# US 6,911,446 B2 · Methods of modulating serine/threonine protein kinase function with quinazoline-based compounds

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- Number: US 6,911,446 B2
- Document ID: US6911446B2
- Status: Granted
- Kind: B2
- Application number: 09/769,360
- Filed: 2001-01-26
- Published: 2001-08-16
- Granted: 2005-06-28
- Earliest claimed: 1997-05-02
- Assignees: Sugen, Inc.
- Inventors: Peng C. Tang; Gerald McMahon; Heinz Weinberger; Bernhard Kutscher; Harald App
- Web page: https://patentgrep.com/patent/US6911446B2

## CPC

- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 239/84: Nitrogen atoms
- C07D 239/94: Nitrogen atoms
- C07D 239/95: with hetero atoms directly attached in positions 2 and 4
- G01N 33/573: for enzymes or isoenzymes
- G01N 33/5758: {involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites}
- G01N 2333/91215: with a definite EC number (2.7.1.-)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

The present invention is directed in part towards methods of modulating the function of serine/threonine protein kinases with quinazoline-based compounds. The methods incorporate cells that express a serine/threonine protein kinase, such as RAF. In addition, the invention describes methods of preventing and treating serine/threonine protein kinase-related abnormal conditions in organisms with a compound identified by the invention. Furthermore, the invention pertains to quinazoline compounds and pharmaceutical compositions comprising these compounds.

## Claims

### Claim 1

A method of modulating the function of a serine/threonine protein kinase with a quinazoline-based compound, comprising the step of contacting cells expressing said serine/threonine kinase with said compound, or a pharmaceutically acceptable salt thereof,
wherein said function of said serine/threonine protein kinase is related to a cancer selected from the group consisting of lung cancer, ovarian cancer, breast cancer, brain cancer, intra-axial brain cancer, colon cancer, prostate cancer, Kaposi's sarcoma, melanoma, and glioma; and
wherein said compound has the formula set forth in formula I or III:
wherein:
(a) Z is oxygen, NX1, or sulfur, where X1 is selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and five-membered or six-membered heteroaryl or six-membered aryl ring moieties;
(b) n is 0, 1, 2, 3, or 4;
(c) A2, A3, A4 and A5 are independently selected from the group consisting of carbon, nitrogen, oxygen, and sulfur,
provided that if any of A2, A3, A4 and A5 is nitrogen, oxygen, or sulfur, said A2, A3, A4 and A5 is not substituted with R6, R7, R8 or R9;
A1 is nitrogen or carbon;
(d) R1, R2, R3, R4, R5, R6, R7, R8 and R9 are independently selected from the group consisting of:
(i) hydrogen;
(ii) saturated or unsaturated alkyl;
(iii) NX2X3, where X2 and X3 are independently selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and five-membered or six-membered heteroaryl or six-membered aryl ring moieties;
(iv) halogen or trihalomethyl;
(v) a ketone of formula —CO—X4, where X4 is selected from the group consisting of hydrogen, alkyl, and five-membered or six-membered heteroaryl or six-membered aryl ring moieties;
(vi) a carboxylic acid of formula —(X5)n5—COOH or ester of formula —(X6)n6—COOX7, where X5, X6, and X7 and are independently selected from the group consisting of alkyl and five-membered or six-membered heteroaryl or six-membered aryl ring moieties and where n5 and n6 are each independently 0 or 1;
(vii) an alcohol of formula —(X8)n8—OH or an alkoxy moiety of formula —(X8)n8—OX9, where X8 and X9 are independently selected from the group consisting of alkyl and five-membered or six-membered heteroaryl or six-membered aryl ring moieties and where n8 is 0 or 1, and where said ring moieties are optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, trihalomethyl, carboxylate, and ester;
(viii) —NHCOX10, where X10 is selected from the group consisting of alkyl, hydroxyl, and five-membered or six-membered heteroaryl or six-membered aryl ring moieties, wherein said ring moieties are optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, trihalomethyl, carboxylate, and ester;
(ix) —SO2NX11X12, where X11 and X12 are selected from the group consisting of hydrogen, alkyl, and five-membered or six-membered heteroaryl or six-membered aryl ring moieties; and
(x) a five-membered or six-membered heteroaryl or six-membered aryl ring moiety optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, trihalomethyl, carboxylate, and ester moieties;
(e) any adjacent R3, R4, and R5 or any adjacent R6, R7, R8, and R9 are fused together to form a five-membered or six-membered heteroaryl or six-membered aryl ring moiety, wherein said five-membered or six-membered heteroaryl or six-membered aryl ring comprises two carbon atoms of said quinazoline-based compound to which R3, R4, and R5 or R6, R7, R8, and R9 are attached; and
(f) R11 and R12 are independently selected from the group consisting of
(i) hydrogen;
(ii) saturated or unsaturated alkyl; and
(g) Z′ is carbon or nitrogen and R13 and R14 taken together form a five-membered or six-membered heteroaryl ring with Z′ as a ring member.

### Claim 2

A method of modulating the function of a serine/threonine protein kinase with a quinazoline-based compound, comprising the step of contacting cells expressing said serine/threonine kinase with said compound, or a pharmaceutically acceptable salt thereof,
wherein said function of said serine/threonine protein kinase is related to a cancer selected from the group consisting of lung cancer, ovarian cancer, breast cancer, brain cancer, intra-axial brain cancer, colon cancer, prostate cancer, Kaposi's sarcoma, melanoma, and glioma; and
wherein said compound has the formula set forth in formula I or III:
wherein:
(a) Z is oxygen, NX1, or sulfur, where X1 is selected from the group consisting of hydrogen and saturated or unsaturated alkyl;
(b) n is 0, 1 or 2;
(c) A2, A3, A4 and A5 are independently selected from the group consisting of carbon, nitrogen, oxygen, and sulfur,
provided that if any of A2, A3, A4 and A5 is nitrogen, oxygen, or sulfur, said A2, A3, A4 and A5 is not substituted with R6, R7, R8 or R9;
A1 is carbon or nitrogen;
(d) R1 and R2 are independently selected from the group consisting of:
(i) hydrogen;
(ii) saturated or unsaturated alkyl;
(iii) NX2X3, where X2 and X3 are independently selected from the group consisting of hydrogen and saturated or unsaturated alkyl;
(iv) halogen or trihalomethyl; and
(v) five-membered or six-membered heteroaryl ring moiety;
(e) R3, R4, R5, R6, R7, R8 and R9 are independently selected from the group consisting of:
(i) hydrogen;
(ii) saturated or unsaturated alkyl;
(iii) NX4X5, where X4 and X5 are independently selected from the group consisting of hydrogen and saturated or unsaturated alkyl; and
(iv) halogen or trihalomethyl;
(v) —OX7, where X7 is selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and a six-membered aryl or five- or six-membered heteroaryl ring moiety;
(f) any adjacent R3, R4, and R5 or any adjacent R6, R7, R8 and R9 are fused together to form a five-membered or six-membered heteroaryl or six-membered aryl ring moiety, wherein said five-membered or six-membered heteroaryl or six-membered aryl ring comprises two carbon atoms of said quinazoline-based compound to which R3, R4, and R5 or R6, R7, R8, and R9 are attached;
(g) R11 and R12 are independently selected from the group consisting of
(i) hydrogen;
(ii) saturated or unsaturated alkyl; and
(h) Z′ is nitrogen and R13 and R14 taken together form a five-membered or six-membered heteroaryl ring with Z′ as a ring member, wherein said ring is optionally substituted with one, two, or three alkyl, halogen, trihalomethyl, carboxylate, and ester moieties.

### Claim 3

A method of treating an abnormal condition in an organism in need thereof, wherein said abnormal condition is a disease associated with an aberration in a signal transduction pathway characterized by an interaction between a serine/threonine protein kinase and a natural binding partner, and wherein said disease is selected from the group consisting of lung cancer, ovarian cancer, breast cancer, brain cancer, intra-axial brain cancer, colon cancer, prostate cancer, Kaposi's sarcoma, melanoma, and glioma;
said method comprising the step of administering a quinazoline-based compound of formula I or III to said organism:
wherein:
(a) Z is oxygen, NX1, or sulfur, where X1 is selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and five-membered or six-membered heteroaryl or six-membered aryl ring moieties;
(b) n is 0, 1, 2, 3, or 4;
(c) A2, A3, A4 and A5 are independently selected from the group consisting of carbon, nitrogen, oxygen, and sulfur,
provided that if any of A2, A3, A4 and A5 is nitrogen, oxygen, or sulfur, said A2, A3, A4 and A5 is not substituted with R6, R7, R8 or R9;
A1 is carbon or nitrogen;
(d) R1, R2, R3, R4, R5, R6, R7, R8 and R9 are independently selected from the group consisting of:
(i) hydrogen;
(ii) saturated or unsaturated alkyl;
(iii) NX2X3, where X2 and X3 are independently selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and five-membered or six-membered heteroaryl or six-membered aryl ring moieties;
(iv) halogen or trihalomethyl;
(v) a ketone of formula —CO—X4, where X4 is selected from the group consisting of hydrogen, alkyl, and five-membered or six-membered heteroaryl or six-membered aryl ring moieties;
(vi) a carboxylic acid of formula —(X5)n5—COOH or ester of formula —(X6)n6—COOX7, where X5, X6, and X7 and are independently selected from the group consisting of alkyl and five-membered or six-membered heteroaryl or six-membered aryl ring moieties and where n5 and n6 are each independently 0 or 1;
(vii) an alcohol of formula —(X8)n8—OH or an alkoxy moiety of formula —(X8)n8—OX9, where X8 and X9 are independently selected from the group consisting of alkyl and five-membered or six-membered heteroaryl or six-membered aryl ring moieties and where n8 is 0 or 1, and where said ring moieties are optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, trihalomethyl, carboxylate, and ester;
(viii) —NHCOX10, where X10 is selected from the group consisting of alkyl, hydroxyl, and five-membered or six-membered heteroaryl or six-membered aryl ring moieties, wherein said ring moieties are optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, trihalomethyl, carboxylate, and ester;
(ix) —SO2NX11X12, where X11 and X12 are selected from the group consisting of hydrogen, alkyl, and five-membered or six-membered heteroaryl or six-membered aryl ring moieties; and
(x) a five-membered or six-membered heteroaryl or six-membered aryl ring moiety optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, trihalomethyl, carboxylate, and ester moieties;
(e) any adjacent R3, R4, and R5 or any adjacent R6, R7, R8, and R9 are fused together to form a five-membered or six-membered heteroaryl or six-membered aryl ring moiety, wherein said five-membered or six-membered heteroaryl or six-membered aryl ring comprises two carbon atoms of said quinazoline-based compound to which R3, R4, and R5 or R6, R7, R8, and R9 are attached;
(f) R11 and R12 are independently selected from the group consisting of
(i) hydrogen;
(ii) saturated or unsaturated alkyl; and
(g) Z′ is carbon or nitrogen and R13 and R14 taken together form a five-membered or six-membered heteroaryl ring with Z′ as a ring member.

### Claim 4 (depends on 3)

The method of claim 3, wherein said organism is a mammal.

### Claim 5 (depends on 3)

The method of claim 3, wherein said serine/threonine protein kinase is RAF.

### Claim 6

A method of modulating the function of a serine/threonine protein kinase with a quinazoline-based compound, comprising the step of contacting cells expressing said serine/threonine kinase with said compound, or a pharmaceutically acceptable salt thereof,
wherein said function of said serine/threonine protein kinase is related to a cancer selected from the group consisting of lung cancer, ovarian cancer, breast cancer, brain cancer, intra-axial brain cancer, colon cancer, prostate cancer, Kaposi's sarcoma, melanoma, and glioma; and
wherein said compound has the formula set forth in formula V:
wherein:
(a) R1 and R2 are independently selected from the group consisting of:
(i) hydrogen; and
(ii) NX2X3, where X2 and X3 are independently selected from the group consisting of hydrogen and saturated or unsaturated alkyl;
(b) R3, R4, and R5 are independently selected from the group consisting of:
(i) hydrogen;
(ii) saturated or unsaturated alkyl; and
(iii) NX2X3, where X2 and X3 are independently selected from the group consisting of hydrogen and saturated or unsaturated alkyl; and
(c) Z′ is nitrogen and R13 and R14 taken together form a five-membered heteroaryl ring.

### Claim 7

A method of modulating the function of a serine/threonine protein kinase with a quinazoline-based compound, comprising the step of contacting cells expressing said serine/threonine kinase with said compound, or a pharmaceutically acceptable salt thereof,
wherein said function of said serine/threonine protein kinase is related to a cancer selected from the group consisting of lung cancer, ovarian cancer, breast cancer, brain cancer, intra-axial brain cancer, colon cancer, prostate cancer, Kaposi's sarcoma, melanoma, and glioma; and
wherein said quinazoline-based compound has a structure set forth in formula X:
wherein
(a) R1 and R2 are independently selected from the group consisting of hydrogen, and —NH2, provided at least one of R1 and R2 is —NH2;
(b) R3, R4, R5, and R6 are independently selected from the group consisting of
(i) hydrogen;
(ii) saturated or unsaturated alkyl;
(iii) NX4X5, where X4 and X5 are independently selected from the group consisting of hydrogen and saturated or unsaturated alkyl;
(iv) halogen;
(v) C(X6)3, where X6 is selected from the group consisting of fluorine, chlorine, bromine, and iodine; and
(vi) OX7, where X7 is selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and six-membered aryl or five- or six-membered heteroaryl ring moiety.

### Claim 8

A method of treating an abnormal condition in an organism in need thereof, wherein said abnormal condition is a disease associated with an aberration in a signal transduction pathway characterized by an interaction between a serine/threonine protein kinase and a natural binding partner, and wherein said disease is selected from the group consisting of lung cancer, ovarian cancer, breast cancer, brain cancer, intra-axial brain cancer, colon cancer, prostate cancer, Kaposi's sarcoma, melanoma, and glioma;
said method comprising the step of administering a quinazoline-based compound of formula X:
wherein
(a) R1 and R2 are independently selected from the group consisting of hydrogen and —NH2, provided at least one of R1 and R2 is —NH2;
(b) R3, R4, R5, and R6 are independently selected from the group consisting of
(i) hydrogen;
(ii) saturated or unsaturated alkyl;
(iii) NX4X5, where X4 and X5 are independently selected from the group consisting of hydrogen and saturated or unsaturated alkyl;
(iv) halogen;
(v) C(X6)3, where X6 is selected from the group consisting of fluorine, chlorine, bromine, and iodine; and
(vi) OX7, where X7 is selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and a six-membered aryl or five- or six-membered heteroaryl ring moiety.

### Claim 9

A quinazoline compound having the formula I or III:
wherein:
(i) Z is oxygen, NX1, or sulfur, where X1 is selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and five-membered or six-membered heteroaryl or six-membered aryl ring moieties;
(ii) n is 0, 1, 2, 3, or 4;
(iii) A2, A3, A4 and A5 are independently selected from the group consisting of carbon, nitrogen, oxygen, and sulfur,
provided that if any of A2, A3, A4 and A5 is nitrogen, oxygen, or sulfur, said A2, A3, A4 and A5 is not substituted with R6, R7, R8 or R9;
A1 is carbon or nitrogen;
(iv) R1 and R2 are independently selected from the group consisting of:
(a) hydrogen;
(b) saturated or unsaturated alkyl;
(c) NX2X3, where X2 and X3 are independently selected from the group consisting of hydrogen and saturated or unsaturated alkyl;
(d) halogen or trihalomethyl; and
(e) five-membered or six-membered heteroaryl ring moiety;
(v) R3, R4, R5, R6, R7, R8 and R9 are independently selected from the group consisting of:
(a) hydrogen, provided that at least one of R3, R4, R5, R6, R7, R8, and R9, is a non-hydrogen moiety if R2 is —NH2;
(b) saturated or unsaturated alkyl, wherein said R6 is not methyl when R2 is —NH2 and when n=1;
(c) NX13X14, where X13 and X14 are independently selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and six-membered aryl or heteroaryl ring moieties;
(d) halogen or trihalomethyl, wherein said R8 is not chlorine or fluorine when R2 is —NH2 and when n=1;
(e) a ketone of formula —CO—X4, where X4 is selected from the group consisting of hydrogen, alkyl, and five-membered or six-membered heteroaryl or six-membered aryl ring moieties;
(f) a carboxylic acid of formula —(X5)n5—COOH or ester of formula —(X6)n6—COOX7, where X5, X6, and X7 and are independently selected from the group consisting of alkyl and five-membered or six-membered heteroaryl or six-membered aryl ring moieties and where n5 and n6 are each independently 0 or 1;
(g) an alcohol of formula —(X8)n8—OH or an alkoxy moiety of formula —(X8)n8—OX9, where X8 and X9 are independently selected from the group consisting of a alkyl and five-membered or six-membered heteroaryl or six-membered aryl ring moieties and where n8 is 0 or 1, and where said ring moieties are optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, trihalomethyl, carboxylate, and ester;
(h) —NHCOX10, where X10 is selected from the group consisting of alkyl, hydroxyl, and five-membered or six-membered heteroaryl or six-member aryl ring moieties, wherein said ring moieties are optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, trihalomethyl, carboxylate, and ester;
(i) —SO2NX11X12, where X11 and X12 are selected from the group consisting of hydrogen, alkyl, and five-membered or six-membered heteroaryl or six-membered aryl ring moieties; and
(j) a five-membered or six-membered heteroaryl or six-membered aryl ring moiety optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, trihalomethyl, carboxylate, and ester moieties;
(vi) any adjacent R3, R4, and R5 or any adjacent R6, R7, R8, and R9 are fused together to form a five-membered or six-membered heteroaryl or six-membered aryl ring moiety, wherein said five-membered or six-membered heteroaryl or six-membered aryl ring comprises two carbon atoms of said quinazoline compound to which R3, R4, and R5 or R6, R7, R8, and R9 are attached;
(vii) R11 and R12 are independently selected from the group consisting of
(i) hydrogen;
(ii) saturated or unsaturated alkyl; and
(viii) Z′ is carbon or nitrogen and R13 and R14 taken together form a five-membered or six-membered heteroaryl ring with Z′ as a ring member;
with the proviso that the compound of formula (III) is not

### Claim 10

A quinazoline compound having the form I or III:
wherein:
(a) Z is oxygen, NX1, or sulfur, where X1 is selected from the group consisting of hydrogen and saturated or unsaturated alkyl;
(b) n is 0, 1, or 2;
(c) A2, A3, A4 and A5 are independently selected from the group consisting of carbon, nitrogen, oxygen, and sulfur,
provided that if any of A2, A3, A4 and A5 is nitrogen, oxygen, or sulfur, said A2, A3, A4 and A5 is not substituted with R6, R7, R8 or R9;
A1 is carbon or nitrogen;
(d) R1 and R2 are independently selected from the group consisting of:
(i) hydrogen;
(ii) saturated or unsaturated alkyl;
(iii) NX2X3, where X2 and X3 are independently selected from the group consisting of hydrogen and saturated or unsaturated alkyl;
(iv) halogen or trihalomethyl; and
(v) five-membered or six-membered heteroaryl ring moiety;
(e) R3, R4, R5, R6, R7, R8 and R9 are independently selected from the group consisting of:
(i) hydrogen, provided that at least one of R3, R4, R5, R6, R7, R8, and R9, is a non-hydrogen moiety if R2 is —NH2;
(ii) saturated or unsaturated alkyl, wherein said R6 is not methyl when R2 is —NH2 and when n=1;
(iii) NX4X5, where X4 and X5 are independently selected from the group consisting of hydrogen and saturated or unsaturated alkyl;
(iv) halogen or trihalomethyl, wherein said R8 is not chlorine or fluorine when R2 is —NH2 and when n=1; and
(v) —OX7, where X7 is selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and six-membered aryl or five- or six-membered heteroaryl ring moiety;
(f) any adjacent R3, R4, and R5 or any adjacent R6, R7, R8 and R9 are fused together to form a five-membered or six-membered heteroaryl or six-membered aryl ring moiety, wherein said five-membered or six-membered aryl or six-membered heteroaryl ring comprises two carbon atoms of said quinazoline compound to which R3, R4, and R5 or R6, R7, R8, and R9 are attached;
(g) R11 and R12 are independently selected from the group consisting of
(i) hydrogen; and
(ii) saturated or unsaturated alkyl; and
(h) Z′ is nitrogen and R13 and R14 taken together form a five-membered or six-membered heteroaryl ring with Z′ as a ring member, wherein said ring is optionally substituted with one, two, or three alkyl, halogen, trihalomethyl, carboxylate, and ester moieties;
with the proviso that the compound of formula (III) is not

### Claim 11

A quinazoline compound having the structure set forth in formula V:
wherein:
(a) R1 and R2 are independently selected from the group consisting of:
(i) hydrogen;
(ii) NX1X2, where X1 and X2 are independently selected from the group consisting of hydrogen and saturated or unsaturated alkyl; and
(iii) benzyl;
(b) R3, R4, and R5 are independently selected from the group consisting of:
(i) hydrogen;
(ii) saturated or unsaturated alkyl; and
(iii) NX3X4, where X3 and X4 are independently selected from the group consisting of hydrogen and saturated or unsaturated alkyl;
(c) Z′ is nitrogen and R13 and R14 taken together form a five-membered heteroaryl ring;
with the proviso that the compound of formula (V) is not

### Claim 12

A quinazoline compound having a structure set forth in formula X:
wherein
(a) R1 and R2 are independently selected from the group consisting of by hydrogen and —NH2, provided at least one of R1 and R2 is —NH2;
(b) R3, R4, R5, and R6 are independently selected from the group consisting of
(i) hydrogen;
(ii) saturated or unsaturated alkyl;
(iii) NX4X5, where X4 and X5 are independently selected from the group consisting of hydrogen and saturated or unsaturated alkyl;
(iv) halogen;
(v) C(X6)3, where X6 is selected from the group consisting of fluorine, chlorine, bromine, and iodine; and
(vi) OX7, where X7 is selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and a six-membered aryl or five- or six-membered heteroaryl ring moiety;
with the proviso that the compound of formula (X) is not

### Claim 13 (depends on 9, 10)

A pharmaceutical composition comprising a quinazoline compound of any one of claims 9, 10, or 12 or salt thereof, and a physiologically acceptable carrier or diluent.

### Claim 14 (depends on 9)

A method for synthesizing a compound of claim 9, comprising the steps of:
(a) reacting a first reactant with a second reactant to yield said compound, wherein said first reactant has a structure of formula XI:
and wherein said second reactant has a structure of formula (XII):
wherein,
(a) Z is oxygen or sulfur;
(b) n is 0, 1, 2, 3, or 4;
(c) A2, A3, A4, and A5 are independently selected from the group consisting of carbon, nitrogen, oxygen, and sulfur,
provided that if any of A2, A3, A4 and A5 is nitrogen, oxygen, or sulfur, said A2, A3, A4 and A5 is not substituted with R6, R7, R8 or R9;
A1 is carbon or nitrogen;
(d) R1 and R2 are independently selected from the group consisting of:
(i) hydrogen;
(ii) saturated or unsaturated alkyl;
(iii) NX2X3, where X2 and X3 are independently selected from the group consisting of hydrogen and saturated or unsaturated alkyl;
(iv) halogen or trihalomethyl; and
(v) five-membered or six-membered heteroaryl ring moiety;
(e) R3, R4, R5, R6, R7, R8, and R9 are independently selected from the group consisting of:
(i) hydrogen, provided that at least one of R3, R4, R5, R6, R7, R8, and R9 is a non-hydrogen moiety if R2 is —NH2;
(ii) saturated or unsaturated alkyl, wherein said R6 is not methyl when R2 is —NH2 and when n=1;
(iii) NX13X14, where X13 and X14 are independently selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and six-membered aryl or heteroaryl ring moieties;
(iv) halogen or trihalomethyl, wherein said R8 is not chlorine or fluorine when R2 is —NH2 and when n=1;
(v) a ketone of formula —CO—X4, where X4 is selected from the group consisting of hydrogen, alkyl, and five-membered or six-membered heteroaryl or six-membered aryl ring moieties;
(vi) a carboxylic acid of formula —(X5)n5—COOH or ester of formula —(X6)n6—COOX7, where X5, X6, and X7 and are independently selected from the group consisting of alkyl and five-membered or six-membered heteroaryl or six-membered aryl ring moieties and where n5 and n6 are 0 or 1;
(vii) an alcohol of formula —(X8)n8—OH or an alkoxy moiety of formula —(X8)n8—OX9, where X8 and X9 are independently selected from the group consisting of alkyl and five-membered or six-membered heteroaryl or six-membered aryl ring moieties and where n8 is 0 or 1, and where said ring moieties are optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, trihalomethyl, carboxylate, and ester;
(viii) —NHCOX10, where X10 is selected from the group consisting of alkyl, hydroxyl, and five-membered or six-membered heteroaryl or six-membered aryl ring moieties, wherein said ring moieties are optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, trihalomethyl, carboxylate, and ester;
(ix) —SO2NX11X12, where X11 and X12 are selected from the group consisting of hydrogen, alkyl, and five-membered or six-membered heteroaryl or six-membered aryl ring moieties; and
(x) a five-membered or six-membered heteroaryl or six-membered aryl ring moiety optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, trihalomethyl, carboxylate, and ester moieties;
(f) any adjacent R3, R4, and R5 or any adjacent R6, R7, R8, and R9 are fused together to form a five-membered or six-membered heteroaryl or six-membered aryl ring moiety wherein said five-membered or six-membered heteroaryl or six-membered aryl ring comprises two carbon atoms of the ring to which R3, R4, and R5 or R6, R7, R8, and R9 are attached;
(g) R11 and R12 are independently selected from the group consisting of
(i) hydrogen; and
(ii) saturated or unsaturated alkyl; and
(b) collecting a precipitate comprising said compound.

### Claim 15 (depends on 14)

The method of claim 14, wherein said first reactant and said second reactant are mixed in one or more solvents selected from the group consisting of dimethyl sulfoxide, potassium tert-butoxide, and sodium hydride.

### Claim 16 (depends on 14)

The method of claim 14, wherein said ZH moiety is isothiocyanate.

### Claim 17 (depends on 16)

The method of claim 16, wherein said first reactant and said second reactant are mixed in dichloromethane.