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NZ790210A - Novel heterocyclic derivatives useful as SHP2 inhibitors - Google Patents

Novel heterocyclic derivatives useful as SHP2 inhibitors Download PDF

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Publication number
NZ790210A
NZ790210A NZ790210A NZ79021018A NZ790210A NZ 790210 A NZ790210 A NZ 790210A NZ 790210 A NZ790210 A NZ 790210A NZ 79021018 A NZ79021018 A NZ 79021018A NZ 790210 A NZ790210 A NZ 790210A
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NZ
New Zealand
Prior art keywords
amin0
amine
substituted
thio
pyraziny1
Prior art date
Application number
NZ790210A
Inventor
Panliang Gao
Huifeng Han
Shaojing Hu
Di Kang
Cunbo Ma
Xinping Wu
Zilong Xu
Original Assignee
Jacobio Pharmaceuticals Co Ltd
Filing date
Publication date
Application filed by Jacobio Pharmaceuticals Co Ltd filed Critical Jacobio Pharmaceuticals Co Ltd
Publication of NZ790210A publication Critical patent/NZ790210A/en

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Abstract

This invention relates to certain novel pyrazine derivatives (Formula I) as SHP2 inhibitors which is shown as formula I, their synthesis and their use for treating a SHP2 mediated disorder. More particularly, this invention is directed to fused heterocyclic group derivatives useful as inhibitors of SHP2, methods for producing such compounds and methods for treating a SHP2-mediated disorder. SHP2, methods for producing such compounds and methods for treating a SHP2-mediated disorder.

Description

THE DESCRIPTION NOVEL HETEROCYCLIC DERIVATIVES USEFULAS SHP2 INHIBITORS The present application is a divisional of NZ 758458, which is the national phase entry of , the entire disclosure of which is incorporated herein by reference in their entirety.
Technical Field This invention relates to certain novel pyrazine derivatives (Formula I, II, III or IV) as SHP2 tors which is shown as Formula I, II, III or IV, their synthesis and their use for treating a SHP2 mediated disorder. More particularly, this ion is directed to fused heterocyclic derivatives useful as inhibitors of SHP2, s for producing such compounds and methods for treating a SHP2-mediated disorder.
Background Art SHP2 (The Src Homolgy-2 phosphatease) is a non-receptor protein tyrosine phosphatase encoded by the PTPNl1 gene that harbors a cal tyrosine phosphatase domain and two N-terminal Src homology 2 (SH2) domains and a C-terminal tail. The two SH2 domains control the subcellular localization and functional regulation of SHP2. In its inactive state, the N-term inal SH2 domain blocks the PTP domain and this autoinhibition is relieved by binding of the SH2 domains to specific phosphotyrosine sites on receptors or receptor-associated adaptor proteins.
The stimulation, for example, by cytokines or growth factors leads to exposure of the catalytic site resulting in enzym atic activation of SHP2.
SHP2 is widely expressed and participated in multiple cell signaling processes, such as the Ras-Erk, PI3K-Akt, Jak-Stat, Met, FGFR, EGFR, and insulin ors and NF-kB pathways, in which plays an ant role in proliferation, differentiation, cell cycle maintenance and migration.
The hyp eractivation of SHP2 catalytic activity caused by either germline or somatic ons in PTPNl 1 have been identified in patients with Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemias, ysplastic syndrome, B cell acute lym phoblastic leukemia/lym phoma, and acute d leukemia. In addition, activating mutations of PTPNll have been found in solid tumors as well, such as lung cancer, colon cancer, melanoma, neuroblastoma, and cellular carcinoma. Therefore, the presence of activated or up-regulated SHP2 protein in human cancers and other e make SHP2 an excellent target for development of novel ies. The nds of the present invention fulfill the need of small les in order to inhibit the activity of SHP2.
Summary of Invention The present invention relates to heterocyclic ne compounds usefill as SHP2 inhibitors and for the treatment of conditions ed by SHP2. The compounds of the invention have the general structure as Formula I or a pharmaceutically acceptable salt: R3 R4 R4b z"\ I, \\ p Y-<\\A ’7-(R6)n R1 S \fN [Y3_- _ N W R2 \ / R1 Rsa 5b Y1_Y1 Each R1 is independently -H, halogen, -NH2, -CN, -OH, -N02, carboxyl, substituted or unsubstituted -C1_6alkoxy, or substituted or unsubstituted -C1_6alkyl; R2 is -H, halogen, -NH2, -CN, -OH, -N02, -N3, carboxyl, -NHC1_6alkyl, -N(C1_6alkyl)2, -CONH2, -CONHC1_6alkyl, 1_6alkyl)2, -COC1_6alkyl, -NHCOC1_6alkyl, alkyl-CO-C1_6alkyl, substituted or tituted -C1_6alkoxy, substituted or unsubstituted -C1_6alkyl or -C5_10heterocyclic; or R2 combines with R1 to which is adjacent to form a 6-10 membered aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclic ring, and each of the ring systems is independently optionally substituted; Each Y1 is independently N or CRla; Each R13 is independently -H, halogen, -NH2, -CN, -OH, -N02, yl, substituted or unsubstituted lkoxy, or substituted or unsubstituted -C1_6alkyl; R3 is -H or -NH2; Each of R43 and R4b is independently -H, halogen, -NH2, -CN, -OH, -N02, carboxyl, substituted or unsubstituted -C1_6alkoxy, or substituted or unsubstituted -C1_6alkyl; or R43 and R41, together with the carbon atom to which they are both attached form CO, C=NH, or C=N—OH; pisO, 1,20r3; Each of R53 and Rsb is independently -H, halogen, -NH2, -CN, -OH, -N02, carboxyl, substituted or unsubstituted -C1_6alkoxy, or substituted or unsubstituted -C1_6alkyl; or R5,, and R51, together with the carbon atom to which they are both attached form a 3-10 membered heterocyclic or 5-10 membered heteroaryl or C=NR5C, and Rsc is -H, or lkyl; and each of the ring systems is independently optionally substituted; qis0,l,2,3or4; W is absent, -0, -S or -NRW; and RW is -H, halogen, -NH2, -CN, -OH, -NO2, carboxyl, -CO-C1_6alkyl, -CO-OC1_6alkyl, -C1_6alkyl-O- C1_6alkoxy, substituted or unsubstituted -C1_6alkoxy, or substituted or unsubstituted -C1_6alkyl; Ring A is absent or a 3-10 membered ring; = represents a single bond or a double bond; When ring A is absent, Y2 is CR2aR2b, NR2a or O, and Y3 is CR33R3b, NR3a or 0; When ring A is a 3-10 membered ring, i) Y2 is CR2, or N, and Y3 is CR3, or N, when = represents a single bond; or ii) Y2 is C, and Y3 is C, when = represents a double bond; Each of R2,l and R2b is independently -H, halogen, -NH2, -CN, -OH, -NO2, yl, substituted or unsubstituted -C1_6all The t invention further provides some preferred technical solutions with regard to compound of Formula I.
In some embodiments of Formula I: Each R1 is independently -H, halogen, -NH2, -CN, -OH, -NO2, carboxyl, substituted or unsubstituted -C1_6alkoxy, or substituted or unsubstituted kyl; R2 is -H, halogen, -NH2, -CN, -OH, -NO2, -N3, carboxyl, -NHC1_6alkyl, -N(C1_6alkyl)2, -CONH2, -CONHC1_6all In some embodiments of Formula I, each R1 is independently -H; -F; -Cl; -Br; -NH2; -CN; -OH; -N02; carboxyl; -C1_6alkyl; -C1_6alkoxy; -C1_6alkyl substituted with halogen, -NH2, -CN, -OH, -N02, carboxyl, -C1_3alkyl or lkoxy; or lkoxy substituted with halogen, -NH2, -CN, -OH, -N02, carboxyl, -C1_3alkyl or -C1_3alkoxy.
In some embodiments of Formula I, each R1 is independently -H; -F; -Cl; -Br; -NH2; -CN; -OH; -N02; carboxyl; -C1_3alkyl; lkoxy; -C1_6alkyl substituted with -F, -Cl, -Br, -I, -NH2, -CN, -OH, -N02, yl, -C1_3alkyl or -C1_3alkoxy; or lkoxy substituted with -F, -Cl, -Br, -I, -NH2, -CN, -OH, -N02, carboxyl, -C1_3alkyl or -C1_3alkoxy.
In some embodiments of a I, each R1 is independently -H; -F; -Cl; -Br; -NH2; -CN; -OH; -N02; carboxyl; methyl; ethyl; ; isopropyl; methoxy; ethoxy; propoxy; isopropoxy; -C1_3alkyl substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; or C1_3alkoxy substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
In some embodiments of Formula I, each R1 is independently -H; -F; -Cl; -Br; -NH2; -CN; -OH; methyl; ethyl; propyl; isopropyl; methoxy; ethoxy; propoxy; isopropoxy; or methyl substituted with one or more substituents each independently selected from -F, -Cl, -Br, -NH2, -CN, -OH, -NO2, carboxyl, , ethyl, propyl, isopropyl, methoxy, , propoxy or isopropoxy.
In some embodiments of Formula I, each R1 is ndently -C1, or -H.
In some embodiments of Formula 1, R2 is -H; -F; -Cl; -Br; -NH2; -CN; -OH; -NO2; -N3; carboxyl; -C1_6alkyl; -C1_6alkoxy; -NHC1_6alkyl; -N(C1_6alkyl)2; -CONH2; -CONHC1_6alkyl; -CON(C1_6alkyl)2; 6alkyl; -NHCOC1_6alkyl; -N(C1_6alkyl)-CO-C1-6alkyl; -C5_10heterocyclic; lkyl substituted with halogen, -NH2, -CN, -OH, -NO2, carboxyl, -C1_3alkyl or -C1_3alkoxy; or -C1_6alkoxy substituted with halogen, -NH2, -CN, -OH, -NO2, carboxyl, -C1_3alkyl or -C1_3alkoxy.
In some embodiments of Formula 1, R2 is -H; -F; -Cl; -Br; -NH2; -CN; -OH; -NO2; -N3; carboxyl; -C1_3alkyl; lkoxy; -NHC1_3alkyl; -N(C1_3alkyl)2; -CONH2; -CONHC1_3alkyl; -CON(C1_3alkyl)2; -COC1_3alkyl; -NHCOC1_3alkyl; -N(C1_3alkyl)-CO-C1-3alkyl; -C5_10heterocyclic; -C1_6alkyl substituted with -F, -Cl, -Br, -I, -NH2, -CN, -OH, -NO2, carboxyl, -C1_3alkyl or -C1_3alkoxy; or lkoxy tuted with -F, -Cl, -Br, -I, -NH2, -CN, -OH, -NO2, carboxyl, -C1_3alkyl or -C1_3alkoxy.
In some embodiments of Formula 1, R2 is -H; -F; -Cl; -Br; -NH2; -CN; -OH; -NO2; -N3; carboxyl; methyl; ethyl; propyl; isopropyl; methoxy; ethoxy; propoxy; isopropoxy; ; -N(CH3)2; -CONH2; -CONHCH3; -CON(CH3)2; -COCH3; -NH-COCH3; -N(CH3)-COCH3; 5D to"n0- ; -C1_3alkyl tuted with -F, -Cl, -Br, -NH2, -CN, -OH, -NO2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; or koxy substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -NO2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or poxy.
In some embodiments of Formula I, R2 is -H; -F; -Cl; -Br; -NH2; -CN; -OH; -NO2; carboxyl; methyl; ethyl; propyl; isopropyl; methoxy; ; propoxy; isopropoxy; or methyl substituted with one or more tuents each independently selected from -F, -Cl, -Br, -NH2, -CN, -OH, -NO2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
In some embodiments of Formula I, R2 is -NH2.
In some embodiments of Formula I, R2 combines with R1 to which is adjacent to form a 5-10 membered heteroaryl or 5-10 membered heterocyclic ring, and each of the ring systems is ndently optionally substituted with halogen, -NH2, -CN, -OH, -NO2, carboxyl, oxo, =0, , substituted or unsubstituted -C1_6alkoxy, substituted or unsubstituted -C1_6alkyl, -C1_6alkylene-O-C1-6alkyl, -C1_6alkylene-COOH, -C1_6alkylene-NHCONH2, -CO-N(C1_6alky)2, -C1-6alkylene-NHCO-C1-6alkyl, -CO-CO-N(C1_6alkyl)2, _6alkyl, -SONH2, -SOzNH2, -SOCH3, -SOzCH3, -C5_1oheterocyclic or -C5_10heteroaryl.
In some embodiments of Formula I, R2 combines with R1 to which is adjacent to form a -membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 8-membered heterocyclic or 9-membered heterocyclic; and each of the aryl or heterocyclic contains 1 or 2 heteroatoms selected from N or O; and each of the ring systems is independently optionally substituted with -F, -Cl, -Br, -I, -NH2, -CN, -OH, -N02, carboxyl, oxo, =0, , substituted or unsubstituted C1_3alkoxy, substituted or unsubstituted C1_3alkyl, -C1_3alkylene-O-C1-3alkyl, -C1_3alkylene-COOH, -C1_3alkylene-NHCONH2, -CO-N(C1_3alky)2, -C1-3alkylene-NHCO-C1-3alkyl, -CO-CO-N(C1_3alkyl)2, -CO-C1_3alkyl, , -SOzNH2, -SOCH3 or -SOZCH3.
In some embodiments of Formula I, R2 combines with R1 to which is adjacent to form a -membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, ered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic, 7-membered cyclic or ered heterocyclic; and each of the heteroaryl or cyclic contains 1 heteroatom selected from N or O; and each of the ring systems is independently optionally substituted with -F; -Cl; -Br; -NH2; -CN; -OH; -N02; carboxyl; oxo; =0; -CONH2; methyl; ethyl; propyl; isopropyl; methoxy; ; propoxy; isopropoxy; H3; -CH2COOH; -CH2NHCONH2; -CON(CH3)2; -CH2NHCOCH3; N(CH3)2; -COCH3; -C1_3alkyl substituted with halogen, -NH2, -CN, -OH, -N02 or carboxyl; or -C1_3alkoxy substituted with halogen, -NH2, -CN, -OH, -N02 or carboxyl.
In some embodiments of Formula I, R2 combines with R1 to which is adjacent to form a -membered cyclic, and optionally substituted with -F or -COCH3.
In some embodiments of Formula I, R2 and R1 which is adjacent to, together with the aromatic ring they are attached to formDYNig.
In some embodiments of Formula I, each Y1 is independently N or CH.
In some embodiments of Formula I, each of R43 and R4b is independently -H, -F, -Cl, -Br, -I, -NH2, -CN, -OH, -N02, carboxyl, substituted or unsubstituted -C1_6alkoxy, or substituted or unsubstituted -C1_6alkyl; or R43 and R41, together with the carbon atom to which they are both attached form C=O, C=NH, or C=N-OH.
In some embodiments of Formula I, each of R43 and R4b is independently -H; -F; -Cl; -Br; -NH2; -CN; -OH; -N02; carboxyl; lkyl; -C1_3alkoxy; -C1_6alkyl tuted with -F, -Cl, -Br, -I, -NH2, -CN, -OH, -N02, carboxyl, lkyl or -C1_3alkoxy; or C1_6alkoxy substituted with -F, -Cl, -Br, -I, -NH2, -CN, -OH, -N02, yl, -C1_3alkyl or -C1_3alkoxy; or R43 and R41, together with the carbon atom to which they are both attached form C=O.
In some embodiments ofFormula I, each ofR43 or R4b is independently -H; -F; -Cl; -Br; -NH2; -CN; -OH; -N02; yl; methyl; ethyl; ; isopropyl; methoxy; ethoxy; propoxy; isopropoxy; C1_3alkyl tuted with -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; or C1_3alkoxy substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; or R43 and R4b together with the carbon atom to which they are both attached form In some embodiments of Formula I, each of R43 and R4b is independently -H, -NH2, -OH, methyl, ethyl, methoxy, ethoxy; or R43 and R4b together with the carbon atom to which they are both attached form C=O.
In some embodiments of Formula I, p is 0, l, 2 or 3.
In some embodiments of Formula I, each of R53 and Rsb is independently -H; -F; -Cl; -Br; -I; -NH2; -CN; -OH; -N02; carboxyl; -C1_3alkyl; -C1_3alkoxy; -C1_6alkyl substituted with -F, -Cl, -Br, -I, -NH2, -CN, -OH, -N02, carboxyl, -C1_3alkyl or -C1_3alkoxy; or -C1_6alkoxy substituted with -F, -Cl, -Br, -I, -NH2, -CN, -OH, -N02, carboxyl, -C1_3alkyl or -C1_3alkoxy; orR5a and R5b together with the carbon atom to which they are both attached form 3-membered heterocyclic, 4-membered heterocyclic, ered heterocyclic, ered heterocyclic, 7-membered heterocyclic, 8-membered cyclic, 9-membered heterocyclic, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl or 9-membered aryl; and each ofthe heterocyclic or heteroaryl contains 1 or 2 heteroatoms selected from N or O; and each of the ring systems is independently optionally substituted with -H, -F, -Cl, -Br, -I, -NH2, -CN, -OH, -N02, carboxyl, tuted or unsubstituted -C1_3alkoxy, or substituted or unsubstituted -C1_3alkyl.
In some embodiments ofFormula I, each ofR53 or R5b is independently -H, -NH2, -OH, methyl, ethyl, methoxy or ethoxy; or R53 and R51, together with the carbon atom to which they are both attached form a 3-membered heterocyclic, 4-membered heterocyclic, 5-membered cyclic, 6-membered heterocyclic, ered heteroaryl or 6-membered heteroaryl; and each of the heterocyclic or heteroaryl contains 1 heteroatoms ed from N or O.
In some embodiments of Formula I, each of R53 or Rsb is independently -H or -NH2.
In some embodiments of Formula I, W is absent, 0, or NRW.
In some embodiments ofFormula I, W is NRw, and RW is -H, -F, -Cl, -Br, -I, -NH2, -CN, -OH, -N02, yl, -CO-C1_3alkyl, -COOC1_3alkyl, -C1_3alkyl-CO-C1_3alkyl, tuted or unsubstituted -C1_3alkoxy, or substituted or unsubstituted -C1_3alkyl.
In some embodiments of Formula I, W is NRW, and RW is -H; -F; -Cl; -Br; -NH2; -CN; -OH; -N02; carboxyl; methyl; ethyl; propyl; isopropyl; methoxy; ; propoxy; isopropoxy; -CO- methyl; -C1_3alkyl substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; or C1_3alkoxy substituted With -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, , ethyl, propyl, isopropyl, y, ethoxy, propoxy or isopropoxy.
In some embodiments of Formula I, ring A is 6-membered aryl, 7-membered aryl, 8-membered aryl, 9-membered aryl, lO-membered aryl; 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, lO-membered heteroaryl; 3-membered heterocyclic, 4-membered heterocyclic, ered heterocyclic, ered heterocyclic, 7-membered heterocyclic, ered heterocyclic, 9-membered heterocyclic, lO-membered heterocyclic; 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic, 6-membered carbocyclic, 7-membered carbocyclic, 8-membered carbocyclic, 9-membered carbocyclic or bered carbocyclic; and each of the heteroaryl contains 1, 2 or 3 heteroatoms ed from N, O or S; each of the heterocyclic contains 1, 2 or 3 heteroatoms selected from N or O.
In some embodiments of Formula I, ring A is 6-membered aryl, 7-membered aryl, 8-membered aryl; 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl; 3-membered heterocyclic, ered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 8-membered heterocyclic; 3-membered carbocyclic, ered carbocyclic, 5-membered carbocyclic, 6-membered carbocyclic, 7-membered carbocyclic or 8-membered carbocyclic; and each of the heteroaryl contains 1 or 2 heteroatoms selected from N, O or S; each of the heterocyclic ns 1 or 2 atoms selected from N or O. 3 w" w ~~ ‘3‘ In some embodiments of Formula I ring Ais 2}} ,1: U ,iDfiD, x41"" 3i , , SLIM? AN :D a]? ":3 :0 iQ :3 {SQ :D :D EN," ‘4qu \fN fN’O IEN/\ ‘EN ‘13?" ‘35 n H ‘35 N\ ~35" ‘F'I/ ~35 AU AJVNH "Q AU A o 9+3 ALI") ‘3‘ 0 1") H,}S_ ,ho,’"a S, [21:9, :43, "RD (910:3:"1: ,Q::L"::1~Q::1L"::~Q:~Q:::1QNH:liI;j QUQQQ:Q::Q:Q :Q11"?Q1:Q:1L::5.,::::,::Q,:Q,:11,:Q,:Q:::11::111, MQQQQQ o,:::ZJ,::Q: i::Qi:Q,:Q:Q Q '2' 1113;102:132 If: N": i01011Q D":0 :D,:1), :11] :0, 111 some embodiments ofFormulaI ringAis 51>} QQWQQQDQQQQQ Q::Q: In some embodiments of a I, Y2 is CRza or N, and Y3 is CR33 or N.
In some embodiments of Formula I, Y2 is CRza and Y3 is CR33.
In some ments of Formula I, each of R23 and R21, is independently -H; -F; -Cl; -Br; -NH2; -CN; -OH; -N02; carboxyl; -C1_3alkyl; -C1_3alkoxy; -C1_6alkyl substituted with -F, -Cl, -Br, -I, -NH2, -CN, -OH, -N02, carboxyl, -C1_3alkyl or -C1_3alkoxy; or -C1_6alkoxy substituted with -F, -Cl, -Br, -I, -NH2, -CN, -OH, -N02, yl, -C1_3alkyl or -C1_3alkoxy.
In some embodiments of Formula I, each of R23 and R21, is independently -H; -F; -Cl; -Br; -NH2; -CN; -OH; -N02; carboxyl; methyl; ethyl; propyl; isopropyl; methoxy; ; propoxy; isopropoxy; -C1_3alkyl substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; or -C1_3alkoxy substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -N02, yl, , ethyl, propyl, isopropyl, methoxy, ethoxy, y or isopropoxy.
In some embodiments of Formula I, each of R23 and R21, is independently -H or methyl.
In some embodiments of Formula I, R23 is -H or methyl, and R21, is -H.
In some embodiments of Formula I, R23 and R21, are both -H.
In some embodiments of Formula I, Y2 is CH or N, and Y3 is CH or N.
In some embodiments of a I, Y2 is CH, and Y3 is CH.
In some embodiments of Formula I, Y2 is CH, and Y3 is N.
In some embodiments of Formula I, Y2 is N, and Y3 is CH.
In some embodiments ula I, each ofR33 and R3b is independently -H, -F, -Cl, -Br, -NH2, -CN, -OH, -NO2, carboxyl, -C1_3alkyl, -C1_3alkoxy, or -C1_6alkyl or -C1_6alkoxy substituted with -F, -Cl, -Br, -I, -NH2, -CN, -OH, -NO2, carboxyl, -C1_3alkyl or lkoxy.
In some embodiments of Formula I, each of R33 and R3b is independently -H.
In some embodiments of Formula I, each R6 is independently -H, -F, -Cl, -Br, -I, -NR63R6b, -CN, -OH, oxo, =0, carboxyl, -C1_6alkoxy, -C1_6alkyl, -C1_6alkylene-NR63R6b, -C1_6alkylene-O-C1-6alkyl, -C1_6alkylene-CO-OR63, -C1-6alkylene-C5-10heterocyclic, -C1-6alkylene-C5_1oheteoaryl, -C1_6alkylene-CO-NR63R61,, -C1-6alkylene-NR63-CO-NR63R6b, -C1_6alkylene-NR63-CO-C1-6alkyl, -CO-NR63R6b, -NR63R6b, -CO-C1_6alkyl, -CO-C1_6alkylene-NR63R61,, -CO-NR63-C5_loheterocyclic, -CO-NR63-C5-1oheterocyclic, -CO-C5_1oheterocyclic, -O-C1_6alkylene-CO-OR63, -O-C1-6alkylene-CO-NR63R6b, 6alkylene-NR63R6b, -O-C5_1ocarbocyclic, -NR63-CO-C1_6alkyl, -NR63-CO-NR63R61,, -NR63-CO-C5_1oheteoaryl, -NR63-C1_6alkylene-NR63R61,, -NR63-C1-6alkylene-C3_1oheterocyclic, -NR63-C1-6alkylene-C5-10heteroaryl, -S-C1_6alkyl, -SO2NR63R6b, -SO2C1_6alkyl, 3)2, -C5_1oheterocyclic or -C5_1oheteroaryl, and each ofwhich is independently optionally substituted -F, -Cl, -Br, -I, -NH2, -CN, -OH, -NO2, carboxyl, oxo, =0, substituted or unsubstituted -C1_3alkoxy, or substituted or unsubstituted -C1_3alkyl; or two adjacent R6 can be joined together to form a ered aryl; 3-membered carbocyclic, 4-membered yclic, 5-membered carbocyclic, ered carbocyclic; 5-membered heteroaryl, 6-membered heteroaryl; 3-membered heterocyclic, 4-membered cyclic, 5-membered heterocyclic or 6-membered heterocyclic; and and each of heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S; and each of the ring system is independently optionally substituted with halogen, -NH2, -CN, -OH, -NO2, =0, oxo, yl, -CONH2, -PO(C1_6alkyl)2, substituted or unsubstituted -C1_6alkoxy or substituted or unsubstituted -C1_6alkyl.
In some embodiments of Formula I, each R6 is independently -H, -F, -Cl, -Br, -NR63R61,, -CN, -OH, oxo, =0, carboxyl, -C1_6alkoxy, -C1_6alkyl, -C1_6alkylene-NR63R6b, -C1_6alkylene-O-C1-6alkyl, -C1_6alkylene-CO-OR63, -C1-6alkylene-C5-10heterocyclic, -C1-6alkylene-C5_1oheteoaryl, -C1_6alkylene-CO-NR63R61,, -C1-6alkylene-NRGa-CO-NRGBRéb, -CO-NR63R6b, -CO-CO-NR63R6b, -CO-C1_6alkyl, 63-C5_loheterocyclic, -CO-C5_10heterocyclic, -O-C5_1ocarbocyclic, -NR63-CO-C1_6alkyl, -NR63-CO-NR63R61,, -NR63-C1_6alkylene-NR63R61,, -NR63-C1-6alkylene-C3_loheterocyclic, -S-C1_6alkyl, -SO2NR63R6b, -SO2C1_6alkyl, -C5_1oheterocyclic or -C5_1oheteroaryl, and each ofwhich is independently optionally substituted -F, -Cl, Br, -NH2, -OH, carboxyl, oxo, =0, methyl, ethyl, propyl, pyl, methoxy, ethoxy, propoxy or isopropoxy; or two adjacent R6 can be joined together to form a 6-membered aryl; -membered carbocyclic, 5-membered heteroaryl or 5-membered heterocyclic; and and each of heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms ed from N, O or S; and each of the ring system is independently optionally substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -N02, =0, oxo, carboxyl, -CONH2, -PO(CH3)2, methyl, ethyl, , isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
In some embodiments of Formula I, each R6 is independently -H, -F, -Cl, -Br, -NR63R61,, -CN, -OH, oxo, =0, carboxyl, -C1_3alkoxy, -C1_3alkyl, lkylene-NR63R6b, -C1_3alkylene-O-C1-3alkyl, -C1_3alkylene-CO-OR63, -C1-3alkylene-C5-6heterocyclic, -C1-3alkylene-C5_6heteoaryl, -C1_3alkylene-CO-NR63R61,, -C1-3alkylene-NRGa-CO-NRGHRéb, -CO-NR63R6b, -CO-CO-NR63R6b, -CO-C1_3all In some embodiments of Formula I, each R6 is independently -F, -Cl, -Br, =0, -OH, -CN, o ‘g‘OH -NH2, $0" , -CH3, Eé, -CF3, X , -OCH3, -SCH3, -SOCH3, -SOzCH3, 3)2, 0 O Q #Ll/ BinTNHZ -PO(OC2H5)2, -NHSOZCH3, -C(O)NH2, , flag—<0 ,-NHCOCH3, o E 0,0o < c’> ;N N f \N -NHCONHCH3, ",0 fi,Q0 N,—\ ' In";N\"KM" 'E‘"\J, 'E'Qm\ two adjacent R6 can be joined together to form ii?" ,EIN" ,o,r F0.
In some embodiments of Formula I, each R61s independently methyl, ethyl, isopropyl, methoxy, ethoxy, =0, OX0, -OH, -CN, -NH2, -Cl, -BI', -CF3, -OCF3, -SOzNH2, -SOzCH3, -F, o O o o 0 | ,JL / O I O N\ _CH2NH2, .SCH3;$1 III , 33km, 2N\, , Fink, XV°\, *0", 2L" 0H, QLNNOH, 39%;, , O #kaxJLOI-Ia FiloU, £9 3 ifNN \es‘ /N\ \é/H H\ (\o ‘EN HN‘I‘I \re-‘En‘Nhi, HNJO, I {IN/W 9 9 9 9 a K/O, :i/Nd a HNCNH, "54 +5 LDH, or C}.
In some embodiments of Formula 1, ring A and the two adjacent R6 taken together to form s s 0 S Kg) I ‘ 0| I I "If m; "a "m _ / \ \ _ / \ WW VI?" "UH, H H H H 7 7 7 7 7 H7 7 7 7 7 7 fed" fir" 43"" "N AM "A", H H n / \ / \ / \ N — \ N _ \ _. _ _ \ _ _ \ H 11L H wk", 5"" g Qj> £le H E N rrr' H g‘ o N N g’ o E? MD0/ o I HNJ" I \ ‘ \é— S "'5‘ C(j" at)" / / Mf’ «w "a \ 0 £1 8 f it)"e3 3’ 1* 7 7 7 7 7 7 (I;"51:33; I l \ Q3 5‘" ‘é" / s / ME 3‘ \ N 3‘ N u @Né- EEJQNH @NH // "T" / is W/ 5 a a a a "I" "W A" ' @[ji fig?, CE); 4&1) «1:6N «" ‘2 '§//,N\ 40$ "ca6/ N // u u P‘i "M § ' ' H n 9 a a a a a a a a N "I‘M \ III-I _/éNI/\_/ \ N\E N / \ _/ \N / \N /| _/ \ §N|/ /N'/; N'/; ENI/ -gNl/ _/ N 44‘ ENI/N §N|/N\ "5‘:- H H . , H H. H 7 7 7 7 7 7 7 7 7 /\‘i-%/I\§’7\ Ix‘a/ \ w'w kN/PN\ NI/N N N/- Nl/ /|/ N Nb; MOI N//\N\ //; (\N\a H "5‘", H H N H // //§\ //,a‘ , , M'v A w at /N\N \ N’N\ N//\N N C//N\ -g / Nfi -§ / "(N _‘E/ -// N "1: 3L N ‘N\ //\N\ ‘N\ ‘13 / / //N // , 4;: N, g fi/wa 7 7 7 7 7 I I \ N "W "W" N M" "WI, m2 :3 \ \5’1’ I ,\ \ I o,N\ 31’ om? \ \3: I "E / I /§ \"ii, SQ s s u’ /N /N / °/ / / s 1." 1i s N’§~ /N w 7 7 7 7 7 7 7 l J‘AIII sfi‘ "1 J1N 15; , N\ N N N N N ’ / \ \ll'i 1; N1‘1’ N \ \N 111:1;\ I ,N N/ | 11o b: 11>"; KL} 11f» / /N N H ‘, N N N H ‘o /e"~ ".W N ‘, 171. "511 "11,1 , , , , , , N MN \ N ~11 -<’|'l-§111,1 \ 1;; \ ~31 N\ ~f& I \ | \N \N \ \ NW .nhv ‘3‘ \N ‘35 \N :95 N\ Sim :1;- /l1‘ 1% A G: jg kwN , N/J N; N N /I11 I I I N/ E‘ I a a a a a a a a Aw a" 1111m11m ‘1 C(11m11‘mN/N/ ,N/N/g, N/éi‘ ,3le/ //W,/N/ N/N/ , ,’k$. /, I Ni" "LN iii/33,511113 0;)?N301 @631 0:111 KIT 115%E; g00" 11561111111E111 I22 1 mm115"19$?" or '1‘" and each of the ring A is independently optionally substituted with another one or more R6.
In some ments of Formula I, n is 0, l, 2 or 3.
In some embodiments of Formula I, each of R63 and R6b is independently -H; -F;- Cl; -Br; -NH2; -CN; -OH; -N02; carboxyl; -C1_3alkyl; -C1_3alkoxy; -C1_3alkyl substituted with halogen, -NH2, -CN, -OH, -N02, -carboxyl, -C1_3alkyl or -C1_3alkoxy; or -C1_3alkoxy substituted with halogen, -NH2, -CN, -OH, -N02, carboxyl, -C1_3alkyl or -C1_3alkoxy.
In some embodiments of Formula I, each of R63 and R6b is independently -H; -F; -Cl; -Br; -NH2; -CN; -OH; -N02; carboxyl; ; ethyl; propyl; isopropyl; y; ethoxy; y; isopropoxy; -C1_3alkyl substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, y or isopropoxy; or lkoxy substituted with -F, -Cl, Br, -NH2, -CN, -OH, -N02, yl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
In some embodiments of Formula I, each of R63 and R6b is independently -H; -F; -Cl; -Br; -NH2; -CN; -OH; carboxyl; methyl; ethyl; isopropyl; methoxy; methyl substituted with -F, -Cl, -NH2, -OH, yl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; ethyl substituted with -F, -Cl, -NH2, -OH, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; or propyl substituted with -F, -Cl, -NH2, -OH, carboxyl, methyl, ethyl, , isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
In some embodiments of Formula I, each of R63 and R6b is independently -H, -CH3, -OH, or -CH2CH20H.
In some embodiments of Formula I, the compound is of Formula II: R3 is -H or -NH2; Each of R4,, or R4b is independently -H, halogen, -NH2, -CN, -OH, -N02, carboxyl, substituted or unsubstituted -C1_6alkoxy, or tuted or unsubstituted -C1_6alkyl; or R4,l and R41, er with the carbon atom to which they are both attached form C=O, C=NH, or C=N—OH; pisO, 1,20r3; Each of R5,l or R5b is independently -H, halogen, -NH2, -CN, -OH, -N02, carboxyl, substituted or unsubstituted -C1_6alkoxy, or tuted or unsubstituted -C1_6alkyl; or R5,, and R51, together with the carbon atom to which they are both attached form a 3-10 membered heterocyclic or 5-10 membered heteroaryl; and each of the ring systems is independently optionally substituted; q is 0,1, 2, 3 or 4; Ring A is absent or a 3-10 membered ring; = represents a single or double bond; When ring A is absent, Y2 is CRzaRZb, NRza or O, and Y3 is CR33R3b, NR33 or 0; When ring A is a 3-10 membered ring, and, i) Y2 is CRZa or N, and Y3 is CR33 or N, when = represents a single bond; or ii) Y2 is C, and Y3 is C, when = represents a double bond; Each of R23 and sz is independently -H, halogen, -NH2, -CN, -OH, -N02, carboxyl substituted or unsubstituted -C1_6all In some embodiments of Formula 11, each of R43 or R4b is independently -H, halogen, -NH2, -CN, -OH, -N02, yl, substituted or unsubstituted -C1_6alkoxy, or substituted or unsubstituted -C1_6alkyl; or R43 and R41, er with the carbon atom to which they are both attached form C=O.
In some embodiments of Formula 11, each of R43 or R4, is independently -H; -F; -Cl; -Br; -NH2; -CN; -OH; carboxyl; methyl; ethyl; methoxy; ethoxy; methyl substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, methyl, ethyl, y or ethoxy; ethyl substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -N02, yl, methyl, ethyl, methoxy or ethoxy; methoxy substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, methyl, ethyl, methoxy or ethoxy; or ethoxy substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, methyl, ethyl, methoxy or ethoxy; or R43 and R41, together with the carbon atom to which they are both attached form C=O.
In some embodiments of Formula II, p is 0, l or 2.
In some embodiments of Formula II, each of R53 and R5b is ndently -H; -F; -Cl; -Br; -NH2; -CN; -OH; carboxyl; -C1_3alkyl;- C1_3alkoxy; -C1_3alkyl substituted with -F, -Cl, -Br, -I, -NH2, -CN, -OH, -N02, yl, -C1_3alkyl or -C1_3alkoxy; or -C1_3alkoxy substituted with -F, -Cl, -Br, -I, -NH2, -CN, -OH, -N02, carboxyl, -C1_3alkyl or -C1_3alkoxy; or R53 and R5b together with the carbon atom to which they are both attached form a 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic or ered heterocyclic; and each of the heterocyclic contains 1 or 2 heteroatoms selected from N or O; and each of the ring system is independently optionally substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, -C1_6alkyl, or -C1_6alkoxy.
In some embodiments of Formula II, each of R53 or Rsb is independently -H; -Cl; -Br; -NH2; -OH; carboxyl; methyl; ethyl; methoxy; ethoxy; methyl substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, methyl or methoxy; ethyl substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, methyl or methoxy; methoxy substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, methyl or methoxy; or ethoxy tuted with -F, -Cl, -Br, -NH2, -CN, -OH, -N02, yl, methyl or methoxy; or R53 and R5b together with the carbon atom to which they are both attached formHP and *C represents the carbon atom which R53 and R5b attached.
In some embodiments of Formula II, ring A is 6-membered aryl, 7-membered aryl, 8-membered aryl, 9-membered aryl; 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered aryl, 9-membered heteroaryl; 3-membered heterocyclic, 4-membered cyclic, 5-membered heterocyclic, 6-membered heterocyclic, ered heterocyclic, 8-membered heterocyclic, 9-membered heterocyclic; ered yclic, 4-membered carbocyclic, 5-membered carbocyclic, 6-membered carbocyclic, 7-membered carbocyclic, 8-membered carbocyclic or 9-membered carbocyclic; and each of the heteroaryl contains 1, 2 or 3 heteroatoms selected from N, O or S; each of the heterocyclic contains 1, 2 or 3 heteroatoms selected from N or O.
In some embodiments of Formula II, ring A is 6-membered aryl, 7-membered aryl, 8-membered aryl; 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl; 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 8-membered heterocyclic; 3-membered yclic, 4-membered carbocyclic, ered carbocyclic, 6-membered carbocyclic, 7-membered carbocyclic or 8-membered carbocyclic; and each of the heteroaryl contains 1 or 2 heteroatoms ed from N, O or S; each of the heterocyclic contains 1 or 2 heteroatoms selected from N or O.
EU :0 111 some embodlments ofFormula 11 ringAis "M :31 :flHJNj 1D, 11$}? :0 ED jib :0 SD iiQ 21b in :D :foNJJ‘LLLQNH :1? 35:0) N?£:> :L:3]:>9: flm> bmwpfimpmwpwb1 :10ND :1?:CN" :9 3:"3 :NLN :DNEEQi:NN" :]:°5;, 5L" EEK» :EN E? SE" ELI} :LN" El; Ef' W i' it; :10 in"; :: 1:: ‘ c 6 N if? 1&1 $0131 :0 :20 :12"::0" :U111 in :c if):4:,30EU :031$131,;335:31D:6":ULLSEZJQC: :1211:12],11:1,:12;61:1,:cngmgogmgm 1:115: OfOLJGOUOb :1}: "HEQEOQQ BED,:]:>RD :1) 1:]E0‘3‘»: 3/ In some embodiments ofFormula II, ringAis rib} mfi‘ppwmbpppfi Sm2:11; In some embodiments of Formula II, Y2 is CR23 or N, Y3 is CR33 or N.
In some embodiments of Formula II, each of R23, R213, R33 and R31, is independently -H; -F; -Cl; -Br; -NH2; -CN; -OH; -NO2; carboxyl; methyl; ethyl; propyl; isopropyl; methoxy; ethoxy; propoxy; isopropoxy; -C1_3alkyl substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -NO2, carboxyl, methyl, ethyl, , isopropyl, methoxy, , propoxy or isopropoxy; or lkoxy substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -NO2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
In some embodiments of Formula II, each of R23, R213, R33 and R3b is independently -H or methyl.
In some embodiments of Formula II, R23, R2b, R33 and R3b are all -H.
In some embodiments of Formula II, Y2 is CH or N, and Y3 is CH or N.
In some embodiments of Formula II, Y2 is C, and Y3 is C.
In some embodiments of Formula II, each R6 is independently -H, -F, -Cl, -Br, -NH2, -N(CH3)2, -CN, -OH, oxo, =0, carboxyl, -C1_3alkoxy, -C1_3alkyl, -CH2NH2, -C1_3alkylene-OCH3, -CH2-COOH, -CH2-COO-C1_3alkyl, -CH2-C5_1oheterocyclic, -C1_3alkylene-CO-NR63R6b, -CH2NH-CO-NR63R6b, 63R6b, NR63R6b, -CO-C1_3alkyl, -CONH-C5_10heteocyclic, -COmembered heteocyclic, -COmembered heteocyclic, -Omembered carbocyclic, -Omembered carbocyclic, -NH-CO-C1_3alkyl, -NR63-CO-NR63R61,, -NR63-C1_3alkylene-NR63R61,, -NR63-C1-3alkylene-C5_1oheterocyclic, -S-C1_3alkyl, -SO2NH2, -SO2CH3, 5-membered heterocyclic, 6-membered heterocyclic, ered heteroaryl, or 6-membered heteroaryl, and each of which is independently optionally substituted with -F, -Cl, -Br, -NH2, -CN, -OH, oxo, =0, substituted or tituted -C1_3alkoxy, or substituted or tituted -C1_3alkyl; or two adjacent R6 can be joined together to form a 6-membered aryl; ered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic, 5-membered heteroaryl, ered cyclic, 4-membered heterocyclic or 5-membered heterocyclic; and each ofheteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms ed from N, O or S; and each of the ring system is independently optionally substituted with -F, -Cl, -Br, -I, -NH2, -CN, -OH, -N02, =0, oxo, yl, -C0NH2, -P0(C1_3alkyl)2, substituted or unsubstituted -C1_3alkoxy, or substituted or tituted -C1_3alkyl.
In some embodiments of Formula 11, each R6 is independently -F, -Cl, -Br, -NH2, -N(CH3)2, -CN, -0H, oxo, =0, carboxyl, methoxy, ethoxy, methyl, ethyl, isopropyl, -CH2NH2, -CH2CH20CH3, -CH2-C00H, -CH2NH-C0NHCH3, -C0NH2, -C0N(CH3)2, -CONHOH, -C0NHCH2CH20H, -C0-C0N(CH3)2, -C0CH3, -SOZNH2, -SOzCH3, -SCH3, 0 £4 ‘§‘< H H . \ N N l/\o 32,0 ‘SéN /N\ f N‘ \f‘ /N\ -NH-C0CH3, ""‘CNH, Q", L119" Hll/J’ or , U, Q 913, HM", In", V0, and each of which is independently optionally substituted with -F, -NH2, -0H, oxo, =0, or tuted or tituted -C1_3alkyl.
In some embodiments of Formula 11, each R6 is independently methyl, methoxy, =0, oxo, EJLN/ o -OH, -CN, -NH2, -Cl, -BI', -CF3, -OCF3, -SOzNH2, -802CH3, -F, -CH2NH2, I 2L0" , , l 0 IBEN\, 3gkNHz 3i"JJ\ 9L",OH #MNOH 32L)\/0H , , A’\/O\, bOH, *OH, BEOwOH, 0 é—(o N N \§\/N\), ", QM or CO} In some embodiments of Formula 11, ring A and two adjacent R6 taken together to form 3 S :30 o a; o a: 0 3L, ‘3 s "End/w s y; 5 EL, tr": I :Lt" 7| ix, \ {a @317 El "I? -rv 9 a a :5" \ Ya, (E); (g);I0 ° ° 8 IS (g);I | {6): fix| SI \ M gm/ \ - "N1? Em m;/ \ a "5% NW NW H N'w i "Lb" "2"" H 9 9 9 Ma a a '7 H9 a 9H a "m 31> ‘ "" """" M" / \ \ \ / \ "‘"N" " _ _ \ N _ / \ /| _§/ J" l \ H H , .
N H "A H "W" H N 2‘- E N _. I -E '\ @35— 00?N ~;"1:):> @ 5""u (j: \ s u am a, g a N> 9": H 996:0 3’ 0 go) :9"(l: ,@>s rir' 3‘ S o with/ N £3 / NH — H E "> u> (If 2,?" ,1 715 o 0 "'12, H/ O §\ / / o '§‘\I\' 0 ‘§\ / H \0 \N% —§ \ I \ "'44, .3" / / \ I\ \NH @N'E' \ o §_ S "7" "M "a m" S a \ \N- o I I \ \ I g1 , , , , , , , "‘fi.’ / 3.;8\ 3; \§_ o\ \%‘§ \ "km 3"" 3 g" / e‘i r?" 1511" n N "a N H \N-_ 7 7 7 7 7 7 7 I WIN N \ 1),: '§ / N \ f :3; If / / N \ / /§\ N \ _§ / / N \E N/ NH N 7 7 7 7 .Iw Jaw N/ /N 3’ /N 22/ _§ / \ \ N\ '15: I / ‘N i N < < I -E / | smut] N N 3: / N / H N awv /§\ I I H H .HI‘LI' H H ’ ’ 5 a a a a JV" 1:; "MM, "1/ V" 'i/ V" ION; 'g/ —§/ |\ / If 42/ I: N / '7: N / ‘ N / /N N N / N H N "2% H "I" , H H , , , , , , , , J‘I'W I HZ \EL’ MI" //\N \ Mb: /|\ /| //\N\"’z //\N\Lh" N/I /§ \ N N/ N N/g: N/ (\N\‘i/ (\N\E/ H / / / H ; M‘V (A: n I \ N , , , N\ NQN NW '§ ///)\1N \ ‘§ //N \ N \ (/N‘N \L'k, 7 N//\N \E N/ N \ / N \‘g / ‘é'w \ I N/ /.-V‘: \N/ /@i VIM "’1" WM ’ a I \ "LN N E ’ Néjfdjfi’z, \‘711 W , , \ '95 , \E 2/ N In some embodiments of Formula II, each of R63 and R6b is independently -H, -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, substituted or unsubstituted -C1_3alkoxy, or substituted or unsubstituted -C1_3alkyl.
In some embodiments of a II, each of R63 and R6b is independently -H, -Cl, -Br, -NH2, -OH, carboxyl, methyl, ethyl, methoxy, ethoxy propoxy, isopropoxy, methyl substituted with -OH, or ethyl substituted With -OH.
In some embodiments of Formula II, each of R63 and R6b is ndently -H, -CH3, -OH, or -CH2CH20H.
In some embodiments of Formula II, n is 0, l or 2.
In some embodiments of Formula I, the compound is of III: III R1 is -H, -F, -Cl, -Br, -NH2, -CN, -OH, -NO2, yl, substituted or tituted -C1_6alkoxy, or substituted or unsubstituted -C1_6alkyl; R2 is -H, -F, -Cl, -Br, -NH2, -CN, -OH, -NO2, carboxyl, substituted or unsubstituted -C1_6alkoxy, or substituted or unsubstituted -C1_6alkyl; or R1 combines with R2 to which is adjacent to form a 5-10 membered heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N or O, and each of the ring systems is independently optionally substituted with halogen, -NH2, -CN, -OH, -NO2, carboxyl, oxo, =0, -CONH2, substituted or unsubstituted lkoxy, substituted or unsubstituted lkyl, or -CO-C1_6alkyl; Y1 is N or CH; R3 is -H or -NH2; Ring B is a 6-membered aryl, 5-6 membered heteroaryl, 3-6 membered carbocyclic or 3-6 membered heterocyclic; Y3 is CH, N or C; R7 is halogen, -NH2, -CN, -OH, -NO2, yl, oxo, =0, -CONH2, -NH-COCH3, substituted or unsubstituted -C1_6alkoxy, or substituted or unsubstituted lkyl; and m is 0, 1 or 2.
In some embodiments of Formula III, R1 combines with R2 to which is adjacent to form a -membered heterocyclic, 6-membered heterocyclic, 7-membered cyclic, 8-membered heterocyclic, 9-membered heterocyclic or lO-membered heterocyclic; and each of the heterocyclic contains 1 or 2 heteroatoms selected from N or O; and each of the ring systems is independently optionally substituted with -F, -Cl, -Br, -NH2, -CN, -OH, oxo, =0, substituted or unsubstituted -C1_3alkoxy, substituted or unsubstituted lkyl, or -CO-C1_3alkyl.
In some embodiments of Formula III, R1 combines with R2 to which is adjacent to form «"5 ; and the ring systems is independently optionally substituted with -F or -COCH3.
In some embodiments of Formula III, R1 es with R2 to which is nt to form o=jwé©efliflim ‘Jé \ 3’1‘31,": or A /N.
In some ments of Formula III, R7 is -NH2, -CN, oxo, =0, -CONH2, -NH-COCH3, methyl or methoxy.
In some embodiments of Formula III, m is 0 or 1.
In some ments of Formula I, the compound is of Formula IV: R 348:"!\"f N I I R2£6\Y1/ HZN R1 is -H, -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, substituted or unsubstituted -C1_6alkoxy, or substituted or unsubstituted- kyl; R2 is -H, -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, -NHC1_6alkyl, -N(C1_6alkyl)2, substituted or tituted -C1_6alkoxy, or substituted or unsubstituted -C1_6alkyl; or R1 combines with R2 to which is adjacent to form a 5-12 membered heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N or O, and each of the ring systems is independently ally substituted with halogen, -NH2, -CN, -OH, -N02, carboxyl, oxo, =0, -CONH2, substituted or unsubstituted lkoxy, substituted or unsubstituted -C1_6alkyl, or -CO-C1_6alkyl; Y1 is N or CH; R3 is -H or -NH2; Ring D is a 6-membered aryl, 5- membered heteroaryl, 6-membered heteroaryl, 3- membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic, ered carbocyclic, 3-membered heterocyclic, ered heterocyclic, 5-membered heterocyclic, or 6-membered heterocyclic; = represents a single or double bond; and i) Y2 is CR2, or N, and Y3 is CR3, or N, when = represents a single bond; or ii) Y2 is C, and Y3 is C, when = represents a double bond; Each of R23 and R33 is -H, halogen, -NH2, -CN, -OH, -N02, carboxyl, substituted or unsubstituted -C1_6alkoxy, or substituted or unsubstituted -C1_6alkyl; R8 is halogen, -NH2, -CN, -OH, -N02, carboxyl, oxo, =0, -SOzNRgaR8b, -S-C1_6alkyl, -SO-C1_6alkyl, -SOg-C1_6alkyl, gaRgb, -PO(C1_6alkyl)2, -PO(C1_6alkoxy)2, -NRga-C0-C1_6alkyl, CO-NRgaRgb, C5_1ocarbocyclic, C5_1oheterocyclic, -C5_1oheterocyclic or -C5_10heteroaryl, -C5_10aryl, -C1_6alkoxy, or -C1_6alkyl; and each of which is independently optionally tuted; and t is 0, l, 2 or 3; and Each of R821 and Rgb is independently H, halogen, -NH2, -CN, -0H, -N02, carboxyl, substituted or unsubstituted -C1_6alkoxy, or substituted or unsubstituted -C1_6alkyl.
In some embodiments of Formula IV, R2 is -H, -F, -Cl, -Br, -NH2, -CN, -0H, -N02, yl, substituted or unsubstituted -C1_6alkoxy, or substituted or unsubstituted -C1_6alkyl; or R1 combines with R2 to which is adjacent to form a 5-10 membered heterocyclic ring contains 1, 2 or 3 heteroatoms ed from N or 0, and each of the ring s is independently optionally substituted with halogen, -NH2, -CN, -0H, -N02, carboxyl, oxo, =0, -C0NH2, substituted or unsubstituted -C1_6alkoxy, substituted or unsubstituted -C1_6alkyl, or -C0-C1_6alkyl; In some embodiments of Formula IV, R2 is -H, -F, -Cl, -Br, -NH2, -CN, -0H, -N02, carboxyl, -NHC1_3alkyl, -N(C1_3alkyl)2, -C1_3alkoxy, -C1_3alkyl; or R1 combines with R2 to which is adjacent to form a 5-,6-, or 7-membered heterocyclic ring contains 1, or 2 heteroatoms selected from N or 0, and each of the ring systems is independently optionally substituted with -F, -Cl, -Br, -NH2, -CN, -0H, -N02, carboxyl, oxo, =0, -C0NH2, methoxy, ethoxy, methyl, ethyl, thyl, or In some embodiments of Formula IV, R2 is -H, -F, -Cl, -Br, -NH2, -CN, -0H, -N02, carboxyl, -NHCH3, -N(CH3)2, y, ethoxy, methyl, or ethyl; or R1 combines with R2 to which is adjacent to form a 5- membered heterocyclic contains 1 heteroatoms selected from N or 0, or 6-membered heterocyclic ring contains 1 heteroatoms selected from N or 0; and each of the ring systems is independently optionally substituted with -F, -Cl, -Br, -NH2, -CN, -0H, -N02, carboxyl, oxo, =0, -C0NH2, methoxy, ethoxy, methyl, ethyl, -C0-methyl, or -C0-ethyl; In some embodiments of Formula IV, R1 and R2, together with the aromatic ring they are «v'w mu I F2 / \ HN \ / attached to formto Y1 or Y1 and ring F1 or F2 is independently optionally tuted with -F or .
In some embodiments of Formula IV, R1 combines with R2 to which is adjacent to form {EE-F 0 E" In some embodiments of a IV, R2 is -NH2.
In some embodiments of Formula IV, R1 is -H, -F, -Cl, -Br, -NH2, -CN, -0H, -N02, carboxyl, substituted or tituted -C1_3alkoxy, or tuted or unsubstituted -C1_3alkyl.
In some embodiments of Formula IV, R1 is -H, -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, methoxy, ethoxy, methyl, or methyl substituted with one or more substituents selected from halogen.
In some embodiments of Formula IV, R1 is -H; -F; -Cl; -Br; -NH2; -CN; -OH; -N02; yl; methyl; or methyl substituted with one or more substituents selected from -F, -C1, or -Br.
In some embodiments of Formula IV, R1 is -Cl.
In some embodiments of Formula IV, ring D is 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic, 6-membered carbocyclic, 3-membered heterocyclic, 4-membered cyclic, 5-membered cyclic or 6-membered heterocyclic; and each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms ed from N, O or S.
In some embodiments of Formula IV, ring D is 6-membered aryl, ered heteroaryl, 6-membered heteroaryl, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered yclic, 5-membered heterocyclic or 6-membered heterocyclic; and each of the heteroaryl or heterocyclic contains 1 or 2 heteroatoms selected from N, O or S. ~ ~ ‘- ~- o \ 0 .
In some embodiments of Formula IV, ring D is i]>, :33, :0, :D, :1), 3:0], :0, :D :D D,DD O. :‘D‘\ D . s x.
. N , In some embodiments of Formula IV, Y2 is CR23 or N, and Y3 is CR33 or N.
In some embodiments of Formula IV, each ofR23 and R33 is -H, -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, substituted or unsubstituted -C1_3alkoxy, or substituted or unsubstituted -C1_3alkyl.
In some embodiments of Formula IV, each of R23 and R33 is -H, methyl or y.
In some embodiments of Formula IV, Y2 is CH or N, and Y3 is CH or N.
In some embodiments of Formula IV, both Y2 and Y3 are C.
In some embodiments of Formula IV, R8 is -F, -Cl, -Br, -I, -NH2, -CN, -OH, -N02, carboxyl, oxo, =0, -SOzNRgaRgb, 6alkyl, -CO-NRgaRgb, CO-C1_6alkyl, -NRga-CO-NRgaRgb, -O-C5_1ocarbocyclic, -C5_1oheterocyclic or -C5_1oheteroaryl, -C1_6alkoxy, or -C1_6alkyl; and each of which is independently optionally substituted with -F, -Cl, -Br, -NH2, -CN, -OH, oxo, =0, substituted or unsubstituted -C1_3alkoxy, or substituted or unsubstituted -C1_3alkyl.
In some embodiments of a IV, R8 is -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, oxo, =0, -SOzNRgaRgb, -S-C1_3alkyl, -CO-NRgaRgb, -NH-CO-C1_3alkyl, -NH-CO-NRgaRgb, -O-C5_1ocarbocyclic, -C5_1oheterocyclic, -C5_1oheteroaryl, -C1_3alkoxy, or -C1_3alkyl; and each of which is independently optionally tuted with -F, -Cl, -Br, -NH2, -CN, -OH, oxo, =0, lkoxy, or -C1_3alkyl.
In some embodiments of Formula IV, R8 is -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, oxo, =0, methyl, ethyl, proproyl, isopropoyl, methoxy, ethoxy, propoxy, isopropoxy, -SOzNRgaRgb, -S-C1_3alkyl, -CO-NRgaRgb, -NH-CO-C1_3alkyl, -NH-CO-NRgaRgb, -O-C5_1ocarbocyclic, heterocyclic or -C5_1oheteroaryl; and each of which is independently optionally substituted with -F, -Cl, -Br, -NH2, -CN, -OH, oxo, =0, methoxy, ethoxy, methyl, or ethyl.
In some embodiments of a IV, the C5_1ocarbocyclic is 5-membered carbocyclic, 6-membered carbocyclic, 7-membered carbocyclic, 8-membered carbocyclic, ered carbocyclic or lO-membered carbocyclic; the C5_1oheterocyclic is 5-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, ered heterocyclic, 9-membered heterocyclic or lO-membered heterocyclic; and the C5_10heteroaryl is 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl or lO-membered heteroaryl; and each of the heterocyclic or heteroaryl contains 1, 2, 3 or 4 heteroatoms selected from N, O or S.
In some embodiments of Formula IV, R8 is -F, -Cl, -Br, -NH2, -CN, -OH, oxo, =0, methyl, ethyl, isopropoyl, methoxy, -SOzCH3, -SCH3, -CONH2, CH3, NHCH3, J3 2""O "w 3‘:0 HN‘Nl/ \er or o. 7 7 In some embodiments of Formula IV, R8 is -F, -Cl, -Br, -NH2, -CN, -OH, oxo, =0, methyl, CH C 35w methoxy, -SOzCH3, -SCH3, , -NH-COCH3, -NH-CONHCH3, LII-K, ‘50 , Q, In some embodiments of Formula IV, t is 0, l or 2.
In some embodiments of a I, II, III or IV, the compound is (R) -l '-(6-amino -5 -((2-amino-3 -chloropyridinyl)thio)pyrazinyl) -2,3 -dihydrospiro [indene-l , o i n eridin] amine (S) -l '-(6-amino-5 -((2-amino-3 -chloropyridinyl)thio)pyrazinyl) - l ,3 rospiro [indene-2, 4'— .1. eridin]—l-amine (R) -l '-(6-amino -5 -((2-amino-3 -chloropyridinyl)thio)pyrazinyl) -3 ,4-dihydro-2H-spiro[naph thalene-l ,4'— n i n ] amine (R) -l '-(6-amino -5 -((2-amino-3 -chloropyridinyl)thio)pyrazinyl) -5 ,6-dihydrospiro [cyclopent a[b]pyridine-7,4'—piperidin] amine (S) -l '-(6-amino -5 -((2-amino -3 -chloropyridinyl)thio)pyrazinyl) methoxy-l ,3 rospir o[indene-2,4'—piperidin]—l -amine (R) -1 -(4 -((3 -amino -5 -(2-amin0 -2, 3 -dihydr0Spiro[indene- 1 ,4'—piperidin] - 1 '-y1)pyrazinyl)thi0)- 3 3 -diflu0r0ind01iny1)ethan0ne 1-(4-((3 -arnin0-5 -((2R)aminospir0[bicyclo [3 . 1 .0]hexane-3 ,4 '-piperidin] - 1 '-y1)pyrazin-2 -y1)thi 0 -3 ,3 -diflu0r0ind01in 1 ethan-l -0ne (S) -1 '-(6-amino -5 -((2-amin0 -3 -ch10r0pyridiny1)thi0)pyrazinyl) -3 ,4-dihydr0-1H-spir0[naph thalene-2,4'—piperidin] -1 -amine (R) -1 -(6-amino -5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl) -7',8 '-dihydr0-5 'H-spiro [pip eridine-4,6'—quin01in]—7'—amine >—‘ (S) -1 '-(6-amin0-5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl) -5 ,7-dihydr0Spiro [cyclopent a[b]pyridine-6,4'—piperidin] -5 -amine (S) -1 '-(6-amin0-5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl) -5 -meth0xy-1 ,3 -dihydr0spir 0 [indene-2,4'—piperidin] -1 -amine (S) -1 '-(6-amin0-5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl)-4,6-dihydr0Spiro [cyclopent j—A N a[b]thi0 n hene-S,4'— n i n eridin]—4-amine (S) -1 -amino- 1 '-(6-amin0 -5 -((2-amin0 -3 -ch10r0pyridinyl)thi0)pyrazin-2 -y1)-1,3 -dihydroSpiro [i j—A DJ ndene-2,4'-piperidine]carb0nitrile (S) -1 '-(6-amino -5 -((2-amin0 -3 -ch10r0pyridiny1)thi0)pyrazinyl) th0xy-1 ,3 -dihydr0spir j—A L 0 [indene-2,4'—piperidin] -1 -amine (S) -1 '-(6-amino -5 -((2-amin0-3 0pyridiny1)thi0)pyrazin-2 -y1) ch10r0-1,3 -dihydr0Spiro [i ndene-2,4' n i n ]—1-amine (S) -1 - 1 '-(6-amin0 -5 -((2-amin0 -3 -ch10r0pyridinyl)thi0)pyrazin-2 -y1)-1,3 -dihydroSpiro [i j—A O\ ndene-2,4' n i n eridine]—4-carb0nitrile (S) -1 -amino- 1 '-(6-amin0 -5 -((2-amin0 -3 -ch10r0pyridinyl)thi0)pyrazin-2 -y1)-1,3 -dihydroSpiro [i j—A \] ndene-2,4' n i n eridine]—4-carb0xamide (S) -1 min0-5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl)-1,3 -dihydr0Spiro [indene-2, j—A OO 4'—piperidin]—1-amine (S) -1 '-(6-amino -5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1) ch10r0-5 ,7-dihydr0spir0[ j—A O cyclopenta[b]pyridine-6,4'-piperidin]-5 -amine (S) -1 '-(6-amino -5 -((2-amin0 -3 0pyridiny1)thi0)pyrazinyl) -3 -meth0xy-5 ,7-dihydr0spir o i n eridin] amine (S) -1 '-(6-amin0-5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl) -5 ydr0Spiro [cyclopent a[c]pyridine-6,4'—piperidin]amine (S) -1 '-(6-amin0-5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl) -5 ,7-dihydr0Spiro [cyclopent a[c] o ridine-6,4'— oi. ]—5-amine (S) -1 '-(6-amino -5 -((2-amin0 -3 -ch10r0pyridiny1)thi0)pyrazinyl) methy1-1,3 -dihydr0spir0[ -2,4'—piperidin] -1 -amine (S) -1 '-(6-amino -5 min0 -3 -ch10r0pyridiny1)thi0)pyrazinyl) thylsulf0nyl)-1,3 -dih ydrospiro [indene-2,4'—piperidin] -1 -amine (1 S) -1 '-(6-amino -5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1) (methylsulfinyl) -1 ,3 -dih ydrospiro e-2,4'—piperidin] -1 -amine (S) -1 -amino- 1 '-(6-amin0 -5 -((2-amin0 -3 -ch10r0pyridinyl)thi0)pyrazin-2 ,3 -dihydroSpiro [i ndene-2,4' o i o eridine]—6-carb0xamide (S)amin0-1 '-(6-amin0-5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1)-N,N-dimethy1-1 ,3 -dihydr0Spiro[indene-2,4'—piperidine] carb0xamide (S) -1 '-(6-amino -5 -((2-amin0 -3 -ch10r0pyridiny1)thi0)pyrazinyl) rn0-1,3 r0Spiro [i 2,4'—piperidin]—1-amine (S) -1 '-(6-amin0-5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl)br0mo-1,3 -dihydr0Spiro [i 2,4'—piperidin]—1-amine (S) -1 '-(5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl) -5 ,7-dihydr0Spiro [cyclopenta[b]pyrid ine-6,4'—piperidin]—5-amine —(6-amin0-5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl)-1,3 r0spir0 [cyclopent a[a]na o hthalene-2,4' o i o eridin]—3-amine (S) -1 '-(6-amino -5 -((2-amin0-3 -ch10r0pyridinyl)thi0)pyrazin-2 -y1) ch10r0-5 -meth0xy-1,3 -di hydrospiro[indene-2,4'—piperidin]amine (S) -1 '-(6-amin0-5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl)-1,3 -dihydr0Spiro [indene-2, 4'-piperidine]—1,6-diamine (S)-(1-amin0-1'—(6-amin0-5 -((2-amin0-3 -ch10r0pyridin—4-yl)thi0)pyraziny1)-1,3 -dihydr0spir0[ indene-2,4'— ’ ’ ’ ’ o hos o hine oxide (S) -1 '-(6-amino -5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1) (triflu0r0methyl) -1 ,3 -dih dros o ir0[indene-2,4' o i o eridin]—1 -amine (S)-1'-(6-amin0((2-amin0ch10r0pyridiny1)thi0)pyrazinyl)(1H-imidazol-l -y1)-1,3 -d D) O’\ ih dros ndene-2,4'— o i o eridin]—1 -amine (S)-1'-(6-an1in0((2-arninoch10r0pyridiny1)thi0)pyrazinyl)(1H-pyrr01y1)-1,3 -dih DJ \] ydrospiro [indene-2,4'—piperidin] -1 -amine (S) -1 '-(6-amino -5 -((2-amin0 -3 -ch10r0pyridinyl)thi0)pyraziny1) br0m0 -5 -flu0r0- 1 ,3 -dihy DJ 00 droSpiro [indene-2,4'-piperidin] amine (S) -1 '-(6-amin0-5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl) -5 ,6-diflu0r0- 1 ,3 -dihydr0spi r0 e-2,4'— o i o eridin]—1-amine (S) -1 '-(6-amin0-5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl)-6,7-diflu0r0- 1 ,3 -dihydr0spi r0[indene-2,4'—piperidin]—1-amine -arnin0-1'—(6-amino-5 -((2-amin0-3 -ch10r0pyridinyl)thi0)pyrazinyl)-5 -flu0r0-1,3 -dihy drOSoiro[indene-2,4' ooieridin]—6- 1 dimeth lohooshine oxide (S)amin0-1'—(6-amin0-5 -((2-amin0-3 -ch10r0pyridinyl)thi0)pyraziny1)-5 -flu0r0-1,3 -dihy drospiro[indene-2,4'-piperidine]carb0nit1ile (S)amin0-1'—(6-amin0-5 -((2-amin0-3 -ch10r0pyridinyl)thi0)pyraziny1)-5 -flu0r0-1,3 -dihy 4; DJ drospiro[indene-2,4'-piperidine]carb0xamide (S) -1 '-(6-amino -5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1) ch10r0-4,6-dihydr0spir0[ cyclopenta[d]thiazole-5 ,4'—piperidin]amine (R) -1 mino -5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl) -3H-spiro [benzofuran-2,4'— J; kl} o i o eridin]—3-amine (S) -1 -(1 -amin0-1'—(6-amin0-5 -((2-amino -3 0pyridiny1)thi0)pyrazin-2 -y1)-1,3 -dihydr0spir J; O’\ 0 [indene-2,4'—piperidin]yl)urea (S) -1 '-(6-amino -5 -((2-amin0 -3 -ch10r0pyridiny1)thi0)pyraziny1) -5 -br0m0 -1,3 r0Spiro [i ndene-2,4'—piperidin]—1-amine (S) -1 '-(5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl)-1,3 -dihydr0Spiro [indene-2,4'-piperid in] -1 -amine (S) -1 '-(5 -((3 -ch10r0(dimethylamin0)pyridiny1)thi0)pyraziny1) -1 ,3 -dihydr0Spiro [indene-2 ,4'—piperidin]—1-amine (S) -1 '-(5 -((3 -aminochlor0phenyl)thi0)pyrazin-2 -y1)-1,3 -dihydr0Spiro [indene-2,4'—piperidin] -1 -amine (S) -1 '-(5 -((3 -ch10r0meth0xypyridinyl)thi0)pyrazin-2 -y1)-1,3 -dihydr0Spiro [indene-2,4'—pipe ridin] amine (S) -1 '-(6-amin0-5 -((3 -ch10r0(dimethylamin0)pyridiny1)thi0)pyraziny1) -1 ,3 -dihydr0Spiro [indene-2,4'—piperidin]—1-amine (S) -1 '-(6-amin0-5 -((3 -aminochl0r0pheny1)thi0)pyraziny1)-1,3 -dihydr0Spiro[indene-2,4 '-pip eridin] amine (S)-1'—(6-amin0-5 -((3 -ch10r0meth0xypyridiny1)thi0)pyraziny1)-1,3 -dihydr0Spiro [indene- kl} J; 2,4'— 0 i o eridin]—1-amine (S) -1 '-(6-amin0-5 -((2,3 -dichl0r0pheny1)thi0)pyraziny1)-1,3 -dihydr0Spiro [indene-2,4'—piperidi U) U) n] -1 -amine (R) -1 '-(5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl) -3H-spiro [benzofuran-2,4'—piperidin] U} C’\ -3 -amine -arnin0-1'—(6-amino-5 -((2-amin0-3 -ch10r0pyridinyl)thi0)pyraziny1)-1,3 -dihydr0spir0[ U) \] -2,4'-piperidin] -6 -y1)dimethylphosphine oxide (S) -1 '-(6-amin0-5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl)((tetrahydr0-2H-pyran-4 - U) 00 -1,3 -dih dros n iro [indene-2,4' n i n eridin]—1-amine (S)-(1-arnin0-1'—(6-amino-5 -((2-amin0-3 0pyridinyl)thi0)pyraziny1)-1,3 -dihydr0spir0[ -2,4'—piperidin] -6 -y1)(piperidin- 1 ethanone (S) -1 '-(6-amino -5 -((2-amin0-3 -ch10r0pyridinyl)thi0)pyrazin-2 -y1) n10rph01in0-1 ,3 -dihydros n iro [indene-2,4'— n i n eridin]—1-amine (S) -1 '-(6-amin0-5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl) -5 ,6,7-triflu0r0 -1,3 -dihydros O\ p—ax piro[indene-2,4'-piperidin]amine (S) (1 -amin0-1'—(6-amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1)-1,3 r0spir 0 [indene-2,4'—piperidin] y1)m0rph01in-3 -0ne (1 -amin0-1'—(6-amin0-5 -((2-amino-3 -ch10r0pyridiny1)thi0)pyraziny1)-1,3 r0spi O’\ U) ene-2,4'—piperidin]yl)methanesulf0namide (S) -1 '-(6-amin0-5 -((2-amin0-3 0pyridiny1)thi0)pyrazinyl)-1,3 -dihydr0Spiro [cyclopent O’\ J; a[b] a uinoline-2,4' n i n eridin]—1-amine (R) -1 '-(6-amino -5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl) -5 ,7-dihydr0Spiro [cyclopent ridine-6,4'—piperidin]-5 -amine (S)-1'—(6-amin0-5 -((2,3 -dich10r0pyridinyl)thi0)pyrazinyl)-1,3 -dihydr0spir0[indene-2,4'-pip eridin] amine (1R,3R)-1 '-(6-amin0 -5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyraziny1) -1 ,3 -dihydr0Spiro [inde ne-2,4'—piperidine]— 1 ,3 -diamine (S) -1 '-(5 min0-3 -ch10r0pyridiny1)thi0)pyrazinyl)ch10r0-4,6-dihydr0Spiro [cyclopent a[d]thiazole-5 ,4'—piperidin] amine (S) -1 '-(6-amino -5 min0-3 -ch10r0pyridiny1)thi0)pyraziny1)ch10r0-4,6-dihydr0spir0[ c 010 n enta[d]thiazole-5 ,4'— n i n eridin]—6-amine (S) -1 -amino- 1 '-(6-amin0 -5 -((2-amin0 -3 -ch10r0pyridinyl)thi0)pyrazin-2 -y1) -3 H-spir0[ind01izi ne-2,4'—piperidin]—5(1H)-0ne (R) -1 '-(5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl)Spiro[indoline-2,4'-piperidin] -3 -amin \] j—A (R) -1 '-(6-amino -5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl) -6,7-dihydr0Spiro [cyclopent o i o eridin] amine (S)-1'-(6-amin0((2-amin0-3 -ch10r0pyridiny1)thi0)pyraziny1)-3 -ch10r0-5,7-dihydr0spir0[ \] DJ 0 clo..enta[b] ridine-6,4' nieridin]—5-amine (S) -1 '-(6-amino -5 -((2-amin0 -3 -ch10r0pyridinyl)thi0)pyraziny1) (methy1thi0)-1,3 -dihydr0 s n iro e-2,4' n i n eridin]—1-amine (S) -1 '-(6-amino -5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyraziny1)(4-methylpiperaziny1) \] U‘I -1,3 -dihydrospir0[indene-2,4‘-piperidin]—1-amine (S) -1 '-(5 -((2, 3 -dich10r0pyridin-4 -y1)thi0)pyrazin-2 -y1)-1,3 r0Spiro[indene-2,4'—piperidin] -1 \l O’\ -am1ne (S) -1 '-(6-amin0-5 -((2-(triflu0r0methyl)pyridin-3 -y1)thi0)pyrazinyl)-1,3 -dihydr0Spiro [indene-2 i n eridin] -1 -amine (S) -1 -(4 -((3 -amino -5 -(1-amin0-1, 3 -dihydrospir0[indene-2,4'—piperidin]—1'-y1)pyrazinyl)thi0)- 3 3 -diflu0r0ind01iny1)ethan0ne (S) -1 '-(6-amino -5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1) -2 -(tert-butyl)-4,6-dihydros o ir0[c Clo n enta[b]thi0 n hene-S,4'— n i n eridin]—4-amine (S)amin0-1'—(6-amin0-5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyraziny1)-1 ,3 -dihydrospir0[i ndene-2,4'-piperidine]carb0xylic acid (2R)-1 '-(6-amin0-5 -((2-amin0-3 -ch10r0pyridinyl)thi0)pyrazinyl)spir0 lo [3 . 1 .0]hexane -3,4'—piperidin]—2-amine (S) -1 '-(6-amin0-5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl) -5 ydr0Spiro [cyclopent ridine-6,4'—piperidin]amine (S)-1'—(5 -(quin01iny1thi0)pyraziny1)-5 ,7-dihydrospir0[cyclopenta[b]pyridine-6,4'—piperidin] 00 DJ -5 -amine (S) -1 mino -5 -((2,3 -dichlor0phenyl)thi0)pyraziny1) -5 ,7-dihydr0Spiro[cyclopenta[b]pyridi ne-6,4'—piperidin] -5 -amine (S) -1 '-(5 -((3 -ch10r0(dimethylamin0)pyridiny1)thi0)pyrazinyl) -5 ,7-dihydr0Spiro [cyclope pyridine-6,4'-piperidin] -5 -amine (S) -1 '-(5 -(pyridin-4 -y1thi0)pyrazin-2 -y1) -5 ,7-dihydr0Spiro[cyclopenta[b]pyridine-6,4'—piperidin] amine —(6-amin0-5 -((3 -flu0r0pyridiny1)thi0)pyrazinyl) -5 ,7-dihydr0Spiro [cyclopenta[b]pyrid 00 \] ine-6,4'—piperidin]—5-amine (S) -1 '-(6-amino -5 -((3 -flu0r0pyridiny1)thi0)pyrazinyl)-4,6-dihydr0Spiro [cyclopenta[d]thiaz OO 00 ole-5 ,4'— n i n eridin] amine (S) -1 '-(6-amin0-5 -((3 -ch10r0(rnethy1arnin0)pyridinyl)thi0)pyrazin-2 -y1) -5 , 7-dihydroSpiro [c yclopenta[b]pyridine-6,4'—piperidin] -5 -amine diethyl(S) -( 1 - 1 '-(6-amin0-5 -((2-arnin0-3 -ch10r0pyridiny1)thi0)pyrazinyl)-1,3 -dihydr ospiro [indene-2,4 '-piperidin] y1)ph0sphonate (S) -1 '-(6-amin0-5 -((2-amin0-3 -flu0r0pyridinyl)thi0)pyrazin-2 -y1) -5 ,7-dihydr0Spiro[cyclopent o i o eridin]—5-amine (S) -1 '-(5 -((2-amin0-3 -flu0r0pyridiny1)thi0)pyrazinyl) -5 ,7-dihydr0Spiro [cyclopenta[b]pyrid ine-6,4'— n i n eridin]—5-amine (S) -1 '-(6-amino -5 -((3 -ch10r0pyridin-4 i0)pyrazinyl) -5 ,7-dihydr0Spiro [cyclopenta[b]pyrid ine-6,4'— n i n eridin]—5-amine (S) -1 '-(6-amin0-5 -((3 -ch10r0(dimethylamin0)pyridiny1)thi0)pyraziny1) -5 ,7-dihydr0Spiro [cyclopenta[b]pyridine-6,4'—piperidin] -5 -amine (S) -1 '-(5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl)ch10r0-4,6-dihydr0Spiro [cyclopent a[d]thiazole-5 ,4'—piperidin]—4-amine (R)-1'-(6-amin0((2-amin0ch10r0pyridiny1)thi0)pyrazinyl)-3H-spiro[furo[2,3 -b]pyridi ne-2,4'— n i n ]—3-amine (S)-1'—(5 -((3 -amin0ch10r0phenyl)thi0)pyraziny1)-5 ,7-dihydr0spir0[cyclopenta[b]pyridine-6 ,4'-piperidin]—5 -amine (S)-1'—(6-amin0-5 -((3 -aminochl0r0pheny1)thi0)pyraziny1)-5 ,7-dihydr0spir0[cyclopenta[b]p ridine-6,4'— i n ]—5-amine (S) -1 '-(5 -((3 -ch10r0meth0xypyridinyl)thi0)pyrazin-2 -y1) -5 ,7-dihydr0Spiro [cyclopenta[b]py ridine-6,4'—piperidin] -5 -amine (S) -1 '-(6-amin0-5 -((3 -ch10r0meth0xypyridiny1)thi0)pyrazin-2 -y1) -5 ,7-dihydr0Spiro [cyclop enta[b]pyridine-6,4'—piperidin] -5 -amine (S) -1 '-(5 -((5 -chloro-2 -fluoropyridiny1)thio)pyrazinyl) -5 ,7-dihydroSpiro penta[b]pyrid ine-6,4'—piperidin]—5-amine (S)(4 -((3 -amin0-5 -(5 -amin0-5 ,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-1'-y1)pyra 2111yl)thio)-3 ,3 -difluoroindoliny1)ethan0ne (S) -1 '-(5 -((2,3 -dichloropyridiny1)thio)pyrazin-2 -y1) -5 ,7-dihydroSpiro [cyclopenta[b]pyridine-6 ,4'—piperidin] -5 -amine (S) -1 '-(6-amino -5 -((2,3 -dichloropyridinyl)th10)pyrazin-2 -y1) -5 ,7-dihydroSpiro[cyclopenta[b]p yridine-6,4'—piperidin] -5 -amine (S)-1'—(5 -((4-chloropyridin-3 10)pyrazin-2 -y1) -5 , 7-dihydroSpiro[cyclopenta[b]pyridine-6,4'— piperidin] -5 -amine (S) -1 '-(6-amino -5 -((4-chloropyridin-3 -y1)thio)pyrazinyl) -5 ,7-dihydrospiro [cyclopenta[b]pyrid ine-6,4'— .1. eridin]—5-amine (S)-1'—(5 -((3 -aminopyridinyl)th10)pyrazinyl)-5 ,7-dihydroSpiro [cyclopenta[b]pyridine-6,4'—p 1peridin] -5 -amine (S)-1'—(6-amin0-5 -((3 -an11n0pyridiny1)thio)pyrazinyl) -5 ,7-dihydroSpiro[cyclopenta[b]pyrid ine-6,4'—piperidin] -5 -amine (S) -1 '-(5 -((3 ,5 -dichloropyridin-4 -y1)thio)pyrazin-2 -y1) -5 ,7-dihydroSpiro [cyclopenta[b]pyridine-6 i n eridin] -5 -amine (S) -1 '-(6-amino -5 -((3 ,5 -dichloropyridinyl)th10)pyrazinyl)-5 ,7-dihydrospiro[cyclopenta[b]p ridine-6,4'— oi n eridin] -5 -amine (S) -1 '-(5 -((2-an11n0-5 opyridiny1)thio)pyrazinyl) -5 ,7-dihydroSpiro penta[b]pyrid ine-6,4'— .1. eridin]—5-amine (S) -1 '-(6-amin0-5 -((2-amin0-5 -chloropyridiny1)th10)pyrazinyl) -5 ,7-dihydroSpiro [cyclopent a[b]pyridine-6,4'—piperidin] -5 -amine (S) -1 '-(6-amin0-5 -((2-(trifluoromethyl)pyridin-3 -y1)th10)pyrazinyl)-5 ,7-dihydroSpiro [cyclope nta[b]pyridine-6,4'-p1peridin] -5 -amine (S) -1 '-(5 -((3 -chloro-2 -fluoropyridiny1)thio)pyrazinyl) -5 ,7-dihydroSpiro [cyclopenta[b]pyrid ine-6,4'— .1. eridin]—5-amine (S) -1 '-(6-amin0-5 -((3 ofluoropyridiny1)thio)pyrazinyl) -5 ,7-dihydroSpiro [cyclopent a[b]pyridine-6,4'—piperidin] -5 -amine (S)-3 -((5 -(5 -amino -5 ,7-dihydroSpiro penta[b]pyridine-6,4 '-p1peridin] -1 '-y1)pyrazinyl)thi o icolinonitrile (S)((3-an11n0(5 0-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'—piperidin]-1'-y1)pyrazi 11y1)thio)picolin0nitrile (S) -1 '-(5 -((2-chloro-5 -(trifluoromethyl)pyridiny1)th10)pyrazin-2 -y1) -5 ,7-dihydroSpiro [cyclope nta[b]pyridine-6,4'-p1peridin] -5 -amine (S) -1 '-(6-amino -5 -((2-ch10r0-5 -(trifluoromethyl)pyridinyl)thi0)pyrazinyl) -5 ,7-dihydr0Spiro [cyclopenta[b]pyridine-6,4'—piperidin] -5 -amine 1 '-(6 -5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1) -5 ydr0Spiro[cyclopenta[b] o ridine-6,4'— n i n eridin]—5 -amine 1'—(5 -((2-amin0 -3 0pyridinyl)thi0)pyrazinyl)-5 ,7-dihydr0Spiro[cyclopenta[b]pyridine- 6,4'—piperidin] -5 -amine 1'—(6-amin0-5 -((3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1) -5 ,7-dihydr0Spiro [cyclopenta[b]pyridine- 6,4'—piperidin] -5 -amine 1'—(6-amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyraziny1)-1,3 -dihydr0Spiro[indene-2,4 '-pi peridin] amine 1'—(5 -((2-amin0 -3 -ch10r0pyridinyl)thi0)pyrazinyl)-1,3 -dihydr0Spiro [indene-2 ,4'-piperidin] amine 1'—(6-amin0-5 -((3 -aminoch10r0pheny1)thi0)pyraziny1)-5 ydr0Spiro [cyclopenta[b]pyrid 4'— n i n eridin] -5 -amine 1'—(6-amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1) -5 ,7-dihydr0Spiro[cyclopenta[c] pyridine-6,4'—piperidin] -5 -amine 1'—(5 -((3 -amino ch10r0phenyl)thi0)pyrazinyl)-5 ,7-dihydr0Spiro[cyclopenta[b]pyridine-6,4'— piperidin] -5 -amine 1'—(6-amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1) -5 -br0m0 -1,3 -dihydr0Spiro [inde '— n i n eridin]—1-amine 1'—(6-amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1)ch10r0-4,6-dihydr0Spiro [cycl 0 n enta[d]thiazole-5 ,4'— n i n eridin]—4-amine 1'—(5 -((2-amin0 -3 -ch10r0pyridinyl)thi0)pyrazinyl)ch10r0-4,6-dihydr0Spiro[cyclopenta[d] le-S ,4' n i n eridin] amine 1'—(5 -((2-amin0 -3 -ch10r0pyridinyl)thi0)pyrazinyl)-2,3 -dihydrospir0[indene-1,4'-piperidin]— 2-arnine (S)((5 -(1 -amino -1, 3 -dihydr0Spiro [indene-2,4 '-piperidin] -1 '-y1)pyrazinyl)thi0) -3 -ch10r0pyri din01 (S)((3 -5 -(1 -amin0-1,3 -dihydrospir0[indene-2,4'—piperidin]—1'-y1)pyrazinyl)thi0)-3 -c hloro n ridin01 (S)((5 -(5 -amino -5 ,7-dihydr0Spiro [cyclopenta[b]pyridine-6,4 '-piperidin] -1 yrazinyl)thi 0)-3 -ch10r0pyridin01 (S)((3 -amin0-5 -(5 -amin0-5 ,7-dihydrospir0[cyclopenta[b]pyridine-6,4'—piperidin]-1'-y1)pyrazi n 1thi0 ch10r0 ‘ (S) -1 -amino- 1 '-(6-amin0 -5 -((2-amin0 -3 0pyridinyl)thi0)pyrazin-2 -y1)-1,3 -dihydroSpiro [i ndene-2,4'-piperidin]01 (S) -1 -amino- 1 '-(6-amin0 -5 -((2-amin0-3 -ch10r0pyridinyl)thi0)pyrazin-2 -y1)-1,3 -dihydroSpiro [i ndene-2,4'-piperidin]01 1'-(6-amin0((2-amin0 ch10r0pyridinyl)thi0)pyraziny1)-5 -methy1-5,7-dihydr0spir0[cyclopenta[b]pyridine-6,4'-pipe ridin] -5 -amine 1-amin0-1 '-(6-amin0-5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyraziny1) -3H-spir0[ind01izine-2, ,_1 4; o 4E-piperidin]—7(1H)-0ne (2 mg) 1-amin0-1 min0-5 min0-3 -ch10r0pyridiny1)thi0)pyraziny1) -3H-spir0[ind01izine-2, 4'—piperidin]—5(1H)-0ne 3 -((2 -arnin0-3 -ch10r0pyridinyl)thi0) (1-imin0 -1, 3 r0Spiro [indene-2,4 '-piperidin] - 1 '-y1) pyrazinamine 3 -((2-amin0-3 -ch10r0pyridinyl)thi0)(1-imin0 -5 -meth0xy-1,3 -dihydr0Spiro [indene-2,4'—pipe ridin] -1 '-y1)pyrazinamine 3 -((2-amin0-3 -ch10r0pyridinyl)thi0)(4-imin0 -4,6-dihydr0Spiro [cyclopenta[b]thi0phene-5 ,4' -piperidin] - 1 '-y1)pyrazinamine 3 min0-3 -ch10r0pyridinyl)thi0)(1-br0m0imin0-4H,6H-spir0[cyclopenta[c]thi0phen e-5 ,4'—piperidin] -1 '-y1)pyrazinamine 3 -((2-amin0-3 -ch10r0pyridinyl)thi0)(4-imin0-4H,6H-spir0 [cyclopenta[c]thiophene-S ,4'—pip eridin]— 1 '-y1)pyrazinamine 3 min0-3 -ch10r0pyridinyl)thi0)(2-br0m0imin0-4,6-dihydr0Spiro[cyclopenta[b]thi0 phene-S ,4 '-piperidin] -1 '-y1)pyrazinamine 1'—(6-amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazinyl)meth0xy-1,3 -dihydr0Spiro[in dene-2,4'—piperidin]—1 -amine (Z) - 1 '-(6-arnin0-5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl)Spiro [indene-2,4'-piperidin] -1(3H)-0ne oxime (S)-1'-(6-amin0((2-amin0ch10r0pyridiny1)thi0)pyrazinyl)meth0xy-4,6-dihydr0spir0[cyclopenta[d]thiazole-5 ,4'-piper idin] ne (S)-1'-(6-amin0((2-amino-3 - ch10r0pyridiny1)thi0)pyraziny1)-4,6-dihydrospiro[cyclopenta[d]thiazole-5 ,4 '-piperidin] amine (S) -1 '-(5 -((2 0-3 -ch10r0pyridin-4 -y1)thi0)pyrazinyl) -4,6-dihydr0Spiro [cyclopenta[d]thiaz ole-5 ,4'—piperidin] amine 1'—(6-amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1)-4,6-dihydr0Spiro[cyclopenta[d] thiazole-S peridin] amine 1'—(5 -((2-amin0-3 -ch10r0pyridinyl)thi0)pyraziny1)-4,6-dihydrospir0 [cyclopenta[d]thiazole- ,_1 U1 4; U1 4%-piperidin]—4-amine (S)-1 '-(6-an1in0((2-amin0 ch10r0pyridinyl)thi0)pyrazin-2 -y1)-4 ,6-dihydr0Spiro[cyclopenta[d]thiazole-5 ,4'—piperidin] a (S) -1 '-(5 -((2-amin0-3 0pyridiny1)thi0)pyrazinyl)-4,6-dihydr0spiro [cyclopenta[d]thiaz ole-5 peridin] amine (S) -1 '-(6-amin0-5 -((3 -flu0r0- 1 H-ind01y1)thi0)pyrazin-2 -y1)-1, 3 -dihydr0spiro[indene-2,4'—pipe ridin] amine (S) -1 -(1 -amin0-1'—(6-amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1)-1,3 -dihydr0spir 0 [indene-2,4'—piperidin] -6 -y1)ethan0ne (S) -1 -(1 -amin0-1'—(6-amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1)-1,3 -dihydr0spir 0 [indene-2,4'—piperidin] -4 -y1)ethan0ne (R) -1 '-(5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl) -1 -methylspir0 [indoline-2,4'—piperidi n] -3 -amine 1'—(6-amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1)-2,3 -dihydr0spir0[indene-1,4'-pi peridin]amine 1'—(6-amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1) -3 ,4-dihydr0-2H-spir0 [naphthal ene-1,4'-piperidin]amine 1'—(6-amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1) -5 ydr0spiro[cyclopenta[b] pyridine-7,4'—piperidin]amine 1-(6-amin0-5 min0-3 -ch10r0pyridiny1)thi0)pyraziny1)tetrahydr0-1'H,3 'H-spiro [piperid ine-4,2'—pyrr01izin]—1'-amine (1 'S)-1 ino -5 min0-3 -ch10r0pyridiny1)thi0)pyrazinyl)tetrahydr0- 1 'H,3 'H-spiro [p iperidine-4,2'—pyrr01izin] -1 '-arnine 1'—(6-amin0-5 -((2-amin0-3 0pyridiny1)thi0)pyraziny1)-4,6-dihydr0spir0[cyclopenta[b] furan-S peridin] amine (S) -1 '-(6-amin0-5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl)-4,6-dihydr0spiro [cyclopent a [b] furan-S ,4'-piperidin] amine 1'—(6-amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1)-6,7-dihydr0spiro[cyclopenta[b] pyridine-5 ,4'-piperidin]amine 1'—(6-amin0-5 -((2-amino -3 0pyridiny1)thi0)pyrazinyl)hexahydr0spiro [cyclopenta[b]fu 169 ran-5 ,4 '-piperidin] amine (4R)-1 '-(6-amino -5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyraziny1)hexahydr0Spiro[cyclopent 170 a[b]furan-5 ,4'-piperidin]—4-amine 1'—(6-amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1)spiro[bicyclo [3. 1 .0]hexane-3 ,4 '- 171 piperidin]—2-amine 1 '-amino(6 -arnin0-5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyraziny1)tetrahydr0-1'H,3 'H-spi ro [piperidine-4,2'—pyrr01izin] -3 '-0ne (1 'S)-1 '-an1in0-1 -(6-amin0-5 -((2-amin0-3 0pyridinyl)thi0)pyraziny1)tetrahydr0-1'H,3' 1 73 H-spiro[piperidine-4,2'-pyrr01izin]-3'-0ne 1'—(6-amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1)Spiro[bicyclo [3. 1 ane-2,4 '- piperidin] -3 -amine (3R)-1 '-(6-amin0-5 -((2-amin0-3 -ch10r0pyridinyl)thi0)pyrazinyl)spir0 [bicyclo [3 . 1 .0]hexane -2,4'—piperidin]-3 -amine 3 -((2-amin0-3 -ch10r0pyridinyl)thi0)(11-oxa-1,7-diazadispir0[2.0.54.33]d0decanyl)pyrazi namine 1-(4-((3 -arnin0-5 in0spir0 [bicyclo [3 . 1 .0]hexane-3 ,4'—piperidin] -1 '-y1)pyrazin-2 -y1)thi0)-3 ,3 -diflu0r0indoliny1)ethan0ne amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1) methylspir0 [bicyclo [3 . 1 .0] he Kane-3 ,4 '-piperidin] amine (4R)-1 '-(6-amino -5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1) -1 -methylspir0[bicyclo [3. 1 .0]hexane-3 ,4'—piperidin] amine 1'—(6-amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1)Spiro[bicyclo [3 .2 .0]heptane-3 ,4' -piperidin]amine (2R)-1 '-(6-amino -5 min0-3 0pyridiny1)thi0)pyraziny1)Spiro [bicyclo [3 .2 .0]heptan e-3 ,4'—piperidin] amine 1 '-(6 -amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1)hexahydro- 1 H-spiro [pentalene- 2 2 4E , -piperidin] -1 -amine ( 1 R) - 1 '-(6 -amino -5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl)hexahydr0-1H-spiro [penta lene-2,4'-piperidin]amine (3 -arnin0-5 ino-2 ,3 -dihydr0Spiro [indene- 1 ,4'—piperidin] -1 '-y1)pyrazinyl)thi0)-3 ,3 - difluoroindolinyl)ethan0ne 1 '-(6 -amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazinyl)meth0xy-2,3 -dihydr0Spiro [in dene-1,4'-piperidin]amine (R) -1 '-(6-amino -5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyraziny1)meth0xy-2 ,3 -dihydr0spir 0[indene-1,4'—piperidin]amine 1'—(6-amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1)-4,5 -dihydr0Spiro[cyclopenta[b] furan-6,4'—piperidin]amine (R) -1 '-(6-amino -5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl) -4,5 -dihydr0Spiro [cyclopent a [b] furan-6,4'—piperidin] -5 -amine 1-(4-((3 -arnin0-5 -(11-oxa-1,7-diazadispir0 [2.0. 54. 3 3] d0decany1)pyrazin-2 i0)-3 ,3 -diflu0r oindoliny1)ethan0ne 1'—(6-amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazinyl)hexahydr0Spiro [cyclopenta[b] [1 ,4] e-6,4 '-piperidin] -5 -amine (5 S) -1 '-(6-amino -5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl)hexahydr0Spiro [cyclopenta [b] [1 ,4] dioxine-6,4‘-piperidin] -5 -amine 6-an1in0 -1 '-(6-an1in0 -5 -((2-an1in0-3 -ch10r0pyridiny1)thi0)pyraziny1) -6,7-dihydr0Spiro [cycl 0penta[b]pyridine-5 ,4'-piperidin]—2(1H)-0ne (R)an1in0- 1 '-(6-an1in0 -5 -((2-an1in0-3 -ch10r0pyridinyl)thi0)pyraziny1)-6,7-dihydr0spir0[ 193 cyclopenta[b]pyridine-5 ,4 '-piperidin] -2( 1 H)-0ne 2-an1in0 -1 '-(6-an1in0 -5 -((2-an1in0-3 -ch10r0pyridiny1)thi0)pyraziny1) -2,3 -dihydr0 ir0[ 194 indolizine-l peridin] -5 -0ne (S)an1in0- 1 '-(6-an1in0 -5 n1in0 -3 -ch10r0pyridinyl)thi0)pyrazin-2 -y1) -2, 3 -dihydro-SH-s 195 pir0[ind01izine-1,4'-piperidin]—5 -0ne 1'—(6 -an1in0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazin-2 iro[chr0n1ane-4,4'—piperidin] - 196 3-an1ine (S) -1 '-(6-amino -5 -((2-an1in0-3 -ch10r0pyridiny1)thi0)pyraziny1)Spiro [chromane-4,4'-piperid in] -3 -an1ine 1 '-(6 -an1in0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazinyl)n1eth0xy- 1 3 -dihydr0Spiro [in dene-2,4'—piperidin] -1 -an1ine 1'—(6 -an1in0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1) -3 ,4-dihydr0-1H-spir0[naphthal ene-2,4'—piperidin]— 1 -an1ine 1-(6-an1in0-5 -((2-an1in0-3 0pyridiny1)thi0)pyraziny1)-7 ', 8'-dihydr0-5 'H-spiro idi ne-4,6'—quin01in] 1ine 1'—(6 -an1in0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazinyl)-6,7-dihydr0Spiro penta[c] pyridine-5 ,4'-piperidin]an1ine (R) -1 '-(6-amino -5 n1in0-3 -ch10r0pyridiny1)thi0)pyrazinyl) -6,7-dihydr0Spiro [cyclopent a[c]pyridine-5 ,4'-piperidin]an1ine 1'—(6 -an1in0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1)n1eth0xy-3 ,4-dihydr0-1H-spi r0 [naphthalene-2,4'—piperidin] -1 -an1ine (S) -1 '-(6-amino -5 -((2-an1in0-3 -ch10r0pyridinyl)thi0)pyrazin-2 -y1) th0xy-3 ,4-dihydr0- 1H -spir0 [naphthalene-2,4'—piperidin] -1 -an1ine 1'—(6 -an1in0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1) -5 ,6-din1eth0xy-1 ,3 -dihydr0spir 0 [indene-2,4'—piperidin] -1 -an1ine (S) -1 '-(6-amino -5 -((2-an1in0 -3 -ch10r0pyridinyl)thi0)pyraziny1) -5 ,6-din1eth0xy-1, 3 -dihydr0 Spiro [indene-2,4 '-piperidin] an1ine 1-an1in0 -1 '-(6-an1in0 -5 -((2-an1in0-3 -ch10r0pyridiny1)thi0)pyraziny1) -1 3 -dihydr0Spiro [inde ne-2,4'—piperidin]—6-01 1 '-(6 -an1in0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazinyl) -5 -n1eth0xy- 1 3 -dihydr0Spiro [in dene-2,4'-piperidin] -1 -an1ine 1'—(6 -an1in0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazinyl)-4,6-dihydr0Spiro[cyclopenta[b] thiophene-S ,4'-piperidin]an1ine 1-amin0-1 '-(6-amin0-5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyraziny1) -1 3 -dihydr0spiro [inde '—piperidine]carb0nitrile 1'—(6-amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazinyl)meth0xy-1,3 -dihydr0spiro[in dene-2,4'-piperidin] -1 -amine amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyraziny1)-1,3 r0spiro[indene-2,4 '-pi peridine] -1 mine 1-amin0-1 '-(6-amin0-5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyraziny1) -1 3 -dihydr0spiro [inde '—piperidin]01 1'—(6-amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyraziny1)ch10r0-1,3 -dihydr0spiro [inde ne-2,4'—piperidin]—1-amine 1'—(6-amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1)br0m0 -1,3 -dihydr0spiro [inde ne-2,4'—piperidin]—1-amine 1'—(6-amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1)-2,3 -dihydr0spir0[indene-1,4'-pi peridine] -2, 5 -diamine (R) -1 '-(6-amino -5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl) -2,3 -dihydr0spir0[indene-1, 4'-piperidine]-2,5 -diamine 1 '-(6 -amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazinyl)meth0xy-2,3 -dihydr0spiro [in dene- 1 peridin] amine (R) -1 '-(6-amino -5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyraziny1)meth0xy-2 ,3 -dihydr0spir 0[indene-1,4'-piperidin]—2-amine 1-(6-amin0-5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1) - 1 'H,3 'H-spiro [piperidine-4,2'—p yrrolizin] - 1 '-arnine (S) -1 -(6 -arnin0-5 min0-3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1) - 1 'H,3 ro [piperidine-4, 2'—pyrr01izin] -1 '-arnine 1'—(6-amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1) -5 ,7-dihydr0spiro[cyclopenta[c] ne-6,4'—piperidin]amine 2-amin0-1 '-(6-amin0-5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyraziny1) -2,3 -dihydr0spiro [inde ne-1,4'—piperidine]—4-carb0xamide (R)amin0- 1 '-(6-amin0-5 -((2-amin0-3 -ch10r0pyridinyl)thi0)pyraziny1)-2,3 -dihydr0spiro [i ndene- 1 ,4'-piperidine]carb0xamide 2-amin0-1 '-(6-amin0-5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyraziny1) -2,3 -dihydr0spiro [inde ne-1,4'-piperidine]carb0nitrile (R)amin0- 1 '-(6-amin0-5 min0-3 -ch10r0pyridinyl)thi0)pyraziny1)-2,3 -dihydr0spiro [i ndene-1,4'-piperidine]carb0nitrile N-(2-amin0-1'—(6-amino-5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl)-2,3 -dihydr0spiro [i ndene- 1 ,4'-piperidin]y1)acetamide (R)-N-(2-amin0-1'—(6-amin0-5 -((2-amin0-3 0pyridiny1)thi0)pyrazin-2 -y1)-2,3 -dihydr0spi r0 [indene- 1 ,4'—piperidin] yl)acetamide 1'—(6-amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazinyl)(pyrr01idiny1)-1,3 -dihydr0 Spiro [indene-2,4 ridin] amine (S) -1 '-(6-amino -5 -((2-amin0-3 -ch10r0pyridinyl)thi0)pyrazin-2 -y1) (pyrr01idin-1 -y1)-1 ,3 -dih iro [indene-2,4'—piperidin] -1 -amine 1'—(6-amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyraziny1)(1,4-dimethy1-1H-1,2,3 -triaz 01-5 -y1)-1,3 -dihydrospir0[indene-2,4'—piperidin]—1-amine (S)-1'—(6-amin0-5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl)(1,4-dimethyl-1H-1,2,3 -t riazol-S -y1)-1, 3 -dihydr0Spiro [indene-2,4'—piperidin] -1 -amine 1'—(6-amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyraziny1)(methy1thi0)-1,3 -dihydr0spir 0 [indene-2,4'—piperidin] -1 -amine 2-(1 -amin0-1'—(6-amin0-5 -((2-amin0-3 0pyridinyl)thi0)pyraziny1)-1,3 -dihydr0Spiro [in dene-2,4'-piperidin] y1)pr0pan-2 -01 (S) (1 -amin0-1'—(6-amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazin-2 ,3 -dihydr0spir 0 [indene-2,4'—piperidin] y1)pr0pan-2 -01 1 '-(6 -5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1)(methylsulf0nyl) -1 3 -dihydr0 Spiro[indene-2,4'—piperidin]—1-amine N-(1 -amin0-1'—(6-amino-5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl)-1,3 -dihydr0Spiro [i ndene-2,4‘-piperidin]y1)acetamide (S)-N-(1 -amin0-1'—(6-amin0-5 -((2-amino-3 -ch10r0pyridiny1)thi0)pyraziny1)-1,3 -dihydr0spi r0 [indene-2,4'—piperidin] yl)acetamide 1-amin0-1 '-(6-amin0-5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyraziny1) -1 3 -dihydr0Spiro [inde ne-2,4'—piperidine]carb0xamide 1'—(6-amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyraziny1)(cyclopentyloxy)-1,3 -dihydr ospiro[indene-2,4'-piperidin]arnine (S) -1 min0-5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl)(cyclopenty10xy)-1,3 -dih iro [indene-2,4'—piperidin] -1 -amine 1-amin0-1 '-(6-amin0-5 min0-3 -ch10r0pyridiny1)thi0)pyraziny1) -3H-spir0[ind01izine-2, N4;N 4%-piperidin]—7(1H)-0ne 0-1 min0-5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyrazinyl) -5 -flu0r0-1,3 -dihydros N4;w piro[indene-2,4'-piperidin]01 (S)amin0-1'—(6-amin0-5 -((2-amin0-3 -ch10r0pyridinyl)thi0)pyraziny1)-5 -flu0r0-1,3 -dihy droSpiro [indene-2,4'-piperidin]01 1'—(6-amin0-5 -((2-amino -3 -ch10r0pyridiny1)thi0)pyrazin-2 -y1) -5 ,7-dihydr0- 1 H-spiro [cyclopen ta[flindole-6,4'—piperidin] amine (S) -1 mino -5 -((2-amino-3 -chloropyridinyl)thio)pyrazin-2 -yl) -5 ,7-dihydro-1H-spiro[cyclo penta[flindole-6,4'—piperidin]amine 1'—(6-amino-5 -((2-amino -3 -chloropyridinyl)thio)pyrazin-2 -yl) -5 ,7-dihydro-1H-spiro[indeno[5 amine , 6-d] imidazole-6,4'—piperidin] (S) -1 '-(6-amino -5 -((2-amino -3 -chloropyridinyl)thio)pyrazinyl) -5 ,7-dihydro-1H-spiro[inde no [5 ,6-d]imidazole-6,4'—piperidin] amine 1'—(6-amino-5 -((2-amino -3 -chloropyridinyl)thio)pyrazinyl)(1H-tetrazol-S -yl)-1,3 -dihydr ospiro[indene-2,4'-piperidin]amine (S) -1 '-(6-amino -5 -((2-amino -3 -chloropyridinyl)thio)pyrazinyl) (1H-tetrazol-5 -yl)-1,3 -di hydrospiro [indene-2,4 '-piperidin] -1 -amine 1-(1 -amino-1'—(6-amino-5 -((2-amino-3 -chloropyridinyl)thio)pyrazinyl)-1,3 -dihydrospiro [in dene-2,4'-piperidin]yl) -3 -methylurea (S) -1 -(1 -amino-1'—(6-amino-5 -((2-amino -3 -chloropyridinyl)thio)pyrazin-2 -yl)-1,3 -dihydrospir o [indene-2,4'—piperidin] -6 -yl)-3 lurea 1'—(5 -((2-amino -3 -chloropyridinyl)thio)pyrazinyl)-2,3 -dihydrospiro[indene-1,4'—piperidin]— 253 2-amine The present invention also provides a pharmaceutical composition comprising at least one compound or pharmaceutically acceptable salt thereof of Formula I, II, III or IV and at least one pharmaceutically acceptable excipient. Furthermore, in the composition, the said compound or pharmaceutically acceptable salt thereof of Formula I, II, III or IV in a weight ratio to the said ent Within the range from about 0.0001 to about 10.
The t invention additionally provided a use of aboved said pharmaceutical composition for the preparation of a ment.
In some embodiments, the medicament is for treatment or prevention a disease or disorder mediated by the activity of SHP2.
In some embodiments, the e or er mediated by the activity of SHP2 is cancer, cancer asis, cardiovascular disease, an logical disorder, fibrosis, or an ocular disorder.
In some embodiments, the disease or disorder mediated by the activity of SHP2 is one or more selected from Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, head and neck squamous-cell carcinoma, acute myeloid leukemia, breast cancer, geal tumor, lung cancer, colon , head cancer, c carcinoma, lymphoma, glioblastoma, gastric cancer, pancreatic , and combination thereof.
The present invention additionally provided a use of at least one compound or pharmaceutically acceptable salt thereof of a I, II, III or IV for the preparation of a medicament.
In some embodiments, the medicament is for treatment or prevention a disease or disorder mediated by the activity of SHP2.
In some ments, the e or disorder mediated by the activity of SHP2 is cancer, cancer metastasis, cardiovascular disease, an immunological disorder, fibrosis, or an ocular disorder.
In some embodiments, the e or disorderm ediated by the activity of SHP2 is one or more selected from Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic ias, neuroblastoma, melanoma, head and neck us-cell carcinoma, acute d leukemia, breast cancer, esophageal tumor, lung cancer, colon cancer, head cancer, gastric oma, lymphoma, glioblastoma, gastric cancer, pancreatic cancer, and ation thereof.
The present invention additionally provided using at least one compound or pharmaceutically acceptable salt thereof of Formula I, II, III or IV, or pharmaceutical ition described above, which is for the preparation of a ment.
In some embodiments, the medicament is for treatment or prevention a disease or disorder mediated by the activity of SHP2.
In some embodiments, the disease or disorder mediated by the activity of SHP2 is cancer, cancer metastasis, cardiovascular disease, an immunological disorder, fibrosis, or an ocular disorder.
In some ments, the disease or disorder mediated by the activity of SHP2 is one or more selected from Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, head and neck squamous-cell carcinoma, acute myeloid leukemia, breast cancer, esophageal tumor, lung cancer, colon cancer, head cancer, gastric carcinoma, lymphoma, glioblastoma, gastric cancer, pancreatic cancer, and combination thereof.
The present invention additionally provided a method of treating a patient having a condition which is mediated by the activity of SHP2, said method comprising administering to the patient a therapeutically effective amount of at least one compound or pharmaceutically acceptable salt thereof of Formula I, II, III or IV, or the pharmaceutical composition described above.
In some embodiments, the ion mediated by the activity of SHP2 is cancer, cancer metastasis, cardiovascular disease, an immunological disorder, is, or an ocular disorder.
In some embodiments, the condition mediated by the ty of SHP2 is noonan syndrome, leopard me, juvenile myelomonocytic leukemias, liver , neuroblastoma, melanoma, squamous-cell carcinoma ofthe head and neck, acute myeloid ia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, gastric oma, neuroblastoma, lymphoma, astoma, c cancer, pancreatic cancer, and combination f.
The present invention additionally provided a method of treating cancer selected from the group consisting of noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemias, liver cancer, neuroblastoma, melanoma, squamous-cell carcinoma of the head and neck, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, gastric carcinoma, neuroblastoma, lymphoma, glioblastoma, gastric , pancreatic cancer, and combinations thereof, comprising administering to a mammal in need of such treatment an effective amount of at least one compound or pharmaceutically acceptable salt f of Formula I, II, III or IV, or the pharmaceutical composition described above.
The term "halogen", as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo. The preferred halogen groups e F, Cl and Br. The terms "haloC1_6alkyl", 2_6alkenyl", "haloC2_6alkynyl" and "haloC1_6alkoxy" mean a C1_6alkyl, kenyl, C2_6alkynyl or C1_6alkoxy in which one or more (in particular, 1,2 or 3) hydrogen atoms have been replaced by halogen atoms, especially fluorine or chlorine atoms. In some embiment, preferred are fluoroC1_6alkyl, fluoroC2_6alkenyl, fluoroC2_6alkynyl and fluoroC1_6alkoxy groups, in particular fluoroC1_3alkyl, for example, CF3, CHFz, CH2F, CH2CH2F, CH2CHF2, CH2CF3 and fluoroC1_3alkoxy groups, for example, OCF3, OCHFZ, OCHZF, OCHZCHZF, OCHZCHFZ or OCH2CF3, and most especially CF3, OCF3 and OCHFZ.
As used herein, unless ise indicated, alkyl includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties. For example, alkyl radicals include methyl, ethyl, propyl, pyl, cyclcopropyl, n-butyl, yl, sec-butyl, t-butyl, cyclcobutyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclcopentyl, n- hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl. Similary, C1_g, as in kyl is defined to identify the group as having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms in a linear or branched arrangement.
Alkylene means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is d above. For example, methylene (i.e., , ethylene (i.e., -CH2-CH2- or —CH(CH3)-) and propylene (i.e., -CH2-CH2- CH2-, -CH(-CH2-CH3)- or —CH2-CH(CH3)-).
Alkoxy radicals are oxygen ethers formed from the previously described straight, branched chain or cyclic alkyl groups.
The term "aryl", as used herein, unless ise indicated, by itself or as part of another substituent refers to a monocyclic or polycyclic aromatic hydrocarbon. Phenyl and yl are preferred aryls. The most preferred aryl is phenyl.
The term "heterocyclic", as used herein, unless otherwise indicated, by itself or as part of another substituent refers to unsubstituted and tuted mono- or polycyclic non-aromatic, partially unsaturated or fully ted ring system containing one or more heteroatoms. Preferred heteroatoms include N, O, and S, including N—oxides, sulfur oxides, and dioxides. Preferably the ring is three to eight membered and is either fully saturated or has one or more s of unsaturation. Multiple s of substitution, preferably one, two or three, are included within the present definition.
Examples of such heterocyclic groups include, but are not limited to azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofilranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, rpholinyl sulfoxide, thiamorpholinyl sulfone and oxadiazolyl.
The term "heteroaryl", as used herein, unless otherwise indicated, by itself or as part of another substituent refers to an aromatic ring system containing carbon(s) and at least one heteroatom. Heteroaryl may be monocyclic or clic, substituted or unsubstituted. A monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 10 hetero atoms. A clic heteroaryl ring may contain fused, spiro or bridged ring junction, for example, bycyclic aryl is a clic heteroaryl. Bicyclic heteroaryl rings may contain from 8 to 12 member atoms. Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (cabons and heteroatoms). Examples of heteroaryl groups include, but are not limited to thienyl, l, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, lyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, azolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adeninyl, quinolinyl or isoquinolinyl.
The term "cycloalkyl" as used herein, unless otherwise ted, by itself or as part of another substituent refers to a substituted or unsubstituted monocyclic, bicyclic or polycyclic non-aromatic saturated or partially unsatureated hydrocarbon group, which optionally includes an alkylene linker through which the cycloalkyl may be attached. Examplary "cycloalkyl" groups includes but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on.
The term "carbony ", "-C=O", "C=O", "-CO", "-C(O) ", and "CO" refer to the group 271/0}? The term efers to the radical =0.
Whenever the term "alkyl" or "aryl" or either of their prefix roots appear in a name of a substituent (e.g., aralky or dialkylamino) unless otherwise indicated, by itself or as part of another substituent, it shall be reted as ing those limitations given above for "alkyl" and "aryl".
Designated numbers of carbon atoms (e. g., C1-6) shall refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
The substituents the two "R1" of Formula I, II, III or IV can be the same or different. Similar to "R1", and the two "Y1" of Formula I, II, III or IV can be the same or different.
Compounds described herein, such as certain compounds of a I, II, III or IV may contain asymmetrically substituted carbon atoms (or chiral centers) in the R or S configuration.
The present invention includes racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.
The compounds bed herein, when specifically designated as the R- or S- isomer, either in a chemical name or in a drawing, should be understood as an enriched er or S-isomer, respectively. For example, in any of the embodiments described herein, such enriched R- or S-designated isomer can be substantially free (e. g., with less than 5%, less than 1%, or non-detectable, as determined by chiral HPLC) of the other isomer for the respective chiral center.
The enriched R- or S-isomers can be prepared by methods exemplified in this application, such as by using a chiral auxiliary such as R- or S-tert-butylsulfinamide in the synthetic process. Other methods for prepaing the ed R- or ers herein include, but are not limited to, chiral HPLC purifications of a stereoisomeric mixture, such as a racemic mixture. General methods for separating stereoisomers (such as enantiomers and/or diastereomers) using HPLC are known in the art. nds described herein can exist in isotope-labeled or -enriched form containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most abundantly found in nature. es can be radioactive or non-radioactive es.
Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur, fluorine, chlorine, and iodine include, but are not limited to 2H, 3H, 13C, 14C, 15N, 18O, 32F, 358, 18F, 36Cl, and 1251. Compounds that contain other isotopes of these and/or other atoms are within the scope of this invention. In some embodiments, one or more hydrogen atoms of any ofthe compounds described herein can be substituted with deuterium to provide the corresponding deterium-labeled or -enriched compounds.
The term ct" natively referred to herein as "‘patient") as used herein refers to an animal, preferably a mammal, most ably a human, who has been the object of treatment, ation or ment.
The term "ring systems" as used herein, unless otherwise indicated, include but not limite to a carbocyclic ring, a heterocyclic ring, a aromatic ring, etc., may also include only a heterocyclic ring, and/or a heteroaromatic ring, and the like, specifically includes which rings need to be determined according to the context, but anyway the "ring systems" do not include the cycloalkyl based on a C1_6 alkyl or C1_3 alkyl , and do not include the cycloalkoxy based on a C1_6 alkoxy or C1_3 alkoxy group.
Compounds of Formula I, II, III or IV may have different isomeric forms. For example, any asymmetric carbon atom may be present in the (R)-, (S)- or (R,S)—conf1guration, preferably in the (R)- or (S)-conf1guration. Substituents at a double bond or especially a ring may be t m cis-( = Z-) or trans (= E-) form. The compounds may thus be present as mixtures of isomers or preferably as pure isomers, preferably as pure diastereomers or pure enantiomers.
Where the plural form (e. g. nds, salts) is used, this includes the singular (e. g. a single compound, a single salt). "A compound" does not exclude that ( e. g. in a pharmaceutical ation) more than one compound of the Formula I, II, III or IV (or a salt thereof) is present, the "a" merely representing the indefinite article. "A" can thus preferably be read as "one or more", less ably alternatively as "one".
"SHPZ" means "Src Homolgy-2 phosphatase" and is also known as SH-PTPZ, SH-PTP3, Syp, PTPlD, PTPZC, SAP-2 or PTPNll.
Cancers harboring l mutations" include but are not limited to: N5 8Y, D6lY, V; E69K; A72V, T, D; E76G, Q, K (ALL); G6OA: D6lY; E69V; F71K; A72V; T731; E76G, K; R289G; G503V (AML); G6OR, D6lY, V, N; Y62D; E69K; A72T, V; T731; E76K, V, G, A, Q; El39D; G503A, R; Q506P (JMML); G6OV; D6lV; E69K; F71L; A72V; E76A (MDS), Y63C (CMML); Y62C; E69K; T507K (neuroblastoma); V46L; N588; E76V (Lung cancer), R138Q (melanoma); E76G (colon cancer) The term "composition", as used herein, is intended to encompass a product sing the specified ingredients in the specified amounts, as well as any t which results, directly or indirectly, from combinations of the ed ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the present invention as the active ingredient as well as methods of preparing the instant compounds are also part of the t invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the t invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents and such solvates are also intended to be encompassed within the scope of this ion.
The compounds of the present invention may also be present in the form of pharmaceutically able salts. For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts". The pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts. The pharmaceutically acceptable acidic/anionic salt generally takes a form in which the basic nitrogen is ated with an inorganic or organic acid. Representative organic or inorganic acids include hydrochloric, hydrobromic, hydriodic, perchloric, ic, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, c, malic, ic, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, , 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic.
Pharmaceutically acceptable basic/cationic salts e, and are not d to aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium and zinc.
The present invention includes within its scope the prodrugs of the compounds of this invention. In general, such prodrugs will be filnctional derivatives of the nds that are readily converted in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term "administering" shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be cally disclosed, but which converts to the specified compound in vivo after administration to the subject. Conventional ures for the selection and ation of suitable prodrug derivatives are described, for example, ign of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the nds of this invention can be selected by one of ordinary skill in the art to provide compounds that are ally stable and that can be readily synthesized by techniques know in the art as well as those methods set forth herein.
The present ion includes compounds described can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention es all such possible diastereomers as well as their racemic es, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
The above Formula I, II, III or IV is shown without a definitive stereochemistry at certain positions. The present invention includes all stereoisomers of Formula I, II, III or IV and pharmaceutically acceptable salts thereof r, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
When a tautomer of the compound of Formula I, II, III or IV exists, the present ion includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically stated otherwise.
When the compound of Formula I, II, III or IV and pharmaceutically acceptable salts thereof exist in the form of es or polymorphic forms, the present invention includes any possible solvates and polymorphic forms. A type of a solvent that forms the solvate is not particularly limited so long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone or the like can be used.
The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its ponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and c acids. Since the compounds of Formula I, II, III or IV are intended for pharmaceutical use they are preferably provided in substantially pure form, for e at least 60% pure, more suitably at least 75% pure, especially at least 98% pure (% are on a weight for weight .
The pharmaceutical compositions of the present invention comprise a compound represented by Formula I, II, III or IV (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other eutic ingredients or adjuvants. The compositions include compositions suitable for oral, , l, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
In practice, the compounds represented by Formula I, II, III or IV, or a prodrug, or a metabolite, or pharmaceutically acceptable salts thereof, of this ion can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms ing on the form of ation desired for stration, e. g., oral or eral (including intravenous). Thus, the pharmaceutical compositions of the present invention can be presented as te units le for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a on, as a suspension in an aqueous , as a non-aqueous liquid, as an oil-in-water emulsion, or as a water-in- oil liquid emulsion. In addition to the common dosage forms set out above, the compound represented by a I, II, III or IV, or a pharmaceutically acceptable salt thereof, may also be administered by controlled release means and/or delivery devices. The compositions may be ed by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the r that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
Thus, the pharmaceutical compositions of this invention may include a pharmaceutically acceptable carrier and a compound, or a pharmaceutically acceptable salt, of Formula I, II, III or IV. The compounds of Formula I, II, III or IV, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of s carriers include carbon dioxide and nitrogen. In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be employed. For example, water, glycols, oils, ls, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, es and tablets. e of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical rs are employed. Optionally, tablets may be coated by rd aqueous or nonaqueous techniques.
A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or nts. ssed s may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or sing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound ned with an inert liquid diluent. Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient and each cachet or capsule preferably ning from about 0.05mg to about 5g of the active ingredient. For example, a formulation intended for the oral administration to humans may contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total ition. Unit dosage forms will generally contain between from about lmg to about 2g of the active ingredient, typically 25mg, 50mg, lOOmg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, or lOOOmg.
Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as ons or suspensions of the active compounds in water. A le surfactant can be included such as, for e, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a vative can be included to prevent the detrimental growth of microorganisms.
Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the ions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fiangi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
Pharmaceutical compositions of the t invention can be in a form suitable for l use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula I, II, III or IV of this invention, or a pharmaceutically acceptable salt f, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hilic material and water, together with about 5wt% to about lOwt% of the compound, to produce a cream or ointment having a desired consistency. ceutical itions of this ion can be in a form suitable for rectal administration and the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers e cocoa butter and other materials commonly used in the art.
The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.
In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional r ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like. Furthermore, other adjuvants can be ed to render the formulation isotonic with the blood of the ed recipient. Compositions containing a compound described by Formula I, II, III or IV, or pharmaceutically acceptable salts thereof, may also be ed in powder or liquid concentrate form.
Generally, dosage levels on the order of from about 0.01mg/kg to about 150mg/kg of body weight per day are useful in the treatment of the above-indicated ions, or alternatively about 0.5mg to about 7g per t per day. For example, inflammation, cancer, psoriasis, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system (CNS), may be effectively treated by the administration of from about 0.01 to 50mg ofthe compound per kilogram ofbody weight per day, or alternatively about 0.5mg to about 3.5g per patient per day.
It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug ation and the severity of the particular disease undergoing therapy.
These and other s will become apparent from the following written description of the invention.
Examples The ing Examples are provided to better illustrate the present ion. All parts and percentages are by weight and all temperatures are degrees Celsius, unless explicitly stated otherwise. The following abbreviations have been used in the examples: methylformamide THF ydrofilran EA Ethyl acetate Ti(OEt)4 Titanium ethoxide Hex Hexane NMP l-Methylpyrrolidinone MeOH Methanol DMSO Dimethyl sulfoxide DCM Dichloromethane DIEA N,N—Diisopropylethylamine DCE 1,2-Dichloroethane (Boc)20 Di-tert-butyl dicarbonate EtOH Ethanol LDA Lithium diisopropylamide t-BuOH tert-Butanol PPA Polyphosphoric acids AcOH Acetic acid glacial is(triphenylphosphine)p Pd(PPh3)4 AcONa Sodium acetate alladium 1,8-Diazabicyclo[5.4.0]undec- n-BuLi n-But llithium DBU - y 7-6116 Lithium aluminium hydride is(diphenylphosphino)- t-BuOK Potassium tert-butoxide 9,9-d1methylxanthene Sodium ethoxide y amine Triethylamine HCl H d hl ' 'd Tris(dibenzylideneacetone)dip Pd23 ' ' zabenzotriazol-I-y1>-N, N,N',NLtetramethyluronium _— Thin layer tography CY3PH'BF TricyclohexylphOSphonium Preparative thin layer Pre-TLC tetrafluoroborate 4 tography Methanesulfonyl chloride Intermediate A1 Boc—N 0/ ' 0/ O 0 To a solution of 6-methoxy-2,3-dihydro-1H-indenone (1.50 g, 9.25 mmol) in DMF (10 mL) under nitrogen atmosphere was added NaH (60% dispersion in mineral oil, 1.11 g, 27.75 mmol) in portions. The mixture was heated to 60 °C, stirred for 20 min at this temperature. Tert-butyl bis(2-chloroethyl)carbamate (2.46 g, 10.17 mmol) was added dropwise, and the mixture was stirred for 85 min. After cooling to RT, the reaction mixture was diluted with EA (200 mL), washed with brine (3 x 200 mL), dried over anhydrous Na2804, filtered and concentrated under reduced pressure. The e was purified by silica chromatography (eluting with EA : Hex = 1 : 12, v/v) to give tert-butyl 6-methoxyoxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate (557 mg) as a yellow solid. MS: m/z 332 .
The following compounds were synthesized using the above procedure with the corresponding starting materials.
Table 1 Intermediate A2 HO/\/N\/\OH —> j —> a b HO/\/N\/\OH N\ N\ / a soc-Ops c d Step a: A solution of 2,2'-azanediylbis(ethan-l-ol) (198.15 g, 1.88 mol), K2CO3 (520.95 g, 3.77 mol) and methyl)benzene (386.79 g, 2.26 mol) in acetonitrile (2000 mL) was stirred at 90 °C for 2.5 h. After g to RT, the reaction mixture was filtered ed by EA (2 \ 100mL) wash. The e was concentrated under reduced pressure. The residue was purified by silica tography (eluting with MeOH : DCM = l : 10, v/v) to give benzylazanediyl)bis(ethan-l-ol) (89.44 g) as a colorless oil. MS: m/z 196 (M+H)+.
Step b: To a 0 °C solution of 2,2'-(benzylazanediyl)bis(ethan-l-ol) (30.66 g, 0.16 mol) in toluene (300 mL) was added tribromophosphane (69.13 g, 0.26 mol) dropwise. The resulting e was stirred at 105 °C for 16 h. After cooling to RT, the volatiles were removed under reduce pressure. The residue was diluted with water (300 mL), and the pH value was adjusted to 9 with NaOH. The resulting mixture was extracted with EA (3 x 150 mL), the organic layers combined, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give N—benzylbromo-N-(2-bromoethyl) ethan-l-amine (41.58 g) which was used in next step without any further purification. MS: m/z 320 (M+H)+.
Step c: To a 0 °C solution of 6,7-dihydro-5H-cyclopenta[b]pyridinone (1.70 g, 12.77 mmol) in DMF (20 mL) under nitrogen atmosphere was added NaH (60% dispersion in mineral oil, 982 mg, 24.55 mmol) in three portions, and the mixture was heated to 60 °C, d for l h at this temperature. Then N—benzylbromo-N-(2-bromoethyl)ethan-l-amine (4.54 g, 14.14 mmol) was added and stirred at 60 °C for another 1 h. After cooling to RT, the reaction mixture was quenched with water (80 mL), extracted with EA (3 in: 80 mL). The combined organic layers were washed with water (3 X 80 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was d by silica chromatography (eluting with EA) to give l'-benzylspiro[cyclopenta[b]pyridine-6,4'-piperidin]-5(7H)—one (1.14 g). MS: m/z 293 (M+H)+.
Step (1: To a 0 °C solution of l'-benzylspiro[cyclopenta[b]pyridine-6,4'-piperidin]-5(7H)—one (1.05 g, 3.59 mmol) in DCE (10 mL) was added 1-chloroethyl ochloridate (903 mg, 6.32 mmol) dropwise. The resulting mixture was stirred at RT for 1.5 h. The volatiles were removed under reduced pressure and the residue was dissolved in MeOH (20 mL), d at 80 °C for 4 h.
The volatiles were removed under reduced pressure and dissolved in DCM (20 mL). DIEA (1.33 g, .32 mmol) and (Boc)20 (1.38 g, 6.32 mmol) were added. The resulting solution was stirred for 16 h at RT. The reaction e was concentrated under reduced re. The residue was purified by silica chromatography (eluting with EA : Hex = 1 : 1, v/v) to give tert-butyl -oxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (438 mg). MS: m/z 303 (M+H)+.
Intermediate A3 Boc—N/\:>—/<0 Br + Br > —> Boc—N O < _\ a O S ;:OH Br —> BOG—N —> BOG—Mm b r Step a: To a -70 °C solution of 1-(tert-butyl) 4-ethyl piperidine-1,4-dicarboxylate (8.14 g, 31.64 mmol) in THF (80 mL) under nitrogen atmosphere was added LDA (2 M solution in THF/Hex, 24 mL, 48.00mmol) dropwise. After stirred for 70 min at this temperature, 1-bromo(bromomethyl)benzene (7.91 g, 31.64 mmol) was added in portions. The ing solution was stirred for 3 h at -70°C, and carefially quenched with sat. aq. NH4Cl (50 mL). The aqueous layer was separated, and extracted with EA (1 X 80 mL), the c layers combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 1-(tert-butyl) 4-ethyl romobenzyl)piperidine-1,4-dicarboxylate (14.55 g) as a brown oil which was used in next step without any filrther purification. MS: m/z 426 (M+H)+.
Step b: A solution of 1-(tert-butyl) 4-ethyl 4-(4-bromobenzyl)piperidine-1,4-dicarboxylate (14.55 g, 34.13 mmol) and NaOH (8.12 g, 203.00 mmol) in MeOH (80 mL) and water (80 mL) was stirred for 16.5 h at 75 °C. After cooling to RT, the les were removed under reduced pressure. The resulting mixture was extracted with EA (3 X 80 mL). The combined organic layers were dried over anhydrous , filtered and concentrated under reduced pressure to give 4-(4-bromobenzyl)(tert-butoxycarbonyl)piperidinecarboxylic acid (16.87 g) which was used in next step without any filrther purification. MS: m/z 398 (M+H)+.
Step c: A mixture of 4-(4-bromobenzyl)(tert-butoxycarbonyl)piperidinecarboxylic acid (16.87 g, 42.36 mmol) and PPA (60 mL) was stirred for 30 min at 120 °C. The on mixture was poured into ice/water (300 mL), the pH value was adjusted to 10 with NaOH. Then (Boc)20 (13.86 g, 63.53 mmol) was added and stirred for 18 h at RT. The on e was extracted with EA (3 x 150 mL). The combined organic layers were dried over ous NaZSO4, filtered and concentrated under reduced pressure to give tert-butyl 6-bromooxo-1,3-dihydrospiro [indene-2,4'-piperidine]-1'-carboxylate (16.87 g) which was used in next step without any filrther purification. MS: m/z 380 (M+H)+.
The following compounds were synthesized using the above procedure or modifications procedure with the corresponding starting materials.
Table 2 Intermediate A4 Boc-N Boc-N O O A mixture of tert-butyl 6-bromooxo-1,3-dihydrospiro[indene-2,4'-piperidine]- 1'-carboxylate (2.06 g, 5.42 mmol), Pd(PPh3)4 (626 mg, 0.54 mmol), DBU (252 mg, 1.66 mmol), t-BuOH (15 mL), water (15 mL) and potassium ferrocyanide trihyrate (1.16 g, 2.75 mmol) was stirred for 22.5 h at 90 °C under nitrogen atmosphere. After cooling to RT, the mixture was diluted with EA (30 mL), filtered followed by EA (15 mL) wash. The e was washed with brine (1 X mL), dried over anhydrous NaZSO4, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography ng with EA : Hex = 1 : 10, v/v) to give tert-butyl 6-cyanooxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate (1.86 g). MS: m/Z 327 .
The following compounds were synthesized using the above procedure with the corresponding starting materials.
Table 3 Intermediate A5 Boa—Mm ’ Boc—N O O A solution of tert-butyl 4-cyano-l -oxo-l ,3-dihydrospiro[indene-2,4'-piperidine]-1'- carboxylate (0.93 g, 2.85 mmol) and KOH (l .60 g, 28.50 mmol) in MeOH (15 mL) and water (15 mL) was stirred for 2 h at 100 °C. After cooling to RT, the on mixture was diluted with water (30 mL), extracted with EA (60 mL, 30 mL). The combined organic layers were washed with brine (l X 80 mL), dried over anhydrous Na2804, filtered and concentrated under reduced pressure to give tert-butyl 4-carbamoyl-l-oxo- l ydrospiro[indene-2,4'-piperidine]-l'-carboxylate (1.04 g) which was used in next step without any further purification. MS: m/z 345 (M+H)+.
The following compounds were synthesized using the above procedure with the corresponding starting materials.
Table 4 Intermediate A6 B°° "mm— B°° "mm— | 0 o 0 0 To a solution of tert-butyl 6-carbamoyl-l-oxo-l,3-dihydrospiro[indene-2,4'-piperidine]- l'-carboxylate (1.57 g, 4.56 mmol) in DMF (15 mL) was added NaH (60% dispersion in mineral oil, 0.91 g, 22.79 mmol) followed by the addition of CH3I (1 mL, 16.06 mmol). The ing mixture was stirred for 17 h at RT. The reaction was quenched with brine (50 mL), extracted with EA (2 32:. 50 mL). The combined organic layers were washed with brine (l X 100 mL), dried over anhydrous , filtered and concentrated under reduced pressure. The residue was purified by silica tography (eluting with EA : Hex = 1: 3, v/v) to give tert-butyl 6-(dimethylcarbamoyl)—1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate (0.82 g).
MS: m/Z 373 (M+H)+.
Intermediate A7 BOC_N<:>—<0 CN + Nc@ —> BOG—N O_\ a O BOG—N —» Boc—N OH—> OH b 0H 0 o 0 Step a-c: Step (a-c) of Intermediate A 3 was applied to provide 1'-(tert-butoxycarbonyl)oxo-1,3-dihydrospiro[indene-2,4'-piperidine]carboxylic acid. MS: m/Z 346 (M+H)+.
Intermediate A8 Boc-N : g : Boc-N —> : g : Br NH2 0 O A 50 mL sealed tube was charged with tert—butyl ooxo-1,3-dihydrospiro e-2,4'-piperidine]-1'-carboxylate (998 mg, 2.62 mmol), DMSO (8 mL), water (4 mL), CuI (217 mg, 1.14 mmol) and ammonium hydroxide (25%, 4 mL). The resulting e was stirred for 5 days at 100 °C. After g to RT, the reaction mixture was diluted with brine (20 mL) and EA (30 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 6-aminooxo-1,3-dihydrospiro [indene-2,4'-piperidine]-1'-carboxylate (750 mg). MS: m/z 317 (M+H)+.
Intermediate A9 A mixture of tert-butyl 6-bromooxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'- carboxylate (534 mg, 1.40 mmol), methanesulfonamide (371 mg, 3.90 mmol), K2CO3 (1.10 g, 7.95 mmol), N,N'-dimethyl-1,2-ethanediamine (85 mg, 0.96 mmol), CuI (72 mg, 0.38 mmol) in 1,4-dioxane (20 mL) under nitrogen here was stirred for 23 h at 110 °C. An additional portion of methanesulfonamide (370 mg, 3.89 mmol), N,N'-dimethyl-1,2-ethanediamine (85 mg, 0.96 mmol), CuI (75 mg, 0.39 mmol) was added, and stirred for another 7 h at the same temperature. After cooling to RT, the reaction was quenched with water (30 mL), extracted with EA (3 EH 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was d by silica chromatography (eluting with EA : Hex = 2 : 3, v/v) to give tert-butyl 6-(methylsulfonamido)-l-oxo-l,3-dihydrospiro [indene-2,4'-piperidine]-l'-carboxylate (562 mg). MS: m/z 395 (M+H)+.
The following compound was synthesized using the above procedure with the corresponding starting materials.
Table 5 Intermediate A10 Boc—N Boc—N —> A NH2 N NH2 0 o H To a solution of utyl 6-amino-l-oxo-l,3-dihydrospiro[indene-2,4'-piperidine]-1'- carboxylate (0.66 g, 2.09 mmol) in AcOH (5 mL) and water (10 mL) was added a solution of sodium cyanate (0.28 g, 4.31 mmol) in water (2 mL) dropwise. The resulting mixture was stirred for 4 h at 50 °C. After cooling to RT, the pH value of the reaction mixture was adjusted to 12 with ammonium hydroxide (25%) and extracted with DCM (60 mL, 30 mL). The combined organic layers were washed with brine (l X 60 mL), dried over anhydrous NaZSO4, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA : Hex = 2 :1, v/v) to give utyl l-oxoureido-l,3-dihydrospiro[indene-2,4'- piperidine]—l'-carboxylate (0.39 g). MS: m/z 360 (M+H)+.
Intermediate A11 Boc—N BOG—N s/ s/ o o 5 To a 0 °C on of tert-butyl 6-(methylthio)-l-oxo-l,3-dihydrospiro[indene-2,4'- piperidine]—l'-carboxylate (336 mg, 0.97 mmol) in MeOH (20 mL) and water (20 mL) was added potassium peroxymonosulfate (296 mg, 1.76 mmol). The resulting mixture was stirred for l h at 0 °C. The on e was quenched with sat. aq. Na28203 (10 mL), the volatiles were removed under reduced pressure. The resulting mixture was extracted with EA (3 ix: 40 mL), the combined organic layers were dried over anhydrous Na2804, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA : Hex = 4 : 1, v/v) to give tert-butyl 6-(methylsulfinyl)-l-oxo-l,3-dihydrospiro[indene-2,4'-piperidine]—l '- carboxylate (285 mg). MS: m/z 364 (M+H)+.
The following compound was synthesized using the above procedure with the corresponding starting materials.
Table 6 Intermediate A12 A mixture of tert-butyl 6-bromooxo-1,3-dihydrospiro[indene-2 ,4'-piperidine]-1'- ylate (1.51 g, 3.97 mmol), dimethyl(oxo)phosphanium (503 mg, 6.44 mmol), )2 (92 mg, 0.41 mmol), Xantphos (457 mg, 0.79 mmol), K3PO4 (1.57g, 7.40 mmol) and DMF (30 mL) was stirred for 16.5 h at 130 °C under nitrogen atmosphere. After cooling to RT, the reaction mixture was quenched with water (120 mL), extracted with EA (3 ix: 80 mL). The combined organic layers were washed with brine (1 x 120 mL), dried over anhydrous NaZSO4, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with MeOH : DCM = 1 : 30, v/v) to give utyl 6-(dimethylphosphoryl)oxo-1,3- dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate (0.81 g) as a white solid. MS: m/z 378 .
The following compounds were synthesized using the above procedure with the corresponding starting materials.
Table 7 Intermediate A13 —> /\ Br N \ O 0 li/ A mixture of tert-butyl 6-bromooxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'- ylate (1.09 g, 2.87 mmol), 1H-imidazole (180 mg, 2.64 mmol), CuBr (34 mg, 0.24 mmol), Cs2C03 (851 mg, 2.61 mmol), 1,2,3,4-tetrahydrohydroxyquinoline (74 mg, 0.49 mmol) and DMSO (10 mL) was stirred for 23 h at 110 °C under nitrogen atmosphere. After cooling to RT, the on mixture was quenched with water (30 mL), extracted with EA (1 n: 40 mL). The organic layer was dried over anhydrous Na2804, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography ng with EA) to give tert-butyl 6-(1H-imidazolyl)oxo-1,3-dihydrospiro[indene-2,4'-piperidine]—1'-carboxylate (142 mg) as a yellow solid. MS: m/Z 368 (M+H)+.
The following compound was synthesized using the above procedure with the corresponding starting materials.
Table 8 Intermediate A14 0 0 o o A e of 1'-(tert-butoxycarbonyl)oxo-1,3-dihydrospiro[indene-2,4'-piperidine] carboxylic acid (345 mg, 1.00 mmol), piperidine (129 mg, 1.51 mmol) and HATU (422 mg, 1.11 mmol) in DMF was stirred for 1 h at RT. The reaction mixture was diluted with water (30 mL) and EA (30 mL). The organic layer was separated, washed with brine (1 X 30 mL), dried over anhydrous Na2804, filtered and concentrated under reduced pressure to give tert-butyl 1-oxo(piperidinecarbonyl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate (3 80 mg). MS: m/z 413 (M+H)+.
Intermediate A15 Br N 0 0 a A mixture of tert-butyl ooxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'- carboxylate (1.02 g, 2.68 mmol), morpholine (0.67 g, 7.69 mmol), Cu(OAc)2 (0.51 g, 2.81 mmol), DBU (1.03 g, 6.77 mmol) in DMSO (10 mL) was stirred for 23 h at 130 °C under nitrogen atmosphere. After cooling to RT, the reaction mixture was diluted with water (70 mL), extracted with EA (3 x 50 mL). The combined c layers were dried over anhydrous NaZSO4, filtered and concentrated under reduced pressure. The e was purified by silica chromatography (eluting with EA : Hex = 1 : 1, v/v) to give utyl 6-morpholinooxo-1,3-dihydrospiro [indene-2,4'-piperidine]-1'-carboxylate (467 mg). MS: m/z 387 (M+H)+.
Intermediate A16 A mixture of utyl o-l-oxo-l,3-dihydrospiro[indene-2,4'-piperidine]—1'- carboxylate (500 mg, 1.31 mmol), ylpiperazine (270 mg, 2.70 mmol), CszCO3 (1306 mg, 4.01 mmol), Pd2(dba)3 (66 mg, 0.07 mmol) and XantPhos (75 mg, 0.13 mmol) in 1,4-dioxane (18 mL) was stirred for 0.5 h at 100 °C under en atmosphere. After cooling to RT, the reaction mixture was quenched with water, extracted with EA (2 .‘xt 100 mL). The combined organic layers were washed with brine (l x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 6-(4-methylpiperazin-l-yl)oxo-l,3-dihydrospiro [indene-2,4'-piperidine]—l'-carboxylate (0.87 g, crude) which was used in next step without any r purification. MS: m/z 400 (M+H)+.
Intermediate A17 Boc-N/\:>—<0 O OH _, BOG—NW _, O—\ O—\ Boc—N a b Boc-N —> Boc—N \O —’ / \ —’ c d e HO — CI \N Boc—N Boc—N I / \N / O — 0 Step a: To a -60 °C solution of l-(tert-butyl) 4-ethyl piperidine-l,4-dicarboxylate (15.52 g, 60.31 mmol) in THF (100 ml) was added LDA (2 M solution in THF/Hex, 45.00 mL, 90.00 mmol) dropwise under nitrogen atmosphere. The resulting mixture was d to warm to -20 °C and stirred for 50 min. The mixture was cooled to -50 °C, and a solution of CH3I (8.56 g, 60.31 mmol) in THF (20 mL) was added dropwise. The resulting mixture was stirred for 50 min at this temperature. The reaction mixture was carefully quenched with sat. aq. NH4Cl (80 mL), extracted with EA (100 mL, 50 mL). The combined organic layers were dried over ous Na2SO4, filtered and concentrated under reduced pressure to give l-(tert-butyl) 4-ethyl 4-methylpiperidine-l,4-dicarboxylate (17.70 g) which was used without any r purification.
MS: m/z 216 (M+H-56) +.
Step b: To a 0 °C solution of l-(tert-butyl) 4-ethyl 4-methylpiperidine-l,4-dicarboxylate (17.70 g, 65.23 mmol) in THF (150 mL) was added a LiBH4 (2 M solution in THF, 98.00mL, 196.00mmol). The resulting mixture was stirred for 18 h at 70 °C. After cooling to RT, water (100 mL) was added dropwise. The resulting mixture was extracted with EA (200 mL, 100 mL), the combined organic layers were washed with brine (1 X 200 mL), dried over anhydrous , filtered and concentrated under reduced pressure to give tert-butyl roxymethyl)methylpiperidinecarboxylate (12.90 g) which was used in next step without any further purification. MS: m/z 174 (M+H-56) +.
Step c: To a -78 °C solution of oxalyl chloride (10.71 g, 84.38 mmol) in DCM (150 mL) was added a solution ofDMSO (10.99 g, 140.63 mmol) in DCM (30 mL) dropwise, stirred for 30 min at this temperature. A on of tert-butyl 4-(hydroxymethyl)methylpiperidinecarboxylate (12.90 g, 56.25 mmol) in DCM (30 mL) was added dropwise, stirred for 30 min at -78 °C.
Triethylamine (22.77 g, 225.02 mmol) was added dropwise, the resulting mixture was allowed to warm to -20 °C, and stirred for 40 min. The reaction mixture was quenched with water (80 mL).
The aqueous layer was separated and extracted with DCM (1 3:". 80 mL). The combined organic layers were washed with brine (1 X 200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The e was purified by silica chromatography (eluting with EA : Hex = 1 : 20, v/v) to give tert-butyl 4-formylmethylpiperidinecarboxylate (11.82 g).
MS: m/Z 172 (M+H-56) t.
Step d: To a -70 °C solution of 3-chloropyridine (2.25 g, 17.64 mmol) in THF (50 mL) was added LDA (2 M solution in THF/Hex, 11.00 mL, 22.00 mmol) dropwise. The resulting mixture was allowed to warm to -60 °C and d for 1.5 h. A solution of tert-butyl 4-formylmethylpiperidinecarboxylate (3.95 g, 17.37 mmol) in THF (10 mL) was added se at -70 °C. After ng for 1 h, the mixture was quenched with water (50 mL). The aqueous layer was separated and extracted with EA (60 mL, 30 mL). The combined organic layers were washed with brine (1 X1 80 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 4-((3-chloropyridinyl)(hydroxy)methyl) methylpiperidinecarboxylate (8.10 g) which was used in next step without any further purification. MS: m/z 341 (M+H) +.
Step e: To a solution of tert-butyl 4-((3-chloropyridinyl)(hydroxy)methyl) methylpiperidinecarboxylate (8.10 g, 23.76 mmol) in DCM (50 ml) was added Dess-Martin inane (20.12 g, 47.44 mmol). The resulting e was stirred for 16 h at RT. The on mixture was diluted with DCM (100 mL), washed with aq. Na2S203 (25%, 1 X 80 mL), sat. aq.
NaHCO3 (1 X 80 mL) and brine (1 X 100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA : Hex = l :3, v/v) to give tert-butyl 4-(3-chloroisonicotinoyl)methylpiperidine-l-carboxylate (4.81 g). MS: m/z 339 (M+H) +.
Step f: A mixture of tert-butyl hloroisonicotinoyl)methylpiperidine-l-carboxylate (6.31 g, 18.62 mmol), CszCO3 (6.72g, 21.90mmol), pivalic_acid (571 mg, 5.60 mmol), Pd(OAc)2 (0.22 g, 0.98 mmol) and Cy3PH-BF4 (0.70 g, 1.90 mmol) in 1,3,5-mesitylene (40 mL) was stirred for 72 h at 140 °C under nitrogen atmosphere. After cooling to RT, the mixture was filtered followed by EA (3 x 40 mL) wash. The filtrate was concentrated under d pressure. The residue was purified by silica chromatography (eluting with EA : Hex = l : 1, v/v) to give utyl -oxo-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4'-piperidine]-l'-carboxylate (2.82 g). MS: m/z 303 (M+H) +.
The ing compounds were synthesized using the above procedure with the ponding starting materials.
Table 9 Intermediate A18 0H 0/ Cl N Cl N Cl N c| N \ OH \ OMs \ O —> —> | —> I I \ I b / / a c / / Br Br Br Br | C' \ /O \ N / l l Br N / N / Br Br —> —> + —> Boc-N O d e f Boc-N OH Boc-N OH W o O N\ Cl N\ o\ Boc-N I Boc-N + I / / O 0 Step a: To a solution of 3-bromochloropicolinic acid (9.98 g, 42.21 mmol) in MeOH (100 mL) was added H2SO4 (98%, 10.00 mL) dropwise. The mixture was stirred for 3 h at 70 °C. After cooling to RT, the pH value of the reaction e was adjusted to 9 by ammonium hydroxide (25%). The volatiles were removed under reduced pressure. The mixture was diluted with water (60 mL), extracted with EA (1 X 100 mL). The organic layer was washed with brine (1 3a: 60 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give methyl 3-bromochloropicolinate (10.14 g) as an off-white solid. MS: m/z 250 (M+H) +.
Step b: To a 0 °C solution of methyl 3-bromochloropicolinate (10.14 g, 40.48 mmol) in MeOH (150 mL) was added NaBH4 (4.62 g, 122.13 mmol) in portions. The resulting mixture was allowed to warm to RT and stirred for 16 h. The reaction mixture was diluted with brine (110 mL) and MeOH was removed under reduced pressure. The resulting mixture was extracted with EA (100 mL, 80 mL), the organic layers combined, dried over anhydrous Na2SO4, filtered and concentrated under d pressure to give mochloropyridinyl)methanol (8.31 g).
MS: m/z 222 (M+H) t.
Step c: To a -15 °C solution of (3-bromochloropyridinyl)methanol (8.31 g, 37.35 mmol) and triethylamine (7.63 g, 75.40 mmol) in DCM (100 mL) was added MsCl (4.71 g, 41.12 mmol) dropwise. The resulting mixture was allowed to warm to RT and stirred for 2 h. The reaction mixture was quenched with water (50 mL) and the aqueous layer was separated. The organic layer was washed with brine (1 X 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under d pressure to give (3 chloropyridinyl)methyl esulfonate (8.54 g).
MS: m/Z 300 (M+H) t.
Step d: To a -50 °C solution of t-butyl) 4-ethyl piperidine-l,4-dicarboxylate (9.66 g, 37.54 mmol) in THF (30 mL) was added LDA (2 M solution in THF/Hex, 23.00 mL, 46.00 mmol) dropwise under nitrogen atmosphere. The resulting mixture was stirred for l h at this temperature.
A solution of (3-bromochloropyridinyl)methyl methanesulfonate (8.54 g, 28.41 mmol) in THF (15 mL) was added dropwise, the resulting mixture was allowed to warmed to RT and stirred for l h. The reaction mixture was quenched with brine (60 mL) and extracted with EA (1 X 30mL).
The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give t-butyl) 4-ethyl 4-((3-bromochloropyridinyl)methyl)piperidine-1,4- dicarboxylate (17.73 g) which was used in next step t any further purification. MS: m/z 461 (M+H) t.
Step e: A solution of l-(tert-butyl) 4-ethyl bromochloropyridinyl)methyl) piperidine-l,4-dicarboxylate (17.73 g, 38.39 mmol) and NaOH (8.03 g, 200.75 mmol) in MeOH (100 mL) and water (20 mL) was stirred for 16 h at 65 °C. After cooling to RT, the volatiles were removed under reduced pressure and the resulting mixture was diluted with water (150 mL). The pH value was adjusted to 6 with sat. aq. citric acid. The mixture was extracted with EA (2 X 100 mL), the combined organic layers were washed with brine (l X 100 mL), dried over anhydrous , filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA : Hex = l : 10, v/v) to give the e of4-((3 -bromochloropyridinyl)methyl)- l -(tert-butoxycarbonyl)piperidinecarboxylic acid and4-((3-bromomethoxypyridinyl)methyl)- l -(tert-butoxycarbonyl)piperidinecarboxylic acid (18.24 g). MS: m/Z 433 (M+H) t, MS: m/Z 429 (M+H) t.
Step f: To a -15 °C solution of 4-((3-bromochloropyridinyl)methyl)(tert- butoxycarbonyl)piperidinecarboxylic acid and 4-((3-bromomethoxypyridinyl)methyl) (tert-butoxycarbonyl)piperidinecarboxylic acid (3.80 g, 8.76 mmol) in THF (20 mL) was added NaH (60 % dispersion in mineral oil, 0.42 g, 10.50 mmol) in portions under nitrogen atmosphere.
After stirring for 1 h at this temperature, the mixture was cooled to -60 °C. To the e was added n-BuLi (2.5M solution in Hex, 5 mL, 12.50 mmol) dropwise, stirred for 1 h. The reaction mixture was ed with water (20 mL), extracted with EA (1 >41 40 mL). The organic layer was washed with brine (13»: 30 mL), dried over ous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (EA : Hex = 1 : 10, v/v) to give the mixture of tert-butyl 2-chlorooxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'- piperidine]—1'-carboxylate and tert-butyl 2-methoxy-5 -oxo-5 ,7-dihydrospiro[cyclopenta[b] pyridine-6,4'-piperidine]-1'-carboxylate (1.48 g). MS: m/Z 337 (M+H) +. MS: m/Z 333 (M+H) +.
The following compounds were synthesized using the above procedure or modification procedure with the corresponding ng als.
Table 10 N S / \ Boc—N , | />—C| 0' Cl N s a b Boc—N o\/ 0 Step a: To a -78 °C solution of t-butyl) 4-ethyl piperidine-1,4-dicarboxylate (2.83 g, 11.00 mmol) in THF (50 mL) was added LDA (2 M solution in THF/Hex, 6.00 mL, 12.00 mmol) se under nitrogen atmosphere. The resulting mixture was stirred for 1 h at this ature. 2-Chloro(chloromethyl)thiazole (in 3 mL THF, 1.69 g, 10.06 mmol) was added dropwise at -78 °C, and stirred for 1 h. The reaction mixture was quenched with brine (50 mL), ted with EA (2 x: 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA : Hex = 1 : 20, v/v) to give 1-(tert-butyl) 4-ethyl 4-((2-chlorothiazolyl)methyl) piperidine-1,4-dicarboxylate (1.15 g). MS: m/z 389 (M+H) +.
Step b: To a -78 °C solution of 1-(tert-butyl) 4-ethyl 4-((2-chlorothiazolyl)methyl) piperidine-1,4-dicarboxylate (900 mg, 2.31 mmol) in THF (50 mL) was added LDA (2 M solution in THF/Hex, 3.00 mL, 6.00 mmol) dropwise under nitrogen atmosphere. The resulting mixture was stirred for 30 min at this temperature, quenched with brine (30 mL). The resulting mixture was extracted with EA (2 >41 30 mL), the organic layers combined, dried over anhydrous Na2SO4, filtered and trated under reduced pressure to give tert-butyl 2-chlorooxo-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (832 mg).
MS: m/z 343 (M+H) +. ediate A20 OH OH Br \ o —» \ —» \ _.
N N N \ / \ —> Boc—N _N Boc-N O o 0 Step a: To a 0 °C solution of 2-methylnicotinic acid (4.56 g, 33.25 mmol) in THF (50 mL) was added LAH (1.51 g, 39.90 mmol). The resulting mixture was allowed to warm to RT and stirred for 4 h. The reaction mixture was d lly with sat. aq. NH4Cl (50 mL). The ing mixture was filtered, the organic extract was collected and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give (2-methylpyridinyl) methanol as a yellow oil (1.42 g). MS: m/z 124 (M+H) +.
Step b: To a 0 °C mixture of (2-methylpyridinyl) methanol (1.41 g, 11.45 mmol) in DCM (20 mL) was added PBr3 (1.86 g, 6.87 mmol) dropwise. The resulting mixture was allowed to warm to RT and stirred for 1.5 h. The reaction mixture was taken to pH 8 using aq. NaOH (5 M, 10 mL). The aqueous layer was separated and the organic layer was washed with brine (1 :34; 20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 3-(bromomethyl) methylpyridine as a yellow oil (3.52 g) which was used in next step without any further purification. MS: m/z 186 (M+H) +.
Step c: To a -50 °C solution of -butyl 4-ethyl piperidine-1, 4-dicarboxylate (4.63 g, 18.00 mmol) in THF (30 mL) was added LDA (2 M solution in THF/Hex, 12.00 mL, 24.00 mmol) dropwise, d for 1 h at this temperature. 3-(Bromomethyl)methylpyridine (3.25 g, 18.00 mmol) was added, the resulting mixture was allowed to warm to RT and stirred for 16 h. The reaction e was diluted carefully with sat. aq. NH4C1 (50 mL). The aqueous layer was separated and the organic layer was washed with brine (1 :4: 50 mL), dried over anhydrous Na2SO4, d and concentrated under reduced pressure to give 1-(tert-butyl) 4-ethyl methylpyridinyl)methyl)piperidine-1,4-dicarboxylate as a red oil (4.87 g) which was used in next step without any filrther purification. MS: m/z 363 (M+H) +.
Step d: To a -20 °C solution of t-butyl) 4-ethyl 4-((2-methylpyridinyl)methyl) piperidine-1, 4-dicarboxylate (4.23 g, 11.67 mmol) in THF (40 mL) was added LDA (2 M solution in THF/Hex, 12.00 mL, 24.00 mmol) dropwise, the resulting mixture was allowed to warm to RT and stirred for 2 h. The reaction mixture was diluted carefully with brine (50 mL). The aqueous layer was separated and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA : Hex = 1 : 1, v/v) to give tert-butyl 7'-oxo-7',8'-dihydro-5'H-spiro[piperidine-4,6'- quinoline]carboxylate (1.23 g) as a yellow oil. MS: m/z 317 (M+H) +.
Intermediate A2 1 Br Br Br / \ v \b I a I b Boc—N / / __ / \ N \\ N /N \ / — BOO_ —> —> —> N Boc—N C Boc—N d e CN \ 0 Step a: To a -60 °C e of t-BuOK (5.92 g, 52.76 mmol) in 1,2-dimethoxyethane (50 mL) was added a solution of 2-tosylacetonitrile (5.08 g, 26.02 mmol) in 1,2-dimethoxyethane (20 mL) se. To the resulting mixture was added a solution of 2-bromonicotinaldehyde (4.81 g, 25.86 mmol) in 1,2-dimethoxyethane (20 mL) dropwise at -60 °C. After stirring for 1 h at this ature, MeOH was added (50 mL), the resulting mixture was allowed to warm to RT, stirred for 1 h and warmed to 85 °C, stirred for another 1h. After cooling to RT, the volatiles was removed under reduced pressure, d with brine (200 mL) and extracted with EA (3 ix. 150 mL). The combined organic layers were dried over anhydrous Na2SO4, d and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA : Hex = 1 : , v/v) to give 2-(2-bromopyridinyl)acetonitrile (2.21 g). MS: m/z 197 (M+H) +.
Step b: To a 0 °C solution of 2-(2-bromopyridinyl)acetonitrile (2.21 g, 11.21 mmol) in DMF (20 mL) was added NaH (60% sion in mineral oil, 1.12 g, 28.03 mmol) in portions.
The resulting mixture was warmed to 60 °C and d for 1.5 h. Tert-butyl bis(2-chloroethyl)carbamate (3.26 g, 13.46 mmol) was added to the mixture and stirred for 2 h at 60 °C. After cooling to RT, the reaction mixture was quenched with brine (50 mL), extracted with EA (3 x: 100 mL). The combined organic layers were washed with brine (3 X 80 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The e was purified by silica tography (eluting with EA : Hex = 1 : 3, v/v) to give tert-butyl 4-(2-bromopyridinyl)cyanopiperidinecarboxylate (1.56 g). MS: m/z 366 (M+H) +.
Step c: A mixture of tert-butyl 4-(2 -bromopyridinyl)cyanopiperidinecarboxylate (1.56 g, 4.26 mmol), K2CO3 (2.35 g, 17.04 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (1.07 g, 8.52 mmol) and Pd(PPh3)4 (47 mg, 0.041 mmol) in 1,4-dioxane (40 mL) and water (8 mL) was d for 2 h at 110 °C under nitrogen atmosphere. An additional portion of 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (2.15 g, 17.13 mmol) and Pd(PPh3)4 (45 mg, 0.039 mmol) was added and stirred for another 3 h at 110 °C. After cooling to RT, the reaction mixture was diluted with brine (100 mL), extracted with EA (3 x 100 mL), the organic layers combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA : Hex = 2 : 1, v/v) to give tert-butyl 4-cyano(2-methylpyridinyl)piperidinecarboxylate (1.08 g). MS: m/z 302 (M+H) +.
Step d: To a 0 °C solution of tert-butyl 4-cyano(2-methylpyridinyl)piperidine carboxylate (1.08 g, 3.58 mmol) in MeOH (50 mL) was added H2SO4 (98 %, 45 mL) dropwise.
The resulting mixture was stirred for 18 h at reflux ature. After cooling to RT, the reaction mixture was poured into ice/water (200 mL), the pH value was adjusted to 9 with sat. aq. NaOH.
To the mixture was added (Boc)20 (11.00 g, 50.40 mmol) and stirred for 2 h at RT. The reaction mixture was extracted with EA (3 X 100 mL), the organic layers ed, dried over anhydrous Na2SO4, filtered and trated under reduced pressure. The residue was purified by silica chromatography (eluting with EA) to give 1-(tert-butyl) 4-methyl 4-(2-methylpyridinyl)piperidine-1,4-dicarboxylate (467 mg). MS: m/z 335 (M+H) +.
Step e: To a 0 °C solution of 1-(tert-butyl) 4-methyl ethylpyridinyl)piperidine-1,4- dicarboxylate (467 mg, 1.40 mmol) in THF (10.50 mL) was potassium bis(trimethylsilyl)amide (1 M solution in THF, 7.00 mL, 7.00 mmol) dropwise under nitrogen atmosphere. The resulting mixture was allowed to warm to RT and stirred for 3.5 h, then quenched with sat.aq.NH4Cl (10 mL) and extracted with EA (3 ix: 40 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under d pressure. The residue was d by silica tography (eluting with EA) to give tert-butyl 6-oxo-6,7-dihydrospiro[cyclopenta[b]pyridine-5,4'-piperidine]-1'-carboxylate (170 mg). MS: m/z 303 (M+H) +.
Intermediate A22 / / BOG—N —’ Boo—NW —> \ Boc—N —> 0 a b / \ c O HO Boc—N0g —> Boc—N —> Boc—N X > d D? e o O 0 Step a: To a 0 °C e of tert-butyl 4-formylpiperidinecarboxylate (15.00 g, 70.33 mmol) in DMF (60 mL) was added lithium 2-methylpropanolate (6.75 g, 84.44 mmol) in portions. The resulting mixture was stirred for 30 min at 0 °C. To the mixture was added 3-bromopropene (9.73 g, 80.44 mmol) dropwise at 0 °C and stirred for 1 h at this temperature.
The reaction mixture was diluted with brine (100 mL), extracted with EA (3 x: 200 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced re. The residue was purified by silica chromatography (eluting with EA : Hex = 1 : 20, v/v) to give tert-butyl 4-allylformylpiperidinecarboxylate (7.01 g). MS: m/z 254 (M+H) Step b: To a —78 °C solution of tert-butyl lformylpiperidinecarboxylate (7.01 g, 27.63 mmol) in THF (30 mL) was added allylmagnesium bromide (1 M solution in THF, 63.55 mL, 63.55 mmol) dropwise. The resulting e was allowed to warm to RT and stirred for 1.5 h. The reaction mixture was quenched with sat. aq. NH4Cl, extracted with EA (3 X 200 mL). The combined organic layers were washed with brine (1 X 200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced re to give tert-butyl 4-allyl(1-hydroxyallyl)piperidinecarboxylate (7.01 g). MS: m/z 282 (M+H) +.
Step c: To a solution of tert—butyl 4-allyl(1-hydroxyallyl)piperidinecarboxylate (7.00 g, 24.88 mmol) in DCM (50 mL) was added Dess-Martin periodinane (12.66 g, 29.85 mmol) in portions. After stirring for 1.5 h at RT, the reaction mixture was diluted with brine (150 mL) and extracted with EA (3 X 200 mL). The ed organic layers were dried over anhydrous , filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (EA : Hex = 1 : 30, v/v) to give tert-butyl 4-acryloylallylpiperidine carboxylate (5.63 g). MS: m/Z 280 (M+H) +.
Step (1: A e of tert-butyl 4-acryloylallylpiperidinecarboxylate (5.63 g, 20.15 mmol), Grubbs II (428 mg, 0.50 mmol) and toluene (30 mL) was stirred for 3.5 h at 85 °C under nitrogen atmosphere. After cooling to RT, the e was concentrated under reduced re.
The residue was purified by silica chromatography (eluting with EA : Hex = 1 : 5, v/v) to give tert-butyl 1-oxoazaspiro[4.5]decenecarboxylate (3.61 g). MS: m/z 252 (M+H) +.
Step e: To a solution of trimethylsulfoxonium iodide (3.79 g, 17.22 mmol) in DMSO (50 mL) was added NaH (60 % dispersion in mineral oil, 730 mg, 18.25 mmol) in portions. After stirring for 30 min, tert-butyl 1-oxoazaspiro[4.5]decenecarboxylate (a DMSO solution, 3.61 g, 14.36 mmol) was added dropwise. The resulting mixture was stirred for 1.5 h at RT. The reaction mixture was diluted with brine (200 mL), extracted with EA (3 X 200 mL). The combined c layers were washed with brine (3 X 200 mL), dried over ous Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 2-oxospiro[bicyclo[3.1.0]hexane-3,4'- piperidine]-1'-carboxylate (3.60 g). MS: m/z 266 (M+H) +.
Intermediate A23 HOG _> Hm ammo, Mmffi; "m0 Step a: To a -10 °C solution of tetrahydro-2H-pyranol (3.54 g, 34.66 mmol), triethylamine (4.65 g, 45.95 mmol) in DCM (100 mL) was added MsCl (4.61 g, 40.24 mmol) dropwise. After stirring for 30 min, the reaction mixture was diluted with water (100 mL), extracted with DCM (100 mL, 50 mL). The combined organic layers were washed with brine (1 X 50 mL), dried over anhydrous Na2SO4, d and concentrated under reduced pressure to give ydro-2H-pyranyl methanesulfonate (6.74 g). MS: m/z 181 (M+H) +.
Step b: To a solution of 1'-benzylmethoxyspiro[indene-2,4'-piperidin]-1(3H)-one ( 4.35 g, 13.53 mmol) in DCM (200 mL) was added BBr3 (1 M solution in DCM, 15.00 mL, 15.00 mmol), stirred for 13 h at 45 °C. An additional portion of BBr3 (1 M solution in DCM, 5.00 mL, 5.00 mmol) was added and d for 24 h at 45 °C. After cooling to RT, the reaction e was d with water (150 mL), NaHCO3 (20.00 g) was added in portions. The resulting mixture was extracted with DCM (2 >=: 100 mL), the organic layers ed, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 1'-benzylhydroxyspiro[indene-2,4'-piperidin]-1(3H)—one (2.80 g) which was used in next step without any further purification. MS: m/z 308 (M+H) +.
Step c: A mixture of 1'-benzylhydroxyspiro[indene-2,4'-piperidin]-1(3H)-one (2.80 g, 9.11 mmol), tetrahydro-2H-pyranyl methanesulfonate (3.40 g, 18.87 mmol) and K2CO3 (8.23 g, 59.55 mmol) in DMF (60 mL) was d for 5.5 h at 110 °C. An additional portion of tetrahydro-2H-pyranyl methanesulfonate (1 . 10 g, 6.10 mmol) and K2CO3 (4.55 g, 32.92 mmol) was added and stirred for 1.5 h at 110 °C. After cooling to RT, the mixture was diluted with water (300 mL) and EA (600 mL). The aqueous layer was ted and extracted with EA (1 32: 200 mL), the organic layers combined, washed with water (2 X 300 mL) and brine (1 X 300 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica tography (eluting with MeOH : DCM = 1 : 40, v/v) to give 1'-benzyl((tetrahydro-2H-pyranyl)oxy)spiro[indene-2,4'-piperidin]-1(3H)—one (1.70 g). MS: m/z 392 (M+H) +.
Step d: A mixture of 1'-benzyl((tetrahydro-2H-pyranyl)oxy)spiro[indene-2,4'- piperidin]-1(3H)-one (1.70 g, 4.34 mmol) and Pd(OH)2 (10 % on carbon, 1.21 g) in MeOH was stirred for 3 h at RT under hydrogen atmosphere. The reaction mixture was filtered. To the filtration was added (Boc)20 (1.10 g, 5.04 mmol) and stirred for 40 h at RT. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica tography (eluting with EA : Hex = 1 : 5, v/v) to give tert-butyl 1-oxo((tetrahydro-2H-pyranyl)oxy)-1,3-dihydrospiro[indene- 2,4'-piperidine]-1'-carboxylate (1.45 g). MS: m/z 402 (M+H) +.
Intermediate A24 Boc_N / /p\O/\ A e of tert-butyl 6-bromooxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'- ylate (1017 mg, 2.67 mmol), diethyl onate (564 mg, 4.08 mmol), potassium phosphate (1156 mg, 5.45 mmol), Pd(OAc)2 (63 mg, 0.28 mmol) and XantPhos (307 mg, 0.53 mmol) in DMF (10 mL) was stirred for 21 h at 130 °C under nitrogen atmosphere. After cooling to RT, the reaction mixture was quenched with water (60 mL), filtered followed by EA (2 X 30 mL) wash. The layers of the filtration was separated, the aqueous layer was extracted with EA (2 "x: 60 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA) to give tert-butyl 6-(diethoxyphosphoryl)oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate (134 mg) which was used in next step without any further purification. MS: m/z 438 (M+H)+.
Intermediate A25 Boc-N Following procedures of Y. Uto et a]. /Bi00rg. Med. Chem. Lett. 20 (2010) 746 - 754, intermediate A25 was ed.
The following compound was synthesized using the above procedure with the corresponding starting als.
Table 11 Intermediate A26 OJ Br HO \:>—< + O\ _» o Boc—N O \_ 0 O Boc—N b c O Boo-NW \— 0 o Step a: To a -65 °C solution of t-butyl) 4-ethyl piperidine-l,4-dicarboxylate (5.23 g, .32 mmol) in THF (30 ml) was added LDA (2 M solution in x, 12.00 mL, 24.00 mmol) dropwise. The resulting mixture was stirred for 1.0 h at this temperature. obenzaldehyde (3.44 g, 18.59 mmol) was added dropwise at -70 °C. After stirring for l h, the mixture was quenched with brine (40 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give l-(tert-butyl) 4-ethyl 4-((2-bromophenyl)(hydroxy)methyl)piperidine-1,4-dicarboxylate (9.15 g) which was used in next step without any filrther purification. MS: m/z 442 (M+H) +.
Step b: To a -5 °C solution of l-(tert-butyl) 4-ethyl 4-((2-bromophenyl)(hydroxy)methyl) piperidine-l,4-dicarboxylate (9.15 g, 20.68 mmol) in DCM (70 ml) was added Dess-Martin periodinane (18.02 g, 42.49 mmol). The resulting mixture was stirred for 2.5 h at RT. The reaction mixture was washed with aq. Na2S203 (25%, l x 80 mL), sat. aq. NaHCO3 (l X 80 mL) and brine (l 3»: 100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced re. The residue was purified by silica chromatography (eluting with EA : Hex = l : 5, v/v) to give l-(tert-butyl) 4-ethyl 4-(2-bromobenzoyl)piperidine-1,4-dicarboxylate (7.16 g).
MS: m/z 440 (M+H) +.
Step d: To a -80 °C solution of 1-(tert-butyl) 4-ethyl 4-(2-bromobenzoyl)piperidine-1,4- dicarboxylate (2.00 g, 4.54 mmol) in THF (20 mL) was added n-BuLi (2.5 M solution in THF/Hex, 1.80 mL, 4.50 mmol) dropwise under nitrogen atmosphere. The ing mixture was allowed to warm to RT and stirred for 1 h. The reaction mixture was ed with brine (30 mL) and extracted with EA (1 32: 20mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA: Hex = 1 : 10, v/v) to give utyl 1,3-dioxo-1,3-dihydrospiro[indene-2,4'-piperidine]- 1'-carboxylate (500 mg). MS: m/Z 316 (M+H) +.
Intermediate A27 Boc—N Following ures ofJ. Org. Chem. 1999, 64, 5I 0, intermediate A27 was prepared.
Intermediate A28 (3'95" OJ CIS—N Clv—«N 8% a SWOH b SWOMS N§r(3| Boc—N/\:>§/j<\/S N —» _» c o d Boc—NOQE \>—C| o \— 0 Step a: To a 0 °C solution of ethyl 2-chlorothiazolecarboxylate (24.95 g, 130.19 mmol) in MeOH (250 mL) was added NaBH4 (17.29 g, 456.97 mmol) in portions. The resulting mixture was allowed to warm to RT and stirred for 2 h. The reaction mixture was diluted with water (200 mL) and the volatiles were removed under d pressure. The resulting mixture was extracted with EA (2 fr: 200 mL), the combined organic layers were washed with brine (1 x 400 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give (2-chlorothiazolyl)methanol (18.88 g). MS: m/z 150 (M+H)+.
Step b: To a solution of (2-chlorothiazolyl)methanol (18.88 g, 130.19 mmol) and triethylamine (25.56 g, 252.57 mmol) in DCM (200 mL) was added MsCl (15.96 g, 139.30 mmol) dropwise over 15 min. The resulting mixture was stirred for 25 min at RT. The reaction mixture was quenched with brine (200 mL) and the aqueous layer was separated. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under d pressure to give (2-chlorothiazolyl)methyl methanesulfonate which was used in next step without any filrther purification. MS: m/z 228 (M+H)+.
Step c: To a -60 °C solution of 1-(tert-butyl) 4-ethyl piperidine-1,4-dicarboxylate (35.67 g, 138.62 mmol) in THF (200 mL) was added LDA (2 M solution in THF/Hex, 75.00 mL, 150.00 mmol) dropwise over 30 min under nitrogen here. A solution of (2-chlorothiazolyl)methyl methanesulfonate in THF (50 mL) was added dropwise, the resulting mixture was allowed to warmed to RT and stirred for 2 h. The reaction mixture was quenched with brine (300 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA : Hex = 1 : 10, v/v) to give 1-(tert-butyl) l 4-((2-chlorothiazolyl)methyl) piperidine-1,4-dicarboxylate (38.12 g). MS: m/z 389 (M+H)+.
Step d: To a -60 °C solution of 1-(tert-butyl) l 4-((2-chlorothiazolyl)methyl) piperidine-1,4-dicarboxylate (8.51 g, 21.88 mmol) in THF (80 mL) was added LDA (2 M solution in x, 11.00 mL, 22.00 mmol) dropwise under nitrogen atmosphere. Once d, the reaction mixture was quenched with brine (50 mL). The organic layer was ted, dried over anhydrous Na2SO4, filtered and trated under reduced pressure. The residue was purified by silica chromatography (eluting with EA : Hex = 1 : 10, v/v) to give tert-butyl 2-chlorooxo-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (1.93 g).
MS: m/z 343 (M+H)+.
Intermediate A29 s SI Q/OH/ \ _. CL _. BOG—N / OMS a b O : ; S Boc—N | ;’/ S : —> Boc—N C CH \ 0 e Boo—NWS Step (a-c): Step (b-c) of Intermediate A28 and step (b) of Intermediate A3 were applied to provide 1-(tert-butoxycarbonyl)(thiophenylmethyl)piperidinecarboxylic acid.
Step d: A mixture of 1-(tert-butoxycarbonyl)(thiophenylmethyl)piperidine carboxylic acid (4.92 g, 15.12 mmol) and PPA (30.12 g) was d for 5 h at 110 °C. The reaction mixture was poured into ice/water (100 mL), the pH value was adjusted to 10 with NaOH. Then (Boc)20 (5.05 g, 23.14 mmol) was added and stirred for 18 h at RT. The reaction mixture was extracted with EA (2 X 50 mL). The combined organic layers were washed with brine (1 X 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 2-(tert-butyl)oxo-4,6-dihydrospiro[cyclopenta[b]thiophene-5 ,4'-piperidine]-1'-carboxylate (1.70 g). MS: m/Z 364 (M+H)+.
Step e: A mixture of 1-(tert-butoxycarbonyl)(thiophenylmethyl)piperidine carboxylic acid (4.88 g, 15.12 mmol) and HC1 (4M on in 1, 4-dioxane, 8 mL) in DCM (50 mL) was stirred for 1 h at RT. The reaction mixture was concentrated under reduced pressure. PPA (21.15 g) was added and the resulting mixture was stirred for 1.5 h at 110 °C. The on mixture was poured into ice/water (100 mL), the pH value was ed to 10 with NaOH. Then (Boc)20 (5.12 g, 23.46 mmol) was added and stirred for 18 h at RT. The reaction e was extracted with EA (2 x 50 mL). The combined c layers were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA : Hex = 1 : 10, v/v) to give tert-butyl4-oxo-4,6-dihydrospiro [cyclopenta[b]thiophene-5 ,4'-piperidine] - 1 '-carboxylate(2 . 7 1 g).
MS: m/Z 308 (M+H)+.
Intermediate A30 Cl Bn\O Bn\O Bn\0 I \ \ —* —* —> \ —> / OH I | N a N/ OH b N/ O\ c IN/ d O o O Bn \ O /— o o O—Bn OH O-Bn —> Boc-N \ _ —» BOG—N096 —> I e \ f \ 9 N/ /0 / / HO N Ho N OH OH N \ N \ Boc—N — Boc—N Boc-N \ \ \ / 0 O h i HO N HO 0 Step a: To a solution ofphenylmethanol (5.15 g, 47.62 mmol) in DMF (50 mL) was added NaH (60 % dispersion in l oil, 3.01 g, 75.25 mmol) in portions, stirred for 20 min. 4-Chloropicolinic acid (2.68 g, 17.01 mmol) was added and stirred for 3.5 h at 85 °C. After cooling to RT, HC1 (4 M solution in 1,4-dioxane, 10 mL) was added. The resulting mixture was used in next step. MS: m/Z 230 (M+H) +.
Step b: The e was mixed with NaHCO3 (7.51 g, 89.39 mmol), CH3I (1.5 mL) and DMF (10 mL). After stirring for 0.5 h, an additional portion of CH3I (1.5 mL) was added and stirred for 16 h. The reaction mixture was diluted with EA (250 mL), filtered and the filtration was washed with brine (2 X 150 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The e was purified by silica tography (eluting with EA: Hex = 1 : 1, v/v) to give methyl 4-(benzyloxy)picolinate (1.50 g). MS: m/z 244 (M+H) +.
Step c: A mixture of methyl 4-(benzyloxy)picolinate (1.50 g, 6.17 mmol), LiBH4 (2M solution in THF, 9.00 mL, 18.00 mmol) in THF (40 mL) was stirred for 1 h at 50 °C. The reaction e was diluted with MeOH (15 mL) and water (150 mL), extracted with EA (200 mL, 50 mL).
The combined organic layers were washed with brine (2 X 100 mL), dried over anhydrous Na2SO4, filtrated and trated under reduced pressure. The residue was d by silica chromatography (eluting with EA) to give (4-(benzyloxy)pyridinyl)methanol (0.50 g). MS: m/z 216 (M+H) +.
Step d: A mixture of (4-(benzyloxy)pyridinyl)methanol (0.50 g, 2.32 mmol), dess-martin periodinane (1 .25g, 2.95mmol) in DCM (20 mL) was stirred for 1.5 h. The reaction e was diluted with sat.aq.NaHSO3, sat.aq.NaHCO3 and DCM (50 mL). The aqueous layer was separated and extracted with DCM (50 mL). The combined organic layers were dried over anhydrous Na2SO4, ed and concentrated under reduced pressure. The residue was purified by silica chromatography to give 4-(benzyloxy)picolinaldehyde (0.40 g). MS: m/z 214 (M+H) +.
Step e: To a 0 °C solution of 1-(tert-butyl) 4-ethyl dine-1,4-dicarboxylate (0.52 g, 2.02 mmol) in THF (15 mL) was added LDA (2 M solution in THF/Hex, 1.30 mL, 2.60 mmol) dropwise. The resulting mixture was cooled to -70 °C, a solution enzyloxy)picolinaldehyde (0.40 g, 1.88 mmol) in THF (5 mL) was added. The resulting mixture was allowed to warm to -15 °C and stirred for 30 min, then quenched with sat.aq.NH4Cl (10 mL), diluted with water (50 mL) and extracted with EA (1 x 100 mL). The organic layer was washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA : Hex = 1 : 1) to give t-butyl) 4-ethyl 4-((4-(benzyloxy)pyridinyl)(hydroxy)methyl)piperidine-1,4-dicarboxylate (0.25 g). MS: m/z 471 (M+H) +.
Step f: A mixture of 1-(tert-butyl) 4-ethyl 4-((4-(benzyloxy)pyridinyl)(hydroxy) methyl)piperidine-1,4-dicarboxylate (0.25 g, 0.53 mmol), LiBH4 (2 M solution in THF, 1.00 mL, 2.00 mmol) in THF (10 mL) was d for 40 min at 55 °C. The reaction mixture was quenched with MeOH (10 mL), the volatiles were removed under reduced pressure. The residue was diluted with water (150 mL), extracted with EA (1 X 50 mL). The c layer was washed with brine (1 X 30 mL), dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure to give tert-butyl (benzyloxy)pyridinyl)(hydroxy)methyl)(hydroxymethyl)piperidine- l - carboxylate (0.22 g). MS: m/Z 429 (M+H)+.
Step g: A mixture of tert-butyl 4-((4-(benzyloxy)pyridinyl)(hydroxy)methyl) (hydroxymethyl)piperidine-l-carboxylate (0.22 g, 0.51 mmol), Pd (10% on carbon, 0.12 g) in MeOH (20 mL) was stirred for 1.5 h under hydrogen atmosphere. The reaction mixture filtrated follow by MeOH wash and the ion was concentrated under d re to give tert-butyl 4-(hydroxy(4-hydroxypyridinyl)methyl)(hydroxymethyl)piperidine- l - carboxylate (154 mg). MS: m/z 339 (M+H) +.
Step h: To a mixture of tert-butyl 4-(hydroxy(4-hydroxypyridinyl)methyl) (hydroxymethyl)piperidine-l-carboxylate (120 mg, 0.36 mmol) and triphenyl ate (175 mg, 0.67 mmol) in THF (10 mL) was added N,N,N',N'-tetramethylazodicarboxamide (158 mg, 0.68 mmol). The mixture was stirred for 30 min at RT. The reaction was purified by silica chromatography (eluting with MeOH : DCM = l : 7, v/v) to give tert-butyl l-hydroxyoxo- l ,7-dihydro-3H-spiro[indolizine-2,4'-piperidine]-l oxylate (100 mg). MS: m/z 321 (M+H) +.
Step i: A mixture of tert-butyll-hydroxyoxo- l ,7-dihydro-3H-spiro[indolizine-2,4'- piperidine]—l'-carboxylate (0.35 g, 1.09 mmol), artin periodinane (0.72 g, 1.70 mmol) and DCM (35 mL) was stirred for 2 h at RT. The resulting mixture was washed with sat.aq.Na2SO3 (l :v: 20 mL) and sat.aq.NaHCO3 (1 ix: 20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl l,7-dioxo-l,7-dihydro-3H- spiro[indolizine-2,4'-piperidine]-l'-carboxylate (0.33 g). MS: m/z 319 (M+H) +.
The following compounds were synthesized using the above procedure with the corresponding starting materials.
Table 12 Intermediate B1 Following procedures ofW02017211303 A1, intermediate B1 was prepared from 4-iodoindoline-2,3-dione in 3 steps.
Intermediate B2 N SNa CI N NH2 Following procedures ofW02017211303 A1,intermediate B2 was prepared from 3-bromochloropyrazinamine in 2 steps.
The following compounds were synthesized using the above procedure or modifications ure with the ponding starting materials.
Table 13 Intermediate B3 N F N NH2 3-Chlorofluoroiodopyridine (10.10 g, 39.23 mmol) and DMSO (50 mL) was added to a sealed tube, ammonium ide (25%, 50 mL) was added dropwise. The resulting mixture was stirred for 16 h at 80 °C. After cooling to RT, the reaction mixture was poured into water (250 mL), the resulting precipitate was collected, dissolved in DCM (280 mL), washed with brine (1 x: 100 mL), dried over anhydrous NaZSO4, filtered and concentrated under d pressure to give 3-chloroiodopyridinamine (7.01 g). MS: m/z 255 (M+H) +.
The following compounds were synthesized using the above procedure or modification procedure with the corresponding starting materials.
Table 14 Intermediate B4 HZN S‘t/ Nasxfm 0' Cl Cl + (I\ —> N H2N \— N N NH2 / N A mixture of 3-chloroiodopyridinamine (25.53 g, 100.33 mmol), sodium 3-amino chloropyrazinethiolate (20.18 g, 109.92 mmol), Pd2(dba)3 (4.47 g, 4.88 mmol), os (5.81 g, 10.04 mmol) and DIEA (26.12 g, 202.10 mmol) in 1,4-dioxane (10 mL) was stirred for 1.5 h at 70 °C under nitrogen here. After cooling to RT, the reaction mixture was filtered through a pad of Celite followed by l,4-dioxane (30 mL) wash and the filtrate was concentrated under reduced pressure. DCM (100 mL) and EA (100 mL) were added and the resulting mixture was stirred for 40 min. The precipitate was collected, dried in a vacuum oven to give 3-((2-aminochloropyridinyl)thio)chloropyrazinamine (13.86 g). MS: m/z 288 (M+H) The following compounds were synthesized using the above procedure or modification procedure with the corresponding starting materials.
Table 15 EXAMPLE 1 (R)—1 '-(6-amin0((2-amin0ch10ropyridinyl)thi0)pyrazinyl)-2,3-dihydr0spir0 [inde ne-1,4'-piperidin]amine Boc P00 N NI N "a fi + Boc Boc 5°C HzN H2N S-—€_—/_N s-—&P—-N Cl N c| N HZN "2" N_ Jim 9 Step a:A mixture ofCompound lH-indene g, O.10rnol) and LiHMDS (220mL, lmol/L in THF) in THF(120mL) was stirred at -50°C for 1 hour. Tert-butyl bis(2-chloroethy1)carbamate (24.21 g, 0.10mol) was added to the reaction e and stirred at -50°C for 1hr. The reaction was quenched with brine (300mL). The organic extracts were dried with anhydrous Na2804, and concentrated under reduced pressure in vacuo. The residue was purified by column chromatography to afford Compound tert-butyl indene-l,4'-piperidine]-l'-carboxylate as a yellow solid g, 36%). MS: 286 (M+H)+.
Step b:A mixture of Compound utyl indene-l,4'-piperidine]-l'-carboxylate (l 17.02 g, 0.41mol) and borane-methyl sulfide x (10mol/L, 220mL) in THF ) was stirred at 0°Cfor 3 hours. NaOH (2mol/L, 1.2L) and H202 (300mL) was added and stirred at 0°C for 1 hour. The organic extracts were collected, dried over anhydrous Na2SO4 and concentrated under reduced pressure in vacuo to afford the mixture of tert-butyl 2-hydroxy-2,3-dihydrospiro[indene- l ,4'-piperidine]- l '-carboxylate and tert-butyl 3-hydroxy-2,3-dihydrospiro[indene-l,4'-piperidine]—l'-carboxylate as a yellow oil (130.33 g, crude). MS: 304 (M+H)+.
Step c:A mixture of tert-butyl 2-hydroxy-2,3-dihydrospiro[indene-l ,4'-piperidine]—l'-carboxylate and tert-butyl 3-hydroxy-2,3-dihydrospiro[indene-l,4'-piperidine]—l'-carboxylate (130.02g, 0.43mol) and artin periodinane (364.76g, 0.86mol) in DCM (2L) was stirred at 25°C for 12 hours. The on mixture was filtered and the filtrate was washed by saturated sodium bicarbonate solution (1L) and brine (IL). The organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure in vacuo. The e was purified by column chromatography to afford Compound tert-butyl 3-oxo-2,3-dihydrospiro[indene-l,4'-piperidine]-l'-carboxylate as a white solid (41.75g, 34%, 2 steps). MS: 302 (M+H)+.
Step d:To a solution of Compound tert-butyl 3-oxo-2,3-dihydrospiro[indene-l ,4'-piperidine]- l '-carboxylate (41 .01g, 0.14mol) in um(IV) ethoxide (80mL) was added R-(+)-tert-Butylsulflnamide (49.46g, 0.41mol). The resulting mixture was stirred at 85°C for 2 hours. EA (0.5L) and water (0.5L) was added to the reaction mixture. The reaction mixture was filtered and organic extracts were collected. The aqueous solution was extracted with EA (200mL><2). The combined organic extracts were washed with brine (500mL), dried over anhydrous Na2SO4, and trated under reduced pressure in vacuo to afford Compound tert-butyl 3-oxo-2,3-dihydrospiro[indene- l ,4'-piperidine]-l'-carboxylate (132.05g crude). MS: 405(M+H)+. t purification to next step.
Step e:A mixture of Compound tert-butyl 3-oxo-2,3-dihydrospiro[indene-l ,4'-piperidine]-l '-carboxylate (132.02g, 0.33mol) in THF (200mL) was d at -50°C. NaBH4 (7.7lg, 0.51mol) was added to the reaction mixture and allowed to return to room temperature. Reaction was quenched with saturated ammonium chloride solution (100mL). The organic extracts were collected, dried over anhydrous Na2SO4, and concentrated under d pressure in vacuo. The residue was d by column chromatography to afford Compound tert-butyl (((R)-tert-butylsulfinyl)amino)-2,3-dihydrospiro[indene-1,4'-piperidine]—1'-carboxylate as a white solid (27.25g, 49%, 2 steps). MS: 407 (M+H)+.
Step f:A mixture of Compound utyl (R)(((R)-tert-butylsulfinyl)amino)-2 ,3 -dihydrospiro [indene-1 ,4'-piperidine]-1'-carboxylate (1.16g, 3.98mmol), H (3.6mL) in DCM (20mL) was d at 25°C for 1.5 hours. The reaction mixture was concentrated under reduced pressure, The residue was dissolved in NMP (15mL), then 3-((2-aminochloropyridinyl)thio) chloropyrazinamine (1 .03g, 3.59mmol) and K2CO3 (6.60g, 47.76mmol) was added to mixture and stirred at 90°C for 16 hours. H20 (30mL) was added to the reaction mixture and the precipitate was filtered. The filter cake dissolved in DCM (40mL) and washed with brine (40mL). The c extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure in vacuo to afford the Compound (R)-N-((R)—1'-(6-amino((2-aminochloropyridinyl)thio)pyrazinyl)-2 ,3 -dihydrospiro [in dene-1,4'-piperidin]yl)methylpropanesulfinamide (1 .55g, 70%) as a yellow solid.
Step g:To a solution of Compound (R)-N-((R)—1'-(6-amino((2-aminochloropyridinyl)thio)pyrazinyl)-2 ,3 -dihydrospiro [in dene-1,4'-piperidin]yl)methylpropanesulfinamide (1 .52g, 2.72mmol) in DCM (20mL) was added HCl/Dixoane (2mL, 4mol/L). The resulting mixture was stirred at 25°C for 1hour and the precipitate was filtered. The filter cake dispersed in DCM (30mL) and Ammonium hydroxide (5mL) was added to adjust pH>10. The mixture was washed with brine (40mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure in vacuo. The residue was d by column chromatography to afford Compound (R)-1 '-(6-amino-5 -((2-amino-3 -chloropyridinyl)thio)pyrazinyl)-2 ,3 -dihydrospiro [indene- 1 , 4'-piperidin]amine as a yellow solid (530mg, 42%). MS: 454 (M+H)+. 1H NMR (400 MHz, DMSO-d6) 5 7.64 - 7.66 (m, 2H), 7.30 (d, 1H), 7.20 (d, 1H), 7.13 - 7.15 (m, 2H), 6.78 (d, 1H), 4.05 - 4.09 (m, 1H), 3.91 - 3.95 (m, 1H), 3.54 - 3.60 (m, 3H), 3.12 - 3.18 (m, 1H), 2.57 - 2.63 (m, 1H), 1.91 - 2.09 (m, 2H), 1.66 - 1.76 (m, 1H), 1.49 - 1.58 (m, 1H).
EXAMPLE 2 (S)—1 '-(6-amin0((2-amin0chloropyridinyl)thi0)pyrazinyl)—1,3-dihydr0spir0[inden e—2,4'-piperidin]amine 9 0 o 43-" " " HN’S '6 Cd 4cocw / HN’S"'€ We» (>ij 4 NH a b c d C. _s @090‘22»: _N C. ff/ HN N 2 \ HN _ e / \ ’ f N 5/0 H2N \ HCI H2N " / Step a:NaH(60%) (3.63 g, 90.80mmol) was added into the solution of Compound 2,3-dihydro-1H-indenone , 30.27mmol) in DMF (80mL). The mixture was stirred for 30 min at 16°C. Tert-butyl bis(2-chloroethyl) carbamate (8.06g, 33.29mmol) was added dropwise.
And then the mixture was stirred for 16 hours at 60°C. The mixture was quenched with brine (200mL), extracted with EA (100mL><2). The organic layers were combined and washed with brine (100mL><2), dried over anhydrous Na2SO4. After concentrated, the residue was purified by column chromatography to afford the Compound utyl 1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate (1 .21g, 13%) as a dark red oil. MS: 302 (M+H)+.
Step bzAfter the Titanium(IV) ethoxide g) was warmed into 90°C, the compound tert-butyl 1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate (1.2 1 g, 4.01mmol) and (R)methylpropanesulf1namide (1 .22g, mol) were added. After stirred for 19hrs at 90°C. The mixture was poured into EA (200mL), and brine (200mL) was added. After stirred for mins, the solids were filtrated out. The liquid was separated. The organic layer was washed with brine (200mL><2), and dried over anhydrous Na2SO4. The solids were filtrated out, and the filtration was trated under reduced pressure in vacuo. The residue was purified by column chromatography to afford the compound tert-butyl (R,E)((tert-butylsulf1nyl)imino)-1 ,3 -dihydrospiro [indene-2 ,4'-piperidine]—1'-carboxylate (1.01g, 62%) as a black solid. MS: 405 (M+H)+.
Step c:The on of the compound tert-butyl (R,E)((tert-butylsulf1nyl)imino)-1 ,3 -dihydrospiro [indene-2 ,4'-piperidine]—1'-carboxylate (1 .01g, 2.50mmol) in THF (10mL) was cooled in -50°C. NaBH4 , 3.74mmol) was added in portionwise. The e was stirred for 15.5 hours with natural g to room temperature, and then poured into EA (100mL). The mixture was washed with brine (100mL>< 3). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure in vacuo. The residue was ed by column chromatography to afford the Compound tert-butyl (S)—1-(((R)—tert-butylsulf1nyl)amino)-1,3 -dihydrospiro [indene-2 ,4'-piperidine]-1'-carboxylate (580mg, 57%) as a yellow oil. MS: 407 (M+H)+.
Step d:The mixture of the compound tert-butyl (S)(((R)—tert-butylsulflnyl)amino)-1,3 -dihydrospiro [indene-2 ,4'-piperidine]-1'-carboxylate (580mg, ol) and L) in DCM (5mL) was stirred for 40 mins at 20°C. The on was concentrated to afford the compound (R)-N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]yl)methylpropanesulflnamide (520mg, 90%) as a yellow oil. MS: 307 .
Step ezThe mixture of (R)-N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]yl)methylpropanesulflnamide (260mg, 0.62mmol), 3-((2-aminochloropyridinyl) thio)chloropyrazinamine (196mg, 0.68mmol) and K2CO3 (427mg, 3.09mmol) in NMP (8mL) were stirred for 16 hours at 100°C.
The mixture poured into EA (200mL) and washed with brine (200mL>< 3). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure in vacuo. The residue was purified by column chromatography to afford the Compound (R)-N-((S)-1'-(6-amino-5 -((2-aminochloropyridinyl)thio)pyrazinyl)-1,3-dihydrospiro[in dene-2,4'-piperidin]yl)methylpropanesulflnamide (260mg, 65%) as a yellow solid. MS: 558 (M+H)+.
Step szhe nd (R)-N-((S)-1'-(6-amino-5 -((2-aminochloropyridinyl)thio)pyrazinyl)-1,3-dihydrospiro[in dene-2,4'-piperidin]yl)methylpropanesulflnamide (260mg, 0.47mmol) was dissolved in DCM (5mL) and xoane (4mol/L, 5mL) was added dropwise. The mixture was stirred for 30 mins at 20 °C. The mixture was concentrated and the residue was dissolved in methanol (2mL).
And EA (5mL) was added. The solids were ted by filtration to afford the compound (S)-1'-(6-amino((2-amino-3 -chloropyridinyl)thio)pyrazinyl)-1,3 -dihydrospiro [indene-2, 4'-piperidin]amine (123mg, 54%) as an off-white solid. MS: 454 (M+H)+. 1H NMR (400 MHz, DMSO-d6) 5 7.81 (d, 1H), 7.72 (s, 1H), 7.62 (d, 1H), 7.27 - 7.36 (m, 3H), 6.12 (d, 1H), 4.21 - 4.35 (m, 3H), 2.97 - 3.24 (m, 4H), 1.77 - 1.91 (m, 2H), 1.49 - 1.59 (m, 2H).
EXAMPLE 3 (R)—1'-(6—amin0((2-amin0ch10ropyridinyl)thi0)pyrazinyl)-3,4-dihydr0-2H—spir0[ naphthalene-1,4'-piperidin]amine Z: HzN Cl 3422NNfN/ —> SQ!"—N f HzNw _ N — H N2 H N HN \N / /l\ 9 ‘23 2 N .=0s Step azThe solution of the compound tert-butyl bis(2-chloroethyl)carbamate (l l .00g,45.43mmol) in HCl/Dixoane (4mol/L, 200mL) was stirred for 1h at 20°C. The solution was concentrated and the residue was dissolved in DCE (200mL). Triethylamine (22.95 g, 227.14mmol) and benzaldehyde (7.23 g, 68.14mmol) was added to the mixture. And then NaBH(OAc)3 g, 113.57mmol) was added in portionwise. The mixture was stirred for 54 hours at 20°C, and then EA(300mL) and brine (200mL) was added. The c layer was concentrated under reduced pressure in vacuo. The residue was dissolved in HCl solution (2mol/L, 200mL) and extracted with EA (100mL). The pH value ofthe aqueous layer was adjusted to 9 with saturated Na2CO3 solution. The mixture was extracted with EA (200mL). The organic layer was dried over ous Na2SO4 and concentrated to afford the compound ylchloro-N-(2-chloroethyl)ethan-l-amine (8.52 g, 81%) as a colorless oil.
Step bzlnto the solution of the compound N—benzylchloro-N—(2 -chloroethyl)ethan- l -amine (8.52g, 36.70mmol) and 3,4-dihydronaphthalen-2(lH)-one (4.88 g, 33.36mmol) in THF (80mL) and DMSO (50mL) was added Potassium tert-butylate (9.36g, 83.14mmol). The mixture was stirred for 20 hours at 20°C. The mixture was concentrated and diluted with EA (200mL). And then the e was washed with brine (200mL>< 3). The organic layer was dried over anhydrous Na2SO4 and trated. The residue was purified by column chromatography to afford l'-benzyl-3,4-dihydro-2H-spiro[naphthalene-l,4'-piperidin]one (2.32g, 21%) as a black oil.
MS: 306 (M+H)+.
Step c:Into Titanium(IV) ethoxide was added the compound l'-benzyl-3,4-dihydro-2H-spiro[naphthalene-l,4'-piperidin]one (2.32g, 7.60mmol) and (R)methylpropanesulf1namide (2.76g, 22.79mmol). The mixture was stirred for 19h at 100°C. EA (200mL) and water (200mL) was added. The solids were filtrated out. The liquid mixture was ted. The organic layer was washed with brine (100mL>< 5), dried over anhydrous , and concentrated under reduced pressure in vacuo. The residue was purified by column chromatography to afford the compound (R,E)-N—( l '-benzyl-3 ,4-dihydro-2H-spiro [naphthalene-l ,4'-piperidin] ylidene)methylpropan esulf1namide (660mg, 21%) as a yellow oil. MS: 409 .
Step d:The solution of the compound (R,E)-N—( l '-benzyl-3 ydro-2H-spiro [naphthalene-l ,4'-piperidin] ylidene)methylpropan esulf1namide , 1.62mmol) in THF (10mL) was cooled into -50°C. And then NaBH4 (122mg, 3.23mmol)was added in portionwise. The mixture was d for 18h with natural warming to room temperature. The mixture was quenched with water (50mL) and ted with EA (50mL><2). The organic layers were combined and washed with brine (50mL><2), dried over anhydrous Na2SO4 and concentrated under d pressure in vacuo. The residue was purified by column chromatography to afford the compound (R)-N-((R)— l yl-3 ydro-2H-spiro [naphthalene-l ,4'-piperidin] yl)methylpropane-2 -sulf1namide (195mg, 29%) as a yellow oil. MS: 411 (M+H)+.
Step ezlnto the solution of the compound (R)-N-((R)— l '-benzyl-3 ,4-dihydro-2H-spiro [naphthalene-l ,4'-piperidin] methylpropane-2 -sulf1namide (195mg, 0.47mmol) in methanol (5mL) was added palladium hydroxide(20%, 120mg). The mixture was stirred for 18h at 40°C under en atmosphere. The mixture was filtrated and the filtration was concentrated to afford the compound (R)-N-((R)—3 ,4-dihydro-2H-spiro[naphthalene- l ,4'-piperidin] yl)methylpropanesulf1nami de (92mg, 60%). MS: 321 .
Step szhe compound (R)-N-((R)—3 ,4-dihydro-2H-spiro[naphthalene- l ,4'-piperidin] yl)methylpropanesulf1nami de (92mg, 0.29mmol) was dissolved in NMP (3mL). 3-((2-aminochloropyridinyl)thio)chloropyrazinamine (91mg, 0.32mmol) and K2CO3 (198mg, 1.44mmol) were added into. The mixture was d for 3 hours at 100°C, and diluted with EA(30mL) ,washed with brine (30mL>< 3). The organic layer was dried with anhydrous Na2SO4. The residue was purified with C to afford the compound (R)-N-((R)— l '-(6-amino-5 -((2-aminochloropyridinyl)thio)pyrazinyl)-3 ,4-dihydro-2H-spi ro[naphthalene-l,4'-piperidin]yl)methylpropanesulf1namide (18mg, 11%) as an off-white solid.
Step g:In to the solution of the compound (R)-N-((R)— l '-(6-amino-5 -((2-amino-3 -chloropyridinyl)thio)pyrazinyl)-3 ,4-dihydro-2H-spi ro[naphthalene-l,4'-piperidin]yl)methylpropanesulf1namide (18mg, 0.03mmol) in 1,4-dioxane (2mL)was added HCl/Dixoane (4mol/L, 2mL). The mixture was stirred for 30 mins.
The resulted mixture was concentrated and washed with EA for twice. The solid was dried in high vacuum to afford the compound (R)-l '-(6-amino-5 -((2-aminochloropyridinyl)thio)pyrazinyl)-3 ,4-dihydro-2H-spiro[naph thalene-l,4'-piperidin]amine (14mg, 88%) as an off-white solid. MS: 468 (M+H)+.
EXAMPLE 4 (R)—1 '-(6-amin0((2-amin0ch10ropyridinyl)thi0)pyrazinyl)-5,6-dihydr0spir0 [cyclo b] pyridine-7,4'-piperidin] amine 0 N' \ BOCTN Boc~N 9‘ | /\ N / _, \ —> ,9 / N F ’ I _N a b ’S"’€—’d / N c / \ / \ N / \ / N HzN N N NH HN2 N N N 0 I | °=s —> "HZ II \ \ | l/ "N’s ’ \ e S N s N HCI H K C' w \ CI I \ / | H2N N / HZN N Step azNaHMDS (38ml, 2mol/L in THF) was added to the e of the compound 2-fluoromethylpyridine (5.56g, 50.00mmol), l-tert-butyl 4-ethyl piperidine-l,4-dicarboxylate (14. 15 g, 55.00mmol) in toluene (50mL) se at 0°C, then naturally warmed to 20°C and stirred for 24 hours. Reaction mixture was quenched with brine (100mL). The organic extracts were dried over Na2SO4 and concentrated under reduced pressure in vacuo. The residue was d by column chromatography to afford the compound l-(tert-butyl) 4-ethyl 4-(3-methylpyridinyl)piperidine-l,4-dicarboxylate (6.32 g, 36%) as a yellow oil. MS: 349 (M+H)+.
Step b:A mixture of the compound l-(tert-butyl) 4-ethyl 4-(3-methylpyridinyl)piperidine-l ,4-dicarboxylate (4.80g, 13.78mmol), LDA (2mol/L,l7mL) in THF (48mL) was stirred at 0°C for 0.5 hour. The mixture was removed under reduced pressure in vacuo. The residue was purified by column chromatography to afford the compound tert-butyl 6-oxo-5,6-dihydrospiro[cyclopenta[b]pyridine-7,4'-piperidine]-l'-carboxylate , 23%) as a red oil. MS: 303 (M+H)+.
Step c:To a solution of the compound tert-butyl 6-oxo-5,6-dihydrospiro[cyclopenta[b]pyridine-7,4'-piperidine]-l'-carboxylate (0.94g, 3.11mol) in Titanium(IV) ethoxide (5mL) was added R-(+)-tert-Butylsulf1namide ( 1.13 g, ol) . The resulting mixture was stirred at 80°C for 1 hour. EA (30mL) and water (20mL) was added to the reaction mixture. The reaction mixture was ed and organic extracts were collected. The aqueous solution was extracted with EA (10mL><2). The combined organic extracts were washed with brine (50mL), dried over Na2SO4 and concentrated under reduced pressure in vacuo to afford the compound tert-butyl (R,Z)((tert-butylsulfinyl)imino)-5 ,6-dihydrospiro [cyclopenta[b]pyridine-7,4'-piperidine] -1 '-ca rboxylate (2.51g, crude) as a red oil. Without purification to next step.MS: 406(M+H)+.
Step d:A solution of the compound tert-butyl 6-((tert-butylsulfinyl)imino)-5 ,6-dihydrospiro [cyclopenta[b]pyridine-7,4'-piperidine] -1 '-ca rboxylate (2.12 g, crude) in THF (20mL) was stirred at -50°C. NaBH4 (176mg, 4.66mmol) was added to the reaction mixture and lly warmed to room temperature. Reaction was quenched with saturated ammonium chloride solution (30mL). The organic extracts were collected and dried over anhydrous Na2SO4 and concentrated under reduced pressure in vacuo. The e was purified by column chromatography to afford the compound tert-butyl (R)(((S)-tert-butylsulfinyl)amino)-5 ,6-dihydrospiro[cyclopenta[b]pyridine-7,4'-piperidine]-1'- carboxylate (0.21g, 17%, 2 steps) as a yellow solid. MS: 408 (M+H)+.
Step e:A mixture of the compound tert-butyl (R)(((S)-tert-butylsulfinyl)amino)-5 ,6-dihydrospiro[cyclopenta[b]pyridine-7,4'-piperidine]-1'- carboxylate (204mg, ol), CF3COOH (lmL) in DCM(lOmL) was stirred at 25°C for 1.5 hours. The reaction mixture was trated under reduced pressure. The residue was dissolved in NMP(10mL), then 3-((2-aminochloropyridinyl)thio)chloropyrazinamine (144mg, ol) and K2CO3 (0.82g, 6.00mmol) was added to mixture and stirred at 95°C for 16 hours.
H20 (50mL) was added to the reaction mixture. The aqueous solution was extracted with EA (30mL><2). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure in vacuo to afford the compound (S)-N-((R)-1'-(6-amino-5 -((2-aminochloropyridinyl)thio)pyrazinyl)-5 ydrospiro[cy clopenta[b]pyridine-7,4'-piperidin]yl)methylpropanesulfinamide (3 02mg, crude).
Without ation to next step. MS: 559 (M+H)+.
Step f:To a on of the compound (S)-N-((R)-1'-(6-amino-5 -((2-aminochloropyridinyl)thio)pyrazinyl)-5 ydrospiro[cy clopenta[b]pyridine-7,4'-piperidin]yl)methylpropanesulfinamide (302mg, 0.54mmol) in DCM (10mL) was added HCl/Dixoane (4mol/L, lmL). The resulting mixture was stirred at 25°C for 1 hour and the precipitate was filtered. The filter cake dissolved in MeOH (2mL), then DCM (15mL) was added into. The mixture was stirred for 0.5 hour and d to afford the compound (R)-1'-(6-amino((2-aminochloropyridinyl)thio)pyrazinyl)-5 ,6-dihydrospiro[cyclopent a[b]pyridine-7,4'-piperidin]amine (163mg, 71%, 2 steps) as a yellow solid. MS: 455 (M+H)+. 1H NMR (600 MHZ,MeOH-d4) 5 8.69 (d, 1H), 8.54 (d, 1H), 7.92 - 7.96 (m, 1H), ,1H), 7.75(d,1H), 6.58(d,1H), 4.54 - 4.67 (m, 3H), 3.89 - 3.95 (m, 1H), 3.37 - 3.61 (m, 3H), 2.79 - 2.86 (m, 1H), 1.93 - 2.20 (m, 3H).
EXAMPLE 5 (S)—1 '-(6-amino-S-((2-amin0ch10ropyridinyl)thi0)pyrazinyl)meth0xy-1,3-dihydr0 spiro [indene—2,4'-piperidin]amine Boc—N / O/ O/ O/ N —’ HN 0 ‘_S=o b ‘Szo 7\ 7\ ‘82»; H2N CI 3 ifmy _.N _N c. @OCQ c "2" \ / HN\ d N o/ N :0 H2N \ . / HZN 7"\ N Step a: A mixture of tert-butyl oxyoxo-1,3-dihydrospiro[indene-2,4'-piperidine]- 1'-carboxylate (557 mg, 1.68 mmol) and (R)-(+)Methylpropanesulfinamide (610 mg, 5.04 mmol) in Ti(OEt)4 (5 mL) was stirred for 16 h at 100 °C. After cooling to RT, the on mixture was diluted with EA (20 mL) and water (30 mL). The resulting mixture was filtered through a pad of Celite followed by EA wash. The filtrate was washed with brine (1 X 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give utyl (R,Z)((tert-butylsulfinyl)imino)methoxy- 1 ,3 -dihydrospiro[indene-2 ,4'-piperidine]-1'-carbo xylate (0.98 g) which was used in next step t any filrther purification. MS: m/z 435 (M+H) +.
Step b: To a -50 °C solution of tert-butyl (R,Z)((tert-butylsulfinyl)imino)methoxy- 1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate (0.98 g, 2.25 mmol) in THF (10 mL) was added NaBH4 (0.17 g, 4.51 mmol). The resulting mixture was allowed to warm to RT and stirred for 24 h. The reaction mixture was diluted with EA (50 mL) and water (50 mL), the organic layer was separated, washed with brine (1 ,x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA : Hex = 1 : 5, v/v) to give tert-butyl (S)(((R)-tert-butylsulfinyl)amino)methoxy- 1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate (380 mg). MS: m/z 437 (M+H) +.
Step c: To solution of tert-butyl (S)— 1 -(((R)—tert-butylsulfinyl)amino)methoxy- 1 ,3 -dihydrospiro [indene-2 ,4'-piperidine]-1'-carb oxylate (380 mg, 0.87 mmol) in DCM (10 mL) was added TFA (2 mL), and stirred for 1.5 h at RT.
The ing mixture was concentrated under reduced re. The residue was dissolved in NMP (10 mL), 3-((2-aminochloropyridinyl)thio)chloropyrazinamine (301 mg, 1.04 mmol) and K2CO3 (601 mg, 4.35 mmol) was added. The resulting mixture was d for 16 h at 100 °C. After cooling to RT, the reaction mixture was d with water (50 mL) and EA (50 mL).
The aqueous layer was separated, the organic layer was washed with brine (2 X 50 mL), dried over anhydrous Na2SO4, d and concentrated under reduced re. The e was purified by silica chromatography (eluting with MeOH : DCM = l : 20, v/v) to give (R)-N-((S)-l'-(6-amino((2-aminochloropyridinyl)thio)pyrazinyl)methoxy-l,3-dihy drospiro[indene-2,4'-piperidin]yl)methylpropanesulfinamide (254 mg). MS: m/z 588 (M+H) +.
Step d: To a solution of (R)-N-((S)-l'-(6-amino((2-aminochloropyridinyl)thio)pyraz inyl)methoxy- l ,3 -dihydrospiro [indene-2 ,4'-piperidin] -3 -yl)-2 -methylpropanesulfinamid e (254 mg, 0.43 mmol) in l, 4-dioxane (3 mL) was added HCl (4M solution in l, 4-dioxane, 3 mL) se and stirred for 30 min at RT. The reaction mixture was filtered and the collected precipi tate was dried in a vacuum oven to give (S)-l'-(6-amino((2-aminochloropyridinyl)thio)p yrazinyl)methoxy-l,3-dihydrospiro[indene-2,4'-piperidin]-l-amine (221 mg) as a HCl salt.
MS: m/z 484 (M+H) +. 1H NMR (600 MHz, MeOH—d4) 5 7.90 (s, 1H), 7.76 (d, 1H), 7.28 (d, 1H), 7.12 (d, 1H), 6.95 - 6.89 (m, 1H), 6.58 (d, 1H), 4.50 - 4.35 (m, 3H), 3.82 (s, 3H), 3.49 - 3.40 (m, 2H), 3.16 - 3.08 (m, 2H), 2.01 - 1.66 (m, 4H).
The following examples were synthesized using the above procedure or modification procedure using the corresponding Intermediate A and Intermediate B.
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EXAMPLE 82 (S)—1 '-(6-amino((2-amin0chloropyridinyl)thi0)pyrazinyl)—5,7—dihydr0spiro [cyclo b] pyridine-6,4'-piperidin] amine / / / \ \ \ —’ N —’ HN O \$50 b ‘350 7\ 7\ HN : l Cl SXZ}N | : N H2N4€j N ° d N HCI H2N H2N Step a: A mixture of tert-butyl 7-oxo-5,7-dihydrosprilro[cyclopenta[b]pyridine-6,4'-piperi dine]—l'-carboxylate (936 mg, 3.10 mmol) and (R)-(+)Methylpropanesulfinamide (1045 mg, 8.62 mmol) in Ti(OEt)4 (8 mL) was stirred for 2 h at 100 °C. After cooling to RT, the on mixture was diluted with EA (50 mL) and water (50 mL). The resulting mixture was filtered through a pad of Celite followed by EA wash. The c layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give utyl (R,Z)((tert-butylsulfinyl)imino)-5 ,7-dihydrospiro [cyclopenta[b]pyridine-6,4'-piperidine] -1 '-ca rboxylate (1.41 g). MS: m/Z 406 (M+H) t.
Step b: To a -40 °C solution of tert-butyl (R,Z)—7-((tert-butylsulfinyl)imino)-5,7- ospiro[cyclopenta[b]pyridine-6,4'-piperidine]-l'-carboxylate (1.41 g, 3.48 mmol) in THF (50 mL) was added BH3 (l M solution in THF, 10.00 mL, 10.00 mmol). The resulting mixture was d to warm to RT and stirred for l h. The reaction mixture was quenched with brine (100 mL).
The aqueous layer was separated, extracted with EA (1 x 60 mL), the organic layers combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in MeOH (100 mL) and stirred for 15 h at 80 °C. After cooling to RT, the reaction mixture was concentrated under reduced pressure. The residue was d by silica chromatography (eluting with MeOH : DCM = l : 60, v/v) to give tert-butyl (S)—7-(((R)—tert-butylsulfinyl)amino)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-l'- carboxylate (309 mg). MS: m/Z 408 (M+H) t.
Step c: To solution of tert-butyl (S)(((R)-tert-butylsulfinyl)amino)-5,7-dihydrospiro [cyclopenta[b]pyridine-6,4'-piperidine]-l'-carboxylate (309 mg, 0.76 mmol) in DCM (20 mL) was added HCl (4 M solution in EA, 2 mL, 8.00 mmol), and stirred for 1.5 h at RT. The resulting mixture was concentrated under reduced pressure to give 7-dihydrospiro [cyclopenta [b] pyridine-6,4'-piperidin]amine (227 mg). MS: m/z 204 (M+H) +.
Step d: A mixture of (S)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]amine (HCl salt, 227 mg, 1.12 mmol), 3-((2-aminochloropyridinyl)thio)chloropyrazinamine (249 mg, 0.86 mmol) and K2CO3 (1149 mg, 8.31 mmol) in acetonitrile (15 mL) was stirred for 44 h at reflux temperature. After cooling to RT, the reaction mixture was d with brine (100 mL), extracted with EA (2 x 50 mL). The organic layers were combined, dried over anhydrous Na2804, filtered and concentrated under d pressure. The residue was purified by silica chromatography (eluting with MeOH : DCM = 1 : 6, v/v) to give -(6-amino((2-amino-3 -chloropyridinyl)thio)pyrazinyl)-5 ,7-dihydrospiro pent a[b]pyridine-6,4'-piperidin]amine (77 mg). MS: m/z 455 (M+H) +. 1H NMR (400 MHz, MeOH—d4) 5 8.51 (s, 1H), 7.81 (d, 1H), 7.63 (s, 2H), 7.38 (s, 1H), 5.94 (d, 1H), 4.49 - 4.30 (m, 3H), 3.37 - 3.09 (m, 4H), 2.05 - 1.95 (m, 1H), 1.85 - 1.70 (m, 2H), 1.60 - 1.50 (m, 1H).
The following examples were synthesized using the above procedure or modification procedure using the corresponding Intermediate A and Intermediate B. 2-Methylpropanesulfinamide, instead of (R)-(+)MethylPropanesulfinamide, was used in step (a) of Example 82 to give the racemic compounds.
The following examples are compounds with free base, or a pharmaceutically acceptable salt.
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T: 9383-8; A3-managed:Aafiacia -0805 HEEBQEJV 82%-m-oa§-§-m-§§_A -m-A3-managed:Aafiacia EmmvoAmo_Samechficbnvégfino Eviaccaaénméofiégm OS VEEQSOEO-m-§§-§-e-_A 6-82%-N-AE-N-EN§QAO§A&- NBSHEfisomvoho_oh%€?€%© 61%-vo VEEQSOEO-m-§§-§-e-_A 823%-mnN-AE-N-EN§QA0§A&- Sam OS EXAMPLE 133 (S)—4-((5-(1-amin0-1,3-dihydr0spir0[indene-2,4'-piperidin]-1'-yl)pyrazinyl)thi0)—3-chlor0 pyridin-Z-ol Boo—NW / —’ N —’ HN —’ a b c O 13:0 13:0 7\ 7\ _N _N Cl Cl _ s~§I> —> _ s~§:© HNZS=O d H049 HZN Step a-c: Step (a-c) of Example 5 was applied to provide (R)-N-((S)-1'-(5-((3-chloromethoxypyridinyl)thio)pyrazinyl)—1,3-dihydrospiro[indene-2, 4'-piperidin]yl)methylpropanesulf1namide. MS: m/z 558 (M+H) +.
Step d: A mixture of (R)-N-((S)-1'-(5-((3-chloromethoxypyridinyl)thio)pyrazinyl)—1,3-dihydrospiro[indene-2, 4'-piperidin]yl)methylpropanesulf1namide (112 mg, 0.20 mmol), DCM (5 mL) and HCl (4 M on in 1,4-dioxane, 10 mL) was stirred for 17 h at RT. The mixture was concentrated under reduced pressure, dissolved in MeOH (10 mL) and stirred for another 23 h at 60 °C. After cooling to RT, the reaction mixture was concentrated under reduced pressure. The residue was ded in MeOH (2 mL) and EA (20 mL), the resulting precipitate was collected by filtration and dried under reduced pressure to give (S)((5 -(1-amino-1,3 -dihydrospiro [indene-2 ,4'-piperidin]-1'-yl)pyrazinyl)thio)-3 opyri dinol (73 mg). MS: m/z 440 (M+H) +. 1H NMR (400 MHz, DMSO-d6) 5 8.51 (s, 1H), 8.34 (s, 1H), 7.59 (d, 1H), 7.37 - 7.28 (m, 3H), 7.23 (d, 1H), 5.52 (d, 1H), 4.40 - 4.28 (m, 3H), 3.38 - 3.21 (m, 3H), 3.02 - 2.99 (d, 1H), 1.82- 1.75 (m, 2H), 1.60 - 1.52 (m, 2H).
The following examples were synthesized using the above procedure with the corresponding starting materials.
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The following example was synthesized using the above procedure with the corresponding starting materials.
Table 19 MSz+&1HNMR 1H NMR (400 MHz, DMSO—dtfi 5 (S)amino-1'—(6-ami 7.58 - 7.51 (m, 2H), 7.05 (t, 1H), no((2-aminochl 0" 6.87 (d, 1H), 6.65 (d, 1H), 5.94 (d, oropyridinyl)thio)p 1H), 4.27 (d, 2H), 3.9 (s, 1H), 3.36 - 3.18 (m, 2H), 3.08 (d, 1H), 2.69 (d, rospiro[indene-2,4'—pi 1H), 1.88 - 1.68 (m, 2H), 1.57 (d, peridin]—4-ol 1H), 1.43 (d, 1H).
MS: 470(M+H)+.
EXAMPLE 139 1'-(6-amin0((2-amin0chloropyridinyl)thi0)pyrazinyl)methyl-5,7—dihydrospiro [cyclopenta[b] pyridine-6,4'-piperidin]amine \ N\ Boc—N I/ N/ a ‘S=O b 7i 2‘" 5° "N H2N \N/ N 820 Step a: Step (a) of Example 5 was applied to provide tert-butyl (R,Z)-5 -((tert-butylsulfinyl)imino)-5 ,7-dihydrospiro [cyclopenta[b]pyridine-6,4'-piperidine] -1 '-ca rboxylate. MS: m/Z 406 (M+H) t.
Step b: To a -60 °C solution of tert-butyl (R,Z)—5-((tert-butylsulfinyl)imino)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (1.49 g, 3.67 mmol) in THF (15 mL) was added methyllithium (1.3 M on in diethyl ether, 14 mL, 18.20 mmol) dropwise.
The resulting mixture was allowed to warm to RT and stirred for 20 h. The reaction mixture was diluted with water (10 mL) and EA (20 mL), The s layer was collected, NaOH (1.00 g, 25.00 mmol) and (Boc)20 (0.50 mL) was added. The mixture was stirred for 1.5 h at RT. The reaction mixture was extracted with EA (2 x 50 mL), the organic layers combined, washed with brine (1 X 30 mL), dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA : Hex = 1 : 1, v/v) to give tert-butyl )-tert-butylsulfinyl)amino)methyl-5,7-dihydrospiro[cyclopenta[b] pyridine-6,4'-piperidine]-1'-carboxylate (823 mg). MS: m/z 422 (M+H) +.
Step (c-d): Step (c-d) of Example 5 was applied to provide amino((2-amino chloropyridinyl)thio)pyrazinyl)methyl-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-pipe ridin]amine (71 mg). MS: m/z 469 (M+H) +.1H NMR (400 MHz, MeOH—d4) 5 8.50 - 8.44 (m, 1H), 7.93 - 7.87 (m, 1H), 7.67 - 7.61 (m, 2H), 7.41 - 7.35 (m, 1H), 5.97 (d, 1H), 4.54 (m, 2H), 3.35 (d, 1H), 3.23 - 3.08 (m, 3H), 1.92 - 1.78 (m, 2H), 1.57 - 1.48 (m, 2H), 1.44 (s, 3H) .
EXAMPLE 140 l-amino-1'-(6-amin0-5—((2-amin0chloropyridinyl)thi0)pyrazinyl)-3H-spir0 izi ne-2,4'-piperidin]-7(1H)-0ne N \ N \ N \ Boc-N Boc-N Boc—N \ _> \ —> \ 0 O O a b HO MsO N3 N \ N \ _ 482N Boc N Cl s 0 \ d — \Nj—N O H2N H2N \ / H2N N Step a: To a -10 °C solution of tert-butyl 1-hydroxyoxo-1,7-dihydro-3H-spiro[indolizine- 2,4'-piperidine]—l'-carboxylate (100 mg, 0.31 mmol), triethylamine (157 mg, 1.55 mmol) in THF (10 mL) and DCM (2 mL) was added MsCl (66 mg, 0.58 mmol). The resulting sloution was stirred for l h at RT. The reaction solution was diluted with water (50 mL), extracted with DCM (3 23x; 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure to give tert-butyl thylsulfonyl)oxy)oxo- l ,7-dihydro-3H-spiro [indolizine-2 ,4'-piperidine] - l '-carboxylate (155 mg). MS: m/Z 399 (M+H)+.
Step b: A mixture of tert-butyl l-((methylsulfonyl)oxy)oxo- l ,7-dihydro-3H-spiro [indolizine-2 ,4'-piperidine] - l '-carboxylate (155 mg, 0.39 mmol), sodium azide (136 mg, 2.09 mmol) and DMF (5 mL) was stirred for l h at 75 °C and 4 h at 85 °C. After cooling to RT, the reaction mixture was diluted with EA (30 mL), filtered and the ion was concentrated under reduced re. The residue was d by silica chromatography (eluting with MeOH : DCM = l : 10, v/v) to give tert-butyl l-azidooxo-l ,7-dihydro-3H-spiro[indolizine-2,4'-piperidine]-1'- ylate (32 mg). MS: m/z 346 (M+H) +.
Step c: A mixture of tert-butyl l-azidooxo-l,7-dihydro-3H-spiro[indolizine-2,4'-piperidine]-l'-carboxylate (32 mg, 0.093 mmol), Pd (10% on , 15 mg) in EtOH (6 mL) was d for 3 h under hydrogen atmosphere.
The reaction mixture filtrated follow by EtOH wash and the ion was concentrated under reduced pressure to give tert-butyl l-aminooxo-l,7-dihydro-3H-spiro[indolizine-2,4'-piperidine]-l'-carboxylate (26 mg). MS: m/z 320 (M+H) +.
Step d: To solution of tert-butyl ooxo-l,7-dihydro-3H-spiro[indolizine-2,4'-piperidine]-l'-carboxylate (26 mg, 0.081 mmol) in DCM (2 mL) was added TFA (2 mL), and stirred for 30 min at RT. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in NMP (2.5 mL), 3-((2-aminochloropyridinyl)thio)chloropyrazinamine (46 mg, 0.16 mmol) and K2CO3 (395 mg, 2.86 mmol) was added, stirred for 16 h at 95 °C. After cooling to RT, the reaction mixture was diluted DCM (30 mL), filtered and concentrated under reduced pressure. The residue was purified by Pre-TLC (eluting with MeOH : DCM = l : 3, v/v) to give l-amino- l '-(6-amino-5 -((2-amino-3 -chloropyridinyl)thio)pyrazinyl)-3H-spiro [indolizine-2 4'-piperidin]-7(lH)-one (2 mg). MS: m/z 471 (M+H) +.
The following example was sized using the above procedure with the corresponding starting materials.
Table 20 Chemical Name Ms:(M+H>+&1HNMR 1H NMR (400 MHz, MeOH—d4) 7.61 - 7.57 (m, 3H), 6.53 (d, l-amino-l'—(6-amino(( 1H), 6.45 (d, 1H), 5.93 (d, 1H), 2-aminochloropyridin- 4.46 (d, 1H), 4.39 - 4.32 (m, 2H), 4-yl)thio)pyrazinyl)-3 4.14 - 4.08 (m, 1H), 3.84 (d, 1H), H-spiro[indolizine-2,4'—pi 3.28 - 3.11 (m, 2H), 1.99 - 1.91 peridin]—5(lH)-one (m, 1H), 1.83 - 1.75 (m, 1H), 1.70 (d,1H), 1.30 (d, 1H). MS: EXAMPLE 142 3-((2-amin0chlor0pyridinyl)thi0)—6-(1-imin0-1,3-dihydr0spir0 [indene-2,4'-piperidin] - 1'-yl)pyrazinamine <;© 4 / Cl N. a 8‘8; _ wow a $=O b - H2N \ / HN 7\ N Step a: Step (a) of Example 5 was applied to provide tert-butyl (R,Z)((tert-butylsulfinyl)imino)-1,3 -dihydrospiro [indene-2 ,4'-piperidine]—1'-carboxylate. MS: m/z 405 (M+H) +.
Step b: To solution of tert-butyl (R,Z)((tert-butylsulfinyl)imino)—1,3-dihydrospiro[indene- 2,4'-piperidine]—1'-carboxylate (405 mg, 1.00 mmol) in DCM (10 mL) was added TFA (1 mL), and stirred for 1.5 h at RT. The resulting mixture was concentrated under reduced pressure. The e was dissolved in NMP (10 mL), 3-((2-aminochloropyridinyl)thio)chloropyrazinamine (288 mg, 1.00 mmol) and K2CO3 (1.38 g, 10.00 mmol) was added. The resulting e was stirred for 18 h at 100 °C. After cooling to RT, the reaction mixture was diluted with water (50 mL) and extracted with EA (3 X 30 mL). The combined organic layers were washed with brine (1X 100 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced re. The residue was purified by silica chromatography (eluting with MeOH : DCM = 1 : 5, v/v) to give 3-((2-aminochloropyridinyl)thio)(1-imino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl) pyrazinamine (50 mg). MS: m/z 452 (M+H) +. 1H NMR (400 MHz, MeOH—d4) 5 7.83 (d, 1H), 7.74 - 7.37 (m, 5H), 5.96 (d, 1H), 4.58 - 4.43 (m, 2H), 3.28 - 3.12 (m, 4H), 2.06 - 2.01 (m, 2H), 1.60 - 1.56 (m, 2H).
The following examples were synthesized using the above procedure with the corresponding starting materials. é Aw: Arm Em - new i é é new é w? m: é o: é m: new a? 84 m: - "9: 3m Ea 3; i: W3 Arm "Q: - - m3 "Q: é Aw: 3m é "9: EN - a: 51E new i i as é new 63 Em as a: 911E "9: a: new 84 m 8s é m 3.0 5m m new m m2 - .+E+2V©mm as - ME Siam: "9: cam "9: of «22? V? - "m2 AS i is Gwdgm é Gwdgm - oi Em Gwdgm new "E: 8s i c: 3.155 SW .+E+2vw£ "Ev new VVV 03 Aw: am "E: "9: Sm "E: "E: - "m2 Em 9i é Em .+E+2vw£ big 9i new 22 0 6:: i - 9i - mam Em mzz é 8N mzz 8s "m2 mzz 2.0 3m i 64 - mzz OS Em new .+E+2V©mm Hm: "Q: Se n F am F "Q: Q? Em F "Q: 3m "9: F "9: as 0: "m2 Bfiosbm E8825 Exafiacageozo-m-§§-§-m gag"fiioaoaaéafi0-8 -mfictomagvnmésocsm oESm-N-EN§%QQ%J oESm-N-EN§%QQ%-_ Same oEEm-N-ENS Exafiacageozo-m-§§-§-m flOEeameaagfoaéiéé _fl-3683iwofifioiaafigo oESm-N-ENmbaQ%- Exafiacageozo-m-§§-§-m _eavmonmvéaagéaofi0-8 EtofimsvnWenonmofizowfiomofloho TE Exafiacageozo-m-§§-§-m ammoflo%o_SEWEQEY088736-? "5%-.fl-Eccaaénflagging? -ENS% Ewafiacageozo-m-oE§-§-m mechficbnvéfiafiv56-? main"Womenmowfi3_§§Qo~o\mo_ohm -HEUCD EXAMPLE 148 1'-(6-amin0((2-amin0chloropyridinyl)thi0)pyrazinyl)—7—meth0xy-1,3-dihydr0spir 0 [indene-2,4'-piperidin] amine —> —> a N/ b B°°_N: X I 1 _N Cl SX/ N Step a: To a on oftert-butyl oxyoxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate (552 mg, 1.07 mmol) in MeOH (10 mL) was added hydroxylamine hloride (348 mg, 5.01 mmol) and AcONa (822 mg, 10.02 mmol). The resulting mixture was stirred for 4 h at RT. The on mixture was concentrated under reduced pressure. The residue was dissolved in EA (15 mL) and water (15 mL), the organic layer was separated, washed with brine (1 x 15 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl (Z)—1-(hydroxyimino)methoxy-1,3-dihydrospiro[indene-2 ,4'-piperidine]—1'-carboxylate (520 mg) as a yellow solid. MS: m/z 347 (M+H) +.
Step b: A suspension oftert-butyl (Z)—1-(hydroxyimino)methoxy-1,3-dihydrospiro[indene-2 ,4'-piperidine]—1'-carboxylate (5 10 mg, 1.47 mmol) and PtOz (30 mg) in AcOH (10 mL) was stirred for 17 h at 60 °C under hydrogen atmosphere. After cooling to RT, the reaction mixture was diluted with EA (45 mL) and water (45 mL), the aqueous layer was ted and the pH value was taken to 10 with K2CO3 solid. The resulting mixture was extracted with DCM (2 x 30 mL), the combined organic layers were washed with brine (1 X 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 1-aminomethoxy-1,3-dihydrospiro[indene-2,4'-piperidine]—1'-carboxylate (202 mg) as a colorless oil. MS: m/z 333 (M+H) +.
Step c: To on oftert-butyl 1-aminomethoxy-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate (199 mg, 0.60 mmol) in DCM (10 mL) was added TFA (1 mL), and stirred for 1.5 h at RT. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in NMP (5 mL), 3-((2-aminochloropyridinyl)thio)chloropyrazinamine (144 mg, 0.50 mmol) and K2CO3 (691 mg, 5.90 mmol) was added. The resulting mixture was stirred for 3 h at 95 °C. After cooling to RT, the reaction mixture was diluted with water (50 mL) and extracted with EA (1 x 50 mL). The organic layer was washed with brine (1 X 50 mL), dried over anhydrous NaZSO4, filtered and concentrated under reduced pressure. The residue was purified by Pre-TLC (eluting with MeOH : DCM = 1 : 5, V/V) to give 1'-(6-amino-5 -((2-amino-3 -chloropyridinyl)thio)pyrazinyl)methoxy- 1 ,3 -dihydrospiro [in dene-2,4'-piperidin]amine (20 mg). MS: m/z 484 (M+H) +.1H NMR (400 MHz, DMSO—d6) 5 7.66 (s, 1H), 7.64 (d, 1H), 7.36 - 7.28 (m, 1H), 6.90 (d, 1H), 6.88 (d, 1H), 5.75 (d, 1H), 4.29 (s, 1H), 4.20 (d, 1H), 4.09 (d, 1H), 3.83 (s, 3H), 3.30 - 3.15 (m, 2H), 3.10 (d, 1H), 2.96 (d, 1H), 1.87 - 1.76 (m,lH), 1.70 - 1.54 (m, 2H), 1.41 (d, 1H).
The following example was synthesized using the above procedure with the ponding ng materials.
Table 22 1H NMR (400 MHz, MeOH—d4) (Z)-l'—(6-amino((2- 8.40 (d, 1H), 7.63 — 7.58 (m, aminochloropyridin 3H), 7.41 — 7.34 (m, 2H), 5.96 thio)pyrazin-2 -yl (d, 1H), 4.38 (d, 2H), 3.31 — 3.14 )spiro[indene-2,4'—pipe (m, 4H), 1.96 — 1.92 (m, 2H), —l (3H)-one 1.72 — 1.63 (m, 2H). oxime EXAMPLE 150 (S)—1 '-(6-amino-S-((2-amin0ch10ropyridinyl)thi0)pyrazinyl)—2-meth0xy-4,6-dihydr0 Spiro [cyclopenta[d] thiazole-5,4'-piperidin]amine s s Boc-N<:>§/:[ />—C|S Boc—N::><;[ />—C|N/ BOG—Mm />—C|N ’ —’ N N\ HN\ a b O ~s: §:O 7\ 7x 061%)S / N s c. gmH ‘2/:<> N N —> —> —> c ‘3: d H2N HN\ e 74K N_ 5‘0 _N 3 CI S{fNO§IN/>_O\ Step (a-b): Step (a-b) of Example 5 was d to provide tert-butyl (S)—4-(((R)-tert-butylsulfinyl)amino)chloro-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperi dine]—1'-carboxylate. MS: m/z 448 (M+H) +.
Step c: A mixture of tert-butyl(S)(((R)-tert-butylsulfinyl)amino)—2-chloro-4,6- dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]—l'-carboxylate (403 mg, 0.90 mmol) and NaOH (358 mg, 8.95 mmol) in MeOH (15 mL) was stirred for 5 h at 65 °C. After cooling to RT, the les were removed under d pressure. The residue was ved in water and the pH value was taken to 7 by the addition of aq. citric acid. The resulting mixture was extracted with EA (3 x 30 mL), the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl(S)(((R)-tert-butylsulfinyl)amino) methoxy-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]—l'-carboxylate (360 mg) as a brown oil. MS: m/z 444 (M+H) +.
Step (d-e): Step (c-d) of Example 5 was applied to provide(S)—l'-(6-amino((2-amino- 3-chloropyridinyl)thio)pyrazinyl)methoxy-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'- piperidin]amine. MS: m/z 491 (M+H) +.
EXAMPLE 151 (S)—1 '-(6-amino((2-amin0chl0r0pyridinyl)thi0)pyrazinyl)-4,6-dihydr0spiro [cyclo penta[d] thiazole-5,4'-piperidin] amine s s s Boc—NOQE'f—Cl Boc—N::>—Cl Boc—NC>§/:E / Cl / _N 3 / \SQNOQN) Step (a-b): Step (a-b) of Example 5 was applied to provide tert-butyl (((R)—tert—butylsulfinyl)amino)chloro-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperi dine]—1'-carboxylate. MS: m/z 448 (M+H) +.
Step c: A suspension of utyl (S)—4-(((R)—tert—butylsulfinyl)amino)chloro-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperi dine]—1'-carboxylate (2.50 g, 5.58 mmol), TEA (2 mL) and Pd (10 % on carbon, 690 mg) in MeOH (50 mL) was stirred for 24 h at 40 °C under hydrogen atmosphere. The resulting mixture was filtered, and an additional portion of Pd (10 on carbon, 1.32 g) was added to the ion. The resulting mixture was stirred for another 16 h at 50 °C under hydrogen atmosphere. The resulting mixture was filtered, the filtration was concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA : Hex = 1 : 1, v/v) to give tert-butyl (4S)—4-((tert-butylsulfinyl)amino)—4,6-dihydrospiro [cyclopenta[d]thiazole-5 ,4'-piperidine]-1'-car boxylate (1.28 g). MS: m/z 414 (M+H) +.
Step (d-e):Step (c-d) of Example 5 was d to provide(S)-1'-(6-amino((2-amino chloropyridinyl)thio)pyrazinyl)-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidin]a mine. MS: m/z 461 (M+H) +. 1H NMR (400 MHz, DMSO-d6) 5 8.94 (s, 1H), 7.66 - 7.63 (m, 2H), .76 (d, 1H), 4.07 - 3.99 (m, 2H), 3.87 (s, 1H), 3.38 - 3.28 (m, 2H), 2.93 - 2.78 (m, 2H), 1.87 - 1.47 (m, 4H). 2-Methylpropanesulfinamide, instead of (R)-(+)MethylPropanesulfinamide, was used in step (a) of Example 5 to give the racemic compounds.
The following example was synthesized using the above procedure with the corresponding ng materials.
Table 23 1H NMR (400 MHz MeOH—d4) 5 (S)-1'-(5-((2-aminochl 8.97 (s 1H) 8.34 (d 2H) 7.60 (d 0r0pyridinyl)thio)pyra gl/E'/> 1H) 5. 94 (d 1H) 4.43 (d 1H) zinyl)-4,6-dihydrospir 4.33 (d, 1H), 4.23 (s, 1H), 3.48 - o[cyclopenta[d]thiazole-S 3.31 (m, 2H), 3.12 - 3.09 (m, 2H), ,4'—piperidin]—4-amine 2.01 - 1.79 (m, 4H). MS: 446(M+H)+. 1'—(6-amino((2-amino- 1H NMR (400 MHz, MeOH—d4) 5 ropyridinyl)thio 8.88 (s, 1H), 7.62 - 7.58 (d, 2H), )pyrazinyl)-4,6-dihydr 5.94 (d, 1H), 4.33 - 4.14 (m, 2H), ospiro[cyclopenta[d]thiaz 3.98 (s, 1H), 3.44 - 3.30 (m, 2H), ole-5,4'—piperidin]—4-ami 3.05 - 2.95 (m, 2H), 1.96 - 1.69 ne (m, 4H). MS: 461 (M+H)+. 1H NMR (400 MHz, MeOH—d4) 5 1'—(5-((2-aminochloro 8.91 (s, 1H), 8.36 (d, 1H), 8.30 (d, pyridinyl)thio)pyrazin 1H), 7.61 (d,1H), 5.95 (d, 1H), -4,6-dihydrospiro[c 4.35 - 4.24 (m,2H), 4.06 (s, 1H), yclopenta[d]thiazole-5,4'— 3.52 - 3.38 (m, 2H), 3.06 (s, 2H), piperidin]—4-amine 2.00 - 1.75 (m, 4H). MS: 446 (M+H)+.
EXAMPLE 155 (S)—1 '-(6-amino((2-amin0chloropyridinyl)thi0)pyrazinyl)-4,6-dihydr0spiro [cyclo penta[d] thiazole-5,4'-piperidin] amine N N N Boc-N<:><;[ >‘C' Bee-NW\> Boc—NOQES\>—CI s s N\ HN a b $1 ‘Sso 7\ 7\ _N N HZNQ c. oflogm u _firmly n HNZS=° d H2N4® N s 7\ Step a: Step (a) of Example 5 was applied to provide tert-butyl (R,Z)((tert-butylsulfinyl)imino)chloro-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidi ne]—l'-carboxylate. MS: m/z 446 (M+H) +.
Step b: To a -50 °C solution of tert-butyl (R,Z)—6-((tert-butylsulfinyl)imino)chloro-4,6- dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-l'-carboxylate (4.25 g, 9.53 mmol) in THF (30 mL) was added BH3 (l M solution in THF, 30.00 mL, 30.00 mmol). The resulting mixture was allowed to warm to RT and stirred for 18 h. The on mixture was quenched with brine (50 mL).
The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography g with(EA: Hex = l : 2, V/V) to give utyl (S)(((R)-tert-butylsulfinyl)amino)—4,6-dihydrospiro [cyclopenta[d]thiazole-5,4'-piperidine]-l'-carboxylate (1.12 g). MS: m/z 414 (M+H) +.
Step (c-d): Step (c-d) of Example 5 was applied to provide (S)— l '-(6-amino-5 -((2-amino-3 -chloropyridinyl)thio)pyrazinyl)-4,6-dihydrospiro [cyclopent a[d]thiazole-5,4'-piperidin]amine. 1H NMR (400 MHZ, DMSO-d6) 5 9.01 (s, 1H), 7.66 - 7.63 (m, 2H) 5.76 (d, 1H), 4.23 - 4.19 (m, 2H), 4.09 (s, 1H), 3.32 - 3.15 (m, 2H), 2.93 - 2.80 (m, 2H), 1.87 — 1.60 (m, 4H). MS: m/Z 461 (M+H) +.
The following example was synthesized using the above procedure or modification ure with the ponding starting materials.
Table 24 (S)-l'—(5-((2-amino 1H NMR (400 MHz, MeOH—d4) 5 chloropyridinyl)thio 9.07 (s, 1H), 8.37 (d, 1H), 8.30 (d, inyl)-4,6-dihy 1H), 7.60 (d, 1H), 5.95 (d, 1H), 4.48 drospiro[cyclopenta[d] (d, 1H), 4.38 - 4.34 (m, 2H), 3.45 - thiazole-5,4'—piperidin] 3.27(m, 2H), 3.13 - 3.02 (m, 2H), amine EXAMPLE 157 (S)—1 '-(6-amin0((3-flu0r0-1H-ind01yl)thi0)pyrazinyl)-1,3-dihydr0spir0 [indene-2,4'- din] amine FF 84% F ‘N/ N —> / 311/ "mflu 0i"! H2N HN A e of (S)— l -(4-((3 -amino-5 -( l -amino-l ,3 -dihydrospiro [indene-2 ,4'-piperidin] - l '-yl)pyrazinyl)thio)—3 ,3-difiuoroindolin—l-yl)ethan-l-one (86 mg, 0.14 mmol), DCM (5 mL) and HCl (4 M solution in l,4-dioxane, 0.50 mL) was stirred for 0.5 h at RT. The e was concentrated under reduced pressure. The residue was dissolved in MeOH (8 mL) and NaOH (17 mg, 0.43 mmol) was added.
The resulting mixture was stirred for another 21 h at 65 °C. After cooling to RT, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (10 mL) and EA (20 mL). The separated organic layer was washed with brine (10 mL), dried over anhydrous Na2804, filtered and concentrated under pressure. EA (5 mL) and Hex (3 mL) was added and the resulting precipitate was collected by filtration and dried under reduced pressure to give (S)— l '-(6-amino((3-fluoro- l H-indolyl)thio)pyrazinyl)-l ,3-dihydrospiro[indene-2,4'-piper idin]-l-amine (14 mg). 1H NMR (400 MHz, DMSO-d6) 5 7.59 (s, 1H), 7.37 - 7.21 (m, 5H), 7.13 (d, 1H), 7.00 — 6.93 (m, 1H), 6.40 (d, 1H), 4.18 (d, 2H), 3.97 (s, 1H), 3.09 (m, 3H), 2.72 (m, 1H), 1.77 — 1.62 (m, 2H), 1.50 — 1.47 (m, 1H), 1.20 — 1.16 (m, 1H) MS: 461(M+H)+.
EXAMPLE 158 (S)—1-(1-amin0-1 '-(6-amin0((2-amin0ch10ropyridinyl)thi0)pyrazinyl)—1,3-dihydr ospiro [indene-2,4'-piperidin]yl)ethan0ne Boo—NW Boc-Nm Boc—N / CN CN ’ N ’ HN a b 0 \_S=o ‘_S=o 300—Mm CI S422N\ _ N_/)— C> Step c: To a -50 °C solution of tert-butyl (l S)— l -((tert-butylsulfinyl)amino)—6-cyano-l ,3 -dihydrospiro [indene-2 ,4'-piperidine] - l '-carboxyla te (430 mg, 1.00 mmol) in THF (10 mL) was added methylmagnesium bromide (3 M on in THF/Hex, 0.50 mL, 1.50 mmol) dropwise. The resulting mixture was allowed to warmed to RT and stirred for 24 h. The reaction mixture was quenched with brine (10 mL). The organic layer was separated, dried over ous Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl (l S)—6-acetyl- l -((tert-butylsulfinyl)amino)-l ,3 -dihydrospiro [indene-2 peridine] - l oxyla te (0.72 g) which was used in next step without any further purification. MS: m/z 449 (M+H)+.
Step d-e: Step (c-d) of Example 5 was applied to provide (S)— l -( l -amino-l '-(6-amino-5 -((2-amino-3 -chloropyridinyl)thio)pyrazinyl)- l ,3 -dihydrospir o[indene-2,4'-piperidin]yl)ethan-l-one. MS: 496(M+H)+.
The following example was synthesized using the above ure or ation ure with the corresponding starting materials.
Table 25 H NMR (400 MHZ, DMSO-d® 5 (S)(1-amin0-1'—(6-a 7.99 (d, 1H), 7.73 (d, 1H), 7.67 (s, mino-S -((2-amino-3 -c hloropyridinyl)thio) 1H), 7.64 (d, 1H), 7.50 (t, 1H), 5.75 pyrazinyl)-1,3-dihy (d, 1H)» 4-40 (S; 1H); 4-24 (d; 1H); drospiro[indene-2,4'—pi 4.16 (d, 1H), 3.41 - 3.17 (m, 4H), peridin]—4-yl)ethano 2.60 (s, 3H), 1.74 - 1.66 (m, 2H) ne 1.53 — 1.45 (m, 2H). MS: 496(M+H)+.
The following examples can be synthesized using the above methods and appropriate starting Table 26 Chemical Name MS(M+H)+ (R)-1'—(5 -((2-amino-3 -chloropyridi nyl)thio)pyrazinyl) - 1 l spiro ine-2,4‘-piperidin] -3 -am amino-5 -((2-amino-3 -chlorop yridinyl)thio)pyrazinyl)-2,3 - dihydrospiro [indene- 1 ,4 '-piperidin] amine 1'—(6-amino-5 mino-3 -chlorop yridinyl)thio)pyrazinyl)-3 ,4 - dihydro-2H-spiro [naphthalene-1 ,4' -piperidin]amine 1'—(6-amino-5 -((2-amino-3 -chlorop yridinyl)thio)pyrazinyl)-5 ,6 - dihydrospiro [cyclopenta[b]pyridin e-7,4'—piperidin]—6-amine 2 J3 1-(6-amino-5 -((2-amino-3 -chlorop yridinyl)thio)pyrazinyl)tetrah ydro- 1 'H,3 'H-spiro [piperidine-4,2'— pyrrolizin] - 1 '-amine (1 'S)-1 -(6-amin0-5 -((2-amin0-3 -ch 10r0pyridinyl)thi0)pyrazinyl)t etrahydro- 1 'H, 3 'H-spiro [piperidine -4,2'—pyrr01izin] -1 '-arnine 1'—(6-amin0-5 -((2-amino -3 -ch10r0p yridiny1)thi0)pyraziny1)-4,6 - dihydrospiro [cyclopenta [b]furan-S , 4'- n i n ] amine (S) -1 '-(6-amino -5 -((2-amin0-3 -ch1 0r0pyridiny1)thi0)pyrazin-2 -y1) - 4,6-dihydr0spiro[cyclopenta[b]fura n-5 ,4 '-piperidin] amine 1'—(6-amin0-5 -((2-amino -3 -ch10r0p yridiny1)thi0)pyraziny1)-6,7 - dihydrospiro [cyclopenta[b]pyridin e-5,4'—piperidin]—6-amine amin0-5 -((2-amin0-3 -ch10r0p yridiny1)thi0)pyrazin yl)hexahydrospiro [cyclopenta[b]fu ran-5 ,4 '-piperidin] ne (4R)-1'—(6-amin0-5 -((2-amin0-3 -ch 10r0pyridinyl)thi0)pyrazinyl) hexahydrospiro [cyclopenta[b]furan -5 ,4'-piperidin]—4-amine 1'—(6-amin0-5 -((2-amin0-3 0p y1)thi0)pyrazinyl)spir0[ bicyclo[3.1.0]hexane-3,4'—piperidin ]—2-amine 1 '-amino(6-amin0-5 -((2-amin0ch10r0pyridiny1)thi0)pyrazin- 2-y1)tetrahydr0-1 'H,3 ro [piper idine-4,2'—pyrr01izin] -3 '-0ne (1 'S)-1 '-an1in0-1 -(6-amin0-5 -((2-a mino-3 -ch10r0pyridinyl)thi0)pyr azinyl)tetrahydr0-1'H,3 'H-spir0[ nuieridine-4,2'— rrolizin]—3'—0ne 1'—(6-amin0-5 -((2-amin0-3 -ch10r0p yridiny1)thi0)pyrazinyl)spir0[ bicyclo[3.1.0]hexane-2,4'—piperidin ]—3 -amine (3R)-1'—(6-amin0-5 -((2-amin0-3 -ch 10r0pyridinyl)thi0)pyrazinyl) spir0[bicyclo[3.1.0]hexane-2,4'-pip eridin] -3 -amine 3-((2-amin0ch10r0pyridiny1)t hi0)(11-oxa-1,7-diazadispir0[2.0 ]d0decany1)pyrazinami 1-(4-((3-amin0(2-amin0spir0 [bi cyclo[3.1.0]hexane-3,4'-piperidin]— 1'-y1)pyrazinyl)thi0)-3,3-diflu0r oindoliny1)ethan0ne amin0-5 -((2-amin0-3 0p yridiny1)thi0)pyrazin-2 -y1)me thylspir0[bicyclo[3.1.0]hexane-3,4' -piperidin]amine (4R)-1'—(6-amin0-5 -((2-amin0-3 -ch 10r0pyridinyl)thi0)pyrazinyl) hylspir0[bicyclo[3.1.0]hexa 1’16-3 ,4'—piperidin] ne 1'—(6-amin0-5 -((2-amin0-3 -ch10r0p yridiny1)thi0)pyrazinyl)spir0[ bicyclo [3 .2.0]heptane-3 ,4'-piperidi n] amine (2R)-1'—(6-amin0-5 -((2-amin0-3 -ch 10r0pyridinyl)thi0)pyrazinyl) Spiro [bicyclo[3 .2.0]heptane-3 ,4'—pi peridin]amine 1'—(6-amin0-5 -((2-amin0-3 -ch10r0p yridiny1)thi0)pyraziny1)hexah ydro- 1 H-spiro [pentalene-2,4'—piper idin]—1 -amine (1R)-1'—(6-amin0-5 -((2-amin0-3 -ch 10r0pyridinyl)thi0)pyrazinyl) hexahydro- 1 H-spiro [pentalene-2,4' -piperidin] amine 1-(4-((3 -amin0-5 -(2-amin0-2,3 -dih ydrospir0[indene-1,4'-piperidin]—1'- yl)pyrazinyl)thi0) -3 , 3 -difluoroin d01in 1 ethan-l -0ne 1'—(6-amin0-5 -((2-amin0-3 -ch10r0p yridiny1)thi0)pyraziny1)me 2,3 -dihydr0Spiro [indene- 1 ,4' -piperidin]amine (R)-1'—(6-amin0-5 -((2-amin0-3 -ch1 0r0pyridiny1)thi0)pyrazin-2 -y1) - 4-meth0xy-2,3 -dihydr0Spiro [inden —piperidin]—2-amine 1'—(6-amin0-5 -((2-amin0-3 -ch10r0p yridiny1)thi0)pyraziny1)-4,5 - dihydroSpiro [cyclopenta an-6, eridin] -5 -amine (R)-1'—(6-amin0-5 -((2-amin0-3 -ch1 0r0pyridiny1)thi0)pyrazin-2 -y1) - 4, 5 -dihydr0Spiro[cyclopenta[b]fura n-6,4'—piperidin] -5 -amine 1-(4-((3-amin0-5 -(11-oxa-1,7-diaz adispiro[2.0.54.33]d0decanyl)pyr aziny1)thi0)-3 3 -diflu0r0ind01in- 1 han0ne 1'—(6-amin0-5 -((2-amin0-3 -ch10r0p yridiny1)thi0)pyraziny1)hexah ydrospir0[cyclopenta[b][1,4]dioxin e-6,4'— n i n eridin] -5 -amine (5 S)-1'—(6-amin0-5 -((2-amin0-3 -ch 10r0pyridinyl)thi0)pyrazinyl) hexahydrospiro[cyclopenta[b][1,4] dioxine-6,4'—piperidin]amine 6-an1in0-1'—(6-an1in0-5 -((2-an1in0ch10r0pyridiny1)thi0)pyrazin- 2-y1)-6,7-dihydr0spiro [cyclopenta[ dine-5 ,4'-piperidin] -2( 1 H) -O (R)an1in0- 1 '-(6-an1in0-5 -((2 -an1i n0-3 -ch10r0pyridinyl)thi0)pyraz in-2 -y1) -6,7-dihydr0spiro [cyclopen ta[b]pyridine-5 ,4'—piperidin] -2( 1 H) 2-an1in0-1'—(6-an1in0 -5 -((2-aminoch10r0pyridiny1)thi0)pyrazin- 2-yl) -2, 3 -dihydr0-5H-spir0[ind01iz ine-1,4' n i n eridin] -5 -0ne (S)an1in0-1'—(6-an1in0-5 -((2-an1i n0-3 -ch10r0pyridinyl)thi0)pyraz in-2 -y1) -2,3 r0-5H-spiro [indo 1izine-1,4'— n i n eridin] -5 -0ne 1'—(6 -an1in0-5 -((2-amino -3 -ch10r0p yridiny1)thi0)pyrazinyl)spir0[ chr0n1ane-4,4'—piperidin]an1ine (S)-1'—(6-an1in0-5 -((2-an1in0-3 -ch1 idiny1)thi0)pyrazin-2 -y1) s piro[chr0n1ane-4,4'—piperidin]-3 -a 1'—(6-an1in0-5 -((2-an1in0-3 -ch10r0p yridiny1)thi0)pyraziny1)n1e thoxy- 1 ,3 -dihydr0spiro [indene-2,4' - n i n eridin]—1-an1ine 1'—(6-an1in0-5 -((2-an1in0-3 -ch10r0p yridiny1)thi0)pyraziny1)-3 ,4 - dihydro- 1 H-spiro [naphthalene-2,4' - n i n eridin]—1-an1ine 1-(6-an1in0-5 -((2-an1in0-3 0p yridiny1)thi0)pyrazin-2 -y1) -7', 8 '- dihydro-S 'H-spiro [piperidine-4,6 '-q 1'—(6-amin0-5 -((2-amin0-3 -ch10r0p yridiny1)thi0)pyraziny1)-6,7 - dihydroSpiro [cyclopenta[c]pyridine -5 ,4'—piperidin]—6-amine (R)-1'—(6-amin0-5 -((2-amin0-3 -ch1 0r0pyridiny1)thi0)pyrazin-2 -y1) - 6,7-dihydr0Spiro[cyclopenta[c]pyri dine-5 ,4'— n i n eridin] amine amin0-5 -((2-amin0-3 -ch10r0p yridiny1)thi0)pyraziny1)me 3 ,4-dihydr0-1H-spir0[napht halene-2,4'— n i n eridin]—1-amine (S)-1'—(6-amin0-5 -((2-amin0-3 -ch1 0r0pyridiny1)thi0)pyrazin-2 -y1) - 0xy-3 ,4-dihydr0-1H-spir0[n aphthalene-2,4'—piperidin]amine 1'—(6-amin0-5 -((2-amin0-3 -ch10r0p yridiny1)thi0)pyrazinyl)-5 ,6 - dimethoxy- 1 ,3 -dihydr0Spiro [inden e-2,4'—piperidin]—1-amine (S)-1'—(6-amin0-5 -((2-amin0-3 -ch1 0r0pyridiny1)thi0)pyrazin-2 -y1) - , 6-dimeth0xy-1 ,3 -dihydr0Spiro [in ,4' n i n ]—1-amine 1-arnin0-1'—(6-amin0-5 -((2-amin0ch10r0pyridiny1)thi0)pyrazin- 2-y1)-1 ,3 -dihydr0Spiro [indene-2,4'— piperidin]—6-01 1'—(6-amin0-5 min0-3 -ch10r0p yridiny1)thi0)pyraziny1)-5 -me thoxy- 1 ,3 -dihydr0Spiro [indene-2,4' - n i n eridin]—1-amine 1'—(6-amin0-5 -((2-amin0-3 -ch10r0p yridiny1)thi0)pyraziny1)-4,6 - dihydroSpiro [cyclopenta[b]thi0phe ne-S,4'—piperidin]—4-amine 1-amin0-1'-(6-amin0((2-amin0ch10r0pyridiny1)thi0)pyrazin- 2-y1)-1 ,3 -dihydr0Spiro [indene-2,4'— piperidine]—6-carb0nitrile 1'—(6-amin0-5 -((2-amin0-3 -ch10r0p yridiny1)thi0)pyraziny1)me thoxy- 1 ,3 -dihydr0Spiro [indene-2,4' - n i n eridin]—1-amine 1'—(6-amin0-5 -((2-amin0-3 -ch10r0p yridiny1)thi0)pyrazinyl)- 1 ,3 - dihydroSpiro [indene-2,4 '-piperidin e]—1,6-diamine 1-arnin0-1'—(6-amin0-5 -((2-amin0ch10r0pyridiny1)thi0)pyrazin- 2-y1)-1 ,3 -dihydr0Spiro [indene-2,4'— piperidin]—4-01 amin0-5 -((2-amin0-3 0p yridiny1)thi0)pyraziny1)chl 0r0-1,3 r0Spiro [indene-2,4'—pi o eridin]— 1 -amine 1'—(6-amin0-5 -((2-amin0-3 -ch10r0p yridiny1)thi0)pyraziny1)br omo-1,3 r0Spiro [indene-2,4 '- o i n eridin]—1-amine 1'—(6-amin0-5 -((2-amin0-3 -ch10r0p y1)thi0)pyraziny1)-2,3 - dihydroSpiro [indene- 1 ,4 '-piperidin e]—2,5-diamine (R)-1'—(6-amin0-5 -((2-amin0-3 -ch1 0r0pyridiny1)thi0)pyrazin-2 -y1) - 2, 3 -dihydrospir0[indene-1,4'—piperi dine]—2,5 -diamine 1'—(6-amin0-5 -((2-amin0-3 -ch10r0p yridiny1)thi0)pyraziny1)me thoxy-2,3 -dihydr0spir0 [indene- 1 ,4' -piperidin]—2-amine (R)-1'—(6-amin0-5 -((2-amin0-3 -ch1 0r0pyridiny1)thi0)pyrazin-2 -y1) - 6-meth0xy-2,3 -dihydr0Spiro [inden e-1,4'—piperidin]—2-amine 1-(6-amin0-5 -((2-amin0-3 -ch10r0p y1)thi0)pyrazin-2 -y1)- 1 'H, 3 'H-spiro [piperidine-4,2'—pyrr01izin ] - 1 '-arnine (S) -1 in0-5 -((2-amin0-3 -ch10 diny1)thi0)pyrazinyl) - 1' H,3 ro [piperidine-4,2'—pyrroli zin] -1 '-arnine 1'—(6-amin0-5 mino -3 -ch10r0p yridiny1)thi0)pyrazinyl)-5 ,7 - dihydroSpiro [cyclopenta[c]pyridine -6,4'— n i n eridin]—7-amine 2-amin0-1'—(6-amin0-5 -((2-aminoch10r0pyridiny1)thi0)pyrazin- 2-y1) -2,3 -dihydr0spir0[indene-1,4'— o i n eridine] carb0xamide (R)amin0- 1 '-(6-amin0-5 -((2-ami n0-3 -ch10r0pyridinyl)thi0)pyraz in-2 -y1) -2,3 -dihydr0Spiro [indene- 1 4'—piperidine]carb0xamide 2-amin0-1'—(6-amin0-5 -((2-aminoch10r0pyridiny1)thi0)pyrazin- 2-y1) -2,3 -dihydr0spir0[indene-1,4'— piperidine]—4-carb0nitrile (R)amin0-1'-(6-amin0((2-ami n0-3 0pyridinyl)thi0)pyraz in-2 -y1) -2,3 -dihydr0Spiro [indene- 1 4'-piperidine] carbonitrile N-(2-amin0-1'—(6-amin0-5 -((2-ami n0-3 -ch10r0pyridinyl)thi0)pyraz in-2 -y1) -2,3 -dihydr0Spiro [indene- 1 o i n eridin] 1 ide (R)-N-(2-amin0-1 min0-5 -((2- amino-3 -ch10r0pyridiny1)thi0)p yraziny1)-2,3 -dihydr0Spiro [inde ne-1 ,4'—piperidin] -4 -y1)acetamide amin0-5 -((2-amin0-3 -ch10r0p yridiny1)thi0)pyraziny1)(p yrrolidiny1)-1 ,3 -dihydr0Spiro [in dene-2,4' n i n eridin]—1-amine (S)-1'—(6-amin0-5 -((2-amin0-3 -ch1 0r0pyridiny1)thi0)pyrazin-2 -y1) - 6-(pyrr01idin-1 -y1) -1 , 3 -dihydr0spir 0[indene-2,4'—piperidin]—1-amine 1'—(6-amin0-5 -((2-amin0-3 -ch10r0p yridiny1)thi0)pyraziny1)(1 , 4-dimethy1-1H-1,2,3 -triazol-5 -y1)- 1, 3 -dihydr0Spiro[indene-2,4'—piperi din] amine (S)-1'—(6-amin0-5 -((2-amin0-3 -ch1 0r0pyridiny1)thi0)pyrazin-2 -y1) - 6-(1,4-dimethyl-1H-1,2,3 -triazol-5 -y1)-1,3 -dihydr0Spiro [indene-2,4 '-p i n eridin]—1-amine 1'—(6-amin0-5 -((2-amin0-3 0p yridiny1)thi0)pyraziny1)(n1 ethylthio) -1 , 3 -dihydr0Spiro[indene -2,4'—piperidin]—1-amine 2-(1-arnin0-1'-(6-amin0((2-amin 0-3 -ch10r0pyridiny1)thi0)pyrazi )-1,3 -dihydr0Spiro[indene-2, 4'-piperidin] y1)pr0pan01 (S)(1-amin0-1'—(6-amin0-5 -((2-a mino-3 -ch10r0pyridinyl)thi0)pyr aziny1)-1 ,3 -dihydrospir0 [indene 0 r0 n ail-2 -01 1'—(6-amin0-5 -((2-amin0-3 -ch10r0p yridiny1)thi0)pyrazinyl)(m ethylsulfonyl) -1 , 3 r0spiro [in dene-2,4'-piperidin]amine N-(1-amin0-1'—(6-amin0-5 -((2-ami n0-3 0pyridinyl)thi0)pyraz in-2 -y1) - 1 ,3 -dihydr0Spiro [indene-2, 4'-piperidin] y1)acetamide (S)-N—(1-amin0-1'—(6-amin0-5 -((2- amino-3 -ch10r0pyridiny1)thi0)p yraziny1)- 1 ,3 -dihydr0Spiro [inde o i n eridin] -6 - 1 acetamide 1-arnin0-1'—(6-amin0-5 -((2-amin0ch10r0pyridiny1)thi0)pyrazin- 2-y1)-1 ,3 -dihydr0Spiro [indene-2,4'— 0 i n eridine] carb0xamide amin0-5 -((2-amin0-3 -ch10r0p yridiny1)thi0)pyraziny1)(c yclopentyloxy)- 1 ,3 -dihydr0Spiro [in dene-2,4'-piperidin]amine (S)-1'—(6-amin0-5 -((2-amin0-3 -ch1 0r0pyridiny1)thi0)pyrazin-2 -y1) - 6-(cyclopentyloxy)-1,3 -dihydr0spir 0 [indene-2,4'— n i n eridin] -1 -amine (S)amin0-1'—(6-amin0-5 mi n0-3 -ch10r0pyridinyl)thi0)pyraz in-2 -y1) -3H-spiro [indolizine-2,4'—pi peridin]—7(1H)-0ne 1-amin0-1'-(6-amin0((2-amin0ch10r0pyridiny1)thi0)pyrazin- 2-yl) -5 -flu0r0-1,3 -dihydr0Spiro [ind 4'—piperidin] 01 amin0-1'—(6-amin0-5 -((2-ami n0-3 -ch10r0pyridinyl)thi0)pyraz iny1)-5 -flu0r0-1,3 -dihydr0spir0[ indene-2,4' n i n eridin]—6-01 1'—(6-amin0-5 -((2-amin0-3 -ch10r0p yridiny1)thi0)pyrazinyl)-5 ,7 - dihydro- 1 H-spiro [cyclopenta[1]in ole-6,4'-piperidin] amine (S)-1'—(6-amin0-5 -((2-amin0-3 -chl 0r0pyridiny1)thi0)pyrazin-2 -y1) - ,7-dihydr0-1H-spir0[cyclopenta[f ]indole-6,4'-piperidin]amine 1'—(6-amin0-5 -((2-amin0-3 -ch10r0p y1)thi0)pyrazinyl)-5 ,7 - dihydr0-1H-spir0[inden0[5 ,6-d]imi dazole-6,4'— n i n eridin]—7-amine (S)-1'—(6-amin0-5 -((2-amin0-3 -ch1 0r0pyridiny1)thi0)pyrazin-2 -y1) - ,7-dihydr0-1H-spir0[inden0[5 ,6-d ]imidazole-6,4' n i n eridin] amine 1'—(6-amin0-5 -((2-amin0-3 -ch10r0p y1)thi0)pyraziny1)(1 H-tetrazol-S-y1)-1,3 -dihydr0Spiro [i ndene-2,4'—piperidin]—1-amine (S)-1'—(6-amin0-5 min0-3 -ch1 0r0pyridiny1)thi0)pyrazin-2 -y1) - 6-(1H-tetrazol-5 ,3 -dihydrospi r0 [indene-2,4'— n i n eridin]—1-amine 1-(1-amin0-1'—(6-amin0-5 -((2-amin 0-3 -ch10r0pyridiny1)thi0)pyrazi ny1)-1,3 -dihydr0Spiro[indene-2, 4'—piperidin]—6-yl)methylurea (S)(1-amino-1'-(6-amino((2-a mino-3 -chloropyridinyl)thio)pyr azinyl)-1 ,3 rospiro [indene -2,4 '-piperidin] -6 -yl) -3 -methylurea (R) -1 '-(5 -((2-amino-3 -chloropyridi nyl)thio)pyrazinyl) -2,3 -dihyd rospiro[indene-1,4'—piperidin]—2-a PHARMACOLOGICAL TESTING Example A. atase Assay (single dose inhibition) Assay ol: For single dose inhibition assays using 6,8-difluoromethy1umbelliferyl phosphate (DiFMUP) as a substrate, SHP2 samples (diluted to 0.5 nM in reaction buffer) were incubated with dPEG8 peptide for 30 min in reaction buffer[60 mM 3,3-dimethy1 glutarate (pH7.2), 75 mM NaCl, 75 mM KCl, and 1 mM EDTA, 0.05% Tween 20, 2mM dithiothreitol (DTT) ] to active the FTP.
DMSO [0.5% (v/v)] or nds (100nM) were added to the mixture and incubated for 30 min at room temperature. Reactions were initiated by the addition of DiFMUP (12 uM; total reaction volume of 100 uL), and the fluorescence (excitation at 340 nm, emission at 450 nm) of the resulting solutions was measured on a 2104-0020 EnVision Xcite Multilabel Reader (PerkinElmer) after 30min. The ment is carried out in triplicate. The value for the control sample (DMSO) was set to 100%, and the values for the compound-treated samples were expressed as activity relative to the control sample. The inhibition of SHP2 by compounds of the ion were shown in table A Table A SHP2 inhibition SHP2 inhibition SHP2 inhibition Example Example Example 1uM (%)@0.1uM (%)@0.1uM SHP2 inhibition SHP2 inhibition SHP2 inhibition Example e Example (%)@0.111M (%)@0.111M (%)@0.111M 18 35 48 81 81 75 19 49 85 2 2 50 77 21 51 22 53 23 54 24 56 57 SHP2 inhibition SHP2 inhibition SHP2 inhibition Example Example (%)@0~1HM (%)@0.1uM (%)@0.1uM us In e B. Phosphatase Assays (IC50) ICso values were estimated using 6,8-difluoromethylumbelliferyl phosphate (DiFMUP) as a substrate, SHP2 s (diluted to 0.5 nM in reaction buffer) were incubated with dPEG8 peptide for 30 min in reaction buffer[60 mM 3,3-dimethy1 ate (pH7.2), 75 mM NaCl, 75 mM KCl, and 1 mM EDTA, 0.05% Tween 20, 2mM threitol (DTT) ] to active the FTP. DMSO [0.5% (v/v)] or compounds (concentrations ranging from 0.3 nM to 1 uM) were added to the mixture and incubated for 30 min at room temperature. Reactions were initiated by the addition of DiFMUP (12 uM; total reaction volume of 100 uL), and the cence (excitation at 340 nm, emission at 450 nm) of the resulting solutions was measured on a 2104-0020 EnVision Xcite Multilabel Reader (PerkinElmer) after 30min. The IC50 results of the compounds of the invention were shown by table B.
Table B Example C. Cell eration Assay MV11 (4000 cells/well) were plated onto 96-well plates in 100uL medium (IMDM containing 3% FBS, Gibco). For drug treatment, compounds of the invention at various concentrations were added 24 hours after cell plating. At day 8, 30uL MTS/PMS reagents (Promega/Sigma) were added, and the absorbance value was determined according to the supplier's instruction (Promega). The IC50 results of the compounds of the invention were shown by table C.
Table C Example D. p-ERK cellular assay ERKl/2 activation is determined by immunoblotting analysis of cell lysates with an anti-p-ERK1/2 antibody. In brief, MV—4-11 cells were d with a series of compounds ntrations ranging from 0.3 nM to 100 nM) for 2 hours. Total protein was extracted using a RIPA buffer with Halt Protease tor Cocktail (Thermo Fisher Scientific, Rockford, IL, USA). uL of total protein was resolved by SDS-PAGE under reducing conditions and transferred onto polyvinylidene difluoride membranes (Bio-Rad). After blocking in Tris-buffered saline containing % BSA, the ne was incubated overnight with primary antibodies at 4°C, followed by l h incubation with horseradish peroxidase (HRP)-conjugated secondary antibody. The bound secondary antibody was detected using chemiluminescence.
Example E. MV—4-11 xenograft model MV—4-ll cells were expanded in culture, harvested and injected subcutaneously into 5-8 week old female NOD/SCID mice (5X 106 cells/each mouse, n=6-lO/group). Subsequent administration of compound by oral gavage (0.1-10 mpk/dose) started when the mean tumor size reached approximately 100-200 mm3. During the treatment(once or twice a day for 2-4 weeks), the tumor volumes were measured using a caliper. Statistical analysis of difference in tumor volume among the groups were ted using a one-way ANOVA. Vehicle alone was the negative control.
The compounds of the present invention are preferably formulated as pharmaceutical compositions administered by a y of . Most preferably, such compositions are for oral administration. Such pharmaceutical compositions and processes for preparing the same are well known in the art. See, e.g., REMINGTON: THE SCIENCE AND CE OF PHARMACY (A. Gennaro, et al, eds., 19th ed., Mack Publishing Co., 1995). The compounds of Formula I, II, III or IV are generally effective over a wide dosage range.
In summary, the most of compounds descripted here is very potent and selective, with IC50 below 10 nM. They also showed a great anti-tumor efficacy in in vivo . For example, dosages per day normally fall within the range of about 0.2 mg to about 100 mg total daily dose, preferably 0.2 mg to 50 mg total daily dose, more preferably 0.2 mg to 20 mg total daily dose. In some instances dosage levels below the lower limit of the aid range may be more than adequate, while in other cases still larger doses may be employed. The above dosage range is not intended to limit the scope of the invention in any way. It will be understood that the amount of the compound actually administered will be ined by a physician, in the light of the nt circumstances, including the condition to be d, the chosen route of stration, the actual nd or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.
THE

Claims (134)

1. l. A compound of Formula I or pharmaceutically acceptable salt thereof: Wherein, Each R1 is independently -H, halogen, -NH2, -CN, —OH, -N02, carboxyl, substituted or unsubstituted -C1_6alkoxy, or substituted or unsubstituted -C1_6alkyl; R2 is -H, halogen, -NH2, -CN, -OH, -N02, -N3, carboxyl, -NHC1_6alkyl, 6alkyl)2, -CONH2, -CONHC1_6alkyl, -CON(C1_6alkyl)2, 6alkyl, -NHCOC1_6alkyl, alkyl-CO-C1_6alkyl, substituted or tituted -C1_6alkoxy, substituted or unsubstituted -C1_6alkyl or -C5_1oheterocyclic; or R2 combines With R1 to which is adjacent to form a 6-10 membered aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclic ring, and each of the ring systems is ndently ally substituted; Each Y1 is independently N or CRla; Each Rla is independently -H, halogen, -NH2, -CN, -OH, -N02, carboxyl, substituted or unsubstituted -C1_6alkoxy, or substituted or tituted -C1_6alkyl; R3 is -H or -NH2; Each of R43 and R413 is independently -H, halogen, -NH2, —CN, -OH, -N02, carboxyl, substituted or unsubstituted -C1_6alkoxy, or substituted or unsubstituted -C1_6alkyl; or R43 and R41J together with the carbon atom to which they are both attached form CO, C=NH, or C=N-OH; pisO, 1,20r3; Each of R53 and R51J is independently -H, halogen, -NH2, -CN, -OH, -N02, carboxyl, substituted or unsubstituted —C1_6alkoxy, or substituted or unsubstituted -C1_6alkyl; or R5a and R51, together with the carbon atom to which they are both attached form a 3- 10 membered heterocyclic or 5-10 ed heteroaryl or C=NR5C, and R50 is -H, or -C1_6alkyl; and each of the ring systems is independently optionally substituted; qisO, 1,2,3 or4; W is absent, -0, -S or -NRW; and RW is -H, halogen, -NH2, —CN, -OH, -NO2, carboxyl, -CO-C1_6alkyl, -CO-OC1_6alkyl, -C1_6alkyl-O- Cmalkoxy, substituted or unsubstituted -C1-6alkoxy, or tuted or unsubstituted -C1.6alkyl; Ring A is absent or a 3-10 ed ring; = represents a single bond or a double bond; When ring A is absent, Y2 is CR2aR2b, NR2a or O, and Y3 is CR3aR3b, NR3a or 0; When ring A is a 3-10 membered ring, i) Y2 is CR2a or N, and Y3 is CR3a or N, when = represents a single bond; or ii) Y2 is C, and Y3 is C, when = represents a double bond; Each of R281 and R21, is independently -H, n, —NH2, -CN, -OH, -NO2, carboxyl, substituted or unsubstituted -C1_6alkoxy, or substituted or unsubstituted -C1_6alky1; Each of R3a and R31, is independently -H, halogen, -NH2, -CN, -OH, -NO2, carboxyl, substituted or unsubstituted -C1_6alkoxy, or substituted or unsubstituted -C1_6alky1; Each R6 is independently -H, halogen, -NR63R6b, -CN, -OH, -NO2, oxo, =0, carboxyl, -C1_6alkoxy, -C1_6alkyl, -C1_6alkylene-NR63R6b, -C1_6alkylene-O-C1-6alkyl, -C1_6alkylene-CO-OR63, -C1-6alkylene—C3_1oheterocyclic, -C1-6alkylene-C5_loheteoaryl, -C1_6alky1ene-CO-NR63R6b, -C1-6alkylene—NR63—CO-NR63R6b, -C1-6alky1ene-NR6a-CO-C1-6alkyl, -CO-NR63R6b, -CO-CO-NR63R6b, -C3_1ocarbocyclic, -C3_1oheterocyclic, -CO-C1_6alkyl, _6alkylene-NR63R6b, -CO-NR63-C3_1oheterocyclic, -CO-NR63-C3_loheterocyclic, -CO-C3_10heteocyclic, -O-C1_6alkylene-CO-OR63, -O-C1-6alky1ene-CO-NR63R6b, -O—C16alkylene-NR63R6b, -O-C3_locarbocyclic, -O-C3_10heterocyclic, -NR63-CO-C1_6alkyl, -NR63-CO-NR63R6b, CO-C5_10heteoaryl, -NR6a-C1-6alkylene-NR63R6b, C1-6alkylene-C3-loheterocyclic, -NR63-C1-6alkylene-C5_loheteroaryl, -NR63-SO2C1_6alkyl, -S-C]_6a1ky1, -SONR63R6b, -SO2NR63R6b, -SO-C1_6alkyl, -SO2C1_6alkyl, -PO(C1_6alky1)2, -PO(C1_6alkoxy)2, -C3_1oheterocyc1ic or —C5_1oheteroaryl; each of which is independently ally substituted; and n is 0, 1, 2, 3, 4, 5 or 6; or Two nt R6 can be joined together to form a 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, -C3_6heterocyclic or -C3_6carbocyclic, wherein each of the ring s is independently optionally substituted; Each of R621 and R6b is independently -H, halogen, -NH2, -CN, -OH, -N02, carboxyl, substituted or unsubstituted -C1_6alkoxy, or substituted or unsubstituted lkyl.
2. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein: Each R1 is independently -H, halogen, -NH2, -CN, -OH, -N02, carboxyl, substituted or unsubstituted -C1-6alkoxy, or substituted or unsubstituted C1_6a1ky1; R2 is -H, halogen, -NH2, -CN, -OH, -N02, -N3, yl, -NHC1_6alkyl, -N(C1_6alkyl)2, -CONH2, -CONHC1_6alkyl, —CON(C1_6alkyl)2, -COC1_6alkyl, -NH-CO-C1_6alkyl, -NC1-6alkyl-CO-C1_5alkyl, substituted or unsubstituted -C1_6alkoxy, substituted or unsubstituted -C1_6alkyl or heterocyclic; or R2 combines with R1 to which is adjacent to form a 5-10 membered aryl or 5-10 membered heterocyclic ring, and each of the ring systems is independently optionally substituted; Each Y1 is independently N or CRla; Each R13 is independently -H, halogen, -NH2, —CN, -OH, -N02, carboxyl, substituted or unsubstituted -C1_6alkoxy, or substituted or unsubstituted lkyl; R3 is -H or -NH2; Each of R43 and R4b is independently —H, halogen, -NH2, -CN, -OH, -N02, carboxyl, substituted or unsubstituted -C1_6alkoxy, or tuted or unsubstituted lkyl; or R4,, and R4, together with the carbon atom to which they are both attached form CO; pis0,1,2or3; Each of R521 and R51) is ndently -H, halogen, -NH2, -CN, -OH, -N02, carboxyl, substituted or unsubstituted -C1_6alkoxy, or substituted or unsubstituted -C1_6alkyl; or R5,, and R513 together with the carbon atom to which they are both attached form a 3-10 membered heterocyclic or 5-10 membered heteroaryl; and each of the ring systems is independently optionally substituted; qis 1,2,3 or4; W is absent, 0, NRW or S; RW is -H, halogen, -NH2, -CN, -OH, —NO2, carboxyl, -CO-C1_6alkyl, -CO-OC1_6alkyl, substituted or unsubstituted -C1_6alkoxy, or tuted or unsubstituted lkyl; Ring A is absent or a 3-10 rnernbered ring; = represents a single or double bond; When ring A is absent, Y2 is -CR2aR2b, -NR2a or -O, and Y3 is -CR3aR3b, -NR3a or 0; When ring A is a 3-10 membered ring, i) Y2 is CR2a or N, and Y3 is CR3a or N, when = represents a single bond; or ii) Y2 is C, and Y3 is C = represents a double bond; , when Each of R2a and R2!J is independently -H, n, -NH2, -CN, -OH, -NO2, carboxyl, substituted or unsubstituted lkoxy, or substituted or unsubstituted -C1_6alky1; Each of R33 and R31) is independently -H, halogen, -NH2, -CN, -OH, -NO2, yl, substituted or unsubstituted -C1_6alkoxy, or substituted or unsubstituted -C1_6alkyl; Each R6 is independently -H, halogen, 6b, -CN, -OH, -NO2, 0X0, =0, carboxyl, -C1_6alkoxy, -C1_6alkyl, -C1_6alkylene-NR63R6b, -C1_6alkylene-O-C1-6alkyl, -C1_6alkylene-CO-OR63, -C1-6alkylene-C3_1oheterocyclic, -C1-6alkylene-C5_loheteoaryl, -C1_6alkylene-CO-NR63R6b, -C1-6alkylene-NR63—CO—NR6aR6b, -C1-6alkylene-NR6a-CO-C1-6alkyl, -CO-NR63R6b, —CO-CO-NR6aR6b, -CO-C1_6alkyl, -CO-C1_6alkylene-NR63R6b, 6a-C3_1oheterocyclic, -CO-NR63-C3_1oheterocyclic, -CO-C3_1oheteocyclic, -O-C1_6alkylene—CO-OR63, -O-C1-6alkylene-CO-NR63R6b, -O-C1_6alkylene-NR63R6b, -O-C3_1ocarbocyclic, -NR6a-CO-C1_6alkyl, -NR63-CO-NR63R6b, -NR6a-CO-C5_10heteoaryl, -NR6a-C1-6alkylene-NR63R6b, -NR6a-C1-6alkylene-C3_loheterocyclic, -NR63-C1-6alkylene-C5_1oheteroaryl, -S-C1_6alkyl, -SONR63R6b, -SO2NR6aR6b, -SO-C1_6alkyl, -SO2C1_6alkyl, -PO(C1_6alkyl)2, -C3_1oheterocyclic or -C5_10heteroaryl, wherein each of which is independently optionally substituted; and n is 0, 1, 2, 3, 4, 5 or 6; or Two adjacent R6 can be joined together to form a ered aryl, 5-membered heteroaryl, 6-membered heteroaryl, -C3-6heterocyclic or -C3-6carbocyclic, wherein each of the ring system is independently optionally substituted; Each of R63 and R6b is ndently -H, halogen, -NH2, -CN, -OH, -NO2, carboxyl, substituted or unsubstituted -C1_6alkoxy, or substituted or unsubstituted -C1_6alky1.
3. The compound or pharmaceutically able salt thereof of claims lor 2, wherein each R1 is independently -H; -F; -Cl; -Br; -NH2; -CN; -OH; -N02; carboxyl; -C1_6alkyl; -C1_6alkoxy; -C1_6alkyl substituted with halogen, -NH2, -CN, -OH, -N02, carboxyl, -C1_3alkyl or -C1_3alkoxy; or -Cmalkoxy substituted with halogen, -NH2, -CN, -OH, -N02, carboxyl, lkyl or -C1_3alkoxy.
4. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-3, wherein each R1 is independently -H; -F; —Cl; -Br; -NH2; —CN; -OH; -N02; carboxyl; -C1_3alkyl; -C1_3alkoxy; -C1_6alkyl tuted with -F, -Cl, -Br, -I, -NH2, -CN, -OH, -N02, carboxyl, -C1_3alkyl or -C1_3alkoxy; or -C1_6alkoxy substituted with -F, -Cl, -Br, -I, -NH2, -CN, -OH, -N02, carboxyl, -C1_3alkyl or -C1_3alkoxy.
5. The compound or pharmaceutically able salt thereof of any one of claims 1-4, wherein each R1 is independently -H; -F; -Cl; -Br; -NH2; -CN; -OH; -N02; carboxyl; methyl; ethyl; propyl; isopropyl; methoxy; ; propoxy; poxy; lkyl substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; or C1_3alkoxy substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, methyl, ethyl, , isopropyl, y, ethoxy, propoxy or isopropoxy.
6. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-4, wherein each R1 is independently -H; -F; -Cl; -Br; -NH2; -CN; -OH; methyl; ethyl; propyl; isopropyl; methoxy; ethoxy; propoxy; isopropoxy; or methyl tuted with one or more substituents each independently selected from -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
7. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-6, wherein each R1 is independently -C1, or -H.
8. The nd or pharmaceutically acceptable salt thereof of any one of claims 1-7, wherein R2 is -H; -F; -Cl; -Br; -NH2; -CN; -OH; -N02; -N3; yl; —C1_6alkyl; -C1-6alkoxy; -NHC1-6alkyl; -N(C1.6alkyl)2; -CONH2; -CONHC1.6alkyl; -CON(C1-6alkyl)2; -COC1.6alkyl; -NHCOC1.6alkyl; -N(C1-6alkyl)-CO-C1-6alkyl; -C5-1oheterocyclic; -C1.6alkyl substituted with halogen, -NH2, -CN, -OH, -N02, carboxyl, -C1_3alkyl or -C1_3alkoxy; or -C1_6alkoxy substituted with halogen, -NH2, -CN, —OH, -NOZ, carboxyl, -C1_3alkyl or -C1_3alkoxy.
9. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-8, wherein R2 is -H; -F; -Cl; -Br; —NH2; -CN; -OH; -NO2; -N3; carboxyl; -C1_3alkyl; -C1_3alkoxy; -NHC1_3alkyl; -N(C1_3alkyl)2; -CONH2; -CONHC1_3alkyl; -CON(C1_3alkyl)2; -COC1_3alkyl; 1_3alkyl; -N(C1-3alkyl)-CO-C1_3alkyl; -C5_10heterocyclic; -C1_6alkyl tuted with -F, -Cl, -Br, -I, -NH2, -CN, -OH, -NO2, carboxyl, lkyl or -C1_3alkoxy; or -C1_6alkoxy substituted with -F, —Cl, -Br, -I, -NH2, -CN, -OH, —NO2, carboxyl, -C1_3alkyl or -C1_3alkoxy.
10. The compound or ceutically acceptable salt thereof of any one of claims 1-9, n R2 is -H; -F; -Cl; -Br; -NH2; -CN; -OH; -NO2; -N3; carboxyl; methyl; ethyl; propyl; pyl; methoxy; ethoxy; propoxy; isopropoxy; -NHCH3; -N(CH3)2; -CONH2; -CONHCH3; -CON(CH3)2; -COCH3; —NH—COCH3; )-COCH3; ED “0; ; E‘S‘N/fi ‘ng 0; K/Nx; -C1_3alkyl substituted with -F, -Cl, —Br, -NH2, -CN, -OH, -NO2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or poxy; or C1_3alkoxy substituted with -F, -Cl, -Br, -NH2, —CN, —OH, -NO2, carboxyl, methyl, ethyl, propyl, isopropyl, y, ethoxy, propoxy or isopropoxy.
11. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-10, wherein R2 is -H; -F; -Cl; -Br; -NH2; -CN; -OH; -NO2; carboxyl; methyl; ethyl; propyl; isopropyl; methoxy; ethoxy; propoxy; isopropoxy; or methyl substituted with one or more substituents each independently selected from -F, -Cl, -Br, -NH2, -CN, -OH, -NO2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
12. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-1 1, wherein R2 is -NH2.
13. The compound or pharmaceutically able salt thereof of claim 1-7, wherein R2 combines with R1 to which is adjacent to form a 5-10 membered heteroaryl or 5-10 membered heterocyclic ring, and each of the ring systems is independently optionally substituted with halogen, -NH2, -CN, -OH, -NO2, carboxyl, oxo, =0, -CONH2, substituted or unsubstituted lkoxy, tuted or unsubstituted -C1_6alkyl, -C1-6alkylene-O-C1_6alkyl, -C1_6alkylene-COOH, -C16alkylene-NHCONH2, -CO-N(C1_6alky)2, -C1-6alky1ene-NHCO-C1-6alkyl, -CO-CO-N(C1_6alkyl)2, -CO-C1_6alky1, -SONH2, -SO2NH2, -SOCH3, -SO2CH3, -C5_1oheterocyclic or -C5_1oheteroaryl.
14. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-7 or 13, wherein R2 combines with R1 to which is adjacent to form a 5-membered heteroaryl, 6-membered heteroaryl, "i-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, S-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 8-membered heterocyclic or 9—membered cyclic; and each of the heteroaryl or heterocyclic contains 1 or 2 heteroatoms selected from N or O; and each of the ring s is independently optionally substituted with -F, -Cl, -Br, -I, -NH2, -CN, -OH, -NO2, carboxyl, oxo, =0, -CONH2, substituted or unsubstituted C1_3alkoxy, tuted or unsubstituted C1_3alkyl, -C1_3alkylene-O-C1_3alkyl, -C1_3a1ky1ene-COOH, -C1_3alkylene-NHCONH2, C1_3alky)2, -C1_3alkylene-NHCO-C1-3alkyl, -CO-CO-N(C1_3alkyl)2, -CO-C1_3alkyl, -SONH2, -SO2NH2, -SOCH3 or -SO2CH3.
15. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-7 or 13-14, wherein R2 combines with R1 to which is adjacent to form a 5-membered heteroaryl, ered aryl, 7-membered heteroaryl, 8-membered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic or 8-membered heterocyclic; and each ofthe heteroaryl or heterocyclic contains 1 heteroatom selected from N or O; and each of the ring s is independently optionally substituted with -F; -Cl; -Br; -NH2; -CN; -OH; -NO2; yl; oxo; =0; -CONH2; methyl; ethyl; propyl; isopropyl; methoxy; ethoxy; propoxy; isopropoxy; -CH2OCH3; -CH2COOH; -CH2NHCONH2; H3)2; -CH2NHCOCH3; -CO-CON(CH3)2; ; -C1_3alkyl substituted with halogen, -NH2, -CN, -OH, -N02 or yl; or -C1_3alkoxy substituted with halogen, -NH2, -CN, -OH, -N02 or carboxyl.
16. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-7 or 13-15, wherein R2 combines with R1 to which is adjacent to form a 5-membered cyclic, and optionally substituted with -F or -COCH3.
17. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-7 or 13-16, R2, and R1 which is nt to, er with the aromatic ring they are attached to formaj/Ni?.
18. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-17, wherein each Y1 is ndently N or CH.
19. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-18, wherein each of R421 and R41) is independently -H, -F, -Cl, -Br, -I, -NH2, -CN, -OH, -N02, yl, substituted or unsubstituted -Cmalkoxy, or substituted or unsubstituted -C1_6alky1; or R4,, and R4, together with the carbon atom to which they are both ed form C=O, C=NH, or C=N-OH.
20. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-19, wherein each ofR43 and R4;J is independently -H; -F; -Cl; -Br; -NH2; -CN; -OH; -N02; carboxyl; -C1_3alkyl; -C1_3alkoxy; -C1_6alkyl substituted with -F, -Cl, -Br, -I, -NH2, -CN, -OH, -N02, carboxyl, -C1_3alkyl or -C1_3alkoxy; or C1_6alkoxy substituted with -F, -Cl, -Br, -I, -NH2, -CN, -OH, -N02, carboxyl, -C1_3alkyl or -C1_3alkoxy; or R4a and R4, together with the carbon atom to which they are both attached form C=O.
21. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-20, wherein each of R4a or R4, is independently —H; —F; -Cl; -Br; -NH2; -CN; -OH; -N02; carboxyl; methyl; ethyl; propyl; isopropyl; methoxy; ethoxy; propoxy; isopropoxy; kyl substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, methyl, ethyl, propyl, pyl, y, ethoxy, propoxy or isopropoxy; or C1_3alkoxy substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, methyl, ethyl, propyl, pyl, y, ethoxy, propoxy or isopropoxy; or R4,, and R4, together with the carbon atom to which they are both attached form C=O.
22. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-21, wherein each of R421 and R41) is independently -H, -NH2, -OH, methyl, ethyl, methoxy, ethoxy; or R4,, and R413 together with the carbon atom to which they are both attached form C=O.
23. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-22, wherein p is 0, l, 2 or 3.
24. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-23, wherein each of R561 and Rsb is ndently -H; -F; -Cl; -Br; -I; -NH2; -CN; -OH; -N02; carboxyl; -C1_3alkyl; -C1_3alkoxy; -C1_6alkyl substituted with -F, -Cl, -Br, -I, -NH2, -CN, -OH, -N02, yl, lkyl or —C1_3alkoxy; or -C1_6alkoxy substituted with -F, -Cl, -Br, -I, -NH2, -CN, -OH, -N02, carboxyl, -C1_3alkyl or -C1_3alkoxy; or R521 and R5b together with the carbon atom to which they are both attached form 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 8-membered heterocyclic, 9-membered heterocyclic, S-membered heteroaryl, 6—membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl or 9-membered heteroaryl; and each of the heterocyclic or heteroaryl contains 1 or 2 heteroatoms selected from N or O; and each of the ring systems is independently optionally substituted with -H, -F, -Cl, -Br, -I, -NH2, -CN, -OH, -N02, yl, substituted or unsubstituted -C1_3alkoxy, or substituted or unsubstituted -C1_3alkyl.
25. The compound or pharmaceutically acceptable salt f of any one of claims 1-24, wherein each of R53 or R51, is independently -H, -NH2, -OH, , ethyl, methoxy or ethoxy; or R5a and R5b together with the carbon atom to which they are both attached form a 3-membered heterocyclic, 4-membered cyclic, 5-membered heterocyclic, 6-membered heterocyclic, 5-membered aryl or 6-membered heteroaryl; and each of the heterocyclic or heteroaryl contains 1 heteroatoms selected from N or O.
26. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-25, wherein each of R53 or R5b is independently -H or -NH2.
27. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-26, wherein W is absent, 0, or NRW.
28. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-27, n W is NRw, and RW is -H, -F, -Cl, -Br, -I, -NH2, -CN, -OH, -N02, yl, -CO-C1_3alkyl, -COOC1_3alkyl, -C1_3alkyl-CO-C1_3alkyl, substituted or unsubstituted lkoxy, or substituted or unsubstituted -C1_3alkyl.
29. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-28, wherein W is NRw, and RW is -H; -F; -Cl; -Br; -NH2; -CN; -OH; -N02; carboxyl; methyl; ethyl; propyl; isopropyl; methoxy; ethoxy; y; isopropoxy; methyl-CO- methyl; -C1_3alkyl substituted with -F, -Cl, -Br, —NH2, -CN, -OH, -N02, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, , propoxy or isopropoxy; or C1_3alkoxy substituted With -F, -Cl, -Br, -NH2, -CN, -OH, -NO2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, y or isopropoxy.
30. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-29, wherein ring A is ered aryl, 7-membered aryl, 8-membered aryl, 9-membered aryl, lO-membered aryl; 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered aryl, 9-membered heteroaryl, 10-membered heteroaryl; 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 8-membered heterocyclic, 9-membered heterocyclic, 10-membered heterocyclic; 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic, ered carbocyclic, ered carbocyclic, 8-membered carbocyclic, 9-membered yclic or 10-membered carbocyclic; and each ofthe heteroaryl ns 1, 2 or 3 heteroatoms selected from N, O or S; each of the heterocyclic contains 1, 2 or 3 heteroatoms selected from N or O.
31. The nd or pharmaceutically acceptable salt thereof of any one of claims 1-30, Wherein ring A is 6-membered aryl, 7-membered aryl, 8-membered aryl; 5-membered heteroaryl, 6-membered heteroaryl, 7—membered heteroaryl, 8-membered heteroaryl; 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 8-membered heterocyclic; 3-membered carbocyclic, 4-membered carbocyclic, S-membered carbocyclic, 6-membered carbocyclic, 7-membered carbocyclic or 8—membered carbocyclic; and each of the aryl contains 1 or 2 heteroatoms selected from N, O or S; each of the heterocyclic contains 1 or 2 heteroatoms selected from N or O.
32. The compound or pharmaceutically able salt f of any one of claims 1“ Eb ‘1‘“ WV" NH T; 1-31,WhereinringAis}1]>, "N 24“ ,AE,I?5]:I \g‘ ,AQ,}LD,’\r‘éN ‘5? n JED/E ”:1 ~: ~; :s‘ ‘5 x; 12" a“ 5 3‘ 2r“ sir“ 2w 2 371 393 £0,371 ,93 a]? a, a a, 1"’SN *3 FSN’O 5N4 3N g“ ‘3‘ H \ H g N “x (Kin) AL° 2L8 g‘ 213 :1399/ ‘3’ AJVNH ‘LH EU ° AL} :2 lg? :LJQ \gs H x; H H , \eg/ L :LHH, H0iLLLL ~H, :::L L :L, :L\ \ :LN, :12), :QN :11):LN/‘NH jig)filo/NHW531? :LNH;1:>5:? 7::0 H: N ”” 20m in,2: ANH g‘NH\| P{N ,2L»,. 0,2302U,2L1,2Lo, :132%5213,2123 QfiU 20 224032 \,2N',2~/' 223, 2:03;; 2\:TVN5T3 3H2]? 21222C3 2f} iiiwwmh,2122;252:251,L2232L‘i,2©°,:2©,2 , :0: 0023000000 2 “ingiCariiQ
33. The compound or pharrnaceutically acceptable salt f of any one of claims ‘N 2‘ 5w 5" l-32,WhereinringA1s 22>}w]: :36 11:130220,3,:\N \‘ef/LLQLLLLULL‘ng “ O is“ s ~ ~ \_N \ N\ I“; ‘3‘ orig?‘3: N
34. The compound or pharmaceutically able salt thereof of any one of claims 1-33, Y2 is CR2a or N, and Y3 is CR3a or N.
35. The compound or pharrnaceutically acceptable salt thereof of any one of claims 1-34, Y2 is CR2a and Y3 is CR3a.
36. The compound or pharrnaceutically acceptable salt thereof of any one of claims 1-35, wherein each of Rza and R2b is independently -H; -F; -Cl; -Br; -NH2; -CN; -OH; -N02; carboxyl; -C1_3alkyl; -C1_3alkoxy; -C1_6alkyl substituted with -F, -Cl, -Br, -I, -NH2, -CN, -OH, -NO2, carboxyl, -C1_3alkyl or -C1_3alkoxy; or -C1_6alkoxy substituted with -F, -Cl, -Br, -I, -NH2, -CN, -OH, -NO2, carboxyl, —C1_3alkyl or -C1_3alkoxy.
37. The compound or pharmaceutically acceptable salt thereof of claim 36, wherein each of R221 and R2b is independently -H; -F; -Cl; -Br; -NH2; -CN; -OH; -NO2; yl; methyl; ethyl; propyl; isopropyl; methoxy; ethoxy; y; isopropoxy; -C1_3alkyl substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -NO2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, , y or isopropoxy; or -C1-3alkoxy substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -NO2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
38. The compound or pharmaceutically acceptable salt thereof of claim 36 or 37, wherein each of R2a and R21, is independently -H or methyl.
39. The compound or pharmaceutically acceptable salt thereof of any one of claims 36-3 8, wherein R2a is -H or methyl, and R2b is -H.
40. The compound or pharmaceutically acceptable salt thereof of any one of claims 36-3 9, n R2a and R2b are both -H.
41. The compound or ceutically acceptable salt f of any one of claims 1-35, wherein Y2 is CH or N, and Y3 is CH or N.
42. The compound or pharmaceutically acceptable salt thereof of claim 41, wherein Y2 is CH, and Y3 is CH.
43. The compound or pharmaceutically acceptable salt f of claim 41, wherein Y2 is CH, and Y3 is N.
44. The compound or pharmaceutically acceptable salt thereof of claim 41, wherein Y2 is N, and Y3 is CH.
45. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-40, wherein each of R33 and R3b is independently -H, -F, -Cl, -Br, -NH2, -CN, -OH, -NO2, carboxyl, -C1_3alkyl, -C1_3alkoxy, or -C1_6alky1 or —C1_6alkoxy substituted with -F, -Cl, -Br, -I, -NH2, -CN, -OH, -NO2, yl, -C1-3alkyl or -C1-3alkoxy.
46. The compound or pharmaceutically acceptable salt f of claim 45, wherein each of R3a and R31J is independently -H.
47. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-35 and 41-44, wherein each R6 is independently -H, -F, -Cl, -Br, -I, -NR6aR6b, -CN, -OH, OX0, =0, carboxyl, -C1_6alkoxy, -C1_6alkyl, -C1_6alkylene-NR63R6b, -C1-6alkyleneC1_6alkyl, -C1_6alkylene—C0-0R63, -C1-6alkylene-C5_loheterocyclic, -C1-6alkylene-C5_loheteoaryl, -C1_6alkylene-C0-NR63R6b, -C1-6alkylene-NRéa-CO-NR63R6b, -C1-6alkylene-NR6a-C0-C1-6alkyl, -CO-NR63R6b, -C0-C0-NR63R6b, -C0-C1_6alkyl, _6alkylene-NR63R6b, -C0-NR63-C5_loheterocyclic, -C0—NR63-C5_1oheterocyclic, -C0-C5_10heterocyclic, C1_6alkylene-C0-0R6a, 6alkylene-C0—NR63R6b, C1-6alkylene-NR63R6b, C5.1ocarbocyclic, -NR6a-C0-C1.6alkyl, -NR63-C0-NR63R6b, -NR68-C0-C5_10heteoaryl, -NR63-Cl-6alkylene-NR63R6b, -NR53-C1.6alkylene-C3_loheterocyclic, -NR63-C1.6alkylene-C5_1oheteroaryl, -S-C1_6alkyl, -SOZNR63R6b, -SOzC1_6alkyl, -P0(CH3)2, -C5_10heterocyclic or heteroaryl, wherein each of which is independently optionally substituted -F, -Cl, -Br, -I, -NH2, -CN, -0H, -N02, carboxyl, oxo, =0, substituted or unsubstituted —C1_3alkoxy, or substituted or unsubstituted -C1_3alkyl; or Two adjacent R6 can be joined together to form a 6—membered aryl; 3-membered carbocyclic, ered carbocyclic, 5-membered carbocyclic, 6-membered carbocyclic; 5-membered heteroaryl, 6-membered heteroaryl; 3—membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic or 6-membered heterocyclic; and wherein each of heteroaryl or heterocyclic ns 1, 2, 3 or 4 heteroatoms selected from N, 0 or S; and each of the ring system is independently optionally substituted with halogen, -NH2, -CN, -0H, -N02, =0, OX0, carboxyl, , —P0(C1_6alkyl)2, substituted or unsubstituted -C1_6alkoxy or substituted or unsubstituted -C14alkyl.
48. The compound or pharmaceutically acceptable salt thereof of claim 47, n each R6 is independently -H, -F, -Cl, -Br, 6b, -CN, -0H, oxo, =0, carboxyl, -C1_6alkoxy, -C1_6alkyl, -C1_6alkylene-NR63R6b, -C1-6alkyleneC1_6alkyl, -C1_6alkylene-C0-0R63, lkylene-C5_1oheterocyclic, lkylene-C5_loheteoaryl, -C1_6alkylene-CO-NR63R6b, -C1-6alkylene—NR63—C0—NR63R6b, -C0—NR63R6b, -C0-C0-NR6aR6b, -C0-C1.6alkyl, -C0-NR63-C5-loheterocyclic, -C0-C5-10heterocyclic, C5-1ocarbocyclic, -NRga-C0-C1-6alkyl, -NR63-C0-NR63R6b, -NR6a-C1-6alkylene-NR6aR6b, -NRga-C1.6alkylene-C3-loheterocyclic, -S-C1-6alkyl, -SOZNR63R6b, -SOzC1_6alkyl, -C5_10heterocyclic or -C5_10heteroaryl, wherein each of which is independently optionally substituted -F, -Cl, Br, -NH2, -OH, carboxyl, oxo, =0, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; or Two adjacent R6 can be joined together to form a 6-membered aryl; ered carbocyclic, 5-membered heteroaryl or 5—membered heterocyclic; and wherein each of heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N, O or S; and each of the ring system is independently optionally substituted with -F, —Cl, -Br, -NH2, -CN, -OH, -N02, =0, 0X0, carboxyl, -CONH2, -PO(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
49. The compound or pharrnaceutically acceptable salt thereof of claim 47 or 48, wherein each R6 is ndently -H, —F, -Cl, -Br, -NR6aR6b, -CN, -OH, oxo, =0, carboxyl, -C1_3alkoxy, -C1_3alkyl, -C1_3alkylene-NR6aR6b, -C1-3alky1ene-O-C1_3alkyl, -C1_3alkylene-CO-OR63, -C1-3alkylene-Csfiheterocyclic, -C1-3alkylene-C5_6heteoaryl, -C1_3alkylene-CO-NR63R6b, -C1-3alkylene-NR63-CO-NR63R6b, -CO-NR6aR6b, -CO-CO-NR6aR6b, _3alkyl, 6a-C56heterocyclic, -CO-C5_6heterocyclic, -O-C5_6carbocyclic, -NR63-CO-C1_6alkyl, -NR6a-CO—NR6aR6b, -NR6a-C1-3alkylene-NR63R6b, C1-6alkylene-C3_6heterocyclic, -S-C1_3alkyl, —S02NR6aR6b, _3alkyl, -C5_6heterocyclic or -C5_6heteroaryl, wherein each of which is independently optionally substituted with one or more substituents each independently selected from -F, -Cl, Br, -NH2, -OH, carboxyl, oxo, =0, methyl, ethyl, , isopropyl, methoxy, ethoxy, y or isopropoxy; or Two adjacent R6 can be joined together to form a 6-membered aryl; 5-membered yclic, 5-membered heteroaryl or 5—membered heterocyclic; and wherein each of heteroaryl or heterocyclic contains 1, or 2 heteroatoms selected from N, O or S; and each of the ring system is independently optionally substituted with one or more substituents each independently selected from -F, -Cl, -Br, -NH2, -CN, -OH, -N02, =0, oxo, carboxyl, -CONH2, -PO(CH3)2, methyl, ethyl, propyl, isopropyl, y, ethoxy, propoxy or isopropoxy.
50. The compound or pharrnaceutically acceptable salt thereof of any one of claims 1-49, wherein each R6 is independently -F, -Cl, -Br, =0, —OH, -CN, -NH2, 33km , -CH3, 4% 1,? 0H , -CF3, , -OCH3, -SCH3, -SOCH3, -SOZCH3, 3)2, -PO(OC2H5)2, “ ,- -NHSOZCH3,-C(O)NH2, I , fifio , -NHCOCH3, o ,-NHCONHCH3, ”N‘N é”(LN , ENS, or two adjacent R6 can be joined together to formnghu,ENHfiIor, :0
51. The compound or ceutically acceptable salt thereof of any one of claims 1-50, wherein each R6 is independently methyl, ethyl, isopropyl, methoxy, ethoxy, =0, OX0, -OH, -CN, -NH2, -Cl, -BI‘, -CF3, -OCF3, -SOzNH2, -802CH3, -F, -CH2NH2, o 0 ° 0 o | aJkN/ $0H,k\,3ékNHz,o [L gNJk 0 331mm 33L No“ 2% \N -SCH3, I, H ,xvo\,;gpo»+, H u o , , , O \ O 35:0 fiN N‘ n O 2K,?’<)J\OH, D, Q, RENO, fad",/N‘ \veS/Nx n\ is INN, “\NrJo, :5" I 3 N’fio, de , o 44 14°
52. The compound or ceutically acceptable salt thereof of any one of claims . . . | 1-51, where1n r1ng A and the two adjacent R6 taken together to form Fri/\D ,(Dé‘sy O O O S S I oo‘: oorgi SD 0% Is :2: o:: a £5) £1 95) \ / NW "7"” u H H , , , ’ a” a 5” 5 7 fir“ New w; m H H Em Em ECG-m n H / \ / \ \ N a _ N _ _ _ \ \ _ _. \ N \ w \ Em Em KI; WM. “1... “7’" o a a H, (J) 8, H, 7 5 H wan 5’“ <33 i566 H N g()3 FF " "l s‘ o \ l\§- N 3‘ H ”HM ” ll) KO: pig) 5&0 N) ”a fl> : a a 9 , 9 , , , EQQ ”Hg;0 S 1H: O 7kg»?s 0/ / 0 I X: Z) / '§ \ ‘é \ NH NH _§ \ I -§ \ O 0 S «:9;- ‘MiN H, H,’ H, ’ “in / writ S , 9 9 3 ) , H 0 / o \ H “I" ”5 "at “a ‘5. l f / ’ ’ “‘3 a“ $9 ”'5 i, st, si, I“: H M'N 7 7 7 7 7 7 .13er I m, ’ / N\ . %£®~M@©’i~/ N f: DQ-wIDN //§ N ”V" // “m m ‘ ' ' ' 7 7 7 7H 7 7 7 7 ,:w \ N ,‘w ' H 7 7 7 7 7 '7 7 7 7 9: «'~ ,3» ' \ r I -§/|\-/|\ MVfiLi/l -§/|\/ \k/IOI ””2 ”Va N /N N /N E N N/ / N l/ /‘;“ N//\N\ N/N N N‘ . H "5“” ”I ’/ ’/$s~ ”T” N if/ “F”, “7"" , 2*» 4-" ‘N’/e“:, //\N/§N “I“ NN‘NV‘ E, ’ ”W I'm/N“? q“ E, / / / p" ‘ WN N/ / Id -3/ / |\ "‘l" /rr"\ §~ ‘0 O N/éi‘ /N /N 0 O 7 7 | l \ N / N/5 / / N «M N/ /N N H M N’ ‘0 /;i N\ N N \ ”No l/ 24 N\ \N —é
53. The compound or pharmaceutically acceptable salt thereof of any one of claims l-35, 41-44, and 47-52, wherein n is 0, l, 2 or 3.
54. The compound or ceutically acceptable salt thereof of any one of claims l-35, 41-44, and 47-5 3, wherein each ofR621 and R61) is independently -H; -F;- Cl; -Br; -NH2; -CN; -OH; -N02; carboxyl; lkyl; -C1_3alkoxy; lkyl substituted with halogen, -NH2, -CN, -OH, -N02, -carboxyl, -C1_3alkyl or lkoxy; or -C1_3alkoxy substituted with halogen, -NH2, -CN, -OH, -N02, carboxyl, -C1_3alkyl or -C1_3alkoxy.
55. The compound or pharmaceutically acceptable salt thereof of claim 54, wherein each of R621 and R613 is independently -H; -F; —Cl; -Br; -NH2; —CN; -OH; -N02; carboxyl; methyl; ethyl; propyl; isopropyl; methoxy; ethoxy; propoxy; isopropoxy; -C]_3alky1 substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -NOZ, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; or -C1_3alkoxy substituted with -F, -Cl, Br, -NH2, -CN, -OH, -N02, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
56. The compound or pharmaceutically acceptable salt thereof of claim 54 or 55, wherein each of R63 and R6b is independently -H; -F; -Cl; -Br; -NH2; -CN; -OH; carboxyl; methyl; ethyl; isopropyl; methoxy; methyl substituted with -F, -Cl, -NH2, -OH, carboxyl, , ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or poxy; ethyl substituted with -F, -Cl, -NH2, -OH, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; or propyl substituted with -F, —Cl, -NH2, -OH, carboxyl, , ethyl, propyl, isopropyl, methoxy, ethoxy, y or isopropoxy.
57. The compound or pharmaceutically acceptable salt thereof of claim 54-5 6, wherein each of R6a and R6b is independently -H, -CH3, -OH, or -CH2CHZOH.
58. The compound or pharmaceutically able salt thereof of any one of claims 1-57, wherein the compound is of Formula 11: R3 R48R4b Cl 3 \fN/ Y3-’ HZN \ / R53 R5b Wherein, R3 is -H or -NH2; Each of R4,, or R4, is independently —H, halogen, -NH2, -CN, -OH, -N02, carboxyl, substituted or unsubstituted -C1_6alkoxy, or substituted or unsubstituted -C1_6alkyl; or R4,, and R4, er with the carbon atom to which they are both attached form C=O, C=NH, or ; pis0,1,2or3; Each of R521 or R51) is independently -H, n, -NH2, —CN, -OH, -N02, carboxyl, substituted or unsubstituted -C1_6alkoxy, or substituted or unsubstituted -C1_6alkyl; or Rsa and R51J together with the carbon atom to which they are both attached form a 3- 10 membered heterocyclic or 5-10 membered heteroaryl; and each of the ring systems is independently optionally substituted; q is 0,1, 2, 3 or 4; Ring A is absent or a 3-10 membered ring; = represents a single or double bond; When ring A is absent, Y2 is CRZaRZb, NR2a or O, and Y3 is CR33R3b, NR3a or 0; When ring A is a 3-10 membered ring, wherein, i) Y2 is CR2a or N, and Y3 is CR3a or N, when = ents a single bond; or ii) Y2 is C, and Y3 is C, when -—-- ents a double bond; Each of R221 and R21, is independently -H, halogen, -NH2, -CN, -OH, -N02, carboxyl, substituted or unsubstituted -C1_6alkoxy, or substituted or unsubstituted -C1_6alkyl; Each of Rga and Rgb is independently -H, halogen, -NH2, -CN, -OH, -N02, carboxyl, substituted or unsubstituted -C1-6alkoxy, or substituted or unsubstituted -C1_6alkyl; Each R6 is independently -H, halogen, -NR.53R6b, -CN, -OH, -N02, oxo, =0, carboxyl, -C1_6alkoxy, -C1_6alkyl, -C1_6alkylene-NR63R6b, -C1-6alkylene-O-C1_6alkyl, -C1_6alkylene-CO-OR63, —C1-6alkylene—C3_1oheterocyclic, lkylene-C5_loheteoaryl, -C1_6alkylene-CO-NR63R6b, -C1-6alkylene-NR63-CO-NR63R6b, -C1-6alkylene-NR63-CO-C1-6alkyl, -CO-NR63R6b, -CO-CO-NR6aR6b, -CO-C1_6alkyl, -CO-C1_6alkylene-NR63R6b, -CO-NR63—C3_loheterocyclic, -CO-NR6a-C3_1oheterocyclic, _1oheteocyclic, -O-C1_6alkylene-CO—OR63, —O—C1-6alkylene-CO-NR63R6b, -O-C1_6alkylene-NR63R6b, -O-C3_10carbocyclic, —NR63—CO-C1_6alkyl, -NR63-CO-NR63R6b, -NR6a-CO-C5_1oheteoaryl, -NR63-C1-6alkylene-NR63R6b, -NR6a-C1-6alkylene-C3_loheterocyclic, -NR63-C1-6alkylene-C5_1oheteroaryl, -S-C1_6alkyl, -SONR6aR6b, -SOzNR6aR6b, -SO-C1_6alkyl, -SOz-C1_6alkyl, -PO(C1_6alkyl)2, -C3_1oheterocyclic or -C5_1oheteroaryl, wherein each of which is independently optionally substituted; and n is 0, l, 2 or 3; or two adjacent R6 can be joined together to form a 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, -C3_6heterocyclic or -C3_6carbocyclic, wherein each of the ring system is independently optionally tuted; Each of R621 and R61J is independently -H, halogen, -NH2, -CN, -OH, -N02, yl, substituted or unsubstituted -C1_6alkoxy or substituted or unsubstituted -C1_6alkyl.
59. The compound or pharmaceutically acceptable salt f of claim 58, wherein each of R43 or R4; is independently -H, halogen, -NH2, -CN, -OH, -N02, carboxyl, substituted or unsubstituted -C1-6alkoxy, or tuted or unsubstituted -C1.6alkyl; or R43 and R4b together with the carbon atom to which they are both attached form C=O.
60. The compound or pharmaceutically acceptable salt f of claims 58 or 59, wherein each of R4a or R4, is ndently -H; -F; -Cl; -Br; -NH2; -CN; -OH; carboxyl; methyl; ethyl; methoxy; ethoxy; methyl substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, methyl, ethyl, methoxy or ethoxy; ethyl substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, methyl, ethyl, methoxy or ethoxy; methoxy substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -N02, yl, methyl, ethyl, methoxy or ethoxy; or ethoxy substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, methyl, ethyl, methoxy or ethoxy; or R43 and R4; together with the carbon atom to which they are both attached form C=O.
61. The compound or ceutically able salt thereof of any one of claims 58-60, wherein p is 0, 1 or 2.
62. The compound or pharmaceutically acceptable salt thereof of any one of claims 58-61, wherein each of R53 and Rsb is independently -H; -F; -Cl; -Br; -NH2; -CN; -OH; carboxyl; -C1_3alkyl;- C1_3alkoxy; -C1_3alkyl substituted with -F, -Cl, -Br, -I, -NH2, -CN, -OH, -N02, carboxyl, -C1_3alkyl or -C1_3alkoxy; or -C1_3alkoxy substituted with -F, -Cl, -Br, -I, -NH2, -CN, -OH, -N02, carboxyl, -C1_3alkyl or -C1_3alkoxy; or R5a and R5b together with the carbon atom to which they are both attached form a 3-membered heterocyclic, 4-membered cyclic, 5-membered heterocyclic or 6-membered heterocyclic; and each of the heterocyclic contains 1 or 2 heteroatoms selected from N or O; and each of the ring system is ndently optionally substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, -C1_6alkyl, or lkoxy.
63. The compound or pharmaceutically acceptable salt thereof of any one of claims 58-62, wherein each of R521 or R5b is independently -H; -Cl; -Br; -NH2; -OH; carboxyl; ; ethyl; methoxy; ethoxy; methyl substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, methyl or methoxy; ethyl tuted with -F, -Cl, -Br, -NH2, -CN, -OH, -N02, yl, methyl or methoxy; methoxy substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, methyl or y; or ethoxy substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -N02, yl, methyl or methoxy; or R581 and R51J together with the carbon atom to which they are both attached form HN , and *C represents the carbon atom which R53 and R513 attached.
64. The compound or pharmaceutically acceptable salt thereof of any one of claims 58-63, wherein ring A is 6—membered aryl, 7-membered aryl, 8-membered aryl, 9-membered aryl; 5-membered heteroaryl, 6—membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9—membered heteroaryl; 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 8-membered heterocyclic, 9-membered heterocyclic; ered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic, 6-membered carbocyclic, 7-membered carbocyclic, 8-membered carbocyclic or 9-membered carbocyclic; and each ofthe aryl contains 1, 2 or 3 atoms selected from N, O or S; each of the heterocyclic contains 1, 2 or 3 heteroatoms selected from N or O.
65. . The compound or pharmaceutically acceptable salt thereof of any one of claims 58-64, n ring A is 6-membered aryl, 7-membered aryl, 8-membered aryl; 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl; 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 7—membered heterocyclic, 8-membered heterocyclic; 3-membered carbocyclic, 4-membered yclic, 5-membered carbocyclic, ered carbocyclic, 7-membered carbocyclic or 8-membered carbocyclic; and each of the heteroaryl contains 1 or 2 heteroatoms selected from N, O or S; each of the heterocyclic ns 1 or 2 heteroatoms selected from N or O.
66. The compound or ceutically acceptable salt thereof of any one of claims 58-65, Wherein ring A1s if??? :5 :11“\EEO :0 5:1) :0 :0,1D,,E©,A:>,AD,A];>,A©,:‘ If :«r’ ‘5 ‘5 ‘3‘ ‘r" H ~- ~-; w“ ‘, ,a EDiLN) H9}?- 0 7 a H9 721107.11 a’zsa’%\ a ‘e” H x \ 31L}‘3‘ ‘rrr'o 13 2:“ o 3/ ‘e‘é \ \ 2r“ 8 3N \ ‘5 N 13/ 3' CAEOAQVED flags 1' s 231/) 3.; all / N” ~35 ~;/ 5 H if; 331:) 3‘1) \3/DEENH :0 Ne; , fN:\\N 5N?:EN/NH :ZN/O ELM/s, :fiN, 3511:), ,‘EZLN, AIM), 3L”, SEEN/>9 BEEN/NH, All»? :ENH, gig,H\e’J/\ H \ O \ \e’SH ‘g’r0\ ‘g‘s 0 158‘ S I: 3‘s“ \ x. Ti H 513“}’1:)EN 20);,5 ‘3’ ‘5 ,5 "Hf“"L/njfi" g A g A NH} JV11H73U,y :fiI/O, :U, :LS:le :NK/DS [EN/1H, 3‘1”], 39:0] ,3ngHH H \ 3‘5 gs 3:: N :5: 5i :5 /N :2:\ I I mmflgo,ow“w£s A , , EEN\‘£'/N {RES/N ‘§\?€/ng/ VIN NH?“ 1‘3“ 3251;, 4;)“ ,EU, ELM], 2E3 Ag} , Palm/IN, Silo], 2E8], 4E0], is] ‘§H~~H\‘°‘ wwfiwpmmmfimfl>92: ~o~ ~§ ~ ‘3‘ t s \ \ \ \ 3; 19‘ ~56 ‘§ if} :13 if} :' 07’1U,:©%©,%@fi ‘/ ‘ NH, :Q3 3&0c)or""z]::3>.*535
67. The compound or pharmaceutically acceptable salt thereof of any one of claims Fri: ,:]:>,,-J:> :6 :1;KO ‘!" 5/ g" 5N:\\N 58-66, WhereinringAis ED); MQQQD©©pfifi grim.
68. The compound or pharmaceutically acceptable salt thereof of any one of claims 58-67, Y2 is CR2a or N, Y3 is CR321 or N.
69. The compound or pharmaceutically acceptable salt thereof of any one of claims 58-68, wherein each of R23, sz, R33 and R313 is independently —H; -F; —Cl; —Br; -NH2; -CN; -OH; -N02; carboxyl; methyl; ethyl; propyl; isopropyl; methoxy; ethoxy; propoxy; isopropoxy; -C1_3alkyl tuted with -F, -Cl, -Br, -NH2, -CN, -OH, -NOZ, yl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; or -C1_3alkoxy substituted With -F, -Cl, -Br, -NH2, -CN, —OH, -NOZ, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, , propoxy or isopropoxy.
70. The compound or ceutically acceptable salt thereof of any one of claims 58-69, wherein each of R23, sz, Rga and R313 is ndently -H or methyl.
71. 7 l. The compound or pharmaceutically acceptable salt thereof of any one of claims 58-70, wherein R23, sz, Rga and R31, are all -H.
72. The compound or pharmaceutically acceptable salt thereof of any one of claims 58-71, Y2 is CH or N, and Y3 is CH or N.
73. The compound or pharmaceutically acceptable salt thereof of any one of claims 58-67, Y2 is C, and Y3 is C.
74. The compound or pharmaceutically acceptable salt thereof of any one of claims 5 8-73, wherein each R6 is independently -H, -F, -Cl, -Br, -NH2, -N(CH3)2, -CN, -0H, oxo, =0, carboxyl, -C1_3alkoxy, -C1_3alkyl, -CH2NH2, -C1_3alkylene-0CH3, -CH2-C00H, -CH2-C00-C1_3alkyl, -CH2-C5_10heterocyclic, -C1_3alkylene-C0-NR6aR6b, -CH2NH-C0-NR63R6b, -C0-NR63R6b, -C0C0—NR6aR6b, —C0-C1_3alkyl, -C0NH-C5_1oheteocyclic, -C0membered heteocyclic, -C0membered heteocyclic, 5-membered carbocyclic, 6-membered carbocyclic, -NH-C0-C1_3alkyl, -NR6a-C0-NR63R6b, C1-3alkylene-NR6aR6b, —NR6a-C1-3alkylene-C5_loheterocyclic, -S-C1_3alkyl, -SOzNH2, -SOZCH3, 5-membered heterocyclic, 6-membered heterocyclic, 5-membered heteroaryl, or 6-membered heteroaryl, wherein each of which is independently ally substituted with -F, -Cl, -Br, -NH2, -CN, -0H, oxo, =0, substituted or unsubstituted -C1_3alkoxy, or substituted or unsubstituted -C1_3alkyl; or Two nt R6 can be joined together to form a 6-membered aryl; 3-membered yclic, 4-membered carbocyclic, 5—membered carbocyclic, 5-membered heteroaryl, 3-membered heterocyclic, 4-membered cyclic or 5-membered heterocyclic; and wherein each of aryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N, 0 or S; and each of the ring system is independently optionally tuted with -F, -Cl, -Br, -I, -NH2, -CN, -0H, -N02, =0, oxo, carboxyl, -C0NH2, -P0(C1_3alkyl)2, substituted or tituted -C1-3alkoxy, or substituted or unsubstituted -C1-3a1ky1.
75. The compound or pharmaceutically acceptable salt thereof of any one of claims 58-74, wherein each R6 is independently -F, -Cl, -Br, -NH2, -N(CH3)2, -CN, -0H, oxo, =0, yl, methoxy, ethoxy, methyl, ethyl, pyl, -CH2NH2, -CH2CH20CH3, -CH2-C00H, -CH2NH-C0NHCH3, —C0NH2, —C0N(CH3)2, -CONHOH, -CONHCH2CH20H, -CO-CON(CH3)2, —COCH3, 2, -S02CH3, -SCH3, o 44 £4 H M . N (\0 35,0 fiN /N_ N\ \g‘ /N\ -NH-COCH3, “”“O Q“, Q?”, U, ‘3, "{“O, in” E~"”, HL° or $0, wherein each of which is independently optionally substituted with -F, -NH2, -OH, oxo, =0, or substituted or tituted —C1_3alkyl.
76. The compound or aceutically acceptable salt thereof of any one of claims 58-75, wherein each R6 is independently methyl, methoxy, =0, oxo, -OH, -CN, -NH2, -Cl, 0 0 -Br, -CF3, -OCF3, -SOzNH2, sogcm, —F, -CH2NH2, $71 21W, QR, JgLNHZ, WK) 0 o o | XVCK ken-1 k0“ 3EO\/\ H, RANCH, QLH/VOH 203/”. wk 3* xi w r“? “U to "i"? >
77. The compound or pharrnaceutically acceptable salt thereof of any one of claims :3 o 0 a: 58-76, wherein ring A and two adjacent R6 taken together to form ”LED ,EDEE“, s S o 3; o ”Li/~95 S S ‘72,: S \ E’% \ wow a “BEE; i m M" ”W M”, “r" “M “fix H , , a 9 9 , 7 ,H a EL m” 7 N: (”EX-m;/ i u'ugm slip -le\ / \ \ ”NV M“ s ”Dam: '§\'s\ “ ‘9 H ”I” we 2393 O3\ .H \ -§ nI \ H 5"; \ .\;-ms- O} 1mg.”Q3u g H “7 ”'1 H tag”) <95<1;0 "3 3 4:1: 51:):{30 QED rr" 3 ‘3‘ s m H) a) g N) 33:1,?3 3: N3): :3: @1ng\“ 1i iiéfibfmhmfi (Zing/035% ‘1‘1. “Y” {1:0\ \lv‘li‘: \ \ “INV’ Z/fN/i” \\ \\’ \l\’ N/J‘ rig: NW”; :N’5 "w: Nf“ \E’Fm NH ‘3? NH /)NH or - wherein each of the ring A is independently optionally substituted with one or more R6.
78. The compound or pharmaceutically acceptable salt thereof of any one of claims 58-77, wherein each of R621 and Ra) is ndently -H, -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, substituted or unsubstituted -C1_3alkoxy, or substituted or unsubstituted -C1_3alky1.
79. The compound or ceutically acceptable salt thereof of any one of claims 58-78, wherein each of R621 and Ra, is independently -H, -Cl, -Br, -NH2, -OH, carboxyl, methyl, ethyl, methoxy, ethoxy propoxy, isopropoxy, methyl substituted with -OH, or ethyl substituted with -OH.
80. The nd or pharmaceutically acceptable salt thereof of any one of claims 58-79, wherein each of R63 and R61) is independently -H, -CH3, -OH, or —CH2CH20H.
81. The compound or pharmaceutically able salt thereof of any one of claims 58-80, wherein n is 0, l or 2.
82. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-57, wherein the compound is of a 111: wherein, R1 is -H, -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, substituted or unsubstituted -C1_6alkoxy, or substituted or unsubstituted -C1_6alkyl; R2 is -H, -F, -Cl, -Br, -NH2, -CN, -OH, -N02, carboxyl, substituted or tituted -C1_6alkoxy, or substituted or unsubstituted -CMalkyl; or R1 combines with R2 to which is adjacent to form a 5-10 ed heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N or O, and each of the ring systems is independently optionally substituted with halogen, -NH2, —CN, -OH, -N02, carboxyl, oxo, =0, -CONH2, substituted or unsubstituted -Cmalkoxy, substituted or unsubstituted -C1_6alkyl, or -CO-C1_6alkyl; Y1 is N or CH; R3 is -H or -NH2; Ring B is a 6-membered aryl, 5-6 membered heteroaryl, 3-6 ed carbocyclic or 3-6 membered heterocyclic; Y3 is CH, N or C; R7 is n, -NH2, -CN, -0H, —N02, carboxyl, oxo, =0, -C0NH2, -NH-C0CH3, substituted or unsubstituted -C1_6alkoxy, or substituted or unsubstituted -C1_6alkyl; and m is 0, l or 2.
83. The compound or pharmaceutically acceptable salt thereof of claim 82, wherein R1 combines with R2 to which is adjacent to form a 5—membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 8-membered heterocyclic, 9—membered heterocyclic or 10-membered heterocyclic; and each of the heterocyclic ns 1 or 2 heteroatoms selected from N or 0; and each of the ring systems is independently optionally substituted with -F, -Cl, -Br, -NH2, -CN, -0H, 0x0, =0, substituted or unsubstituted -C1_3alkoxy, tuted or unsubstituted lkyl, or -C0-C1_3alkyl.
84. The compound or pharmaceutically acceptable salt thereof of claims 82 or 83, wherein R1 combines with R2 to which is adjacent to form 5' ; and the ring systems is independently optionally substituted with —F or -C0CH3.
85. The compound or pharmaceutically acceptable salt thereof of any one of claims 82-84, wherein R1 combines with R2 to which is adjacent to form fig; .
86. The compound or pharmaceutically acceptable salt f of any one of claims 82-85, wherein ring B is 6-membered aryl, 5-membered aryl, 6-membered heteroaryl, 3-membered carbocyclic, 4—membered yclic, 5-membered carbocyclic, 6-membered carbocyclic, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic or ered heterocyclic; and each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N, 0 or S.
87. The compound or ceutically acceptable salt thereof of any one of claims ‘35 ‘5 0 ‘3‘ ‘3 \ x; ~35 ‘3‘ N\ ‘9; 82-86, wherein ring B is 33>, $119,213 {>20 4f? all) or 43
88. The compound or pharmaceutically acceptable salt thereof of any one of claims 82-87, wherein R7 is -NH2, -CN, 0x0, =0, -C0NH2, CH3, methyl or methoxy.
89. The compound or pharmaceutically acceptable salt thereof of any one of claims 82-88, wherein m is 0 or 1.
90. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-57, wherein the compound is of Formula IV: R s N I _(I 1 \Nf D’ R8) t R2 \ / H2N R1 is -H, -F, -Cl, -Br, -NH2, -CN, -OH, -NO2, carboxyl, substituted or unsubstituted -C1_6alkoxy, or substituted or unsubstituted- l; R2 is -H, -F, -Cl, -Br, -NH2, -CN, -OH, -NO2, carboxyl, -NHC1_6alkyl, -N(C1_6alkyl)2, substituted or unsubstituted -C1_6alkoxy, or tuted or unsubstituted -C1_6alkyl; or R1 es with R2 to which is adjacent to form a 5-12 membered heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N or O, and each of the ring systems is independently optionally substituted with halogen, —NH2, -CN, -OH, -NO2, carboxyl, oxo, =0, , tuted or unsubstituted -C1_6alkoxy, substituted or unsubstituted -C1_6alkyl, or -CO-C1_6alkyl; Y1 is N or CH; R3 is -H or -NH2; Ring D is a 6-membered aryl, 5- membered heteroaryl, 6-membered heteroaryl, 3- membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic, 6-membered carbocyclic, 3-membered heterocyclic, 4—membered heterocyclic, 5-membered heterocyclic, or 6-membered cyclic; = represents a single or double bond; and i) Y2 is CR2,l or N, and Y3 is CR3a or N, when = represents a single bond; or ii) Y2 is C, and Y3 is C, when = represents a double bond; Each of R2a and R3a is -H, halogen, -NH2, -CN, -OH, -NO2, carboxyl, substituted or unsubstituted lkoxy, or substituted or unsubstituted -C1-6a1ky1; R8 is halogen, -NH2, -CN, -OH, -NO2, carboxyl, oxo, =0, -SOzNRgaRgb, -S-C1_6alkyl, -SO-C1_6alkyl, -SO2-C1_6alkyl, -CO-NRgaRgb, -PO(C1_6alkyl)2, -PO(C1_6alkoxy)2, -NRga-CO-C1_6alkyl, -NRga-CO-NRgaRgb, —O-C5_1ocarbocyclic, -O-C5_1oheterocyclic, -C5_1oheterocyclic or -C5_10heteroaryl, -C5_10aryl, -C1_6alkoxy, or -C1_6alkyl; and each of which is independently optionally substituted; andt is 0, 1, 2 or 3; and Each of R821 and Rgb is independently H, halogen, -NH2, -CN, -OH, -NO2, carboxyl, substituted or tituted -C1_6alkoxy, or substituted or unsubstituted -C1_6alkyl.
91. The compound or pharmaceutically acceptable salt thereof of claim 90, n R2 is -H, -F, -Cl, -Br, -NH2, -CN, -OH, -NO2, carboxyl, substituted or unsubstituted lkoxy, or substituted or unsubstituted -C1.6alky1; or R1 combines with R2 to which is adjacent to form a 5-10 membered heterocyclic ring contains 1, 2 or 3 heteroatoms ed from N or O, and each of the ring systems is ndently optionally substituted with halogen, -NH2, -CN, -OH, -NO2, carboxyl, oxo, =0, , substituted or unsubstituted koxy, substituted or unsubstituted -C1_6alkyl, or -CO-C1_6alkyl;
92. The compound or pharmaceutically acceptable salt thereof of claim 90 or 91, wherein R2 is -H, -F, -Cl, -Br, -NH2, -CN, -OH, -NO2, carboxyl, -NHC1_3alkyl, -N(C1_3alkyl)2, lkoxy, -C1_3alkyl; or R1 combines with R2 to which is adjacent to form a 5-,6-, or 7-membered heterocyclic ring contains 1, or 2 heteroatoms selected from N or O, and each of the ring systems is independently optionally tuted with -F, -Cl, -Br, -NH2, -CN, -OH, -NO2, carboxyl, oxo, =0, , methoxy, ethoxy, methyl, ethyl, -CO-methyl, or -CO-ethyl;
93. The compound or pharmaceutically able salt thereof of any one of claims 90-92, wherein R2 is -H, -F, -Cl, -Br, —NH2, -CN, -OH, -NO2, carboxyl, -NHCH3, -N(CH3)2, methoxy, , methyl, or ethyl; or R1 combines with R2 to which is adjacent to form a 5- membered heterocyclic contains 1 heteroatoms selected from N or O, or 6-membered heterocyclic ring contains 1 heteroatoms selected from N or O; and each ofthe ring systems is independently optionally substituted with -F, -Cl, -Br, -NH2, -CN, -OH, -NO2, carboxyl, oxo, =0, —CONH2, methoxy, ethoxy, methyl, ethyl, -CO-methyl, or -CO-ethyl;
94. The compound or pharmaceutically acceptable salt thereof of any one of claims 90-93, wherein R1, and R2, together with the aromatic ring they are attached to forrnto l I W WW I F2 / \ HN \ / Y1 or Y1 wherein ring F1 or F2 is independently optionally substituted with -F or -COCH3.
95. The compound or pharmaceutically acceptable salt thereof of any one of claims 90-94, whereln R1 comb1nes w1th R2 to Wthh 1s nt to form. . . . . . °‘
96. The compound or pharmaceutically acceptable salt thereof of any one of claims 90-93, n R2 is -NH2.
97. The compound or pharmaceutically able salt thereof of any one of claims 90-93 and 96, wherein R1 is -H, -F, -Cl, -Br, -NH2, -CN, —OH, -NOz, carboxyl, substituted or tituted -C1_3alkoxy, or substituted or unsubstituted -C1_3alkyl.
98. The compound or pharmaceutically acceptable salt thereof of any one of claims 90-93 or 96-97, wherein R1 is -H, -F, -Cl, -Br, —NH2, —CN, -OH, -N02, carboxyl, methoxy, ethoxy, methyl, or methyl substituted with one or more substituents selected from halogen.
99. The compound or pharmaceutically acceptable salt thereof of any one of claims 90-93 or 96-98, wherein R1 is -H; -F; -Cl; -Br; -NH2; -CN; -OH; -N02; carboxyl; methyl; or methyl tuted with one or more substituents selected from -F, -C1, or -Br.
100. The compound or pharmaceutically acceptable salt thereof of any one of claims 90-93 or 96-99, wherein R1 is -C1.
101. The compound or ceutically acceptable salt thereof of any one of claims 90-100, wherein ring D is 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic, 6-membered carbocyclic, 3-membered heterocyclic, 4—membered heterocyclic, 5-membered heterocyclic or 6-membered heterocyclic; and each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N, O or S.
102. The compound or pharmaceutically able salt thereof of any one of claims 90-101, wherein ring D is 6-membered aryl, S-membered heteroaryl, ered heteroaryl, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered yclic, 5-membered heterocyclic or 6—membered heterocyclic; and each of the heteroaryl or heterocyclic contains 1 or 2 heteroatoms selected from N, O or S.
103. The compound or pharmaceutically able salt thereof of any one of claims T; ‘5]: :3" EN ‘9": ° ‘3‘ o ‘E’N \‘SN ‘3‘ N\ I Q | 90-102, wherein ring D is 31>, A , 31>, SLED, 31:), Flo], ”HQ, 3&0, 31:), ~-: ~; \ ‘fls we io,n D O.D
104. The nd or pharmaceutically acceptable salt thereof of any one of claims 90-103, wherein Y2 is CR2a or N, and Y3 is CR3a or N.
105. The compound or ceutically acceptable salt thereof of any one of claims 90-104, wherein each of R2a and R321 is -H, -F, -Cl, -Br, -NH2, -CN, -0H, -N02, carboxyl, substituted or unsubstituted -C1_3alkoxy, or tuted or unsubstituted -C1_3alky1.
106. The compound or pharmaceutically acceptable salt f of any one of claims 90-105, wherein each of R23 and R3a is -H, methyl or methoxy.
107. The compound or pharmaceutically acceptable salt thereof of any one of claims 90-106, wherein Y2 is CH or N, and Y3 is CH or N.
108. The compound or pharmaceutically acceptable salt thereof of any one of claims , wherein both Y2 and Y3 are C.
109. The compound or pharmaceutically acceptable salt thereof of any one of claims 90-108, wherein R8 is -F, -Cl, -Br, -I, -NH2, -CN, -0H, -N02, carboxyl, oxo, =0, -SOzNRgaRgb, -S-C1_6alkyl, -CO-NRgaR8b, -NRga-C0-C1_6alkyl, -NRga-CO-NRgaRgb, C5_1ocarbocyclic, -C5_1oheterocyclic or —C5_1oheteroaryl, -C1_6alkoxy, or lkyl; wherein each ofwhich is independently optionally substituted with -F, -Cl, -Br, -NH2, -CN, -0H, oxo, =0, substituted or unsubstituted lkoxy, or substituted or unsubstituted -C1_3alkyl.
110. The nd or pharmaceutically acceptable salt f of any one of claims 90-109, wherein R8 is -F, -Cl, -Br, -NH2, -CN, -0H, -N02, carboxyl, oxo, =0, -SOzNRgaRgb, -S-C1_3alkyl, -CO-NRgaRgb, —NH—C0-C1_3alkyl, -NH-CO-NRgaRgb, C5-1ocarbocyclic, -C5.1oheterocyclic, -C5-10heteroary1, -C1-3a1koxy, or -C1.3alky1; wherein each of which is independently optionally substituted with -F, -Cl, -Br, -NH2, -CN, -0H, 0X0, =0, -C1.3alkoxy, or -C1-3alkyl.
111. The compound or pharmaceutically acceptable salt thereof of any one of claims 90-110, wherein R8 is -F, -Cl, -Br, -NH2, -CN, -0H, -N02, carboxyl, oxo, =0, methyl, ethyl, proproyl, isopropoyl, methoxy, ethoxy, y, isopropoxy, -SOzNRgaRgb, -S-C1_3alkyl, gaR8b, -C1_3alkyl, -NH-CO-NRgaRgb, C5_1ocarbocyclic, -C5_1oheterocyclic or -C5_1oheteroaryl; wherein each of which is independently optionally substituted With -F, -Cl, -Br, -NH2, -CN, -0H, oxo, =0, methoxy, ethoxy, methyl, or ethyl.
112. The compound or pharmaceutically acceptable salt thereof of of any one of claims 90-111, wherein the C5_1ocarbocyclic is 5—membered yclic, 6-membered carbocyclic, 7-membered carbocyclic, 8—membered carbocyclic, 9-membered carbocyclic or 10-membered carbocyclic; the C5.1oheterocyclic is ered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 8-membered heterocyclic, ered heterocyclic or lO-membered heterocyclic; and the C5_10heteroaryl is 5-membered heteroaryl, 6—membered heteroaryl, ?-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl or lO-membered heteroaryl; and each of the heterocyclic or heteroaryl contains 1, 2, 3 or 4 heteroatoms selected from N, 0 or S.
113. The compound or pharmaceutically able salt thereof of any one of claims 90-112, wherein R8 is -F, -Cl, -Br, -NH2, -CN, -0H, oxo, =0, methyl, ethyl, isopropoyl, methoxy, -SOzCH3, -SCH3, -CONH2, -NH-COCH3, -NH-CONHCH3, 35:0 , Q,
114. The compound or pharmaceutically acceptable salt thereof of any one of claims 90-113, wherein R8 is -F, -Cl, -Br, -NH2, —CN, -0H, oxo, =0, methyl, y, -SOzCH3, OH \c‘f/ , I >3 TN"/ -SCH3, l-CONH2,-NH-COCH3, -NH-CONHCH3, 33K, 3’0 D”NW/N \IN/\N or .
115. The compound or pharmaceutically acceptable salt thereof of any one of claims 90-114, wherein t is 0, l or 2.
116. 1 16. The nd or ceutically acceptable salt thereof of claim l-l 15, wherein the compound is (R)-l '-(6-amino-5 -((2-aminochloropyridinyl)thio)pyrazin-2 -yl) -2,3 -dihydrospiro[i ndene-l ,4'-piperidin] amine —(6-amin0-5 -((2-amin0ch1oropyridiny1)thio)pyraziny1)-1,3 r0spir0 [i ndene-Z ,4' o i o eridin]—1-amine —(6-amin0-5 -((2-aminoch10ropyridiny1)thio)pyrazin-2 -y1) ihydro-2H-sp iro [na o hthalene-1,4' o i o eridin] amine (R)-1'—(6-amino-5 -((2-aminochloropyridiny1)thio)pyraziny1)-5,6-dihydrospiro[c yclopenta[b]pyridine-7,4'-piperidin]amine (S)-1'-(6-amino-5 -((2-aminochloropyridinyl)thio)pyraziny1)methoxy-1,3 -dih dros o iro indene-2,4'- o i o eridin amine (R)(4-((3 -amino-5 ino-2 ,3-dihydrospiro[indene-1,4’-piperidin]—1’-y1)pyrazin 1)thi0)-3,3 -diflu0r0ind01in 1)ethan—1-one 1-(4-((3 -amino-5 -((2R)amin0spir0[bicyclo[3.1 .0]hexane-3,4'-piperidin]—1'-y1)pyrazin -2 - 1)thi0)-3 , 3 -diflu0roi11d01i11-1 - 1)ethan0ne (S)-1'—(6-amin0-5 -((2-ami110ch10ropyridiny1)thi0)pyrazin-2 -y1) -3,4-dihydr0-1H-sp iro [11a ohthalene-2,4' o i o eridin]amine (R)(6-amin0-5 -((2-ami110ch10r0pyridiny1)thi0)pyrazin-2 -y1) -7 ',8'-dihydr0-5'H-s ‘ [o i o eridine-4,6'— uinolin]—7‘-amine (S)-1'—(6-amin0-5 -((2-amin0ch10r0pyridiny1)thi0)pyraziii-2 -y1) -5 ,7-dihydr0spir0 [0 do o enta[b] o ridine-6,4' o i o ] -5 -amine (S)-1 '-(6-amin0-5 -((2-aminoch10r0pyridiny1)thi0)pyrazin-2 -y1) -5 -meth0xy-1 ,3 -dih ,— ,— dros o ir0[indene-2,4' o i o eridin]—1-amine (S)-1'-(6-amino((2-amin0chloropyridiny1)thio)pyraziny1)-4,6-dihydr0spir0[c ,— l\.) 010 o enta[b]thi0 ohene-5,4'- oi o eridin]—4-amine (S)amin0-1'-(6-amin0-5 -((2-aminochloropyridiny1)thio)pyraziny1)-1,3 -dihyd ,— U) rospir0[indene-2,4'-piperidine]carbonitrile (S)-1 '-(6-amin0-5 -((2-aminoch10ropyridiny1)thio)pyrazin-2 -y1)methoxy-1 ,3 -dih dros o iro[indene-2,4‘ o i o eridin]amine (S)-1'—(6-amino-5 -((2-aminoch10ropyridiny1)thio)pyraziny1)ch10r0-1,3 -dihyd ros o iro[indene-2,4' i o eridin]amine amino-1'-(6-amino((2-aminochloropyridiny1)thio)pyraziny1)-1,3 -dihyd ros o iro indene-2,4'- oi o eridine carbonitri1e (S)amino-1'-(6-amino((2-aminochloropyridiny1)thio)pyraziny1)-1,3 -dihyd ._. \] o[indene-Z,4'-piperidine]carb0xamide (S)-1 '-(6-ami110-5 -((2-ami110ch1oropyridiny1)thi0)pyrazin-2 -y1)-1,3 -dihydrospir0 [i .— 00 ndene-2,4' o i o eridin]amine (S)-1'—(6-amin0-5 -((2-amin0ch10r0pyridin—4-y1)thi0)pyraziny1)ch10r0-5 ,7-dihyd ros o ir0[c Clo oenta[b] o ridine-6,4'- o i o eridin]amine (S)-1 '-(6-amin0-5 -((2-amin0ch10ropyridiny1)thi0)pyrazin-2 -y1) -3 -methoxy-5 ,7-dih l\.) O dros o ir0[c clo o enta[c] o ridine-6,4'- i o eridin] amine —(6-amin0-5 -((2-aminoch1oropyridiny1)thio)pyraziny1)-5,7-dihydrospiro[c clo o enta[c] idine-6,4‘- o i o ]-?-amine (S)-1'—(6-amin0-5 -((2-aminoch1oropyridiny1)thio)pyraziny1)-5,7-dihydrospiro[c 010 o enta[c] o ridine-6,4'- o i o eridin]amine (S)-1'-(6-amino-5 -((2-aminochloropyridinyl)thio)pyraziny1)methy1-1,3 -dihy dros o iro [indene-Z ,4' - o i o eridin]amine (S)-1'—(6-amin0-5 -((2-amin0—3-ch10r0pyridin—4-yl)thi0)pyraziny1)(methylsu1fony1) -1,3 -dih dros o iro [indene-Z ,4'— oi o eridin]amine (1 S)-1 '-(6-amin0-5 -((2-ami110ch10r0pyridin-4—yl)thi0)py1'aziny1)(methylsu1finy1 )-1, 3 -dih dros o iro [indene-2,4'- oi o eridin]amine (S)amin0-1'-(6-ami110-5 -((2-amin0ch10ropyridiny1)thi0)pyraziny1)-1,3 -dihyd l\.) 0\ ms o ir0[indene-2,4'- o i o eridine]carboxamide (S)-1 -amin0-1 '-(6-amin0-5 -((2-amin0chloropyridiny1)thi0)pyrazin-2 -y1)-N,N-dim l\.) \] eth 1-1,3 -dih dros o ir0[indene-2,4'- i o eridine]carb0xamide (S)-1'—(6-amin0-5 -((2-amin0ch10r0pyridiny1)thi0)pyraziny1)br0m0-1,3-dihyd ms o ir0[indene-2,4' oi o eridin]—1-amine (S)-1 '-(6-amin0-5 min0ch10r0pyridiny1)thio)pyraziny1)br0m0-1,3-dihyd l\.) \0 ms o dene-2,4' oi o eridin]—1-amine (S)-1 '-(5-((2-amin0-3 -ch10r0pyridiny1)thio)pyraziny1)-5,7-dihydr0spir0[cyc10pent a[b] o ridine-6,4‘- oi o eridin]—5-amine (S)-1'—(6-amin0-5 -((2-amin0ch1oropyridiny1)thio)pyraziny1)-1,3 -dihydr0spir0 [c U) ,— nta[a]naphthalene-2,4'-piperidin]amine (S)-1'—(6-amin0-5 -((2-aminoch10r0pyridiny1)thio)pyrazin-2 -y1)ch10r0-5 -methox U.) N -1,3 -dih dros o iro[indene-2,4'- o i o eridin]amine (S)-1'—(6-amino-5 -((2-aminoch1oropyridiny1)thio)pyraziny1)-1,3 -dihydrospiro [i U.) U.) 2,4'- o i o eridine]-1,6-diamine (S)-(1-amino-1'-(6-amino((2-aminochloropyridiny1)thio)pyraziny1)-1,3 -dihy U.) 4; dros oiro[indene-2,4' (S)-1 min0((2-amin0—3-ch10r0pyridin—4-y1)thi0)pyraziny1)(trifluoromethy1) U) U1 -1 ,3 -dihydroSpiro[indene-Z ,4'—piperidin] -1 -amine U.) 0\ (S)-1'—(6-amin0-5 -((2-ami110ch10r0pyridiny1)thi0)pyraziny1)(1H-imidazol y1)-1,3 -dihydr0Spiro e-2,4'-piperidin] amine (S)-1'—(6-amin0-5 -((2-amin0chloropyridiny1)thio)pyraziny1) ( 1 H-pyrroly1) U) \l -1,3 -dih dros o iro [indene-2,4'— oi o eridin]amine (S)-1'—(6-amin0-5 -((2-aminoch10ropyridiny1)thio)pyrazin-2 -y1)bromo-5 -fluoro- 1, 3 -dih dros o iro [indene-2,4'- o i o eridin]amine (S)-1'—(6-amin0-5 -((2-aminoch1oropyridiny1)thio)pyrazin-2 -y1) -5,6-difluor0-1,3 -di piro[indene-2,4'-piperidin]amine (S)-1'-(6-amino-5 -((2-aminochloropyridinyl)thio)pyrazin-2 -y1)-6,7-dif1uoro-1,3 -di h dros o iro indene-Z ,4'- o i o eridin amine (S)-(1-amino-1'-(6-amino((2-aminochloropyridiny1)thio)pyrazin-2 -y1) -5 - 1, 3 -dih dros o iro [indene-2,4'- oi o eridin] 1)dimeth 1o hos o hine oxide (S)-1 -amin0-1 '-(6-ami110((2-amin0ch10ropyridiny1)thi0)pyrazin-2 -y1)-5 -flu0r0- 1,3-dih dros o iro[indene-2,4‘- oi o eridine]carbonitri1e (S)-1 -amin0-1 '-(6-ami110-5 -((2-amin0ch10ropyridiny1)thi0)pyrazin-2 -y1)-5 -flu0r0- 1,3-dih dros o iro[indene-2,4‘- oi o e]carboxamide (S)-1'-(6-amin0((2-ami110ch10ropyridiny1)thi0)pyraziny1)ch10r0-4,6-dihyd ms o ir0[c 010 o ]thiazole-5,4'— o i o eridin]amine (R)-1 '-(6-amin0-5 -((2-amin0ch10r0pyridiny1)thi0)pyrazin-2 -y1)-3H-spir0 [benzofur an-2,4'- o i o eridin] amine (S)(1-amin0-1'—(6-amin0((2-amin0ch10r0pyridiny1)thi0)pyraziny1)-1,3 -di h dI'OSoiI‘0[1Ildene-2,4' din] Durea (S)-1'—(6-amino-5 -((2-amin0ch10r0pyridiny1)thi0)pyrazin-2 -y1) -5 -br0m0-1,3-dihyd ros o ir0[indene-2,4' oi o eridin]—1-amine (S)-1 '-(5 -((2-amin0-3 -ch10r0pyridinyl)thio)pyrazin-2 -y1)-1 ,3 -dihydrospiro[indene-2,4 4; oo '-piperidin]—1-amine (S)-1 '-(5 -((3 -ch10r0(dimethylamino)pyridiny1)thio)pyrazin-2 -y1)-1,3 -dihydrospir0[ indene-2,4' o i o eridin]amine (S)-1'—(5 -((3 -aminoch10ropheny1)thio)pyraziny1)-1,3-dihydrospiro[indene-2,4'-pip eridin]—1-amine (S)-1'-(5 -((3 -ch10romethoxypyridiny1)thio)pyrazin-2 -y1)-1,3 -dihydrospiro[indene- 2,4'- oi o eridin amine (S)-1'-(6-amino-5 h10ro(dimethylamino)pyridiny1)thio)pyrazin-2 -y1)-1,3-dihy drospiro[indene-2,4'-piperidin]amine (S)-1 '-(6-ami110-5 -((3 -ami110ch1orophenyl)thi0)pyrazin-2 -y1)-1,3 -dihydrospir0[indene U] U.) -2,4'- oi o eridin] amine (S)-1'—(6-amin0-5 -((3-ch10r0meth0xypyridiny1)thio)pyraziny1)-1,3 -dihydr0spir o[indene-2,4'— i o eridin]amine (S)-1'—(6-amin0-5 -((2,3 -dich10r0phenyl)thio)pyraziny1)-1,3-dihydrospiro[indene-2,4'- U1 U1 i o eridin]—1-amine (R)-1'—(5 -((2-amin0ch10r0pyridinyl)thio)pyrazin-2 -y1)-3H-spiro[benzofuran-2,4'-p U1 0\ i o eridin] -3 -amine (S)-(1-amin0-1'-(6-amin0((2-aminochloropyridiny1)thio)pyraziny1)-1,3-dihy dros o iro[indene-2,4'- o i o eridin] 1 dimeth 1 hos ohine oxide (S)-1'-(6-amino-5 -((2-aminochloropyridiny1)thio)pyraziny1)((tetrahydro-2H- o ran 1)0x ) 1,3-dih drOSoiro[indene -ooieridin]amine (S)-(1-amin0-1'-(6-amin0((2-amin0—3-ch10r0pyridin—4-y1)thi0)pyraziny1)-1,3 -dihy U1 \0 dros o iro[indene-2,4‘- ' ' ' ' o eridin-l - 1)methanone (S)-1'—(6-amin0-5 -((2-ami110ch10r0pyridin—4-y1)thi0)pyraziny1)m0rph01in0-1 ,3 - dih dros o iro[indene-2,4‘ oi o eridin]amine (S)-1'—(6-amin0-5 -((2-amin0ch1oropyridiny1)thi0)pyrazin-2 -y1) -5 ,6,7-triflu0r0-1,3 - O\ .— dih dIOSoir0[indene-2,4' din]amine (S)(1-amin0-1'-(6-amin0((2-amin0ch10ropyridiny1)thi0)pyraziny1)-1,3 -di 0\ l\.) h drOSoiro[indene-2,4' ooieridin] 1)m0roh01inone (S)-N-(1-amin0-1'—(6-amin0((2-amin0ch10r0pyridiny1)thi0)pyraziny1)-1,3 -di 0\ U) h dIOSoir0[indene-2,4' din] 1)methanesulfonamide (S)-1'—(6-amin0-5 -((2-amin0ch1oropyridiny1)thio)pyraziny1)-1,3 -dihydr0spir0 [c 010 o ] o uinoline-2,4'- oi o eridin]amine (R)-1 min0-5 -((2-amin0ch10r0pyridiny1)thio)pyraziny1)-5,7-dihydr0spir0[c 0\ U1 010 o ] o ridine-6,4‘- o i o eridin]amine (S)-1'—(6-amin0-5 -((2,3 0r0pyridinyl)thio)pyraziny1)-1,3 -dihydrospiro[indene -2,4'-piperidin] ne (1R,3R)-1'—(6-amin0((2-amin0chloropyridiny1)thio)pyraziny1)-1,3 -dihydrosp O\ \] iro[indene-2,4'— oi o eridine] -1 ,3-diamine (S)-1'—(5 -((2-amin0-3 -ch10ropyridiny1)thio)pyraziny1)ch10ro-4,6-dihydr0Spiro [c 010 o enta[d]thiazole-5 ,4'- oi o eridin]amine (S)-1'-(6-amino-5 -((2-aminochloropyridinyl)thio)pyrazin-2 -y1)chloro-4,6-dihyd ros o iro[c Clo o enta[d]thiazole-5,4'- o i o eridin]amine (S)amin0-1'—(6-amin0((2-amin0—3-ch10r0pyridiny1)thi0)pyraziny1)-3H-spiro[ indolizine-Z,4'-piperidi11]-5(1H)-one \] .— (R)-1 '-(5-((2-ami110-3 -ch10r0pyridinyl)thi0)pyraziny1)spir0[indoline-2,4'-piperidin ]-3 -amine (R)-1'-(6-amin0((2-amin0chloropyridiny1)thio)pyraziny1)-6,7-dihydr0spir0[c \] l\.) clo n enta[b] o ridine-5,4' n i o eridin]amine (S)-1'—(6-amin0-5 -((2-aminoch10ropyridiny1)thio)pyrazin-2 -y1) -3 -ch10r0-5 ,7-dihyd ros o ir0[c clo o enta[b] o ridine-6,4'- o i o eridin]amine —(6-amin0-5 -((2-aminochloropyridinyl)thio)pyraziny1)(methy1thio)-1,3 -dihydrospiro[indene-2,4‘-piperidin]—1-amine (S)-1'-(6-amino-5 -((2-aminochloropyridiny1)thio)pyraziny1)(4-methy1pipera zin-l1,3-dih dros-iro -2,4'---ieridin -l-amine (S)-1'-(5 -((2 ,3 -dichloropyridiny1)thio)pyrazinyl)-1,3-dihydrospiro[indene-2,4’-pip \] ON eridin]amine (S)-1 '-(6-ami110-5 -((2-(triflu0r0methyl)pyridin—3-yl)thi0)pyrazin-2 -y1)-1,3 -dihydr0spir0[ \] \] indene-2,4' o i o eridin]amine (S)(4-((3-amin0-5 -(1-ami110-1,3-dihydrospir0[indene-2,4'-piperidin]—1'-y1)pyrazin \] 00 )-3 , 3 -diflu0r0ind01in 1)ethan-1 -one (S)-1'—(6-amin0-5 -((2-amin0ch10r0pyridiny1)thi0)pyraziny1)(tert-buty1)—4,6-d \l \O ih dros o ir0[c clo o enta[b]thi0 ohene-5,4'- i o eridin]amine (S)amin0-1'-(6-amin0-5 -((2-amin0ch10r0pyridiny1)thi0)pyraziny1)-1,3 -dihyd ros o iro [indene-2 ,4'- o i o eridine] carb0x lic acid (2R)-1'—(6-amin0-5 -((2-aminoch10r0pyridin—4-y1)thio)pyraziny1)Spiro[bicyclo [3 . 1 . 0]hexane-3,4' o i o eridin] amine (S)-1'-(6-amino((2-amin0chloropyridiny1)thio)pyraziny1)-5,7-dihydr0spir0[c clo o enta[b] n ridine-6,4‘ o i o ]—7-amine (S)-1 '-(5 -(quin01iny1thi0)pyraziny1)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'—p 00 U) iperidin] -5 -amine (S)-1'—(6-amin0-5 -((2,3 -dich10r0phenyl)thio)pyraziny1)-5 ,7-dihydroSpiro[cyclopenta[ b] o ridine-6,4‘ o i o eridin]amine (S)-1'-(5-((3-ch10ro(dimethylamino)pyridinyl)thio)pyraziny1)-5,7-dihydrospir0[ c clo . enta[b] idine-6,4'- i . eridin]amine (S)-1'-(5-(pyridiny1thio)pyrazinyl)-5 ydrospiro[cyclopenta[b]pyridine-6,4’-pi eridin amine (S)-1'-(6-amino-5 -((3 -fluoropyridinyl)thio)pyrazinyl) -5 ,7-dihydrospiro [cyclopenta [b]pyridine-6,4'—piperidin] amine (S)-1 '-(6-ami110-5 -((3 pyridinyl)thio)pyraziny1)-4,6-dihydrospiro penta OO 00 [d]thiazole-5 ,4' o i o eridin] amine (S)-1 '-(6-amin0-5 -((3-ch10r0(methy1amino)pyridiny1)thio)pyrazin-2 -y1)-5 ,7-dihydr 0s o iro [c 010 o enta[b] o idine-6,4'- oi o eridin] amine diethy1(S)-(1-amin0-1'-(6-amin0((2-aminoch10ropyridiny1)thio)pyrazin-2 -y1)-1, 3-dih drOSoooir0[indene-2,4'-ieridin] 1) hOSohonate KO .— (S)-1'—(6-amin0-5 -((3-chloro-Z-(dimethylamin0)pyridinyl)thi0)pyraziny1)-5,7-dihy drOSoiro[c c10ooe11ta[b] -6,4'— 'oeridin]amine (S)-1'—(5 -((2-amino-3 -ch10r0pyridinyl)thio)pyrazin—2 -y1)ch10r0-4,6-dihydr0spir0[c \O U] do o enta[d]thiazole-5,4' oi o eridin]amine (R)-1'—(6-amin0-5 -((2-ami110ch1oropyridiny1)thi0)pyraziny1)-3H-spir0[fur0[2,3 - b] o ridine-2,4' o i o eridin]—3-amine (S)-1'-(5-((3-amin0ch10r0pheny1)thi0)pyraziny1)-5,7-dihydr0spir0[cyclopenta[b]p \O \] ridine-6,4' o i o eridin]—5-amine (S)-1'—(6-amin0-5 -((3-aminochl0r0pheny1)thi0)pyraziny1)-5,7-dihydr0spir0[cyclop enta[b] idine-6,4‘ o i o eridin]—5-amine (S)-1 '-(5 -((3-ch10r0meth0xypyridiny1)thi0)pyraziny1)-5,7-dihydr0spir0[cyc10pe nta[b] o ridine-6,4‘- o i o eridin]—5-amine (S)-1 '-(6-amin0-5 -((3-ch10r0meth0xypyridiny1)thio)pyrazin-2 -y1) -5 ydr0spir 0 [c 010 o enta[b] o -6,4‘- o i o eridin] amine (S)-1 '-(5 -((5 -ch10r0flu0r0pyridinyl)thio)pyraziny1)-5,7-dihydrospiro [cyclopenta [b]pyridine-6,4'—piperidin] ne (S)-1'—(6-amin0-5 h10r0flu0r0pyridiny1)thio)pyraziny1)-5,7-dihydrospiro[c o ridine-6,4' o i o eridin]amine (S)-1'-(5 -((2 ,3 -dichloropyridinyl)thio)pyraziny1)-5 ,7-dihydrospiro[cyclopenta[b]p ridine-6,4'- o i o eridin] amine (S)-1'—(6-amin0-5 -((2,3 -dich10r0pyridiny1)thi0)pyrazin-2 -y1)-5 ,7-dihydrospiro[cyc10p enta[b]pyridine-6,4'—piperidin] amine 106 (S)-1'-(5-((4-ch10ropyridi11y1)thi0)pyrazinyl)-5,7-dihydrospiro[cyclopenta[b]pyridi ne-6,4'-piperidin]amine (S)-1'—(6-amin0-5 -((4-ch10r0pyridiny1)thio)pyraziny1)-5,7-dihydrospir0[cyclopent a[b] o ridine-6,4‘- oi o ]—5-amine (S)-1 '-(5 -((3 -amin0pyridiny1)thi0)pyrazinyl)-5,7-dihydrospiro[cyc10penta[b]pyridi ne-6,4‘- o i o eridin]—5-amine (S)-1'—(6-amino-5 -((3 -aminopyridinyl)thio)pyraziny1) -5 ,7-dihydroSpiro[cyclopenta [b]pyridine-6,4'-piperidin] amine (S)-1'-(5 -((3 ,5 -dichloropyridinyl)thio)pyraziny1)-5 ,7-dihydrospiro[cyclopenta[b]p ridine-6,4'- o i o eridin amine (S)-1'-(6-amin0-5 -((3 ,5 -dich10ropyridiny1)thio)pyrazin-2 -y1)-5 ,7-dihydrospiro[cyc10p enta[b] o ridine-6,4' o i o eridin] -5 -amine (S)-1'—(5 -((2-amino-5 -ch1oropyridinyl)thi0)pyrazin-2 -y1)-5 ,7-dihydrospir0[cyc10pent o ridine-6,4‘- oi o eridin]amine (S)-1'—(6-amin0-5 mi110ch1oropyridiny1)thi0)pyrazin-2 -y1) -5 ydrospir0 [c clo o ] o ridine-6,4' o i o eridin] -5 -amine (S)-1 '-(6-amin0-5 -((2-(trifluoromethyl)pyridiny1)thi0)pyrazin-2 -y1)-5 ,7-dihydr0spir0[ c 010 o enta[b] o ridine-6,4‘- oi o eridin]amine (S)-1 '-(5 -((3 -ch10r0fluoropyridiny1)thi0)pyraziny1)-5 ,7-dihydr0spir0[cyc10penta o ridine-6,4' oi o eridin] -5 -amine (S)-1 '-(6-amin0-5 -((3-ch10r0fluoropyridin—4-y1)thi0)pyrazin-2 -y1) -5 ,7-dihydr0spir0[c clo o enta[b] o -6,4‘ o i o ] -5 -amine (S)-3 -((5 -(5 -amin0-5 ,7 -dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-1'-y1)pyrazin -2 - 1)thi0) o icolinonitrile (S)-3 -((3-amin0-5 -(5 -amin0-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4‘-piperidin]-1'-y 1)pyraziny1)thi0)picolinonitrile (S)-1 '-(5 -((2 -ch10r0-5 -(triflu0r0methyl)pyridiny1)thi0)pyrazin-2 -y1) -5 ,7-dihydrospir0[ c clo o enta[b] o ridine-6,4‘- oi o eridin]amine (S)-1'-(6-amino((2-ch10r0(trifluoromethyl)pyridiny1)thio)pyraziny1)-5,7-dihy dros o ir0[c Clo o enta[b] o ridine-6,4'- oi o eridin] ne 1'-(6-amino-5 -((2-amino-3 -chloropyridinyl)thio)pyrazin-2 -y1)-5 ,7-dihydroSpiro[cyclo o ] o ridine-6,4'- o i o eridin]amine 1'-(5 -((2 -amino-3 -ch10ropyridinyl)thio)pyraziny1)-5 ,7-dihydrospiro[cyclopenta[b] pyridine-6,4'—piperidin] amine 1'-(6-amin0-5 -((3 -ch10ropyridi11—4-yl)thio)pyraziny1)-5 ,7-dihydrospiro[cyclopenta[b] o ridine-6,4' o i o eridin] -5 -amine 1'-(6-amino-5 -((2-amin0chloropyridiny1)thi0)pyrazin-2 -y1)-1 ,3 -dihydr0Spiro[inde ne-2,4‘- o i o eridin]—1-amine 1'-(5 -((2 -amin0-3 -ch10r0pyridiny1)thio)pyraziny1)-1 ,3 -dihydrospiro[indene-2,4'-pi o ]—1-amine 1'-(6-amin0-5 -((3 -amin0ch10r0pheny1)thio)pyraziny1) -5 ,7-dihydrospiro[cyc10pent a[b] idine-6,4'- oi o eridin]amine 1'-(6-amino-5 -((2-aminochloropyridiny1)thio)pyraziny1)-5 ,7-dihydrospiro[cyclo o enta[c] o ridine-6,4'- o i o eridin] amine 1'-(5 -((3 -aminochloropheny1)thio)pyraziny1)-5,7-dihydrospiro[cyclopenta[b]pyridi ne-6,4'- o i o eridin]amine 1'-(6-amin0-5 -((2-amin0chloropyridin—4-y1)thi0)pyrazin-2 -y1)-5 -br0mo-1,3 -dihydros o iro[indene-2,4‘ o i o eridin]amine 1'-(6-amin0-5 -((2-ami110chl0r0pyridinyl)thi0)pyrazin-2 -y1)ch10r0-4,6-dihydros o ir0[c Clo o enta[d]thiazole-5 ,4'- o i o eridin]amine 1'-(5 -((2 -amin0-3 -ch10r0pyridi11—4-yl)thio)pyrazin—2-y1)ch10r0-4,6-dihydrospir0[cyc1 0 o enta[d]thiazole-5 ,4'- o i o eridin]amine 1'-(5 -((2 -amin0-3 -ch10r0pyridiny1)thio)pyrazin—2-y1)-2 ,3 -dihydrospir0[indene-1,4'-pi o eridin] amine (S)((3-amin0-5 -(1-amin0-1,3-dihydr0spir0[indene-2,4'-piperidin]-1'-y1)pyrazin-2 -y1)t hi0)-3 -ch10r0 o ridin01 ((5 -(5 -5 ,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-1'-y1)pyrazin -2 - 1)thi0)-3 -ch10r0 o idin01 (S)((3-amin0-5 -(5 -amin0-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'—piperidin]-1'-y 1)pyrazin-2 -y1)thi0) ch10r0pyridin01 (S)amin0-1'—(6-amin0((2-amin0ch10ropyridiny1)thio)pyraziny1)-1,3 -dihyd ros o ir0[indene-2,4' oi o ] 01 (S)amino-1'-(6-amino((2-amin0chloropyridiny1)thio)pyraziny1)-1,3 -dihyd ros o iro[indene-2,4'- oi o ]ol 1'-(6-amino-5 -((2-amino ch10ropyridiny1)thio)pyrazin-Z-y1)methy1-5,7-dihydrospiro[cyclopenta[b]pyridine- 6,4'-piperidin]amine 1 -amino-1 mino((2-aminoch10ropyridiny1)thio)pyraziny1)-3H-spir0[ind 01izine-2,4'-piperidin]—7(1H)-0ne (2 mg) 1-amin0-1'—(6-amino((2-aminoch10ropyridiny1)thio)pyraziny1)-3H-spir0[ind 01izine-2,4‘-piperidin]-5(1H)-one 3 -((2 -3 -ch10r0pyridiny1)thio)(1 -imin0-1,3 -dihydrospiro [indene-Z perid in] -1 '-y1)pyrazinamine 3 -((2 -amin0-3 -ch10r0pyridiny1)thi0)(1 -iminomethoxy-1,3-dihydrospiro [indene- 2,4'-piperidin]—1'-y1)pyrazinamine 3 -((2 -amino-3 -chloropyridiny1)thio)(4-imino-4,6-dihydrospiro[cyclopenta[b]thiop hene-S,4'-piperidin]-1'-y1)pyrazinamine 3 -((2 -amino-3 -ch10ropyridiny1)thio)(1-bromoimino-4H,6H-spiro[cyclopenta[c] thiophene-S ,4'-piperidin]-1'-y1)pyrazinamine 3 -((2 -amin0-3 -ch10r0pyridiny1)thio)(4-imin0-4H,6H-spiro[cyclopenta[c]thiophene -5 ,4'-piperidi11] - 1 yrazinamine 3 -((2 -3 -ch10r0pyridi11—4-y1)thi0)(2-br0m0imino-4,6-dihydrospir0[cyclopent a[b]thi0phene-5,4'-piperidi11]—1'-y1)pyrazinamine 1'-(6-amin0-5 -((2-ami110chl0r0pyridinyl)thi0)pyrazin-Z -y1)meth0xy-1,3 -dihydr ospiro[indene-2,4'-piperidin]amine (Z)-1'—(6-amin0-5 -((2-amin0ch10r0pyridin—4-y1)thi0)pyraziny1)spir0 [indene-Z ,4'-pi peridin] - 1 (3H)-0ne oxime (S)-1'-(6-amino-5 -((2-aminochloropyridinyl)thio)pyrazinyl)—2—methoxy-4,6-dihydr0spiro[cyclopenta[d]thiazole- 5 ,4'-piperidin] amine (S)-1'-(6-amino-5 -((2-amino-3 - chloropyridinyl)thio)pyrazin-2—yl)—4,6-dihydrospiro[cyclopenta[d]thiazole-5 ,4'-piperidin] amine (S)-1 '-(5 -((2-amin0-3 -ch10r0pyridiny1)thio)pyraziny1)-4,6-dihydrospiro[cyc10pent a[d]thiazole-5 ,4'-piperidin] amine 1'-(6-amin0-5 minochloropyridiny1)thio)pyraziny1)-4,6-dihydroSpiro[cyclo penta[d]thiazole-5,4'-piperidin]amine 1'-(5 -((2 -amino-3 -ch10ropyridiny1)thio)pyraziny1)-4,6-dihydrospiro[cyclopenta[d]t hiazole-S ,4'-piperidin] amine -(6-amino-5 -((2-amino ch10r0pyridin—4-y1)thio)pyrazin-Z-y1)-4,6-dihydrospir0[cyclopenta[d]thiazole-5,4'-piperi din]—6-amine (S)-1 '-(5 -((2-amin0-3 -ch10r0pyridiny1)thi0)pyraziny1) -4,6-dihydr0spir0[cyc10pent a[d]thiazole-5,4'-piperidin] amine (S)-1'—(6-amin0-5 -((3-flu0r0-1H-indolyl)thio)pyraziny1)-1,3 rospiro[indene- ,— (J1 \] , -piperidin]—1-amine (1-amin0-1'-(6-amino((2-aminochloropyridiny1)thio)pyraziny1)-1,3 -di hydrospiro[indene-2,4'-piperidin]yl)ethanone (S)(1-amin0-1'-(6-amino((2-aminochloropyridiny1)thio)pyraziny1)-1,3 -di hydrospiro[indene-Z,4'-piperidin]yl)ethan-l -one (R)-1'-(5 -((2-aminoch10ropyridinyl)thio)pyraziny1)-1 lspiro [indoline-Z ,4’ -piperidin] -3 -amine 1'-(6-amin0-5 -((2-amin0chloropyridin—4-yl)thi0)pyrazin-2 -y1)-2 ,3 -dihydroSpiro[inde ne-l ,4'-piperidi11] amine 1'-(6-amin0-5 -((2-ami110chl0r0pyridinyl)thi0)pyrazin-2 -y1)-3 ,4-dihydr0-2H-spir0[ naphthalene-1,4'-piperidi11]—2-amine 1'-(6-amin0-5 -((2-ami110chl0r0pyridin-4—yl)thi0)pyrazin-Z -y1)-5,6-dihydrospir0[cyc10 penta[b]pyridine-7,4'-piperidin]amine 1-(6-amin0((2-amin0-3 -chloropyridiny1)thio)pyraziny1)tetrahydr0-1 'H,3 'H-spir ridine-4,2'-pyrr01izin]-1‘-amine (1 'S)-1 -(6-amin0-5 -((2-amin0ch10r0pyridin—4-y1)thio)pyraziny1)tetrahydr0-1'H,3'H -spir0[piperidine-4,2'-pyrr01izin]-1'-amine 1'-(6-amin0-5 -((2-amin0chloropyridiny1)thio)pyraziny1)-4,6-dihydr0Spiro[cyclo penta[b] furan-S ,4'-piperidin] amine (S)-1'—(6-amin0-5 -((2-amin0ch1oropyridiny1)thio)pyrazin-2 -y1)-4,6-dihydrospir0 [c yclopenta[b] S,4'-piperidin]amine 1'-(6-amin0-5 -((2-amin0chl0r0pyridinyl)thio)pyraziny1)-6,7-dihydrospiro[cyclo penta[b]pyridine-5 ,4'-piperidin]amine 1'-(6-amino-5 -((2-amino-3 -chloropyridinyl)thio)pyraziny1)hexahydrospiro[cyclop ]furan-S ,4'-piperidin] amine (4R)-1'-(6-amino-5 -((2-aminochloropyridinyl)thio)pyraziny1)hexahydrospiro [c yclopenta[b] furan-S peridin]amine 1'-(6-amino-5 -((2-amino-3 -chloropyridinyl)thio)pyraziny1)spiro[bicyclo [3 . 1 .O]hex ane-3 ,4'-piperidin] amine 1'-amin0-1 -(6-amino((2-amin0chloropyridinyl)thi0)pyraziny1)tetrahydr0-1 'H ,3 'H-spiro [piperidine-4,2'-pyrr01izin] -3 '-0ne (1 'S)-1 '-amin0-1 -(6-amin0-5 -((2-aminochlor0pyridiny1)thio)pyraziny1)tetrahydr 0-1'H,3'H-spiro [piperidine-4,2'-pyrr01izin] -3 '-one 1'-(6-amin0-5 -((2-amin0-3 -ch10r0pyridinyl)thio)pyraziny1)spiro[bicyc10[3.1 .0]hex ane-2,4'—piperidin]—3 -amine '—(6-amino-5 -((2-aminochloropyridiny1)thio)pyraziny1)spiro[bicyclo[3.1 . 0]hexane-2,4'-piperidin] -3 -amine 3 -((2 -amino-3 opyridiny1)thio)(1 l-oxa-l ,7-diazadispiro [2 .0 . 54. 33]dodecan-7 - y1)pyrazinamine (3 -amin0-5 -(2-aminospiro[bicyclo[3.1.0]hexane-3,4’-piperidin]—1’-y1)pyrazin-2 -y1) thi0)-3 ,3 -difluoroind01iny1)ethanone 1'-(6-amin0-5 -((2-ami110chloropyridiny1)thi0)pyrazin-2 -y1)methy1spir0[bicyc10[ H \1 00 LR ._i O]hexane-3,4‘-piperidi11]amine (4R)-1 '-(6-amin0-5 -((2-ami110ch10ropyridiny1)thi0)pyrazin-2 -y1)-1 -methy1spir0 [bi cycle [3. 1 .0]hexane-3 ,4'-piperidi11] ami11e 1'-(6-amin0-5 -((2-amin0-3 -ch1oropyridiny1)thi0)pyrazin-Z -y1)Spiro[bicyc10 [3 .2 .0]hep tame-3 ,4'-piperidin] amine (2R)-1'—(6-amin0-5 -((2-amin0ch10r0pyridin—4-y1)thi0)pyraziny1)spir0[bicyc10 [3 .2. 0]heptane-3,4'-piperidin] amine 1'-(6-amin0-5 -((2-amin0ch1oropyridin-4—y1)thio)pyraziiiy1)hexahydr0-1H-spir0[pe ntalene-2,4'-piperidin]amine (1R)-1 '-(6-amin0-5 -((2-amin0ch10r0pyridin—4-y1)thio)pyraziny1)hexahydr0-1H-spi r0[pentalene-2,4'-piperidin]amine 1-(4-((3 -amin0-5 -(2-amin0-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-y1)pyraziny1)th i0)-3 , 3 -diflu0r0ind01iny1)ethanone 1'-(6-amin0-5 -((2-amin0-3 0pyridinyl)thio)pyraziny1)methoxy-2,3 r ospiro[indene-1,4'-piperidin]—2-amine (R)-1'-(6-amino-5 -((2-aminochloropyridiny1)thio)pyrazin-2 -y1)methoxy-2 ,3 -dih ydrospiro[indene-1,4'-piperidin]amine 1'-(6-amino-5 -((2-aminochloropyridiny1)thio)pyraziny1)-4,5 -dihydrospiro[cyc10 penta[b] furan-6,4'-piperidin] amine —(6-amin0-5 -((2-aminoch10r0pyridinyl)thi0)pyrazin-2 -y1) -4,5-dihydrospir0 [c nta[b] furan-6,4'—piperidin] amine 1-(4-((3 -amino-5 -(11-oxa-1,7-diazadispir0[2.0.54.33]d0decany1)pyraziny1)thi0)-3 ,3 1 8 9 -dif1uoroind01iny1)ethan0ne 1'-(6-amin0-5 -((2-amin0-3 -chl0r0pyridinyl)thio)pyrazin-Z-y1)hexahydrospir0[cyclop enta[b][1,4]di0xine-6,4'-piperidin]amine (5 S)-1'—(6-amin0-5 min0ch10ropyridiny1)thio)pyraziny1)hexahydrospiro[cy c10penta[b] [1,4]dioxine-6,4'—piperidin]amine 6-amin0-1'—(6-amino((2-aminochloropyridiny1)thio)pyraziny1)-6,7-dihydros piro[cyclopenta[b]pyridine-5 ,4‘-piperidin]-2(1H)-one amino-1'-(6-amino((2-aminochloropyridiny1)thio)pyrazin-2 -y1)-6,7-dihyd rospiro[cyclopenta[b]pyridine-5 ,4'-piperidin]-2( 1 H)-one 2-amino-1'—(6-amino((2-aminoch10r0pyridiny1)thio)pyraziny1)-2,3 -dihydr0-5 H-spiro [indolizine- 1 peridi11] -5 -011e (S)amin0-1 '-(6-ami110-5 -((2-amin0ch10r0pyridiny1)thi0)pyraziny1)-2 ,3 -dihyd r0-5H-spiro[indolizine- 1 ,4'-piperidin] 011e 1'-(6-amin0-5 -((2-ami110-3 0pyridinyl)thi0)pyrazin-Z-y1)spir0[chromane-4,4'-pi peridin] -3 -amine (S)-1 '-(6-amin0-5 -((2-amin0ch10r0pyridin-4—yl)thi0)pyrazin-2 -y1)Spiro[chr0mane-4,4 '-piperidin]—3-amine 1'-(6-amin0-5 -((2-amin0chloropyridiny1)thio)pyraziny1)meth0xy-1,3 -dihydr ospiro[indene-2,4'-piperidin]amine 1'-(6-amin0-5 -((2-amin0chloropyridiny1)thio)pyrazin-2 -y1)-3 ,4-dihydr0-1H-spir0[ naphthalene-2,4'—piperidin] -1 -amine 1-(6-amin0((2-amin0-3 -chloropyridinyl)thi0)pyraziny1)-7 ',8'-dihydr0-5'H-spiro [piperidine-4,6'—quin01in]-7'-amine 1'-(6-amin0-5 -((2-amin0chloropyridinyl)thi0)pyraziny1)-6,7-dihydrospiro[cyclo c]pyridine-5,4'-piperidin]amine (R)-1'—(6-amino-5 -((2-aminochloropyridiny1)thio)pyraziny1)-6,7-dihydrospir0[c yclopenta[c]pyridine-5 ,4'-piperidin]amine 1'-(6-amino-5 minochloropyridiny1)thio)pyraziny1)methoxy-3,4-dihydr o-1H-spiro[naphthalene-2,4‘-piperidin]amine (S)-1'-(6-amino-5 -((2-aminochloropyridinyl)thio)pyrazin-2 -y1)methoxy-3 ,4-dih ydro-1H-spir0[naphthalene-2,4'-piperidin]amine 1'-(6-amin0-5 -((2-ami110-3 -chl0r0pyridinyl)thi0)pyrazin-2 -y1)-5 ,6-dimeth0xy-1,3 -dih ydrospiro[indene-2,4'—piperidin]amine (S)-1'—(6-amin0-5 -((2-amin0ch10ropyridiny1)thio)pyraziny1)-5 ,6-dimeth0xy-1,3 -dihydr0spir0 [indene-2,4'-piperidin] -1 -amine 1-amin0-1'—(6-amino((2-amin0ch10ropyridiny1)thio)pyraziny1)-1,3 -dihydros ndene-2,4'—piperidin] 01 1'-(6-amino-5 -((2-aminochloropyridiny1)thio)pyrazin-2 -y1)-5 -methoxy-1,3 -dihydr ospiro[indene-2,4'-piperidin]amine 1'-(6-amino-5 -((2-aminochloropyridiny1)thio)pyraziny1)-4,6-dihydroSpiro[cyclo b]thiophene-5 ,4'-piperidin]amine 1-amin0-1'—(6-amino((2-aminochloropyridiny1)thio)pyraziny1)-1,3 -dihydros piro[indene-2,4'-piperidine] carb0nitrile 1'-(6-amin0-5 -((2-aminochl0r0pyridinyl)thi0)pyraziny1)meth0xy-1,3 -dihydr ospiro[indene-2,4'—piperidi11]amine amin0-5 mi110ch10r0pyridinyl)thi0)pyrazin-2 -y1)-1,3 -dihydr0Spiro[inde ne-2,4'-piperidine]-1,6-diamine 1-amin0-1'—(6-amin0((2-ami110ch10r0pyridiny1)thi0)pyraziny1)-1,3 r0s piro[indene-2,4'-piperidin] 01 1'-(6-amin0-5 -((2-amin0chloropyridiny1)thi0)pyraziny1)ch10r0-1,3-dihydr0s piro[indene-2,4'-piperidin] amine 1'-(6-amin0-5 -((2-amin0chloropyridiny1)thio)pyraziny1)br0m0-1 ,3 -dihydr0s ndene-2,4'-piperidin]amine 1'-(6-amino-5 -((2-amin0chloropyridiny1)thi0)pyrazin-2 -y1)-2 ,3 -dihydr0Spiro[inde ne-1,4'-piperidine]-2,5 -diamine (R)-1 '-(6-amin0-5 -((2-amin0ch10ropyridiny1)thio)pyrazin-2 -y1) -2,3-dihydr0spir0 [i ndene- 1 ,4'-piperidine] -2,5 -diamine 1'-(6-amin0-5 -((2-aminochl0r0pyridinyl)thio)pyraziny1)methoxy-2,3 -dihydr N )— 00 ospiro[indene-1,4'-piperidin]—2-amine (R)-1'-(6-amino-5 -((2-aminochloropyridiny1)thio)pyrazin-2 -y1)methoxy-2 ,3 -dih N r— Ko ydrospiro[indene-1,4'-piperidin]amine 1-(6-amino((2-amino-3 -chloropyridiny1)thio)pyraziny1)-1’H,3’H-spiro[piperidin e-4,2'-pyrr01izin]-1'-amine (S)(6-amin0((2-aminoch10ropyridiny1)thi0)pyraziny1)-1'H,3'H-spiro [piper idine-4,2'—pyrr01izin] -1 '-ami11e amino-5 -((2-amin0-3 -chloropyridjny1)thi0)pyrazin-2 -y1)-5 ,7-dihydr0Spiro[cyclo penta[c]pyridine-6,4'—piperidin]-?-amine 2-amin0-1'—(6-amino((2-amin0chloropyridiny1)thio)pyraziny1)-2,3 -dihydr0s piro[indene-1,4'-piperidine]carb0xamide amin0-1'—(6-amin0((2-amin0ch10ropyridiny1)thio)pyrazin-2 -y1)-2 ,3 -dihyd r0spir0[indene-1,4'-piperidine]carboxamide 2-amin0-1'-(6-amino((2-aminochloropyridiny1)thio)pyraziny1)-2,3 -dihydros piro[indene-1,4'-piperidine]carbonitrile (R)amino-1'—(6-amino((2-aminochloropyridiny1)thio)pyrazin-2 -y1)-2 ,3 -dihyd rospiro[indene-1,4'-piperidine]carbonitri1e N—(2-amin0-1'—(6-amino((2-amin0ch10ropyridin-4—y1)thio)pyrazin-2 -y1)-2 ,3 -dihyd [\J [\J \] r0spir0[indene-1,4'-piperidi11]y1)acetamide (R)-N-(2-amin0-1'-(6-ami110((2-amin0ch10r0pyridiny1)thi0)pyrazin-2 -y1)-2 ,3 -di hydrospiro[indene- 1 ,4'-piperidi11]y1)acetamide 1'-(6-amin0-5 -((2-ami110ch1oropyridinyl)thi0)pyraziny1)(pyrr01idiny1)-1,3 -dihydrospir0 [indene-2,4'-piperidin] -1 -amine (S)-1'—(6-amin0-5 -((2-amin0chloropyridiny1)thio)pyraziny1)(pyrr01idin-1 -y1) -1 ,3 -dihydr0Spiro [indene-2,4‘-piperidin] -1 -amine 1'-(6-amin0-5 -((2-amin0-3 -chloropyridiny1)thio)pyraziny1)(1,4-dimethy1-1H-1, 2, 3 -triazol-5 ,3 -dihydrospiro[indene-2,4'-piperidin]amine (S)-1'—(6-amin0-5 -((2-amin0ch10r0pyridiny1)thi0)pyraziny1)(1,4-dimethy1-1 [\J U) l\.) H-1,2,3 ol-5 -y1)-1,3 -dihydrospir0[indene—2,4'-piperidin]—1-amine 1'-(6-amin0-5 -((2-amin0chloropyridiny1)thi0)pyraziny1)(methy1thi0)-1,3-dih ydrospiro[indene-2,4'-piperidin]amine 2-(1-amin0-1'—(6-amino-5 -((2-amin0chloropyridiny1)thio)pyraziny1)-1,3 -dihydr ospiro[indene-2,4'—piperidin] y1)pr0pan01 (S)(1-amino-1'-(6-amino((2-aminochloropyridiny1)thio)pyraziny1)-1,3 -di hydrospiro [indene-Z,4'-piperidin]y1)propanol 1'-(6-amino-5 -((2-amino-3 -chloropyridiny1)thio)pyraziny1)(methylsu1fony1)-1,3 -dihydrospiro[indene-2,4'-piperidin]amine N-( 1 -amino-1 '-(6-amino((2-aminochloropyridiny1)thio)pyraziny1)-1,3 -dihyd o[indene-Z,4'-piperidin]y1)acetamide (S)-N-(1-amino-1'-(6-ami110((2-aminoch10ropyridiny1)thi0)pyraziny1)-1,3 -di piro[indene-2,4'-piperidin]y1)acetamide 1-amino-1'—(6-amino((2-amin0chloropyridiny1)thio)pyraziny1)-1,3 -dihydr0s piro[indene-2,4'—piperidine] carb0xamide 1'-(6-amin0-5 -((2-amin0chl0r0pyridinyl)thio)pyraziny1)(cyc10penty10xy)-1, 3-dihydr0spir0[indene-2,4'-piperidin]amine (S)-1'—(6-amino-5 -((2-aminochloropyridiny1)thio)pyraziny1)(cyclopenty10xy) -1,3 -dihydrospiro[indene-2,4'-piperidin]amine 1-amino-1'-(6-amino((2-aminochloropyridiny1)thio)pyraziny1)-3H-spiro[ind 242 olizine-Z,4'-piperidin]-7(1H)-one 1-amin0-1'-(6-amino((2-aminoch10r0pyridiny1)thio)pyraziny1)fluor0-1,3 - 243 dihydrospiro[indene-2,4'-piperidin]01 (S)amin0-1'—(6-amino((2-amin0ch10ropyridiny1)thi0)pyraziny1)-5 - 244 1,3-dihydr0spir0[indene-2,4‘-piperidin] 01 1'-(6-amin0-5 -((2-ami110ch10r0pyridinyl)thi0)pyrazin-Z -y1)-5 ,7-dihydr0-1H-spir0[ cyclopenta[f]indole-6,4‘-piperidin]amine (S)-1'—(6-amin0-5 -((2-amin0ch10r0pyridin—4-y1)thi0)pyrazin-2 -y1) -5 ,7-dihydr0-1H-sp ir0[cyclopenta[f]indole-6,4‘-piperidin]amine 1'-(6-amin0-5 -((2-amin0chloropyridiny1)thi0)pyrazin-2 -y1)-5 ,7-dihydr0- 1 H-spiro [i nden0[5,6-d]imidazole-6,4'-piperidin]amine (S)-1'—(6-amin0-5 min0ch10r0pyridiny1)thio)pyrazin-2 -y1) -5 ,7-dihydr0-1H-sp 248 ir0[inden0 [5 ,6-d] imidazole-6,4'-piperidin] amine 1'-(6-amino-5 -((2-amin0chloropyridiny1)thi0)pyraziny1)(1H-tetrazol-5 -y1)-1, drospir0[indene-2,4'-piperidin]amine (S)-1'—(6-amin0-5 -((2-amin0ch10ropyridiny1)thi0)pyraziny1)(1H-tetrazol-5 -y1 )-1, 3 -dihydr0spir0 [indene-2,4‘-piperidin] amine 1-(1-amin0-1'—(6-amin0-5 -((2-amin0chloropyridiny1)thio)pyraziny1)-1,3 -dihydr ospiro[indene—2,4'-piperidin]y1)methylurea (S)(1-amino-1'-(6-amino((2-aminochloropyridiny1)thio)pyraziny1)-1,3 -di hydrospiro[indene-Z,4'-piperidin] y1)methy1urea 1'-(5 -((2 -3 -ch10ropyridiny1)thio)pyraziny1)-2 ,3 -dihydrospiro[indene-1,4’-pi peridin] amine
117. A pharmaceutical composition comprising at least one compound or pharmaceutically acceptable salt thereof as defined in any one of claims 1-116 and at least one pharmaceutically able ent.
118. The pharmaceutical composition according to claim 117, wherein, the said compound or pharmaceutically acceptable salt thereof in a weight ratio to the said excipient within the range from about 0.0001 to about 10.
119. Use of a pharmaceutical composition of as defined in claim 117 or 118 for the preparation of a ment.
120. The use according to claim 119, wherein the medicament is for treatment or prevention a disease or disorder mediated by the activity of SHP2.
121. The use according to claim 1 19 or l20,wherein, the e or disorder mediated by the ty of SHP2 is cancer, cancer metastasis, cardiovascular disease, an immunological disorder, s, or an ocular disorder.
122. The use according to any one of claim 119-121, wherein, the disease or disorder mediated by the activity of SHP2 is one or more selected from Noonan Syndrome, Leopard Syndrome, juvenile onocytic leukemias, neuroblastoma, melanoma, head and neck squamous-cell carcinoma, acute myeloid leukemia, breast , esophageal tumor, lung cancer, colon cancer, head cancer, gastric carcinoma, lymphoma, astoma, gastric cancer, pancreatic cancer, and combination thereof.
123. Use of at least one compound or pharmaceutically acceptable salt thereof any one of claims 1-116 for the preparation of a medicament.
124. The use according to claim 123, the medicament is for treatment or prevention a disease or disorder mediated by the activity of SHP2.
125. The use according to claim 123 or 124, wherein, the disease or disorder mediated by the activity of SHP2 is cancer, cancer metastasis, cardiovascular disease, an immunological disorder, fibrosis, or an ocular disorder.
126. The use according to any one of claims 123-125, wherein, the e or disorderm d by the activity of SHP2 is one or more selected from Noonan me, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, head and neck squamous—cell carcinoma, acute myeloid ia, breast cancer, esophageal tumor, lung cancer, colon cancer, head cancer, gastric carcinoma, lymphoma, glioblastoma, c cancer, pancreatic cancer, and combination thereof.
127. At least one compound or pharmaceutically acceptable salt thereof as d in any one of claims 1-116, pharmaceutical ition of as defined in claim 117 or 118, which is for the preparation of a medicament.
128. The use according to claim 12?, wherein, the medicament is for treatment or prevention a disease or disorder mediated by the activity of SHP2.
129. The use according to claim 127 or 128, wherein, the disease or er mediated by the activity of SHP2 is cancer, cancer metastasis, cardiovascular disease, an immunological disorder, fibrosis, or an ocular disorder.
130. The use according to any one of claims 127-129, wherein, the disease or disorder mediated by the activity of SHP2 is one or more selected from Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, head and neck squamous-cell carcinoma, acute myeloid leukemia, breast cancer, esophageal tumor, lung cancer, colon cancer, head cancer, gastric carcinoma, lymphoma, glioblastoma, gastric cancer, pancreatic cancer, and combination thereof.
131. A method of treating a patient having a condition which is ed by the activity of SHP2, said method comprising administering to the patient a therapeutically effective amount of at least one nd or pharmaceutically acceptable salt thereof as defined in any one of claims 1-1 16, or the pharmaceutical composition of claim 1 17 or 1 18.
132. The method according to claim 131 wherein the condition mediated by the activity of SHP2 is cancer, cancer metastasis, cardiovascular disease, an immunological disorder, fibrosis, or an ocular disorder.
133. The method according to claim 131, wherein the condition mediated by the activity of SHP2 is noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemias, liver cancer, neuroblastoma, ma, squamous-cell carcinoma of the head and neck, acute myeloid leukemia, breast cancer, geal cancer, lung cancer, colon cancer, head cancer, gastric carcinoma, lastoma, ma, glioblastoma, gastric cancer, pancreatic cancer, and combination thereof.
134. A method of treatng cancer ed from the group consisting of noonan syndrome, d me, le myelomonocytic leukemias, liver cancer, neuroblastoma, melanoma, squamous—cell carcinoma of the head and neck, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, gastric carcinoma, lastoma, lymphoma, glioblastoma, gastric cancer, pancreatic , and combinations thereof, comprising administering to a mammal in need of such treatment an effective amount of at least one compound or ceutically acceptable salt thereof as defined in any one of claims 1-116, or the pharmaceutical composition of claim 117 or 118.
NZ790210A 2018-03-23 Novel heterocyclic derivatives useful as SHP2 inhibitors NZ790210A (en)

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