885500-38-9

Upstream product

• 956460-41-6 C₁₇H₂₅ClN₂O₂ 
• 887129-20-6 C₂₂H₃₃ClN₂O₄ 
• 741687-06-9 1-tert-butyl 4-methyl 4-benzylpiperidine-1,4-dicarboxylate 
• 167263-11-8 N-tert-butyloxycarbonyl-4-benzylpiperidine-4-carboxylic acid 
• 741687-09-2 tert-butyl 4-amino-4-benzylpiperidine-1-carboxylate 
• 104-83-6 1-Chloro-4-(chloromethyl)benzene 
• 885500-37-8 4-(4-chlorobenzyl)piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester 
• 885653-43-0 4-(4-chlorobenzyl)-piperidin-4-ylamine 
• 956460-42-7 C₂₂H₃₃ClN₂O₄ 
• 170284-71-6 1-(tert-butoxycarbonyl)-4-(4-chlorobenzyl)piperidine-4-carboxylic acid 

Relevant academic research and scientific papers

Discovery of 4-amino-l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4- carboxamides as selective, orally active inhibitors of protein kinase B (Akt)

Protein kinase B (PKB or Akt) is an important component of intracellular signaling pathways regulating growth and survival. Signaling through PKB is frequently deregulated in cancer, and inhibitors of PKB therefore have potential as antitumor agents. The optimization of lipophilic substitution within a series of 4-benzyl-l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-amines provided ATP-competitive, nanomolar inhibitors with up to 150-fold selectivity for inhibition of PKB over the closely related kinase PKA. Although active in cellular assays, compounds containing 4-amino-4-benzylpiperidines underwent metabolism in vivo, leading to rapid clearance and low oral bioavailability. Variation of the linker group between the piperidine and the lipophilic substituent identified 4-amino-l-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)piperidine-4- carboxamides as potent and orally bioavailable inhibitors of PKB. Representative compounds modulated biomarkers of signaling through PKB in vivo and strongly inhibited the growth of human tumor xenografts in nude mice at well-tolerated doses.

Identification of 4-(4-aminopiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidines as selective inhibitors of protein kinase B through fragment elaboration

Fragment-based screening identified 7-azaindole as a protein kinase B inhibitor scaffold. Fragment elaboration using iterative crystallography of inhibitor-PKA-PKB chimera complexes efficiently guided improvements in the potency and selectivity of the compounds, resulting in the identification of nanomolar 6-(piperidin-1-yl)purine, 4-(piperidin-1-yl)-7-azaindole, and 4-(piperidin-1-yl)pyrrolo[2,3-d]pyrimidine inhibitors of PKBβ with antiproliferative activity and showing pathway inhibition in cells. A divergence in the binding mode was seen between 4-aminomethylpiperidine and 4-aminopiperidine containing molecules. Selectivity for PKB vs PKA was observed with 4-aminopiperidine derivatives, and the most PKB-selective inhibitor (30-fold) showed significantly different bound conformations between PKA and PKA-PKB chimera.

PHARMACEUTICAL COMPOUNDS

The invention provides compounds of the formula (I): or salts, solvates, tautomers or N-oxides thereof, wherein J1-J2 is CH=CH, N=CH, CH=N, HN-C(O) or CH2CO; T is N or CH and GP is as defined in the claims. The compounds have activity as inhibitors of PKA and PKB kinases and are useful in the treatment of cancers.

PHARMACEUTICAL COMPOUNDS

Compounds of the formula (I), and salts, solvates, tautomers and N-oxide thereof; wherein TG is selected from groups (1) and (2): wherein the asterisk (*) represents the point of attachment of the group E to the group X; Rla is an optionally substituted aryl or heteroaryl group; Rlb is hydrogen or a group Rla; X is an optionally substituted bicyclic heterocyclic group having 8 to 12 ring members of which up to 5 are heteroatoms selected from O, N and S; and A, E, R2, R3, R4, Q1 and Q2 are as defined in the claims; provided that when E is aryl or heteroaryl, then Q2 is other than a bond; and further provided that the moiety (a) is other than a group (BG1) or (BG2); wherein (BGl) and (BG2) are each optionally substituted; T is N or CRZ; J1-J2 is selected from N=C(RZ), (RZ)C=N, (RZ)N-C(O), (RZ)2C-C(O), N=N and (RZ)C=C(R6); J4 -J3 is a group N=C(RZ) or a group (RZ)N-CO; and RZ is hydrogen or a substituent. The compounds of the formula (I) have PKA and PKB kinase inhibiting activity and are useful in the treatment of cancers.

PHARMACEUTICAL COMPOUNDS

The invention provides a compound of the formula (I) or salts, solvates, tautomers or N-oxides thereof, wherein T is N or CR5; J1-J2 is N=C(R6), (R7)C=N, (R8)N-C(O), (R8)2C-C(O), N=N or (R7)C=C(R6); E is a monocyclic carbocyclic or heterocyclic group of 5 or 6 ring members, the heterocyclic group containing up to 3 heteroatoms selected from O, N and S; Q1 is a bond or a saturated C1-3 hydrocarbon linker group, one of the carbon atoms in the linker group being optionally be replaced by an oxygen or nitrogen atom, or an adjacent pair of carbon atoms may be replaced by CONRq or NRqCO where Rq is hydrogen or methyl, or Rq is a C1-4 alkylene chain linked to R1 or a carbon atom of Q1 to form a cyclic moiety; and wherein the carbon atoms of the linker group Q1 may optionally bear one or more substituents selected from fluorine and hydroxy; Q2 is a bond or a saturated hydrocarbon linker group containing from 1 to 3 carbon atoms, wherein one of the carbon atoms in the linker group may optionally be replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group may optionally bear one or more substituents selected from fluorine and hydroxy, provided that the hydroxy group when present is not located at a carbon atom α with respect to the G group; and provided that when E is aryl or heteroaryl, then Q2 is other than a bond; G is hydrogen, NR2R3, OH or SH provided that when E is aryl or heteroaryl and Q2 is a bond, then G is hydrogen; R1 is hydrogen or an aryl or heteroaryl group, with the proviso that when R1 is hydrogen and G is NR2R3, then Q2 is a bond; and R2, R3, R4, R6 and R8 are as defined in the claims, wherein the compound is for use in: (a) the treatment or prophylaxis of a disease or condition in which the modulation (e.g. inhibition) of ROCK kinase or protein kinase P70S6K is indicated; and/or (b) the treatment of a subject or patient population in which the modulation (e.g. inhibition) of ROCK kinase or protein kinase P70S6K is indicated.

PHARMACEUTICAL COMPOUNDS

The invention provides a compound of the formula (I) or a salt, solvate, tautomer or N-oxide thereof for use in the treatment or prophylaxis of a disease state or condition mediated by protein kinase A and/or protein kinase B, wherein the ring Q is a benzene ring; J2-J1 is N=CR7 or R1aN-CO; G is OH or NR5R6; E is CONR7, NR7CO, C(R8)=C(R8) or (X)m(CR8R8a)n where X is O, S or NR7; provided that when J2-J1 is R1aN-CO, E is other than NR7CO; m and n are each 0 or 1, where m + n = 1 or 2; A is a bond and R4 and R4a are absent, or A is a saturated optionally substituted C1-7 hydrocarbon linker group having a maximum chain length of 5 atoms extending between E and G, one carbon atom in the linker group A being optionally replaced by O or N; R1,Rla, R2, and R3 are each H; halogen; C1-6 hydrocarbyl optionally substituted by halogen, OH or C1-2 alkoxy; CN; CONHR8; NH2; NHCOR10 or NHCONHR10; R4 is H or C1-4 alkyl; R4a is H, C1-4 alkyl or a group R9; R5 and R6 are each selected from H, R9 and C1-4 hydrocarbyl optionally substituted by halogen, C1-2 alkoxy or R9;or NR5R6 forms a saturated 4-7 membered monocyclic heterocyclic group; R7 is H or C1-4 alkyl; R8 and R8a each H or saturated C1-4 hydrocarbyl optionally substituted by fluorine; R9is a monocyclic or bicyclic carbocyclic or heterocyclic group containing up to 3 ring heteroatoms selected from N, O and S; or R4, R4a and A together form a saturated monocyclic 4-7 membered heterocycle; or NR5R6, R4 and A form a saturated 4-7 membered monocyclic heterocycle; or R4,together with R7 or R8 and A and E form a 4-7 membered saturated monocyclic heterocycle; or NR5R6 and R7 or R8 together with A and E form a 4-7 membered saturated monocyclic heterocycle; and R10 is optionally substituted phenyl or benzyl.