# US 2014/0154772 A1 · Inhibitors of human phosphatidylinositol 3-kinase delta

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- Number: US 2014/0154772 A1
- Document ID: US20140154772A1
- Status: Published application
- Kind: A1
- Application number: 14/092,287
- Filed: 2013-11-27
- Published: 2014-06-05
- Earliest claimed: 2000-04-25
- Assignees: ICOS Corporation
- Applicants: ICOS Corporation
- Inventors: Chanchal SADHU; Ken DICK; Jennifer TREIBERG; C. Gregory SOWELL; Edward A. KESICKI; Amy OLIVER
- Web page: https://patentgrep.com/patent/US20140154772A1

## CPC

- A61K 31/506: not condensed and containing further heterocyclic rings
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 3/14: for calcium homeostasis (vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04)
- A61P 7/08: Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock (artificial tears A61P27/04)
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 17/04: Antipruritics
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 25/02: for peripheral neuropathies
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 233/66: having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
- C07D 233/66: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 473/00: Heterocyclic compounds containing purine ring systems
- C07D 473/16: two nitrogen atoms
- C07D 473/24: one nitrogen and one sulfur atom
- C07D 473/30: attached in position 6, e.g. hypoxanthine
- C07D 473/32: Nitrogen atom
- C07D 473/34: attached in position 6, e.g. adenine
- C07D 473/38: attached in position 6
- C07D 473/40: with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
- C07D 487/04: Ortho-condensed systems
- C12N 9/1205: {Phosphotransferases with an alcohol group as acceptor (2.7.1), e.g. protein kinases}
- C12N 9/99: Enzyme inactivation by chemical treatment
- C12Y 207/01137: Phosphatidylinositol 3-kinase (2.7.1.137)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12Y: ENZYMES

## 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.

## Claims

### Claim 1

A method of 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 C(Rb)2, 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, CF3, OCF3, N(Ra)2, CN, OC(═O)Ra, C(═O)Ra, C(═O)ORa, arylORb, Het, NRaC(═O)C1-3alkyleneC(═O)Ra, arylOC1-3-alkyleneN(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, OC2-4-alkyleneN(Ra)2, OC1-4alkyleneCH(ORb)CH2N(Ra)2, OC1-4alkyleneHet, OC2alkyleneORa, 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, arylOC1-3-alkyleneN(Ra)2, arylOC(═O)Rb, NHC(═O)C1-3alkyleneC3-8-heterocycloalkyl, 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, C1-8alkyl, 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, C1-8alkyl, C3-8cycloalkyl, C3-8heterocycloalkyl, C1-3alkyleneN(Rc)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, heteroC3alkyl, C1-3alkyleneheteroC1-3alkyl, arylheteroC1-3alkyl, aryl, heteroaryl, arylC1-3alkyl, heteroarylC1-3alkyl, C1-3alkylenearyl, and C1-3alkyleneheteroaryl;
Rc is selected from the group consisting of hydrogen, C1-6alkyl, C3-8cycloalkyl, aryl, and heteroaryl;
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.

### Claim 2 (depends on 1)

The method according to claim 1 wherein the compound is selected from the group consisting of
2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-6,7-dimethoxy-3H-quinazolin-4-one
2-(6-aminopurin-o-ylmethyl)-6-bromo-3-(2-chlorophenyl)-3H-quinazolin-4-one
2-(6-aminopurin-o-ylmethyl)-2-chlorophenyl)-7-fluoro-3H-quinazolin-4-one
2-(6-aminopurin-9-ylmethyl)-6-chloro-3-(2-chlorophenyl)-3H-quinazolin-4-one
2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-5-fluoro-3H-quinazolin-4-one
2-(6-aminopurin-o-ylmethyl)-5-chloro-3-(2-chlorophenyl)-3H-quinazolin-4-one
2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-5-methyl-3H-quinazolin-4-one
2-(6-aminopurin-9-ylmethyl)-8-chloro-3-(2-chlorophenyl)-3H-quinazolin-4-one
2-(6-aminopurin-9-ylmethyl)-3-biphenyl-2-yl-5-chloro-3H-quinazolin-4-one
5-chloro-2-(9H-purin-6-ylsulfanylmethyl)-3-o-tolyl-3H-quinazolin-4-one
5-chloro-3-(2-fluorophenyl)-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one
2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-fluorophenyl)-3H-quinazolin-4-one
3-biphenyl-2-yl-5-chloro-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one
5-chloro-3-(2-methoxyphenyl)-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one
3-(2-chlorophenyl)-5-fluoro-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one
3-(2-chlorophenyl)-6,7-dimethoxy-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one
6-bromo-3-(2-chlorophenyl)-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one
3-(2-chlorophenyl)-8-trifluoromethyl-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one
3-(2-chlorophenyl)-2-(9H-purin-6-ylsulfanylmethyl)-3H-benzo[g]quinazolin-4-one
6-chloro-3-(2-chlorophenyl)-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one
8-chloro-3-(2-chlorophenyl)-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one
3-(2-chlorophenyl)-7-fluoro-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one
3-(2-chlorophenyl)-7-nitro-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one
3-(2-chlorophenyl)-6-hydroxy-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one
5-chloro-3-(2-chlorophenyl)-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one
3-(2-chlorophenyl)-5-methyl-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one
3-(2-chlorophenyl)-6,7-difluoro-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one
3-(2-chlorophenyl)-6-fluoro-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one
2-(6-aminopurin-9-ylmethyl)-3-(2-isopropylphenyl)-5-methyl-3H-quinazolin-4-one
2-(6-aminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one
3-(2-fluorophenyl)-5-methyl-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one
2-(6-aminopurin-9-ylmethyl)-5-chloro-3-o-tolyl-3H-quinazolin-4-one
2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-methoxyphenyl)-3H-quinazolin-4-one
2-(2-amino-9H-purin-6-yl sulfanylmethyl)-3-cyclopropyl-5-methyl-3H-quinazolin-4-one
3-cyclopropylmethyl-5-methyl-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one
2-(6-aminopurin-9-ylmethyl)-3-cyclopropylmethyl-5-methyl-3H-quinazolin-4-one
2-(2-amino-9H-purin-6-ylsulfanylmethyl)-3-cyclopropylmethyl-5-methyl-3H-quinazolin-4-one
5-methyl-3-phenethyl-2-(9H-purin-6-ylsulfanyl methyl)-3H-quinazolin-4-one
2-(2-amino-9H-purin-6-ylsulfanylmethyl)-5-methyl-3-phenethyl-3H-quinazolin-4-one
3-cyclopentyl-5-methyl-2-(9H-purin-6-ylsulfanyl methyl)-3H-quinazolin-4-one
2-(6-aminopurin-9-ylmethyl)-3-cyclopentyl-5-methyl-3H-quinazolin-4-one
3-(2-chloropyridin-3-yl)-5-methyl-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one
2-(6-aminopurin-9-ylmethyl)-3-(2-chloropyridin-3-yl)-5-methyl-3H-quinazolin-4-one
3-methyl-4-[5-methyl-4-oxo-2-(9H-purin-6-ylsulfanyl methyl)-4H-quinazolin-3-yl]-benzoic acid
3-cyclopropyl-5-methyl-2-(9H-purin-6-ylsulfanyl methyl)-3H-quinazolin-4-one
2-(6-aminopurin-9-ylmethyl)-3-cyclopropyl-5-methyl-3H-quinazolin-4-one
5-methyl-3-(4-nitrobenzyl)-2-(9H-purin-6-ylsulfanyl methyl)-3H-quinazolin-4-one
3-cyclohexyl-5-methyl-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one
2-(6-aminopurin-9-ylmethyl)-3-cyclohexyl-5-methyl-3H-quinazolin-4-one
2-(2-amino-9H-purin-6-ylsulfanylmethyl)-3-cyclohexyl-5-methyl-3H-quinazolin-4-one
5-methyl-3-(E-2-phenyl cyclopropyl)-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one
3-(2-chlorophenyl)-5-fluoro-2-[(9H-purin-6-ylamino)methyl]-3H-quinazolin-4-one
2-[(2-amino-9H-purin-6-ylamino) methyl]-3-(2-chlorophenyl)-5-fluoro-3H-quinazolin-4-one
5-methyl-2-[(9H-purin-6-ylamino) methyl]-3-o-tolyl-3H-quinazolin-4-one
2-[(2-amino-9H-purin-6-ylamino) methyl]-5-methyl-3-o-tolyl-3H-quinazolin-4-one
2-[(2-fluoro-9H-purin-6-ylamino) methyl]-5-methyl-3-o-tolyl-3H-quinazolin-4-one
(2-chlorophenyl)-dimethylamino-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one
5-(2-benzyloxyethoxy)-3-(2-chlorophenyl)-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one
6-aminopurine-9-carboxylic acid 3-(2-chlorophenyl)-5-fluoro-4-oxo-3,4-dihydro-quinazolin-2-ylmethyl ester
N-[3-(2-chlorophenyl)-5-fluoro-4-oxo-3,4-dihydro-quinazolin-2-ylmethyl]-2-(9H-purin-6-ylsulfanyl)acetamide
2-[1-(2-fluoro-9H-purin-6-ylamino) ethyl]-5-methyl-3-o-tolyl-3H-quinazolin-4-one
5-methyl-2-[1-(9H-purin-6-ylamino) ethyl]-3-o-tolyl-3H-quinazolin-4-one
2-(6-dimethylaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one
5-methyl-2-(2-methyl-6-oxo-1,6-dihydro-purin-7-ylmethyl)-3-o-tolyl-3H-quinazolin-4-one
5-methyl-2-(2-methyl-6-oxo-1,6-dihydro-purin-9-ylmethyl)-3-o-tolyl-3H-quinazolin-4-one
2-(amino-dimethylaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one
2-(2-amino-9H-purin-6-ylsulfanylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one
2-(4-amino-1,3,5-triazin-2-ylsulfanylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one
5-methyl-2-(7-methyl-7H-purin-6-ylsulfanylmethyl)-3-o-tolyl-3H-quinazolin-4-one
5-methyl-2-(2-oxo-1,2-dihydro-pyrimidin-4-ylsulfanylmethyl)-3-o-tolyl-3H-quinazolin-4-one
5-methyl-2-purin-7-ylmethyl-3-o-tolyl-3H-quinazolin-4-one
5-methyl-2-purin-9-ylmethyl-3-o-tolyl-3H-quinazolin-4-one
5-methyl-2-(9-methyl-9H-purin-6-ylsulfanylmethyl)-3-o-tolyl-3H-quinazolin-4-one
2-(2,6-Diamino-pyrimidin-4-ylsulfanylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one
5-methyl-2-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-ylsulfanylmethyl)-3-o-tolyl-3H-quinazolin-4-one
5-methyl-2-(2-methylsulfanyl-9H-purin-6-ylsulfanyl methyl)-3-o-tolyl-3H-quinazolin-4-one
2-(2-hydroxy-9H-purin-6-ylsulfanylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one
5-methyl-2-(1-methyl-1H-imidazol-2-yl sulfanyl methyl)-3-o-tolyl-3H-quinazolin-4-one
5-methyl-3-o-tolyl-2-(1H-[1,2,4]triazol-3-ylsulfanylmethyl)-3H-quinazolin-4-one
2-(2-amino-6-chloro-purin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one
2-(6-aminopurin-7-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one
2-(7-amino-1,2,3-triazolo[4,5-d]pyrimidin-3-yl methyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one
2-(7-amino-1,2,3-triazolo[4,5-d]pyrimidin-1-yl methyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one
2-(6-amino-9H-purin-2-ylsulfanylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one
2-(2-amino-6-ethylamino-pyrimidin-4-ylsulfanylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one
2-(3-amino-5-methylsulfanyl-1,2,4-triazol-1-yl methyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one
2-(5-amino-3-methylsulfanyl-1,2,4-triazol-1-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one
5-methyl-2-(6-methylaminopurin-9-ylmethyl)-3-o-tolyl-3H-quinazolin-4-one
2-(6-benzylaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one
2-(2,6-diaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one
5-methyl-2-(9H-purin-6-ylsulfanylmethyl)-3-o-tolyl-3H-quinazolin-4-one
3-isobutyl-5-methyl-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one
N-{2-[5-Methyl-4-oxo-2-(9H-purin-6-ylsulfanylmethyl)-4H-quinazolin-3-yl]-phenyl}-acetamide
5-methyl-3-(E-2-methyl-cyclohexyl)-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one
2-[5-methyl-4-oxo-2-(9H-purin-6-ylsulfanylmethyl)-4H-quinazolin-3-yl]-benzoic acid
3-{2-[(2-dimethylaminoethyl)methylamino]phenyl}-5-methyl-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one
3-(2-chlorophenyl)-5-methoxy-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one
3-(2-chlorophenyl)-5-(2-morpholin-4-yl-ethylamino)-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one
3-benzyl-5-methoxy-2-(9H-purin-6-ylsulfanylmethyl)-3H-quinazolin-4-one
2-(6-aminopurin-9-ylmethyl)-3-(2-benzyloxyphenyl)-5-methyl-3H-quinazolin-4-one;
2-(6-aminopurin-9-ylmethyl)-3-(2-hydroxyphenyl)-5-methyl-3H-quinazolin-4-one;
2-(1-(2-amino-9H-purin-6-ylamino)ethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;
5-methyl-2-[1-(9H-purin-6-ylamino)propyl]-3-o-tolyl-3H-quinazolin-4-one;
2-(1-(2-fluoro-9H-purin-6-ylamino)propyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;
2-(1-(2-amino-9H-purin-6-ylamino)propyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;
2-(2-benzyloxy-1-(9H-purin-6-ylamino)ethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;
2-(6-aminopurin-9-ylmethyl)-5-methyl-3-{2-(2-(1-methylpyrrolidin-2-yl)-ethoxy)-phenyl}-3H-quinazolin-4-one;
2-(6-aminopurin-9-ylmethyl)-3-(2-(3-dimethylaminopropoxy)-phenyl)-5-methyl-3H-quinazolin-4-one;
2-(6-aminopurin-9-ylmethyl)-5-methyl-3-(2-prop-2-ynyloxyphenyl)-3H-quinazolin-4-one; and
2-{2-(1-(6-aminopurin-9-ylmethyl)-5-methyl-4-oxo-4H-quinazolin-3-yl]-phenoxy}-acetamide.

### Claim 3

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 C(Rb)2, 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, CF3, OCF3, N(Ra)2, CN, OC(═O)Ra, C(═O)Ra, C(═O)ORa, arylORb, Het, NRaC(═O)C1-3alkyleneC(═O)ORa, arylOC1-3-alkyleneN(Ra) arylOC(═O) Ra, C1-4alkyleneC(═O)ORa, OC1-4alkyleneC(═O)ORa, C1-4 alkyleneOC1-4alkyleneC(═O)ORa, C(═O)NRaSO2Ra, C1-4alkyleneN(Ra) C2-6alkenyleneN(Ra)2, C(═O)NRaC1-4alkyleneORa, C(═O)NRaC1-4alkyleneHet, OC2-4-alkyleneN(Ra)2, OC1-4alkyleneCH(ORb)CH2N(Ra)2, OC1-4-alkyleneHet, OC2-4alkyleneORa, OC2-4alkyleneNRaC(═O)ORa, NRaC1-4alkyleneN(Ra)2, NRaC(═O)Ra, NRaC(═O)N(Ra)2, N(SO2C1-4 alkyl)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, arylOC1-3-alkyleneN(Ra)2, arylOC(═O)Rb, NHC(═O)C1-3alkyleneC3-8-heterocycloalkyl, NHC(═O)C1-3alkyleneHet, OC1-4alkyleneOC1-3alkyleneC(═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)NRaC1-4-alkyleneORa, 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, C1-4-alkyleneOC1-4alkyleneORa, 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(Rc)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, heteroC1-3alkyl, C1-3alkyleneheteroC1-3alkyl, arylheteroC1-3alkyl, aryl, heteroaryl, arylC1-3alkyl, heteroarylC1-3alkyl, C1-3alkylenearyl, and C1-3alkyleneheteroaryl;
Rc is selected from the group consisting of hydrogen, C1-6alkyl, C3-8cycloalkyl, aryl, and heteroaryl;
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.

### Claim 4

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 C(Rb)2, 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, CF3, OCF3, N(Ra)2, CN, OC(═O)Ra, C(═O)Ra, C(═O)ORa, arylORb, Het, NRaC(═O)C1-3alkyleneC(═O)ORa, arylOC1-3-alkyleneN(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, OC2-4-alkyleneN(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(SO2C2-4alkyl), SO2N(Ra)2, OSO2CF3, C1-3alkylenearyl, C1-4alkyleneHet, C1-6alkyleneORb, C1-3alkyleneN(Ra)2, C(═O)N(Ra) NHC(═O)C, —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) SO2Ra, SO2N(Ra)2, S(═O)Ra, S(═O)N(Ra)2, C(═O)NRaC1-4-alkyleneORa, 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) 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(Rc)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, heteroC1-3alkyl, C1-3alkyleneheteroC1-3alkyl, arylheteroC1-3alkyl, aryl, heteroaryl, arylC1-3alkyl, heteroarylC1-3alkyl, C1-3alkylenearyl, and C1-3alkyleneheteroaryl;
Rc is selected from the group consisting of hydrogen, C1-6alkyl, C3-8cycloalkyl, aryl, and heteroaryl;
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.

### Claim 5 (depends on 4)

The compound of claim 4 wherein X is selected from the group consisting of CH2, CH2CH2, CH═CH, CH(CHO, CH(CH2CH3), CH2CH(CH3), and C(CH3)2.

### Claim 6 (depends on 5)

The compound of claim 5 wherein Y is selected from the group consisting of null, S, and NH.

### Claim 7 (depends on 5)

The compound of claim 5 wherein the A ring system is selected from the group consisting of

### Claim 8 (depends on 7)

The compound of claim 7 wherein the A ring system is substituted with one to three substituents selected from the group consisting of N(Ra)2, halo, C1-3alkyl, S(C1-3alkyl), ORa, and

### Claim 9 (depends on 8)

The compound of claim 8 wherein the A ring system is substituted with one to three substituents selected from the group consisting of NH2, NH(CHO, N(CH3)2, NHCH2C6H5, NH(C2H5), Cl, F, CH3, SCH3, OH, and

### Claim 10 (depends on 5)

The compound of claim 5 wherein le and R2, independently, selected from the group consisting of hydrogen, ORa, halo, C1-6alkyl, CF3, NO2, N(Ra)2, NRaC1-3alkyleneN(Ra)2, and OC1-3alkyleneORa. Specific substituents include, but are not limited to, H, OCH3, Cl, Br, F, CH3, CF3, NO2, OH, N(CH3)2,
and O(CH2)2OCH2C6H5, or R1 and R2 are taken together to form a five- or six-membered ring.

### Claim 11 (depends on 5)

The compound of claim 5 wherein R3 is selected from the group consisting of C1-6alkyl, aryl, heteroaryl, C3-8cycloalkyl, C3-8heterocycloalkyl, C(═O)ORa, C1-4alkyleneHet, C1-4alkylenecycloalkyl, C1-4alkylenearyl, C1-4alkyleneC(═O)C1-4alkylenearyl, C1-4alkyleneC(═O)ORa, C1-4alkyleneC(═O)N(Ra)2, C1-4alkyleneC(═O) Het, C1-4alkyleneN(Ra)2, and C1-4alkyleneNRaC—(═O)Ra.

### Claim 12 (depends on 5)

The compound of claim 5 wherein R3 is selected from the group consisting of ORa, C1-6alkyl, aryl, heteroaryl, NO2, N(Ra)2, NRaC(═O)Ra, C(═O) OC2H5, CH2CH(CH3)2,

### Claim 13 (depends on 4)

The compound of claim 4 wherein R3 is substituted with a substituent selected from the group consisting of halo, ORa, C1-6alkyl, aryl, heteroaryl, NO2, N(Ra)NRaSO2CF3, NRaC(═O)Ra, C(═O)ORa, SO2N(Ra)2, CN, C(═O)Ra, C1-4alkyleneN(Ra)2, OC1-4alkyleneC≡CRa, OC1-4alkyleneC(═O)N(Ra)2, OC1-4alkylenearyl, OC1-4alkyleneheteroaryl, OC1-4alkyleneHet, OC1-4alkyleneN(Ra)2, and N(Ra)C1-4alkyleneN(Ra)2.

### Claim 14 (depends on 4)

The compound of claim 4 wherein R3 is substituted with a substituent selected from the group consisting of Cl, F, CH3, CH(CH3)2, OH, OCH3, OCH2C6H5, O(CH2)3N(CH3)2, OCH2C≡CH, OCH2C(═O)NH2, C6H5, NO2, NH2, NHC(═O)CH3, CO2H, and N(CH3)CH2CH2N(CH3)2, and

### Claim 15 (depends on 4)

The compound of claim 4 selected from the group consisting of:
2-(6-aminopurin-9-ylmethyl)-3-(2-benzyloxyphenyl)-5-methyl-3H-quinazolin-4-one;
2-(6-aminopurin-9-ylmethyl)-3-(2-hydroxyphenyl)-5-methyl-3H-quinazolin-4-one;
2-(1-(2-amino-9H-purin-6-ylamino)ethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;
5-methyl-2-[1-(9H-purin-6-ylamino)propyl]-3-o-tolyl-3H-quinazolin-4-one;
2-(1-(2-fluoro-9H-purin-6-ylamino)propyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;
2-(1-(2-amino-9H-purin-6-ylamino)propyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;
2-(2-benzyloxy-1-(9H-purin-6-ylamino)ethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;
2-(6-aminopurin-9-ylmethyl)-5-methyl-3-{2-(2-(1-methylpyrrolidin-2-yl)-ethoxy)-phenyl}-3H-quinazolin-4-one;
2-(6-aminopurin-9-ylmethyl)-3-(2-(3-dimethylaminopropoxy)-phenyl)-5-methyl-3H-quinazolin-4-one;
2-(6-aminopurin-9-ylmethyl)-5-methyl-3-(2-prop-2-ynyloxyphenyl)-3H-quinazolin-4-one; and
2-{2-(1-(6-aminopurin-9-ylmethyl)-5-methyl-4-oxo-4H-quinazolin-3-yl]-phenoxy}-acetamide.