THE DESCRIPTION

NOVEL HETEROCYCLIC DERIVATIVES USEFUL AS SHP2 INHIBITORS Technical Field

This invention relates to certain novel pyrazine derivatives (Formula I, II, III or IV) as SHP2 inhibitors which is shown as Formula I, II, III or IV, their synthesis and their use for treating a SHP2 mediated disorder. More particularly, this invention is directed to fused heterocyclic derivatives useful as inhibitors of SHP2, methods 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 PTPN11 gene that harbors a classical 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-terminal SH2 domain blocks the PTP domain and this autoinhibition is relieved by binding of the SH2 domains to specific phospho tyrosine 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 enzymatic activation of SHP2.

SHP2 is widely expressed and participated in multiple cell signaling processes, such as the

Ras-Erk, PBK-Akt, Jak-Stat, Met, FGFR, EGFR, and insulin receptors and NF-kB pathways, in which plays an important role in proliferation, differentiation, cell cycle maintenance and migration.

The hyperactivation of SHP2 catalytic activity caused by either germline or somatic mutations in PTPN11 have been identified in patients with Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemias, myelodysplastic syndrome, B cell acute lymphoblastic leukemia/lymphoma, and acute myeloid leukemia. In addition, activating mutations of PTPN11 have been found in solid tumors as well, such as lung cancer, colon cancer, melanoma, neuroblastoma, and hepatocellular carcinoma. Therefore, the presence of activated or up-regulated SHP2 protein in human cancers and other disease make SHP2 an excellent target for development of novel therapies. The compounds of the present invention fulfill the need of small molecules in order to inhibit the activity of SHP2. Summary of Invention

The present invention relates to heterocyclic pyrazine compounds useful as SHP2 inhibitors and for the treatment of conditions mediated by SHP2. The compounds of the invention have the general structure as Formula I or a pharmaceutically acceptable salt:

I

Each Ri is independently -H, halogen, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, substituted or unsubstituted -Ci_6alkoxy, or substituted or unsubstituted -Ci_6alkyl;

Pv ₂ is -H, halogen, -NH ₂ , -CN, -OH, -N0 ₂ , -N ₃ , carboxyl, -NHCi _-6 alkyl, -N(Ci _-6 alkyl) ₂ , -CONH ₂ , -CONHCi _-6 alkyl, -CON(Ci _-6 alkyl) ₂ , -COCi _-6 alkyl, -NHCOCi _-6 alkyl,

-NCi _-6 alkyl-CO-Ci _-6 alkyl, substituted or unsubstituted -Ci _-6 alkoxy, substituted or unsubstituted -Ci _-6 alkyl or -C _5- i ₀ heterocyclic; or

R ₂ combines with Ri 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 Yi is independently N or CRi _a ;

Each Ri _a is independently -H, halogen, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, substituted or unsubstituted -Ci_6alkoxy, or substituted or unsubstituted

R ₃ is -H or -NH ₂ ;

Each of R4a and R ₄ b is independently -H, halogen, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, substituted or unsubstituted -Ci_6alkoxy, or substituted or unsubstituted -Ci_6alkyl; or

R _4a and R4b together with the carbon atom to which they are both attached form CO, C=NH, or C=N-OH;

p is 0, 1, 2 or 3;

Each of R _5a and R ₅ b is independently -H, halogen, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, substituted or unsubstituted -Ci _-6 alkoxy, or substituted or unsubstituted -Ci _-6 alkyl; or

R5 _a and Rs _b together with the carbon atom to which they are both attached form a 3-10 membered heterocyclic or 5-10 membered heteroaryl or and each of the ring systems is independently optionally substituted;

q is 0, 1, 2, 3 or 4; W is absent, -O, -S or -NR _W ; and R _w is -H, halogen, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, -CO-Ci_ ₆ alkyl, -CO-OCi_ ₆ alkyl, -Ci_ ₆ alkyl-0- substituted or unsubstituted

or substituted or unsubstituted -Ci _-6 alkyl;

Ring A is absent or a 3-10 membered ring;

— represents a single bond or a double bond;

When ring A is absent, Y ₂ is CR _2a R ₂ b, NR _2a or O, and Y ₃ is CR _3a R¾, NR _3a or O;

When ring A is a 3-10 membered ring,

i) Y ₂ is CR _2a or N, and Y ₃ is CR _3a or N, when = represents a single bond; or ii) Y ₂ is C, and Y ₃ is C, when— represents a double bond;

Each of R _2a and R _2b is independently -H, halogen, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, substituted or unsubstituted -Ci_ ₆ alkoxy, or substituted or unsubstituted -Ci_ ₆ alkyl;

Each of R _3a and R _¾ is independently -H, halogen, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, substituted or unsubstituted -Ci_ ₆ alkoxy, or substituted or unsubstituted -Ci_ ₆ alkyl;

Each R<5 is independently -H, halogen, -NR _6a R _6b , -CN, -OH, -N0 ₂ , oxo, =0, carboxyl, -Ci-6alkoxy, -Ci-6alkylene-NR6 _a R6b, -Ci-ealkylene-O-Ci-ealkyl, -Ci-ealkylene-CO-ORsa, -Ci-6alkylene-C _3- ioheterocyclic, -Ci-ealkylene-Cs-ioheteoaryl, -Ci-6alkylene-CO-NR6 _a R6b,

-Ci _-6 alkylene-NR6 _a -CO-NR _6a R6b, -Ci _-6 alkylene-NR6 _a -CO-Ci _-6 alkyl, -CO-NR _6a R ₆ b,

-CO-CO-NR6 _a R5b, -C _3- iocarbocyclic, -C _3- ioheterocyclic, -CO-Ci_6alkyl,

-CO-Ci _-6 alkylene-NR6 _a R6b, -CO-NR6 _a -C _3- i ₀ heterocyclic, -CO-NR6 _a -C _3- i ₀ heterocyclic,

-CO-C _3- ioheteocyclic, -0-Ci _-6 alkylene-CO-OR _6a , -0-Ci _-6 alkylene-CO-NR6 _a R ₆ b,

-0-Ci _-6 alkylene-NR _6a R _6b , -O-C _3- i ₀ carbocyclic, -O-C _3- i ₀ heterocyclic, -NR _6a -CO-Ci _-6 alkyl, -NRea-CO-NReaRfib^NRea-CO-Cs-ioheteoaryl, -NR6 _a -Ci _-6 alkylene-NR _6a R6b,

-NR _6a -Ci _-6 alkylene-C _3- ioheterocyclic, -NR _6a -Ci _-6 alkylene-C _5- ioheteroaryl, -NR _6a -S0 ₂ Ci _-6 alkyl, -S-Ci _-6 alkyl, -SONR^, -SO^Re.Re _b , -SO-Ci _-6 alkyl, -S0 ₂ Ci _-6 alkyl, -PO(Ci _-6 alkyl) ₂ ,

-PO(Ci_ ₆ alkoxy) ₂ , -C _3- ioheterocyclic or -Cs-ioheteroaryl; each of which is independently optionally substituted; and n is 0, 1, 2, 3, 4, 5 or 6; or

Two adjacent R<5 can be joined together to form a 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, -C _3-6 heterocyclic or -C _3-6 carbocyclic, and each of the ring systems is independently optionally substituted;

Each of s _a and R _6b is independently -H, halogen, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, substituted or unsubstituted -Ci_ ₆ alkoxy, or substituted or unsubstituted -Ci- ₆ alkyl.

The present invention further provides some preferred technical solutions with regard to compound of Formula I.

In some embodiments of Formula I: Each Ri is independently -H, halogen, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, substituted or unsubstituted -Ci_ ₆ alkoxy, or substituted or unsubstituted Ci_ ₆ alkyl;

R ₂ is -H, halogen, -NH ₂ , -CN, -OH, -N0 ₂ , -N ₃ , carboxyl, -NHCi _-6 alkyl, -N(Ci _-6 alkyl) ₂ , -CONH ₂ , -CONHCi _-6 alkyl, -CON(Ci _-6 alkyl) ₂ , -COCi _-6 alkyl, -NH-CO-Ci _-6 alkyl,

-NCi _-6 alkyl-CO-Ci _-6 alkyl, substituted or unsubstituted -Ci _-6 alkoxy, substituted or unsubstituted -Ci- ₆ alkyl or -Cs-ioheterocyclic; or

R ₂ combines with Ri 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;

Each Yi is independently N or CRi _a ;

Each Ri _a is independently -H, halogen, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, substituted or unsubstituted -Ci_ ₆ alkoxy, or substituted or unsubstituted

R ₃ is -H or -NH ₂ ;

Each of R4a and R ₄ b is independently -H, halogen, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, substituted or unsubstituted -Ci_ ₆ alkoxy, or substituted or unsubstituted -Ci_ ₆ alkyl; or

R _4a and R4b together with the carbon atom to which they are both attached form CO;

p is 0, 1, 2 or 3;

Each of R _5a and R _5b is independently -H, halogen, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, substituted or unsubstituted -Ci_ ₆ alkoxy, or substituted or unsubstituted -Ci_ ₆ alkyl; or

Rs _a and Rs _b 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 1, 2, 3 or 4;

W is absent, O, NR _W or S;

R _w is -H, halogen, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, -CO-Ci _-6 alkyl, -CO-OCi _-6 alkyl, substituted or unsubstituted -Ci_ ₆ alkoxy, or substituted or unsubstituted -Ci_ ₆ alkyl;

Ring A is absent or a 3-10 membered ring;

— represents a single or double bond;

When ring A is absent, Y ₂ is -CR _2a R ₂ b, -NR _2a or -O, and Y ₃ is -CR _3a R%, -NR _3a or O;

When ring A is a 3-10 membered ring,

i) Y ₂ is CR _2a or N, and Y ₃ is CR _3a or N, when = represents a single bond; or ii) Y ₂ is C, and Y ₃ is C , when = represents a double bond;

Each of R _2a and R¾ is independently -H, halogen, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, substituted or unsubstituted -Ci_ ₆ alkoxy, or substituted or unsubstituted -C _h alky!; Each of R _3a and R% is independently -H, halogen, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, substituted or unsubstituted -Ci_ ₆ alkoxy, or substituted or unsubstituted -Ci_ ₆ alkyl;

Each R<5 is independently -H, halogen, -NRea sb, -CN, -OH, -N0 ₂ , oxo, =0, carboxyl, -Ci_6alkoxy, -C _1-6 alkyl, -Ci.6alkylene-NR6 _a R6b, -C _1-6 alkylene-0-C _1-6 alkyl, -Ci.6alkylene-CO-OR6 _a , -Ci _-6 alkylene-C _3- i ₀ heterocyclic, -Ci _-6 alkylene-C _5- i ₀ heteoaryl, -Ci _-6 alkylene-CO-NR6 _a R6b,

-Ci _-6 alkylene-NR6 _a -CO-NR _6a R6b, -Ci _-6 alkylene-NR6 _a -CO-Ci _-6 alkyl, -CO-NR _6a R ₆ b,

-CO-CO-NRgaReb, -CO-Ci _-6 alkyl, -CO-Ci _-6 alkylene-NR6aR ₆ b, -CO-NR _6a -C _3- i ₀ heterocyclic, -CO-NR6a-C _3- i ₀ heterocyclic, -CO-C _3- i ₀ heteocyclic, -0-Ci _-6 alkylene-CO-OR6 _a ,

-0-Ci _-6 alkylene-CO-NR _6a R6b, -0-Ci _-6 alkylene-NR _6a R6b, -O-C _3- i ₀ carbocyclic, -NR _6a -CO-Ci _-6 alkyl, -NR6 _a -CO-NR _6a R ₆ b, -NRea-CO-Cs-ioheteoaryl, -NR6 _a -Ci _-6 alkylene-NR _6a R6b,

-NR6 _a -Ci- ₆ alkylene-C _3- ioheterocyclic, -NRsa-Ci-ealkylene-Cs-ioheteroaryl, -S-C _1-6 alkyl,

-SONRgaReb, -S0 ₂ NR6aR6b, -SO-Ci _-6 alkyl, -S0 ₂ Ci _-6 alkyl, -PO(Ci _-6 alkyl) ₂ , -C _3- i ₀ heterocyclic or -C5-ioheteroaryl, and each of which is independently optionally substituted; and n is 0, 1, 2, 3, 4, 5 or 6; or

Two adjacent Rg can be joined together to form a 6-membered aryl, 5-membered heteroaryl,

6-membered heteroaryl, -C _3-6 heterocyclic or -C _3-6 carbocyclic, and each of the ring system is independently optionally substituted;

Each of Rga and Rgb is independently -H, halogen, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, substituted or unsubstituted -Ci _-6 alkoxy, or substituted or unsubstituted -Ci _-6 alkyl.

In some embodiments of Formula I, each Ri is independently -H; -F; -CI; -Br; -NH ₂ ; -CN;

-OH; -N0 ₂ ; carboxyl; -Ci _-6 alkyl; -Ci _-6 alkoxy; -Ci _-6 alkyl substituted with halogen, -NH ₂ , -CN,

-OH, -N0 ₂ , carboxyl, -Ci _-3 alkyl or -Ci _-3 alkoxy; or -Ci _-6 alkoxy substituted with halogen, -NH ₂ ,

-CN, -OH, -N0 ₂ , carboxyl, -Ci _-3 alkyl or -Ci _-3 alkoxy.

In some embodiments of Formula I, each Ri is independently -H; -F; -CI; -Br; -NH ₂ ; -CN; -OH; -N0 ₂ ; carboxyl; -Ci _-3 alkyl; -Ci _-3 alkoxy; -Ci _-6 alkyl substituted with -F, -CI, -Br, -I, -NH ₂ ,

-CN, -OH, -N0 ₂ , carboxyl, -Ci _-3 alkyl or -Ci _-3 alkoxy; or -Ci _-6 alkoxy substituted with -F, -CI, -Br,

-I, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, -Ci _-3 alkyl or -Ci _-3 alkoxy.

In some embodiments of Formula I, each Ri is independently -H; -F; -CI; -Br; -NH ₂ ; -CN;

-OH; -N0 ₂ ; carboxyl; methyl; ethyl; propyl; isopropyl; methoxy; ethoxy; propoxy; isopropoxy; -Ci _-3 alkyl substituted with -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; or Ci _-3 alkoxy substituted with -F, -CI, -Br,

-NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy. In some embodiments of Formula I, each Ri is independently -H; -F; -CI; -Br; -NH ₂ ; -CN; -OH; methyl; ethyl; propyl; isopropyl; methoxy; ethoxy; propoxy; isopropoxy; or methyl substituted with one or more substituents each independently selected from -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula I, each Ri is independently -CI, or -H.

In some embodiments of Formula I, R ₂ is -H; -F; -CI; -Br; -NH ₂ ; -CN; -OH; -N0 ₂ ; -N ₃ ;

carboxyl; -Ci _-6 alkyl; -Ci _-6 alkoxy; -NHCi _-6 alkyl; -N(Ci _-6 alkyl) ₂ ; -CONH ₂ ; -CONHCi _-6 alkyl;

-CON(Ci _-6 alkyl) ₂ ; -COCi _-6 alkyl; -NHCOCi _-6 alkyl; -N(Ci _-6 alkyl)-CO-Ci _-6 alkyl; -C _5- i ₀ heterocyclic; -Ci _-6 alkyl substituted with halogen, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, -Ci _-3 alkyl or -Ci _-3 alkoxy; or -Ci _-6 alkoxy substituted with halogen, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, -Ci _-3 alkyl or -Ci _-3 alkoxy.

In some embodiments of Formula I, R ₂ is -H; -F; -CI; -Br; -NH ₂ ; -CN; -OH; -N0 ₂ ; -N ₃ ;

carboxyl; -Ci _-3 alkyl; -Ci _-3 alkoxy; -NHCi _-3 alkyl; -N(Ci _-3 alkyl) ₂ ; -CONH ₂ ; -CONHCi _-3 alkyl;

-CON(Ci _-3 alkyl) ₂ ; -COCi _-3 alkyl; -NHCOCi _-3 alkyl; -N(Ci _-3 alkyl)-CO-Ci _-3 alkyl; -C _5- i ₀ heterocyclic; -Ci _-6 alkyl substituted with -F, -CI, -Br, -I, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, -Ci _-3 alkyl or

-Ci _-3 alkoxy; or -Ci _-6 alkoxy substituted with -F, -CI, -Br, -I, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, -Ci _-3 alkyl or -Ci _-3 alkoxy.

In some embodiments of Formula I, R ₂ is -H; -F; -CI; -Br; -NH ₂ ; -CN; -OH; -N0 ₂ ; -N ₃ ;

carboxyl; methyl; ethyl; propyl; isopropyl; methoxy; ethoxy; propoxy; isopropoxy; -NHCH ₃ ; - -CONH ₂ ; -CONHCH -CON(CH ₃ ) ₂ ; -COCH ₃ ; -NH-COCH ₃ ; -N(CH ₃ )-COCH ₃ ; -Ci _-3 alkyl substituted with -F, -CI, -Br, -NH ₂ , -CN, -OH,

-N0 ₂ , carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; or

Ci _-3 alkoxy substituted with -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula I, R ₂ is -H; -F; -CI; -Br; -NH ₂ ; -CN; -OH; -N0 ₂ ; carboxyl; methyl; ethyl; propyl; isopropyl; methoxy; ethoxy; propoxy; isopropoxy; or methyl substituted with one or more substituents each independently selected from -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula I, R ₂ is -NH ₂ .

In some embodiments of Formula I, R combines with Ri 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, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, oxo, =0, -CONH ₂ , substituted or unsubstituted -Ci _-6 alkoxy, substituted or unsubstituted -Ci _-6 alkyl, -Ci _-6 alkylene-0-Ci _-6 alkyl, -Ci _-6 alkylene-COOH, -Ci _-6 alkylene-NHCONH ₂ , -CO-N(Ci _-6 alky) ₂ , -Ci _-6 alkylene-NHCO-Ci _-6 alkyl, -CO-CO-N(Ci _-6 alkyl) ₂ , -CO-Ci _-6 alkyl, -SONH ₂ , -S0 ₂ NH ₂ , -SOCH ₃ , -S0 ₂ CH ₃ , -C5-ioheterocyclic or -Cs-ioheteroaryl.

In some embodiments of Formula I, R ₂ combines with Ri to which is adjacent to form a 5-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 heteroaryl or heterocyclic contains 1 or 2 heteroatoms selected from N or O; and each of the ring systems is independently optionally substituted with -F, -CI, -Br, -I, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, oxo, =0, -CONH ₂ , substituted or unsubstituted Ci _-3 alkoxy, substituted or unsubstituted Ci _-3 alkyl, -Ci _-3 alkylene-0-Ci _-3 alkyl, -Ci _-3 alkylene-COOH, -Ci _-3 alkylene-NHCONH ₂ , -CO-N(Ci _-3 alky) ₂ , -Ci _-3 alkylene-NHCO-Ci _-3 alkyl, -CO-CO-N(Ci _-3 alkyl) ₂ , -CO-Ci _-3 alkyl, -SONH ₂ , -S0 ₂ NH ₂ , -SOCH ₃ or -S0 ₂ CH ₃ .

In some embodiments of Formula I, R ₂ combines with Ri to which is adjacent to form a

5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic or 8-membered heterocyclic; and each of the heteroaryl or heterocyclic contains 1 heteroatom selected from N or

O; and each of the ring systems is independently optionally substituted with -F; -CI; -Br; -NH ₂ ;

-CN; -OH; -N0 ₂ ; carboxyl; oxo; =0; -CONH ₂ ; methyl; ethyl; propyl; isopropyl; methoxy; ethoxy; propoxy; isopropoxy; -CH ₂ OCH ₃ ; -CH ₂ COOH; -CH ₂ NHCONH ₂ ; -CON(CH ₃ ) ₂ ; -CH ₂ NHCOCH ₃ ; -CO-CON(CH ₃ ) ₂ ; -COCH ₃ ; -Ci _-3 alkyl substituted with halogen, -NH ₂ , -CN, -OH, -N0 ₂ or carboxyl; or -Ci _-3 alkoxy substituted with halogen, -NH ₂ , -CN, -OH, -N0 ₂ or carboxyl.

In some embodiments of Formula I, R combines with Ri to which is adjacent to form a

5-membered heterocyclic, and optionally substituted with -F or -COCH ₃ .

In some embodiments of Formula I, R and Ri which is adjacent to, together with the aromatic

In some embodiments of Formula I, each Yi is independently N or CH.

In some embodiments of Formula I, each of R4 _a and R ₄ b is independently -H, -F, -CI, -Br, -I, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, substituted or unsubstituted -Ci_ ₆ alkoxy, or substituted or unsubstituted -Ci_ ₆ alkyl; or R _4a and R _4b together with the carbon atom to which they are both attached form C=0, C=NH, or C=N-OH.

In some embodiments of Formula I, each of R _4a and R ₄ b is independently -H; -F; -CI; -Br; -NH ₂ ; -CN; -OH; -N0 ₂ ; carboxyl; -Ci _-3 alkyl; -Ci _-3 alkoxy; -Ci _-6 alkyl substituted with -F, -CI, -Br, -I, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, -Ci _-3 alkyl or -Ci _-3 alkoxy; or Ci _-6 alkoxy substituted with -F, -CI, -Br, -I, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, -Ci _-3 alkyl or -Ci _-3 alkoxy; or R4 _a and R4b together with the carbon atom to which they are both attached form C=0.

In some embodiments of Formula I, each of R^ or R _4b is independently -H; -F; -CI; -Br; -NH ₂ ; -CN; -OH; -N0 ₂ ; carboxyl; methyl; ethyl; propyl; isopropyl; methoxy; ethoxy; propoxy;

isopropoxy; Ci _-3 alkyl substituted with -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; or Ci _-3 alkoxy substituted with -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; or R4 _a and R4b together with the carbon atom to which they are both attached form C=0.

In some embodiments of Formula I, each of R4 _a and R _4b is independently -H, -NH ₂ , -OH, methyl, ethyl, methoxy, ethoxy; or R _4a and R ₄ b together with the carbon atom to which they are both attached form C=0.

In some embodiments of Formula I, p is 0, 1, 2 or 3.

In some embodiments of Formula I, each of R _5a and R ₅ b is independently -H; -F; -CI; -Br; -I; -NH ₂ ; -CN; -OH; -N0 ₂ ; carboxyl; -Ci _-3 alkyl; -Ci _-3 alkoxy; -Ci _-6 alkyl substituted with -F, -CI, -Br, -I, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, -Ci _-3 alkyl or -Ci _-3 alkoxy; or substituted with -F, -CI, -Br, -I, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, -Ci _-3 alkyl or -Ci _-3 alkoxy; orR _5a and R _5b 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, 5-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, -CI, -Br, -I, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, substituted or unsubstituted -Ci _-3 alkoxy, or substituted or unsubstituted -Ci _-3 alkyl.

In some embodiments of Formula I, each of Rs _a or R _5b is independently -H, -NH ₂ , -OH, methyl, ethyl, methoxy or ethoxy; or R _5a and Rs _b together with the carbon atom to which they are both attached form a 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 5-membered heteroaryl or 6-membered heteroaryl; and each of the heterocyclic or heteroaryl contains 1 heteroatoms selected from N or O.

In some embodiments of Formula I, each of R _5a or Rs _b is independently -H or -NH ₂ .

In some embodiments of Formula I, W is absent, O, or NR _W .

In some embodiments of Formula I, W is NRw, and R _w is -H, -F, -CI, -Br, -I, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, -CO-Ci _-3 alkyl, -COOCi _-3 alkyl, -Ci _-3 alkyl-CO-Ci _-3 alkyl, substituted or unsubstituted -Ci _-3 alkoxy, or substituted or unsubstituted -Ci _-3 alkyl. In some embodiments of Formula I, W is NRw, and R _w is -H; -F; -CI; -Br; -NH ₂ ; -CN; -OH; -N0 ₂ ; carboxyl; methyl; ethyl; propyl; isopropyl; methoxy; ethoxy; propoxy; isopropoxy;

methyl-CO- methyl; -Ci _-3 alkyl substituted with -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; or Ci _-3 alkoxy substituted with -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, 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, 10-membered aryl; 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 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, 6-membered carbocyclic, 7-membered carbocyclic, 8-membered carbocyclic, 9-membered carbocyclic or 10-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 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, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 8-membered heterocyclic; 3-membered carbocyclic, 4-membered 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 contains 1 or 2 heteroatoms selected from N or O.

|_| Υ J £ ΛΟ ΑΟ Ο Α Χ ΝΗ Υ

10 3 50 ίο ;¾ο 3ο ίο 3ο io to so X» to so. 50, 56, :ύ , 2 6 , 30 , ;ιο , , so , ;ίθ , ιο , ίο , ο « , :ίο , ¾ο , ¾ο ,

In some embodiments of Formula I, Y ₂ is CR _2a or N, and Y ₃ is CR _3a or N.

In some embodiments of Formula I, Y ₂ is CR _2a and Y ₃ is CR _3a .

In some embodiments of Formula I, each of R _2a and R _2b is independently -H; -F; -CI; -Br; -NH ₂ ; -CN; -OH; -N0 ₂ ; carboxyl; -C _1-3 alkyl; -Ci _-3 alkoxy; -C _1-6 alkyl substituted with -F, -CI, -Br, -I, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, -Ci _-3 alkyl or -Ci _-3 alkoxy; or -Ci _-6 alkoxy substituted with -F, -CI, -Br, -I, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, -Ci _-3 alkyl or -Ci _-3 alkoxy.

In some embodiments of Formula I, each of R _2a and R _¾ is independently -H; -F; -CI; -Br; -NH ₂ ; -CN; -OH; -N0 ₂ ; carboxyl; methyl; ethyl; propyl; isopropyl; methoxy; ethoxy; propoxy; isopropoxy; -Ci _-3 alkyl substituted with -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; or -Ci _-3 alkoxy substituted with -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula I, each of R _2a and R _¾ is independently -H or methyl. In some embodiments of Formula I, R _a is -H or methyl, and R _¾ is -H.

In some embodiments of Formula I, R _a and R _¾ are both -H.

In some embodiments of Formula I, Y is CH or N, and Y ₃ is CH or N. In some embodiments of Formula I, Y ₂ is CH, and Y ₃ is CH.

In some embodiments of Formula I, Y ₂ is CH, and Y ₃ is N.

In some embodiments of Formula I, Y ₂ is N, and Y ₃ is CH.

In some embodiments of Formula I, each of R _3a and R% is independently -H, -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, -Ci _-3 alkyl, -Ci _-3 alkoxy, or -Ci _-6 alkyl or -Ci _-6 alkoxy substituted with -F, -CI, -Br, -I, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, -Ci _-3 alkyl or -Ci _-3 alkoxy.

In some embodiments of Formula I, each of R _3a and R _¾ is independently -H.

In some embodiments of Formula I, each R ₆ is independently -H, -F, -CI, -Br, -I, -NR6 _a R6b, -CN, -OH, oxo, =0, carboxyl, -Ci _-6 alkoxy, -Ci _-6 alkyl, -Ci _-6 alkylene-NR _6a R6b,

-Ci _-6 alkylene-0-Ci _-6 alkyl, -Ci _-6 alkylene-CO-OR6 _a , -Ci _-6 alkylene-C _5- ioheterocyclic,

-Ci-ealkylene-Cs-ioheteoaryl, -Ci-6alkylene-CO-NR6 _a R6b, -Ci-6alkylene-NR6 _a -CO-NR6 _a R6b, -Ci _-6 alkylene-NR6 _a -CO-Ci _-6 alkyl, -CO-NR6 _a R _6b , -CO-CO-NR6 _a R6 _b , -CO-Ci _-6 alkyl,

-CO-Ci-6alkylene-NR6 _a R6b, -CO-NRea-Cs-ioheterocyclic, -CO-NRea-Cs-ioheterocyclic,

-CO-Cs-ioheterocyclic, -0-Ci _-6 alkylene-CO-OR _6a , -0-Ci _-6 alkylene-CO-NR _6a R ₆ b,

-0-Ci _-6 alkylene-NR6 _a R6b, -O-C _5- i ₀ carbocyclic, -NR6 _a -CO-Ci _-6 alkyl, -NR _6a -CO-NR6 _a R6b,

-NRsa-CO-Cs-ioheteoaryl, -NR6 _a -Ci-6alkylene-NR6 _a R6b, -NR6 _a -Ci-6alkylene-C _3- ioheterocyclic, -NR6 _a -Ci _-6 alkylene-C _5- ioheteroaryl, -S-Ci _-6 alkyl, -S0 ₂ NR6 _a R6b, -S0 ₂ Ci _-6 alkyl, -PO(CH ₃ ) ₂ , -C5-ioheterocyclic or -Cs-ioheteroaryl, and each of which is independently optionally substituted -F, -CI, -Br, -I, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, oxo, =0, substituted or unsubstituted -Ci _-3 alkoxy, or substituted or unsubstituted -Ci _-3 alkyl; or two adjacent R ₆ can be joined together to form a

6-membered aryl; 3-membered carbocyclic, 4-membered 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 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, -NH ₂ , -CN, -OH, -N0 ₂ , =0, oxo, carboxyl, -CONH ₂ , -PO(Ci _-6 alkyl) ₂ , substituted or unsubstituted -Ci _-6 alkoxy or substituted or unsubstituted -Ci _-6 alkyl.

In some embodiments of Formula I, each 5 is independently -H, -F, -CI, -Br, -NRea sb, -CN, -OH, oxo, =0, carboxyl, -Ci _-6 alkoxy, -Ci _-6 alkyl, -Ci _-6 alkylene-NR6 _a R6b, -Ci _-6 alkylene-0-Ci _-6 alkyl, -Ci- ₆ alkylene-CO-OR6 _a , -Ci-ealkylene-Cs-ioheterocyclic, -Ci-ealkylene-Cs-ioheteoaryl,

-Ci _-6 alkylene-CO-NR6 _a R ₆ b, -Ci _-6 alkylene-NR6 _a -CO-NR _6a R6b, -CO-NRe.Reb, -CO-CO-NReaReb, -CO-Ci_ ₆ alkyl, -CO-NRea-Cs-ioheterocyclic, -CO-Cs-ioheterocyclic, -O-Cs-iocarbocyclic,

-NR6a-CO-Ci _-6 alkyl, -NRea-CO-NRea , -NR6a-Ci _-6 alkylene-NR ₆ aR6b,

-NR6a-Ci _-6 alkylene-C _3- ioheterocyclic, -S-Ci _-6 alkyl, -S0 ₂ NR _6a R6b, -S0 ₂ Ci _-6 alkyl, -C5-ioheterocyclic or -Cs-ioheteroaryl, and each of which is independently optionally substituted -F, -CI, Br, -NH ₂ , -OH, carboxyl, oxo, =0, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; or two adjacent 5 can be joined together to form a 6-membered aryl; 5-membered carbocyclic, 5-membered heteroaryl or 5-membered heterocyclic; and and 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, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , =0, oxo, carboxyl, -CONH ₂ , -PO(CH ₃ ) ₂ , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula I, each R ₆ is independently -H, -F, -CI, -Br, -NR _6a R<5b, -CN, -OH, oxo, =0, carboxyl, -Ci _-3 alkoxy, -Ci _-3 alkyl, -Ci _-3 alkylene-NR6 _a R6b, -Ci _-3 alkylene-0-Ci _-3 alkyl, -Ci _-3 alkylene-CO-OR6a, -Ci _-3 alkylene-C5-6heterocyclic, -Ci _-3 alkylene-C5-6heteoaryl,

-Ci _-3 alkylene-CO-NR6aR ₆ b, -Ci _-3 alkylene-NR ₆ a-CO-NR ₆ aR6b, -CO-NRgaReb, -CO-CO-NRgaReb, -CO-Ci _-3 alkyl, -CO-NR6 _a -C5- ₆ heterocyclic, -CO-Cs-eheterocyclic, -O-Cs-ecarbocyclic,

-NR6a-CO-Ci _-6 alkyl, -NRea-CO-NRea , -NR6 _a -Ci _-3 alkylene-NR ₆ aR6b,

-NR6a-Ci- ₆ alkylene-C _3-6 heterocyclic, -S-Ci _-3 alkyl, -S0 ₂ NR6 _a R6b, -S0 ₂ Ci _-3 alkyl, -Cs-eheterocyclic or -C5_ ₆ heteroaryl, and each of which is independently optionally substituted with one or more substituents each independently selected from -F, -CI, Br, -NH ₂ , -OH, carboxyl, oxo, =0, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; or two adjacent R ₆ can be joined together to form a 6-membered aryl; 5-membered carbocyclic, 5-membered heteroaryl or 5-membered heterocyclic; and and 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, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , =0, oxo, carboxyl, -CONH ₂ , -PO(CH ₃ ) ₂ , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula I, each R ₆ is independently -F, -CI, -Br, =0, -OH, -CN,

-NH ₂ , ^OH , -CH ₃ , ^{~ ~} , -CF ₃ , ¾ ^0H , -OCH ₃ , -SCH ₃ , -SOCH ₃ , -S0 ₂ CH ₃ , -PO(CH ₃ ) ₂ ,

O O \ ) H

-PO(OC ₂ H ₅ ) ₂ , - -C(0) H ₂ , i , ¼\H , -NHCOCH ₃ , I ,

NHCONHCH ₃ , ?, * " ,, ₀ r two adjacent Rg can be joined together to form

In some embodiments of Formula I, each R ₆ is independently methyl, ethyl, isopropyl, methoxy, ethoxy, =0, oxo, -OH, -CN, -NH ₂ , -CI, -Br, -CF ₃ , -OCF ₃ , -S0 ₂ NH ₂ , -S0 ₂ CH ₃ , -F



is independently optionally substituted with another one or more R ₆ .

In some embodiments of Formula I, n is 0, 1, 2 or 3.

In some embodiments of Formula I, each ₆ b is independently -H; -F;- CI; -Br; -NH ₂ ; -CN; -OH; -N0 ₂ ; carboxyl; -C _h alky!; -C _h alky! substituted with halogen, -NH ₂ , -CN, -OH, -N0 ₂ , -carboxyl, -Ci _-3 alkyl or -Ci _-3 alkoxy; or -Ci _-3 alkoxy substituted with halogen, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, -Ci _-3 alkyl or -Ci _-3 alkoxy.

In some embodiments of Formula I, each of sa and R ₆ b is independently -H; -F; -CI; -Br; -NH ₂ ; -CN; -OH; -N0 ₂ ; carboxyl; methyl; ethyl; propyl; isopropyl; methoxy; ethoxy; propoxy; isopropoxy; -Ci _-3 alkyl substituted with -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; or -Ci _-3 alkoxy substituted with -F, -CI, Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula I, each of R6a and R ₆ b is independently -H; -F; -CI; -Br; -NH ₂ ; -CN; -OH; carboxyl; methyl; ethyl; isopropyl; methoxy; methyl substituted with -F, -CI, -NH ₂ , -OH, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; ethyl substituted with -F, -CI, -NH ₂ , -OH, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; or propyl substituted with -F, -CI, -NH ₂ , -OH, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula I, each of sa and R ₆ b is independently -H, -CH ₃ , -OH, or

In some embodiments f Formula I, the compound is of Formula II:

II

R ₃ is -H or -NH ₂ ;

Each of R4a or R _4b is independently -H, halogen, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, substituted or unsubstituted -Ci _-6 alkoxy, or substituted or unsubstituted -Ci _-6 alkyl; or

R _4a and R4b together with the carbon atom to which they are both attached form C=0, C=NH, or C=N-OH;

p is 0, 1, 2 or 3;

Each of R _5a or R _5b is independently -H, halogen, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, substituted or unsubstituted -Ci_6alkoxy, or substituted or unsubstituted -Ci-6alkyl; or

R _5a and R ₅ b 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, Y ₂ is CR _2a R ₂ b, NR _2a or O, and Y ₃ is CR _3a R¾, NR _3a or O;

When ring A is a 3-10 membered ring, and,

i) Y ₂ is CR _2a or N, and Y ₃ is CR _3a or N, when— represents a single bond; or ii) Y ₂ is C, and Y ₃ is C, when— represents a double bond;

Each of R _2a and R _¾ is independently -H, halogen, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, substituted or unsubstituted -Ci _-6 alkoxy, or substituted or unsubstituted -Ci _-6 alkyl;

Each of R _3a and R _¾ is independently -H, halogen, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, substituted or unsubstituted -Ci _-6 alkoxy, or substituted or unsubstituted -Ci _-6 alkyl;

Each s is independently -H, halogen, -NRsaRsb, -CN, -OH, -N0 ₂ , oxo, =0, carboxyl, -Ci _-6 alkoxy, -Ci _-6 alkyl, -Ci _-6 alkylene-NR6 _a R6b, -Ci _-6 alkylene-0-Ci _-6 alkyl, -Ci _-6 alkylene-CO-OR6 _a , -Ci-6alkylene-C _3- ioheterocyclic, -Ci-ealkylene-Cs-ioheteoaryl, -Ci-6alkylene-CO-NR6 _a R6b,

-Ci _-6 alkylene-NR6 _a -CO-NR _6a R6b, -Ci _-6 alkylene-NR6 _a -CO-Ci _-6 alkyl, -CO-NR _6a R ₆ b,

-CO-CO-NRe _a R6b, -CO-Ci _-6 alkyl, -CO-Ci _-6 alkylene-NR6 _a R ₆ b, -CO-NR _6a -C _3- i ₀ heterocyclic, -CO-NR5 _a -C _3- ioheterocyclic, -CO-C _3- ioheteocyclic, -O-Ci-ealkylene-CO-ORsa,

-0-Ci _-6 alkylene-CO-NR _6a R6b, -0-Ci _-6 alkylene-NR _6a R6b, -O-C _3- i ₀ carbocyclic, -NR _6a -CO-Ci _-6 alkyl, -NR6 _a -CO-NR _6a R ₆ b, -NRea-CO-Cs-ioheteoaryl, -NR6 _a -Ci _-6 alkylene-NR _6a R6b,

-NR6 _a -Ci _-6 alkylene-C _3- ioheterocyclic, -NR6 _a -Ci _-6 alkylene-C _5- ioheteroaryl, -S-Ci _-6 alkyl,

-SONReaReb, -S0 ₂ NRe _a R6b, -SO-Ci _-6 alkyl, -S0 ₂ -Ci _-6 alkyl, -PO(Ci _-6 alkyl) ₂ , -C _3- i ₀ heterocyclic or -C _5- i ₀ heteroaryl, and each of which is independently optionally substituted; and n is 0, 1, 2 or 3; or two adjacent R<5 can be joined together to form a 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, -C _3-6 heterocyclic or -C _3-6 carbocyclic, and each of the ring system is independently optionally substituted;

Each of R _f o and R ₆ b is independently -H, halogen, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, substituted or unsubstituted -Ci _-6 alkoxy or substituted or unsubstituted -Ci _-6 alkyl.

In some embodiments of Formula II, each of R4 _a or R4 is independently -H, halogen, -NH , -CN, -OH, -N0 ₂ , carboxyl, substituted or unsubstituted -Ci_ ₆ alkoxy, or substituted or

unsubstituted -Ci _-6 alkyl; or R4 _a and R4b together with the carbon atom to which they are both attached form C=0.

In some embodiments of Formula II, each of R4 _a or R4b is independently -H; -F; -CI; -Br; -NH ₂ ; -CN; -OH; carboxyl; methyl; ethyl; methoxy; ethoxy; methyl substituted with -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, methyl, ethyl, methoxy or ethoxy; ethyl substituted with -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, methyl, ethyl, methoxy or ethoxy; methoxy substituted with -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, methyl, ethyl, methoxy or ethoxy; or ethoxy substituted with -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, methyl, ethyl, methoxy or ethoxy; or R _4a and R4b together with the carbon atom to which they are both attached form C=0.

In some embodiments of Formula II, p is 0, 1 or 2.

In some embodiments of Formula II, each of R _5a and R _5b is independently -H; -F; -CI; -Br;

-NH ₂ ; -CN; -OH; carboxyl; -Ci _-3 alkyl;- Ci _-3 alkoxy; -Ci _-3 alkyl substituted with -F, -CI, -Br, -I, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, -Ci _-3 alkyl or -Ci _-3 alkoxy; or -Ci _-3 alkoxy substituted with -F, -CI, -Br, -I, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, -Ci _-3 alkyl or -Ci _-3 alkoxy; or R _5a and R _5b together with the carbon atom to which they are both attached form a 3-membered heterocyclic, 4-membered heterocyclic, 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 independently optionally substituted with -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, -Ci _-6 alkyl, or

-Ci_ ₆ alkoxy.

In some embodiments of Formula II, each of R _5a or R ₅ b is independently -H; -CI; -Br; -NH ₂ ; -OH; carboxyl; methyl; ethyl; methoxy; ethoxy; methyl substituted with -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, methyl or methoxy; ethyl substituted with -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, methyl or methoxy; methoxy substituted with -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, methyl or methoxy; or ethoxy substituted with -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, methyl or methoxy; or R _5a and Rs _b together with the carbon atom to which they are both attached and *C represents the carbon atom which R _5a and Rs _b 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 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; 3-membered carbocyclic, 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 carbocyclic, 4-membered 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 contains 1 or 2 heteroatoms selected from N or O.

In some embodiments of Formula II, Y ₂ is CR _2a or N, Y ₃ is CR _3a or N.

In some embodiments of Formula II, each of R _2a , R ₂ b, R _3a and R¾ is independently -H; -F; -CI;

-Br; -NH ₂ ; -CN; -OH; -N0 ₂ ; carboxyl; methyl; ethyl; propyl; isopropyl; methoxy; ethoxy;

propoxy; isopropoxy; -Ci _-3 alkyl substituted with -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; or -Ci _-3 alkoxy substituted with -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In some embodiments of Formula II, each of R _2a , R _2b , R _3a and R _¾ is independently -H or methyl.

In some embodiments of Formula II, R _2a , R ₂ b, R _3a and R¾ are all -H.

In some embodiments of Formula II, Y ₂ is CH or N, and Y ₃ is CH or N.

In some embodiments of Formula II, Y ₂ is C, and Y ₃ is C.

In some embodiments of Formula II, each 5 is independently -H, -F, -CI, -Br, -NH ₂ , -N(CH ₃ ) ₂ , -CN, -OH, oxo, =0, carboxyl, -Ci _-3 alkoxy, -Ci _-3 alkyl, -CH ₂ NH ₂ , -Ci _-3 alkylene-OCH ₃ , -CH ₂ -COOH, -CH ₂ -COO-Ci _-3 alkyl, -CH ₂ -C _5- i ₀ heterocyclic, -Ci _-3 alkylene-CO-NR _6a R6b,

-CH ₂ NH-CO-NR _6a R _6b , -CO-NR^R^, -COCO-NR _6a R _6b , -CO-Ci _-3 alkyl, -CONH-C _5- i ₀ heteocyclic, -CO-5-membered heteocyclic, -CO-6-membered heteocyclic, -O-5-membered carbocyclic, -O-6-membered carbocyclic, -NH-CO-Ci _-3 alkyl, -NR _6a -CO-NR _6a R _6b ,

-NR6a-Ci _-3 alkylene-NR _6a R6b, -NR6 _a -Ci _-3 alkylene-C _5- i ₀ heterocyclic, -S-Ci _-3 alkyl, -S0 ₂ NH ₂ , -S0 ₂ CH ₃ , 5-membered heterocyclic, 6-membered heterocyclic, 5-membered heteroaryl, or 6-membered heteroaryl, and each of which is independently optionally substituted with -F, -CI, -Br, -NH ₂ , -CN, -OH, oxo, =0, substituted or unsubstituted -Ci _-3 alkoxy, or substituted or unsubstituted -Ci _-3 alkyl; or two adjacent R ₆ can be joined together to form a 6-membered aryl; 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic, 5-membered heteroaryl, 3-membered heterocyclic, 4-membered heterocyclic or 5-membered heterocyclic; and 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, -CI, -Br, -I, -NH ₂ , -CN, -OH, -NO ₂ , =0, oxo, carboxyl, -CONH ₂ , -PO(Ci.3alkyl) ₂ , substituted or unsubstituted -Ci _-3 alkoxy, or substituted or unsubstituted -Ci-3alkyl.

In some embodiments of Formula II, each is independently -F, -CI, -Br, -NH ₂ , -N(CH ₃ ) ₂ , -CN, -OH, oxo, =0, carboxyl, methoxy, ethoxy, methyl, ethyl, isopropyl, -CH ₂ NH ₂ ,

-CH ₂ CH ₂ OCH ₃ , -CH ₂ -COOH, -CH ₂ NH-CONHCH ₃ , -CONH ₂ , -CON(CH ₃ ) ₂ , -CONHOH, - -CO-CON(CH ₃ ) ₂ , -COCH ₃ , -S0 ₂ NH ₂ , -S0 ₂ CH ₃ , -SCH ₃ ,

, and each of which is independently optionally substituted with -F, -NH ₂ , -OH, oxo, =0, or substituted or unsubstituted -Ci _-3 alkyl.

In some embodiments of Formula II, each is independently methyl, methoxy, =0, oxo,

-OH, -CN, -NH ₂ , -CI, -Br, -CF ₃ , -OCF ₃ , -S0 ₂ NH ₂ , -S0 ₂ CH ₃ , -F, -CH ₂ NH ₂ , ^K ϊ , ^OH ,

In some embodiments of Formula II, ring A and two adjacent R ₆ taken together to form

21

optionally substituted with one or more R ₆ .

In some embodiments of Formula II, each of s _a and R _6b is independently -H, -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, substituted or unsubstituted -Ci _-3 alkoxy, or substituted or unsubstituted -Ci _-3 alkyl.

In some embodiments of Formula II, each of R _6a and R _6b is independently -H, -CI, -Br, -NH ₂ , -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 R6a and R _6b is independently -H, -CH ₃ , -OH, or

-CH ₂ CH ₂ OH.

In some embodiments of Formula II, n is 0, 1 or 2.

In some embodiments of Formula I, the compound is of III:

Ri is -H, -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, substituted or unsubstituted

-Ci_6alkoxy, or substituted or unsubstituted -Ci_6alkyl;

R ₂ is -H, -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, substituted or unsubstituted

-Ci_6alkoxy, or substituted or unsubstituted -Ci_6alkyl; or

Ri combines with R ₂ 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, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, oxo, =0, -CONH ₂ , substituted or unsubstituted -Ci _-6 alkoxy, substituted or unsubstituted -Ci _-6 alkyl, or -CO-Ci _-6 alkyl;

Yi is N or CH;

R ₃ is -H or -NH ₂ ;

Ring B is a 6-membered aryl, 5-6 membered heteroaryl, 3-6 membered carbocyclic or 3-6 membered heterocyclic;

Y ₃ is CH, N or C;

R ₇ is halogen, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, oxo, =0, -CONH ₂ , -NH-COCH ₃ , substituted or unsubstituted -Ci_6alkoxy, or substituted or unsubstituted -Ci-6alkyl; and m is 0, 1 or 2.

In some embodiments of Formula III, Ri combines with R ₂ 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 contains 1 or 2 heteroatoms selected from N or O; and each of the ring systems is independently optionally substituted with -F, -CI, -Br, -NH ₂ , -CN, -OH, oxo, =0, substituted or unsubstituted -Ci _-3 alkoxy, substituted or unsubstituted -Ci _-3 alkyl, or -CO-Ci _-3 alkyl.

In some embodiments of Formula III, Ri combines with R to which is adjacent to form

< ; and the ring systems is independently optionally substituted with -F or -COCH ₃ .

In some embodiments of Formula III, Ri combines with R ₂ to which is adjacent to form

In some embodiments of Formula III, ring B 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. In some embodiments of Formula III, ring B is

In some embodiments of Formula III, R ₇ is -NH ₂ , -CN, oxo, =0, -CONH ₂ ,

methyl or methoxy.

In some embodiments of Formula III, m is 0 or 1.

In some embodiments of Formula I the compound is of Formula IV:

IV

Ri is -H, -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, substituted or unsubstituted

-Ci_6alkoxy, or substituted or unsubstituted- Ci_6alkyl;

R ₂ is -H, -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, -NHCi _-6 alkyl, -N(Ci _-6 alkyl) ₂ , substituted or unsubstituted -Ci_6alkoxy, or substituted or unsubstituted -Ci_6alkyl; or

Ri combines with R 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, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, oxo, =0, -CONH ₂ , substituted or unsubstituted -Ci _-6 alkoxy, substituted or unsubstituted -Ci _-6 alkyl, or -CO-Ci _-6 alkyl;

Yi is N or CH;

R ₃ is -H or -NH ₂ ;

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 heterocyclic;

— represents a single or double bond; and

i) Y ₂ is CR _2a or N, and Y ₃ is CR _3a or N, when— represents a single bond; or ii) Y ₂ is C, and Y ₃ is C, when— represents a double bond;

Each of R _2a and R _3a is -H, halogen, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, substituted or unsubstituted -Ci_6alkoxy, or substituted or unsubstituted -C _h alky!;

R ₈ is halogen, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, oxo, =0, -S0 ₂ NR _8a R8 _b , -S-Ci _-6 alkyl, -SO-Ci _-6 alkyl, -S0 ₂ -Ci _-6 alkyl, -CO-NR _8a R _8b , -PO(Ci _-6 alkyl) ₂ , -PO(Ci _-6 alkoxy) _2, -NR8a-CO-Ci _-6 alkyl, -NR _8a -CO-NR ₈ aRsb, -0-C _5- iocarbocyclic, -0-C _5- ioheterocyclic, -C5-ioheterocyclic or -Cs-ioheteroaryl, -Cs-ioaryl, -Ci_ ₆ alkoxy, or -Ci_ ₆ alkyl; and each of which is independently optionally substituted; and t is 0, 1, 2 or 3; and

Each of R _8a and R ₈ b is independently H, halogen, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, substituted or unsubstituted -Ci _-6 alkoxy, or substituted or unsubstituted -Ci _-6 alkyl.

In some embodiments of Formula IV, R ₂ is -H, -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, substituted or unsubstituted -Ci _-6 alkoxy, or substituted or unsubstituted -Ci _-6 alkyl; or Ri combines with R ₂ 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, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, oxo, =0, -CONH ₂ , substituted or unsubstituted -Ci_6alkoxy, substituted or unsubstituted -Ci_6alkyl, or -CO-Ci_6alkyl;

In some embodiments of Formula IV, R ₂ is -H, -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, -NHCi_3alkyl, -N(Ci.3alkyl) ₂ , -Ci _-3 alkoxy, -Ci _-3 alkyl; or Ri combines with R ₂ 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 substituted with -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, oxo, =0, -CONH ₂ , methoxy, ethoxy, methyl, ethyl, -CO-methyl, or -CO-ethyl;

In some embodiments of Formula IV, R ₂ is -H, -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, -NHCH ₃ , -N(CH ₃ ) ₂ , methoxy, ethoxy, methyl, or ethyl; or Ri combines with R ₂ 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 of the ring systems is independently optionally substituted with -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, oxo, =0, -CONH ₂ , methoxy, ethoxy, methyl, ethyl, -CO-methyl, or -CO-ethyl;

In some embodiments of Formula IV, Ri and R ₂ , together with the aromatic ring they are

I , attached to formto ^γ ι , or ^γ ι and ring Fl or F2 is independently optionally substituted with -F or -COCH ₃ .

In some embodiments of Formula IV, Ri combines with R ₂ to which is adjacent to form

In some embodiments of Formula IV, R ₂ is -NH ₂ .

In some embodiments of Formula IV, Ri is -H, -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, substituted or unsubstituted -Ci _-3 alkoxy, or substituted or unsubstituted -Ci _-3 alkyl. In some embodiments of Formula IV, Ri is -H, -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, methoxy, ethoxy, methyl, or methyl substituted with one or more substituents selected from halogen.

In some embodiments of Formula IV, Ri is -H; -F; -CI; -Br; -NH ₂ ; -CN; -OH; -N0 ₂ ; carboxyl; methyl; or methyl substituted with one or more substituents selected from -F, -CI, or -Br.

In some embodiments of Formula IV, Ri is -CI.

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 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.

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, 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.

In some embodiments of Formula IV, ring D is

In some embodiments of Formula IV, Y ₂ is CR _2a or N, and Y ₃ is CR _3a or N.

In some embodiments of Formula IV, each of R _2a and R _3a is -H, -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, substituted or unsubstituted -Ci _-3 alkoxy, or substituted or unsubstituted -Ci _-3 alkyl.

In some embodiments of Formula IV, each of R _2a and R _3a is -H, methyl or methoxy.

In some embodiments of Formula IV, Y ₂ is CH or N, and Y ₃ is CH or N.

In some embodiments of Formula IV, both Y ₂ and Y ₃ are C.

In some embodiments of Formula IV, R ₈ is -F, -CI, -Br, -I, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, oxo, =0, -S0 ₂ NR _8a R _8b , -S-Ci _-6 alkyl, -CO-NR _8a R _8b , -NR _8a -CO-Ci _-6 alkyl, -NR _8a -CO-NR _8a R _8b , -0-C ₅ -iocarbocyclic, -Cs-ioheterocyclic or -Cs-ioheteroaryl, -Ci- ₆ alkoxy, or -Ci- ₆ alkyl; and each of which is independently optionally substituted with -F, -CI, -Br, -NH ₂ , -CN, -OH, oxo, =0, substituted or unsubstituted -Ci _-3 alkoxy, or substituted or unsubstituted -Ci _-3 alkyl.

In some embodiments of Formula IV, R ₈ is -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, oxo, =0, -S0 ₂ NR _8a R _8b , -S-Ci _-3 alkyl, -CO-NR _8a R _8b , -NH-CO-Ci _-3 alkyl, -NH-CO-NR _8a R _8b ,

-0-C ₅ -iocarbocyclic, -Cs-ioheterocyclic, -Cs-ioheteroaryl, -Ci _-3 alkoxy, or -Ci _-3 alkyl; and each of which is independently optionally substituted with -F, -CI, -Br, -NH ₂ , -CN, -OH, oxo, =0, -Ci _-3 alkoxy, or -Ci _-3 alkyl. In some embodiments of Formula IV, R ₈ is -F, -CI, -Br, -NH ₂ , -CN, -OH, -N0 ₂ , carboxyl, oxo, =0, methyl, ethyl, proproyl, isopropoyl, methoxy, ethoxy, propoxy, isopropoxy, -S0 ₂ NR _8a R ₈ b, -S-Ci _-3 alkyl, -CO-NR _8a R _8b , -NH-CO-Ci _-3 alkyl, -NH-CO-NR _8a R _8b , -O-C _5- i ₀ carbocyclic,

-C5-ioheterocyclic or -Cs-ioheteroaryl; and each of which is independently optionally substituted with -F, -CI, -Br, -NH ₂ , -CN, -OH, oxo, =0, methoxy, ethoxy, methyl, or ethyl.

In some embodiments of Formula IV, the Cs-iocarbocyclic is 5-membered carbocyclic, 6-membered carbocyclic, 7-membered carbocyclic, 8-membered carbocyclic, 9-membered carbocyclic or 10-membered carbocyclic; the Cs.ioheterocyclic is 5-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 8-membered heterocyclic, 9-membered heterocyclic or 10-membered heterocyclic; and the Cs-ioheteroaryl is 5-membered heteroaryl,

6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl or 10-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, R ₈ is -F, -CI, -Br, -NH ₂ , -CN, -OH, oxo, =0, methyl, eth l, isopro oyl, methoxy, -S0 ₂ CH ₃ , -SCH ₃ , -CONH ₂ , -NH-COCH ₃ , -NH-CONHCH ₃ ,

In some embodiments of Formula IV, R ₈ is -F, -CI, -Br, -NH ₂ , -CN, -OH, oxo, =0, methyl, methoxy, -S0 ₂ CH ₃ , -SCH ₃ , -CONH ₂ , -NH-COCH ₃ , -NH-CONHCH ₃ ,

In some embodiments of Formula IV, t is 0, 1 or 2.

In some embodiments of Formula I, II, III or IV, the compound is

(R)-l -(4-((3-amino-5-(2-amino-2,3-dihydrosp

3 , 3 -difluoroindolin- 1 -yl) ethan- 1 -one

l-(4-((3-amino-5-((2R)-2-aminospiro[bicyclo^

o)-3,3-difluoroindolin-l -yl)ethan-l -one

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-3,4-dihydro-lH-spiro[^^ thalene-2,4'-piperidin]-l -amine

(R)-l -(6-amino-5-((2-amino-3-chloropyridin-4-yl)

eridine-4,6'-quinolin]-7'-amine

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-5,7-dihydrospiro[cyclopent a[b]pyridine-6,4'-piperidin]-5-amine

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-5-methoxy-l ,3-dihydro o[indene-2,4'-piperidin]-l -amine

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-4,6-dihydrospiro[cyclopent a[b]thiophene-5,4'-piperidin]-4-amine

(S)-l-amino-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thi o)pyrazin-2-yl)-l,3-dihydrospiro[i ndene-2,4'-piperidine]-6-carbonitrile

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-4-methoxy-l ,3-dihydrospir o[indene-2,4'-piperidin]-l -amine

(S)-l '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)-6-chloro-l,3-dihydrospiro[i ndene-2,4'-piperidin]-l -amine

(S)-l-amino-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thi o)pyrazin-2-yl)-l,3-dihydrospiro[i ndene-2,4'-piperidine]-4-carbonitrile

(S)-l-amino-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thi o)pyrazin-2-yl)-l,3-dihydrospiro[i ndene-2,4'-piperidine]-4-carboxamide

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-l,3-dihydrospiro[indene-2, 4'-piperidin]-l -amine

(S)-l '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)-2-chloro-5,7-dihydrospiro[ cyclopenta[b]pyridine-6,4'-piperidin]-5-amine

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-3-methoxy-5,7-dihydrospir o[cyclopenta[c]pyridine-6,4'-piperidin]-7-amine

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-5,7-dihydrospiro[cyclopent a[c]pyridine-6,4'-piperidin]-7-amine

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-5,7-dihydrospiro[cyclopent a[c]pyridine-6,4'-piperidin]-5-amine

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-6-methyl-l,3-dihydrospiro[ indene-2,4'-piperidin]-l -amine

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-6-(methylsulfonyl)-l,3-dih ydrospiro [indene-2,4'-piperidin] - 1 -amine (l S)-l '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)-6-(methylsulfi^ ydrospiro [indene-2,4'-piperidin] - 1 -amine

(S)-l-amino-l'-(6-amino-5-((2-amino-3-chloro

ndene-2,4'-piperidine]-6-carboxamide

(S)-l-amino-l '-(6-amino-5-((2-amino-3-chloropyri^

-dihydrospiro[indene-2,4'-piperidine]-6-carboxamide

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-^^

ndene-2,4'-piperidin]-l -amine

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-4-bromo-l,3-dihydrospiro[i ndene-2,4'-piperidin]-l -amine

(S)-l'-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)- 5,7-dihydrospiro[cyclopenta[b]pyrid ine-6,4'-piperidin]-5-amine

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-l,3-dihydrospiro[cyclopent a[a]naphthalene-2,4'-piperidin]-3-amine

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-6-chloro-5-methoxy-l,3-di hydrospiro [indene-2,4'-piperidin] - 1 -amine

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-l,3-dihydrospiro[indene-2, 4'-piperidine]-l,6-diamine

(S)-(l -amino- 1 '-(6-amino-5-((2-amino-3 -chloropyridin-4-yl)thio)pyrazin-2-yl)- 1 ,3 -dihydrospiro [ indene-2,4'-piperidin]-4-yl)dimethylphosphine oxide

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-6-(trifluoromethyl)-l,3-dih ydrospiro [indene-2,4'-piperidin] - 1 -amine

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-6-(lH-imidazol-l -yl)-l,3-d ihydrospiro[indene-2,4'-piperidin]-l -amine

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-6-(lH-pyrrol-l -yl)-l,3-dih ydrospiro [indene-2,4'-piperidin] - 1 -amine

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-6-bromo-5-fluoro-l,3-dihy drospiro[indene-2,4'-piperidin]-l -amine

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-5,6-difluoro-l,3-dihydrospi ro[indene-2,4'-piperidin]-l -amine

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-6,7-difluoro-l,3-dihydrospi ro[indene-2,4'-piperidin]-l -amine

(S)-(l-amino-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)th io)pyrazin-2-yl)-5-fluoro-l,3-dihy drospiro[indene-2,4'-piperidin]-6-yl)dimethylphosphine oxide

(S)-l -amino- 1 '-(6-amino-5-((2-amino-3 -chloropyridin-4-yl)thio)pyrazin-2-yl)-5 -fluoro- 1 ,3 -dihy drospiro[indene-2,4'-piperidine]-6-carbonitrile

(S)-l -amino- 1 '-(6-amino-5-((2-amino-3 -chloropyridin-4-yl)thio)pyrazin-2-yl)-5 -fluoro- 1 ,3 -dihy drospiro[indene-2,4'-piperidine]-6-carboxamide (S)-l '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)-2-chloro-4,6-dihydro cyclopenta[d]thiazole-5,4'-piperidin]-4-amine

(R)-l '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)-3H-spiro[benzofuran-^ piperidin]-3-amine

(S)-l-(l -amino-l'-(6-amino-5-((2-amino-3-chlo^

o[indene-2,4'-piperidin]-6-yl)urea

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-5-bromo-l,3-dihydrosp^^^ ndene-2,4'-piperidin]-l -amine

(S)-l'-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)- l,3-dihydrospiro[indene-2 in] -1 -amine

(S)-l'-(5-((3-chloro-2-(dimethylamino)pyridin-4-yl)thio)pyra zin-2-yl)-l,3-dihydrospiro[inden^ ,4'-piperidin]-l -amine

(S)-l'-(5-((3-amino-2-chlorophenyl)thio)pyrazin-2-yl)-l,3-di hydrospiro[indene-2,4'-piperidm^ -amine

(S)-l '-(5-((3-chloro-2-methoxypyridin-4-yl)thio)pyrazin-2-yl)-l,3 -dihydrospiro[indene-2,4'-pi^ ridin]-l -amine

(S)-l'-(6-amino-5-((3-chloro-2-(dimethylamino)pyridin-4-yl)t hio)pyrazin-2-yl)-l,3-dihydrospiro [indene-2,4'-piperidin]- 1 -amine

(S)-l'-(6-amino-5-((3-amino-2-chlorophenyl)thio)pyrazin-2-yl )-l,3-dihydrospiro[indene-2,4'-pip eridin]-l -amine

(S)-l'-(6-amino-5-((3-chloro-2-methoxypyridin-4-yl)thio)pyra zin-2-yl)-l,3-dihydrospiro[indene- 2,4'-piperidin]-l -amine

(S)-l'-(6-amino-5-((2,3-dichlorophenyl)thio)pyrazin-2-yl)-l, 3-dihydrospiro[indene-2,4'-piperW^ n]-l -amine

(R)-l '-(5-((2-amino-3-chloropyridin-4-yl)thio^

-3 -amine

(S)-(l-amino-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)th io)pyrazin-2-yl)-l,3-dihydrospiro[ indene-2,4'-piperidin]-6-yl)dimethylphosphine oxide

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-6-((tetrahydro-2H-pyran-4- yl)oxy)-l ,3-dihydrospiro[indene-2,4'-piperidin]-l -amine

(S)-(l-amino-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)th io)pyrazin-2-yl)-l,3-dihydrospiro[ indene-2,4'-piperidin]-6-yl)(piperidin-l-yl)methanone

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-6-morpholino-l,3-dihydros piro[indene-2,4'-piperidin]-l -amine

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-5,6,7-trifluoro-l,3-dihydros piro[indene-2,4'-piperidin]-l -amine

(S)-4-(l -amino-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyr azin-2-yl)-l,3-dihydrospir o[indene-2,4'-piperidin]-6-yl)morpholin-3-one (S)-N-(l -amino-l'-(6-amino-5-((2-amino-3-cU^

63

ro[indene-2,4'-piperidin]-6-yl)methanesulfonamide

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-l,3-dihydrospiro[cycl^

64

a[b]quinoline-2,4'-piperidin]-l -amine

(R)-l '-(6-amino-5-((2-amino-3-chloropyridm^

65

a[c]pyridine-6,4'-piperidin]-5-amine

(S)-l'-(6-amino-5-((2,3-dichloropyridin-4-yl)thio)pyrazin-2- yl)-l,3-dihydrospiro[indene-2,^

66

eridin]-l -amine

(lR,3R)-l '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)-l,3-dihydrospiro[inde

67

ne-2,4'-piperidine]- 1 ,3 -diamine

(S)-l'-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)- 2-chloro-4,6-dihydrospiro[cyclopent

68

a[d]thiazole-5,4'-piperidin]-6-amine

(S)-l '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)-2-chloro-4,6-dihydrospiro[

69

cyclopenta[d]thiazole-5,4'-piperidin]-6-amine

(S)-l-amino-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thi o)pyrazin-2-yl)-3H-spiro[indolm

70

ne-2,4'-piperidin]-5(lH)-one

(R)-l '-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)spiro[ indoline-2,4'-piperidin]-3-amm

71

e

(R)-l '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)-6,7-dihydrospiro[cyclopent

72

a[b]pyridine-5,4'-piperidin]-6-amine

(S)-l '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)-3-chloro-5,7-dihydrospiro[

73

cyclopenta[b]pyridine-6,4'-piperidin]-5-amine

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-6-(methylthio)-l,3-dihy^

74

spiro[indene-2,4'-piperidin]-l -amine

(S)-l '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)-6-(4-methylpiperazin-l-yl)

75

-l,3-dihydrospiro[indene-2,4'-piperidin]-l-amine

(S)-l'-(5-((2,3-dichloropyridin-4-yl)thio)pyrazm^

76

-amine

(S)-l'-(6-amino-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyr azin-2-yl)-l,3-dihydrospiro[m^

77

,4'-piperidin]-l -amine

(S)-l-(4-((3-amino-5-(l-amino-l,3-dihydrospiro[indene-2,4'-p iperidin]-l'-yl)pyrazin-2-yl)thio)^

78

3 , 3 -difluoroindolin- 1 -yl) ethan- 1 -one

(S)-l '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)-2-(tert-butyl)-4,6-dihydros

79

piro[cyclopenta[b]thiophene-5,4'-piperidin]-4-amine

(S)-l-amino-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thi o)pyrazin-2-yl)-l,3-dihydrospiro[i

80

ndene-2,4'-piperidine]-6-carboxylic acid

(2R)-l '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)spiro[bicyclo[3.1.0]hexane

81

-3,4'-piperidin]-2-amine (S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4^

82

a[b]pyridine-6,4'-piperidin]-7-amine

(S)-l'-(5-(quinolin-4-ylthio)pyrazin-2-yl)-5,7-dihydrospiro[ cyclopenta[b]pyridine-6,4'-pip

83

-5 -amine

(S)-l'-(6-amino-5-((2,3-dichlorophenyl)

84

ne-6,4'-piperidin]-5-amine

(S)-l'-(5-((3-chloro-2-(dimethylamino)pyridin-4-yl)thio)pyra zin-2-yl)-5,7-dihydrosp

85

nta[b]pyridine-6,4'-piperidin]-5-amine

(S)-l '-(5-(pyridin-4-ylthio)pyrazin-2-yl)-5,7-dihydrospiro[cyclop enta[b]pyridine-6,4'-piperi

86

5 -amine

(S)-l'-(6-amino-5-((3-fluoropyridin-4-yl)thio)pyrazin-2-yl)- 5,7-dihydrospiro[cyclopenta[b]pyrid

87

ine-6,4'-piperidin]-5-amine

(S)-l'-(6-amino-5-((3-fluoropyridin-4-yl)thio)pyrazin-2-yl)- 4,6-dihydrospiro[cyclopenta[d]thiaz

88

ole-5,4'-piperidin]-4-amine

(S)-l'-(6-amino-5-((3-chloro-2-(methylamino)pyridin-4-yl)thi o)pyrazin-2-yl)-5,7-dihydrospiro[c

89

yclopenta[b]pyridine-6,4'-piperidin]-5-amine

diethyl(S)-( 1 -amino- 1 '-(6-amino-5-((2-amino-3 -chloropyridin-4-yl)thio)pyrazin-2-yl)- 1 ,3 -dihydr

90

ospiro[indene-2,4'-piperidin]-6-yl)phosphonate

(S)-l'-(6-amino-5-((2-amino-3-fluoropyridin-4-yl)thio)pyrazi n-2-yl)-5,7-dihydrospiro[cyclopent

91

a[b]pyridine-6,4'-piperidin]-5-amine

(S)-l'-(5-((2-amino-3-fluoropyridin-4-yl)thio)pyrazin-2-yl)- 5,7-dihydrospiro[cyclopenta[b]pyrid

92

ine-6,4'-piperidin]-5-amine

(S)-l'-(6-amino-5-((3-chloropyridin-4-yl)thio)pyrazin-2-yl)- 5,7-dihydrospiro[cyclopenta[b]pyrid

93

ine-6,4'-piperidin]-5-amine

(S)-l'-(6-amino-5-((3-chloro-2-(dimethylamino)pyridin-4-yl)t hio)pyrazin-2-yl)-5,7-dihydrospiro

94

[cyclopenta[b]pyridine-6,4'-piperidin]-5-amine

(S)-l'-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)- 2-chloro-4,6-dihydrospiro[cyclopent

95

a[d]thiazole-5,4'-piperidin]-4-amine

(R)-l '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)-3H-spiro[furo[2,3-b]pyri

96

ne-2,4'-piperidin]-3-amine

(S)-l'-(5-((3-amino-2-chlorophenyl)thio)pyrazin-2-yl)-5,7-di hydrospiro[cyclopenta[b]pyridine-6

97

,4'-piperidin]-5-amine

(S)-l'-(6-amino-5-((3-amino-2-chlorophenyl)thio)pyrazin-2-yl )-5,7-dihydrospiro[cyclopenta[b]p

98

yridine-6,4'-piperidin]-5-amine

(S)-l '-(5-((3-chloro-2-methoxypyridin-4-yl)thio)pyrazin-2-yl)-5,7 -dihydrospiro[cyclopenta[b]py

99

ridine-6,4'-piperidin]-5-amine

(S)-l'-(6-amino-5-((3-chloro-2-methoxypyridin-4-yl)thio)pyra zin-2-yl)-5,7-dihydrospiro[cyclop

100

enta[b]pyridine-6,4'-piperidin]-5-amine (S)-l'-(5-((5-chloro-2-fluoropyridin-4-yl)thio)pyrazin-2-yl) -5,7-dihydrospiro[cyclope

101

ine-6,4'-piperidin]-5-amine

(S)-l'-(6-amino-5-((5-chloro-2-fluoropyridin-

102

a[b]pyridine-6,4'-piperidin]-5-amine

(S)-l-(4-((3-amino-5-(5-amino-5,7-dihydrospiro[^^

103

zin-2-yl)thio)-3 ,3 -difluoroindolin- 1 -yl)ethan- 1 -one

(S)-l'-(5-((2,3-dichloropyridin-4-yl)thio)pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridi^^

104

,4'-piperidin]-5-amine

(S)-l'-(6-amino-5-((2,3-dichloropyridin-4-yl)thio)pyrazin-2- yl)-5,7-dihydrospiro[cyclopenta[^

105

yridine-6,4'-piperidin]-5-amine

(S)-l'-(5-((4-chloropyridin-3-yl)thio)pyrazin-2-yl)-5,7-dihy drospiro[cyclopenta[b]pyridm^

106

piperidin]-5-amine

(S)-l'-(6-amino-5-((4-chloropyridin-3-yl)thio)pyrazin-2-yl)- 5,7-dihydrospiro[cyclopenta[b

107

ine-6,4'-piperidin]-5-amine

(S)-l'-(5-((3-aminopyridin-4-yl)thio)pyrazin-2-yl)-5,7-dihyd rospiro[cyclopenta[b]pyridm^

108

iperidin]-5-amine

(S)-l'-(6-amino-5-((3-aminopyridin-4-yl)thio)pyrazin-2-yl)-5 ,7-dihydrospiro[cyclopenta[b]p^

109

ine-6,4'-piperidin]-5-amine

(S)-l'-(5-((3,5-dichloropyridin-4-yl)thio)pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridm^

1 10

,4'-piperidin]-5-amine

(S)-l'-(6-amino-5-((3,5-dichloropyridin-4-yl)thio)pyrazin-2- yl)-5,7-dihydrospiro[cyclopenta^^

1 1 1

yridine-6,4'-piperidin]-5-amine

(S)-l'-(5-((2-amino-5-chloropyridin-4-yl)

1 12

ine-6,4'-piperidin]-5-amine

(S)-l'-(6-amino-5-((2-amino-5-chloropyridin-4-yl)thio)pyrazi n-2-yl)-5,7-dihydrospiro[cyc

1 13

a[b]pyridine-6,4'-piperidin]-5-amine

(S)-l'-(6-amino-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyr azin-2-yl)-5,7-dihydro

1 14

nta[b]pyridine-6,4'-piperidin]-5-amine

(S)-l'-(5-((3-chloro-2-fluoropyridin-4-yl)thio)pyrazin-2-yl) -5,7-dihydrospiro[cyclopenta[b]py^^

1 15

ine-6,4'-piperidin]-5-amine

(S)-l'-(6-amino-5-((3-chloro-2-fluoropyridin-4-yl)thio)pyraz in-2-yl)-5,7-dihydrospiro[c^

1 16

a[b]pyridine-6,4'-piperidin]-5-amine

(S)-3-((5-(5-amino-5,7-dihydrospiro[cyclopenta^

1 17

o)picolinonitrile

(S)-3-((3-amino-5-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyr idine-6,4'-piperidin]-l'-yl)pyrazi

1 18

n-2-yl)thio)picolinonitrile

(S)-l'-(5-((2-chloro-5-(trifluoromethyl)pyridin-4-yl)thio)py razin-2-yl)-5,7-dihydrospi^^

1 19

nta[b]pyridine-6,4'-piperidin]-5-amine (S)-l '-(6-amino-5-((2-chloro-5-(trifluoromethyl)pyridin-4-yl)thio )pyrazin-2-yl)-5,^

120

[cyclopenta[b]pyridine-6,4'-piperidin]-5-amine

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)-5,7-dihydrospiro[c^

121

pyridine-6,4'-piperidin]-5-amine

1 '-(5 -((2-amino-3 -chloropyridin-4-yl)thio^

122

6,4'-piperidin]-5-amine

l'-(6-amino-5-((3-chloropyridin-4-yl)thio)pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyri

123

6,4'-piperidin]-5-amine

1 '-(6-amino-5-((2-amino-3 -chloropyridin-4-yl)thio)pyrazin-2-yl)- 1 ,3 -dihydrospiro[indene-2,4'-pi

124

peridin]-l -amine

l'-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-l,3- dihydrospiro[indene-2,4'^

125

1 -amine

l'-(6-amino-5-((3-amino-2-chlorophenyl)thio)pyrazin-2-yl)-5, 7-dihydrospiro[cyclopenta[b]pyrid

126

ine-6,4'-piperidin]-5-amine

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)-5,7-dihydrospiro[cyclopenta[c]

127

pyridine-6,4'-piperidin]-5-amine

l'-(5-((3-amino-2-chlorophenyl)thio)pyrazin-2-yl)-5,7-dihydr ospiro[cyclopenta[b]pyridine-6,4'-

128

piperidin]-5-amine

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)-5-bromo-l,3-dihydrospiro[m^

129

ne-2,4'-piperidin]-l -amine

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)-2-chloro-4,6-dihydrospiro[cycl

130

openta[d]thiazole-5,4'-piperidin]-4-amine

l'-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-2-ch loro-4,6-dihydrospiro[cyclopenta[d]

131

thiazole-5,4'-piperidin]-4-amine

1 '-(5 -((2-amino-3 -chloropyridin-4-yl)thio)pyrazin-2-yl)-2,3-dihydrospiro[inde ne- 1 ,4'-piperidin]-

132

2-amine

(S)-4-((5-(l -amino-l,3-dihydrospiro[indene-2,4'-piperidin]-l '-yl)pyrazin-2-yl)thio)-3-chlorop^

133

din-2-ol

(S)-4-((3-amino-5-(l -amino-l,3-dihydrospiro[indene-2,4'-piperidin]-l'-yl)pyrazin -2-yl)thio)-3-c

134

hloropyridin-2-ol

(S)-4-((5-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6, 4'-piperidin]-l '-yl)pyrazin-2-yl)thi

135

o) -3 -chloropyridin-2-o 1

(S)-4-((3-amino-5-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyr idine-6,4'-piperidin]-l'-yl)pyrazi

136

n-2-yl)thio)-3-chloropyridin-2-ol

(S)-l-amino-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thi o)pyrazin-2-yl)-l,3-dihydrospiro[i

137

ndene-2,4'-piperidin]-6-ol

(S)-l-amino-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thi o)pyrazin-2-yl)-l,3-dihydrospiro[i

138

ndene-2,4'-piperidin]-4-ol l'-(6-amino-5-((2-amino-3-

139 chloropyridin-4-yl)thio)pyrazin-2-yl)-5-methyl-5,7-dihydrosp iro[cyclopenta[b]pyridm^

ridin]-5-amine

l-amino-l '-(6-amino-5-((2-amino-3-chloropy

140 4'-piperidin]-7(lH)-one (2 mg)

l-amino-l '-(6-amino-5-((2-amino-3-chloropy

141 4'-piperidin]-5(lH)-one

3-((2-amino-3-chloropyridin-4-yl)thio)-6-(l-m

142 pyrazin-2-amine

3-((2-amino-3-chloropyridin-4-yl)thio)-6-(

143 ridin] - 1 '-yl)pyrazin-2-amine

3-((2-amino-3-chloropyridin-4-yl)thio)-6-(4-imino-4,6-dihydr ospiro[cyclopenta[^

144 -piperidin]- 1 '-yl)pyrazin-2-amine

3-((2-amino-3-chloropyridin-4-yl)thio)-6-(l-bromo-4-imino-4H ,6H-spiro[cyclopen^

145 e-5,4'-piperidin]-l '-yl)pyrazin-2-amine

3-((2-amino-3-chloropyridin-4-yl)thio)-6-(4-m

146 eridin]- 1 '-yl)pyrazin-2-amine

3-((2-amino-3-chloropyridin-4-yl)thio)-6-(2-bromo-4-imino-4, 6-dihydrospiro

147 phene-5 ,4'-piperidin] - 1 '-yl)pyrazin-2-amine

l'-(6-amino-5-((2-amino-3-chloropyridin-4^

148 dene-2,4'-piperidin]-l -amine

(Z)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)spiro[indene-2,4'-^

149 -l(3H)-one oxime

(S)-l'-(6-amino-5-((2-amino-

3-chloropyridin-4-yl)thio)pyrazin-2-yl)-2-methoxy-4,6-dih ydrospiro[cyclopenta[d]thiazole-5,4'-piper

150

idin]-4-amine

(S)-l'-(6-amino-5-((2-amino-3-

151 chloropyridin-4-yl)thio)pyrazin-2-yl)-4,6-dihydrospiro[cyclo penta[d]thiazole-5,4'-piperidin]-4-amm

(S)-l '-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4,6-d ihydrospiro[cyclopenta[d

152 ole-5,4'-piperidin]-4-amine

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)-4,6-dihydrospi^^

153 thiazole-5,4'-piperidin]-4-amine

1 '-(5 -((2-amino-3 -chloropyridin-4-yl)^

154 5,4'-piperidin]-4-amine

(S) '-(6-amino-5-((2-amino-3- chloropyridin-4-yl)thio)pyrazin-2-yl)-4,6-dihydrospiro[cyclo penta[d]thiazole-5,4'-piperidin

155

mine (S)-l'-(5-((2-amino-3-chloropyridin-4-yl)thio^

156 ole-5,4'-piperidin]-6-amine

(S)-l'-(6-amino-5-((3-fluoro-lH ndol-4-yl)tM

157 ridin]-l -amine

(S)-l-(l -amino-l'-(6-amino-5-((2-amino-3-cU

158 o[indene-2,4'-piperidin]-6-yl)ethan-l -one

(S)-l-(l -amino-l'-(6-amino-5-((2-amino-3-chloro^

159 o[indene-2,4'-piperidin]-4-yl)ethan-l -one

(R)-l '-(5-((2-amino-3-chloropyridin-4-yl)thio^

160 n] -3 -amine

1 '-(6-amino-5-((2-amino-3 -chloropyridin-4-yl)thio)pyrazin-2-yl)-2,3 -dihydrospiro[indene- 1 ,4'-pi

161 peridin]-2-amine

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)^^

162 ene- 1 ,4 '-piperidin] -2 -amine

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)-5,6-dihydrospiro[cyclopenta[b]

163 pyridine-7,4'-piperidin]-6-amine

l-(6-amino-5-((2-amino-3-chloropyridin-4-yl)ΐhio)pyrazin-2- yl)ΐeΐrahydro-lΉ,3Ή-spiro[piperid

164 ine-4,2'-pyrrolizin]- 1 '-amine

(l'S)-l-(6-amino-5-((2-amino-3-chloropyridin-4-yl)ΐhio)pyra zin-2-yl)ΐeΐrahydro-lΉ,3Ή-spiro[p

165 iperidine-4,2'-pyrrolizin]-l '-amine

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)-4,6-dihydrospiro[cyclopenta[b]

166 furan-5 ,4'-piperidin] -4-amine

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-4,6-dihydrospiro[cyclopent

167 a[b]furan-5,4'-piperidin]-4-amine

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)-6,7-dihydrospiro[cyclopenta[b]

168 pyridine-5,4'-piperidin]-6-amine

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)hexahydrospiro[cyclopenta[b]fu

169 ran-5,4'-piperidin]-4-amine

(4R)-l '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)hexahydrospiro[cyclopent

170 a[b]furan-5,4'-piperidin]-4-amine

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)^^

171 piperidin]-2-amine

1 '-amino- 1 -(6-amino-5 -((2-amino-3 -chloropyridin-4-yl)thio)pyrazin-2-yl)tetrahydro- 1 'H,3'H-spi

172 ro[piperidine-4,2'-pyrrolizin]-3'-one

(l'S)-l'-amino-l-(6-amino-5-((2-amino-3-chloropyridin-4-yl)t hio)pyrazin-2-yl)tetrahydro-l'H

173 H-spiro[piperidine-4,2'-pyrrolizin]-3'-one l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)spiro[bicyclo[3.1

174 piperidin]-3-amine

(3R)-l '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)spiro[bicyclo[3.1.0]hexane

175 -2,4'-piperidin]-3-amine

3-((2-amino-3-chloropyridin-4-yl)thio)-6-(l l-oxa-l,7-diazadispiro[2.0.5 ⁴ .3 ³ ]dodecan-7-yl)pyrazi

176 n-2-amine

l-(4-((3-amino-5-(2-aminospiro[bicyclo[3.1.0]hexane-3,4'-pip eridin]-l '-yl)pyrazin-2-yl)thio)-3,3

177 -difluoroindolin-1 -yl)ethan-l -one

l'-(6-amino-5-((2-amino-3-chloropyridin-^

178 xane-3,4'-piperidin]-4-amine

(4R)-l '-(6-amino-5-((2-amino-3-chloropyridin-4-y^^

179 .0]hexane-3,4'-piperidin]-4-amine

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)spiro[bicyclo[3.2.0]

180 -piperidin]-2-amine

(2R)-l '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)spiro[bicyclo[3.2.0]he

181 e-3,4'-piperidin]-2-amine

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)hexahydro-lH-spk^

182 2,4'-piperidin]-l -amine

(lR)-l '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)hexahydro-lH-spiro[penta

183 lene-2,4'-piperidin]-l -amine

l-(4-((3-amino-5-(2-amino-2,3-dihydrospiro[indene-l ,4'-piperidin]-l '-yl)pyrazin-2-yl)thio)-3,3-

184 difluoroindolin- 1 -yl)ethan- 1 -one

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)-4-methoxy-2,3-dihydrospiro[in

185 dene-l,4'-piperidin]-2-amine

(R)-l '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)-4-methoxy-2,3-dihydrospir

186 o[indene-l,4'-piperidin]-2-amine

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)-4,5-dihydrospiro[cyclopenta[b]

187 furan-6,4'-piperidin]-5-amine

(R)-l '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)-4,5-dihydrospiro[cyclopent

188 a[b]furan-6,4'-piperidin]-5-amine

l-(4-((3-amino-5-(l l-oxa-l,7-diazadispiro[2.0.5 ⁴ .3 ³ ]dodecan-7-yl)pyrazin-2-yl)thio)-3,3-difluor

189 oindolin- 1 -yl)ethan- 1 -one

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)hexahydrospiro[cyclopenta[b][l

190 ,4]dioxine-6,4'-piperidin]-5-amine

(5S)-l '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)hexahydrospiro[cyclopenta

191 [b][l,4]dioxine-6,4'-piperidin]-5-amine 6-amino-l '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)-6,7-dihy

192 openta[b]pyridine-5,4'-piperidin]-2(lH)-one

(R)-6-amino-l'-(6-amino-5-((2-amino-3-chloro

193 cyclopenta[b]pyridine-5,4'-piperidin]-2(lH)-one

2-amino-l '-(6-amino-5-((2-amino-3-chloropyridin^

194 indolizine-l,4'-piperidin]-5-one

(S)-2-amino-l'-(6-amino-5-((2-amino-3-chloropyrM^

195 piro[indolizine-l,4'-piperidin]-5-one

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)spiro[chroman^

196 3 -amine

(S)-l '-(6-amino-5-((2-amino-3-chloropyridm^

197 in] -3 -amine

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)-6-methoxy-l,3-dihydrospiro[m

198 dene-2,4'-piperidin]-l -amine

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)-3,4-dihydro-lH-spiro[nap

199 ene-2,4'-piperidin]- 1 -amine

l-(6-amino-5-((2-amino-3-chloropyridin-4-yl)ΐhio)pyrazin-2- yl)-7',8'-dihydro-5Ή-spiro[piperidi

200 ne-4,6'-quinolin]-7'-amine

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)-6,7-dihydrospiro[cyclopenta[c]

201 pyridine-5,4'-piperidin]-6-amine

(R)-l '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)-6,7-dihydrospiro[cyclopent

202 a[c]pyridine-5,4'-piperidin]-6-amine

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)-6-methoxy-3,4-dihydro-lH-spi

203 ro [naphthalene -2,4'-piperidin]-l -amine

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-6-methoxy-3,4-dihydro-lH

204 -spiro[naphthalene-2,4'-piperidin]-l -amine

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)-5,6-dimethoxy-l ,3-dihydrospir

205 o[indene-2,4'-piperidin]-l -amine

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-5,6-dimethoxy-l,3-dihydro

206 spiro[indene-2,4'-piperidin]-l -amine

l-amino-l '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)-l,3-dihydrospiro[inde

207 ne-2,4'-piperidin]-6-ol

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)-5-methoxy-l,3-dihydrospiro[in

208 dene-2,4'-piperidin]-l -amine

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)-4,6-dihydrospiro[cyclopenta[b]

209 thiophene-5,4'-piperidin]-4-amine l-amino-l '-(6-amino-5-((2-amino-3-chloropyridm^

210 ne-2,4'-piperidine]-6-carbonitrile

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)

211 dene-2,4'-piperidin]-l -amine

1 '-(6-amino-5-((2-amino-3 -chloropyridin-4-yl)thio)pyrazin-2-yl)- 1 ,3 -dihydrospiro[indene-2,4'-pi

212 peridine]-l ,6-diamine

l-amino-l '-(6-amino-5-((2-amino-3-chloropy

213 ne-2,4'-piperidin]-4-ol

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)-6-chloro-l,3-dih^

214 ne-2,4'-piperidin]- 1 -amine

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)-6-bromo-l,3-dihydrospiro[m^

215 ne-2,4'-piperidin]-l -amine

1 '-(6-amino-5-((2-amino-3 -chloropyridin-4-yl)thio)pyrazin-2-yl)-2,3 -dihydrospiro[indene- 1 ,4'-pi

216 peridine]-2,5-diamine

(R)-l '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)-2,3-dihydrospiro[indene-l _^

217 4'-piperidine]-2,5 -diamine

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)-6-methoxy-2,3-dihydrospiro[in

218 dene-l,4'-piperidin]-2-amine

(R)-l '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)-6-methoxy-2,3-dihydrospir

219 o[indene-l,4'-piperidin]-2-amine

l-(6-amino-5-((2-amino-3-chloropyridin-4-yl^

220 yrrolizin]- 1 '-amine

(S)-l-(6-amino-5-((2-amino-3-chloropyridin-4-yl)ΐhio)pyrazi n-2-yl)-lΉ,3Ή-spiro[piperidine-4,

221 2'-pyrrolizin]-l '-amine

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)-5,7-dihydrospiro[cyclopenta[c]

222 pyridine-6,4'-piperidin]-7-amine

2-amino-l '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)-2,3-dihydrospiro[ind

223 ne-l,4'-piperidine]-4-carboxamide

(R)-2-amino-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thi o)pyrazin-2-yl)-2,3-dihydrospiro[i

224 ndene-l,4'-piperidine]-4-carboxamide

2-amino-l '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)-2,3-dihydrospiro[ind

225 ne-l,4'-piperidine]-4-carbonitrile

(R)-2-amino-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thi o)pyrazin-2-yl)-2,3-dihydrospiro[i

226 ndene- 1 ,4'-piperidine]-4-carbonitrile

N-(2-amino-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio )pyrazin-2-yl)-2,3-dihydrospiro[i

227 ndene- l,4'-piperidin]-4-yl)acetamide (R)-N-(2-amino-l'-(6-amino-5-((2-amino-3-c^

228 ro[indene-l,4'-piperidin]-4-yl)acetamide

1 '-(6-amino-5-((2-amino-3 -chloropyridin-4-yl)thio)pyrazin-2-yl)-6-(pyrrolidin- 1 -yl)- 1 ,3 -dihydro

229 spiro[indene-2,4'-piperidin]-l -amine

(S)-l '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)-6-(pyrrolidin-l-yl)-l,3-dih

230 ydrospiro [indene-2,4'-piperidin] - 1 -amine

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)-6-(l,4-dimethyl-lH-l,2,3-tri

231 ol-5-yl)-l,3-dihydrospiro[indene-2,4'-piperidin]-l -amine

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-6-(l,4-dimethyl-lH-l,2,3-t

232 riazol-5 -yl)- 1 ,3 -dihydrospiro [indene-2,4'-piperidin] - 1 -amine

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)-6-(methylthio)-l,3-dihydr^

233 o[indene-2,4'-piperidin]-l -amine

2-(l -amino-l'-(6-amino-5-((2-amino-3-chloro

234 dene-2,4'-piperidin]-6-yl)propan-2-ol

(S)-2-(l -amino-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyr azin-2-yl)-l,3-dihydrospir

235 o[indene-2,4'-piperidin]-6-yl)propan-2-ol

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)-6-(methylsulfonyl)-l,3-dihydr^

236 spiro[indene-2,4'-piperidin]-l -amine

N-(l -amino-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyr azin-2-yl)-l,3-dihydrospiro[i

237 ndene-2,4'-piperidin]-6-yl)acetamide

(S)-N-(l -amino-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyr azin-2-yl)-l,3-dihydrospi

238 ro[indene-2,4'-piperidin]-6-yl)acetamide

l-amino-l '-(6-amino-5-((2-amino-3-chloropyridm^

239 ne-2,4'-piperidine]-6-carboxamide

1 '-(6-amino-5-((2-amino-3 -chloropyridin-4-yl)thio)pyrazin-2-yl)-6-(cyclopentyloxy)- 1 ,3 -dihydr

240 ospiro[indene-2,4'-piperidin]-l -amine

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-6-(cyclopentyloxy)-l,3-dih

241 ydrospiro [indene-2,4'-piperidin] - 1 -amine

l-amino-l '-(6-amino-5-((2-amino-3-chloropyridin^

242 4'-piperidin] -7(1 H)-one

l-amino-l '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)-5-fluoro-l,3-dihydros

243 piro[indene-2,4'-piperidin]-6-ol

(S)-l -amino- 1 '-(6-amino-5-((2-amino-3 -chloropyridin-4-yl)thio)pyrazin-2-yl)-5 -fluoro- 1 ,3 -dihy

244 drospiro[indene-2,4'-piperidin]-6-ol

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)-5,7-dihydro-lH-spiro[cyclopen

245 ta[f]indole-6,4'-piperidin]-7-amine (S)-l '-(6-ammo-5-((2-amino-3-chloropyridin-4-yl)

246 penta[fJindole-6,4'-piperidin]-7-amine

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)-5,7-dihydro-lH-spi^^

247 ,6-d]imidazole-6,4'-piperidin]-7-amine

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-5,7-dihydro-lH-sp

248 no[5,6-d]imidazole-6,4'-piperidin]-7-amine

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)-6-(lH etrazol-5-yl)-l,3-

249 ospiro[indene-2,4'-piperidin]-l -amine

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-6-(lH etrazol-5-yl^

250 hydrospiro [indene-2,4'-piperidin] - 1 -amine

l-(l -amino-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyr azin-2-yl)-l,3-dihydrospiro

251 dene-2,4'-piperidin]-6-yl)-3-methylurea

(S)-l-(l -amino-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyr azin-2-yl)-l,3-dihydrospir

252 o[indene-2,4'-piperidin]-6-yl)-3-methylurea

1 '-(5 -((2-amino-3 -chloropyridin-4-yl)thio)pyrazin-2-yl)-2,3-dihydrospiro[inde ne- 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 excipient within the range from about 0.0001 to about 10.

The present invention additionally provided a use of aboved said pharmaceutical composition 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 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 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, 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 use of at least one compound or pharmaceutically acceptable salt thereof of Formula 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 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 embodiments, the disease or disorderm ediated 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 using at least one compound or pharmaceutically acceptable salt thereof of Formula I, II, III or IV, or pharmaceutical composition described above, which is 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 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 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, 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 condition mediated by the activity of SHP2 is cancer, cancer metastasis, cardiovascular disease, an immunological disorder, fibrosis, or an ocular disorder.

In some embodiments, the condition mediated by the activity of SHP2 is 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 cancer, pancreatic cancer, and combination thereof.

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 cancer, 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 thereof of Formula I, II, III or IV, or the pharmaceutical composition described above.

The term "halogen", as used herein, unless otherwise indicated, means fiuoro, chloro, bromo or iodo. The preferred halogen groups include F, CI and Br. The terms "haloCi-6alkyl",

"haloC ₂ - ₆ alkenyl", "haloC ₂ - ₆ alkynyl" and "haloCi- ₆ alkoxy" mean a C ₂ - ₆ alkenyl, C ₂ - ₆ lkynyl or Ci_ ₆ alkoxy 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 fiuoroCi _-6 alkyl, fluoroC _2-6 alkenyl, fluoroC _2-6 alkynyl and fluoroCi _-6 alkoxy groups, in particular fiuoroCi _-3 alkyl, for example, CF ₃ , CHF ₂ , CH ₂ F, CH ₂ CH ₂ F, CH ₂ CHF ₂ , CH ₂ CF ₃ and

fiuoroCi _-3 alkoxy groups, for example, OCF ₃ , OCHF ₂ , OCH ₂ F, OCH ₂ CH ₂ F, OCH ₂ CHF ₂ or OCH ₂ CF ₃ , and most especially CF ₃ , OCF ₃ and OCHF ₂ .

As used herein, unless otherwise indicated, alkyl includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, cyclcopropyl, n-butyl, isobutyl, 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, Ci _-8 , as in Ci _-8 alkyl 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 defined above. For example, methylene (i.e., -CH ₂ -), ethylene (i.e., -CH ₂ -CH ₂ - or -CH(CH ₃ )-) and propylene (i.e., -CH ₂ -CH ₂ - CH ₂ -, -CH(-CH ₂ -CH ₃ )- or -CH ₂ -CH(CH ₃ )-).

Alkoxy radicals are oxygen ethers formed from the previously described straight, branched chain or cyclic alkyl groups.

The term "aryl", as used herein, unless otherwise indicated, by itself or as part of another substituent refers to a monocyclic or polycyclic aromatic hydrocarbon. Phenyl and naphthyl 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 substituted mono- or polycyclic non-aromatic, partially unsaturated or fully saturated 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 degrees of unsaturation. Multiple degrees 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, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiamorpholinyl 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 polycyclic, 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 polycyclic heteroaryl ring may contain fused, spiro or bridged ring junction, for example, bycyclic heteroaryl is a polycyclic 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, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adeninyl, quinolinyl or isoquinolinyl.

The term "cycloalkyl" as used herein, unless otherwise indicated, 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.

o The term "carbonyl", "-C=0", "C=0", "-CO", "-C(O) ", and "CO" refer to the group .

The term "oxo"refers 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 interpreted as including those limitations given above for "alkyl" and "aryl". Designated numbers of carbon atoms (e.g., - 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 "Ri" of Formula I, II, III or IV can be the same or different. Similar to "Ri", and the two "Yi" of Formula I, II, III or IV can be the same or different.

Compounds described herein, such as certain compounds of Formula 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 described 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 R-isomer 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 enriched R- or S-isomers 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.

Compounds 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. Isotopes can be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur, fluorine, chlorine, and iodine include, but are not limited to ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ 0, ³² P, ³⁵ S, ¹⁸ F, ³⁶ C1, and ¹²⁵ I. 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 of the compounds described herein can be substituted with deuterium to provide the corresponding deterium-labeled or -enriched compounds.

The term "subject" (alternatively referred to herein as "patient") as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

The term "ring systems" as used herein, unless otherwise indicated, include but not limite to a carbocyclic ring, a heterocyclic ring, a heteroaromatic 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 C _1-6 alkyl or C _1-3 alkyl ogroup, and do not include the cycloalkoxy based on a Ci-6 alkoxy or C _1-3 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)-configuration, preferably in the (R)- or (S)-configuration. Substituents at a double bond or especially a ring may be present 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. compounds, 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 formulation) 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 preferably alternatively as "one".

"SHP2" means "Src Homolgy-2 phosphatase" and is also known as SH-PTP2, SH-PTP3, Syp,

PTP1D, PTP2C, SAP-2 or PTPN11.

Cancers harboring "PTPN11 mutations" include but are not limited to: N58Y, D61Y, V; E69K; A72V, T, D; E76G, Q, K (ALL); G60A: D61Y; E69V; F71K; A72V; T731; E76G, K; R289G; G503V (AML); G60R, D61Y, V, N; Y62D; E69K; A72T, V; T731; E76K, V, G, A, Q; E139D; G503A, R; Q506P (JMML); G60V; D61V; E69K; F71L; A72V; E76A (MDS), Y63C (CMML); Y62C; E69K; T507K (neuroblastoma); V46L; N58S; E76V (Lung cancer), R138Q (melanoma); E76G (colon cancer)

The term "composition", as used herein, is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified 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 present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present 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 invention.

The compounds of the present invention may also be present in the form of pharmaceutically acceptable 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 protonated with an inorganic or organic acid. Representative organic or inorganic acids include hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic,

hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic,

p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifiuoroacetic.

Pharmaceutically acceptable basic/cationic salts include, and are not limited 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 functional derivatives of the compounds 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 specifically disclosed, but which converts to the specified compound in vivo after administration to the subject. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in' esign 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 compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques know in the art as well as those methods set forth herein.

The present invention includes compounds described can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, 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. Further, 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 invention 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 solvates 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 corresponding 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 organic acids. Since the compounds of Formula I, II, III or rV are intended for pharmaceutical use they are preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure, especially at least 98% pure (%> are on a weight for weight basis).

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 therapeutic ingredients or adjuvants. The compositions include compositions suitable for oral, rectal, topical, 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 invention 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 depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable 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 solution, as a suspension in an aqueous liquid, 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 Formula 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 prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier 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 gaseous 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, alcohols, 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, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard 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 adjuvants. Compressed tablets 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 dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened 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 containing 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 composition. 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 solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative 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 conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. 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 present invention can be in a form suitable for topical 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 thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 5wt% to about 10wt% of the compound, to produce a cream or ointment having a desired consistency.

Pharmaceutical compositions of this invention 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 include 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 carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound described by Formula I, II, III or IV, or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.

Generally, dosage levels on the order of from about O.Olmg/kg to about 150mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5mg to about 7g per patient 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 of the compound per kilogram of body 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 combination and the severity of the particular disease undergoing therapy.

These and other aspects will become apparent from the following written description of the invention.

Examples The following Examples are provided to better illustrate the present invention. 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:

1,8-Diazabicyclo[5.4.0]undec- n-BuLi n-Butyllithium

DBU

7-ene LAH Lithium aluminium hydride

XantPhos 4 , 5 -B is(diphenylphosphino)- t-BuOK Potassium tert-butoxide

9,9-dimethylxanthene

NaOEt Sodium ethoxide

TEA Triethylamine

TFA Triethylamine

CH ₃ I Iodomethane

HC1 Hydrochloric acid

Pd(OAc) ₂ Palladium diacetate

RT Room temperature

Tris(dibenzylideneacetone)dip

Pd ₂ (dba) ₃ min minute(s)

alladium(O)

h hour(s)

2-(7-Azabenzotriazol-l-yl)-N,

aq aqueous

HATU Ν,Ν',Ν'-tetramethyluronium

sat saturated

hexafluorophosphate

TLC Thin layer chromatography

Cy ₃ PH-BF Tricyclohexylphosphonium

Preparative thin layer tetrafluoroborate Pre-TLC

4 chromatography

MsCl Methanesulfonyl chloride

Intermediate Al

To a solution of 6-methoxy-2,3-dihydro-lH-inden-l-one (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 Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA : Hex = 1 : 12, v/v) to give tert-butyl 6-methoxy-l-oxo-l,3-dihydrospiro[indene-2,4'-piperidine]-r-c arboxylate (557 mg) as a yellow solid. MS: m/z 332 (M+H) ⁺ .

The following compounds were synthesized using the above procedure with the

corresponding starting materials.

Table 1

Intermedia

Step a: A solution of 2,2'-azanediylbis(ethan-l-ol) (198.15 g, 1.88 mol), K ₂ C0 ₃ (520.95 g, 3.77 mol) and (bromomethyl)benzene (386.79 g, 2.26 mol) in acetonitrile (2000 mL) was stirred at 90 °C for 2.5 h. After cooling to RT, the reaction mixture was filtered followed by EA (2 X lOOmL) wash. The filtrate was concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with MeOH : DCM = 1 : 10, v/v) to give

2,2'-(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 mixture 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 Na ₂ S0 ₄ and filtered. The filtrate was concentrated under reduced pressure to give N-benzyl-2-bromo-N-(2-bromoethyl) ethan-1 -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]pyridin-5-one (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, stirred for 1 h at this temperature. Then N-benzyl-2-bromo-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 X 80 mL). The combined organic layers were washed with water (3 X 80 mL), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA) to give

r-benzylspiro[cyclopenta[b]pyridine-6,4'-piperidin]-5(7H) -one (1.14 g). MS: m/z 293 (M+H) ⁺ .

Step d: To a 0 °C solution of r-benzylspiro[cyclopenta[b]pyridine-6,4'-piperidin]-5(7H)-on e (1.05 g, 3.59 mmol) in DCE (10 mL) was added 1 -chloroethyl carbonochloridate (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), stirred at 80 °C for 4 h. The volatiles were removed under reduced pressure and dissolved in DCM (20 mL). DIEA ( 1.33 g, 10.32 mmol) and (Boc) ₂ 0 (1.38 g, 6.32 mmol) were added. The resulting solution was stirred for 16 h at RT. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA : Hex = 1 : 1, v/v) to give tert-butyl

5-oxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperid ine]-r-carboxylate (438 mg). MS: m/z 303 (M+H) ⁺ . Intermediate A3

Step a: To a -70 °C solution of 1 -(tert-butyl) 4-ethyl piperidine-l,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,

l-bromo-4-(bromomethyl)benzene (7.91 g, 31.64 mmol) was added in portions. The resulting solution was stirred for 3 h at -70°C, and carefully quenched with sat. aq. NH ₄ C1 (50 mL). The aqueous layer was separated, and extracted with EA (1 X 80 mL), the organic layers combined, dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give

1 -(tert-butyl) 4-ethyl 4-(4-bromobenzyl)piperidine-l,4-dicarboxylate (14.55 g) as a brown oil which was used in next step without any further purification. MS: m/z 426 (M+H) ⁺ .

Step b: A solution of 1 -(tert-butyl) 4-ethyl 4-(4-bromobenzyl)piperidine-l,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 volatiles were removed under reduced pressure. The resulting mixture was extracted with EA (3 X 80 mL). The combined organic layers were dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give 4-(4-bromobenzyl)-l-(tert-butoxycarbonyl)piperidine-4-carbox ylic acid (16.87 g) which was used in next step without any further purification. MS: m/z 398 (M+H) ⁺ .

Step c: A mixture of 4-(4-bromobenzyl)-l-(tert-butoxycarbonyl)piperidine-4-carbox ylic acid (16.87 g, 42.36 mmol) and PPA (60 mL) was stirred for 30 min at 120 °C. The reaction mixture was poured into ice/water (300 mL), the pH value was adjusted to 10 with NaOH. Then (Boc) ₂ 0 (13.86 g, 63.53 mmol) was added and stirred for 18 h at RT. The reaction mixture was extracted with EA (3 X 150 mL). The combined organic layers were dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give tert-butyl 6-bromo-l-oxo-l ,3-dihydrospiro [indene-2,4'-piperidine]-l'-carboxylate (16.87 g) which was used in next step without any further purification. MS: m/z 380 (M+H) ⁺ .

The following compounds were synthesized using the above procedure or modifications procedure with the corresponding starting materials.

Intermediate A4

A mixture of tert-butyl 6-bromo-l-oxo-l ,3-dihydrospiro[indene-2,4'-piperidine]- l'-carboxylate (2.06 g, 5.42 mmol), Pd(PPh ₃ ) 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 filtrate was washed with brine (1 X 30 mL), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA : Hex = 1 : 10, v/v) to give tert-butyl 6-cyano-l-oxo-l ,3-dihydrospiro[indene-2,4'-piperidine]-r-carboxylate (1.86 g). MS: m/z 327 (M+H) ⁺ .

The following compounds were synthesized using the above procedure with the

corresponding starting materials.

Table 3

Intermediate A5

A solution of tert-butyl 4-cyano-l-oxo-l,3-dihydrospiro[indene-2,4'-piperidine]- - carboxylate (0.93 g, 2.85 mmol) and KOH (1.60 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 reaction mixture was diluted with water (30 mL), extracted with EA (60 mL, 30 mL). The combined organic layers were washed with brine

(1 X 80 mL), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give tert-butyl 4-carbamoyl-l-oxo-l,3-dihydrospiro[indene-2,4'-piperidine]-r -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

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 CH ₃ I (1 mL, 16.06 mmol). The resulting mixture was stirred for 17 h at RT. The reaction was quenched with brine (50 mL), extracted with

EA (2 X 50 mL). The combined organic layers were washed with brine (1 X 100 mL), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA : Hex = 1 : 3, v/v) to give tert-butyl

6-(dimethylcarbamoyl)-l-oxo-l,3-dihydrospiro[indene-2,4'- piperidine]- -carboxylate (0.82 g). MS: m/z 373 (M+H) ⁺ .

Intermediat

Step a-c: Step (a-c) of Intermediate A 3 was applied to provide

-(tert-butoxycarbonyl)-l-oxo-l,3-dihydrospiro[indene-2,4'-pi peridine]-6-carboxylic acid. MS: m/z 346 (M+H) ⁺ .

Intermediate A

A 50 mL sealed tube was charged with tert-butyl 6-bromo-l-oxo-l,3-dihydrospiro

[indene-2,4'-piperidine]-l'-carboxylate (998 mg, 2.62 mmol), DMSO (8 mL), water (4 mL), Cul (217 mg, 1.14 mmol) and ammonium hydroxide (25%, 4 mL). The resulting mixture was stirred for 5 days at 100 °C. After cooling to RT, the reaction mixture was diluted with brine (20 mL) and EA (30 mL). The organic layer was separated, dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give tert-butyl 6-amino-l-oxo-l,3-dihydrospiro

[indene-2,4'-piperidine]-r-carboxylate (750 mg). MS: m/z 317 (M+H) ⁺ .

Intermediate

A mixture of tert-butyl 6-bromo-l-oxo-l,3-dihydrospiro[indene-2,4'-piperidine]-r- carboxylate (534 mg, 1.40 mmol), methanesulfonamide (371 mg, 3.90 mmol), K ₂ C0 ₃ (1.10 g, 7.95 mmol), N,N'-dimethyl-l,2-ethanediamine (85 mg, 0.96 mmol), Cul (72 mg, 0.38 mmol) in 1,4-dioxane (20 mL) under nitrogen atmosphere was stirred for 23 h at 110 °C. An additional portion of methanesulfonamide (370 mg, 3.89 mmol), N,N'-dimethyl-l,2-ethanediamine (85 mg, 0.96 mmol), Cul (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 X 50 mL). The combined organic layers were dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified 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]-r-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

Intermediat

To a solution of tert-butyl 6-amino-l-oxo-l,3-dihydrospiro[indene-2,4'-piperidine]-r- 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 (1 X 60 mL), dried over anhydrous Na ₂ S0 ₄ , 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 l-oxo-6-ureido-l,3-dihydrospiro[indene-2,4'- piperidine]-l'-carboxylate (0.39 g). MS: m/z 360 (M+H) ⁺ .

Intermediate

To a 0 °C solution 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 1 h at 0 °C. The reaction mixture was quenched with sat. aq. Na ₂ S ₂ 0 ₃ (10 mL), the volatiles were removed under reduced pressure. The resulting mixture was extracted with EA (3 X 40 mL), the combined organic layers were dried over anhydrous Na ₂ S0 ₄ , 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'-piperi dine]-r- 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 A

A mixture of tert-butyl 6-bromo-l-oxo-l ,3-dihydrospiro[indene-2,4'-piperidine]- - carboxylate (1.51 g, 3.97 mmol), dimethyl(oxo)phosphanium (503 mg, 6.44 mmol), Pd(OAc) ₂ (92 mg, 0.41 mmol), Xantphos (457 mg, 0.79 mmol), K ₃ P0 ₄ (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 X 80 mL). The combined organic layers were washed with brine (1 X 120 mL), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with MeOH : DCM = 1 : 30, v/v) to give tert-butyl 6-(dimethylphosphoryl)-l-oxo-l ,3- dihydrospiro[indene-2,4'-piperidine]-r-carboxylate (0.81 g) as a white solid. MS: m/z 378 (M+H) ⁺ .

The following compounds were synthesized using the above procedure with the

corresponding starting materials.

Table 7

Intermediate

A mixture of tert-butyl 6-bromo-l-oxo-l ,3-dihydrospiro[indene-2,4'-piperidine]-r- carboxylate (1.09 g, 2.87 mmol), lH-imidazole (180 mg, 2.64 mmol), CuBr (34 mg, 0.24 mmol), Cs ₂ C0 ₃ (851 mg, 2.61 mmol), l ,2,3,4-tetrahydro-8-hydroxyquinoline (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 reaction mixture was quenched with water (30 mL), extracted with EA (1 X 40 mL). The organic layer was dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA) to give tert-butyl

6-(lH-imidazol-l-yl)-l-oxo-l,3-dihydrospiro[indene-2,4'-p iperidine]-r-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

Intermedia

A mixture of r-(tert-butoxycarbonyl)-l-oxo-l,3-dihydrospiro[indene-2,4'-p iperidine]-6- 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 Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give tert-butyl l-oxo-6-(piperidine-l-carbonyl)-l,3-dihydrospiro[indene-2,4' -piperidine]-r-carboxylate (380 mg). MS: w/z 413 (M+H) ⁺ .

Intermediate

A mixture of tert-butyl 6-bromo-l-oxo-l,3-dihydrospiro[indene-2,4'-piperidine]-r- 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 organic layers were dried over anhydrous Na ₂ S0 ₄ , 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 6-morpholino-l-oxo-l,3-dihydrospiro

[indene-2,4'-piperidine]-r-carboxylate (467 mg). MS: m/z 387 (M+H) ⁺ . Intermediat A16

A mixture of tert-butyl 6-bromo-l-oxo-l,3-dihydrospiro[indene-2,4'-piperidine]- - carboxylate (500 mg, 1.31 mmol), 1-methylpiperazine (270 mg, 2.70 mmol), CS ₂ CO ₃ (1306 mg, 4.01 mmol), Pd ₂ (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 nitrogen atmosphere. After cooling to RT, the reaction mixture was quenched with water, extracted with EA (2 X 100 mL). The combined organic layers were washed with brine (1 X 100 mL), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give tert-butyl 6-(4-methylpiperazin-l-yl)-l-oxo-l,3-dihydrospiro [indene-2,4'-piperidine]-l'-carboxylate (0.87 g, crude) which was used in next step without any further purification. MS: m/z 400 (M+H) ⁺ .

Intermediate A17

Step a: To a -60 °C solution of 1 -(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 allowed to warm to -20 °C and stirred for 50 min. The mixture was cooled to -50 °C, and a solution of CH ₃ I (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. NH ₄ C1 (80 mL), extracted with EA (100 mL, 50 mL). The combined organic layers were dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give 1 -(tert-butyl) 4-ethyl

4-methylpiperidine-l,4-dicarboxylate (17.70 g) which was used without any further purification. MS: m/z 216 (M+H-56) ⁺ .

Step b: To a 0 °C solution of 1 -(tert-butyl) 4-ethyl 4-methylpiperidine-l,4-dicarboxylate (17.70 g, 65.23 mmol) in THF (150 mL) was added a LiBH ₄ (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 Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give tert-butyl

4-(hydroxymethyl)-4-methylpiperidine-l-carboxylate (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 of DMSO (10.99 g, 140.63 mmol) in DCM (30 mL) dropwise, stirred for 30 min at this temperature. A solution of tert-butyl 4-(hydroxymethyl)-4-methylpiperidine-l-carboxylate (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 X 80 mL). The combined organic layers were washed with brine (1 X 200 mL), dried over anhydrous Na ₂ S0 _4j filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA : Hex = 1 : 20, v/v) to give tert-butyl 4-formyl-4-methylpiperidine-l-carboxylate (11.82 g).

MS: m/z 172 (M+H-56) ⁺ .

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 stirred for 1.5 h. A solution of tert-butyl

4-formyl-4-methylpiperidine-l-carboxylate (3.95 g, 17.37 mmol) in THF (10 mL) was added dropwise at -70 °C. After stirring 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 X 80 mL), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give tert-butyl 4-((3-chloropyridin-4-yl)(hydroxy)methyl)-4- methylpiperidine-l-carboxylate (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-chloropyridin-4-yl)(hydroxy)methyl)-4- methylpiperidine-l-carboxylate (8.10 g, 23.76 mmol) in DCM (50 ml) was added Dess-Martin periodinane (20.12 g, 47.44 mmol). The resulting mixture was stirred for 16 h at RT. The reaction mixture was diluted with DCM (100 mL), washed with aq. Na ₂ S ₂ 0 ₃ (25%, 1 X 80 mL), sat. aq.

NaHC0 ₃ (1 X 80 mL) and brine (1 X 100 mL). The organic layer was dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA : Hex = 1 :3, v/v) to give tert-butyl

4- (3-chloroisonicotinoyl)-4-methylpiperidine-l-carboxylate (4.81 g). MS: m/z 339 (M+H) ⁺ .

Step f: A mixture of tert-butyl 4-(3-chloroisonicotinoyl)-4-methylpiperidine-l-carboxylate (6.31 g, 18.62 mmol), Cs ₂ C0 ₃ (6.72g, 21.90mmol), pivalic_acid (571 mg, 5.60 mmol), Pd(OAc) ₂ (0.22 g, 0.98 mmol) and Cy ₃ PH-BF ₄ (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 reduced pressure. The residue was purified by silica chromatography (eluting with EA : Hex = 1 : 1, v/v) to give tert-butyl

5- oxo-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4'-piperidine]- r-carboxylate (2.82 g). MS: m/z 303 (M+H) ⁺ .

The following compounds were synthesized using the above procedure with the

corresponding starting materials.

Table 9

Intermediate A18

Step a: To a solution of 3-bromo-6-chloropicolinic acid (9.98 g, 42.21 mmol) in MeOH (100 mL) was added H ₂ S0 ₄ (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 mixture 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 X 60 mL), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give methyl 3-bromo-6-chloropicolinate (10.14 g) as an off-white solid. MS: m/z 250 (M+H) ⁺ .

Step b: To a 0 °C solution of methyl 3-bromo-6-chloropicolinate (10.14 g, 40.48 mmol) in MeOH (150 mL) was added NaBH ₄ (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 Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give (3-bromo-6-chloropyridin-2-yl)methanol (8.31 g). MS: m/z 222 (M+H) ⁺ .

Step c: To a -15 °C solution of (3-bromo-6-chloropyridin-2-yl)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 Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give (3-bromo-6-chloropyridin-2-yl)methyl methanesulfonate (8.54 g). MS: m/z 300 (M+H) ⁺ .

Step d: To a -50 °C solution of 1 -(tert-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 1 h at this temperature. A solution of (3-bromo-6-chloropyridin-2-yl)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 1 h. The reaction mixture was quenched with brine (60 mL) and extracted with EA (1 X 30mL). The organic layer was dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give 1 -(tert-butyl) 4-ethyl 4-((3-bromo-6-chloropyridin-2-yl)methyl)piperidine-l,4- dicarboxylate (17.73 g) which was used in next step without any further purification. MS: m/z 461 (M+H) ⁺ .

Step e: A solution of 1 -(tert-butyl) 4-ethyl 4-((3-bromo-6-chloropyridin-2-yl)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 (1 X 100 mL), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA : Hex = 1 : 10, v/v) to give the mixture

of4-((3-bromo-6-chloropyridin-2-yl)methyl)-l-(tert-butoxy carbonyl)piperidine-4-carboxylic acid and4-((3-bromo-6-methoxypyridin-2-yl)methyl)-l-(tert-butoxyc arbonyl)piperidine-4-carboxylic acid (18.24 g). MS: m/z 433 (M+H) ⁺ , MS: m/z 429 (M+H) ⁺ . Step f: To a -15 °C solution of 4-((3-bromo-6-chloropyridin-2-yl)methyl)-l-(tert- butoxycarbonyl)piperidine-4-carboxylic acid and 4-((3-bromo-6-methoxypyridin-2-yl)methyl)-l- (tert-butoxycarbonyl)piperidine-4-carboxylic 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 mixture was added n-BuLi (2.5M solution in Hex, 5 mL, 12.50 mmol) dropwise, stirred for 1 h. The reaction mixture was quenched with water (20 mL), extracted with EA (1 X 40 mL). The organic layer was washed with brine (1 X 30 mL), dried over anhydrous Na ₂ S0 ₄ , 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-chloro-5-oxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'- piperidine]-l'-carboxylate and tert-butyl 2-methoxy-5-oxo-5,7-dihydrospiro[cyclopenta[b] pyridine-6,4'-piperidine]-r-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 starting materials.

Table 10

Intermediate A19

Step a: To a -78 °C solution of 1 -(tert-butyl) 4-ethyl piperidine-l,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) dropwise under nitrogen atmosphere. The resulting mixture was stirred for 1 h at this temperature. 2-Chloro-5-(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), extracted with

EA (2 X 30 mL). The combined organic layers were dried over anhydrous Na ₂ S0 ₄ , 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-chlorothiazol-5-yl)methyl) piperidine-l,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-chlorothiazol-5-yl)methyl) piperidine-l,4-dicarboxylate (900 mg, 2.31 mmol) in THF (50 mL) was added LDA (2 M solution in THF/Hex, 3.00 niL, 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 X 30 mL), the organic layers combined, dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give tert-butyl

2-chloro-4-oxo-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4 '-piperidine]-l '-carboxylate (832 mg). MS: m/z 343 (M+H) ⁺ .

Intermediate A20

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 diluted carefully with sat. aq. NH ₄ C1 (50 mL). The resulting mixture was filtered, the organic extract was collected and dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give (2-methylpyridin-3-yl) methanol as a yellow oil (1.42 g). MS: m/z 124 (M+H) ⁺ .

Step b: To a 0 °C mixture of (2-methylpyridin-3-yl) methanol (1.41 g, 11.45 mmol) in DCM

(20 mL) was added PBr ₃ (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 X. 20 mL), dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure to give 3-(bromomethyl) -2-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 1-tert-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, stirred for 1 h at this temperature. 3-(Bromomethyl)-2-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 mixture was diluted carefully with sat. aq. NH ₄ C1 (50 mL). The aqueous layer was separated and the organic layer was washed with brine (1 X 50 mL), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give l-(tert-butyl) 4-ethyl

4-((2-methylpyridin-3-yl)methyl)piperidine-l,4-dicarboxyl ate as a red oil (4.87 g) which was used in next step without any further purification. MS: m/z 363 (M+H) ⁺ .

Step d: To a -20 °C solution of l-(tert-butyl) 4-ethyl 4-((2-methylpyridin-3-yl)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 Na ₂ S0 ₄ , 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]-l-carboxylate (1.23 g) as a yellow oil. MS: m/z 317 (M+H) ⁺ .

Intermediate A21

Step a: To a -60 °C mixture 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) dropwise. 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 temperature, 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 lh. After cooling to RT, the volatiles was removed under reduced pressure, diluted with brine (200 mL) and extracted with EA (3 X 150 mL). The combined organic layers were dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA : Hex = 1 : 10, v/v) to give 2-(2-bromopyridin-3-yl)acetonitrile (2.21 g). MS: m/z 197 (M+H) ⁺ .

Step b: To a 0 °C solution of 2-(2-bromopyridin-3-yl)acetonitrile (2.21 g, 11.21 mmol) in DMF (20 mL) was added NaH (60% dispersion in mineral oil, 1.12 g, 28.03 mmol) in portions. The resulting mixture was warmed to 60 °C and stirred 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 Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA : Hex = 1 : 3, v/v) to give tert-butyl

4-(2-bromopyridin-3-yl)-4-cyanopiperidine-l-carboxylate (1.56 g). MS: m/z 366 (M+H) ⁺ .

Step c: A mixture of tert-butyl 4-(2-bromopyridin-3-yl)-4-cyanopiperidine-l-carboxylate (1.56 g, 4.26 mmol), K ₂ C0 ₃ (2.35 g, 17.04 mmol), 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (1.07 g, 8.52 mmol) and Pd(PPh ₃ ) ₄ (47 mg, 0.041 mmol) in 1,4-dioxane (40 mL) and water (8 mL) was stirred for 2 h at 110 °C under nitrogen atmosphere. An additional portion of

2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (2.15 g, 17.13 mmol) and Pd(PPh ₃ ) 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 Na ₂ S0 ₄ , 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-4-(2-methylpyridin-3-yl)piperidine-l-carboxylate (1.08 g). MS: m/z 302 (M+H) ⁺ .

Step d: To a 0 °C solution of tert-butyl 4-cyano-4-(2-methylpyridin-3-yl)piperidine-l- carboxylate (1.08 g, 3.58 mmol) in MeOH (50 mL) was added H ₂ S0 ₄ (98 %, 45 mL) dropwise. The resulting mixture was stirred for 18 h at reflux temperature. 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) ₂ 0 (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 combined, dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA) to give 1 -(tert-butyl) 4-methyl

4-(2-methylpyridin-3-yl)piperidine-l,4-dicarboxylate (467 mg). MS: m/z 335 (M+H) ⁺ .

Step e: To a 0 °C solution of 1 -(tert-butyl) 4-methyl 4-(2-methylpyridin-3-yl)piperidine-l,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.NH ₄ Cl (10 mL) and extracted with EA (3 X 40 mL). The combined organic layers were dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA) to give tert-butyl

6-oxo-6,7-dihydrospiro[cyclopenta[b]pyridine-5,4'-piperid ine]-r-carboxylate (170 mg). MS: m/z 303 (M+H) ⁺ . Intermediate A22

Step a: To a 0 °C mixture of tert-butyl 4-formylpiperidine-l-carboxylate (15.00 g, 70.33 mmol) in DMF (60 mL) was added lithium 2-methylpropan-2-olate (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-bromoprop-l-ene (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 Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA : Hex = 1 : 20, v/v) to give tert-butyl 4-allyl-4-formylpiperidine-l-carboxylate (7.01 g). MS: m/z 254 (M+H)

+

Step b: To a -78 °C solution of tert-butyl 4-allyl-4-formylpiperidine-l-carboxylate (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 mixture was allowed to warm to RT and stirred for 1.5 h. The reaction mixture was quenched with sat. aq. NH ₄ C1, extracted with EA (3 X 200 mL). The combined organic layers were washed with brine (1 X 200 mL), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give tert-butyl

4-allyl-4-(l-hydroxyallyl)piperidine-l-carboxylate (7.01 g). MS: m/z 282 (M+H) ⁺ .

Step c: To a solution of tert-butyl 4-allyl-4-(l-hydroxyallyl)piperidine-l -carboxylate (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 combined organic layers were dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica

chromatography (EA : Hex = 1 : 30, v/v) to give tert-butyl 4-acryloyl-4-allylpiperidine-l- carboxylate (5.63 g). MS: m/z 280 (M+H) ⁺ .

Step d: A mixture of tert-butyl 4-acryloyl-4-allylpiperidine-l -carboxylate (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 mixture was concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA : Hex = 1 : 5, v/v) to give tert-butyl l-oxo-8-azaspiro[4.5]dec-2-ene-8-carboxylate (3.61 g). MS: w/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 l-oxo-8-azaspiro[4.5]dec-2-ene-8-carboxylate (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 organic layers were washed with brine (3 X 200 mL), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give tert-butyl 2-oxospiro[bicyclo[3.1.0]hexane-3,4'- piperidine]-l'-carboxylate (3.60 g). MS: m/z 266 (M+H) ⁺ . Intermediate A

Step a: To a -10 °C solution of tetrahydro-2H-pyran-4-ol (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 Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give

tetrahydro-2H-pyran-4-yl methanesulfonate (6.74 g). MS: m/z 181 (M+H) ⁺ .

Step b: To a solution of r-benzyl-6-methoxyspiro[indene-2,4'-piperidin]-l(3H)-one ( 4.35 g, 13.53 mmol) in DCM (200 mL) was added BBr ₃ (1 M solution in DCM, 15.00 mL, 15.00 mmol), stirred for 13 h at 45 °C. An additional portion of BBr ₃ (1 M solution in DCM, 5.00 mL, 5.00 mmol) was added and stirred for 24 h at 45 °C. After cooling to RT, the reaction mixture was diluted with water (150 mL), NaHC0 ₃ (20.00 g) was added in portions. The resulting mixture was extracted with DCM (2 X 100 mL), the organic layers combined, dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give

r-benzyl-6-hydroxyspiro[indene-2,4'-piperidin]-l(3H)-one (2.80 g) which was used in next step without any further purification. MS: m/z 308 (M+H) ⁺ .

Step c: Amixture of r-benzyl-6-hydroxyspiro[indene-2,4'-piperidin]-l(3H)-one (2.80 g, 9.11 mmol), tetrahydro-2H-pyran-4-yl methanesulfonate (3.40 g, 18.87 mmol) and K ₂ C0 ₃ (8.23 g, 59.55 mmol) in DMF (60 mL) was stirred for 5.5 h at 110 °C. An additional portion of tetrahydro-2H-pyran-4-yl methanesulfonate (1.10 g, 6.10 mmol) and K ₂ CO ₃ (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 separated and extracted with EA (1 X 200 mL), the organic layers combined, washed with water (2 X 300 mL) and brine (1 X 300 mL), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with MeOH : DCM = 1 : 40, v/v) to give

r-benzyl-6-((tetrahydro-2H-pyran-4-yl)oxy)spiro[indene-2, 4'-piperidin]-l(3H)-one (1.70 g). MS: m/z 392 (M+H) ⁺ .

Step d: A mixture of l'-benzyl-6-((tetrahydro-2H-pyran-4-yl)oxy)spiro[indene-2,4' - piperidin]-l(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) ₂ 0 (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 chromatography (eluting with EA : Hex = 1 : 5, v/v) to give tert-butyl

l-oxo-6-((tetrahydro-2H-pyran-4-yl)oxy)-l,3-dihydrospiro[ indene- 2,4'-piperidine]-l'-carboxylate (1.45 g). MS: m/z 402 (M+H) ⁺ .

Intermediate A

A mixture of tert-butyl 6-bromo-l-oxo-l,3-dihydrospiro[indene-2,4'-piperidine]-r- carboxylate (1017 mg, 2.67 mmol), diethyl phosphonate (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 Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA) to give tert-butyl

6-(diethoxyphosphoryl)-l-oxo-l,3-dihydrospiro[indene-2,4'-pi peridine]-r-carboxylate (134 mg) which was used in next step without any further purification. MS: m/z 438 (M+H) ⁺ . Intermediate A25

Following procedures of Y. Uto et al. / Bioorg. Med. Chem. Lett. 20 (2010) 746 - 754, intermediate A25 was prepared.

The following compound was synthesized using the above procedure with the correspond starting materials.

Table 11

Intermediat

Step a: To a -65 °C solution of 1 -(tert-butyl) 4-ethyl piperidine-l,4-dicarboxylate (5.23 g, 20.32 mmol) in THF (30 ml) was added LDA (2 M solution in THF/Hex, 12.00 mL, 24.00 mmol) dropwise. The resulting mixture was stirred for 1.0 h at this temperature. 2-Bromobenzaldehyde (3.44 g, 18.59 mmol) was added dropwise at -70 °C. After stirring for 1 h, the mixture was quenched with brine (40 mL). The organic layer was separated, dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give 1 -(tert-butyl) 4-ethyl

4-((2-bromophenyl)(hydroxy)methyl)piperidine-l,4-dicarbox ylate (9.15 g) which was used in next step without any further purification. MS: m/z 442 (M+H) ⁺ .

Step b: To a -5 °C solution of 1 -(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. Na ₂ S ₂ 0 ₃ (25%, 1 x 80 mL), sat. aq. NaHC0 ₃ (1 X 80 mL) and brine

(1 X 100 mL). The organic layer was dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA : Hex = 1 : 5, v/v) to give 1 -(tert-butyl) 4-ethyl 4-(2-bromobenzoyl)piperidine-l,4-dicarboxylate (7.16 g). MS: m/z 440 (M+H) ⁺ .

Step d: To a -80 °C solution of l-(tert-butyl) 4-ethyl 4-(2-bromobenzoyl)piperidine-l,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 resulting mixture was allowed to warm to RT and stirred for 1 h. The reaction mixture was quenched with brine (30 mL) and extracted with EA (1 X. 20mL). The organic layer was dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA : Hex = 1 : 10, v/v) to give tert-butyl l,3-dioxo-l,3-dihydrospiro[indene-2,4'-piperidine]- l'-carboxylate (500 mg). MS: m/z 316 (M+H) ⁺ . Intermediate A27

Following procedures of J Org. Chem. 1999, 64, 5504-5510, intermediate A27 was prepared.

Intermediate A28

Step a: To a 0 °C solution of ethyl 2-chlorothiazole-4-carboxylate (24.95 g, 130.19 mmol) in MeOH (250 mL) was added NaBH ₄ (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 reduced pressure. The resulting mixture was extracted with

EA (2 X 200 mL), the combined organic layers were washed with brine (1 400 mL), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give

(2-chlorothiazol-4-yl)methanol (18.88 g). MS: m/z 150 (M+H) ⁺ .

Step b: To a solution of (2-chlorothiazol-4-yl)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 Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give (2-chlorothiazol-4-yl)methyl methanesulfonate which was used in next step without any further purification. MS: m/z 228 (M+H) ⁺ .

Step c: To a -60 °C solution of 1 -(tert-butyl) 4-ethyl piperidine-l,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 atmosphere. A solution of

(2-chlorothiazol-4-yl)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 Na ₂ S0 ₄ , 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) 4-ethyl 4-((2-chlorothiazol-4-yl)methyl) piperidine-l,4-dicarboxylate (38.12 g). MS: m/z 389 (M+H) ⁺ .

Step d: To a -60 °C solution of 1 -(tert-butyl) 4-ethyl 4-((2-chlorothiazol-4-yl)methyl) piperidine-l,4-dicarboxylate (8.51 g, 21.88 mmol) in THF (80 mL) was added LDA (2 M solution in THF/Hex, 11.00 mL, 22.00 mmol) dropwise under nitrogen atmosphere. Once finished, the reaction mixture was quenched with brine (50 mL). The organic layer was separated, dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA : Hex = 1 : 10, v/v) to give tert-butyl

2-chloro-6-oxo-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4 '-piperidine]-l'-carboxylate (1.93 g). MS: m/z 343 (M+H) ⁺ . Intermediate

Step (a-c): Step (b-c) of Intermediate A28 and step (b) of Intermediate A3 were applied to provide 1 -(tert-butoxycarbonyl)-4-(thiophen-2-ylmethyl)piperidine-4-c arboxylic acid.

Step d: A mixture of l-(tert-butoxycarbonyl)-4-(thiophen-2-ylmethyl)piperidine-4- carboxylic acid (4.92 g, 15.12 mmol) and PPA (30.12 g) was stirred 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) ₂ 0 (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 Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give tert-butyl 2-(tert-butyl)-4-oxo-4,6-dihydrospiro[cyclopenta[b]thiophene -5,4'-piperidine]-r-carboxylate (1.70 g). MS: m/z 364 (M+H) ⁺ .

Step e: A mixture of l-(tert-butoxycarbonyl)-4-(thiophen-2-ylmethyl)piperidine-4- carboxylic acid (4.88 g, 15.12 mmol) and HC1 (4M solution 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 reaction mixture was poured into ice/water (100 mL), the pH value was adjusted to 10 with NaOH. Then (Boc) ₂ 0 (5.12 g, 23.46 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 100 mL), dried over anhydrous Na ₂ S0 ₄ , 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]-r-carboxylate(2.71g). MS: m/z 308 (M+H) ⁺ .

Intermediate A30

Step a: To a solution of phenylmethanol (5.15 g, 47.62 mmol) in DMF (50 mL) was added NaH (60 % dispersion in mineral 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 mixture was mixed with NaHC0 ₃ (7.51 g, 89.39 mmol), CH ₃ I (1.5 mL) and DMF (10 mL). After stirring for 0.5 h, an additional portion of CH ₃ I (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 Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (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), LiBH ₄ (2M solution in THF, 9.00 mL, 18.00 mmol) in THF (40 mL) was stirred for 1 h at 50 °C. The reaction mixture 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 Na ₂ S0 ₄ , filtrated and concentrated under reduced pressure. The residue was purified by silica

chromatography (eluting with EA) to give (4-(benzyloxy)pyridin-2-yl)methanol (0.50 g). MS: m/z 216 (M+H) ⁺ .

Step d: A mixture of (4-(benzyloxy)pyridin-2-yl)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 mixture was diluted with sat.aq.NaHS0 ₃ , sat.aq.NaHC0 ₃ and DCM (50 mL). The aqueous layer was separated and extracted with DCM (50 mL). The combined organic layers were dried over anhydrous Na ₂ S0 ₄ , filtrated 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 l-(tert-butyl) 4-ethyl piperidine-l,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 of 4-(benzyloxy)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.NH ₄ Cl (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 Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA : Hex = 1 : 1) to give l-(tert-butyl) 4-ethyl 4-((4-(benzyloxy)pyridin-2-yl)(hydroxy)methyl)piperidine-l,4 -dicarboxylate (0.25 g). MS: m/z All (M+H) ⁺ .

Step f: A mixture of l-(tert-butyl) 4-ethyl 4-((4-(benzyloxy)pyridin-2-yl)(hydroxy) methyl)piperidine-l,4-dicarboxylate (0.25 g, 0.53 mmol), LiBH ₄ (2 M solution in THF, 1.00 mL, 2.00 mmol) in THF (10 mL) was stirred 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 organic layer was washed with brine

(1 X 30 mL), dried over anhydrous Na ₂ S0 ₄ , filtrated and concentrated under reduced pressure to give tert-butyl 4-((4-(benzyloxy)pyridin-2-yl)(hydroxy)methyl)-4-(hydroxymet hyl)piperidine- 1 - carboxylate (0.22 g). MS: m/z 429 (M+H) ⁺ .

Step g: A mixture of tert-butyl 4-((4-(benzyloxy)pyridin-2-yl)(hydroxy)methyl)-4- (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 filtration was concentrated under reduced pressure to give tert-butyl 4-(hydroxy(4-hydroxypyridin-2-yl)methyl)-4-(hydroxymethyl)pi peridine- 1 - carboxylate (154 mg). MS: m/z 339 (M+H) ⁺ .

Step h: To a mixture of tert-butyl 4-(hydroxy(4-hydroxypyridin-2-yl)methyl)-4- (hydroxymethyl)piperidine-l -carboxylate (120 mg, 0.36 mmol) and triphenyl phosphate (175 mg, 0.67 mmol) in THF (10 mL) was added Ν,Ν,Ν',Ν'-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 = 1 : 7, v/v) to give tert-butyl

l-hydroxy-7-oxo-l,7-dihydro-3H-spiro[indolizine-2,4'-pipe ridine]- -carboxylate (100 mg). MS: w/z 321 (M+H) ⁺ .

Step i: A mixture of tert-butyll-hydroxy-7-oxo-l,7-dihydro-3H-spiro[indolizine-2, 4'- piperidine]-l'-carboxylate (0.35 g, 1.09 mmol), Dess-Martin 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.Na ₂ S0 ₃ (1

X 20 mL) and sat.aq.NaHC0 ₃ (1 X 20 mL). The organic layer was dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give tert-butyl l,7-dioxo-l,7-dihydro-3H- spiro[indolizine-2,4'-piperidine]-r-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 Bl

Following procedures of WO2017211303 Al, intermediate Bl was prepared from

4-iodoindoline-2,3-dione in 3 steps. Intermediate B2

Following procedures of WO2017211303 Al, intermediate B2 was prepared from

3-bromo-6-chloropyrazin-2-amine in 2 steps.

The following compounds were synthesized using the above procedure or modifications procedure with the corresponding starting materials.

Tab

Intermediate B3

3-Chloro-2-fluoro-4-iodopyridine (10.10 g, 39.23 mmol) and DMSO (50 mL) was added to a sealed tube, ammonium hydroxide (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 Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give 3-chloro-4-iodopyridin-2-amine (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

Intermedia

A mixture of 3-chloro-4-iodopyridin-2-amine (25.53 g, 100.33 mmol), sodium 3-amino-5- chloropyrazine-2-thiolate (20.18 g, 109.92 mmol), Pd ₂ (dba) ₃ (4.47 g, 4.88 mmol), XantPhos (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 atmosphere. After cooling to RT, the reaction mixture was filtered through a pad of Celite followed by 1,4-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-amino-3-chloropyridin-4-yl)thio)-6-chloropyrazin-2- amine (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)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-2,3-dihydrospiro[inde ne-l,4'-piperidin]-2-amine

Step a:A mixture of Compound IH-indene (11.62g, O.lOmol) and LiHMDS (220mL, lmol/L in THF) in THF(120mL) was stirred at -50°C for 1 hour. Tert-butyl bis(2-chloroethyl)carbamate (24.2 lg, O.lOmol) was added to the reaction mixture and stirred at -50°C for lhr. The reaction was quenched with brine (300mL). The organic extracts were dried with anhydrous Na ₂ S0 ₄ , and concentrated under reduced pressure in vacuo. The residue was purified by column chromatography to afford Compound tert-butyl spiro[indene-l,4'-piperidine]-l'-carboxylate as a yellow solid (10.36g, 36%). MS: 286 (M+H) ⁺ .

Step b:A mixture of Compound tert-butyl spiro[indene-l,4'-piperidine]-l'-carboxylate (117.02g, 0.41mol) and borane-methyl sulfide complex (lOmol/L, 220mL) in THF (800mL) was stirred at 0°Cfor 3 hours. NaOH (2mol/L, 1.2L) and H ₂ 0 ₂ (300mL) was added and stirred at 0°C for 1 hour. The organic extracts were collected, dried over anhydrous Na S0 ₄ and concentrated under reduced pressure in vacuo to afford the mixture of tert-butyl

2-hydroxy-2,3-dihydrospiro[indene- 1 ,4'-piperidine]- 1 '-carboxylate and tert-butyl

3-hydroxy-2,3-dihydrospiro[indene-l,4'-piperidine]- -carboxylate as a yellow oil (130.33g, crude). MS: 304 (M+H) ⁺ .

Step c:A mixture of tert-butyl

2- hydroxy-2,3-dihydrospiro[indene-l,4'-piperidine]- -carboxylate and tert-butyl

3- hydroxy-2,3-dihydrospiro[indene-l,4'-piperidine]- -carboxylate (130.02g, 0.43mol) and Dess-Martin periodinane (364.76g, 0.86mol) in DCM (2L) was stirred at 25°C for 12 hours. The reaction mixture was filtered and the filtrate was washed by saturated sodium bicarbonate solution (1L) and brine (1L). The organic extracts were dried over anhydrous Na S0 ₄ and concentrated under reduced pressure in vacuo. The residue was purified by column chromatography to afford Compound tert-butyl 3-oxo-2,3-dihydrospiro[indene-l,4'-piperidine]-r-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]-r-carboxyl ate (41.01g, 0.14mol) in Titanium(IV) ethoxide (80mL) was added R-(+)-tert-Butylsulfinamide (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 Na ₂ S0 ₄ , and concentrated under reduced pressure in vacuo to afford Compound tert-butyl 3-oxo-2,3-dihydrospiro[indene-l,4'-piperidine]-r-carboxylate (132.05g crude). MS: 405(M+H) ⁺ . Without purification to next step.

Step e:A mixture of Compound tert-butyl

3-oxo-2,3-dihydrospiro[indene-l,4'-piperidine]- -carboxylate (132.02g, 0.33mol) in THF (200mL) was stirred at -50°C. NaBH ₄ (7.71g, 0.51mol) was added to the reaction mixture and allowed to return to room temperature. Reaction was quenched with saturated ammonium chloride solution (lOOmL). The organic extracts were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated under reduced pressure in vacuo. The residue was purified by column chromatography to afford Compound tert-butyl

(R)-2-(((R) ert-butylsulfinyl)amino)-2,3-dihydrospiro[indene-l,4'-piperi dine]- -carboxylate as a white solid (27.25g, 49%, 2 steps). MS: 407 (M+H) ⁺ .

Step f: A mixture of Compound tert-butyl

(R)-2-(((R)-tert-butylsulfinyl)amino)-2,3-dihydrospiro[inden e-l,4'-piperidine]- -carboxylate (1.16g, 3.98mmol), CF ₃ COOH (3.6mL) in DCM (20mL) was stirred 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-amino-3-chloropyridin-4-yl)thio)-6- chloropyrazin-2-amine (1.03g, 3.59mmol) and K ₂ C0 ₃ (6.60g, 47.76mmol) was added to mixture and stirred at 90°C for 16 hours. H ₂ 0 (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 organic extracts were dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure in vacuo to afford the Compound

(R)-N-((R)- -(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl )-2,3-dihydrospiro[in dene-l,4'-piperidin]-2-yl)-2-methylpropane-2-sulfinamide (1.55g, 70%) as a yellow solid.

Step g:To a solution of Compound

(R)-N-((R)- -(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl )-2,3-dihydrospiro[in dene-l,4'-piperidin]-2-yl)-2-methylpropane-2-sulfinamide (1.52g, 2.72mmol) in DCM (20mL) was added HCl/Dixoane (2mL, 4mol/L). The resulting mixture was stirred at 25°C for lhour 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 Na2S04 and concentrated under reduced pressure in vacuo. The residue was purified by column chromatography to afford Compound

(R)- -(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl )-2,3-dihydrospiro[indene-l, 4'-piperidin]-2-amine as a yellow solid (530mg, 42%). MS: 454 (M+H) ⁺ . 1H NMR (400 MHz, DMSO-d6) δ 7.64 - 7.66 (m, 2H), 7.30 (d, IH), 7.20 (d, IH), 7.13 - 7.15 (m, 2H), 6.78 (d, IH), 4.05 - 4.09 (m, IH), 3.91 - 3.95 (m, IH), 3.54 - 3.60 (m, 3H), 3.12 - 3.18 (m, IH), 2.57 - 2.63 (m, IH), 1.91 - 2.09 (m, 2H), 1.66 - 1.76 (m, IH), 1.49 - 1.58 (m, IH). EXAMPLE 2

(S)- 1 '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)- 1 ,3-dihydrospiro [inden e-2,4'-piperidin]-l-amine

Step a:NaH(60%) (3.63g, 90.80mmol) was added into the solution of Compound

2,3-dihydro-lH-inden-l-one (4.00g, 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 Na ₂ S04. After concentrated, the residue was purified by column chromatography to afford the Compound tert-butyl

l-oxo-l,3-dihydrospiro[indene-2,4'-piperidine]-l'-carboxy late (1.21g, 13%) as a dark red oil. MS: 302 (M+H) ⁺ .

Step b:After the Titanium(IV) ethoxide (12.00g) was warmed into 90°C, the compound tert-butyl l-oxo-l,3-dihydrospiro[indene-2,4'-piperidine]-r-carboxylate (1.21g, 4.01mmol) and (R)-2-methylpropane-2-sulfinamide (1.22g, 12.04mmol) were added. After stirred for 19hrs at 90°C. The mixture was poured into EA (200mL), and brine (200mL) was added. After stirred for 15 mins, the solids were filtrated out. The liquid was separated. The organic layer was washed with brine (200mL><2), and dried over anhydrous Na ₂ S04. The solids were filtrated out, and the filtration was concentrated under reduced pressure in vacuo. The residue was purified by column chromatography to afford the compound tert-butyl

(R,E)-l-((tert-butylsulfinyl)imino)-l,3-dihydrospiro[inde ne-2,4'-piperidine]-r-carboxylate (l .Olg, 62%) as a black solid. MS: 405 (M+H) ⁺ .

Step c:The solution of the compound tert-butyl

(R,E)-l-((tert-butylsulfinyl)imino)-l,3-dihydrospiro[inde ne-2,4'-piperidine]-r-carboxylate (l .Olg, 2.50mmol) in THF (lOmL) was cooled in -50°C. NaBH ₄ (142mg, 3.74mmol) was added in portionwise. The mixture was stirred for 15.5 hours with natural warming to room temperature, and then poured into EA (lOOmL). The mixture was washed with brine (100mL><3). The organic layer was dried over anhydrous Na2S04 and concentrated under reduced pressure in vacuo. The residue was purified by column chromatography to afford the Compound tert-butyl

(S)- 1 -(((R)-tert-butylsulfinyl)amino)- 1 ,3-dihydrospiro[indene-2,4'-piperidine]-r-carboxylate (580mg, 57%) as a yellow oil. MS: 407 (M+H) ⁺ .

Step d:The mixture of the compound tert-butyl

(S)- 1 -(((R)-tert-butylsulfinyl)amino)- 1 ,3-dihydrospiro[indene-2,4'-piperidine]- -carboxylate (580mg, 1.43mmol) and TFA (ImL) in DCM (5mL) was stirred for 40 mins at 20°C. The solution was concentrated to afford the compound

(R)-N-((S)- 1 ,3-dihydrospiro[indene-2,4'-piperidin]- 1 -yl)-2-methylpropane-2-sulfinamide (520mg, 90%) as a yellow oil. MS: 307 (M+H) ⁺ .

Step e:The mixture of

(R)-N-((S)- 1 ,3-dihydrospiro[indene-2,4'-piperidin]- 1 -yl)-2-methylpropane-2-sulfinamide (260mg, 0.62mmol), 3-((2-amino-3-chloropyridin-4-yl) thio)-6-chloropyrazin-2-amine (196mg,

0.68mmol) and K ₂ C03 (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 Na2S04 and concentrated under reduced pressure in vacuo. The residue was purified by column chromatography to afford the Compound

(R)-N-((S)- -(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl )-l ,3-dihydrospiro[in dene-2,4'-piperidin]-l-yl)-2-methylpropane-2-sulfinamide (260mg, 65%) as a yellow solid. MS:

558 (M+H) ⁺ .

Step f:The compound

(R)-N-((S)- -(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl )-l ,3-dihydrospiro[in dene-2,4'-piperidin]-l-yl)-2-methylpropane-2-sulfinamide (260mg, 0.47mmol) was dissolved in

DCM (5mL) and HCl/Dixoane (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 collected by filtration to afford the compound

(S)- -(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl )-l ,3-dihydrospiro[indene-2, 4'-piperidin]-l -amine (123mg, 54%) as an off-white solid. MS: 454 (M+H) ⁺ . 1H NMR (400 MHz,

DMSO-d6) δ 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)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-3,4-dihydro-2H-spiro[ naphthalene- 1 ,4'-piperidin] -2-amine

Step a:The solution of the compound tert-butyl bis(2-chloroethyl)carbamate

(11.00g,45.43mmol) in HCl/Dixoane (4mol/L, 200mL) was stirred for lh at 20°C. The solution was concentrated and the residue was dissolved in DCE (200mL). Triethylamine (22.95g, 227.14mmol) and benzaldehyde (7.23g, 68.14mmol) was added to the mixture. And then

NaBH(OAc) ₃ (24.07g, 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 organic layer was concentrated under reduced pressure in vacuo. The residue was dissolved in HCl solution (2mol/L, 200mL) and extracted with EA (lOOmL). The pH value of the aqueous layer was adjusted to 9 with saturated Na ₂ C0 ₃ solution. The mixture was extracted with EA (200mL). The organic layer was dried over anhydrous Na ₂ S0 ₄ and concentrated to afford the compound

N-benzyl-2-chloro-N-(2-chloroethyl)ethan-l -amine (8.52g, 81%) as a colorless oil.

Step b:Into the solution of the compound N-benzyl-2-chloro-N-(2-chloroethyl)ethan-l -amine (8.52g, 36.70mmol) and 3,4-dihydronaphthalen-2(lH)-one (4.88g, 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 mixture was washed with brine (200mLx3). The organic layer was dried over anhydrous Na ₂ S0 ₄ and concentrated. The residue was purified by column chromatography to afford

-benzyl-3,4-dihydro-2H-spiro[naphthalene-l,4'-piperidin]-2-o ne (2.32g, 21%) as a black oil. MS: 306 (M+H) ⁺ .

Step c:Into Titanium(IV) ethoxide was added the compound

-benzyl-3,4-dihydro-2H-spiro[naphthalene-l,4'-piperidin]-2-o ne (2.32g, 7.60mmol) and (R)-2-methylpropane-2-sulfinamide (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 separated. The organic layer was washed with brine (100mL><5), dried over anhydrous Na ₂ S0 ₄ , and concentrated under reduced pressure in vacuo. The residue was purified by column chromatography to afford the compound

(R,E)-N-( -benzyl-3,4-dihydro-2H-spiro[naphthalene-l,4'-piperidin]-2-y lidene)-2-methylpropan e-2-sulfinamide (660mg, 21%) as a yellow oil. MS: 409 (M+H) ⁺ .

Step d:The solution of the compound

(R,E)-N-( -benzyl-3,4-dihydro-2H-spiro[naphthalene-l,4'-piperidin]-2-y lidene)-2-methylpropan e-2-sulfinamide (660mg, 1.62mmol) in THF (lOmL) was cooled into -50°C. And then NaBH4 (122mg, 3.23mmol)was added in portionwise. The mixture was stirred for 18h with natural warming to room temperature. The mixture was quenched with water (50mL) and extracted with EA (50mLx2). The organic layers were combined and washed with brine (50mLx2), dried over anhydrous Na2S04 and concentrated under reduced pressure in vacuo. The residue was purified by column chromatography to afford the compound

(R)-N-((R)- -benzyl-3,4-dihydro-2H-spiro[naphthalene-l,4'-piperidin]-2-y l)-2-methylpropane-2 -sulfinamide (195mg, 29%) as a yellow oil. MS: 411 (M+H) ⁺ .

Step e:Into the solution of the compound

(R)-N-((R)- -benzyl-3,4-dihydro-2H-spiro[naphthalene-l,4'-piperidin]-2-y l)-2-methylpropane-2 -sulfinamide (195mg, 0.47mmol) in methanol (5mL) was added palladium hydroxide(20%, 120mg). The mixture was stirred for 18h at 40°C under hydrogen 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]- 2-yl)-2-methylpropane-2-sulfinami de (92mg, 60%). MS: 321 (M+H) ⁺ .

Step f:The compound

(R)-N-((R)-3,4-dihydro-2H-spiro[naphthalene-l,4'-piperidin]- 2-yl)-2-methylpropane-2-sulfinami de (92mg, 0.29mmol) was dissolved in NMP (3mL).

3-((2-amino-3-chloropyridin-4-yl)thio)-6-chloropyrazin-2-ami ne (91mg, 0.32mmol) and K ₂ C0 ₃ (198mg, 1.44mmol) were added into. The mixture was stirred for 3 hours at 100°C, and diluted with EA(30mL) ,washed with brine (30mL><3). The organic layer was dried with anhydrous Na ₂ S0 ₄ . The residue was purified with Pre-TLC to afford the compound

(R)-N-((R)-r-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio) pyrazin-2-yl)-3,4-dihydro-2H-spi ro[naphthalene-l,4'-piperidin]-2-yl)-2-methylpropane-2-sulfi namide (18mg, 11%) as an off-white solid.

Step g:In to the solution of the compound

(R)-N-((R)-r-(6-amino-5-((2-amino-3-chloropyridin-4-yl)th io)pyrazin-2-yl)-3,4-dihydro-2H-spi ro[naphthalene-l,4'-piperidin]-2-yl)-2-methylpropane-2-sulfi namide (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)- -(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl )-3,4-dihydro-2H-spiro[naph thalene-l,4'-piperidin]-2-amine (14mg, 88%) as an off-white solid. MS: 468 (M+H) ⁺ . EXAMPLE 4

(R)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-5,6-dihydrospiro[cyclo penta[b]pyridine-7,4'-piperidin]-6-amine

Step a:NaHMDS (38ml, 2mol/L in THF) was added to the mixture of the compound 2-fluoro-3-methylpyridine (5.56g, 50.00mmol), 1-tert-butyl 4-ethyl piperidine-l,4-dicarboxylate (14.15g, 55.00mmol) in toluene (50mL) dropwise at 0°C, then naturally warmed to 20°C and stirred for 24 hours. Reaction mixture was quenched with brine (lOOmL). The organic extracts were dried over Na ₂ S0 ₄ and concentrated under reduced pressure in vacuo. The residue was purified by column chromatography to afford the compound 1 -(tert-butyl) 4-ethyl

4-(3-methylpyridin-2-yl)piperidine-l,4-dicarboxylate (6.32g, 36%) as a yellow oil. MS: 349 (M+H) ⁺ .

Step b:A mixture of the compound 1 -(tert-butyl) 4-ethyl

4-(3-methylpyridin-2-yl)piperidine-l,4-dicarboxylate (4.80g, 13.78mmol), LDA (2mol/L,17mL) 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 ]- -carboxylate (0.95g, 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'-piperid ine]- -carboxylate (0.94g, 3.1 lmol) in Titanium(IV) ethoxide (5mL) was added R-(+)-tert-Butylsulfinamide ( 1.13g, 9.33mmol) . 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 filtered 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 Na ₂ S0 ₄ and concentrated under reduced pressure in vacuo to afford the compound tert-butyl

(R,Z)-6-((tert-butylsulfinyl)imino)-5,6-dihydrospiro[cyclope nta[b]pyridine-7,4'-piperidine]- -ca rboxylate (2.5 lg, crude) as a red oil. Without purification to next step.MS: 406(M+H) ⁺ .

Step d: A solution of the compound tert-butyl

(R,Z)-6-((tert-butylsulfinyl)imino)-5,6-dihydrospiro[cycl openta[b]pyridine-7,4'-piperidine]-l ^L rboxylate (2.12g, crude) in THF (20mL) was stirred at -50°C. NaBH ₄ (176mg, 4.66mmol) was added to the reaction mixture and naturally warmed to room temperature. Reaction was quenched with saturated ammonium chloride solution (30mL). The organic extracts were collected and dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure in vacuo. The residue was purified by column chromatography to afford the compound tert-butyl

(R)-6-(((S)-tert-butylsulfinyl)amino)-5,6-dihydrospiro[cyclo penta[b]pyridine-7,4'-piperidine]- - carboxylate (0.21g, 17%, 2 steps) as a yellow solid. MS: 408 (M+H) ⁺ .

Step e:A mixture of the compound tert-butyl

(R)-6-(((S)-tert-butylsulfinyl)amino)-5,6-dihydrospiro[cy clopenta[b]pyridine-7,4'-piperidine]- - carboxylate (204mg, 0.50mmol), CF ₃ COOH (ImL) in DCM(lOmL) was stirred at 25°C for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in NMP(lOmL), then 3-((2-amino-3-chloropyridin-4-yl)thio)-6-chloropyrazin-2-ami ne (144mg, 0.50mmol) and K ₂ C0 ₃ (0.82g, 6.00mmol) was added to mixture and stirred at 95°C for 16 hours. H ₂ 0 (50mL) was added to the reaction mixture. The aqueous solution was extracted with EA (30mLx2). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure in vacuo to afford the compound

(S)-N-((R)- -(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl )-5,6-dihydrospiro[cy clopenta[b]pyridine-7,4'-piperidin]-6-yl)-2-methylpropane-2- sulfinamide (302mg, crude).

Without purification to next step. MS: 559 (M+H) ⁺ .

Step f:To a solution of the compound

(S)-N-((R)- -(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl )-5,6-dihydrospiro[cy clopenta[b]pyridine-7,4'-piperidin]-6-yl)-2-methylpropane-2- sulfinamide (302mg, 0.54mmol) in DCM (lOmL) was added HCl/Dixoane (4mol/L, ImL). 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 filtered to afford the compound (R)- -(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl )-5,6-dihydrospiro[cyclopent a[b]pyridine-7,4'-piperidin]-6-amine (163mg, 71%, 2 steps) as a yellow solid. MS: 455 (M+H) ⁺ . 1H NMR (600 MRz,MeOH-d4) δ 8.69 (d, 1H), 8.54 (d, 1H), 7.92 - 7.96 (m, 1H), 7.88(s,lH), 7.75(d,lH), 6.58(d,lH), 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-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)-6-methoxy- 1 ,3-dihydro spiro[indene-2,4'- i eridin]-l-amin

Step a: A mixture of tert-butyl 6-methoxy-l-oxo-l ,3-dihydrospiro[indene-2,4'-piperidine]- l'-carboxylate (557 mg, 1.68 mmol) and (R)-(+)-2-Methyl-2-propanesulfinamide (610 mg, 5.04 mmol) in Ti(OEt) ₄ (5 mL) was stirred for 16 h at 100 °C. After cooling to RT, the reaction 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 Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give tert-butyl

(R,Z)-l-((tert-butylsulfinyl)imino)-6-methoxy-l ,3-dihydrospiro[indene-2,4'-piperidine]-r-carbo xylate (0.98 g) which was used in next step without any further purification. MS: m/z 435 (M+H) ⁺ .

Step b: To a -50 °C solution of tert-butyl (R,Z)-l-((tert-butylsulfinyl)imino)-6-methoxy- l,3-dihydrospiro[indene-2,4'-piperidine]-r-carboxylate (0.98 g, 2.25 mmol) in THF (10 mL) was added NaBH ₄ (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 Na ₂ S0 ₄ , 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)-l-(((R)-tert-butylsulfinyl)amino)-6-methoxy- l,3-dihydrospiro[indene-2,4'-piperidine]-r-carboxylate (380 mg). MS: m/z 437 (M+H) ⁺ .

Step c: To solution of tert-butyl

(S)-l-(((R)-tert-butylsulfinyl)amino)-6-methoxy-l ,3-dihydrospiro[indene-2,4'-piperidine]-r-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 resulting mixture was concentrated under reduced pressure. The residue was dissolved in NMP (10 mL), 3-((2-amino-3-chloropyridin-4-yl)thio)-6-chloropyrazin-2-ami ne (301 mg, 1.04 mmol) and K ₂ C0 ₃ (601 mg, 4.35 mmol) was added. The resulting mixture was stirred for 16 h at 100 °C. After cooling to RT, the reaction mixture was diluted 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 Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with MeOH : DCM = 1 : 20, v/v) to give

(R)-N-((S)- -(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl )-5-methoxy-l,3-dihy drospiro[indene-2,4'-piperidin]-3-yl)-2-methylpropane-2-sulf inamide (254 mg). MS: m/z 588 (M+H) ⁺ .

Step d: To a solution of (R)-N-((S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio )pyraz in-2-yl)-5 -methoxy- 1 ,3 -dihydrospiro [indene-2 ,4'-piperidin] -3 -yl)-2 -methylpropane-2 -sulfinamid e (254 mg, 0.43 mmol) in 1, 4-dioxane (3 mL) was added HC1 (4M solution in 1, 4-dioxane, 3 mL) dropwise 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)- -(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)p yrazin-2-yl)-6-methoxy-l,3-dihydrospiro[indene-2,4'-piperidi n]-l-amine (221 mg) as a HCl salt. MS: m/z 484 (M+H) ⁺ . ^J H NMR (600 MHz, MeOH-d4) δ 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.

The following examples are compounds with free base, or a pharmaceutically acceptable salt.

Table 16

EXAMPLE 82

(S)- 1 '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)-5,7-dihydrospiro [cyclo penta[b]pyridine-6,4'-piperidin]-7-amine

Step a: A mixture of tert-butyl 7-oxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperi dine]-l'-carboxylate (936 mg, 3.10 mmol) and (R)-(+)-2-Methyl-2-propanesulfinamide (1045 mg, 8.62 mmol) in Ti(OEt) ₄ (8 mL) was stirred for 2 h at 100 °C. After cooling to RT, the reaction 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 organic layer was separated, dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give tert-butyl

(R,Z)-7-((tert-butylsulfinyl)imino)-5,7-dihydrospiro[cyclope nta[b]pyridine-6,4'-piperidine]-l ^L rboxylate (1.41 g). MS: m/z 406 (M+H) ⁺ .

Step b: To a -40 °C solution of tert-butyl (R,Z)-7-((tert-butylsulfinyl)imino)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-r-carbox ylate (1.41 g, 3.48 mmol) in THF (50 mL) was added BH ₃ (1 M solution in THF, 10.00 mL, 10.00 mmol). The resulting mixture was allowed to warm to RT and stirred for 1 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 Na ₂ S0 ₄ , 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 purified by silica

chromatography (eluting with MeOH : DCM = 1 : 60, v/v) to give tert-butyl

(S)-7-(((R)-tert-butylsulfinyl)amino)-5,7-dihydrospiro[cy clopenta[b]pyridine-6,4'-piperidine]-r- carboxylate (309 mg). MS: m/z 408 (M+H) ⁺ .

Step c: To solution of tert-butyl (S)-7-(((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 HC1 (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 (S)-5,7-dihydrospiro [cyclopenta [b] pyridine-6,4'-piperidin]-7-amine (227 mg). MS: m/z 204 (M+H) ⁺ .

Step d: A mixture of (S)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-7 -amine (HC1 salt, 227 mg, 1.12 mmol), 3-((2-amino-3-chloropyridin-4-yl)thio)-6-chloropyrazin-2-ami ne (249 mg, 0.86 mmol) and K ₂ CO ₃ (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 diluted with brine (100 mL), extracted with EA (2 X 50 mL). The organic layers were combined, dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica

chromatography (eluting with MeOH : DCM = 1 : 6, v/v) to give

(S)-r-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin -2-yl)-5,7-dihydrospiro[cyclopent a[b]pyridine-6,4'-piperidin]-7-amine (77 mg). MS: m/z 455 (M+H) ⁺ . 1H NMR (400 MHz, MeOH-d4) 6 S.5 l (s, 1H), 7.81 (d, IH), 7.63 (s, 2H), 7.38 (s, 1H), 5.94 (d, IH), 4.49 - 4.30 (m, 3H), 3.37 - 3.09 (m, 4H), 2.05 - 1.95 (m, IH), 1.85 - 1.70 (m, 2H), 1.60 - 1.50 (m, IH).

The following examples were synthesized using the above procedure or modification procedure using the corresponding Intermediate A and Intermediate B.

2-Methylpropane-2-sulfinamide, instead of (R)-(+)-2-Methyl-2-Propanesulfinamide, 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.

Table 17

EXAMPLE 133

(S)-4-((5-(l-amino-l,3-dihydrospiro[indene-2,4'-piperidin]-l ^, -yl)pyrazin-2-yl)thio)-3-chloro pyridi -2-ol

Step a-c: Step (a-c) of Example 5 was applied to provide

(R)-N-((S)- -(5-((3-chloro-2-methoxypyridin-4-yl)thio)pyrazin-2-yl)-l,3- dihydrospiro^

4'-piperidin]-l-yl)-2-methylpropane-2-sulfinamide. MS: m/z 558 (M+H) ⁺ .

Step d: A mixture of

(R)-N-((S)- -(5-((3-chloro-2-methoxypyridin-4-yl)thio)pyrazin-2-yl)-l,3- dihydrospiro[

4'-piperidin]-l-yl)-2-methylpropane-2-sulfinamide (112 mg, 0.20 mmol), DCM (5 mL) and HC1 (4 M solution 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 suspended in MeOH (2 mL) and EA (20 mL), the resulting precipitate was collected by filtration and dried under reduced pressure to give

(S)-4-((5-(l-amino-l,3-dihydrospiro[indene-2,4'-piperidin]-r -yl)pyrazin-2-yl)thio)-3-chloropyri din-2-ol (73 mg). MS: m/z 440 (M+H) ⁺ . 1H NMR (400 MHz, DMSO-d6) δ 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.

The following examples are compounds, or a pharmaceutically acceptable salt. Table 18

EXAMPLE 137

(S)- 1-amino- 1 '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)- 1 ,3-dihydrosp iro[indene-2,4'-piperidin]-6-ol

To a mixture of

(S)-r-(6-amino-5-((2-amino-3-chloropyridm^

o[indene-2,4'-piperidin]-l -amine (74 mg, 0.14 mmol) in DCM (2 mL) was added BBr3 (1 M solution in DCM, 0.71 mL). The resulting mixture was stirred for 6 h at RT. The volatiles were removed under reduced pressure, the residue suspended in water, the resulting solid was filtered off and the pH value of the filtrate was adjusted to 7 with sat.aq.NaHC03. The resulting precipitate was collected by filtration and dried in a vacuum oven to give

(S)-l-amino-r-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio )pyrazin-2-yl)-l ,3-dihydrospiro[i ndene-2,4'-piperidin]-6-ol (7 mg). MS: m/z 470 (M+H) ⁺ .

The following example was synthesized using the above procedure with the corresponding starting materials.

Table 19

EXAMPLE 139

l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2- yl)-5-methyl-5,7-dihydrospiro [c lopenta[b]pyridine-6,4'-piperidin]-5-amine

Step a: Step (a) of Example 5 was applied to provide tert-butyl

(R,Z)-5-((tert-butylsulfinyl)imino)-5,7-dihydrospiro[cyclope nta[b]pyridine-6,4'-piperidine]- rboxylate. MS: m/z 406 (M+H) ⁺ .

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]- -carboxylate (1.49 g, 3.67 mmol) in THF (15 mL) was added methyllithium (1.3 M solution 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 aqueous layer was collected, NaOH (1.00 g, 25.00 mmol) and (Boc) ₂ 0 (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 Na ₂ S0 ₄ , 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 5-(((S)-tert-butylsulfinyl)amino)-5-methyl-5,7-dihydrospiro[ cyclopenta[b] pyridine-6,4'-piperidine]-r-carboxylate (823 mg). MS: m/z 422 (M+H) ⁺ .

Step (c-d): Step (c-d) of Example 5 was applied to provide l'-(6-amino-5-((2-amino-3- chloropyridin-4-yl)thio)pyrazin-2-yl)-5^

ridin]-5-amine (71 mg). MS: m/z 469 (M+H) ⁺ .1H NMR (400 MHz, MeOH-d4) δ 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-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)py razin-2-yl)-3H-spiro[indolizi -2,4'-piperidin]-7(lH)-one

Step a: To a -10 °C solution of tert-butyl l-hydroxy-7-oxo-l,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 1 h at RT. The reaction solution was diluted with water (50 mL), extracted with DCM (3 X 50 mL). The combined organic layers were dried over anhydrous Na ₂ S0 ₄ , filtrated and concentrated under reduced pressure to give tert-butyl

l-((methylsulfonyl)oxy)-7-oxo-l,7-dihydro-3H-spiro[indoli zine-2,4'-piperidine]-r-carboxylate

(155 mg). MS: m/z 399 (M+H) ⁺ .

Step b: A mixture of tert-butyl

l-((methylsulfonyl)oxy)-7-oxo-l,7-dihydro-3H-spiro[indoli zine-2,4'-piperidine]-r-carboxylate (155 mg, 0.39 mmol), sodium azide (136 mg, 2.09 mmol) and DMF (5 mL) was stirred for 1 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 filtration was concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with MeOH : DCM = 1 : 10, v/v) to give tert-butyl

l-azido-7-oxo-l,7-dihydro-3H-spiro[indolizine-2,4'-piperi dine]-r- carboxylate (32 mg). MS: m/z 346 (M+H) ⁺ .

Step c: A mixture of tert-butyl

l-azido-7-oxo-l,7-dihydro-3H-spiro[indolizine-2,4'-piperi dine]-r-carboxylate (32 mg, 0.093 mmol), Pd (10% on carbon, 15 mg) in EtOH (6 mL) was stirred for 3 h under hydrogen atmosphere.

The reaction mixture filtrated follow by EtOH wash and the filtration was concentrated under reduced pressure to give tert-butyl

l-amino-7-oxo-l,7-dihydro-3H-spiro[indolizine-2,4'-piperi dine]-r-carboxylate (26 mg). MS: m/z

320 (M+H) ⁺ .

Step d: To solution of tert-butyl

l-amino-7-oxo-l,7-dihydro-3H-spiro[indolizine-2,4'-piperi dine]-r-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-amino-3-chloropyridin-4-yl)thio)-6-chloropyrazin-2-ami ne (46 mg, 0.16 mmol) and K ₂ C0 ₃

(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 = 1 : 3, v/v) to give

l-amino-r-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio) pyrazin-2-yl)-3H-spiro[indolizine-2,

4'-piperidin]-7(lH)-one (2 mg). MS: m/z All (M+H) ⁺ .

The following example was synthesized using the above procedure with the corresponding starting materials. Table 20

EXAMPLE 142

3-((2-amino-3-chloropyridin-4-yl)thio)-6-(l-imino-l,3-dihydr ospiro[indene-2,4'-piperidin]- l'-yl)pyrazin-2-amine

Step a: Step (a) of Example 5 was applied to provide tert-butyl

(R,Z)-1 -((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)-l-((tert-butylsulfinyl)imino)-l ,3-dihydrospiro[indene-

2,4'-piperidine]-l'-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 residue was dissolved in NMP (10 mL), 3-((2-amino-3-chloropyridin-4-yl)thio)-6-chloropyrazin-2-ami ne (288 mg, 1.00 mmol) and K ₂ C0 ₃ (1.38 g, 10.00 mmol) was added. The resulting mixture 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 (IX 100 mL), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with MeOH : DCM = 1 : 5, v/v) to give

3-((2-amino-3-chloropyridin-4-yl)thio)-6-(l -imino-l ,3-dihydrospiro[indene-2,4'-piperidin]-r^ pyrazin-2-amine (50 mg). MS: m/z 452 (M+H) ⁺ . 1H NMR (400 MHz, MeOH-d4) δ 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.

EXAMPLE 148

1 '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)-7-methoxy- 1 ,3-dihydrospir o[indene-2 '-piperidin]-l-amine

Step a: To a solution oftert-butyl

7-methoxy-l-oxo-l,3-dihydrospiro[indene-2,4'-piperidine]- -carboxylate (552 mg, 1.07 mmol) in MeOH (10 mL) was added hydroxylamine hydrochloride (348 mg, 5.01 mmol) and AcONa (822 mg, 10.02 mmol). The resulting mixture was stirred for 4 h at RT. The reaction 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 Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give tert-butyl

(Z)-l-(hydroxyimino)-7-methoxy-l,3-dihydrospiro[indene-2,4'- piperidine]- -carboxylate (520 mg) as a yellow solid. MS: m/z 347 (M+H) ⁺ .

Step b: A suspension oftert-butyl

(Z)-l-(hydroxyimino)-7-methoxy-l,3-dihydrospiro[indene-2, 4'-piperidine]- -carboxylate (510 mg, 1.47 mmol) and Pt0 ₂ (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 separated and the pH value was taken to 10 with K ₂ C0 ₃ 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 Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give tert-butyl

l-amino-7-methoxy-l,3-dihydrospiro[indene-2,4'-piperidine ]-r-carboxylate (202 mg) as a colorless oil. MS: m/z 333 (M+H) ⁺ .

Step c: To solution oftert-butyl

l-amino-7-methoxy-l,3-dihydrospiro[indene-2,4'-piperidine ]-r-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-amino-3-chloropyridin-4-yl)thio)-6-chloropyrazin-2- amine (144 mg, 0.50 mmol) and K ₂ CO ₃ (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 Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by Pre-TLC (eluting with MeOH : DCM = 1 : 5, v/v) to give

r-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)-7-methoxy-l ,3-dihydrospiro[in dene-2,4'-piperidin]-l-amine (20 mg). MS: m/z 484 (M+H) ⁺ .1H NMR (400 MHz, DMSO-d6) δ 7.66 (s, IH), 7.64 (d, IH), 7.36 - 7.28 (m, IH), 6.90 (d, IH), 6.88 (d, IH), 5.75 (d, IH), 4.29 (s, IH), 4.20 (d, IH), 4.09 (d, IH), 3.83 (s, 3H), 3.30 - 3.15 (m, 2H), 3.10 (d, IH), 2.96 (d, IH), 1.87 - 1.76 (m,lH), 1.70 - 1.54 (m, 2H), 1.41 (d, IH).

The following example was synthesized using the above procedure with the corresponding starting materials.

Table 22

EXAMPLE 150

(S)-l'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazi n-2-yl)-2-methoxy-4,6-dihydro spiro[cyclopenta[d]thiazole-5,4'-piperidin]-4-amine

Step (a-b): Step (a-b) of Example 5 was applied to provide tert-butyl

(S)-4-(((R)-tert-butylsulfinyl)amino)-2-chloro-4,6-dihydr ospiro[cyclopenta[d]thiazole-5,4'-piperi dine]-l'-carboxylate. MS: m/z 448 (M+H) ⁺ .

Step c: A mixture of tert-butyl(S)-4-(((R)-tert-butylsulfinyl)amino)-2-chloro-4,6 - dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]- -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 volatiles were removed under reduced pressure. The residue was dissolved 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 Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give tert-butyl(S)-4-(((R)-tert-butylsulfinyl)amino)-2- methoxy-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidi ne]- -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-5-((2-amino- 3-chloropyridin-4-yl)thio)pyrazin-2-yl)-2-methoxy-4,6-dihydr ospiro[cyclopenta[d]thiazole-5,4'- piperidin]-4-amine. MS: m/z 491 (M+H) ⁺ .

EXAMPLE 151

(S)- 1 '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)-4,6-dihydrospiro [cyclo penta d]thiazole-5,4'-piperidin]-4-amine

Step (a-b): Step (a-b) of Example 5 was applied to provide tert-butyl

(S)-4-(((R)-tert-butylsulfinyl)amino)-2-chloro-4,6-dihydrosp iro[cyclopenta[d]thiazole-5,4'-piperi dine]-l'-carboxylate. MS: m/z 448 (M+H) ⁺ .

Step c: A suspension of tert-butyl

(S)-4-(((R)-tert-butylsulfinyl)amino)-2-chloro-4,6-dihydrosp iro[cyclopenta[d]thiazole-5,4'-piperi dine]-l'-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 filtration. 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[cyclopen ta[d]thiazole-5,4'-piperidine]- -car boxylate (1.28 g). MS: m/z 414 (M+H) ⁺ .

Step (d-e):Step (c-d) of Example 5 was applied to provide(S)-l 6-amino-5-((2-amino-3- chloropyridin-4-yl)thio)pyrazin-2-yl)-4,6-dihydrospiro[cyclo penta[d]thiazole-5,4'-piperidin]-4 mine. MS: m/z 461 (M+H) ⁺ . 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 7.66 - 7.63 (m, 2H), 5.76 (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-Methylpropane-2-sulfinamide, instead of (R)-(+)-2-Methyl-2-Propanesulfinamide, 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 starting materials.

Table 23

EXAMPLE 155

(S)- 1 '-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-y l)-4,6-dihydrospiro [cyclo penta thiazole-5,4'-piperidin]-6-amine

Step a: Step (a) of Example 5 was applied to provide tert-butyl

(R,Z)-6-((tert-butylsulfinyl)imino)-2-chloro-4,6-dihydrospir o[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)-2-chloro-4,6- dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]- -carboxylate (4.25 g, 9.53 mmol) in THF

(30 mL) was added BH ₃ (1 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 reaction mixture was quenched with brine (50 mL).

The organic layer was separated, dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica chromatography eluting with(EA : Hex = 1 : 2, v/v) to give tert-butyl (S)-6-(((R)-tert-butylsulfinyl)amino)-4,6-dihydrospiro

[cyclopenta[d]thiazole-5,4'-piperidine]-r-carboxylate (1.12 g). MS: m/z 414 (M+H) ⁺ . Step (c-d): Step (c-d) of Example 5 was applied to provide

(S)- -(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl )-4,6-dihydrospiro[cyclopent a[d]thiazole-5,4'-piperidin]-6-amine. 1H NMR (400 MHz, DMSO-d6) δ 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 procedure with the corresponding starting materials.

Table 24

EXAMPLE 157

(S)-l'-(6-amino-5-((3-fluoro-lH-indol-4-yl)thio)pyrazin-2-yl )-l,3-dihydrospiro[indene-2,4'- piperi in]-l-amine

A mixture of

(S)-l-(4-((3-amino-5-(l-amino-l ,3-dihydrospiro[indene-2,4'-piperidin]- -yl)pyrazin-2-yl)thio)-3 ,3-difluoroindolin-l-yl)ethan-l-one (86 mg, 0.14 mmol), DCM (5 mL) and HC1 (4 M solution in 1,4-dioxane, 0.50 mL) was stirred for 0.5 h at RT. The mixture 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 Na ₂ S0 ₄ , 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-5-((3-fluoro-lH-indol-4-yl)thio)pyrazin-2-yl )-l ,3-dihydrospiro[indene-2,4'-piper idin]-l-amine (14 mg). 1H NMR (400 MHz, DMSO-d6) δ 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, 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)-l-(l-amino-l'-(6-amino-5-((2-amino-3-chloropyridin-4- yl)thio)pyrazin-2-yl)-l,3-dihydr ospiro[indene-2,4'-piperidin]-6-yl)ethan-l-one

Step a-b: Step (a-b) of Example 5 was applied to provide tert-butyl

(lS)-l-((tert-butylsulfinyl)amino)-6-cyano-l,3-dihydrospi ro[indene-2,4'-piperidine]- -carboxyla te. MS: m/z 432 (M+H) ⁺ .

Step c: To a -50 °C solution of tert-butyl

(lS)-l-((tert-butylsulfinyl)amino)-6-cyano-l,3-dihydrospi ro[indene-2,4'-piperidine]- -carboxyla te (430 mg, 1.00 mmol) in THF (10 niL) was added methylmagnesium bromide (3 M solution 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 anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give tert-butyl

(lS)-6-acetyl-l-((tert-butylsulfinyl)amino)-l,3-dihydrospiro [indene-2,4'-piperidine]-r-carboxyla 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)- 1 -( 1 -amino-r-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyra zin-2-yl)- 1 ,3-dihydrospir o[indene-2,4'-piperidin]-6-yl)ethan-l-one. MS: 496(M+H) ⁺ .

The following example was synthesized using the above procedure or modification procedure with the corresponding starting materials. Table 25

The following examples can be synthesized using the above methods and appropriate starting materials:

Table 26

piperidine-4,2'-pyrrolizin]-3'-one

dioxine-6,4'-piperidin]-5-amine

dine]-2,5 -diamine H ₂ N— </ > H ₂ N

piperidine]-4-carbonitrile

-2,4'-piperidin]-l -amine

peridin]-7(lH)-one

4'-piperidin]-6-yl)-3-methylurea

/) ^H

mine

PHARMACOLOGICAL TESTING

Example A. Phosphatase Assay (single dose inhibition)

Assay Protocol:

For single dose inhibition assays using 6,8-difluoro-4-methylumbelliferyl 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-dimethyl glutarate (pH7.2), 75 mM NaCl, 75 mM KC1, and 1 mM EDTA, 0.05% Tween 20, 2mM dithiothreitol ( DTT ) ] to active the PTP. DMSO [0.5%) (v/v)] or compounds (ΙΟΟηΜ) were added to the mixture and incubated for 30 min at room temperature. Reactions were initiated by the addition of DiFMUP (12 μΜ; total reaction volume of 100 \L), 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 experiment 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 invention were shown in table A

Table A

SHP2 inhibition SHP2 inhibition SHP2 inhibition

Example Example Example

(%)@0.1μΜ (%)@0.1μΜ (%)@0.1μΜ

17 81 47 81 80 75

18 35 48 81 81 75

19 86 49 85 82 72

20 86 50 77 83 91

21 49 51 85 89 90

22 30 53 84 90 71

23 71 54 69 91 88

24 70 56 71 92 92

25 72 57 55 93 94

26 57 58 73 94 64

27 79 59 69 95 73

28 75 60 70 96 66

29 77 61 74 97 86

31 70 62 76 98 81

32 85 63 93 99 89

33 81 64 66 100 88

34 71 65 0 101 83

35 70 66 72 102 81

36 65 67 63 103 76

37 76 68 82 104 87

38 75 69 89 106 82

39 67 70 30 107 77

40 74 71 86 108 71

41 69 72 28 109 71

42 49 73 80 110 61

43 79 74 76 111 82

44 88 75 16 112 87

45 68 78 67 113 80

46 69 79 58 114 96 SHP2 inhibition SHP2 inhibition SHP2 inhibition

Example Example Example

(%)@0.1μΜ (%)@0.1μΜ (%)@0.1μΜ

115 86 130 94 145 79

116 79 131 83 146 82

117 81 132 78 148 72

118 81 133 76 149 28

119 61 134 78 150 84

120 87 135 86 151 86

122 88 136 83 153 82

123 50 137 89 154 82

124 84 138 82 156 80

125 86 140 14 157 78

126 81 141 41 158 90

127 83 142 17 159 88

128 84 143 72

129 74 144 80

Example B. Phosphatase Assays (IC50)

IC ₅₀ values were estimated using 6,8-difluoro-4-methylumbelliferyl 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-dimethyl glutarate (pH7.2), 75 mM NaCl, 75 mM KCl, and 1 mM EDTA, 0.05% Tween 20, 2mM dithiothreitol (DTT) ] to active the PTP. DMSO [0.5% (v/v)] or compounds (concentrations ranging from 0.3 nM to 1 μΜ) were added to the mixture and incubated for 30 min at room temperature. Reactions were initiated by the addition of DiFMUP (12 μΜ; total reaction volume of 100 μί), and the fluorescence (excitation at 340 nm, emission at 450 nm) of the resulting solutions was measured on a 2104-0020 En Vision Xcite Multilabel Reader (PerkinElmer) after 30min. The IC ₅₀ results of the compounds of the invention were shown by table B.

Table B

Example IC ₅₀ (nM) Example IC ₅₀ (nM) Example IC ₅₀ (nM)

26 11 84 3 121 56

30 3 85 6 146 12

44 4 86 14 151 7

57 16 87 9 152 3

81 8 88 36 155 3

Example C. Cell Proliferation Assay

MV-4-11 (4000 cells/well) were plated onto 96-well plates in ΙΟΟμί 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, 30μΙ. MTS/PMS reagents (Promega/Sigma) were added, and the absorbance value was determined according to the supplier's instruction (Promega). The IC ₅₀ results of the compounds of the invention were shown by table C.

Table C

Example D. p-ERK cellular assay

ERK1/2 activation is determined by immunob lotting analysis of cell lysates with an anti-p-ERKl/2 antibody. In brief, MV-4-11 cells were treated with a series of compounds (concentrations ranging from 0.3 nM to 100 nM) for 2 hours. Total protein was extracted using a RIPA buffer with Halt Protease Inhibitor Cocktail (Thermo Fisher Scientific, Rockford, IL, USA). 10 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 5% BSA, the membrane was incubated overnight with primary antibodies at 4°C, followed by 1 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-4-11 cells were expanded in culture, harvested and injected subcutaneously into 5-8 week old female NOD/SCID mice (5 l0 ⁶ cells/each mouse, n=6-10/group). Subsequent administration of compound by oral gavage (0.1-10 mpk/dose) started when the mean tumor size reached approximately 100-200 mm ³ . 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 evaluated 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 variety of routes. 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 PRACTICE OF

PHARMACY (A. Gennaro, et al, eds., 19 ^th 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 models. 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 aforesaid 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 determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.