocyclic or bicyclic ring systems (e.g., having two fused or bridging rings) or spirocyclic ring systems. In some embodiments, the heterocycloalkyl group is a monocyclic group having one, two, or three heteroatoms independently selected from nitrogen, sulfur, and oxygen. The carbon atoms and heteroatoms forming the ring of the heterocycloalkyl group may optionally be oxidized to form oxo or sulfide groups or other oxidative bonds (e.g., C(O), S(O), C(S), or S(O)2, N-oxide, etc.), or the nitrogen atom may be quaternized. Heterocycloalkyl groups can be bonded via ring-forming carbon atoms or ring-forming heteroatoms. In some embodiments, heterocycloalkyl groups contain 0 to 3 double bonds. In some embodiments, heterocycloalkyl groups contain 0 to 2 double bonds. Moles having one or more aromatic rings fused with (i.e., sharing a common bond with) a heterocycloalkyl ring, such as benzo or thienyl derivatives like piperidine, morpholine, or azepine, are also included in the definition of heterocycloalkyl groups. Heterocycloalkyl groups containing fused aromatic rings can be bonded via any ring-forming atoms, including the ring-forming atoms of the fused aromatic ring.

[0061] In some cases, the definition or embodiment refers to a specific ring (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise specified, these rings may bond with any of their ring members, provided that the valence of the atoms is not exceeded. For example, an azetidine ring may bond at any position on its ring, while an azetidine-3-yl ring bonds at the 3-position.

[0062] In some embodiments associated with compounds of formula I, “alkyl” refers to a fully saturated branched or linear hydrocarbon moiety having up to 20 carbon atoms. Unless otherwise specified, alkyl refers to a hydrocarbon moiety having 1 to 7 carbon atoms (C1-C7 alkyl) or 1 to 4 carbon atoms (C1-C4 alkyl). Representative examples of alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tery-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. Substitutive alkyls are alkyl groups containing one or more substituents, such as 1, 2, or 3, selected from halogen, hydroxy, or alkoxy groups.

[0063] In embodiments associated with some compounds of formula I, the term "carbonyl" as used herein refers to the C=O functional group and includes aldehydes (HC=O)-. In some embodiments associated with compounds of formula I, the "halogen" (or "halo") is preferably chloro or fluoro, but may also be bromo or iodine.

[0064] In embodiments associated with several compounds of formula I, the halo-substituted alkyl and halo-substituted alkoxy can be either linear or branched, and include methoxy, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, etc.

[0065] In some embodiments associated with compounds of formula I, "aryl" means a monocyclic or fused bicyclic aromatic ring assembly containing 6 to 10 ring carbon atoms. For example, the aryl may be phenyl or naphthyl, and is preferably phenyl.

[0066] In some embodiments associated with compounds of formula I, "arylene" refers to a divalent group derived from an aryl group. The aryl group may be optionally substituted with 1 to 5 suitable substituents such as alkyl or halo.

[0067] In embodiments associated with some compounds of formula I, "heteroaryl" is defined as above for aryls, wherein one or more ring members are heteroatoms. For example, a (C5-C10) heteroaryl consists of members represented by at least five carbon atoms, but these carbon atoms can be replaced by heteroatoms. As a result, (C5-C10) heteroaryls include pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzo[1,3]dioxole, imidazolyl, benzimidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, thienyl, etc. The heteroaryl group may optionally be substituted with one to five suitable substituents such as alkyl or halo.

[0068] In some embodiments associated with compounds of Formula I, "cycloalkyl" means a monocyclic, fused, dicyclic, or crosslinked polycyclic assembly containing the indicated number of ring atoms, whether saturated or partially unsaturated. For example, (C3-C10)cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, and the like. The cycloalkyl group may be optionally substituted with 1 to 5 suitable substituents, such as alkyl or halo.

[0069] In embodiments associated with some compounds of formula I, “heterocycloalkyl” means a cycloalkyl as defined herein, but in which one or more of the indicated ring carbons are replaced by a moiety selected from -O-, -N=, -NR-, -C(=O)-, -S-, -S(=O)-, or -SO2- (where R is hydrogen, (C1-C4) alkyl, or nitrogen protecting group). For example, (C3-C8) heterocycloalkyls used herein include morpholino, pyrrolidinyl, pyrrolidinyl-2-one, piperazinyl, piperidinyl, piperidinylone, 1,4-dioxa-8-aza-spiro[4.5]deca-8-yl, thiomorpholino, sulfanomorpholino, sulfonomorpholino, etc. The heterocycloalkyl group may optionally be substituted with 1 to 5 suitable substituents such as alkyl or halo.

[0070] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise specified, all stereoisomers, such as enantiomers and diastereomers, are intended. Compounds of the present invention containing asymmetrically substituted carbon atoms may be isolated in optically active forms or in racemic forms. Methods for producing optically active forms from optically inert starting materials are known in the art, such as by dividing racemic mixtures or by stereoselective synthesis. Many geometric isomers, such as olefins and C=N double bonds, may also exist in the compounds described herein, and all such stable isomers are intended in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as mixtures of isomers or as separated isomers.

[0071] The separation of racemic mixtures of compounds can be carried out by any of the many methods known in the art. One method involves fractional crystallization using chiral splitting acids, which are optically active organic acids that form salts. Suitable splitting agents for use in fractional crystallization are optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids such as β-camphorsulfonic acid in D and L forms. Other splitting agents suitable for fractional crystallization include stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycenol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[0072] Racemic mixtures can also be separated by elution using a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). The appropriate composition of the elution solvent can be determined by those skilled in the art.

[0073] In some embodiments, the compounds of the present invention have an (R) configuration. In other embodiments, the compounds have an (S) configuration. In compounds having two or more chiral centers, each chiral center in the compound may independently be (R) or (S) unless otherwise specified.

[0074] The compounds of the present invention may have an asymmetric carbon atom and may exist as two or more stereoisomers. The carbon-carbon bond of the compound of formula I is shown herein by a solid line. [ka] wedge-shaped solid line [ka] or a wedge-shaped dotted line [ka] The following are used to describe the relationships between chiral carbon atoms. Using a solid line to describe a bond with a chiral carbon atom is intended to include all possible stereoisomers of that carbon atom (e.g., specific enantiomers, racemic mixtures, etc.). Using either a wedge-shaped solid line or a dotted line to describe a bond with a chiral carbon atom indicates that only the indicated stereoisomers are included. The compounds of the present invention may contain two or more chiral carbon atoms. In such compounds, using a solid line to describe a bond with a chiral carbon atom indicates that all possible stereoisomers are included. For example, unless otherwise specified, the compounds of the present invention may exist as enantiomers and diastereomers, or as racemates and mixtures thereof. Using a solid line to describe a bond with one or more chiral carbon atoms in a compound of the present invention, and using a wedge-shaped solid line or dotted line to describe a bond with other chiral carbon atoms in the same compound, indicates the presence of a mixture of diastereomers.

[0075] It will be understood that the compounds of the present invention are not limited to the specific enantiomers shown, but also include all stereoisomers and mixtures thereof.

[0076] One embodiment of the compound of formula I is: [ka] This is shown.

[0077] Stereoisomers include cis and trans isomers, optical isomers, e.g., R and S-enantiomers, diastereomers, geometric isomers, rotational isomers, conformational isomers, and tautomers of the compounds of the present invention (including compounds exhibiting two or more isomers; and mixtures thereof (such as racemates and diastereomer pairs)). Acid addition salts or base addition salts in which the counterion is optically active, e.g., d-lactate or l-lysine, or racemates, e.g., dl-tartrate or dl-arginine.

[0078] When any racemic mixture crystallizes, two different forms are possible in the crystal. The first form is the racemic compound (true racemic mixture) described above, which produces one homogeneous form of crystal containing equimolar amounts of both enantiomers. The second form is a racemic mixture or aggregate, which produces equimolar amounts of two forms of crystals, each containing a single enantiomer.

[0079] The compounds of the present invention may exhibit tautomerism and structural isomerism. For example, the compounds of the present invention may exist in the form of several tautomers, such as enol and imine forms, and keto and enamine forms, as well as geometric isomers and mixtures thereof. Such tautomer forms are included within the scope of the compounds of the present invention. Tautomers exist in solution as mixtures of tautomer pairs. In solid form, one tautomer is usually dominant. Even if one tautomer is described, the present invention encompasses all tautomers of the compounds of the present invention. Tautomer forms are obtained by exchanging a single bond with an adjacent double bond along with the simultaneous transfer of a proton. Tautomer forms include prototropic tautomers, which are isomer-protonated states having the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imoid acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions in the heterocyclic system, such as 1H- and 3H-imidazoles, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. The tautomer forms may be in equilibrium or sterically fixed to form 1 by appropriate substitution.

[0080] The present invention encompasses all compounds labeled with pharmaceutically acceptable isotopes in which one or more atoms are replaced by atoms having the same atomic number but different atomic mass and mass number from those predominantly found in nature.

[0081] Examples of isotopes suitable for inclusion in the compound of the present invention include: 2H and 3 Hydrogen such as H, 11 C, 13 C and 14 Carbon such as C, 36 Chlorine such as Cl 18 Fluorine such as F 123 I and 125 Iodine such as I 13 N and 15 Nitrogen such as N, 15 O, 17 O and 18 Oxygen such as O, 32 Phosphorus such as P, and 35 Examples include sulfur isotopes such as S.

[0082] Compounds labeled with specific isotopes of the present invention, such as compounds incorporating radioactive isotopes, are useful for studying the tissue distribution of drugs and / or substrates. The radioactive isotope tritium, i.e., 3 H, and carbon-14, i.e. 14 C is particularly useful for this purpose in terms of its ease of incorporation and its rapid detection means. Deuterium, i.e. 2 Substitution with heavier isotopes, such as 1H, may confer certain therapeutic benefits, such as greater metabolic stability, resulting in an increased half-life in vivo or a reduced dose, and thus may be preferable under certain circumstances. 11 C, 18 F, 15 O and 13 Positron-emitting isotopes such as 1N are useful in positron emission tomography (PET), a study used to test substrate receptor occupancy.

[0083] The isotope-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art, or by methods similar to those described in the following examples and preparations, using suitable isotope-labeled reagents instead of previously used unlabeled reagents. Synthetic methods for incorporating isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, NY, Appleton-Century-Crofts, 1971; The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey, and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotope-labeled compounds can be used in various studies, such as NMR spectroscopy, metabolic experiments, and / or assays.

[0084] Substitution with heavier isotopes, such as deuterium, may confer certain therapeutic benefits, such as greater metabolic stability, an increased in vivo half-life, or a reduced dose, and thus may be preferable under certain circumstances (A. Kerekes et al., J. Med. Chem. 2011, 54, 201-210; R. Xu et al., J. Label Compd. Radiopharm. 2015, 58, 308-312).

[0085] As used herein, the term “compound” encompasses all stereoisomers, geometric isomers, tautomers, and isotopes of the described structures. The term also refers to the compounds of the present invention, regardless of how they are produced, for example, by synthesis through biological processes (e.g., metabolic processes or enzymatic transformations) or a combination thereof.

[0086] All compounds and their pharmaceutically acceptable salts may exist together with other substances such as water and solvents (e.g., as hydrates and solvates), or may be isolated. When in a solid state, the compounds and salts described herein may occur in various forms, for example, as solvates, including hydrates. Unless otherwise explicitly stated, the compounds may be in any solid state, such as polymorphs or solvates, and references to compounds and their salts herein should be understood to encompass any solid state of the compound.

[0087] In some embodiments, the compounds of the present invention, or salts thereof, are substantially isolated. "Substantially isolated" means that the compound is separated at least partially, or substantially, from the environment in which it was formed or detected. Partial isolation may include, for example, compositions rich in the compounds of the present invention. Substantial isolation may include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds of the present invention, or salts thereof.

[0088] The term "medically acceptable" is used herein to mean, within the bounds of appropriate medical judgment, any compound, material, composition and / or dosage form that is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complicating factors, and with a reasonable and consistent benefit / risk ratio.

[0089] As used herein, the terms “ambient temperature” and “room temperature” are understood in the art to generally refer to the approximate temperature of the room in which the reaction takes place, for example, a temperature of about 20°C to about 30°C, or the reaction temperature.

[0090] The present invention also encompasses pharmaceutically acceptable salts of the compounds described herein. The term "pharmaceutically acceptable salt" means a derivative of a disclosed compound in which the parent compound is modified by converting the present acidic or base moiety into the form of a salt. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of basic residues such as amines with inorganic or organic acids; and alkali or organic salts of acidic residues such as carboxylic acids. The pharmaceutically acceptable salts of the present invention also encompass non-toxic salts of parent compounds formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be produced by reacting the free acid or base of these compounds with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture thereof; Generally, non-aqueous media such as ether, ethyl acetate, alcohol (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile (MeCN) are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th Ed., (Mack Publishing Company, Easton, 1985), p. 1418; Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19; and Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley, 2002). In some embodiments, the compounds described herein encompass N-oxide forms.

[0091] The compounds of the present invention may exist in the form of pharmaceutically acceptable salts, such as acid addition salts and base addition salts of the compounds of the present invention. As used herein, the term "pharmaceutically acceptable salt" includes salts of acidic or basic groups that may be present in the compounds of the present invention. The compounds of the present invention also include N-oxides and / or tautomers thereof of such compounds.

[0092] Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, cansylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, Examples include salts of lactate, maleate, maleate, malonate, mesylate, methyl sulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinawheate.

[0093] Suitable base addition salts are formed from bases that form non-toxic salts. Examples include salts of aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc. Hemi salts of acids and bases, such as hemisulfates and hemicalcium salts, can also be formed.

[0094] For information on appropriate salts, refer to Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Stahl and Wermuth (Wiley-VCH, 2002). As used herein, the terms “Formula I” and “Formula I or any pharmaceutically acceptable salt thereof” are defined to encompass all forms of the compound of Formula I, including its hydrates, solvates, isomers, crystalline and amorphous forms, isomorphs, polymorphs, metabolites, and prodrugs.

[0095] The present invention also relates to prodrugs of the compounds of the present invention. Certain derivatives of such compounds of the present invention that, when administered internally or applied externally, themselves have little or no pharmacological activity can be converted to the compounds of the present invention having desired activity, for example, by hydrolysis. Such derivatives are referred to as “prodrugs.” Further information on the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (Ed. E. Roche, American Pharmaceutical Association).

[0096] The prodrugs according to the present invention can be produced, for example, by replacing a suitable functional group present in the compound of the present invention with a specific part known to those skilled in the art as a "pro part," as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).

[0097] Some examples of prodrugs according to the present invention include, but are not limited to: (i) The compound of the present invention contains a carboxylic acid functional group to which a functional group is appropriately affixed to a metabolically unstable group (such as an ester or carbamate); (ii) When the compound of the present invention contains an alcohol functional group to which a functional group is appropriately affixed to a metabolically unstable group (ether, ester, carbamate, acetal, ketal, etc.); and (iii) When the compound of the present invention contains a first or second amino functional group or an amide, which is appropriately functionalized to a metabolically unstable group, for example, a hydrolyzable group (amide, carbamate, urea, phosphonate, sulfonate, etc.). It includes.

[0098] Further examples of substituents following the above example, as well as examples of other prodrug types, can be found in the references mentioned above. Furthermore, certain compounds of the present invention can themselves act as prodrugs of other compounds of the present invention. Metabolites of the compounds of the present invention, i.e., compounds formed in vivo after drug administration, are also included within the scope of the invention.

[0099] Hereafter, all references to the compounds of the present invention include references to their salts, solvates, multicomponent complexes and liquid crystals, as well as references to salts of their solvates, multicomponent complexes and liquid crystals.

[0100] The compounds of the present invention include the compounds of the invention, including all of their polymorphs and crystalline phases as described above, their prodrugs and isomers (including optical isomers, geometric isomers and tautomers) as described below, and isotope-labeled compounds of the present invention.

[0101] synthesis The compounds of the present invention, including their salts, can be produced using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes, such as the synthetic route shown in the scheme below.

[0102] The reactions for producing the compounds of the present invention can be carried out in suitable solvents that can be readily selected by those skilled in the art in the field of organic synthesis. Suitable solvents can be those that are substantially inactive with the starting materials (reactants), intermediates, or products at the reaction temperature, for example, in the range from the freezing temperature to the boiling temperature. A given reaction can be carried out in one solvent or in a mixture of more than one solvent. Depending on the individual reaction step, those skilled in the art can select suitable solvents for each step.

[0103] The preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be easily determined by those skilled in the art. The chemical properties of protecting groups are described, for example, in Kocienski, Protecting Groups (Thieme, 2007); Robertson, Protecting Group Chemistry (Oxford University Press, 2000); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Ed. (Wiley, 2007); Peturssion et al., "Protecting Groups in Carbohydrate Chemistry" J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed. (Wiley, 2006).

[0104] The reaction can be monitored according to any appropriate method known in the field. For example, product formation can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) It can be monitored by spectroscopic means such as infrared spectroscopy, spectrophotometric methods (e.g., UV-Vis spectroscopy), and mass spectroscopy, or by chromatographic methods such as high-performance liquid chromatography (HPLC) or thin-layer chromatography (TLC).

[0105] The following scheme provides general guidance related to the production of the compounds of the present invention. Those skilled in the art will understand that the production shown in the scheme can be modified or optimized using general knowledge of organic chemistry to produce various compounds of the present invention.

[0106] The compound of formula A1 can be prepared, for example, by the method shown in scheme 1. Scheme 1 [ka]

[0107] Chloride S-3 can be produced from compounds of formulas S-1 and S-2 using cross-coupling methods such as Suzuki (in the presence of a palladium cycle catalyst precursor such as Xphos Pd G2) or Stille (in the presence of a palladium catalyst such as (PPh3)2PdCl2 and a base such as triethylamine). Compound S-3 can then be coupled with amine S-4 in the presence of a base (e.g., cesium carbonate) to obtain octahydrocyclopenta[c]pyrrole S-5.

[0108] In addition, the compounds described herein may be prepared according to the following reaction scheme and subsequent commentary. Unless otherwise noted, the variable groups of the above formulas are as described above in the reaction scheme and subsequent commentary. In general, the compounds of the present invention may be prepared by methods including methods similar to those known in the field of chemistry, taking into consideration the descriptions contained herein in particular. Specific methods for preparing the compounds of the present invention are provided as further features of the invention and are described in the following reaction scheme. Other methods are described in the experimental section.

[0109] First, it should be noted that in producing the compounds of the present invention, some of the production methods useful for producing the compounds described herein may require protection of remote functional groups (e.g., primary amines, secondary amines, carboxyls present in the precursor). The need for such protection will vary depending on the characteristics of the remote functional groups and the conditions of the production method. The requirements for such production can be readily determined by those skilled in the art. The use of such protection / deprotection is also within the scope of the art. For a general description of protecting groups and their use, see TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0110] For example, certain compounds contain primary amines or carboxylic acids that, if left unprotected, might interfere with the reaction at other sites on the molecule. Therefore, such functional groups may be protected with suitable protecting groups that can be removed in subsequent steps. Suitable protecting groups for amines and carboxylic acids include those commonly used in peptide synthesis (for amines, Nt-butoxycarbonyl, benzyloxycarbonyl, and 9-fluorenylmethyleneoxycarbonyl; and for carboxylic acids, lower alkyl or benzyl esters, etc.) that, under the described reaction conditions, are generally not chemically reactive and can typically be removed without chemically altering other functional groups on the compound.

[0111] Scheme 2 [ka]

[0112] Scheme 3 [ka]

[0113] Scheme 4 [ka]

[0114] Regarding scheme 2, the coupling between borate and halo-pyrazine is R 1 and Y 1 and Y 2 It is understood to be comprehensive, encompassing the range of R. Similarly, X and Z are R 8 and R 9 It shall extend to the scope of. Schemes 3 and 4 describe the preparation of AF intermediates that can be converted to the final product by methods generally well known to those skilled in the art.

[0115] Compounds of the present invention having a chiral center may exist as stereoisomers such as racemates, enantiomers, or diastereomers. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from a suitable optically pure precursor, or separation of a racemate using, for example, chiral high-pressure liquid chromatography (HPLC). Alternatively, a racemate (or racemic precursor) may be reacted with a suitable optically active compound, such as an alcohol, or, if the compound contains an acidic or basic moiety, with an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomer mixture may be separated by chromatography and / or fractional crystallization, and one or both of the diastereomers may be converted to the corresponding pure enantiomer by means well known to those skilled in the art. Chiral compounds (and their chiral precursors) can be obtained in enantiomer-rich forms using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of hydrocarbons (typically heptane or hexane containing 0-50% (typically 2-20%) isopropanol and 0-5% alkylamine (typically 0.1% diethylamine)). The eluate is concentrated to obtain a concentrated mixture. Conglomerates of stereoisomers may be separated by conventional techniques known to those skilled in the art. See, for example, E.L. Eliel, "Stereochemistry of Organic Compounds" (Wiley, New York, 1994) (its disclosure is incorporated herein by attribution).

[0116] If the compounds of the present invention contain an alkenyl or alkenylene group, cis / trans (or Z / E) geometric isomers are possible. The cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization. The salts of the present invention can be prepared according to methods well known to those skilled in the art.

[0117] The compounds of the present invention, which are inherently basic, have the ability to form a wide variety of salts with various inorganic and organic acids. While such salts must be pharmaceutically acceptable for administration to animals, in practice, it is often preferable to first isolate the compounds of the present invention from the reaction mixture as pharmaceutically unacceptable salts, then simply convert the latter back to a free base compound by treatment with an alkaline reagent, and subsequently convert the free base back into a pharmaceutically acceptable acid addition salt. Acid addition salts of the base compounds of the present invention can be produced by treating the base compound with substantially equivalent amounts of selected inorganic or organic acids in an aqueous solvent or a suitable organic solvent such as methanol or ethanol. Evaporation of the solvent yields the desired solid salt. The desired salt can be precipitated from the solution by adding a suitable inorganic or organic acid to the free base solution in an organic solvent.

[0118] Compounds that are inherently acidic have the ability to form base salts with various pharmaceutically acceptable cations. Examples of such bases include alkali metal or alkaline earth metal salts, particularly sodium and potassium salts. All of these salts are produced by conventional techniques. The chemical bases used as reagents to produce the pharmaceutically acceptable base salts of the present invention are bases that form non-toxic base salts with the acidic compounds of the present invention. These salts can be produced by any suitable method, for example, by treating a free acid with an inorganic or organic base such as an amine (first, second, or third amine), alkali metal hydroxide, or alkaline earth metal hydroxide. These salts can also be produced by treating the corresponding acidic compound with an aqueous solution containing the desired pharmaceutically acceptable cation, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be produced by mixing a lower alkanolic solution of the acidic compound with the desired alkali metal alkanoid, and then evaporating the resulting solution to dryness in the same manner as described above. In any case, it is preferable to use stoichiometric amounts of reagents to ensure the completeness of the reaction and the maximum yield of the desired final product.

[0119] If the compound of the present invention is a base, the desired pharmaceutically acceptable salt may be produced by any suitable method available in the art, for example, by treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid, or with an organic acid such as pyranosidylic acid (such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, glucuronic acid, or galacturonic acid), an alpha-hydroxy acid such as citric acid or tartaric acid, an amino acid such as aspartic acid or glutamic acid, an aromatic acid such as benzoic acid or cinnamic acid, or a sulfonic acid such as p-toluenesulfonic acid or ethanesulfonic acid.

[0120] In some embodiments, pharmaceutically acceptable salts are hydrochlorides, including, for example, hemi-hydrochlorides, mono-hydrochlorides, and di-hydrochlorides.

[0121] A pharmaceutically acceptable salt of the compound of the present invention may be obtained by one or more of the following three methods: (i) A method comprising the step of reacting a compound of the present invention with a desired acid or base; (ii) A method comprising the step of removing an acid- or base-unstable protecting group from a suitable precursor of the compound of the present invention using a desired acid or base, or opening a suitable cyclic precursor, such as a lactone or lactam; or (iii) A method comprising the steps of reacting a salt of the compound of the present invention with a suitable acid or base, or converting it to another salt using a suitable ion exchange column; It may be manufactured using [a specific method / technology].

[0122] All three methods are typically carried out in solution. The resulting salt may be precipitated and collected by filtration, or recovered by evaporating the solvent. The degree of ionization of the resulting salt may vary from fully ionized to nearly unionized. Polymorphs can be manufactured according to techniques well known to those skilled in the art.

[0123] The cis / trans isomers may be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from a suitable optically pure precursor, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-pressure liquid chromatography (HPLC).

[0124] Alternatively, the racemic mixture (or racemic precursor) may be reacted with a suitable optically active compound, such as an alcohol, or, if the compound contains an acidic or basic moiety, with a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomer mixture may be separated by chromatography and / or fractional crystallization, and one or both of the diastereomers may be converted to the corresponding pure enantiomers by means well known to those skilled in the art.

[0125] The chiral compounds of the present invention (and their chiral precursors) may be obtained in an enantiomer-rich form on an asymmetric resin using chromatography, typically HPLC, with a mobile phase consisting of hydrocarbons (typically heptane or hexane containing 0-50% by volume (typically 2-20% by volume) isopropanol and 0-5% by volume of alkylamine (typically 0.1% diethylamine)). The eluate is concentrated to obtain a concentrated mixture.

[0126] When any racemic mixture crystallizes, two different forms are possible in the crystal. The first form is the racemic compound (true racemic mixture) described above, which produces one homogeneous form of crystal containing equimolar amounts of both enantiomers. The second form is a racemic mixture or aggregate, which produces equimolar amounts of two forms of crystals, each containing a single enantiomer.

[0127] Both crystalline forms present in a racemic mixture have the same physical properties, although they may have different physical properties compared to a true racemic mixture. Racemic mixtures can be separated by conventional techniques known to those skilled in the art—see, for example, Stereochemistry of Organic Compounds, EL Eliel and SH Wilen (Wiley, 1994).

[0128] The present invention also encompasses isotope-labeled compounds of the present invention in which one or more atoms have the same atomic number but different atomic masses or mass numbers from those commonly found in nature. The isotope-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art, or by methods similar to those described herein, using appropriately isotope-labeled reagents instead of otherwise unlabeled reagents.

[0129] The prodrugs according to the present invention can be produced, for example, by replacing a suitable functional group present in the compound of the present invention with a specific part known to those skilled in the art as a "pro part," as described, for example, in Design of Prodrugs, H. Bundgaard (Elsevier, 1985).

[0130] SHP2 This disclosure provides a method for modulating (e.g., inhibiting) SHP2 activity by contacting SHP2 with the compounds of the present invention or pharmaceutically acceptable salts thereof. In some embodiments, contact may involve administering the compounds provided herein or pharmaceutically acceptable salts thereof to a patient.

[0131] In yet another embodiment, the present invention provides a method for treating a disease in which, in animals, preferably humans, modulation of SHP2 activity can prevent, inhibit or improve the pathological condition and / or symptoms of the disease, the method comprising administering to the animal, preferably human, a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. The compounds of the present disclosure may be used alone, in combination with other agents or therapeutic agents, or as adjuvants or neoadjuvants for treating a disease. Any of the compounds, including any embodiment of the present disclosure, may be used for the uses described herein.

[0132] In yet another embodiment, the present invention provides the use of the compounds of the present invention in the manufacture of pharmaceuticals for treating diseases in animals, in which SHP2 activity is involved in the pathogenesis and / or symptoms of the disease. As used herein, "SHP2" means "Src homology-2 phosphatase," and is also known as SH-PTP2, SH-PTP3, Syp, PTP1D, PTP2C, SAP-2, or PTPN11.

[0133] The following are some examples of "PTPN11 mutations" that induce cancer, but are not limited to: N58Y;D61Y,V;E69K;A72V,T,D;E76G,Q,K(ALL);G60A;D61Y;E69V;F71K;A72V;T73I;E76G,K;R289G;G503V(AML);G60R;D61Y,V,N;Y62D;E69K;A72T,V;T7 Examples include 3I;E76K, V, G, A, Q;E139D;G503A, R;Q506P(JMML);G60V;D61V;E69K;F71L;A72V;E76A(MDS);Y63C(CMML);Y62C;E69K;T507K(neuroblastoma);V46L;N58S;E76V(lung cancer);R138Q(melanoma);E76G(colon cancer).

[0134] In yet another embodiment, the present invention provides a method for treating a disease, wherein in animals, preferably humans, the modulation of SHP2 activity can prevent, inhibit or improve the pathological condition and / or symptoms of the disease, comprising administering to animals, preferably humans, a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, simultaneously or sequentially with an anticancer drug.

[0135] Src homology-2 phosphatase (SHP2) is a protein tyrosine phosphatase encoded by the PTPN11 gene that contributes to 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 pathway. SHP2 mediates the activation of Erk1 and Erk2 (Erk1 / 2, Erk)MAP kinases by receptor tyrosine kinases such as ErbB1, ErbB2, and c-Met.

[0136] SHP2 possesses two N-terminal Src homology 2 domains (N--SH2 and C--SH2), a catalytic domain (PTP), and a C-terminal tail. The two SH2 domains regulate the intracellular localization and functional regulation of SHP2. The molecule exists in an inactive structure that inhibits its own activity via a binding network involving the remainder from both the N--SH2 and PTP domains. In response to growth factor stimulation, SHP2 binds via its SH2 domain to specific tyrosine-phosphorylated sites on docking proteins such as Gab1 and Gab2. This binding induces a structural change that leads to the activation of SHP2.

[0137] Mutations in PTPN11 have been identified in several human diseases, including Noonan syndrome, Leopard syndrome, Curzon syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and cancers of the breast, lung, and colon. SHP2 is a key downstream signaling molecule for various receptor tyrosine kinases, including platelet-derived growth factor receptor (PDGF-R), fibroblast growth factor receptor (FGF-R), and epidermal growth factor receptor (EGF-R). SHP2 is also a key downstream signaling molecule for activating the mitochondrial-activated protein (MAP) kinase pathway, which can lead to cell transformation, a prerequisite for cancer development. Knockdown of SHP2 significantly inhibited cell proliferation in lung cancer cell lines with SHP2 mutations or EML4 / ALK translocations, as well as in EGFR-amplified lung and esophageal cancer cells. SHP2 is also activated downstream of oncogenes in gastric cancer, anaplastic large cell lymphoma, and gliablastoma.

[0138] Diseases and disorders that can be treated or prevented by administering the compounds of the present invention to patients in need include, for example, Noonan syndrome, Leopard syndrome, Cruzon syndrome, Jackson-Weiss syndrome, Beare-Stevenson-Curtis-Gyrate, Apert syndrome, Pfeiffer syndrome, and Muenck syndrome. Examples include: syndrome, Setzle-Kotzen syndrome, chondrodysplasia, SADDAN (severe chondrodysplasia with growth retardation and acanthosis nigricans), type I fatal dysplasia, type II fatal dysplasia, chondrodysplasia, Kallmann syndrome, myeloproliferative syndrome, juvenile myelomonocytic leukemia, multiple myeloma, 8P11 myeloproliferative syndrome (EMS), pancreatic adenocarcinoma, prostate cancer, astrocytoma, transitional cell carcinoma of the bladder, thyroid cancer, cervical cancer, colorectal cancer, peripheral T-cell lymphoma, seminomas, neuroblastoma, melanoma, acute myeloid leukemia, chronic myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma, and gliablastoma.

[0139] Noonan syndrome (NS) and Leopard syndrome (LS) -- PTPN11 mutations cause LS (multiple lentigenes, electrocardiogram conduction abnormalities, binocular eccentricity, pulmonary valve stenosis, genital abnormalities, developmental delay, sensorineural hearing loss) and NS (congenital abnormalities including cardiac defects, craniofacial abnormalities, and dwarfism). These disorders are both part of a range of autosomal dominant syndromes caused by germline mutations in components of the RAS / RAF / MEK / ERK mitogen-activated protein kinase pathway, which are necessary for normal cell proliferation and differentiation. Abnormal regulation of this pathway has a significant impact on cardiac development in particular, leading to a variety of abnormalities, including valve septal defects and / or hypertrophic cardiomyopathy (HCM). Disruption of the MAPK signaling pathway has been established as central to these diseases, and several candidate genes along this pathway have been identified in humans, including mutations in KRAS, NRAS, SOS1, RAF1, BRAF, MEK1, MEK2, SHOC2, and CBL. The most commonly mutated gene in NS and LS is PTPN11. Germline mutations in PTPN11 (SHP2) are found in approximately 50% of NS patients and in almost all LS patients who share certain characteristics with NS. In NS, Y62D and Y63C substitutions of the protein are among the most common mutations, with little alteration. Both of these mutations affect the non-catalyzative structure of SHP2 without disrupting the binding of the phosphatase to its phosphorylation signaling partner.

[0140] Curzon syndrome, also known as branchial arch syndrome, is an autosomal dominant genetic disorder. This syndrome affects the first branchial (or pharyngeal) arches, which are precursors to the maxilla and mandible. Because the branchial arches are a crucial developmental feature during fetal growth, disruptions to their development can have persistent and widespread consequences.

[0141] Somatic mutations in PTPN11 (SHP2) occur in approximately 35% of patients with juvenile myelomonocytic leukemia (JMML), a childhood myeloproliferative disorder (MPD). These gain-of-function mutations are typically point mutations that prevent autoinhibition between the catalytic domain and the N-SH2 domain, either in the N-SH2 domain or the phosphatase domain, resulting in SHP2 activity.

[0142] Acute myeloid leukemia—PTPN11 mutations have been identified in approximately 10% of childhood acute leukemias, such as myelodysplastic syndrome (MDS); approximately 7% of B-cell acute lymphoblastic leukemia (B-ALL); and approximately 4% of acute myeloid leukemia (AML).

[0143] Mutations in NS and leukemia cause changes in the amino acids located at the boundary formed by the N--SH2 and PTP domains in the self-inhibitory SHP2 structure, disrupting inhibitory intramolecular interactions and leading to hyperactivity of the catalytic domain.

[0144] SHP2 acts as a positive regulator in receptor tyrosine kinase (RTK) signaling. RTK modification (EGFR amp Her2 amp FGFR amp Met amp Cancers containing translocation / activated RTKs (i.e., ALK, BCR / ABL) include esophageal cancer, breast cancer, lung cancer, colon cancer, gastric cancer, glioma, and head and neck cancer.

[0145] Esophageal cancer is a malignant tumor of the esophagus. It has various subtypes, mainly squamous cell carcinoma (<50%) and adenocarcinoma. Rapid RTK expression occurs in esophageal cancer, adenocarcinoma, and squamous cell carcinoma. Therefore, the SHP2 inhibitor of the present invention can be used in innovative therapeutic strategies.

[0146] Breast cancer is the leading cause of cancer death in women, and patients are developing resistance to currently available drugs. There are four main subtypes of breast cancer, including luminal A, luminal B, Her2-like, and triple-negative / basal cell-like. Triple-negative breast cancer (TNBC) is a highly invasive form of breast cancer for which there is no specific targeted therapy. Epidermal growth factor receptor I (EGFR) has emerged as a promising target for TNBC. Inhibition of Her2 and EGFR via SHP2 may be a promising treatment for breast cancer.

[0147] Lung cancer—NSCLC currently accounts for approximately 85% of lung cancers (primarily adenocarcinoma and squamous cell carcinoma) and is a leading cause of cancer-related mortality. While cytotoxic chemotherapy still plays a vital role in treatment, targeted therapies based on genetic mutations in tumors, such as EGFR and ALK, appear to be more responsive to targeted therapy.

[0148] Colon cancer—It is known that approximately 30% to 50% of colorectal tumors have mutated (abnormal) KRAS, and BRAF mutations occur in 10-15% of colorectal cancers. In a small group of patients whose colorectal tumors have been shown to overexpress EGFR, these patients show a favorable clinical response to anti-EGFR therapy.

[0149] Gastric cancer is one of the most common types of cancer. Abnormal expression of tyrosine kinases, such as that reflected by abnormal tyrosine phosphorylation in gastric cancer cells, is known in this field. Three receptor-tyrosine kinases, namely c-met (HGF receptor), FGF receptor 2, and erbB2 / neu, are frequently amplified in gastric cancer. Thus, disruption of different signaling pathways may contribute to the progression of different types of gastric cancer.

[0150] Neuroblastoma is a progressive sympathetic nervous system tumor in children, accounting for approximately 8% of all childhood cancers. Genomic modifications of the anaplastic lymphoma kinase (ALK) gene are hypothesized to contribute to the development of neuroblastoma.

[0151] Head and neck squamous cell carcinoma (SCCHN) -- High levels of EGFR expression are associated with poor prognosis and resistance to radiotherapy in various cancers, primarily head and neck squamous cell carcinoma (SCCHN). Blocking the EGFR signaling pathway leads to receptor stimulation, inhibition of cell proliferation, and reduction of invasiveness and metastasis. Therefore, EGFR is the most important target for novel anticancer therapies in SCCHN.

[0152] In yet another embodiment, the present invention relates to a compound having the ability to inhibit the activity of SHP2. In yet another embodiment, the present invention relates to a method for producing the compound of the present invention, and a pharmaceutical composition comprising such compound.

[0153] Another aspect of the present invention relates to a method for treating SHP2-mediated disorders, comprising the step of administering a therapeutically effective amount of the compound of the present invention to a patient in need. In one embodiment, the present invention relates to the method described above, wherein the SHP2-mediated disorder is a cancer selected from, but not limited to, JMML; AML; MDS; B-ALL; neuroblastoma; esophageal cancer; breast cancer; lung cancer; colon cancer; gastric cancer; and head and neck cancer.

[0154] The compounds of the present invention may also be useful in the treatment of other diseases or conditions associated with abnormal activity of SHP2. Thus, in a further embodiment, the present invention relates to a method for treating disorders selected from NS;LS;JMML;AML;MDS;B-ALL;neuroblastoma;esophageal cancer;breast cancer;lung cancer;colon cancer;gastric cancer;head and neck cancer.

[0155] In yet another embodiment, the present invention relates to the use of the compounds of the present invention (or pharmaceutical compositions comprising the compounds of the present invention) in the treatment of one or more diseases described herein; where the response to treatment is beneficial, as described, for example, by partially or completely eliminating to the point of complete cure or relief of one or more signs of the disease.

[0156] As used herein, the term "in contact" means bringing together the suggested parts in an in vitro or in vivo system such that they are physically close enough to interact with each other. The interchangeable terms “individual” or “patient” refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, most preferably humans.

[0157] As used herein, the term "therapeutically effective dose" refers to the amount of compound administered that would alleviate, to some extent, one or more signs of the disorder to be treated. In the context of the treatment of SHP2-mediated diseases such as cancer, the therapeutically effective dose refers to the amount that is effective in inhibiting phosphatase.

[0158] As used herein, the term “to treat” means, unless otherwise specified, to regress, alleviate, inhibit or prevent the progression of, a disorder or symptom, or one or more signs of such disorder or symptom to which such term applies. As used herein, the term “treatment” means a therapeutic action such as “to treat” as defined immediately above, unless otherwise specified. The term “to treat” also includes adjuvant and neoadjuvant treatments of the subject. The terms “to treat” or “treatment” may also mean one or more (1) inhibiting a disease; for example, inhibiting a disease, symptom or disorder in an individual experiencing or exhibiting a lesion or symptom of a disease, symptom or disorder (i.e., preventing further progression of the lesion and / or symptom); and (2) improving a disease; for example, improving a disease, symptom or disorder in an individual experiencing or exhibiting a lesion or symptom of a disease, symptom or disorder (i.e., regressing the lesion and / or symptom), such as reducing the severity of the disease.

[0159] In some embodiments, the compounds of the present invention are useful in preventing any of the diseases mentioned herein or reducing the risk of their progression, for example, in individuals who have not yet experienced or displayed any disease lesions or symptoms but are susceptible to the disease, symptoms or disorder.

[0160] Combination therapy In yet another embodiment, the present invention relates to an SHP2 inhibitor of the present invention that is used in combination with another pharmacologically active compound, or with two or more pharmacologically active compounds, particularly useful in the treatment of cancer. For example, the compounds of the present invention described above or pharmaceutically acceptable salts thereof may be administered simultaneously, sequentially, or separately in combination with chemotherapeutic agents, such as mitotic inhibitors such as taxanes, vinca alkaloids, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, or vinflunin, and one or more other anticancer agents selected from, for example, cisplatin, 5-fluorouracil, or 5-fluoro-2-4(1H,3H)-pyrimidinedione (5FU), flutamide, or gemcitabine.

[0161] Such combinations may offer significant benefits in therapy, including synergistic activity. In yet another embodiment, the present invention relates to a method for treating SHP2-mediated disorder, comprising the step of administering to a patient in need a therapeutically effective amount of a chemotherapeutic agent in combination with a therapeutically effective amount of the compound of the present invention.

[0162] In yet another embodiment, the present invention relates to the following compounds: CR-ABL inhibitors: Imatinib (Gleevec®); Inilotinib hydrochloride; Nilotinib (Tasigna®); Dasatinib (BMS-345825); Bosutinib (SKI-606); Ponatinib (AP24534); Bafetinib (INNO406); Danucertib (PHA-739358), AT9283 (CAS 1133385-83-7); Salacatinib (AZD0530); and N-[2-[(1S,4R)-6-[[4-(cyclobutylamino)-5-(trifluoromethyl)-2-pyrimidinyl]amino]-1,2,3,4-tetrahydronaphthalene-1,4-imine-9-yl]-2-oxoethyl]acetamide (PF-03814735, CAS 942487-16-3); and LGX818

[0163] ALK inhibitors: PF-2341066 (XALKORI®; crizotinib); 5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidine-1-yl)phenyl)pyrimidine-2,4-diamine; GSK1838705A; and CH5424802 BRAF inhibitors: vemurafenib (PLX4032); and dabrafenib FLT3 inhibitors: Sunitinib malate (sold by Pfizer under the brand name Sutent®); and PKC412 (midostaurin) MEK inhibitor: Trametinib

[0164] Vascular endothelial growth factor (VEGF) receptor inhibitors: bevacizumab (marketed by Genentech / Roche under the trademark name Avastin®), axitinib (also known as N-methyl-2-[[3-[(E)-2-pyridine-2-ylethenyl]-1H-indazole-6-yl]sulfanil]benzamide, PCT publication number WO (as described in 01 / 002369), brivanib alaninate ((S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indole-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-yloxy)propan-2-yl)2-aminopropanoate, also known as BMS-582664), motesanib (N-(2,3-dihydro-3,3-dimethyl-1H-indole-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide, as described in PCT publication number WO 02 / 066470), pasireotide (also known as SOM230, as described in PCT publication number WO 02 / 010192), sorafenib (marketed under the trade name Nexavar®);

[0165] HER2 receptor inhibitors: trastuzumab (marketed by Genentech / Roche under the trademark Herceptin®), neratinib (also known as HKI-272, (2E)-N-[4-[[3-chloro-4-[(pyridine-2-yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinoline-6-yl]-4-(dimethylamino)buta-2-enamide, listed in PCT publication number WO 05 / 028443), lapatinib or lapatinib ditosylate (marketed by GlaxoSmithKline under the trademark Tykerb®); D20 antibodies: Rituximab (marketed by Genentech / Roche under the trademark names Riuxan® and MabThera®), Tositumomab (marketed by GlaxoSmithKline under the trademark name Bexxar®), Ofatumumab (marketed by GlaxoSmithKline under the trademark name Arzerra®);

[0166] Tyrosine kinase inhibitors: Erlotinib hydrochloride (marketed by Genentech / Roche under the trademark name Tarceva®), linifanib (N-[4-(3-amino-1H-indazole-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea, also known as ABT869, available from Genentech), sunitinib malate (marketed by Pfizer under the trade name Sutent®), bosutinib (4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazine-1-yl)propoxy]quinoline-3-carbonitrile, also known as SKI-606, listed in U.S. Patent No. 6,780,996), dasatinib (Bristol-Myers) (Sold by Squibb under the brand name Sprycel®), Almara (also known as pazolanib, sold by GlaxoSmithKline under the brand name Votrient®), Imatinib and Imatinib Mesylate (sold by Novartis under the brand names Gilvec® and Gleevec®);

[0167] DNA synthesis inhibitors: Capecitabine (marketed by Roche under the trademark Xeloda®), gemcitabine hydrochloride (marketed by Eli Lilly and Company under the trademark Gemzar®), nelarabine ((2R,3S,4R,5R)-2-(2-amino-6-methoxypurine-9-yl)-5-(hydroxymethyl)oxolan-3,4-diol, marketed by GlaxoSmithKline under the trade names Arranon® and Atriance®);

[0168] Antitumor agent: Oxaliplatin (sold by Sanofi-Aventis under the trade name Eloxatin®, and listed in U.S. Patent No. 4,169,846);

[0169] Epidermal growth factor receptor (EGFR) inhibitors: gefitonib (marketed under the trade name Iressa®), N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3''S'')-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide (marketed under the trade name Tovok® by Boehringer Ingelheim), cetuximab (marketed under the trade name Erbitux® by Bristol-Myers Squibb), panitumumab (marketed under the trade name Vectibix® by Amgen); HER dimerization inhibitor: Pertuzumab (marketed by Genentech under the trademark name Omnitarg®);

[0170] Human granulocyte colony-stimulating factor (G-CSF) regulator: Filgrastim (sold by Amgen under the trade name Neupogen®); Immunomodulators: aftuzumab (available from Roche), pegfilgrastim (sold by Amgen under the brand name Neulasta®), lenalidomide (also known as CC-5013 and sold under the brand name Revlimid®), thalidomide (sold under the brand name Thalomid®);

[0171] CD40 inhibitor: Dasetuzumab (also known as SGN-40 or huS2C6, available from Seattle Genetics, Inc.); Pro-apoptotic receptor agonist (PARA): Dulanermin (also known as AMG-951, available from Amgen / Genentech); Hedgehog antagonist: 2-chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)-benzamide (also known as GDC-0449, listed in PCT publication number WO 06 / 028958);

[0172] PI3K inhibitors: 4-[2-(1H-indazole-4-yl)-6-[[4-(methylsulfonyl)piperazine-1-yl]methyl]thieno-[3,2-d]pyrimidine-4-yl]morpholine (also known as GDC0941, listed in PCT publication numbers WO 09 / 036082 and WO 09 / 055730), 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinoline-3-yl)-2,3-dihydroimidazo[4,5-c]-quinoline-1-yl]phenyl]propionitrile (also known as BEZ235 or NVP-BEZ235, listed in PCT publication number WO 06 / 122806);

[0173] Phospholipase A2 inhibitor: Anagrelide (marketed under the trade name Agrylin®); BCL-2 inhibitor: 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-N-[[4-[[(1R)-3-(4-morpholinyl)-1-[(phenylthio)methyl]propyl]amino]-3-[(trifluoromethyl)sulfonyl]phenyl]sulfonyl]benzamide (also known as ABT-263, listed in PCT publication number WO 09 / 155386);

[0174] Mitogen-activated protein kinase (MEK) inhibitor: XL-518 (CAS number 1029872-29-4, available from ACC Corp.); Aromatase inhibitors: exemestane (sold by Pfizer under the brand name Aromasin®), letrozole (sold by Novartis under the brand name Femara®), anastrozole (sold under the brand name Arimidex®);

[0175] Topoisomerase I inhibitors: Irinotecan (sold by Pfizer under the trademark name Camptosar®), Topotecan hydrochloride (sold by GlaxoSmithKline under the brand name Hycamtin®); Topoisomerase II inhibitors: Etoposide (also known as VP-16 and etoposide phosphate, marketed under the trade names Toposar®, VePesid®, and Etopophos®), Teniposide (also known as VM-26, marketed under the trade name Vamon®);

[0176] mTOR inhibitors: Temsirolimus (sold by Pfizer under the trade name Torisel®), ridafololimus (formerly known as deferolimus, (1R,2R,4S)-4-[(2R)-2[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.0 4,9 Hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl dimethylphosphinate, also known as AP23573 and MK8669 (listed in PCT publication number WO 03 / 064383), everolimus (sold by Novartis under the trade name Afinitor®);

[0177] Osteoclastic bone resorption inhibitor: 1-hydroxy-2-imidazole-1-yl-phosphonoethyl phosphonic acid monohydrate (sold by Novartis under the trade name Zometa®); CD33 antibody drug conjugate: gemtuzumab ozogamicin (sold by Pfizer / Wyeth under the trade name Mylotarg®); CD22 antibody-drug conjugate: Inotuzumab ozogamicin (also known as CMC-544 and WAY-207294, available from Hangzhou Sage Chemical Co., Ltd.);

[0178] CD20 antibody drug conjugate: ibritumomab / tiuxetan (marketed under the brand name Zevalin®); Somatostatin analog: Octreotide (also known as octreotide acetate, sold under the trade names Sandostatin® and SandostatinLAR®); Synthetic interleukin-11 (IL-11): Oprelbequine (sold by Pfizer / Wyeth under the trade name Neumega®);

[0179] Synthetic erythropoietin: Darbepoetin alpha (sold by Amgen under the trade name Aranesp®); Nuclear factor kappa B receptor activator (RANK) inhibitor: denosumab (marketed by Amgen under the trade name Prolia®); Thrombopoietin mimic peptide body: romiprostim (sold by Amgen under the brand name Nplate®);

[0180] Cell proliferation stimulant: Palifermin (sold by Amgen under the trade name Kepivance®); Anti-insulin-like growth factor-1 receptor (IGF-1R) antibodies: Figitumumab (also known as CP-751,871, available from ACC Corp), Lobatumumab (CAS number 934235-44-6); Anti-CS1 antibody: elotuzumab (HuLuc63, CAS number 915296-00-3);

[0181] CD52 antibody: Alemtuzumab (marketed under the trade name Campath®); CTLA-4 inhibitors: Tremelimumab (an IgG2 monoclonal antibody available from Pfizer, CP-675,206, formerly known as tisilimmab), Ipilimumab (a CTLA-4 antibody, also known as MDX-010, CAS number 477202-00-9); Histone deacetylase inhibitors (HDIs): Vorinostat (sold by Merck under the brand name Zolinza®);

[0182] Alkylating agents: Temozolomide (sold by Schering-Plough / Merck under the trade names Temodar® and Temodal®), Dactinomycin (also known as Actinomycin-D, sold under the trade name Cosmegen®), Melphalan (also known as asL-PAM, L-sarcolydin, and phenylalanine mustard, sold under the trade name Alkeran®), Altretamine (also known as hexamethylmelamine (HMM)) These include carmustine (sold under the brand name Hexalen®), bendamustine (sold under the brand name Treanda®), busulfan (sold under the brand names Busulfex® and Myleran®), carboplatin (sold under the brand name Paraplatin®), lomustine (also known as CCNU and sold under the brand name CeeNU®), and cisplatin (also known as CDDP). Also known as Platinol® and Platinol®-AQ, these include chlorambucil (sold under the trade name Leukeran®), cyclophosphamide (sold under the trade names Cytoxan® and Neosar®), dacarbazine (also known as DTIC, DIC, and imidazole carboxamide, sold under the trade name DTIC-Dome®), and altoretamine (sold under the trade name Hexalen®). , also known as hexamethylmelamine (HMM), ifosfamide (sold under the brand name Ifex®), procarbazine (sold under the brand name Matulane®), mechloretamine (also known as nitrogen mustard, mustine, and mechloroetamine hydrochloride, sold under the brand name Mustargen®), streptozocin (sold under the brand name Zanosar®), thiotepa (also known as thiophosphoamide, TESPA, and TSPA,Sold under the brand name Thioplex (registered trademark);

[0183] Biological response modifiers: Bacillus calmet-guelin (marketed under the trade names theraCys® and TICE® BCG), Denileukin diphthyrox (marketed under the trade name Ontak®);

[0184] Anticancer antibiotics: Doxorubicin (marketed under the trade names Adriamycin® and Rubex®), Bleomycin (marketed under the trade name Lenoxane®), Daunorubicin (also known as Daunorubicin hydrochloride, Daunomycin, and Rubidomycin hydrochloride, marketed under the trade name Cerubidine®), Daunorubicin liposomal (DaunoXome®), Mitoxantrone (also known as DHAD, marketed under the trade name Novantrone®), Epirubicin (marketed under the trade name Ellence®), Idarubicin (marketed under the trade names Idamycin® and Idamycin PFS®), Mitomycin C (marketed under the trade name Mutamycin®);

[0185] Microtubule inhibitors: Estramustine (sold under the trade name Emcyl®); Cathepsin K inhibitor: Odanocatib (also known as MK-0822, N-(1-cyanocyclopropyl)-4-fluoro-N 2 -{(1S)-2,2,2-trifluoro-1-[4'-(methylsulfonyl)biphenyl-4-yl]ethyl}-L-leucinamide, available from Lanzhou Chon Chemicals, ACC Corp., and ChemieTek, and listed in PCT publication number WO 03 / 075836);

[0186] Epothiron B analog: Ixabepylone (sold by Bristol-Myers Squibb under the trade name Lxempra®); Heat shock protein (HSP) inhibitor: Tanespimycin (also known as 17-allylamino-17-demethoxygeldanamycin, KOS-953, and 17-AAG, available from SIGMA and listed in U.S. Patent No. 4,261,989); TpoR agonist: Eltrombopug (sold by GlaxoSmithKline under the trade names Promacta® and Revolade®);

[0187] Antimitotic agent: Docetaxel (sold by Sanofi-Aventis under the trade name Taxotere®); Adrenocorticosteroid inhibitors: Aminoglutethimide (sold under the brand name Cytadren®);

[0188] Antiandrogens: Niltamide (marketed under the trade names Nilandron® and Anandron®), bicalutamide (marketed under the trade name Casodex®), and flutamide (marketed under the trade name Fulexin®); Androgens: Fluoxymesterone (sold under the brand name Halotestin®); Proteasome inhibitors: Bortezomib (marketed under the brand name Velcade®);

[0189] CDK1 inhibitor: Arbocidib (also known as flubopirdol or HMR-1275, 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methyl-4-piperidinyl]-4-clomenone, and listed in U.S. Patent No. 5,621,002);

[0190] Gonadotropin-releasing hormone (GnRH) receptor agonists: leuprolide or leuprolide acetate (available from Bayer AG under the brand names Viadure®, Sanofi-Aventis under the brand name Eligard®, and Abbott Lab under the brand name Lupron®);

[0191] Taxane antitumor agents: Cabazitaxel (1-hydroxy-7β,10β-dimethoxy-9-oxo-5β,20-epoxytac-11-ene-2-α,4,13α-triyl-4-acetate-2-benzoate-13-[(2R,3S)-3-{[(tert-butoxy-)carbonyl]amino}-2-hydroxy-3-phenylpropanoate), Larotax Cell((2α,3Xi,4α,5β,7α,10β,13α)-4,10-bis(acetyloxy)-13-({(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-9-oxo-5,20-epoxy-7,19-cyclotac-11-en-2-ylbenzoate);

[0192] 5HT1a receptor agonist: xaliproden (SR57746, also known as 1-[2-(2-naphthyl)ethyl]-4-[3-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine, listed in U.S. Patent No. 5,266,573); HPC vaccines: Cervarix (registered trademark) sold by GlaxoSmithKline, and Gardasil (registered trademark) sold by Merck; Iron chelating agent: Novartis sells Deferacinox (under the trade name Exjade®);

[0193] Antimetabolites: Claribine (2-chlorodeoxyadenosine sold under the brand name Leustatin®), 5-fluorouracil (sold under the brand name Adrucil®), 6-thioguanine (sold under the brand name Purinethol®), Pemetrexd (sold under the brand name Alimta®), cytarabine (also known as arabinosylcytosine (Ara-C) and sold under the brand name Cytosar-U®), cytarabine liposomal (also known as liposomal Ara-C and sold under the brand name DepoCyt®), decitabine (sold under the brand name Dacogen®) ), hydroxyurea (sold under the trade names Hydrea®, Droxia®, and Mylocel®), fludarabine (sold under the trade name Fludara®), phloxuridine (sold under the trade name FUDR®), cladribine (sold under the trade name Leustatin®, also known as 2-chlorodeoxyadenosine (2-CdA)), methotrexate (also known as ametopterin, methotrexate sodium (MTX), sold under the trade names Rheumatrex® and Trexall®), pentostatin (sold under the trade name Nipent®);

[0194] Bisphosphonates: Pamidronate (sold under the brand name Aredia®), Zoledronic acid (sold under the brand name Zometa®); Demethylating agents: 5-azacitidine (sold under the brand name Vidaza®), decitabine (sold under the brand name Dacogen®);

[0195] Plant alkaloids: Protein-bound paclitaxel (marketed under the trade name Abraxane®), vinblastine (also known as vinblastine sulfate, vincaleucoblastine, and VLB, marketed under the trade names Alkaban-AQ® and Velban®), vincristine (also known as vincristine sulfate, LCR, and VCR, marketed under the trade names Oncovin® and VincasarPfs®), vinorelbine (marketed under the trade name Navelbine®), paclitaxel (marketed under the trade names Taxol and Onxal®);

[0196] Retinoids: Alitretinoin (sold under the brand name Panretin®), Tretinoin (all retinoic acids, also known as ATRA, sold under the brand name Vesanoid®), Isotretinoin (13-cis-retinoic acid, sold under the brand names Accutane®, Amnesteem®, Claravis®, Clarus®, Decutan®, Isotane®, Izotech®, Oratane®, Isotret®, and Sotret®), Bexarotene (sold under the brand name Targretin®);

[0197] Glucocorticosteroids: Hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, hydrocortisone phosphate, Ala-Cort®, Solu-Cortef®, Hydrocort) (Sold under the trade names Acetate® and Lanacort®), Dexamethasone ((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one), Prednisolone (Sold under the trade names Delta-Cortel®, Orapred®, Pediapred® and Prelone®), Prednisone (Deltasone®, Liquid) (Sold under the trade names Red (registered trademark), Meticorten (registered trademark), and Orasone (registered trademark)), methylprednisolone (sold under the trade names 6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, Duralone (registered trademark), Medralone (registered trademark), Medrol (registered trademark), M-Prednisol (registered trademark), and Solu-Medrol (registered trademark));

[0198] Cytokines: Interleukin-2 (also known as aldesleukin and IL-2, marketed under the trade name Proleukin®), Interleukin-11 (also known as opleukin, marketed under the trade name Neumega®), Alpha-interferon alpha (also known as IFN-alpha, marketed under the trade names Intron® A and Roferon-A®);

[0199] Estrogen receptor downregulator: Fulvestrant (sold under the brand name Faslodex®); Anti-estrogens: Tamoxifen (sold under the brand name Novaldex®); Toremifene (sold under the brand name Fareston®); Selective estrogen receptor modulators (SERMs): raloxifene (marketed under the brand name Evista®);

[0200] Luteinizing hormone-releasing hormone (LHRH) agonist: Goserelin (sold under the brand name Zoladex®); Progesterone: Megestrol (also known as Megastrol acetate, sold under the brand name Megace®);

[0201] Various cytotoxic agents: allocenic trioxide (sold under the trade name Trisenox®), asparaginase (also known as L-asparaginase or Elvinia L-asparaginase, sold under the trade names Elspar® and Kidrolase®) This invention relates to the compound of the present invention when combined with [the specified element].

[0202] In yet another embodiment, the present invention relates to the following adjunctive therapies: Antiemetics: NK-1 receptor antagonists: Casopitant (marketed by GlaxoSmithKline under the trade names Rezonic® and Zunrisa®); and Cell protective agents: Amifostin (commercially sold under the trade name Ethyol®), Leucovorin (also known as calcium leucovorin, citroborum factor, and folinic acid) This invention relates to the compound of the present invention when combined with [the specified element].

[0203] When multiple medications are administered to a patient, they may be administered simultaneously, separately, sequentially, or in combination (for example, in the case of more than two medications).

[0204] Prescription, dosage form, and administration The compounds of this disclosure, when used as pharmaceuticals, may be administered in the form of pharmaceutical compositions. Thus, this disclosure provides compositions comprising compounds represented by formula I, formula A1, or any of the formulas described herein, the compounds listed in any of the claims and described herein, or pharmaceutically acceptable salts thereof, or any embodiment thereof, and at least one pharmaceutically acceptable carrier or excipient. These compositions may be prepared by methods well known in the pharmaceutical art and may be administered by various routes depending on the area to be treated, whether topical or systemic treatment is suggested.

[0205] Pharmaceutical compositions suitable for delivering the compounds of the present invention and methods for producing them will be obvious to those skilled in the art. Such compositions and methods for producing them can be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).

[0206] The compounds of the present invention may be administered by any method that enables delivery of the compounds to the site of action. These methods include oral, intraduodenal, parenteral injection (including intravenous, subcutaneous, intramuscular, or intravascular injection or infusion), topical, and rectal administration. Parenteral administration may be in the form of a single bolus dose or, for example, by a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder, or oily bases, thickeners, etc., may be essential or optional.

[0207] In yet another embodiment, the present invention relates to the method described above, wherein the compound is administered parenterally. In yet another embodiment, the present invention relates to the above-described method, wherein the compound is administered intramuscularly, intravenously, subcutaneously, orally, transpulmonaryly, subdurally, locally, or intranasally. In yet another embodiment, the present invention relates to the method described above, wherein the compound is administered systemically.

[0208] In yet another embodiment, the initial dose is administered intrauterine (either directly or to the mother). In a particular embodiment, the initial dose is administered before the blood-brain barrier is fully formed. In another embodiment, the initial dose is administered within one week of the subject's birth. In another embodiment, the initial dose is administered within one month of the subject's birth. In another embodiment, the initial dose is administered within three months of the subject's birth. In another embodiment, the initial dose is administered within six months of the subject's birth.

[0209] In a particular embodiment, the present invention relates to the method described above, wherein the patient is a mammal. In a particular embodiment, the present invention relates to the method described above, wherein the patient is a primate. In a particular embodiment, the present invention relates to the method described above, wherein the patient is a human being.

[0210] The compounds of the present invention must be evaluated for their biopharmaceutical properties, such as solubility and solution stability (characteristics at various pH levels), and permeability, in order to select the most suitable dosage form and route of administration for the proposed treatment.

[0211] The compounds of the present invention, intended for pharmaceutical use, may be administered as crystalline or amorphous products. They can be obtained as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze-drying, spray-drying, or evaporative drying. For this purpose, drying may be performed using microwaves or radio frequencies.

[0212] They may be administered alone, in combination with one or more other compounds of the present invention, or in combination with one or more other agents (or as any combination thereof). Generally, they will be administered as formulations in conjunction with one or more pharmaceutically acceptable excipients. The term “excipient” is used herein to describe any component other than the compounds of the present invention. The choice of excipients will largely depend on factors such as the individual administration method, the effect of the excipients on solubility and stability, and the characteristics of the dosage form.

[0213] In the preparation of the compositions of the present invention, the active ingredient is typically mixed with an excipient, diluted with the excipient, or encapsulated in such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When the excipient is used as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as aerosols in a solid or liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injections, and sterile packaged powders containing, for example, up to 10% by weight of the active compound.

[0214] In manufacturing a formulation, the active compound can be ground to provide an appropriate particle size before being combined with other components. If the active compound is substantially insoluble, it can be ground to a particle size smaller than 200 mesh. If the active compound is substantially water-soluble, it can be ground to adjust the particle size to provide a substantially uniform distribution in the formulation, for example, about 40 mesh.

[0215] The compounds of the present invention may be ground using known grinding operations, such as wet grinding, to obtain particle sizes suitable for tablet form and other formulation forms. The finely divided (nanoparticle) preparations of the present invention may be manufactured by methods known in the art; see, for example, WO 2002 / 000196.

[0216] Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulation may additionally include lubricants such as talc, magnesium stearate, and mineral oil; humectants; emulsifiers and suspending agents; preservatives such as methyl- and propyl hydroxybenzoates; sweeteners; and flavoring agents. The compositions of the present invention may be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient by utilizing operations known in the art.

[0217] In some embodiments, the pharmaceutical composition comprises silicified microcrystalline cellulose (SMCC) and at least one compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the silicified microcrystalline cellulose comprises about 98 w / w% microcrystalline cellulose and about 2 w / w% silicon dioxide.

[0218] The compounds of the present invention may also be used in rapidly dissolving, rapidly disintegrating dosage forms, such as those described by Liang and Chen (2001) in Expert Opinion in Therapeutic Patents, 11(6), 981-986.

[0219] In some embodiments, the composition is a sustained-release composition comprising at least one compound or a pharmaceutically acceptable salt thereof as described herein and at least one pharmaceutically acceptable carrier or excipient. In some embodiments, the composition comprises at least one compound or a pharmaceutically acceptable salt thereof as described herein and at least one component selected from microcrystalline cellulose, lactose monohydrate, hydroxypropyl methylcellulose, and polyethylene oxide. In some embodiments, the composition comprises at least one compound or a pharmaceutically acceptable salt thereof as described herein and microcrystalline cellulose, lactose monohydrate, and hydroxypropyl methylcellulose. In some embodiments, the composition comprises at least one compound or a pharmaceutically acceptable salt thereof as described herein and microcrystalline cellulose, lactose monohydrate, and polyethylene oxide. In some embodiments, the composition further comprises magnesium stearate or silicon dioxide. In some embodiments, the microcrystalline cellulose is Avicel PH102®. In some embodiments, the lactose monohydrate is Fast-flo 316®. In some embodiments, hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208 K4M (e.g., Methocell K4 M Premier®) and / or hydroxypropyl methylcellulose 2208 K100LV (e.g., Methocell K00LV®). In some embodiments, polyethylene oxide is polyethylene oxide WSR 1105 (e.g., Polyox WSR 1105®).

[0220] In some embodiments, the composition is produced using a wet granulation method. In some embodiments, the composition is produced using a dry granulation method.

[0221] The drug administration plan can be adjusted to obtain the desired optimal response. For example, a bolus may be administered as a single dose, or in divided doses over time, or the dose may be proportionally decreased or increased as required by the treatment situation. It is particularly advantageous to formulate parenteral compositions in unit dosage forms to facilitate administration and ensure uniformity of dosage. As used herein, unit dosage forms refer to physically separate units suitable for use as unit doses for treating mammalian subjects; each unit contains a predetermined amount of the active compound calculated to produce the desired therapeutic effect when combined with the required pharmaceutical carrier.

[0222] Thus, those skilled in the art will understand that, based on the disclosures provided herein, the dosage and administration are adjusted according to methods well known in the field of therapeutics. That is, the maximum acceptable dose can be immediately established, and the effective amount that provides a detectable therapeutic benefit to the patient can also be determined, as this is the time requirement for administering each drug to provide a detectable therapeutic benefit to the patient. Accordingly, although specific dosages and administration plans are shown herein as typical examples, these examples do not in any way limit the dosages and administration plans that can be provided to patients in carrying out the present invention.

[0223] It should be noted that the dosage may vary depending on the type and severity of the symptoms to be alleviated, and may include single or multiple doses. Furthermore, it should be understood that for individual subjects, specific dosing plans should be adjusted over time to individual needs and according to the professional judgment of those administering or managing the composition, and that the range of dosages shown herein is illustrative and not intended to limit the scope and implementation of the composition described in the claims. For example, the dose may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and / or laboratory values. Thus, the present invention includes intra-patient dose increases as determined by those skilled in the art.

[0224] The determination of appropriate dosages and administration plans for activators is well known in the relevant art and will be understood as being mastered by those skilled in the art once they have acquired the techniques disclosed herein.

[0225] The dosage of the compound of the present invention will depend on the subject being treated, the severity of the disorder or symptom, the dosage rate, the pharmacokinetics of the compound, and the discretion of the prescribing physician.

[0226] However, the effective dose, in single or divided doses, is in the range of approximately 0.001 to 100 mg per kg of body weight per day, preferably about 1 to 35 mg / kg / day. For a person weighing 70 kg, this would be approximately 0.05 to 7 g / day, preferably about 0.1 to 2.5 g / day. In some cases, a dose level lower than the lower limit of the above range may be sufficient, while in other cases, even higher doses can be used without causing any adverse side effects; however, such higher doses are first divided into several smaller doses to be administered throughout the day.

[0227] The compounds of the present invention may be administered orally. Oral administration may include swallowing so that the compounds enter the gastrointestinal tract and / or so that the compounds enter the bloodstream directly from the oral cavity by buccal, lingual, or sublingual administration.

[0228] Formulations suitable for oral administration include tablets; soft or hard capsules containing multiple or nanoparticles, liquid or powder; lozenges (including liquid-filled); chews; gels; rapidly dispersible dosage forms; films; ovules; sprays; and solid, semi-solid, and liquid systems such as buccal / mucosal adhesive patches.

[0229] When manufacturing solid compositions such as tablets, the main active ingredient is mixed with pharmaceutical excipients to form a solid preliminary formulation composition containing a homogeneous mixture of the compounds of the present invention. In these homogeneous preliminary formulation compositions, the active ingredient is typically evenly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0230] The tablets may also optionally contain surfactants such as sodium lauryl sulfate and polysorbate 80, and flow promoters such as silicon dioxide and talc. If present, the surfactants may constitute 0.2% to 5% by weight of the tablet, and the flow promoters may constitute 0.2% to 1% by weight of the tablet.

[0231] In dose-dependent tablet formulations, the drug may constitute 1% to 80% by weight of the dosage form, more typically 5% to 60% by weight. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropylcellulose, starch, alpha-starch, and sodium alginate. Generally, the disintegrant will constitute 1% to 25% by weight of the dosage form, preferably 5% to 20% by weight.

[0232] The tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. The lubricant generally constitutes 0.25% to 10% by weight, preferably 0.5% to 3% by weight, of the tablet.

[0233] Other possible ingredients include antioxidants, colorants, flavoring agents, preservatives, and flavor masking agents.

[0234] Binders are generally used to impart tackiness to tablets. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, alpha-starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. Tablets may also contain lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, glucose, sucrose, sorbitol, microcrystalline cellulose, starch, and dibasic calcium phosphate dihydrate.

[0235] A typical tablet contains up to 80% of the drug, about 10% to 90% by weight of a binder, about 0% to 85% by weight of a diluent, about 2% to 10% by weight of a disintegrant, and about 0.25% to 10% by weight of a lubricant.

[0236] The tablet blend may be compressed directly or by rollers to form tablets. Alternatively, the tablet blend or a portion of the blend may be subjected to wet, dry, or melt granulation, melt jelly, or extrusion before tableting. The final formulation may consist of one or more layers, which may or may not be coated; it may be further encapsulated.

[0237] Tablet formulations are described in Pharmaceutical Dosage Forms: Tablets, Vol. 1, H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

[0238] Disposable oral films for human or animal use are typically flexible, water-soluble or water-swellable thin film formulations that dissolve rapidly or adhere to mucous membranes, and may typically contain the compounds of the present invention, film-forming polymers, binders, solvents, humectants, plasticizers, stabilizers or emulsifiers, viscosity modifiers, and other solvents. Some of the components of the formulation may perform two or more functions.

[0239] The compounds of the present invention may be water-soluble or water-insoluble. Water-soluble compounds typically contain 1% to 80% by weight of solute, more typically 20% to 50% by weight. Poorly soluble compounds may contain a higher proportion of solute, typically up to 88% by weight. Alternatively, the compounds of the present invention may be in the form of multiparticle beads.

[0240] The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrophilic colloids, and is typically formulated in the range of 0.01 to 99% by weight, and more typically in the range of 30 to 80% by weight.

[0241] Other possible ingredients include antioxidants, colorants, flavor enhancers and odor modifiers, preservatives, saliva stimulants, coolants, cosolvents (including oils), emollients, fillers, defoamers, surfactants, and flavor masking agents.

[0242] The film according to the present invention is typically manufactured by coating a peelable backing support or backing paper with a thin aqueous film and drying it by evaporation. This operation may be carried out in a drying oven or tunnel, typically in a combined coating dryer, or by freeze-drying or vacuum drying.

[0243] Orally administered solid dosage forms may be formulated to be immediate-release and / or modified-release. Modified-release formulations include delayed-release, sustained-release, pulsed-release, controlled-release, targeted-release, and programmed-release formulations.

[0244] A suitable modified-release formulation for the purpose of the invention is described in U.S. Patent No. 6,106,864. Other suitable release techniques, such as high-energy dispersion, permeability, and coated particles, are described in detail in Pharmaceutical Technology On-line, 25(2), 1-14, Verma et al. (2001). Achieving controlled release using chewing gum is described in WO 00 / 35298.

[0245] The compounds of the present invention may also be administered directly into the bloodstream, muscle, or viscera. Suitable means of parenteral administration include intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​substernal, intracranial, intramuscular, intrabursal, and intradermal administration. Suitable devices for parenteral administration include needle (including microneedle) syringes, needle-free syringes, and injection techniques.

[0246] Parenteral formulations are typically aqueous solutions that may contain salts, carbohydrates, and buffers (preferably with a pH of 3 to 9), but in some applications, they are more preferably formulated as sterile, non-aqueous solutions or as dry forms that can be used in conjunction with a suitable vehicle, such as sterile, pyrogenic-free water.

[0247] Under sterile conditions, the production of parenteral formulations, for example, by lyophilization, can be easily achieved using standard compounding techniques well known to those skilled in the art.

[0248] The solubility of the compound of the present invention used in the production of parenteral solutions can be increased by employing appropriate formulation techniques, such as adding a dissolution accelerator.

[0249] Parenteral formulations may be formulated to be immediate and modified-release. Modified-release formulations include delayed-release, sustained-release, pulsed-release, controlled-release, targeted-release, and programmed-release formulations. Such compounds of the present invention may be formulated as solids, semi-solids, or thixotropic liquids for administration as suspensions or as implantable depots providing modified-release of the active compound. Examples of such formulations include semi-solids and suspensions containing drug-coated stents and drug-loaded dl-lactic acid / glycolic acid copolymer (PGLA) microspheres.

[0250] The compounds of the present invention may also be administered topically, intradermally, or transdermally to the skin or mucous membranes. Topical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, gauze, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers may be incorporated—see, for example, J Pharm Sci, 88(10), 955-958, Finnin and Morgan (December 1999).

[0251] Other means of local administration include electroporation, electrophoresis, sonic electrophoresis, ultrasonic electrophoresis, and microneedle or needle-free injection (e.g., Powderject®, Bioject®, etc.).

[0252] Topically administered formulations may be formulated to be immediate and / or modified-release. Modified-release formulations include delayed-release, sustained-release, pulsed-release, controlled-release, targeted-release, and programmed-release formulations.

[0253] The compounds of the present invention may also be administered intranasally or by inhalation, typically in the form of a dry powder from a dry powder inhaler (either alone or as a mixture in a dry blend with lactose, or as mixed component particles mixed with phospholipids such as phosphatidylcholine, for example), as an aerosol spray from a pressurized vessel, pump, spray, atomizer (preferably an atomizer that generates a fine mist using electrohydrodynamics), or nebulizer, with or without a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, or as a nasal solution. When used intranasally, the powder may contain a bioadhesion agent, such as chitosan or cyclodextrin.

[0254] A pressure vessel, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound of the present invention, for example, ethanol, aqueous ethanol, or another suitable substance to disperse, solubilize, or extend the release of the activator, a propellant as a solvent, and any surfactant such as sorbitan trioleate, oleic acid, or oligolactic acid.

[0255] Before use in dry powder or suspension formulations, the drug product is pulverized to a size suitable for inhalation delivery (typically less than 5 microns). This can be achieved by any suitable grinding method, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high-pressure homogenization, or spray drying.

[0256] Capsules (e.g., capsules made from gelatin or hydroxypropyl methylcellulose), blisters, and cartridges for use in inhalers or injectors may be formulated to contain a powder mixture of the compounds of the present invention, a suitable powder base such as lactose or starch, and a performance modifier such as l-leucine, mannitol, or magnesium stearate. Lactose may be in anhydrous or monohydrate form, preferably the latter. Other suitable excipients include dextrin, glucose, mannitol, sorbitol, xylitol, fructose, sucrose, and trehalose.

[0257] A suitable liquid formulation for use in an atomizer that generates a fine mist using electrohydrodynamics may contain 1 μg to 20 mg of the compound of the present invention per operation, and the operating volume may vary from 1 μl to 100 μl. A typical formulation may contain the compound of the present invention, propylene glycol, sterile water, ethanol, and sodium chloride. Glycerol and polyethylene glycol are examples of alternative solvents that can be used instead of propylene glycol.

[0258] Appropriate flavoring and deodorizing agents such as menthol and levomenthol, or sweeteners such as saccharin or sodium saccharin, may be added to these formulations of the present invention intended for inhalation / intranasal administration.

[0259] Formulations for inhalation / intranasal administration may be formulated to be immediate and / or modified-release, for example, using PGLA. Modified-release formulations include delayed-release, sustained-release, pulsed-release, controlled-release, targeted-release, and programmed-release formulations.

[0260] In the case of dry powder inhalers and aerosols, the unit dose is determined by a valve mechanism that delivers a measured amount. The units according to the invention are typically arranged to administer a measured dose or "puff" containing 0.05 g to 1 g of the compound of the invention.

[0261] The compounds of the present invention may be administered transrectally or transvaginally, for example, in the form of suppositories, pessaries, or enemas. Cocoa butter is the traditional suppository base, but various substitutes may be used as appropriate.

[0262] Formulations for transrectal or transvaginal administration may be formulated to be immediate and / or modified-release. Modified-release formulations include delayed-release, sustained-release, pulsed-release, controlled-release, targeted-release, and programmed-release formulations.

[0263] The compounds of the present invention may also be administered directly to the eye or ear, typically in the form of a micronized suspension or solution in a pH-adjusted, sterile isotonic line. Other formulations suitable for transocular or transaural administration include ointments, gels, biodegradable (e.g., absorbent gel sponge, collagen) and non-biodegradable (e.g., silicone) implants, wafers, lenses, and particle or vesicle systems such as niosomes or liposomes. Linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers, such as hydroxypropyl methylcellulose, hydroxyethylcellulose, or methylcellulose, or heteropolysaccharide polymers, such as gellan gum, may be formulated together with preservatives such as benzalkonium chloride. Such formulations may also be delivered by electrophoresis.

[0264] Formulations for transocular or transaural administration may be formulated to be immediate and / or modified-release. Modified-release formulations include delayed-release, sustained-release, pulsed-release, controlled-release, targeted-release, or programmed-release formulations.

[0265] The compounds of the present invention may be combined with soluble macromolecules such as cyclodextrins and their suitable derivatives, or polyethylene glycol-containing polymers, to improve their solubility, dissolution rate, taste masking, bioavailability, and / or stability for use in any of the above-described administration methods.

[0266] For example, drug-cyclodextrin complexes have proven to be generally useful in most dosage forms and routes of administration. Both inclusion- and non-inclusion-type complexes may be used. As an alternative to direct complexation with the drug, cyclodextrin may be used as an auxiliary additive, i.e., as a carrier, diluent, or solubilizer. The most commonly used for these purposes are alpha-cyclodextrin, beta-cyclodextrin, and gamma-cyclodextrin, examples of which are described in International Patent Application Nos. WO 91 / 11172, WO 94 / 02518, and WO 98 / 55148.

[0267] Because the present invention has embodiments relating to the treatment of diseases / symptoms described herein using a combination of active ingredients that may be administered separately, the present invention also relates to combining separate pharmaceutical compositions into a kit. The kit comprises two separate pharmaceutical compositions: a compound of the present invention, its prodrug, or a salt of such compound or prodrug, and the second compound described above. The kit includes means for containing the separate compositions, such as a container, a separate bottle, or a separate foil packet. Typically, the kit includes instructions for administering the separate ingredients. This kit form is particularly advantageous when it is preferred that the separate ingredients be administered in different dosage forms (e.g., orally and parenterally) and at different dosing intervals, or when the prescribing physician desires to titrate the individual ingredients of the present invention.

[0268] An example of such a kit is the so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs generally consist of a sheet of a relatively rigid material covered with a foil, preferably made of a transparent plastic material. During the packaging process, a recess is formed in the plastic wheel. The recess has the size and shape of the tablet or capsule to be packaged. The tablet or capsule is then placed in the recess, and the plastic wheel is sealed with the sheet of the relatively rigid material, with the side of the wheel facing the direction opposite to the direction in which the recess was formed. As a result, the tablet or capsule is sealed in the recess between the plastic wheel and the sheet. Preferably, the strength of the sheet is such that pressure can be applied to the recess by hand, thereby forming an opening in the sheet at the location of the recess, allowing the tablet or capsule to be removed from the blister pack. The tablet or capsule can then be removed through the opening.

[0269] The kit may preferably provide, for example, a memory aid in the form of a number next to a tablet or capsule, where the number corresponds to the number of days in the administration plan, and the identified tablet or capsule is to be taken. Another example of such a memory aid is a calendar printed on a card, for example, "Week 1, Monday, Tuesday, etc... Week 2, Monday, Tuesday, etc..." Another variation of the memory aid will be readily apparent. The "daily dose" can be a single tablet or capsule, or multiple pills or capsules, to be taken on a given day. Furthermore, the daily dose of the compound of the present invention may consist of one tablet or capsule, while the daily dose of a second compound may consist of several tablets or capsules. The reverse is also true. The memory aid must reflect this.

[0270] In yet another specific embodiment of the present invention, a dispenser is provided that is designed to dispense daily doses in a single dose in the intended order. The dispenser is preferably equipped with a memory aid to further facilitate adherence to the treatment plan. One example of such a memory aid is a mechanical counter that indicates the number of daily doses dispensed. Another example of such a memory aid is a battery-powered microchip memory, combined with a liquid crystal reader or an audible reminder signal, which in turn reads data on when the last daily dose was taken and / or reminds the user of data on when the next dose should be taken.

[0271] Liquid formulations include suspensions, solutions, syrups, and elixirs. Such formulations may be used as fillers in soft or hard capsules (e.g., made from gelatin or hydroxypropyl methylcellulose), and typically contain a carrier, e.g., water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, one or more emulsifiers and / or suspending agents. Liquid formulations may also be made, for example, from sachets by restoring a solid. In addition, liquid forms in which the compounds and compositions of the present invention can be formulated for oral or injectable administration include aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions, and flavored emulsions, as well as elixirs and similar pharmaceutical vehicles, containing edible oils such as cottonseed oil, sesame oil, cocoa butter, or peanut oil.

[0272] The compounds of the present invention can also be combined with appropriate carriers to improve delivery, stability, and / or efficacy when administered to a patient. All publications cited herein, including but not limited to issued patents, patent applications, and academic articles, are, with due attribution, considered to be part of this specification.

[0273] The present invention is described above with reference to the disclosure of embodiments, but those skilled in the art will readily understand that the embodiments detailed below are merely illustrative of the present invention. It should be understood that various modifications can be made without departing from the spirit of the invention. Accordingly, the present invention is limited only by the claims.

[0274] In the following examples and preparations, "BOC", "Boc", or "boc" means N-tert-butoxycarbonyl, "DCM" (CH2Cl2) means methylene chloride, "DIPEA" or "DIEA" means diisopropylethylamine, "DMA" means N,N-dimethylacetamide, "DMF" means NN-dimethylformamide, "DMSO" means dimethyl sulfoxide, "DPPP" means 1,3-bis(diphenylphosphin)propane, "HOAc" means acetic acid, and "IPA" means isopropyl alcohol. "MTBE" means methyl t-butyl ether, "NMP" means 1-methyl-2-pyrrolidinone, "TEA" means triethylamine, "TFA" means trifluoroacetic acid, "DCM" means dichloromethane, "SiO2" means ethyl acetate, "MgSO4" means magnesium sulfate, "NaSO4" means sodium sulfate, "MeOH" means methanol, "EtOH" means ethanol, "H2O" means water, "HCl" means hydrochloric acid, "POCl3" means phosphorus oxychloride, "DMSO" means dimethyl sulfoxide, "K2CO3" means potassium carbonate, "N" means normal, "M" means mole, "mL" means milliliter, "mmol" means millimoles, "μmol" means micromoles, "eq" means equivalent, "℃" means degrees Celsius, and "Pa" means Pascals. [Examples]

[0275] The yields reported herein refer to the pure product (unless otherwise specified). Analytical TLC was performed using Merck silica gel 60F. 254The work was performed on aluminum-lined plates. The compounds were visualized with UV light and / or stained with iodine, ninhydrin, or potassium permanganate solution, followed by drying. Flash column chromatography was performed on silica gel. 1 ¹H-NMR spectra were recorded using a Bruker 400 MHz, Avance II spectrometer with a 5 mm DUL (Dual) 13C probe, and a Bruker 400 MHz, Avance III HD spectrometer with a BBFO (Broad Band Fluorine Observe) probe. Chemical shifts (Λ) are expressed in parts per million (ppm) relative to the peak of the deuterated solvent in which the sample is prepared. Splitting patterns are designated as s (singlet), d (doublet), t (triplet), q (quadruplet), m (multilet), and bs (broad singlet).

[0276] The following solvents, reagents, or scientific terms may be referred to by their abbreviations: [Table 1]

[0277] Intermediates A and B: Synthesis of tert-butyl ((3aR,5s,6aS)-5-methyloctahydrocyclopenta[c]pyrrole-5-yl)carbamate (intermediate A) and tert-butyl ((3aR,5r,6aS)-5-methyloctahydrocyclopenta[c]pyrrole-5-yl)carbamate (intermediate B) [ka]

[0278] Step 1: Synthesis of 2,3,3a,4,7,7a-hexahydro-1H-isoindole [ka] A solution of lithium aluminum hydride (44 g, 1.15 mol) in THF (2.2 L) at 0°C, stirred, was added dropwise to a solution of 3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione (70 g, 0.46 mol) in THF (500 mL). The reaction mixture was stirred at 60°C for 12 hours. After observing the consumption of the starting material by TLC, the reaction mixture was cooled to 0°C and quenched with THF:water (70 mL, 9:1), followed by 15% NaOH aqueous solution (70 mL) and water (140 mL) for 2 hours. The quenching rate was carefully controlled to maintain the internal temperature below 25°C. The resulting mixture was stirred at room temperature for 1 hour, filtered through a Celite bed, and then washed with DCM (3 x 300 mL). The filtrate was collected and concentrated under reduced pressure to obtain 2,3,3a,4,7,7a-hexahydro-1H-isoindole (50 g, yield 87%) as a brown semi-solid. MS(ESI+ve):124.0 1 H NMR (400MHz, CDCl3) δ 5.29(s,2H), 3.88(bs,1H), 3.26(m,2H), 2.82(m,2H), 2.41-2.19(m,4H), 1.96(m,2H)

[0279] Step 2: Synthesis of benzyl 1,3,3a,4,7,7a-hexahydro-2H-isoindole-2-carboxylate [ka] To a stirred solution of 2,3,3a,4,7,7a-hexahydro-1H-isoindole (90 g, 0.73 mol) in DCM (2 L), Et3N (316 mL, 2.19 mol) and Cbz-Cl (135 mL) were added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The reaction process was monitored by TLC, and it was observed that the starting materials were consumed. The reaction mixture was diluted with ice-cold water (500 mL) and extracted with RINKAN (3 x 500 mL). The organic layer was separated, washed with brine (500 mL), dried (Na2SO4), filtered, and evaporated to dryness. The residue was purified by column chromatography using silica gel (100-200 mesh) and a gradient (20% siRNA in hexane) to obtain benzyl 1,3,3a,4,7,7a-hexahydro-2H-isoindole-2-carboxylate (140 g, 74%) as a brown semi-solid. MS(ESI+ve):258.08 1 H-NMR(400MHz;DMSO-d6):δ 7.31-7.42(m,5H), 5.62(s,2H), 5.05(s,2H), 3.38-3.43(m,2H), 3.02-3.07(m,2H), 2.18-2.22(m,4H), 1.79-1.82(m,2H)

[0280] Step 3: Synthesis of 2,2'-(1-((benzyloxy)carbonyl)pyrrolidine-3,4-diyl)diacetic acid [ka] A stirred solution of benzyl 1,3,3a,4,7,7a-hexahydro-2H-isoindole-2-carboxylate (130 g, 0.50 mol) in pentane (2 L) was to be mixed with potassium permanganate (239 g, 1.51 mol) and tetrabutylammonium bromide (24.4 g, 0.077 mol) in water (600 mL) at 0°C. The resulting suspension was stirred at room temperature for 3 hours. The progress of the reaction was monitored by TLC, and it was observed that the starting materials were consumed. The reaction mixture was filtered through a Celite bed, and the bed was washed with water (2 L). The filtrates were combined and washed with ethyl acetate (1 L) to separate the organic layer. The aqueous layer was collected, acidified with 1N hydrochloric acid solution to adjust the pH to approximately 1, and extracted with ethyl acetate (3 x 1 L). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 2,2'-(1-((benzyloxy)carbonyl)pyrrolidine-3,4-diyl)diacetic acid (132 g, crude product) as a brown semi-solid, which was used in the next step without further purification. MS(ESI+ve):322.15

[0281] Step 4: Synthesis of benzyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate [ka] To a stirred solution of 2,2'-(1-((benzyloxy)carbonyl)pyrrolidine-3,4-diyl)diacetic acid (132 g, 0.411 mol) in acetic anhydride (1.3 L), sodium acetate (40.4 g, 0.493 mol) was added under an inert atmosphere, and the resulting suspension was stirred at 120°C for 5 hours. The progress of the reaction was monitored by TLC, and it was observed that the starting material was consumed. The reaction mixture was cooled to room temperature, and the solid material was separated by filtration and subsequently washed with ethyl acetate (500 mL). The filtrates were combined and concentrated under vacuum to obtain the crude material, which was subjected to column chromatography and purified using 100-200 mesh silica gel and 30% ethyl acetate / hexane as the eluent to obtain benzyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (57 g, 53%) as an off-white solid. MS(ESI+ve):260.2 1 H-NMR(400MHz;DMSO-d6):δ 7.30-7.36(m,5H), 5.05(s,2H), 3.59-3.62(m,2H), 3.17-3.20(m,2H), 2.89(s,2H), 2.37-2.42(m,2H), 2.07-2.12(m,2H)

[0282] Step 5: Synthesis of benzyl 5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate [ka] To a stirred solution of benzyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (39.6 g, 0.15 mol) in EtOH (650 mL), sodium borohydride (9.8 g, 0.26 mol) was added dropwise at 0°C under an argon atmosphere. The reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC, and it was observed that the starting material was consumed. The reaction mixture was concentrated under reduced pressure until dry, diluted with ice-cold water (550 mL), and extracted with ELISA (3 x 350 mL). The organic layers were combined, washed with brine (500 mL), dried (Na2SO4), filtered, and evaporated under vacuum to obtain benzyl 5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (44.1 g, crude) as a brown semi-solid. MS(ESI+ve):262.19 1 H-NMR(400MHz;DMSO-d6):δ 7.31-7.36(m,5H), 5.05(s,2H), 4.60-4.63(m,1H), 3.42-3.48(m,2H), 3. 30-3.33(m,2H), 2.54-2.59(m,2H), 1.97-2.08(m,2H), 1.29-1.35(m,2H)

[0283] Step 6: Synthesis of benzyl 5-((methylsulfonyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate [ka] To a stirred solution of benzyl 5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (44 g, 0.16 mol) in DCM (700 mL), Et3N (70 mL, 0.50 mol) and MsCl (26 mL, 0.33 mol) were added dropwise at 0°C under an argon atmosphere. The reaction mixture was stirred at room temperature for 3 hours. The progress of the reaction was monitored by TLC, and it was observed that the starting materials were consumed. The reaction mixture was diluted with ice-cold water (550 mL) and extracted with DCM (3 x 350 mL). The organic layers were combined, washed with brine (300 mL), dried (Na2SO4), filtered, and evaporated under vacuum to obtain benzyl 5-((methylsulfonyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (55.6 g, crude) as a brown semi-solid. This material was used in the next step without further refinement. MS(ESI+ve):340.2 1 H-NMR(400MHz;DMSO-d6):δ 7.31-7.36(m,5H), 5.05(s,2H), 3.48-3.53(m,2H), 3.29-3.33(m,3H), 3.13(s,3H), 2.65-2.69(m,2H), 2.26-2.29(m,2H), 1.68-1.74(m,2H)

[0284] Step 7: Synthesis of benzyl 5-cyanohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate [ka] NaCN (23.8 g, 0.48 mol) was added to a stirred solution of benzyl 5-((methylsulfonyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (55 g, 0.16 mol) in DMSO (850 mL). The reaction mixture was stirred at 80 °C for 6 hours. The progress of the reaction was monitored by TLC, and it was observed that the starting material was consumed. The resulting mixture was diluted with ice-cold water (850 mL) and extracted with RINKAN (3 x 350 mL). The organic layers were combined, washed with brine (500 mL), dried (Na2SO4), filtered, and concentrated to dryness. The crude residue was subjected to column chromatography and purified with 15% RINKAN in hexane to obtain benzyl 5-cyanohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (27 g, 61%) as an off-white solid. MS(ESI+ve):271.15 1 H-NMR(400MHz;DMSO-d6):δ 7.31-7.35(m,5H), 5.03(s,2H), 3.48-3.53(m,2H), 3.17-3.20(m,1H), 3. 08-3.13(m,2H), 2.79-2.83(m,2H), 1.97-2.03(m,2H), 1.88-1.92(m,2H)

[0285] Step 8: Synthesis of benzyl 5-cyano-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate [ka] To a stirred solution of benzyl 5-cyanohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (27 g, 0.10 mol) in THF (900 mL), LiHMDS (120 mL, 0.12 mol, 1 M in THF) was added dropwise over 15 minutes at -78°C. The reaction mixture was stirred for 30 minutes, and then MeI (18.4 g, 0.13 mol) was added. The resulting mixture was stirred at room temperature for a further 2 hours. The progress of the reaction was monitored by TLC, and it was observed that the starting material was consumed. The reaction mixture was diluted with water (500 mL) and extracted with RINKAN (3 x 150 mL). The organic layer was separated, washed with brine (300 mL), dried (Na2SO4), filtered, and concentrated to dryness to obtain benzyl 5-cyano-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (27.5 g, crude) as a brown semi-solid mixture of diastereomers (in a ratio of approximately 3:1 via LC-MS), which was used in the next step without further purification. MS(ESI+ve):285.12 1 H-NMR(400MHz;DMSO-d6):δ 7.31-7.35(m,5H), 5.05(s,2H), 3.48-3.53(m,2H), 3.27-3.30(m,2H), 2.79-2.83(m,2H), 1.98-2.03(m,2H), 1.87-1.90(m,2H), 1.31(s,3H)

[0286] Steps 9 & 10: Synthesis of 2-((benzyloxy)carbonyl)-5-methyloctahydrocyclopenta[c]pyrrole-5-carboxylic acid [ka] A solution of benzyl 5-cyano-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (27 g, 0.09 mol) in concentrated HCl (60 mL) was heated at 110°C for 16 hours. The progress of the reaction was monitored by TLC, and it was observed that the starting material was consumed. The reaction mixture was concentrated to dryness to obtain a residue, which was dissolved in acetone / water (30 mL, 1:1). Na2CO3 (49.9 g, 0.47 mol) and then Cbz-Cl (17.5 mL, 0.12 mol) were added at 0°C. The reaction mixture was stirred at room temperature for 7 hours. After the consumption of the starting material was observed by TLC, the reaction mixture was concentrated under vacuum to remove the acetone, and washed with ELISA (3 x 250 mL) to remove nonpolar impurities. The aqueous layer was acidified with citric acid (pH approximately 3) and extracted with DCM (5 x 50 mL). The organic layer was separated, washed with brine (300 mL), dried (Na2SO4), filtered, and evaporated under vacuum to obtain 2-((benzyloxy)carbonyl)-5-methyloctahydrocyclopenta[c]pyrrole-5-carboxylic acid (14 g, crude) as an off-white solid, which was a mixture of diastereomers (approximately 3:1 ratio by LCMS), and was used in the next step without further purification. MS(ESI-ve):302.0 1 H-NMR(400MHz;DMSO-d6):δ 12.19(s,1H), 7.31-7.35(m,5H), 5.05(s,2H), 3.39-3.44(m,2H), 3.18-3.24(m,2H), 2.71-2.75(m,2H) , 2.64-2.66(m,1H), 2.31-2.35(m,1H), 1.83-1.86(m,2H), 1.72-1.78(m,2H), 1.23(s,1H), 1.19(s,3H)

[0287] Step 11: Synthesis of benzyl 5-(azidocarbonyl)-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate [ka] To a stirred solution of 2-((benzyloxy)carbonyl)-5-methyloctahydrocyclopenta[c]pyrrole-5-carboxylic acid (14.1 g, 0.04 mol) in THF (280 mL), Et3N (16.2 mL, 0.11 mol) and ethyl chloroformate (6.64 mL, 0.06 mol) were added dropwise at -20°C. The reaction mixture was stirred at -20°C for 10 minutes, and then a solution of NaN3 (7.56 g, 0.11 mol) in water (30 mL) was added dropwise. The resulting mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC, and it was observed that the starting materials were consumed. The reaction mixture was diluted with water (250 mL) and extracted with ELISA (3 x 150 mL). The organic layer was separated, washed with brine (200 mL), dried (Na2SO4), filtered, and evaporated under vacuum to obtain benzyl 5-(azidocarbonyl)-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (13.3 g, crude) as a semi-solid mixture of diastereomers (approximately 3:1 ratio), which was used in the next step without further purification. MS(ESI+ve):329.1

[0288] Steps 12 & 13: Synthesis of benzyl (3aR,5s,6aS)-5-((tert-butoxycarbonyl)amino-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate and benzyl (3aR,5r,6aS)-5-((tert-butoxycarbonyl)amino)-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate [ka] A solution of benzyl 5-(azidocarbonyl)-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (13.2 g, 0.04 mol) in toluene (132 mL) was heated at 80°C for 2 hours. Then, t-BuOH (66 mL) and PTSA (0.69 g, 0.004 mol) were added to the reaction mixture and stirred at the same temperature for 3 hours. The progress of the reaction was monitored by TLC, and it was observed that the starting materials were consumed. The reaction mixture was concentrated, diluted with water (250 mL), and extracted with ELISA (3 x 150 mL). The organic layer was separated, washed with brine (250 mL), dried (Na2SO4), filtered, and evaporated to dryness under vacuum. The residue was purified by preparative HPLC (according to the conditions shown in Table 3) to obtain benzyl (3aR,5s,6aS)-5-((tert-butoxycarbonyl)amino-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (2.5 g) as a white solid and benzyl (3aR,5r,6aS)-5-((tert-butoxycarbonyl)amino)-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (9.5 g) as a white solid. The stereochemistry of both was determined using 2D-NOESY.

[0289] Analytical data of benzyl (3aR,5s,6aS)-5-((tert-butoxycarbonyl)amino-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate MS(ESI+ve):375.16 1 H-NMR(400MHz;DMSO-d6):δ 7.31-7.35(m,5H), 6.57(bs,1H), 5.05(s,2H), 3.35-3.38(m,2H), 3.18-3.22(m,2H) , 2.64-2.69(m,2H), 2.33-2.36(m,2H), 1.36(s,9H), 1.28(s,3H), 1.14-1.18(m,2H)

[0290] Analytical data of benzyl (3aR,5r,6aS)-5-((tert-butoxycarbonyl)amino)-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate MS(ESI+ve):375.19 1 H-NMR(400MHz;DMSO-d6):δ 7.31-7.35(m,5H), 6.78(bs,1H), 5.05(s,2H), 3.39-3.43(m,2H), 3.28-3.32(m,2H) , 2.60-2.63(m,2H), 1.84-1.88(m,2H), 1.73-1.77(m,2H), 1.36(s,9H), 1.19(s,3H)

[0291] Step 14: Synthesis of tert-butyl ((3aR,5s,6aS)-5-methyloctahydrocyclopenta[c]pyrrole-5-yl)carbamate (intermediate A) [ka] To a stirred solution of benzyl (3aR,5s,6aS)-5-((tert-butoxycarbonyl)amino)-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (2.5 g, 0.006 mol) in MeOH (25 mL), Pd / C (0.73 g, 30% w / w) was added under an N2 atmosphere. The reaction mixture was stirred at room temperature under an H2 atmosphere for 2 hours. The progress of the reaction was monitored by TLC, and it was observed that the starting material was consumed. The reaction mixture was filtered through a Celite bed and washed with MeOH (80 mL). The filtrate was evaporated under vacuum to obtain tert-butyl ((3aR,5s,6aS)-5-methyloctahydrocyclopenta[c]pyrrole-5-yl)carbamate (intermediate A, 1.36 g, 85%) as an off-white solid. MS(ESI+ve):241.0 1 H-NMR (400MHz; CD3OD): δ 2.69-2.74(m,6H), 2.31-2.36(m,2H), 1.42(s,9H), 1.36(s,3H), 1.10-1.15(m,2H) 13 C-NMR (400MHz; DMSO-d6): 154.4, 76.9, 62.5, 53.5, 45.0, 42.7, 28.3, 23.8

[0292] Step 15: Synthesis of tert-butyl ((3aR,5r,6aS)-5-methyloctahydrocyclopenta[c]pyrrole-5-yl)carbamate (Compound-A) [ka] A stirred solution of benzyl (3aR,5r,6aS)-5-((tert-butoxycarbonyl)amino)-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (8.2 g, 0.02 mol) in MeOH (82 mL) was mixed with Pd / C (2.4 g, 30% w / w) under an N2 atmosphere. The reaction mixture was stirred at room temperature under an H2 atmosphere for 2 hours. The progress of the reaction was monitored by TLC, and it was observed that the starting material was consumed. The reaction mixture was filtered through a Celite bed and washed with MeOH (250 mL). The filtrate was evaporated to dryness under vacuum. The residue was triturated with diethyl ether and pentane to obtain tert-butyl ((3aR,5r,6aS)-5-methyloctahydrocyclopenta[c]pyrrole-5-yl)carbamate (intermediate B, 5.06 g, 96%) as an off-white solid. MS(ESI+ve):241.0 1 H-NMR(400MHz;CD3OD):δ 2.79-2.82(m,2H), 2.69-2.74(m,2H), 2.63-2.65(m,2H), 2.02-2.07(m,2H), 1.54-1.58(m,2H), 1.42(s,9H), 1.27(s,3H) 13 C-NMR (400MHz; DMSO-d6): 154.4, 76.9, 59.9, 53.3, 44.8, 41.6, 28.3, 24.5

[0293] Example 1: Synthesis of (3aR,5r,6aS)-2-(6-amino-5-(2-chloro-3-methylphenyl)pyrazine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-amine hydrochloride [ka]

[0294] Step 1: Synthesis of 2-(2-chloro-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and (2-chloro-3-methylphenyl)boronic acid [ka] To a stirred solution of 1-bromo-2-chloro-3-methylbenzene (2 g, 9.73 mmol) in 1,4-dioxane (15 mL), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.7 g, 14.6 mmol) and potassium acetate (2.86 g, 29.1 mmol) were added. The reaction mixture was degassed with argon for 10 minutes. Next, Pd(PPh3)2Cl2 (1.02 g, 1.45 mmol) was added, and the mixture was heated at 85°C for 12 hours with stirring. The color of the reaction mixture changed from yellow to red, and finally to black. The progress of the reaction was monitored by TLC, and it was observed that the starting materials were consumed. The reaction mixture was cooled to room temperature, filtered through Celite, and then washed with ethyl acetate (100 mL). The filtrate was concentrated to dryness under reduced pressure, and a mixture of the products (1.5 g, 60% purity by LC-MS) was obtained as a red oil, which was used directly in the next step.

[0295] Step 2: Synthesis of 6-chloro-3-(2-chloro-3-methylphenyl)pyrazine-2-amine [ka] A mixture of boronic acid and ester (0.3 g, crude) and sodium carbonate (0.46 g, 4.31 mmol) was added to a stirred solution of 3-bromo-6-chloropyrazine-2-amine (0.3 g, 1.43 mmol) in THF:H2O (20 ml, 9:1). The reaction mixture was degassed with argon for 10 minutes, and Pd(PPh3)4 (0.16 g, 0.14 mmol) was added. The reaction mixture was again degassed with argon and heated at 80°C with stirring for 12 hours. The progress of the reaction was monitored by TLC, and it was observed that the starting materials were completely consumed. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with water (20 mL) and extracted with HCl (3 x 20 mL). The organic layers were combined, washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography [silica gel (100-200 mesh), gradient of 4%-6% ethyl acetate in hexane] to obtain 6-chloro-3-(2-chloro-3-methylphenyl)pyrazine-2-amine (0.28 g, 76%) as a yellow solid. MS(ESI+ve):253.92 1 H-NMR(400MHz;DMSO-d6):δ 7.82(s,1H), 7.44-7.46(d,J=7.20Hz,1H), 7.32-7.36(t,J=7.6Hz,1H), 7.20-7.22(d,J=6.8Hz,1H), 6.51(bs,2H), 2.40(s,3H)

[0296] Step 3: Synthesis of tert-butyl ((3aR,5r,6aS)-2-(6-amino-5-(2-chloro-3-methylphenyl)pyrazine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-yl)carbamate [ka] To a stirred solution of 6-chloro-3-(2-chloro-3-methylphenyl)pyrazine-2-amine (0.22 g, 0.92 mmol) in DMF (5 mL), tert-butyl ((3aR,5r,6aS)-5-methyloctahydrocyclopenta[c]pyrrole-5-yl)carbamate (intermediate B, 0.24 g, 0.96 mmol) and cesium carbonate (0.89 g, 2.74 mmol) were added. The reaction mixture was heated at 140 °C for 16 hours. The progress of the reaction was monitored by TLC, and it was observed that the starting materials were consumed (Note: the Boc protecting group was partially removed). The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (3 x 15 mL). The organic solutions were combined, dried over anhydrous sulfate, and concentrated under vacuum to obtain tert-butyl ((3aR,5r,6aS)-2-(6-amino-5-(2-chloro-3-methylphenyl)pyrazine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-yl)carbamate (42%) of the compound, together with (3aR,5r,6aS)-2-(6-amino-5-(2-chloro-3-methylphenyl)pyrazine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-amine hydrochloride (compound from Example 1; 16%). The yield of the mixture was 380 mg, which was carried over to the next stage without further purification. MS(ESI+ve):458.12

[0297] Step 4: Synthesis of (3aR,5r,6aS)-2-(6-amino-5-(2-chloro-3-methylphenyl)pyrazine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-amine hydrochloride [ka] HCl (g) was purged over a solution of the crude product mixture (0.37g) derived from step 3 in DCM (15mL) for 20 minutes. The reaction was monitored by LC-MS, and it was observed that the starting material had been consumed. Volatile substances were removed under reduced pressure, and the mixture was tritulate with MTBE (20mL). The resulting residue was purified by preparative HPLC to obtain the denoted compound (57mg) (preparative HPLC method shown in Table 3). MS(ESI+ve):358.27 1 H-NMR(400MHz;CD3OD):δ 7.43-7.45(d,J=8Hz,1H), 7.33-7.37(t,J=7.56Hz,1H), 7.24-7.26(m,1H), 7.24(s,1H), 3.55- 3.59(m,4H), 3.03-3.04(m,2H), 2.45(s,3H), 2.19-2.24(m,2H), 1.74-1.79(m,2H), 1.42(s,3H)

[0298] The compounds of Examples 2-6 were prepared from intermediate B using the same method as in Example 1. The compounds of Examples 7 and 8 were prepared using only intermediate A as the starting amine, using the same method as in Example 1. The spectral data for Examples 2-8 are shown in Table 1.

[0299] Table 1 [Table 2] [Table 3]

[0300] *This compound was prepared in Example 1, Step 3, using 6-chloro-3-(2,3-dichlorophenyl)pyrazine-2-amine (from Example 9, Step 1) instead of 6-chloro-3-(2-chloro-3-methylphenyl)pyrazine-2-amine, according to the procedure provided in Example 1.

[0301] Example 9: 6-((3aR,5r,6aS)-5-(aminomethyl)-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-yl)-3-(2,3-dichlorophenyl)pyrazine-2-amine and 6-((3aR,5s,6aS)-5-(aminomethyl)-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-yl)-3-(2,3-dichlorophenyl)pyrazine-2-amine [ka]

[0302] Step 1: Synthesis of 6-chloro-3-(2,3-dichlorophenyl)pyrazine-2-amine [ka] To a stirred solution of 3-bromo-6-chloropyrazine-2-amine (2 g, 9.61 mmol) in ACN:H2O (20 ml, 9:1), (2,3-dichlorophenyl)boronic acid (2, 2.7 g, 14.2 mmol) and tribasic potassium phosphate (6.10 g, 28.8 mmol) were added. The reaction mixture was degassed with argon for 10 minutes, and Pd(dppf)Cl2CH2Cl2 (0.78 g, 0.96 mmol) was added. The reaction mixture was again degassed with argon and heated at 130°C for 18 hours with stirring. The progress of the reaction was monitored by TLC, and it was observed that the starting materials were completely consumed. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with water (100 mL) and extracted with siRNA (3 x 200 mL). The organic layers were combined, washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography [silica gel (100-200 mesh), gradient of 10-12% ethyl acetate in hexane] to obtain 6-chloro-3-(2,3-dichlorophenyl)pyrazine-2-amine (1.0 g, 38%) as a yellow solid. MS(ESI+ve):274.12 1H-NMR (400MHz; CDCl3): δ 8.02(s,1H), 7.58-7.60(d,J=8.02Hz,1H), 7.32-7.36(m,2H), 4.63(bs,2H)

[0303] Step 2: Synthesis of (3aR,6aS)-5-methyloctahydrocyclopenta[c]pyrrole-5-carbonitrile [ka] To a stirred solution of benzyl (3aR,6aS)-5-cyano-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1 g, 3.51 mol; derived from intermediates A and B, synthesized in step 8) in EtOH (30 mL), Pd / C (0.3 g, 30% w / w) was added under an N2 atmosphere. The reaction mixture was stirred at room temperature under an H2 atmosphere for 3 hours. The progress of the reaction was monitored by TLC, and it was observed that the starting materials were completely consumed. The reaction mixture was filtered through a Celite bed and then washed with EtOH (80 mL). The filtrate was evaporated to dryness under vacuum. The residue was triturated with diethyl ether to obtain (3aR,6aS)-5-methyloctahydrocyclopenta[c]pyrrole-5-carbonitrile (0.5 g, crude) as a sticky brown solid that was a diastereomer mixture (in a ratio of approximately 3:1 according to LCMS), which was used in the next step without further purification. MS(ESI+ve):151.1

[0304] Step 3: (3aR,6aS)-2-(6-amino-5-(2,3-dichlorophenyl)pyrazine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-carbonitrile [ka] (3aR,6aS)-5-methyloctahydrocyclopenta[c]pyrrole-5-carbonitrile (0.32 g, 2.16 mmol) was stirred in DMF (8 mL) and 6-chloro-3-(2,3-dichlorophenyl)pyrazine-2-amine (0.65 g, 2.38 mmol) and cesium carbonate (2.11 g, 6.49 mmol) were added. The reaction mixture was heated at 140 °C for 12 hours. The progress of the reaction was roughly monitored by TLC and LC-MS, and it was observed that the starting materials were consumed. The reaction mixture was cooled to room temperature and volatiles were removed under reduced pressure. The obtained material was diluted with water (80 mL) and extracted with ethyl acetate (3 x 25 mL). The organic solutions were combined, dried over anhydrous sulfate, and concentrated under vacuum. The residue was subjected to flash chromatography and purified using 100-200 mesh silica gel and 10-20% ethyl acetate / hexane as eluent to obtain (3aR,6aS)-2-(6-amino-5-(2,3-dichlorophenyl)pyrazine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-carbonitrile as a yellow solid diastereomer mixture (0.26 g, yield: 31%). 1 The resulting product (obtained in a ratio of approximately 3:1 according to 1H NMR) was used in the next step without further diastereomer separation. MS(ESI+ve):388.10 1 H-NMR(400MHz;CD3OD):δ 7.58-7.59(d,J=4Hz,1H), 7.30-7.48(m,1H), 7.34-7.36(m,1H), 7.22(s,1H), 3.58-3.60( m,4H), 3.10-3.13(m,2H), 2.30-2.32(m,2H), 1.50-1.52(m,2H), 1.49(s,1H), 1.43(s,3H)

[0305] Step 4: Synthesis of 6-((3aR,6aS)-5-(aminomethyl)-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-yl)-3-(2,3-dichlorophenyl)pyrazine-2-amine [ka] A solution of (3aR,6aS)-2-(6-amino-5-(2,3-dichlorophenyl)pyrazine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-carbonitrile (5, 0.24 g, 0.61 mmol) in THF (5 mL) was added dropwise to a stirred solution of LAH (48 mg, 1.23 mmol) in THF (5 mL) at 0°C. The reaction mixture was stirred at room temperature for 1 hour. After the SM was consumed as observed by TLC, the reaction mixture was cooled to 0°C and quenched with THF:water (9 mL, 9:1), followed by 15% NaOH aqueous solution (2 mL) and water (3 mL) for 30 minutes. The quenching was performed at a careful rate so that the internal temperature remained below 20°C. The resulting mixture was stirred at room temperature for 1 hour, filtered through a Celite bed, and then washed with DCM:EtOH (40 mL, 1:1). The filtrate was collected and concentrated under reduced pressure to obtain (3aR,6aS)-2-(6-amino-5-(2,3-dichlorophenyl)pyrazine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-carbonitrile (6, crude product 220 mg) in a diastereomer ratio of approximately 2:1. This was purified by SFC (Lux Amylose column, mobile phase CO2 / 0.2%DEA / EtOH (60:40) and reversed phase) to obtain compound 9a as the TFA salt (main product, 20 mg, 98% according to LCMS) and compound 9b as the TFA salt (by-product, 12 mg, 91% according to LCMS). Detailed data on reversed phase purification are shown in Table 3.

[0306] 6-((3aR,5r,6aS)-5-(aminomethyl)-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-yl)-3-(2,3-dichlorophenyl)pyrazine-2-amine(9a): [ka] MS(ESI+ve):392.26 1H NMR(400MHz,CD3OD) δ 7.62-7.65(dd,J=1.24Hz,7.92Hz,1H), 7.40-7.43(t,J=7.76Hz,1H), 7.35-7.37(dd,J=1.32Hz,7.72Hz,1H), 7.22(s,1H) , 3.58-3.60(m,2H), 3.49-3.51(m,2H), 3.04-3.06(m,2H), 2.96(s,2H),1.90-1.95(m,2H), 1.44-1.49(m,2H), 1.15(s,3H)

[0307] 6-((3aR,5s,6aS)-5-(aminomethyl)-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-yl)-3-(2,3-dichlorophenyl)pyrazine-2-amine(9b): MS(ESI+ve):392.13 1 H NMR(400MHz,CD3OD) δ 7.63-7.65(dd,J=1.32Hz,6.42Hz,1H), 7.36-7.40(m,2H), 7.22(s,1H), 3.56-3.60(m,2H), 3.49 -3.51(m,2H), 2.94-2.96(m,2H), 2.89(s,2H), 2.02-2.07(m,2H), 1.46-1.51(m,2H), 1.22(s,3H)

[0308] Example 10: Synthesis of (3aR,5r,6aS)-2-(4-amino-5-(2-chloro-3-methylphenyl)pyrimidine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-amine hydrochloride [ka]

[0309] Step 1: Synthesis of 2-chloro-5-(2-chloro-3-methylphenyl)pyrimidine-4-amine [ka] To a stirred solution of 5-bromo-2-chloropyrimidine-4-amine (0.5 g, 2.39 mmol) in THF:H2O (15 ml, 9:1), 2-chloro-3-methylphenyl)boronic acid (2, 0.61 g, 3.58 mol) and sodium carbonate (0.71 g, 7.17 mmol) were added. The reaction mixture was degassed with argon for 10 minutes, and Pd(PPh3)4 (0.27 g, 0.24 mmol) was added. The reaction mixture was again degassed with argon and heated at 85°C for 16 hours with stirring. The progress of the reaction was monitored by TLC, and it was observed that the starting materials were consumed. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with water (20 mL) and extracted with siRNA (3 x 20 mL). The organic layers were combined, washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography [silica gel (100-200 mesh), gradient of 6-8% ethyl acetate in hexane] to obtain 2-chloro-5-(2-chloro-3-methylphenyl)pyrimidine-4-amine (0.4 g, 67%) as a pale yellow solid. MS(ESI+ve):254.14 1 H-NMR (400MHz; DMSO-d6): δ 7.82(s,1H), 7.44-7.46(d,J=7.20Hz,1H), 7.32-7.36(t,J=7.6Hz,1H), 7.18-7.20(d,J=6.8Hz,1H), 2.40(s,3H)

[0310] Step 2: Synthesis of tert-butyl ((3aR,5r,6aS)-2-(4-amino-5-(2-chloro-3-methylphenyl)pyrimidine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-yl)carbamate [ka] To a stirred solution of 2-chloro-5-(2-chloro-3-methylphenyl)pyrimidine-4-amine (0.22 g, 0.91 mmol) in DMF (5 mL), tert-butyl ((3aR,5r,6aS)-5-methyloctahydrocyclopenta[c]pyrrole-5-yl)carbamate (intermediate B, 0.24 g, 0.96 mmol) and cesium carbonate (0.89 g, 2.74 mmol) were added. The reaction mixture was heated at 140 °C for 16 hours. The progress of the reaction was monitored by TLC, and it was observed that the starting materials were consumed (Note: the Boc protecting group was partially removed). The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (3 x 20 mL). The organic solutions were combined, dried over anhydrous sulfate, and concentrated under vacuum to obtain 13% (3aR,5r,6aS)-2-(4-amino-5-(2-chloro-3-methylphenyl)pyrimidine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-amine together with 23% (3aR,5r,6aS)-2-(4-amino-5-(2-chloro-3-methylphenyl)pyrimidine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-amine (compound of the example, 348 mg, crude product by LC-MS), which was carried over to the next step without further purification.

[0311] Step 3: Synthesis of (3aR,5r,6aS)-2-(4-amino-5-(2-chloro-3-methylphenyl)pyrimidine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-amine hydrochloride [ka] A solution of the crude product (0.34 g) derived from step 2 was stirred at 0°C in DCM (25 mL) and purged with HCl gas for 20 minutes. The resulting mixture was heated to room temperature, volatiles were removed under reduced pressure, and then triturated with MTBE (20 mL). The resulting residue was purified by preparative HPLC to obtain (3aR,5r,6aS)-2-(4-amino-5-(2-chloro-3-methylphenyl)pyrimidine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-amine·HCl as a yellow solid (15 mg). The preparative HPLC method is described in Table 3. MS(ESI+ve):358.21 1 H-NMR (400 MHz; DMSO-d6):δ 1 H-NMR(400MHz;CD3OD):δ 7.59(s,1H), 7.32-7.34(d,J=8.00Hz,1H), 7.25-7.28(t,J=7.60Hz,1H), 7.12-7.14(d,J=7.60Hz,1H) , 3.55-3.64(m,4H), 2.93-2.95(m,2H), 2.43(s,3H), 2.14-2.19(m,2H), 1.69-1.74(m,2H), 1.38(s,3H)

[0312] The compounds of Examples 11, 12, and 13 were prepared in the same manner as in Example 10, and the analytical data is shown in Table 2. Table 2: [Table 4]

[0313] Preparative HPLC purification conditions are provided in Table 3. Table 3: Preparative HPLC purification conditions [Table 5] [Table 6]

[0314] The compounds of the present invention were evaluated for their ability to selectively inhibit SHP2 activity. The inhibitory properties of the compounds of the present invention described herein can be revealed by testing with one of the following assays.

[0315] Example A: SHP2 Inhibition Assay SHP2 is allosterically activated via binding to its Src homology 2 (SH2) domain of a bis-tyrosyl-phosphorylated peptide. Subsequent activation steps result in the release of the SHP2 autoinhibitory interface, thereby sequentially activating the SHP2 PTP and making substrate recognition and reactive catalysis available. The catalytic activity of SHP2 is monitored using the surrogate substrate DiFMUP in a prompt fluorescence assay format. More specifically, the phosphatase reaction is carried out at room temperature in a 384-well low-flange black flat-bottom polystyrene non-binding surface plate (Corning, catalog no. 3575) with a final reaction volume of 25 μL and the following assay buffer conditions: 60 mM HEPES, pH 7.2, 75 mM NaCl, 75 mM KCl, 1 mM EDTA, 0.05% P-20, and 5 mM DTT. Inhibition of SHP2 from test compounds (varying in concentrations from 0.003 to 100 μM) is monitored by assay (0.5 nM SHP2 incubated with 0.5 μM peptide IRS1_pY1172(dPEG8)pY1222 (sequence H2N-LN(pY)IDLDLV-(dPEG8)LST(pY)ASINFQK-amide) (SEQ ID NO: 1)). After incubation at 25°C for 30-60 minutes, the surrogate substrate DiFMUP (Invitrogen, catalog no. D6567, 200 μM) is added to the reactant and incubated at 25°C for 30 minutes (200 μM for constructs with residues 2-593, 100 μM for constructs with residues 1-525).

[0316] Next, the reaction is quenched by adding 5 μL of 160 μM bpV (Phen) solution (Enzo Life Sciences, catalog number ALX-270-204). The fluorescence signal is monitored using a PerkinElmer Envision 2101 multi-label microplate reader. The inhibition percentage is normalized by the total ERK signal and compared to the DMSO vehicle control.

[0317] Example B: SHP2 allosteric inhibition assay SHP2 is allosterically activated via binding to its Src homology 2 (SH2) domain of a bis-tyrosyl-phosphorylated peptide. The subsequent activation process leads to the release of SHP2's autoinhibitory interface, which sequentially activates SHP2 protein tyrosine phosphatase (PTP), making substrate recognition and reactive catalysis available. The catalytic activity of SHP2 is monitored using the surrogate substrate DiFMUP in a prompt fluorescence assay format.

[0318] More specifically, the phosphatase reaction is performed at room temperature in a 384-well low-flange black flat-bottom polystyrene non-binding surface plate (Corning, catalog no. 3575) with a final reaction volume of 25 μL and the following assay buffer conditions: 60 mM HEPES, pH 7.2, 75 mM NaCl, 75 mM KCl, 1 mM EDTA, 0.05% P-20, and 5 mM DTT.

[0319] Inhibition of SHP2 by the compounds of the present invention (with concentrations varying from 0.003 to 100 μM) is monitored by assay (incubating 0.5 nM SHP2 with 0.5 μM peptide IRS1_pY1172(dPEG8)pY1222 (sequence: H2N-LN(pY)IDLDLV(dPEG8)LST(pY)ASINFQK-amide) (SEQ ID NO: 1)). See, for example, U.S. Patent Publication 2017 / 204080, SEQ ID NO: 1. After incubation at 25°C for 30–60 minutes, the surrogate substrate DiFMUP (Invitrogen, catalog no. D6567) is added to the reactant and incubated at 25°C for 30 minutes. The reaction is then quenched by adding 5 μl of 160 μM bpV (Phen) solution (Enzo Life Sciences, catalog no. ALX-270-204). Using a microplate reader (Envision, Perki-Elmer), the fluorescence signal is monitored using excitation and emission wavelengths of 340 nm and 450 nm, respectively. The inhibitor dose-response curve may be analyzed using a normalized IC50 regression curve fitted with a control-based normalization.

[0320] Example C: p-ERK cell assay p-ERK cell assay using Alpha Screen® Sure Fire™ Phospho-ERK 1 / 2 Kit (PerkinElmer): KYSE-520 cells (30,000 cells / well) were grown overnight in 96-well plate cultures and treated with Shp2 inhibitors at concentrations of 20, 6.6, 2.2, 0.74, 0.24, 0.08, and 0.027 μM at 37°C for 2 hours. Incubation was completed by adding 30 μL of lysis buffer (PerkinElmer) supplied by the SureFire phospho-extracellular signal-regulated kinase (pERK) assay kit (PerkinElmer). Samples were processed according to the manufacturer's instructions. Fluorescence signals from pERK were measured twice using a 2101 multi-label reader (Perkin Elmer Envision). Inhibition percentages were normalized by the total ERK signal and compared to a DMSO vehicle control.

[0321] Example D: Colony formation assay and cell proliferation assay KYSE-520 cells (1500 cells / well) are plated in 300 μL of medium (RPMI-1640, Lonza containing 10% FBS) on a 24-well plate. For drug treatment, the compound of the present invention is added at various concentrations (20, 10, 5, 2.5, 1.25 μM) 24 hours and 5 days after plating the cells. On day 11, colonies are stained with 0.2% crystal violet (MP Biomedicals) and then dissolved in 20% acetic acid for quantification using a Spectramax reader (Thermo Scientific). In the cell proliferation assay, cells (1500 cells / well) are plated in 100 μL of medium (RPMI-1640, Lonza containing 10% FBS) on a 96-well plate. On day 6, 50 μL of Celltiter-Glo reagent (Promega) was added, and the luminescence signal was measured according to the supplier's (Promega) instructions.

[0322] Example E: Protein tyrosine phosphatase (PTP) assay and IC of inhibitors 50 measurement The phosphatase activity of SHP2 was monitored using the surrogate substrate DiFMUP in a fluorescence assay format. The phosphatase reaction was performed at room temperature on a 96-well black flat-bottom polystyrene plate with a final reaction volume of 100 μL using the following assay buffer conditions: 60 mM HEPES, pH 7.2, 75 mM NaCl, 75 mM KCl, 1 mM EDTA, 0.05% Tween-20, and 5 mM DTT.

[0323] Compound IC 50 To determine the inhibitors, eight dose-response curves were created twice with overlapping data. The compounds were incubated with 100 ng / mL of human recombinant SHP2 and 0.5 μM of the activating peptide IRS1_pY1172(dPEG8)pY1222 (sequence H2N-LN(pY)IDLDLV(dPEG8)LST(pY)ASINFQK-amide) (SEQ ID NO: 1) at concentrations ranging from 0 μM to 10 μM. After incubation at room temperature (23-27°C) for 30 minutes, the surrogate substrate DiFMUP (200 μM) was added to the reaction mixture, and the mixture was incubated at room temperature for another 30 minutes. Fluorescence signals were monitored using a microplate reader (Spectramax M5e, Molecular Dynamics) at excitation and emission wavelengths of 340 nm and 450 nm, respectively. Inhibitor dose-response curves were analyzed using SoftmaxPro v5.2 software.

[0324] Compounds in Examples 1, 2, 4, 5, 7, 8, 11, and 12 were subjected to IC (Implantable Cholesterol) assay according to the assay described above. 50 It was found to be an SHP2 inhibitor with a concentration of less than 9 μM. The compound of Example 13 was tested according to the assay described above, and IC 50 It was found to be greater than 10 μM.

[0325] In addition to the modifications described herein, various modifications of the present invention will be apparent to those skilled in the art from the foregoing description. Such modifications are also within the scope of the appended claims. References cited herein, including, but not limited to, all patents, patent applications, and publications, are incorporated herein by reference, provided that their sources are clearly indicated.

Claims

1. Formula A1: 【Chemistry 1】 [In the formula: L is O, S, or absent; X １ is N or CR Ｘ１ And; X ２ is N or CR Ｘ２ And; Y １ is N or CR Ｙ１ And; Y ２ is N or CR Ｙ２ And; Here, X １ , X ２ , Y １ and Y ２ are at most three and simultaneously N; R １ C ６－１０ Ariel, C ３－１４ The cycloalkyl group is a 5-14 member heteroaryl group, or a 4-14 member heterocycloalkyl group, each being Cy １ Hello, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, CN, NO ２ , 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 It may be substituted with one, two, three, four, or five substituents selected more independently, where C １－６ Alkyl, C ２－６ Alkenyl and C ２－６ Alkynyl is Cy １ , halo, CN, NO ２ , 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<000...​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ R ２ａ , R ２ｂ , R ４ａ , R ４ｂ , R ５ａ , R ５ｂ , R ７ａ , and R ７ｂ These are H and C, which are independent of each other. １－４ Alkyl, C １－４ Alkoxy, amino, hydroxy, C ３－８ Cycloalkyl and C １－４ Selected from alkylaminos; R ３ and R ６ These are H, F, or C, each independently. １－４ Selected from alkyl groups; R ８ and R ９ These are H, Halo, and C, each independent of the others. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－４ 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 More selected, where the alkyl, C ２－６ Alkenyl and C ２－６ Alkinyl is a 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 They may be substituted with one, two, or three substituents selected more independently; Here R ８ and R ９ At least one of them is a group other than H; R Ｘ１ , R Ｘ２ , R Ｙ１ , and R Ｙ２ These are H and Cy, each independent of the others. ２ Hello, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, 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 Selected from, where C １－６ Alkyl, C ２－６ Alkenyl and C ２－６ Alkinil is Cy ２ Hello, 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 They may be substituted with one, two, or three substituents selected more independently; Each Cy １ C ６－１０ Ariel, C ３－７ A cycloalkyl group is independently selected from 5-10 membered heteroaryl groups and 4-10 membered heterocycloalkyl groups, each being a halo, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5-10 member heteroaryl-C １－４ Alkyl, 4-10 member heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , 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 They may be substituted with one, two, three, or four substituents selected more independently; Each Cy ２ C ６－１０ Ariel, C ３－７ A cycloalkyl group is independently selected from 5-10 membered heteroaryl groups and 4-10 membered heterocycloalkyl groups, each being a halo, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5-10 member heteroaryl-C １－４ Alkyl, 4-10 member heterocycloalkyl-C １－４ Alkyl, 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 They may be substituted with one, two, three, or four substituents selected more independently; Each R ａ１ , R ｂ１ , R ｃ１ , R ｄ１ , R ａ３ , R ｂ３ , R ｃ３ , and R ｄ３ H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ６－１０ Ariel, 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 member heteroaryl-C １－４ Alkyl and 4-10 member heterocycloalkyl-C １－４ Selected independently of alkyl, where R ａ１ , R ｂ１ , R ｃ１ , R ｄ１ , R ａ３ , R ｂ３ , R ｃ３ , and R ｄ３ of C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ６－１０ Ariel, 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 member heteroaryl-C １－４ Alkyl and 4-10 member heterocycloalkyl-C １－４ Alkyl is halo, C １－４ Alkyl, C １－４ Haloalkyl, C ２－６ Alkenil, C ２－６ Alkinyl, 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 They may be substituted with one, two, or three substituents selected more independently; Or R ｃ１ and R ｄ２ Together with the N atom to which they bond, they form CN, halo, and C １－４ Alkyl, C １－４ Haloalkyl, C １－６ Haloalkyl, C ２－６ Alkenil, C ２－６ Alkinyl, 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 Forming a 4-7 member heterocycloalkyl group which may be substituted with one, two, or three substituents selected more independently; Or R ｃ３ and R ｄ３ Together with the N atom to which they bond, they form CN, halo, and C １－４ Alkyl, C １－４ Haloalkyl, C １－６ Haloalkyl, C ２－６ Alkenil, C ２－６ Alkinyl, 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 Forms a 4-7 member heterocycloalkyl group which may be substituted with one, two, or three substituents selected more independently; Each R ａ２ , R ｂ２ , R ｃ２ , and R ｄ２ H and C １－４ Selected independently of alkyl; Each R ａ４ , R ｂ４ , R ｃ４ , and R ｄ４ H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ６－１０ Ariel, 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 member heteroaryl-C １－４ Alkyl and 4-10 member heterocycloalkyl-C １－４ Selected independently of alkyl, where C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ６－１０ Ariel, 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 member heteroaryl-C １－４ Alkyl and 4-10 member heterocycloalkyl-C １－４ Alkyl compounds are OH, CN, amino, halo, and C, respectively. １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl and C １－６ It may be substituted with one, two, or three substituents independently selected from the haloalkoxy; and Each R ｅ１ , R ｅ２ , R ｅ３ , and R ｅ４ H, C １－４ Independently selected from alkyl and CN; Herein, each of the heteroaryl or heterocycloalkyl groups comprises one, two, three, or four ring-forming heteroatoms independently selected from O, N, and S; and Here, one or more ring-forming C or N atoms of any of the heterocycloalkyl groups described above may be replaced with oxo (=O) groups. 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, wherein L is S, or a pharmaceutically acceptable salt thereof.

5. X １ A compound according to any one of claims 1 to 4, wherein N is present, or a pharmaceutically acceptable salt thereof.

6. X １ CR Ｘ１ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

7. X ２ A compound according to any one of claims 1 to 6, wherein N is present, or a pharmaceutically acceptable salt thereof.

8. X ２ CR Ｘ２ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.

9. X １ CR Ｘ１ X ２ A compound according to any one of claims 1 to 6, wherein N is present, or a pharmaceutically acceptable salt thereof.

10. Y １ A compound according to any one of claims 1 to 9, wherein is N, or a pharmaceutically acceptable salt thereof.

11. Y １ CR Ｙ１ The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

12. Y ２ A compound according to any one of claims 1 to 11, wherein N is present, or a pharmaceutically acceptable salt thereof.

13. Y ２ CR Ｙ２ The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

14. X １ CR Ｘ１ X ２ If N is Y ２ A compound according to any one of claims 1 to 6, wherein N is present, or a pharmaceutically acceptable salt thereof.

15. X １ CR Ｘ１ X ２ If N is Y １ A compound according to any one of claims 1 to 6, wherein N is present, or a pharmaceutically acceptable salt thereof.

16. X １ CR Ｘ１ X ２ N is Y １ If N is Y ２ A compound according to any one of claims 1 to 6, wherein N is present, or a pharmaceutically acceptable salt thereof.

17. R １ However, C ６－１０ It is an aryl or 5-14 member heteroaryl, each being Cy １ Hello, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, CN, NO ２ , 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 They may be substituted with one, two, three, four, or five substituents selected more independently, where the alkyl, C ２－６ Alkenyl and C ２－６ Alkinil, Cy １ Hello, CN, NO ２ , 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 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 selected more independently.

18. R １ is a phenyl or 6-membered heteroaryl, and each is Cy １ Hello, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, CN, NO ２ , 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 They may be substituted with one, two, three, four, or five substituents selected more independently, where the alkyl, C ２－６ Alkenyl and C ２－６ Alkinil, Cy １ Hello, CN, NO ２ , 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 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 selected more independently.

19. R １ is phenyl or a 6-membered heteroaryl, each of which is Cy １ , halo, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, CN, NO ２ , 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 here, where the alkyl, C ２－６ alkenyl, and C ２－６ alkynyl are Cy １ , halo, CN, NO ２ , 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 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 selected more independently.

20. R １ is phenyl or 6-membered heteroaryl, each of which is halo, C １－６ alkyl, C １－６ haloalkyl, CN, NO ２ 2, OR ａ１ 2, SR ａ１ 2, C(O)R ｂ１ 2, C(O)NR ｃ１ 2R ｄ１ 2, C(O)OR ａ１ 2, NR ｃ１ 2R ｄ１ 2, NR ｃ１ 2C(O)R ｂ１ 2, NR ｃ１ 2C(O)OR ａ１ 2, NR ｃ１ 2C(O)NR ｃ１ 2R ｄ１ 2, NR ｃ１ 2, S(O)R ｂ１ 2, NR ｃ１ 2, S(O) ２ 2R ｂ１ 2, NR ｃ１ 2, S(O) ２ 2, NR ｃ１ 2R ｄ１ 2, S(O)R ｂ１ 2, S(O)NR ｃ１ 2R ｄ１ 2, S(O) ２ 2R ｂ１ and S(O) ２ 2, NR ｃ１ 2R ｄ１ and may be substituted with 1, 2, 3, 4 or 5 substituents independently selected therefrom, wherein the alkyl, C ２－６ alkenyl, and C ２－６ alkynyl are halo, C １－６ alkyl, C １－６ haloalkyl, CN, NO<00009九十九8>2, OR ａ１ 2, SR ａ１ 2, C(O)R ｂ１ 2, C(O)NR ｃ１ 2R ｄ１ 2, C(O)OR ａ１ 2, NR ｃ１ 2R ｄ１ 2, NR ｃ１ 2C(O)R ｂ１ 2, NR ｃ１ 2C(O)OR<0001十天10>2, 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 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 selected more independently.

21. R １ However, F, Cl, methyl, and CF ３ A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, which is a phenyl that may be substituted with one, two, or three substituents selected more independently.

22. R １ However, F, Cl, methyl, and CF ３ A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, which is a pyridyl that may be substituted with one, two, or three substituents selected more independently.

23. R ３ and R ６ A compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein both are H.

24. R ２ａ , R ２ｂ , R ４ａ , R ４ｂ , R ５ａ , R ５ｂ , R ７ａ , and R ７ｂ A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein all of the atoms are H.

25. R ８ and R ９ However, H, Haro, C １－６ Alkyl, C １－４ Haloalkyl, OR ａ２ , and NR ｃ２ R ｄ２ Each is independently selected, where the alkyl is a halo, OR ａ２ , and NR ｃ２ R ｄ２ A compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, which may be substituted with one, two, or three substituents selected more independently.

26. R ８ and R ９ However, H, C １－４ Alkyl, OH, and NH ２ Each is selected independently, where the alkyl is NH ２ A compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, which may be substituted with.

27. R ８ and R ９ However, methyl and NH ２ A compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, which is selected independently of each other.

28. R Ｘ１ , R Ｘ２ , R Ｙ１ , and R Ｙ２ However, H, C １－６ Alkyl and NR ｃ３ R ｄ３ Each is selected independently, and here C １－６ Alkyl, Cy ２ Hello, 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 A compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, which may be substituted with one, two, or three substituents selected more independently.

29. R Ｘ１ However, H, C １－６ Alkyl and NR ｃ３ R ｄ３ Selected from, where C １－６ Alkyl, Cy ２ Hello, 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 A compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, which may be substituted with one, two, or three substituents selected more independently.

30. R Ｘ１ is methyl and NH ２ A compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, selected from among them.

31. R Ｘ２ A compound according to any one of claims 1 to 30, wherein is H, or a pharmaceutically acceptable salt thereof.

32. R Ｙ１ A compound according to any one of claims 1 to 31, wherein is H, or a pharmaceutically acceptable salt thereof.

33. R Ｙ２ A compound according to any one of claims 1 to 32, wherein is H, or a pharmaceutically acceptable salt thereof.

34. Formula A2: 【Chemistry 2】 A compound according to any one of claims 1 to 33, as shown in [the relevant document], or a pharmaceutically acceptable salt thereof.

35. Formula A2a or A2b: 【Transformation 3】 A compound according to any one of claims 1 to 33, as shown in [the relevant document], or a pharmaceutically acceptable salt thereof.

36. Formulas A3a, A3b, or A3c: 【Chemistry 4】 A compound according to any one of claims 1 to 33, as shown in [the relevant document], or a pharmaceutically acceptable salt thereof.

37. (3aR,5r,6aS)-2-(6-amino-5-(2-chloro-3-methylphenyl)pyrazine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-amine; (3aR,5r,6aS)-2-(6-amino-5-(2,3-dichlorophenyl)pyrazine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-amine; (3aR,5r,6aS)-2-(6-amino-5-(2-chloro-3-fluorophenyl)pyrazine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-amine; (3aR,5r,6aS)-2-(6-amino-5-(2-chloropyridine-3-yl)pyrazine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-amine; (3aR,5r,6aS)-2-(6-amino-5-(3-chloro-2-fluorophenyl)pyrazine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-amine; (3aR,5r,6aS)-2-(6-amino-5-(2-chloro-3-(trifluoromethyl)phenyl)pyrazine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-amine; (3aR,5s,6aS)-2-(6-amino-5-(2,3-dichlorophenyl)pyrazine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-amine; (3aR,5s,6aS)-2-(6-amino-5-(2-chloro-3-methylphenyl)pyrazine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-amine; 6-((3aR,5r,6aS)-5-(aminomethyl)-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-yl)-3-(2,3-dichlorophenyl)pyrazine-2-amine; 6-((3aR,5s,6aS)-5-(aminomethyl)-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-yl)-3-(2,3-dichlorophenyl)pyrazine-2-amine; (3aR,5r,6aS)-2-(4-amino-5-(2-chloro-3-methylphenyl)pyrimidine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-amine; (3aR,5r,6aS)-2-(4-amino-5-(2,3-dichlorophenyl)pyrimidine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-amine; (3aR,5r,6aS)-2-(4-amino-5-(2-chloro-3-fluorophenyl)pyrimidine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-amine; and (3aR,5r,6aS)-2-(4-amino-5-(2-chloropyridine-3-yl)pyrimidine-2-yl)-5-methyloctahydrocyclopenta[c]pyrrole-5-amine; A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is more selected.

38. A pharmaceutical composition comprising a compound according to any one of claims 1 to 37, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

39. A method for treating or preventing a disease in a patient, comprising administering to the patient in need of such treatment or prevention a therapeutically effective amount of a compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein the disease is mediated by the activity of SHP2.

40. The diseases include Noonan syndrome, Leopard syndrome, Cruzon syndrome, Jackson-Weiss syndrome, Beer-Stevenson-Curtis-Girata syndrome, Apert syndrome, Pfeiffer syndrome, Muenck syndrome, Seetzle-Kotzen-like syndrome, chondrodysplasia, SADDAN (severe chondrodysplasia with growth retardation and acanthosis nigricans), type I fatal dysplasia, type II fatal dysplasia, chondrodysplasia, Kallmann syndrome, myeloproliferative syndrome, and juvenile myelomonal syndrome. The method according to claim 39, selected from cystic leukemia, multiple myeloma, 8P11 myeloproliferative syndrome (EMS), pancreatic adenocarcinoma, prostate cancer, astrocytoma, transitional cell carcinoma of the bladder, thyroid cancer, cervical cancer, colorectal cancer, peripheral T-cell lymphoma, seminomas, neuroblastoma, melanoma, acute myeloid leukemia, chronic myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma, and gliablastoma.

41. Formula I: 【Transformation 5】 [In the formula: Y １ It is selected from CH and N; Y ２ CR １２ and selected from N; Y ３ NH and CR ８ R ９ More selected; R １ The group is selected from (C6-C10)aryl, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl, and 5-9 membered heteroaryl groups containing 1 to 4 heteroatoms selected from N, O, and S; where the aryl or heteroaryl is 1 to 5 R １０ Substitution with the base is also acceptable; R ２ａ and R ２ｂ Each of these is independently selected from hydrogen, (C1-C4) alkyl, (C1-C4) alkoxy, amino, hydroxy, (C3-C8) cycloalkyl, (C1-C4) alkylamino, and di(C1-C4) alkylamino; R ３ is hydrogen, fluoro, or (C1-C4) alkyl; R ４ａ and R ４ｂ Each of these is independently selected from hydrogen, halo, carbonyl, (C1-C4) alkyl, (C1-C4) alkoxy, amino, hydroxy, (C3-C8) cycloalkyl, (C1-C4) alkylamino, and di(C1-C4) alkylamino; R ５ａ and R ５ｂ is independently selected from hydrogen, halo, carbonyl, (C1-C4) alkyl, (C1-C4) alkoxy, amino, hydroxy, (C3-C8) cycloalkyl, (C1-C4) alkylamino and di(C1-C4) alkylamino; R ６ is selected from hydrogen, fluoro, or (C1-C4) alkyl; R ７ａ and R ７ｂ Each of these is independently selected from hydrogen, carbonyl, (C1-C4) alkyl, (C1-C4) alkoxy, amino, hydroxy, (C3-C8) cycloalkyl, (C1-C4) alkylamino, and di(C1-C4) alkylamino; R ８ This is selected from a 5-9 membered heteroaryl group containing hydrogen, (C1-C4) alkyl, (C3-C6) cycloalkyl, (C6-C10) aryl, and 1-4 heteroatoms selected from N, O, and S; R ９ NH ２ (C1-C4) alkylamino, di(C1-C4) alkylamino, NH ２ - (CH ２ )-, (C1-C4)alkyl-NH-(CH ２ )-, and di[(C1-C4)alkyl]N-(CH ２ ) - Selected from; Each R １０ Halo, amino, hydroxy, N ３ , (C1-C4) alkyl, hydroxy-substituted (C1-C4) alkyl, halo-substituted (C1-C4) alkyl, amino-substituted (C1-C4) alkyl, -C(O)OR １１ and -NHC(O)R １１ Selected more independently; Each R １１ is independently selected from hydrogen, phenyl, and naphthyl; where phenyl may be substituted with methoxy; R １２ This includes hydrogen, halo, cyano, (C1-C4) alkyl, (C1-C4) alkoxy, amino-carbonyl, halo-substituted (C1-C4) alkyl, halo-substituted (C1-C4) alkoxy, hydroxy-substituted (C1-C4) alkyl, amino-substituted (C1-C4) alkyl, and -S(=O)R. １２ａ , -SO ２ R １２ａ , -C(=S)R １２ａ , -C(=O)NR １２ａ R １２ｂ , -C(NH)NR １２ａ R １２ｂ and -NR １２ａ C(=O)R １２ｂ Selected from; where each R １２ａ and R １２ｂ [This is independently selected from hydrogen and (C1-C4) alkyl groups.] The compound indicated by or a pharmaceutically acceptable salt thereof.

42. Y １ N is Y ２ CR １２ And R １２ is hydrogen; Y ３ CR ８ R ９ And; R １ R has 1 or 2 １０ The compound according to claim 41, which is a (C6-C10) aryl that may be substituted with a group.

43. R １０ The compound according to claim 42, wherein each group is independently a halo.

44. Each R １０ The compound according to claim 43, wherein the group is independently chloro or fluoro.

45. Y ３ CR ８ R ９ And; R ８ The compound according to claim 44, wherein is hydrogen or (C1-C4) alkyl.

46. Y ３ CR ８ R ９ And; R ９ NH ２ The compound according to claim 45, selected from (C1-C4) alkylamino and di(C1-C4) alkylamino.

47. Y ３ CR ８ R ９ And; R ９ NH ２ - (CH ２ )-, (C1-C4)alkyl-NH-(CH ２ )-, and di[(C1-C4)alkyl]N-(CH ２ ) - A compound according to claim 45, selected from the above.

48. A pharmaceutical composition comprising the compound of claim 41 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

49. A method for treating a disease or disorder mediated by the activity of SHP2, comprising administering to a person in need of such treatment a prophylactic or therapeutically effective amount of the compound of claim 41 or a pharmaceutically acceptable salt thereof.

50. The method according to claim 49, wherein the disease or disorder mediated by the activity of SHP2 is selected from Noonan syndrome, Leopard syndrome, Cruzon syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, head and neck squamous cell carcinoma, gastric cancer, anaplastic large cell lymphoma, and gliablastoma.

Images