# US 8,785,456 B2 · Substituted isoquinolin-1(2H)-ones, and methods of use thereof

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- Number: US 8,785,456 B2
- Document ID: US8785456B2
- Status: Granted
- Kind: B2
- Application number: 13/403,394
- Filed: 2012-02-23
- Published: 2012-06-14
- Granted: 2014-07-22
- Earliest claimed: 2008-01-04
- Assignees: Intellikine LLC
- Applicants: Pingda Ren; Yi Liu; Troy Edward Wilson; Liansheng Li; Katrina Chan; Christian Rommel
- Inventors: Pingda Ren; Yi Liu; Troy Edward Wilson; Liansheng Li; Katrina Chan; Christian Rommel
- Web page: https://patentgrep.com/patent/US8785456B2

## CPC

- A61K 31/4725: containing further heterocyclic rings
- A61K 31/131: acyclic
- A61K 31/196: the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/52: Purines, e.g. adenine
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61N 5/10: X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy (A61N5/01 takes precedence)
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 27/00: Drugs for disorders of the senses
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- 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
- C07D 473/34: attached in position 6, e.g. adenine
- C07D 487/04: Ortho-condensed systems
- A61N 5/1007: {Arrangements or means for the introduction of sources into the body}
- A61N 2005/109: {Neutrons}
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- 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)
- A61N: ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY (measurement of bioelectric currents A61B; surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body A61B18/00; anaesthetic apparatus in general A61M; incandescent lamps H01K; infrared radiators for heating H05B)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

Chemical entities that modulate PI3 kinase activity, pharmaceutical compositions containing the chemical entities, and methods of using these chemical entities for treating diseases and conditions associated with P13 kinase activity are described herein.

## Claims

### Claim 1

A method of inhibiting a phosphatidyl inositol-3 kinase (PI3 kinase) in a subject, comprising administering to the subject an effective amount of a compound of Formula I-1:
or a pharmaceutically acceptable salt thereof, wherein:
B is a moiety of Formula II:
wherein:
Wc is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, and
q is an integer of 0, 1, 2, 3, or 4;
X is a bond or —(CH(R9))z—, and z is an integer of 1;
Y is —N(R9)—;
Wd is:
R1 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, amido, alkoxycarbonyl, sulfonamido, halo, cyano, or nitro;
R2 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heteroarylalkyl, alkoxy, amino, halo, cyano, hydroxy or nitro;
R3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, amido, amino, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy or nitro; and
each instance of R9 is independently hydrogen, alkyl, or heterocycloalkyl.

### Claim 2 (depends on 1)

The method of claim 1, wherein the inhibition takes place in a subject suffering from a disorder, wherein the disorder is a cancer or an inflammatory disease,
wherein the cancer is leukemia lymphoma; and
wherein the inflammatory disease is asthma, emphysema, allergy, dermatitis, rheumatoid arthritis, psoriasis, lupus erythematosus, graft versus host disease, inflammatory bowel disease, eczema, scleroderma,Crohn's disease, atherosclerosis, encephalomyelitis, or multiple sclerosis.

### Claim 3 (depends on 2)

The method of claim 2, wherein the leukemia is B-cell acute lymphoblastic leukemia (B-ALL), acute lymphocytic leukemia, T-cell acute lymphocytic leukemia, adult T-cell leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), mastocytosis, or mast cell cancer.

### Claim 4 (depends on 2)

The method of claim 2, wherein the lymphoma is diffuse large B-cell lymphoma, B-cell immunoblastic lymphoma, small non-cleaved cell lymphoma, human lymphotropic virus-type 1 (HTLV-1) leukemia/lymphoma, adult T-cell lymphoma, AIDS-related lymphoma, Hodgkin disease, or non-Hodgkin lymphomas.

### Claim 5 (depends on 2)

The method of claim 2, further comprising administering one or more therapeutic agents selected from chemotherapeutic agents, cytotoxic agents, and radiation.

### Claim 6 (depends on 1)

The method of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

The method of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

The method of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

The method of claim 1, wherein the subject is a mammal.

### Claim 10 (depends on 9)

The method of claim 9, wherein the mammal is a human.

### Claim 11 (depends on 2)

The method of claim 2, wherein the disorder is rheumatoid arthritis, and the amount of the compound is effective to ameliorate one or more symptoms associated with rheumatoid arthritis selected from a reduction in the swelling of the joints, a reduction in serum anti-collagen levels, a reduction in bone resorption, a reduction in cartilage damage, a reduction in pannus, and a reduction in inflammation, and a combination thereof.

### Claim 12 (depends on 1)

The method of claim 1, wherein the compound is administered in combination with an mTOR inhibitor.

### Claim 13 (depends on 1)

The method of claim 1, wherein the compound is administered in combination with one or more of an agent that inhibits IgE production or activity, 2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoic acid, an mTOR inhibitor, rapamycin, a TORC1 inhibitor, a TORC2 inhibitor, an anti-IgE antibody, corticosteroid, a leukotriene inhibitor, omalizumab, a combination of fluticasone and salmeterol, montelukast, or tiotropium bromide.

### Claim 14 (depends on 1)

The method of claim 1, wherein the compound is administered in combination with one or more of a mitotic inhibitor, an alkylating agent, an anti-metabolite, an intercalating antibiotic, a growth factor inhibitor, a cell cycle inhibitor, an enzyme, a topoisomerase inhibitor, an anti-hormone, an angiogenesis inhibitor, or an anti-receptor kinase antibody.

### Claim 15 (depends on 1)

The method of claim 1, wherein the compound is administered in combination with one or more of Imatinib mesylate, bortezomib, bicalutamide, gefitinib, alkylating agents, alkyl sulfonates, ethylenimines, altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide, trimethylolomelamine, antibiotics, anti-metabolites, denopterin, ancitabine, 6-azauridine, carmofur, dideoxyuridine, doxifluridine, enocitabine, androgens, anti-adrenals, folic acid replenisher, arabinoside, thiotepa, taxanes, anti-hormonal agents, aromatase inhibiting 4(5)-imidazoles, gemcitabine, cisplatin, carboplatin, vincristine, vinorelbine, vinblastin, daunorubicin, doxorubicin, mitoxantrone, anastrozole, or an anti-receptor tyrosine kinase antibody selected from the group consisting of cetuximab, panitumumab, trastuzumab, anti CD20 antibody, rituximab, tositumomab, alemtuzumab, bevacizumab, and gemtuzumab.

### Claim 16 (depends on 1)

The method of claim 1, wherein the compound is administered in combination with one or more of non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, chloroquine, hydroxychloroquine, azathioprine, cyclophosphamide, methotrexate, cyclosporine, anti-CD20 antibodies, etanercept, infliximab, adalimumab, or interferon beta 1-alpha.

### Claim 17 (depends on 1)

The method of claim 1, wherein the B moiety of the compound of Formula I-1 is:
wherein Wc is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl;
q is an integer of 0 or 1;
R1 is hydrogen, alkyl, or halo;
R2 is alkyl or halo; and
R3 is hydrogen, alkyl, or halo.

### Claim 18 (depends on 1)

The method of claim 1, wherein X is —(CH(R9))z—, and Y is —NH—.

### Claim 19 (depends on 1)

The method of claim 1, wherein R3 is —H, —CH3, —CH2CH3, —CF3, —Cl or —F.

### Claim 20 (depends on 1)

The method of claim 1, wherein R3 is —CH3 or —Cl.

### Claim 21 (depends on 17)

The method of claim 17, wherein X is —(CH(R9))z—, wherein R9 is methyl and z is 1; and
Wd is

### Claim 22 (depends on 17)

The method of claim 17, wherein R3 is —CH3 or —Cl.

### Claim 23 (depends on 1)

The method of claim 1, wherein the compound of Formula I-1 is predominately in an (S)-stereochemical configuration.

### Claim 24 (depends on 23)

The method of claim 23, wherein the compound of Formula I-1 is the S-enantiomer having an enantiomeric purity greater than 90%.

### Claim 25 (depends on 1)

The method of claim 1, wherein the compound has a structure of Formula V-A2:

### Claim 26 (depends on 25)

The method of claim 25, wherein the B moiety of the compound is:
wherein Wc is aryl or cycloalkyl.

### Claim 27 (depends on 25)

The method of claim 25, wherein R3 is methyl or chloro.

### Claim 28 (depends on 25)

The method of claim 25, wherein R3 is chloro.

### Claim 29 (depends on 25)

The method of claim 25, wherein the B moiety of the compound is substituted or unsubstituted phenyl.

### Claim 30 (depends on 25)

The method of claim 25, wherein the B moiety of the compound is substituted or unsubstituted cycloalkyl.

### Claim 31 (depends on 25)

The method of claim 25, wherein the B moiety of the compound is a phenyl that is unsubstituted or substituted with fluoro.

### Claim 32 (depends on 25)

The method of claim 25, wherein Wc is aryl or heterocycloalkyl.

### Claim 33 (depends on 32)

The method of claim 32, wherein Wc is phenyl.

### Claim 34 (depends on 25)

The method of claim 25, wherein Wc is cyclopropyl.

### Claim 35 (depends on 25)

The method of claim 25, wherein Wc is substituted by at least one of —CH3, —CH2CH3, —CF3, —Cl or —F.

### Claim 36 (depends on 1)

The method of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 37 (depends on 1)

The method of claim 1, wherein the compound has the following structure:
or a pharmaceutically acceptable salt thereof.

### Claim 38 (depends on 37)

The method of claim 37, wherein the compound is the S-enantiomer having an enantiomeric purity greater than 90%.

### Claim 39 (depends on 1)

The method of claim 1, wherein the compound has the following structure:
or a pharmaceutically acceptable salt thereof.

### Claim 40 (depends on 1)

The method of claim 1, wherein the compound is present in a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

### Claim 41 (depends on 2)

The method of claim 2, wherein the subject is a human.

### Claim 42 (depends on 2)

The method of claim 2, wherein the disorder is rheumatoid arthritis.

### Claim 43 (depends on 2)

The method of claim 2, wherein the disorder is asthma.

### Claim 44 (depends on 2)

The method of claim 2, wherein the disorder is cancer selected from leukemia and lymphoma.

### Claim 45 (depends on 2)

The method of claim 2, wherein the B moiety of the compound of Formula I-1 is:
wherein Wc is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl;
q is an integer of 0 or 1;
R1 is hydrogen, alkyl, or halo;
R2 is alkyl or halo; and
R3 is hydrogen, alkyl, or halo.

### Claim 46 (depends on 2)

The method of claim 2, wherein X is —(CH(R9))z—, and Y is —NH—.

### Claim 47 (depends on 2)

The method of claim 2, wherein R3 is —H, —CH3, —CH2CH3, —CF3, —Cl or —F.

### Claim 48 (depends on 2)

The method of claim 2, wherein R3 is —CH3 or —Cl.

### Claim 49 (depends on 45)

The method of claim 45, wherein X is —(CH(R9))z—, wherein R9 is methyl and z is 1; and
Wd is

### Claim 50 (depends on 45)

The method of claim 45, wherein R3 is —CH3 or —Cl.

### Claim 51 (depends on 2)

The method of claim 2, wherein the compound of Formula I-1 is predominately in an (S)-stereochemical configuration.

### Claim 52 (depends on 51)

The method of claim 51 , wherein the compound of Formula I-1 is the S-enantiomer having an enantiomeric purity greater than 90%.

### Claim 53 (depends on 2)

The method of claim 2, wherein the compound has a structure of Formula V-A2:

### Claim 54 (depends on 53)

The method of claim 53, wherein the B moiety of the compound is:
wherein Wc is aryl or cycloalkyl.

### Claim 55 (depends on 53)

The method of claim 53, wherein R3 is methyl or chloro.

### Claim 56 (depends on 53)

The method of claim 53, wherein R3 is chloro.

### Claim 57 (depends on 53)

The method of claim 53, wherein the B moiety of the compound is substituted or unsubstituted phenyl.

### Claim 58 (depends on 53)

The method of claim 53, wherein the B moiety of the compound is substituted or unsubstituted cycloalkyl.

### Claim 59 (depends on 53)

The method of claim 53, wherein the B moiety of the compound is a phenyl that is unsubstituted or substituted with fluoro.

### Claim 60 (depends on 53)

The method of claim 53, wherein Wc is aryl or heterocycloalkyl.

### Claim 61 (depends on 60)

The method of claim 60, wherein Wc is phenyl.

### Claim 62 (depends on 53)

The method of claim 53, wherein Wc is cyclopropyl.

### Claim 63 (depends on 53)

The method of claim 53, wherein Wc is substituted by at least one of —CH3, —CH2CH3, —CF3, —Cl or —F.

### Claim 64 (depends on 2)

The method of claim 2, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 65 (depends on 2)

The method of claim 2, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 66 (depends on 2)

The method of claim 2, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 67 (depends on 2)

The method of claim 2, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 68 (depends on 2)

The method of claim 2, wherein the compound has the following structure:
or a pharmaceutically acceptable salt thereof.

### Claim 69 (depends on 68)

The method of claim 68, wherein the compound is the S-enantiomer having an enantiomeric purity greater than 90%.

### Claim 70 (depends on 2)

The method of claim 2, wherein the compound has the following structure:
or a pharmaceutically acceptable salt thereof.

### Claim 71 (depends on 2)

The method of claim 2, wherein the compound is present in a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

### Claim 72 (depends on 2)

The method of claim 2, wherein the compound is administered in combination with one or more of: a mitotic inhibitor, an alkylating agent, an anti-metabolite, an intercalating antibiotic, a growth factor inhibitor, a cell cycle inhibitor, an enzyme, a topoisomerase inhibitor, an anti-hormone, an angiogenesis inhibitor, or an anti-receptor kinase antibody.

### Claim 73 (depends on 2)

The method of claim 2, wherein the compound is administered in combination with an mTOR inhibitor.

### Claim 74 (depends on 2)

The method of claim 2, wherein the compound is administered in combination with one or more of: 2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoic acid, an mTOR inhibitor, rapamycin, a TORC1 inhibitor, a TORC2 inhibitor, an anti-IgE antibody, corticosteroid, a leukotriene inhibitor, a combination of fluticasone and salmeterol, and tiotropium bromide.

### Claim 75 (depends on 2)

The method of claim 2, wherein the compound is administered in combination with one or more of: Imatinib mesylate, bortezomib, bicalutamide, gefitinib, alkylating agents, alkyl sulfonates, ethylenimines, altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide, trimethylolomelamine, antibiotics, anti-metabolites, denopterin, ancitabine, 6-azauridine, carmofur, dideoxyuridine, doxifluridine, enocitabine, androgens, anti-adrenals, folic acid replenisher, arabinoside, thiotepa, taxanes, anti-hormonal agents, aromatase inhibiting 4(5)-imidazoles, gemcitabine, cisplatin, carboplatin, vincristine, vinorelbine, vinblastin, daunorubicin, doxorubicin, mitoxantrone, anastrozole, cetuximab, panitumumab, trastuzumab, rituximab, tositumomab, alemtuzumab, bevacizumab, gemtuzumab, montelukast, and omalizumab.

### Claim 76 (depends on 2)

The method of claim 2, wherein the compound is administered in combination with one or more of: non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, chloroquine, hydroxychloroquine, azathioprine, cyclophosphamide, methotrexate, cyclosporine, anti-CD20 antibodies, etanercept, infliximab, adalimumab, and interferon beta 1-alpha.

### Claim 77 (depends on 44)

The method of claim 44, further comprising administering one or more therapeutic agents selected from chemotherapeutic agents, cytotoxic agents, and radiation.

### Claim 78

A method of inhibiting a phosphatidyl inositol-3 kinase (PI3 kinase) in a subject suffering from a cancer, comprising administering to the subject an effective amount of a compound having the following structure:
or a pharmaceutically acceptable salt thereof,
wherein the cancer is leukemia or lymphoma.

### Claim 79 (depends on 78)

The method of claim 78, wherein the compound is the S-enantiomer having an enantiomeric purity greater than 90%.

### Claim 80 (depends on 78)

The method of claim 78, wherein the leukemia is B-cell acute lymphoblastic leukemia (B-ALL), acute lymphocytic leukemia, T-cell acute lymphocytic leukemia, adult T-cell leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), mastocytosis, mast cell cancer.

### Claim 81 (depends on 78)

The method of claim 78, wherein the lymphoma is diffuse large B-cell lymphoma, B-cell immunoblastic lymphoma, small non-cleaved cell lymphoma, human lymphotropic virus-type 1 (HTLV-1) leukemia/lymphoma, AIDS-related lymphoma, adult T-cell lymphoma, Hodgkin disease, or non-Hodgkin lymphomas.

### Claim 82 (depends on 78)

The method of claim 78, further comprising administering one or more therapeutic agents selected from chemotherapeutic agents, cytotoxic agents, and radiation.

### Claim 83 (depends on 78)

The method of claim 78, wherein the compound is administered in combination with one or more of: a mitotic inhibitor, an alkylating agent, an anti-metabolite, an intercalating antibiotic, a growth factor inhibitor, a cell cycle inhibitor, an enzyme, a topoisomerase inhibitor, an anti-hormone, an angiogenesis inhibitor, or an anti-receptor kinase antibody.

### Claim 84 (depends on 78)

The method of claim 78, wherein the compound is administered in combination with one or more of: Imatinib mesylate, bortezomib, bicalutamide, gefitinib, alkylating agents, alkyl sulfonates, ethylenimines, altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide, trimethylolomelamine, antibiotics, anti-metabolites, denopterin, ancitabine, 6-azauridine, carmofur, dideoxyuridine, doxifluridine, enocitabine, androgens, anti-adrenals, folic acid replenisher, arabinoside, thiotepa, taxanes, anti-hormonal agents, aromatase inhibiting 4(5)-imidazoles, gemcitabine, cisplatin, carboplatin, vincristine, vinorelbine, vinblastin, daunorubicin, doxorubicin, mitoxantrone, anastrozole, cetuximab, panitumumab, trastuzumab, rituximab, tositumomab, alemtuzumab, bevacizumab, and gemtuzumab.

### Claim 85 (depends on 78)

The method of claim 78, wherein the compound is administered in combination with one or more of: bortezomib, alkylating agents, anti-metabolites, denopterin, pteropterin, trimetrexate, ancitabine, 6-azauridine, carmour, dideoxyuridine, doxifluridine, enocitabine, androgens, taxanes, anti-hormonal agents, gemcitabine, cisplatin, carboplatin, vincristine, vinorelbine, vinblastin, mitomycin C, daunorubicin, doxorubicin, mitoxantrone, and anastrozole.

### Claim 86

A method of inhibiting a phosphatidyl inositol-3 kinase (PI3kinase) in a subject suffering from a cancer, comprising administering to the subject an effective amount of a compound having the following structure:
or a pharmaceutically acceptable salt thereof,
wherein the cancer is leukemia or lymphoma.

### Claim 87 (depends on 86)

The method of claim 86, wherein the leukemia is B-cell acute lymphoblastic leukemia (B-ALL), acute lymphocytic leukemia, T-cell acute lymphocytic leukemia, adult T-cell leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), mastocytosis, or mast cell cancer.

### Claim 88 (depends on 86)

The method of claim 86, wherein the lymphoma is diffuse large B-cell lymphoma, B-cell immunoblastic lymphoma, small non-cleaved cell lymphoma, human lymphotropic virus-type 1 (HTLV-1) leukemia lymphoma, AIDS-related lymphoma, adult T-cell lymphoma, Hodgkin disease, or non-Hodgkin lymphomas.

### Claim 89 (depends on 86)

The method of claim 86, further comprising administering one or more therapeutic agents selected from chemotherapeutic agents, cytotoxic agents, and radiation.

### Claim 90 (depends on 86)

The method of claim 86, wherein the compound is administered in combination with one of more of: a mitotic inhibitor, an alkylating agent, an anti-metabolite, an intercalating antibiotic, a growth factor inhibitor, a cell cycle inhibitor, an enzyme, a topoisomerase inhibitor, an anti-hormone, an angiogenesis inhibitor, or an anti-receptor kinase antibody.

### Claim 91 (depends on 86)

The method of claim 86, wherein the compound is administered in combination with one or more of: Imatinib mesylate, bortezomib, bicalutamide, gefitinib, alkylating agents, alkyl sulfonates, ethylenimines, altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide, trimethylolomelamine, antibiotics, anti-metabolites, denopterin, ancitabine, 6-azauridine, carmofur, dideoxyuridine, doxifluridine, enocitabine, androgens, anti-adrenals, folic acid replenisher, arabinoside, thiotepa, taxanes, anti-hormonal agents, aromatase inhibiting 4(5)-imidazoles, gemcitabine, cisplatin, carboplatin, vincristine, vinorelbine, vinblastin, daunorubicin, doxorubicin, mitoxantrone, anastrozole, cetuximab, panitumumab, trastuzumab, rituximab, tositumomab, alemtuzumab, bevacizumab, and gemtuzumab.

### Claim 92 (depends on 86)

The method of claim 86, wherein the compound is administered in combination with one or more of: bortezomib, alkylating agents, anti-metabolites, denopterin, pteropterin, ancitabine, 6-azauridine, carmofur, dideoxyuridine, doxifluridine, enocitabine, androgens, taxanes, anti-hormonal agents, gemcitabine, cisplatin, carboplatin, vincristine, vinorelbine, vinblastin, ifosfamide, mitomycin C, daunorubicin, doxorubicin, mitoxantrone, and anastrozole.

### Claim 93

A method of inhibiting phosphatidyl inositol-3 kinase (PI3 kinase) in a subject suffering from an inflammatory disease, comprising administering to the subject an effective amount of a compound having the following structure:
or a pharmaceutically acceptable salt thereof,
wherein the inflammatory disease is asthma, emphysema, allergy, dermatitis, rheumatoid arthritis, psoriasis, lupus erythematosus, graft versus host disease, inflammatory bowel disease, eczema, scleroderma, Crohn's disease, atherosclerosis, encephalomyelitis, or multiple sclerosis.

### Claim 94 (depends on 93)

The method of claim 93, wherein the compound is the S-enantiomer having an enantiomeric purity greater than 90%.

### Claim 95 (depends on 93)

The method of claim 93, wherein the inflammatory disease is rheumatoid arthritis.

### Claim 96 (depends on 93)

The method of claim 93, wherein the compound is administered in combination with one or more of: non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, chloroquine, hydroxychloroquine, azathioprine, cyclophosphamide, methotrexate, cyclosporine, anti-CD20 antibodies, etanercept, infliximab, adalimumab, and interferon beta 1-alpha.

### Claim 97

A method of inhibiting a phosphatidyl inositol-3 kinase (PI3 kinase) in a subject: suffering from an inflammatory disease, comprising administering to the subject an effective amount of a compound having the following structures:
or a pharmaceutically acceptable salt thereof,
wherein the inflammatory disease is asthma, emphysema, allergy, dermatitis, rheumatoid arthritis, psoriasis, lupus erythematosus, graft versus host disease, inflammatory bowel disease, eczema, scleroderma, Crohn's disease, atherosclerosis, encephalomyelitis, or multiple sclerosis.

### Claim 98 (depends on 97)

The method of claim 97, wherein the inflammatory disease is rheumatoid arthritis.

### Claim 99 (depends on 97)

The method of claim 97, wherein the compound is administered in combination with one or more of: non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, chloroquine, hydroxychloroquine, azathioprine, cyclophosphamide, methotrexate, cyclosporine, anti-CD20 antibodies, etanercept, infliximab, adalimumab, and interferon beta 1-alpha.

### Claim 100

A method of inhibiting a phosphatidyl inositol-3 kinase(PI3 kinase) in a subject suffering from a respiratory disease, comprising administering to the subject an effective amount of a compound having the following structure:
or a pharmaceutically salt thereof,
wherein the respiratory disease is asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, or bronchiectasis.

### Claim 101 (depends on 100)

The method of claim 100, wherein the compound is the S-enantiomer having an enantiomeric purity greater than 90%.

### Claim 102 (depends on 100)

The method of claim 100, wherein the respiratory disease is asthma.

### Claim 103 (depends on 100)

The method of claim 100, wherein the compound is administered in combination with one or more of: 2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoic acid, an mTOR inhibitor, rapamycin, a TORC1 inhibitor, a TORC2 inhibitor, an anti-IgE antibody, corticosteroid, a leukotriene inhibitor, a combination of fluticasone and salmeterol, montelukast, and tiotropium bromide.

### Claim 104

A method of inhibiting a phosphatidyl inositol-3 kinase (PI3 kinase) in a subject suffering from a respiratory disease, comprising administering to the subject an effective amount of a compound having the following structure:
or a pharmaceutically acceptable salt thereof,
wherein the respiratory disease is asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, or bronchiectasis.

### Claim 105 (depends on 104)

The method of claim 104, wherein the respiratory disease is asthma.

### Claim 106 (depends on 104)

The method of claim 104, wherein the compound is administered in combination with one or more of: 2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoic acid, an mTOR inhibitor, rapamycin, a TORC2 inhibitor, an anti-IgE antibody, corticosteroid, a leukotriene inhibitor, a combination of fluticasone and salmeterol, and tiotropium bromide.

### Claim 107 (depends on 104)

The method of claim 104, wherein the compound is administered in combination with montelukast or omalizumab.

### Claim 108 (depends on 1)

The method of claim 1, wherein the inhibition takes place in a subject suffering from a disorder, wherein the disorder is an immune disease, wherein the immune disease is acute disseminated encephalomyelitis (ADEM), Addiosn's disease, antiphospholipid antibody syndrome (APS), aplastic anemia, autoimmune hepatitis, coeliac disease, Crohn's disease, Diabetes mellitus (type 1), Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, lupus erythematosus, multiple sclerosis, myasthenia gravis, opoclonus myoclonus syndrome (OMS), optic neuritis, Ord's thyroiditis, oemphigus, polyarthritis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopecia universalis, Chagas's disease, chronic fatigue syndrome, dysautonomia, endometriosis, hidradenitis suppurativea, interstitial cystitis, neuromyotonia, sareoidosis, scleroderma, ulcerative colitis, vitiligo, or vulvodynia.

### Claim 109 (depends on 1)

The method of claim 1, wherein the inhibition takes place in a subject suffering front a disorder, wherein the disorder is a respiratory disease, wherein the respiratory disease is asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, or bronchiectasis.

### Claim 110 (depends on 86)

The method of claim 86, wherein the compound is administered in combination with an mTOR inhibitor.

### Claim 111 (depends on 86)

The method of claim 86, wherein the compound is administered in combination with one or more of: 2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoic acid, an mTOR inhibitor, rapamycin, a TORC1 inhibitor, a TORC2 inhibitor, an anti-IgE antibody, corticosteroid, a leukotriene inhibitor, a combination of fluticasone and salmeterol, and tiotropium bromide.

### Claim 112 (depends on 2)

The method of claim 2, wherein the compound is administered in combination with one or more of nitrogen mustards.

### Claim 113 (depends on 112)

The method of claim 112, wherein the nitrogen mustard is chlorambucil, chlornaphazine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, or uracil mustard.

### Claim 114 (depends on 2)

The method of claim 2, wherein the compound is administered in combination with one or more of nitrosurea.

### Claim 115 (depends on 114)

The method of claim 114, wherein the nitrosurea is carmustine, chlorozotocin, fotemustine, lomustine, nimustine, or ranimustine.

### Claim 116 (depends on 2)

The method of claim 2, wherein the compound is administered in combination with one or more of anti-estrogens or anti-androgens.

### Claim 117 (depends on 2)

The method of claim 2, wherein the compound is administered in combination with one or more of: methotrexate, trimetrexate, 5-fluorouracil (5-FU), fludarabine, thiamiprine, thioguanine, azacitidine, cytarabine, floxuridine, mercaptopurine, pteropterin, onapristone, paclitaxel, docetaxel, tamoxifen, raloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, toremifene, and mitomycin C.

### Claim 118 (depends on 86)

The method of claim 86, wherein the cancer is chronic lymphocytic leukemia.

### Claim 119 (depends on 86)

The method of claim 86, wherein the cancer is non-Hodgkin lymphomas.

### Claim 120 (depends on 86)

The method of claim 86, wherein the cancer is acute lymphocytic leukemia (ALL).

### Claim 121 (depends on 86)

The method of claim 86, wherein the cancer is diffuse large B-cell lymphoma.

### Claim 122 (depends on 86)

The method of claim 86, wherein the cancer is myelodysplastic syndrome (MDS).

### Claim 123 (depends on 86)

The method of claim 86, wherein the cancer is adult T-cell lymphoma.

### Claim 124 (depends on 86)

The method of claim 86, wherein the cancer is acute myelogenous leukemia (AML).

### Claim 125 (depends on 86)

The method of claim 86, wherein the cancer is chronic myelogenous leukemia (CML).

### Claim 126 (depends on 86)

The method of claim 86, wherein the cancer is myeloproliferative disorders.

### Claim 127 (depends on 86)

The method of claim 86, wherein the cancer is mast cell cancer.

### Claim 128 (depends on 86)

The method of claim 86, wherein the cancer is Hodgkin disease.

### Claim 129 (depends on 86)

The method of claim 86, wherein the cancer is B-cell acute lymphoblastic leukemia.

### Claim 130 (depends on 86)

The method of claim 86, wherein the cancer is T-cell acute lymphoblastic leukemia.

### Claim 131 (depends on 86)

The method of claim 86, wherein the cancer is multiple myeloma (MM).

### Claim 132 (depends on 86)

The method of claim 86, wherein the compound is administered in combination with one or more of nitrogen mustards or rituximab.

### Claim 133 (depends on 132)

The method of claim 132, wherein the nitrogen mustard is chlorambucil, chlomaphazine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, or uracil mustard.

### Claim 134 (depends on 86)

The method of claim 86, wherein the compound is administered in combination with one or more of nitrosureas.

### Claim 135 (depends on 134)

The method of claim 134, wherein the nitrosurea is carmustine, chlorozotocin, fotemustine, lomustine, nimustine, or ranimustine.

### Claim 136 (depends on 86)

The method of claim 86, wherein the compound is administered in combination with one or more of anti-estrogens or anti-androgens.

### Claim 137 (depends on 86)

The method of claim 86, wherein the compound is administered in combination with one or more of: methotrexate, trimetrexate, 5-fluorouracil (5-FU), fludarabine, thiamiprine, thioguanine, azacitidine, cytarabine, floxuridine, mercaptopurine, pteropterin, onapristone, paclitaxel, docetaxel, tamoxifen, raloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, toremifene, and mitomycin C.

### Claim 138 (depends on 132)

The method of claim 132, wherein the nitrogen mustard is chlorambucil.

### Claim 139 (depends on 118)

The method of claim 118, wherein the compound is administered in combination with rituximab.

### Claim 140 (depends on 118)

The method of claim 118, wherein the compound is administered in combination with one or more nitrogen mustards.

### Claim 141 (depends on 119)

The method of claim 119, wherein the compound is administered in combination with rituximab.

### Claim 142 (depends on 119)

The method of claim 119, wherein the compound is administered in combination with at least one of nitrogen mustards.

### Claim 143 (depends on 68)

The method of claim 68, wherein the compound of Formula I-1 is the S-enantiomer having an enantiomeric purity greater than 95%.

### Claim 144 (depends on 68)

The method of claim 68, wherein the compound of Formula I-1 is the S-enantiomer having an enantiomeric purity greater than 80%.

### Claim 145 (depends on 68)

The method of claim 68, wherein the compound of Formula I-1 is the S-enantiomer having an enantiomeric purity greater than 55%.

### Claim 146 (depends on 39)

The method of claim 39, wherein the subject is a mammal.

### Claim 147 (depends on 146)

The method of claim 146, wherein the mammal is a human.

### Claim 148 (depends on 97)

The method of claim 97, wherein the inflammatory disease is asthma.

### Claim 149 (depends on 97)

The method of claim 97, wherein the inflammatory disease is emphysema.

### Claim 150 (depends on 97)

The method of claim 97, wherein the inflammatory disease is allergy.

### Claim 151 (depends on 97)

The method of claim 97, wherein the inflammatory disease is dermatitis.

### Claim 152 (depends on 97)

The method of claim 97, wherein the inflammatory disease is psoriasis.

### Claim 153 (depends on 97)

The method of claim 97, wherein the inflammatory disease is lupus erythematosus.

### Claim 154 (depends on 97)

The method of claim 97, wherein the inflammatory disease is graft versus host disease.

### Claim 155 (depends on 97)

The method of claim 97, wherein the inflammatory disease is inflammatory bowel disease.

### Claim 156 (depends on 97)

The method of claim 97, wherein the inflammatory disease is eczema.

### Claim 157 (depends on 97)

The method of claim 97, wherein the inflammatory disease is scleroderma.

### Claim 158 (depends on 97)

The method of claim 97, wherein the inflammatory disease is Crohn's disease.

### Claim 159 (depends on 97)

The method of claim 97, wherein the inflammatory disease is atherosclerosis.

### Claim 160 (depends on 97)

The method of claim 97, wherein the inflammatory disease is encephalomyelitis.

### Claim 161 (depends on 97)

The method of claim 97, wherein the inflammatory disease is multiple sclerosis.

### Claim 162 (depends on 86)

The method of claim 86, wherein the cancer is hairy cell leukemia.

### Claim 163 (depends on 86)

The method of claim 86, wherein the cancer is myelodysplasia.

### Claim 164 (depends on 86)

The method of claim 86, wherein the cancer is mastocytosis.

### Claim 165 (depends on 86)

The method of claim 86, wherein the cancer is B-cell immunoblastic lymphoma.

### Claim 166 (depends on 86)

The method of claim 86, wherein the cancer is small non-cleaved cell lymphoma.

### Claim 167 (depends on 86)

The method of claim 86, wherein the cancer is human lymphotropic virus-type 1 (HTLV-1) leukemia/lymphoma.

### Claim 168 (depends on 86)

The method of claim 86, wherein the cancer is AIDS-related lymphoma.

### Claim 169 (depends on 86)

The method of claim 86, wherein the cancer is adult T-cell leukemia/lymphoma.

### Claim 170 (depends on 86)

The method of claim 86, wherein the cancer is adult T-cell leukemia.