# US 8,772,287 B2 · Pyrimidinyl and 1,3,5-triazinyl benzimidazole sulfonamides and their use in cancer therapy

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- Number: US 8,772,287 B2
- Document ID: US8772287B2
- Status: Granted
- Kind: B2
- Application number: 13/914,385
- Filed: 2013-06-10
- Published: 2013-10-31
- Granted: 2014-07-08
- Earliest claimed: 2009-03-27
- Assignees: VetDC, Inc.
- Applicants: VetDC, Inc.
- Inventors: Gordon William Rewcastle; Swarnalatha Akuratiya Gamage; Jack Urquhart Flanagan; Anna Claire Giddens; Kit Yee Tsang
- Web page: https://patentgrep.com/patent/US8772287B2

## CPC

- C07D 491/08: Bridged systems
- A61K 31/5355: Non-condensed oxazines and containing further heterocyclic rings
- A61K 31/541: Non-condensed thiazines containing further heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/02: Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
- 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 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/04: Antipruritics
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 21/04: for myasthenia gravis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/20: Hypnotics; Sedatives
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- 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 31/10: Antimycotics
- A61P 31/12: Antivirals
- A61P 33/00: Antiparasitic 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
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 473/34: attached in position 6, e.g. adenine
- C07D 487/04: Ortho-condensed systems
- C07D 498/08: Bridged systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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

## Abstract

Provided herein are pyrimidinyl and 1,3,5-triazinyl benzimidazole sulfonamides, e.g., compounds of Formulae IA, IB, and IC, and their pharmaceutical compositions, preparation, and use as agents or drugs for cancer therapy, either alone or in combination with radiation and/or other anticancer drugs.

## Claims

### Claim 1

A method for the treatment of a PI3K-mediated cancer, comprising administration to a mammal in need thereof, a therapeutically effective dose of a composition in an amount effective to inhibit PI3K enzyme activity, comprising a compound of Formula IA:
or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof;
or a pharmaceutically acceptable salt, or prodrug thereof;
wherein:
R1 and R2 are each independently (a) hydrogen, cyano, halo, or nitro; (b) C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1b, —C(O)NR1bR1c, —C(NRa)NR1bR1c, —OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1c, —OC(═NR1a)NR1bR1c, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1c, —OS(O)2NR1bR1c, —NR1bR1c, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1c, —NR1aC(═NR1d)NR1bR1c, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1c, —NR1aS(O)2NR1bR1c, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1c, or —S(O)2NR16R1c; wherein each R1a, R1b, R1c, and Rid is independently (i) hydrogen; (ii) C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R1b and R1c together with the N atom to which they are attached form heterocyclyl;
R3 and R4 are each independently hydrogen or C1-6 alkyl; or R3 and R4 are linked together to form a bond, C1-6 alkylene, C1-6heteroalkylene, C2-6alkenylene, or C2-6 heteroalkenylene;
R5 is independently C1-6 alkyl C2-6alkenyl, each optionally substituted with one or more substituents, each of which is independently selected from the group consisting of heterocyclyl and —NRfRg, or R5 is —NR5mR5n, where R5m and R5n are each independently hydrogen, C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
R6 is independently hydrogen or C1-6 alkyl;
Q is C1-6 alkylene, C2-6alkenylene, C2-6alkynylene, C3-7cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene;
T1 is independently a bond, C1-6 alkylene, —O—, or —NR8—;
T2 is independently a bond, C1-6 alkylene, or —NR8—; wherein each R8 is independently hydrogen, C1-6 alkyl, C2-6alkenyl, or C2-6alkynyl; and
with the proviso that at least one of the two atoms that are directly attached to the —SO2— group is nitrogen;
X, Y, and Z are each independently a nitrogen atom or CR9, with the proviso that at least two of X, Y, and Z are nitrogen atoms; where R9 is hydrogen or C1-6 alkyl;
wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene in R1, R2, R3, R4, R6, R8, R9, R1a, R1b, R1c, R1d R5m, R5n, Q, T1, and T2, is optionally substituted with one or more groups, each independently selected from (a) cyano, halo, and nitro; (b) C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1; and (c) —C(O)Ra, —C(O)ORa, —C(O)NRbRc, —C(NRa)NRbRc, —ORa, —OC(O)Ra, —OC(O)ORa, —OC(O)NRbRc, —OC(═NRa)NRbRc, —OS(O)Ra—OS(O)NRbRc, —OS(O)2NRbRc, —NRbRc, —NRaC(O)Rd, —NRaC(O)ORd, —NRaC(O)NRbRc, —NRaC(═NRd)NRbRc, —NRaS(O)Rd, —NRaS(O)2Rd, —NRaS(O)NRbRc, —NRaS(O)2NRbRc, —SRa, —S(O)Ra, —S(O)2Ra, —S(O)NRbRc, and —S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen; (ii) C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q1; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q1;
wherein each Q1 is independently selected from the group consisting of (a) cyano, halo, and nitro; (b) C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)Re, —C(O)ORe, —C(O)NRfRg, —C(NRe)NRfRg, —ORe, —OC(O)Re, —OC(O)ORe, —OC(O)NRfRg, —OC(═NRe)NRfRg, —OS(O)Re, —OS(O)2Re, —OS(O)NRfRg, —OS(O)2NRfRg, —NRfRg, —NReC(O)Rh, —NReC(O)ORh, —NReC(O)NRfRg, —NReC(═NRh)NRfRg, —NReS(O)Rh, —NReS(O)2Rh, —NReS(O)NRfRg, —NReS(O)2NRfRg, —SRe, —S(O)Re, —S(O)2Re, —S(O)NRfRg, and —S(O)2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C3-7cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.

### Claim 2 (depends on 1)

The method of claim 1, wherein the compound has the structure of Formula II:

### Claim 3 (depends on 1)

The method of claim 1, wherein R1 is independently hydrogen or —OR1a, where R1a is C1-6 alkyl, optionally substituted with —NRfRg; and Rf and Rg are each independently hydrogen or C1-6 alkyl.

### Claim 4 (depends on 3)

The method of claim 3, wherein R1 is hydrogen, methoxy, or dimethylaminopropoxy.

### Claim 5 (depends on 1)

The method of claim 1, wherein R2 is independently hydrogen, C1-6 alkyl, or —NR1bR1c; where R1b and R1c are each independently (a) hydrogen; or (b) C1-6 alkyl, C2-6alkenyl, or C2-6alkynyl, each optionally substituted with one or more substituents, where each substituent is independently —ORe and —NRfRg.

### Claim 6 (depends on 5)

The method of claim 5, wherein R2 is independently hydrogen or amino.

### Claim 7 (depends on 1)

The method of claim 1, wherein R3 and R4 are each independently hydrogen or C1-6 alkyl, optionally substituted with one or more groups.

### Claim 8 (depends on 7)

The method of claim 7, wherein R3 and R4 are hydrogen.

### Claim 9 (depends on 1)

The method of claim 1, wherein R5 is independently —(CR5aR5b)m—R5c, where R5a and R5b are each independently (a) hydrogen, cyano, or nitro; or (b) C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C3-7cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; each optionally substituted with one or more substituents; R5c is hydrogen, —NR5dR5e, or heterocyclyl; R5d and R5e are each independently hydrogen or C1-6 alkyl; and m is an integer of 0, 1, 2, or 3; and where each alkyl and heterocyclyl is independently, optionally substituted with one or more groups.

### Claim 10 (depends on 9)

The method of claim 9, wherein R5a is hydrogen.

### Claim 11 (depends on 9)

The method of claim 9, wherein R5b is hydrogen.

### Claim 12 (depends on 9)

The method of claim 9, wherein R5c is hydrogen.

### Claim 13 (depends on 9)

The method of claim 9, wherein R5c is —NR5dR5e, and R5d and R5e are each independently hydrogen or C1-6 alkyl, optionally substituted with one or more groups.

### Claim 14 (depends on 13)

The method of claim 13, wherein R5d is hydrogen or methyl.

### Claim 15 (depends on 13)

The method of claim 13, wherein R5e is hydrogen or methyl.

### Claim 16 (depends on 9)

The method of claim 9, wherein R5c is amino, methylamino, or dimethylamino.

### Claim 17 (depends on 9)

The method of claim 9, wherein m is 1, 2, or 3.

### Claim 18 (depends on 1)

The method of claim 1, wherein R5 is independently methyl, ethenyl, dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, or pyrrolidinylethyl.

### Claim 19 (depends on 1)

The method of claim 1, wherein R6 is independently C1— alkyl, optionally substituted with one to three halo.

### Claim 20 (depends on 19)

The method of claim 19, wherein R6 is independently methyl, fluoromethyl, difluoromethyl, or trifluoromethyl.

### Claim 21 (depends on 1)

The method of claim 1, wherein Q is independently C3-7 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclene.

### Claim 22 (depends on 21)

The method of claim 21, wherein Q is independently cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, phenylene, azetidinylene, pyrrolidinylene, piperidinylene, piperazinylene, pyrrolylene, thiazolylylene, pyrazolylene, or pyridylene.

### Claim 23 (depends on 21)

The method of claim 21, wherein Q is independently 1,3-azetidinylene, 1,3-pyrrolidinylene, 1,3-piperidinylene, 1,4-piperidinylene, or 1,4-piperazinylene.

### Claim 24 (depends on 1)

The method of claim 1, wherein T1 is independently a bond or methylene.

### Claim 25 (depends on 1)

The method of claim 1, wherein T2 is independently —NR8—.

### Claim 26 (depends on 25)

The method of claim 25, wherein R8 is independently hydrogen or C1-6 alkyl.

### Claim 27 (depends on 26)

The method of claim 26, wherein R8 is independently hydrogen or methyl.

### Claim 28 (depends on 1)

The method of claim 1, wherein the compound is selected from the group consisting of:
2-(difluoromethyl)-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;
2-(difluoromethyl)-4-methoxy-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;
2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole;
({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)-N,N-dimethylmethylamine;
N-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-dimethylamine;
N-[3-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)propyl]-N,N-dimethylamine;
2-(difluoromethyl)-4-methoxy-1-(4-(4-morpholinyl)-6-{4-[(4-morpholinylmethyl)sulfonyl]-1-piperazinyl}-1,3,5-triazin-2-yl)-1H-benzimidazole;
2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(4-morpholinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;
2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[3-(4-morpholinyl)propyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;
N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}methanesulfonamide;
N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-methylmethanesulfonamide;
N-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-[1-(methylsulfonyl)-4-piperidinyl]amine;
N-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-methyl-N-[1-(methylsulfonyl)-4-piperidinyl]amine;
2-(difluoromethyl)-4-methoxy-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-6-ylamine;
2-(difluoromethyl)-4-methoxy-1-[4-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;
N-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperidinyl}sulfonyl)ethyl]-N,N-dimethylamine;
2-(difluoromethyl)-4-methoxy-1-[4-[1-(methylsulfonyl)-3-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;
2-(difluoromethyl)-4-methoxyl-[4-{[1-(methylsulfonyl)-4-piperidinyl]oxy}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;
N1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N3,N3-dimethyl-N′-[1-(methylsulfonyl)-3-piperidinyl]-1,3-propanediamine;
4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-3-piperidinyl]-6-(4-morpholinyl)-N-[3-(4-morpholinyl)propyl]-1,3,5-triazin-2-amine;
N1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N3,N3-dimethyl-N′-[1-(methylsulfonyl)-4-piperidinyl]-1,3-propanediamine;
4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-N-[3-(4-morpholinyl)propyl]-1,3,5-triazin-2-amine;
4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-{3-[4-(methylsulfonyl)-1-piperazinyl]propyl}-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;
N-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinyl}-N-[3-(dimethylamino)propyl]methanesulfonamide;
N-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-diethylamine;
2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(1-piperidinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;
N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-2-(dimethylamino)ethanesulfonamide;
N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-2-(dimethylamino)-N-methylethanesulfonamide;
N-{4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl}-2-(dimethylamino)ethanesulfonamide;
N-{4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl}-2-(dimethylamino)-N-methylethanesulfonamide;
N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}-2-(dimethylamino)ethanesulfonamide;
N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}-2-(dimethylamino)-N-methylethanesulfonamide;
trans-N-(4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}cyclohexyl)methanesulfonamide;
cis-N-(4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}cyclohexyl)methanesulfonamide;
N-[2-({4-[4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-dimethylamine;
N-[2-({4-[4-[6-amino-2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-dimethylamine;
2-(difluoromethyl)-4-methoxy-1-{4-[4-(methylsulfonyl)-1-piperazinyl]-6-tetrahydro-2H-pyran-4-yl-1,3,5-triazin-2-yl}-1H-benzimidazole;
4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N,N-dimethyl-1-piperazinesulfonamide;
1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N,N-dimethyl-4-piperidinesulfonamide;
1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-methyl-4-piperidinesulfonamide;
1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-[2-(dimethylamino)ethyl]-4-piperidinesulfonamide;
1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-methyl-3-pyrrolidinesulfonamide;
1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-[2-(dimethylamino)ethyl]-3-pyrrolidinesulfonamide;
N-(5-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-2-pyridinyl)methanesulfonamide;
N-(5-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-2-pyridinyl)-N-methylmethanesulfonamide;
4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;
3-{4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-[4-(methylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-8-oxa-3-azabicyclo[3.2.1]octane;
2-(difluoromethyl)-4-methoxy-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-2-pyrimidinyl]-1H-benzimidazole;
4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-3-azetidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;
4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[1-(methylsulfonyl)-3-azetidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;
N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}methanesulfonamide;
N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}-N-methylmethanesulfonamide;
4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[(3R)-1-(methylsulfonyl)pyrrolidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;
4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[(3R)-1-(methylsulfonyl)pyrrolidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;
4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[(3S)-1-(methylsulfonyl)pyrrolidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;
4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[(3S)-1-(methylsulfonyl)pyrrolidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;
N-{(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]pyrrolidinyl}methanesulfonamide;
N-{(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]pyrrolidinyl}-N-methylmethanesulfonamide;
N-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]pyrrolidinyl}methanesulfonamide;
N-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]pyrrolidinyl}-N-methylmethanesulfonamide;
4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[(3R)-1-(methylsulfonyl)piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;
4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[(3R)-1-(methylsulfonyl)piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;
4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[(3S)-1-(methylsulfonyl)piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;
4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[(3S)-1-(methylsulfonyl)piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;
N-{(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinyl}methanesulfonamide;
N-{(3R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinyl}-N-methylmethanesulfonamide;
N-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidinyl}methanesulfonamide;
N-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperndinyl}-N-methylmethanesulfonamide;
N-{2-[(4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]oxy}-1-piperidinyl)sulfonyl]ethyl}-N,N-dimethylamine;
2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[(1-{[2-(4-morpholinyl)ethyl]sulfonyl}-4-piperidinyl)oxy]-1,3,5-triazin-2-yl}-1H-benzimidazole;
N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-[3-(dimethylamino)propyl]-methanesulfonamide;
N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-[3-(4-morpholinyl)propyl]-methanesulfonamide;
2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(1-pyrrolidinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole;
3-[2-({4-[4-[2-(Difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-8-oxa-3-azabicyclo[3.2.1]octane;
2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole;
N-[3-({2-(difluoromethyl)-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-4-yl}oxy)propyl]-N,N-dimethylamine;
4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine;
2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-4-pyrimidinamine;
N-[3-({2-(difluoromethyl)-1-[4-{[1-(methylsulfonyl)-4-piperidinyl]oxy}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-4-yl}oxy)propyl]-N,N-dimethylamine;
and enantiomers, mixtures of enantiomers, or mixtures of two or more diastereomers thereof; and pharmaceutically acceptable salts, and prodrugs thereof.

### Claim 29 (depends on 1)

The method of claim 1, wherein the composition further comprises one or more pharmaceutically acceptable carriers.

### Claim 30 (depends on 29)

The method of claim 29, wherein the composition further comprises a second therapeutic agent.

### Claim 31 (depends on 29)

The method of claim 29, wherein the composition is formulated for single dose administration.

### Claim 32 (depends on 29)

The method of claim 29, wherein the composition is formulated as oral, parenteral, or intravenous dosage form.

### Claim 33 (depends on 32)

The method of claim 32, wherein the oral dosage form is a tablet or capsule.

### Claim 34 (depends on 1)

The method of claim 1, wherein the PI3K-mediated cancer is hemangiosarcoma.

### Claim 35 (depends on 1)

The method of claim 1, wherein the PI3K-mediated cancer is a mastocytosis.

### Claim 36 (depends on 1)

The method of claim 1, wherein the PI3K-mediated cancer is breast cancer.

### Claim 37 (depends on 1)

The method of claim 1, wherein the PI3K-mediated cancer is osteosarcoma.

### Claim 38 (depends on 1)

The method of claim 1, wherein the PI3K-mediated cancer is melanoma.

### Claim 39 (depends on 1)

The method of claim 1, wherein the PI3K-mediated cancer is lymphoma.

### Claim 40 (depends on 1)

The method of claim 1, wherein the PI3K-mediated cancer is renal cell carcinoma.

### Claim 41 (depends on 1)

The method of claim 1, wherein the PI3K-mediated cancer is astrocytoma.

### Claim 42 (depends on 1)

The method of claim 1, wherein the PI3K-mediated cancer is bladder cancer.

### Claim 43 (depends on 1)

The method of claim 1, wherein the PI3K-mediated cancer is non-small cell lung cancer.

### Claim 44 (depends on 1)

The method of claim 1, wherein the PI3K-mediated cancer is colon or rectal cancer.

### Claim 45 (depends on 1)

The method of claim 1, wherein the PI3K-mediated cancer is ovarian cancer.

### Claim 46 (depends on 1)

The method of claim 1, wherein the PI3K-mediated cancer is multiple myeloma.

### Claim 47 (depends on 1)

The method of claim 1, wherein the PI3K-mediated cancer is non-Hodgkin lymphoma.

### Claim 48 (depends on 1)

The method of claim 1, wherein the PI3K-mediated cancer is leukemia.

### Claim 49 (depends on 1)

The method of claim 1, wherein the PI13K-mediated cancer is promyelocytic leukemia.

### Claim 50 (depends on 1)

The method of claim 1, wherein the compound has the structure of Formula Ia, wherein:
R1 is independently hydrogen, methoxy, or dimethylamino propoxy;
R2 is independently hydrogen or amino;
R3 and R4 are hydrogen; or R3 and R4 are linked together to form ethylene;
R5 is independently methyl, ethenyl, dimethylaminomethyl, dimethylaminoethyl, or dimethylaminopropyl;
R6 is difluoromethyl;
Q is phenylene, optionally substituted with one or more substituents;
T1 is independently a bond, —O—, or —NR8—;
T2 is independently a bond or —NR8—, with the proviso that the atom is attached to —SO2R5 is nitrogen;
Each R8 is independently hydrogen or methyl; and
X, Y, and Z are each independently a nitrogen atom or CH, with the proviso that at least two of X, Y, and Z are nitrogen atoms.

### Claim 51 (depends on 50)

The method of claim 50, wherein T1 is a bond.

### Claim 52 (depends on 50)

The method of claim 50, wherein T2 is —NH—.

### Claim 53 (depends on 1)

The method of claim 1, wherein the compound is N-{4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl}-2-(dimethylamino)ethanesulfonamide.

### Claim 54 (depends on 1)

The method of claim 1, wherein the compound is N-{4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl}-2-(dimethylamino)-N-methylethanesulfonamide.

### Claim 55 (depends on 1)

The method of claim 1, wherein the compound is N-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperidinyl}sulfonyl)ethyl]-N,N-dimethylamine.

### Claim 56 (depends on 1)

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

### Claim 57 (depends on 1)

The method of claim 1, wherein the mammal is a dog or a cat.

### Claim 58 (depends on 1)

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