US 6,800,620 B2 · Inhibitors of human phosphatidylinositol 3-kinase delta

Abstract

Methods of inhibiting phosphatidylinositol 3-kinase delta isoform (PI3Kδ) activity, and methods of treating diseases, such as disorders of immunity and inflammation, in which PI3Kδ plays a role in leukocyte function are disclosed. Preferably, the methods employ active agents that selectively inhibit PI3Kδ, while not significantly inhibiting activity of other PI3K isoforms. Compounds are provided that inhibit PI3Kδ activity, including compounds that selectively inhibit PI3Kδ activity. Methods of using PI3Kδ inhibitory compounds to inhibit cancer cell growth or proliferation are also provided. Accordingly, the invention provides methods of using PI3Kδ inhibitory compounds to inhibit PI3Kδ-mediated processes in vitro and in vivo.

Claims43

Dependent claims

A method of inhibiting the growth or proliferation of chronic myelogenous leukemia cells comprising contacting the cells with a compound that selectively inhibits phosphatidylinositol 3-kinase delta activity in the cancer cells relative to other Type I PI3K isoforms in a cell-based assay.

A compound having a structure

wherein Y is selected from the group consisting of null, S, and NH;
R4 is selected from the group consisting of H, halogen, NO2, OH, OCH3, CH3, and CF3;
R5 is selected from the group consisting of H, OCH3, and halo;
or R4 and R5 together with C-6 and C-7 of the quinazoline ring system define a 5- or 6-membered aromatic ring optionally containing one or more O, N, or S atoms;
R6 is selected from the group consisting of C1-C6alkyl, phenyl, halophenyl, alkoxyphenyl, alkylphenyl, biphenyl, benzyl, pyridinyl, 4-methylpiperazinyl, C(═O)OC2H5, and morpholinyl;
Rd, independently, is selected from the group consisting of NH2, halo, C1-3alkyl, S(C1-3alkyl), OH, NH(C1-3alkyl), N(C1-3alkyl)2, NH(C1-3alkylenephenyl), and
q is 1 or 2;
and pharmaceutically acceptable salts and solvates thereof,
provided that at least one of R4 and R5 is other than H when R6 is phenyl or 2-chlorophenyl.

6 more elements

A compound having a general structural formula

wherein A is an optionally substituted monocyclic or bicyclic ring system containing at least two nitrogen atoms, and at least one ring of the system is aromatic;
X is selected from the group consisting of CHRb, CH2CHRb, and CH═C(Rb);
Y is selected from the group consisting of null, S, SO, SO2, NH, O, C(═O), OC(═O), C(═O)O, and NHC(═O)CH2S;
R1 and R2, independently, are selected from the group consisting of hydrogen, C1-6alkyl, aryl, heteroaryl, halo, NHC(═O)C1-3alkyleneN(Ra)2, NO2, ORa, OCF3, N(Ra)2, CN, OC(═O)Ra, C(═O)Ra, C(═O)ORa, arylORb, Het, NRaC(═O)C1-3alkyleneC(═O)ORa, arylOC1-3alkyleneN(Ra)2, arylOC(═O)Ra, C1-4alkyleneC(═O)ORa, OC1-4alkyleneC(═O)ORa, C1-4alkyleneOC1-4alkyleneC(═O)ORa, C(═O)NRaSO2Ra, C1-4alkyleneN(Ra)2, C2-6alkenyleneN(Ra)2, C(═O)NRaC1-4alkyleneORa, C(═O)NRaC1-4alkyleneHet, OC2-4alkyleneN(Ra)2, OC1-4alkyleneCH(ORb)CH2N(Ra)2, OC1-4alkyleneHet, OC2-4alkyleneORa, OC2-4alkyleneNRaC(═O)ORa, NRaC1-4alkyleneN(Ra)2, NRaC(═O)Ra, NRaC(═O)N(Ra)2, N(SO2C1-4alkyl)2, NRa(SO2C1-4alkyl), SO2N(Ra)2, OSO2CF3, C1-3alkylenearyl, C1-4alkyleneHet, C1-6alkyleneORb, C1-3alkyleneN(Ra)2, C(═O)N(Ra)2, NHC(═O)C1-C3alkylenearyl, C3-8cycloalkyl, C3-8heterocycloalkyl, arylOC1-3alkyleneN(Ra)2, arylOC(═O)Rb, NHC(═O)C1-3alkyleneC3-8heterocycloalkyl, NHC(═O)C1-3alkyleneHet, OC1-4alkyleneOC1-4alkyleneC(═O)ORb, C(═O)C1-4alkyleneHet, and NHC(═O)haloC1-6alkyl;
or R1 and R2 are taken together to form a 3- or 4-membered alkylene or alkenylene chain component of a 5- or 6-membered ring, optionally containing at least one heteroatom;
R3 is selected from the group consisting of optionally substituted hydrogen, C1-6alkyl, C3-8cycloalkyl, C3-8heterocycloalkyl, C1-4alkylenecycloalkyl, C2-6alkenyl, C1-3alkylenearyl, arylC1-3alkyl, C(═O)Ra, aryl, heteroaryl, C(═O)ORa, C(═O)N(Ra)2, C(═S)N(Ra)2, SO2Ra, SO2N(Ra)2, S(═O)Ra, S(═O)N(Ra)2, C(═O)NRaC1-4alkyleneORa, C(═O)NRaC1-4alkyleneHet, C(═O)C1-4alkylenearyl, C(═O)C1-4alkyleneheteroaryl, C1-4alkylenearyl optionally substituted with one or more of halo, SO2N(Ra)2, N(Ra)2, C(═O)ORa, NRaSO2CF3, CN, NO2, C(═O)Ra, ORa, C1-4alkyleneN(Ra)2, and OC1-4alkyleneN(Ra)2, C1-4alkyleneheteroaryl, C1-4alkyleneHet, C1-4alkyleneC(═O)C1-4alkylenearyl, C1-4alkyleneC(═O)C1-4alkyleneheteroaryl, C1-4alkyleneC(═O)Het, C1-4alkyleneC(═O)N(Ra)2, C1-4alkyleneORa, C1-4alkyleneNRaC(═O)Ra, C1-4alkyleneOC1-4alkyleneORa, C1-4alkyleneN(Ra)2, C1-4alkyleneC(═O)ORa, and C1-4alkyleneOC1-4alkyleneC(═O)ORa;
Ra is selected from the group consisting of hydrogen, C1-6alkyl, C3-8cycloalkyl, C3-8heterocycloalkyl, C1-3alkyleneN(Ra)2, aryl, arylC1-3alkyl, C1-3alkylenearyl, heteroaryl, heteroarylC1-3alkyl, and C1-3alkyleneheteroaryl;
or two Ra groups are taken together to form a 5- or 6-membered ring, optionally containing at least one heteroatom;
Rb is selected from the group consisting of hydrogen, C1-6alkyl, aryl, heteroaryl, arylC1-3alkyl, heteroarylC1-3alkyl, C1-3alkylenearyl, and C1-3alkyleneheteroaryl;
Het is a 5- or 6-membered heterocyclic ring, saturated or partially or fully unsaturated, containing at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur, and optionally substituted with C1-4alkyl or C(═O)ORa;
and pharmaceutically acceptable salts and solvates thereof,
with the provisos that if X—Y is CH2S, then R3 is different from
and if X—Y is CH2S, then R3 is different from —CH2CH(OH)CH2OH substituted phenyl.

10 more elements

A method for disrupting leukocyte function comprising contacting leukocytes with a compound having a structure

wherein A is an optionally substituted monocyclic or bicyclic ring system containing at least two nitrogen atoms, and at least one ring of the system is aromatic;
X is selected from the group consisting of CHRb, CH2CHRb, and CH═C(Rb);
Y is selected from the group consisting of null, S, SO, SO2, NH, O, C(═O), OC(═O), C(═O)O, and NHC(═O)CH2S;
R1 and R2, independently, are selected from the group consisting of hydrogen, C1-6alkyl, aryl, heteroaryl, halo, NHC(═O) C1-3alkyleneN(Ra)2, NO2, ORa, OCF3, N(Ra)2, CN, OC(═O)Ra, C(═O)Ra, C(═O)ORa, arylORb, Het, NRaC(═O)C1-3alkyleneC(═O)ORa, arylOC1-3alkyleneN(Ra)2, arylOC(═O)Ra, C1-4alkyleneC(═O)ORa, OC1-4alkyleneC(═O)ORa, C1-4alkyleneOC1-4alkyleneC(═O)ORa, C(═O)-NRaSO2Ra, C1-4alkyleneN(Ra)2, C2-6alkenyleneN(Ra)2, C(═O)NRaC1-4alkyleneORa, C(═O)NRaC1-4alkyleneHet, OC2-4alkyleneN(Ra)2, OC1-4alkyleneCH (ORb)CH2N(Ra)2, OC1-4alkyleneHet, OC2-4alkyleneORa, OC2-4alkyleneNRaC(═O)ORa, NRaC1-4alkyleneN(Ra)2, NRaC(═O)Ra, NRaC(═O)N(Ra)2, N(SO2C1-4alkyl)2, NRa(SO2C1-4alkyl), SO2N(Ra)2, OSO2CF3, C1-3alkylenearyl, C1-4alkyleneHet, C1-6-alkyleneORb, C1-3alkyleneN(Ra)2, C(═O)N(Ra)2, NHC(═O)C1-C3alkylenearyl, C3-8cycloalkyl, C3-8heterocycloalkyl, arylOC1-3alkyleneN(Ra)2, arylOC(═O)Rb, NHC(═O)C1-3alkyleneC3-8heterocycloalkyl, NHC(═O)C1-3-alkyleneHet, OC1-4alkyleneOC1-4alkyleneC(═O)ORb, C(═O)C1-4alkyleneHet, and NHC(═O)haloC1-6alkyl;
or R1 and R2 are taken together to form a 3- or 4-membered alkylene or alkenylene chain component of a 5- or 6-membered ring, optionally containing at least one heteroatom;
R3 is selected from the group consisting of optionally substituted hydrogen, C1-6alkyl, C3-8cycloalkyl, C3-8heterocycloalkyl, C1-4alkylenecycloalkyl, C2-6alkenyl, C1-3alkylenearyl, arylC1-3alkyl, C(═O)Ra, aryl, heteroaryl, C(═O)ORa, C(═O)N(Ra)2, C(═S)N(Ra)2, SO2Ra, SO2N(Ra)2, S(═O)Ra, S(═O)N(Ra)2, C(═O)NRaC1-4alkyleneORa, C(═O)NRaC1-4alkyleneHet, C(═O)C1-4alkylenearyl, C(═O)C1-4alkyleneheteroaryl, C1-4alkylenearyl substituted with one or more of SO2N(Ra)2, N(Ra)2, C(═O)ORa, NRaSO2CF3, CN, NO2, C(═O)Ra, ORa, C1-4alkyleneN(Ra)2, and OC1-4alkyleneN(Ra)2, C1-4alkyleneheteroaryl, C1-4alkyleneHet, C1-4alkyleneC(═O)C1-4alkylenearyl, C1-4alkyleneC(═O)C1-4alkyleneheteroaryl, C1-4alkyleneC(═O)Het, C1-4alkyleneC(═O)N(Ra)2, C1-4alkyleneORa, C1-4alkyleneNRaC(═O)Ra, C1-4alkyleneOC1-4alkyleneORa, C1-4alkyleneN(Ra)2, C1-4alkyleneC(═O)ORa, and C1-4alkyleneOC1-4alkyleneC(═O)ORa;
Ra is selected from the group consisting of hydrogen, C1-6alkyl, C3-8cycloalkyl, C3-8heterocycloalkyl, C1-3alkyleneN(Ra)2, aryl, arylC1-3alkyl, C1-3alkylenearyl, heteroaryl, heteroarylC1-3alkyl, and C1-3alkyleneheteroaryl;
or two Ra groups are taken together to form a 5- or 6-membered ring, optionally containing at least one heteroatom;
Rb is selected from the group consisting of hydrogen, C1-6alkyl, aryl, heteroaryl, arylC1-3alkyl, heteroarylC1-3alkyl, C1-3alkylenearyl, and C1-3alkyleneheteroaryl;
Het is a 5- or 6-membered heterocyclic ring, saturated or partially or fully unsaturated, containing at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur, and optionally substituted with C1-4alkyl or C(═O)ORa;
and pharmaceutically acceptable salts and solvates,
in an amount sufficient to inhibit phosphatidylinositol 3-kinase delta activity in said leukocytes.

9 more elements

A method of inhibiting kinase activity of a phosphatidylinositol 3-kinase delta polypeptide comprising contacting the polypeptide with a compound having a structure

wherein A is an optionally substituted monocyclic or bicyclic ring system containing at least two nitrogen atoms, and at least one ring of the system is aromatic;
X is selected from the group consisting of CHRb, CH2CHRb, and CH═C(Rb);
Y is selected from the group consisting of null, S, SO, SO2, NH, O, C(═O), OC(═O), C(═O)O, and NHC(═O)CH2S;
R1 and R2, independently, are selected from the group consisting of hydrogen, C1-6alkyl, aryl, heteroaryl, halo, NHC(═O)C1-3alkyleneN(Ra)2, NO2, ORa, OCF3, N(Ra)2, CN, OC(═O)Ra, C(═O)Ra, C(═O)ORa, arylORb, Het, NRaC(═O)C1-3alkyleneC(═O)ORa, arylOC1-3alkyleneN(Ra)2, arylOC(═O)Ra, C1-4alkyleneC(═O)ORa, OC1-4alkyleneC(═O)ORa, C1-4alkyleneOC1-4alkyleneC(═O)ORa, C(═O)-NRaSO2Ra, C1-4alkyleneN(Ra)2, C2-6alkenyleneN(Ra)2, C(═O)NRaC1-4alkyleneORa, C(═O)NRaC1-4alkyleneHet, OC2-4alkyleneN(Ra)2, OC1-4alkyleneCH(ORb)CH2N(Ra)2, OC1-4alkyleneHet, OC2-4alkyleneORa, OC2-4alkyleneNRaC(═O)ORa, NRaC1-4alkyleneN(Ra)2, NRaC(═O)Ra, NRaC(═O)N(Ra)2, N(SO2C1-4alkyl)2, NRa(SO2C1-4alkyl), SO2N(Ra)2, OSO2CF3, C1-3alkylenearyl, C1-4alkyleneHet, C1-6alkyleneORb, C1-3alkyleneN(Ra)2, C(═O)N(Ra)2, NHC(═O)C1-C3alkylenearyl, C3-8cycloalkyl, C3-8heterocycloalkyl, arylOC1-3alkyleneN(Ra)2, arylOC(═O)Rb, NHC(═O)C1-3alkyleneC3-8heterocycloalkyl, NHC(═O)C1-3alkyleneHet, OC1-4alkyleneOC1-4alkyleneC(═O)ORb, C(═O)C1-4alkyleneHet, and NHC(═O)haloC1-6alkyl;
or R1 and R2 are taken together to form a 3- or 4-membered alkylene or alkenylene chain component of a 5- or 6-membered ring, optionally containing at least one heteroatom;
R3 is selected from the group consisting of optionally substituted hydrogen, C1-6alkyl, C3-8cycloalkyl, C3-8heterocycloalkyl, C1-4alkylenecycloalkyl, C2-6alkenyl, C1-3alkylenearyl, arylC1-3alkyl, C(═O)Ra, aryl, heteroaryl, C(═O)ORa, C(═O)N(Ra)2, C(═S)N(Ra)2, SO2Ra, SO2N(Ra)2, S(═O)Ra, S(═O)N(Ra)2, C(═O)NRaC1-4alkyleneORa, C(═O)NRaC1-4alkyleneHet, C(═O)C1-4alkylenearyl, C(═O)C1-4alkyleneheteroaryl, C1-4alkylenearyl optionally substituted with one or more of halo, SO2N(Ra)2, N(Ra)2, C(═O)ORa, NRaSO2CF3, CN, NO2, C(═O)Ra, ORa, C1-4alkyleneN(Ra)2, and OC1-4alkyleneN(Ra)2, C1-4alkyleneheteroaryl, C1-4alkyleneHet, C1-4alkyleneC(═O)C1-4alkylenearyl, C1-4alkyleneC(═O)C1-4alkyleneheteroaryl, C1-4alkyleneC(═O)Het, C1-4alkyleneC(═O)N(Ra)2, C1-4alkyleneORa, C1-4alkyleneNRaC(═O)Ra, C1-4alkyleneOC1-4alkyleneORa, C1-4alkyleneN(Ra)2, C1-4alkyleneC(═O)ORa, and C1-4alkyleneOC1-4alkyleneC(═O)ORa;
Ra is selected from the group consisting of hydrogen, C1-6alkyl, C3-8cycloalkyl, C3-8heterocycloalkyl, C1-3alkyleneN(Ra)2, aryl, arylC1-3alkyl, C1-3-alkylenearyl, heteroaryl, heteroarylC1-3alkyl, and C1-3alkyleneheteroaryl;
or two Ra groups are taken together to form a 5- or 6-membered ring, optionally containing at least one heteroatom;
Rb is selected from the group consisting of hydrogen, C1-6alkyl, aryl, heteroaryl, arylC1-3alkyl, heteroarylC1-3alkyl, C1-3alkylenearyl, and C1-3alkyleneheteroaryl;
Het is a 5- or 6-membered heterocyclic ring, saturated or partially or fully unsaturated, containing at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur, and optionally substituted with C1-4alkyl or C(═O)ORa;
and pharmaceutically acceptable salts and solvates thereof.

8 more elements

Dependencies are inferred from the claim text.

Inhibitors of human phosphatidylinositol 3-kinase delta

Life of this patent

Inhibitors of human phosphatidylinositol 3-kinase delta

Life of this patent

Abstract

Claims43