US 20200108071A1VIE INI (19 ) United States (12 ) Patent Application Publication ( 10 ) Pub . No .: US 2020/0108071 A1 Chin et al. (43 ) Pub . Date : Apr. 9 , 2020 (54 ) IMIDAZOPYRIMIDINE DERIVATIVES Publication Classification (51 ) Int. Cl. (71 ) Applicant: Gilead Sciences , Inc., Foster City , CA A61K 31/519 (2006.01 ) (US ) A61K 45/06 (2006.01 ) C07D 519/00 (2006.01 ) ( 72 ) Inventors: Gregory Chin , San Francisco , CA C07D 487/04 (2006.01 ) (US ) ; Michael O'Neil Hanrahan C070 471/04 (2006.01 ) Clarke , Redwood City , CA (US ) ; C070 471/10 (2006.01 ) Xiaochun Han , Santa Clara , CA (US ) ; (52 ) U.S. CI. Tim Hansen , San Francisco , CA ( US ) ; CPC A61K 31/519 (2013.01 ) ; A61K Yunfeng Eric Hu , San Mateo , CA ( 2013.01 ) ; CO7D 471/10 (2013.01 ) ; C07D (US ) ; Dmitry Koltun , Foster City , CA 487/04 (2013.01 ) ; C070 471/04 (2013.01 ) ; (US ) ; Ryan McFadden , Foster City , C07D 519/00 ( 2013.01 ) CA (US ) ; Michael R. Mish , Foster ( 57 ) ABSTRACT City , CA (US ) ; Eric Q. Parkhill , Union The present disclosure provides a compound of Formula ( I ) : City , CA (US ) ; David Sperandio , Palo Alto , CA (US ) ; Lianhong Xu , Palo Alto , CA (US ) ; Hai Yang , San Mateo , CA (US ) R ? ( 21 ) Appl . No.: 16 /591,092 N N B ; ( 22 ) Filed : Oct. 2 , 2019 ZZ2 Related U.S. Application Data or a pharmaceutically acceptable salt thereof as described herein . The present disclosure also provides pharmaceutical (60 ) Provisional application No. 62 / 857,386 , filed on Jun . compositions comprising a compound of Formula I, pro 5 , 2019, provisional application No. 62 /740,800 , filed cesses for preparing compounds of Formula I , therapeutic on Oct. 3 , 2018 . methods for treating cancers. US 2020/0108071 A1 Apr. 9, 2020 IMIDAZOPYRIMIDINE DERIVATIVES [ 0007 ] In one aspect, provided is a compound having the structure of formula I : CROSS REFERENCE TO RELATED APPLICATIONS [0001 ] This application claims the benefit of U.S. provi sional application Ser . No.62 / 740,800 filed on Oct. 3 , 2018 R and U.S. provisional application Ser. No. 62/ 857,386 filed on Jun . 5 , 2019. The entire contents of these applications are N incorporated herein by reference in their entirety . N B ; FIELD [0002 ] The present disclosure relates generally to com Z =a 22 pounds that have SHP2 inhibitory action , pharmaceutical compositions comprising said compounds , and methods of or a pharmaceutically acceptable salt thereof, wherein : making and using said compounds and pharmaceutical com A is selected from C6-10aryl , 5-10 membered heteroaryl , positions . C3-12cycloalkyl, and 4-12 membered heterocyclyl; each A is optionally substituted with one to six R4 independently BACKGROUND selected from halo , cyano , hydroxyl, azido , nitro , C1- alkyl , [0003 ] SHP2 (SH2 domain -containing protein tyrosine -NR Ra24" kylene - OH , oxo, = NRal phosphatase - 2 ) also known as PTPN11 ( protein tyrosine SRai, 9 CORC2, CONRalRa2 phosphatase , non -receptor type 11) is a cytoplasmic tyrosine COOR , -N (RC2 ) C ( O )Ra2 , N (R2 ) C ( O )OR2 kinase encoded by the PTPN11 gene . SHP2 can be activated N (R2 ) C (O )-NR2R42 -N (R2 ) SO ,R2 by a wide range of cytokines and growth factors and plays SO ,R2 , S02ORC2, SONRA'Ra2 , OSO , essential roles in development and homeostasis by regulat NRR2. O ( CO ) -N - Ra'ra , Cz.cycloalkyl , 3-8 ing key intracellular signaling pathways such as the RAS membered heterocyclyl, Co- laryl , 5-10 membered het mitogen activated kinase (MAPK ) pathway . eroaryl , Cl- alkylene- C3-2cycloalkyl , C1- alkylene [ 0004 ] The SHP2 protein contains two N - terminal SH2 (3-8 membered heterocyclyl) , C - alkylene- C6-1oaryl , and domains and a C - terminal phosphatase domain . The SH2 C - alkylene- (5-10 membered heteroaryl ); domains act as a conformational switch controlling the wherein the C3 - cycloalkyl, 3-8 membered heterocyclyl, activation and sub -cellular localization of SHP2 . In its C6-10aryl, 5-10 membered heteroaryl, C - alkylene -Cz . auto - inhibited form , the SH2 domains of SHP2 bind and scycloalkyl , C - alkylene-( 3-8 membered heterocyclyl) , physically occlude the catalytic site . Binding of the SH2 C - alkylene -C6-10aryl , and C -alkylene- ( 5-10 mem domains to phosphoproteins switches SHP2 to an open bered heteroaryl) of R4 are independently optionally substi conformation allowing substrates access to the catalytic site . tuted with one to three groups selected from halo , cyano , Phosphorylation of two tyrosine residues on the C - terminal hydroxyl, C1- alkyl , C - haloalkyl, C - alkoxyl, and tail of SHP2 can recruit proteins important for downstream C1-4alkylene - OH ; and signaling, thus SHP2 has catalytic and scaffolding functions . wherein the 5-10 membered heteroaryl of A , and R4 contains [ 0005 ] Somatic mutations in SHP2 which disrupt auto one to five heteroatoms independently selected from S , N , inhibition have been found in juvenile myelomonocytic and O , and optionally comprises one to three C ( O ) or one leukemia ( JMML) , acute leukemias, and are found rarely in S ( O ) 2 ; neuroblastomas, AML /MDS , CMML , melanoma , and can L is selected from a bond , -S ( O ) ; -N (RI ) cers of the lung , breast , colon and thyroid . Germline muta C (RL2R23 ) — , C (RL2R23 ) -C( R?2R23 ) , C (R2 ) EC tions in SHP2 have been identified in about half of patients (R2 ) , and C ( O ) with Noonan's syndrome and in most patients with LEOP Rlis selected from H , C1- galkyl, C3-6cycloalkyl, 3-6 mem ARD syndrome. SHP2 , therefore , represents a target for bered heterocyclyl, C ( O ) C1- talkyl , (SO2 ) -C1 development of novel therapies for the treatment of various talkyl, and 5-6 membered heteroaryl ; wherein each C3-6cy diseases . cloalkyl, 3-6 membered heterocyclyl , and 5-6 membered heteroaryl of R?l is optionally substituted with one to three SUMMARY groups selected from halo , C - alkyl , and C - haloalkyl; and [ 0006 ] The present disclosure provides compounds that R22 and RL3 are independently selected from H , halo , are SHP2 inhibitors . The disclosure also provides compo hydroxyl, C1- alkyl, Chaloalkyl, Calkylene -OH , and sitions , including pharmaceutical compositions , kits that C3-6cycloalkyl ; wherein each C1- alkylene -OH , and C3-6cy include the compounds, and methods of using ( or adminis cloalkyl of R22 and R23 is optionally substituted with one to tering ) and making the compounds . The compounds pro three halo ; or vided herein are useful in treating diseases, disorders , or R22 and R23 together with the atom to which they are conditions that are associated with SHP2 modulation . The attached form a 3-6 membered cycloalkyl or heterocyclyl; disclosure also provides compounds for use in therapy . The wherein the 3-6 membered cycloalkyl or heterocyclyl is disclosure further provides compounds for use in a method optionally substituted with one to three groups selected from of treating a disease , disorder, or condition that is associated halo , hydroxyl , C1-4alkoxyl , ( SO2) C1- galkyl , oxo , and with SHP2 modulation . Moreover, the disclosure provides nitro ; uses of the compounds in the manufacture of a medicament z and Z are independently selected from N and CR3; for the treatment of a disease , disorder or condition that is wherein R3 is selected from H , halo , hydroxyl, cyano , associated with SHP2 modulation . C -4alkyl, Cl- haloalkyl, Cl- 4alkoxyl , C1-4alkylene- OH , US 2020/0108071 A1 Apr. 9, 2020 2 -NRC RC , C ( O )ORCI , Co- loaryl , and 5-10 membered wherein the ring E is selected from cycloalkyl, hetercyclyl , heteroaryl ; wherein each Co- 10aryl, and 5-10 membered aryl, and heteroaryl; and wherein the ring E is optionally heteroaryl of R3 is independently optionally substituted with substituted with one to three groups selected from halo , one to three groups independently selected from halo , cyano , hydroxyl, azido , nitro , Cl- alkyl , C1-6haloalkyl, hydroxyl, cyano , C1- alkyl, C - haloalkyl, C- alkoxyl , C1- alkoxyl , C - alkylene -OH , oxo , NR SRI -N (R1 ) SORCI , and SO , RCI; Oral, -NRalRa2 , CORa2, CONRalRa2 R ' is selected from H , halo , - NRC RC2 , C - alkyl, and C.4 COOR2 N ( R ^ 2 ) C ( O ) R22, N ( Ra2) C ( O ) ORa2 haloalkyl; -N (R2 ) C ( O ) -NR2RaRa2, -N (Ra2SO , Ra2 B is selected from SO , Ra2, SO , OR2 SO , NRIR2, 0 - S02 NR Ra2 , O (CO ) NRIR 2, C3.gcycloalkyl , 3-8 mem bered heterocyclyl, Co- loaryl, 5-10 membered heteroaryl, C alkylene -C3 - cycloalkyl, C. alkylene-( 3-8 mem bered heterocyclyl) , C1- alkylene -C6-10aryl , and Cl N 4alkylene-( 5-10 membered heteroaryl) ; ( R22) ?, and Ral is selected from H , C1- alkyl, C1- haloalkyl, C1-4alky Yol 11 lene- OH , C - alkylene- COOR (2 , C1- alkylene- C . (R2 ) m - X2 4alkoxyl, and -C( O ) -NH2; Ra2 is selected from H ,Calkyl , C - haloalkyl, C - alky (R2 ) m lene- OH , C3- cycloalkyl , 3-8 membered heterocyclyl, Co- loaryl , and 5-10 membered heteroaryl; wherein the C -4alkyl, C1- haloalkyl , C1- alkylene -OH , C3-8 cycloalkyl, * (R22 ) heteroaryl3-8 membered of Ra2 heterocyclyl are independently , Co- loaryl optionally, and 5-6 memberedsubstituted with one to three groups selected from halo , cyano , Xl is selected from CRPZ CHR ?, CH2- , hydroxyl, COORa3, C alkyl, C - haloalkyl, C. alky NR2— , and S (O ) — ; lene -OH , and C1-4alkoxyl1 ; wherein Ra3 is selected from H , X2 is selected from CR -22 CHR22 CH Calkyl , and C -haloalkyl; O 9 NH , -NR22 COM , and S ( O ) ; X is selected from CH and N ; Rel and Rº2 are independently selected from H , C1- alkyl, each R ’ is independently selected from halo , cyano , nitro , and C1-