SUBSTITUTED-(QUINAZOLINYL)PHENYL THIOPHENYL-SULFONYLUREAS, METHODS FOR MAKING AND INTERMEDIATES THEREOF

1 . A process for preparing compound of formula VIII:

or a pharmaceutically acceptable salt, hydrate or solvate derivative thereof wherein

each X 1 is independently selected from the group consisting of:

halogen, polyhaloalkyl, —OR 3 , —SR 3 , —CN, —NO 2 , —SO 2 R 3 , —C 1-10 -alkyl, —C 3-8 -cycloalkyl, aryl, aryl-substituted by 1-4 R 3 groups, amino, amino-C 1-8 -alkyl, C 1-3 -acylamino, C 1-3 -acylamino-C 1-8 -alkyl, C 1-6 -alkylamino, C 1-6 -alkylamino C 1-8 alkyl, C 1-6 dialkylamino, C 1-6 dialkylamino C 1-8 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 -alkyl, carboxy-C 1-6 -alkyl, C 1-3 -alkoxycarbonyl, C 1-3 -alkoxycarbonyl-C 1-6 -alkyl, carboxy C 1-6 alkyloxy, hydroxy, hydroxy C 1-6 alkyl, and a 5 to 10 membered fused or non-fused aromatic or nonaromatic heterocyclic ring system, having 1 to 4 heteroatoms independently selected from N, O, and S, with the proviso that the carbon and nitrogen atoms, when present in the heterocyclic ring system, are unsubstituted, mono- or di-substituted independently with 0-2 R 4 groups;

each X 2 is independently selected from the group consisting of C 1-6 -alkoxy, C 1-6 -alkyl, C 1-6 -alkylamino, hydroxy, halogen, cyano, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxyl, carbo-C 1-6 -alkoxy and carboxamide;

each R 1 is selected from the group consisting of —OR 3 , —SR 3 , —CN, amino, C 1-6 -alkylamino and C 1-6 dialkylamino;

each R 3 and R 4 are independently selected from the group consisting of:

hydrogen, halogen, —CN, —NO 2 , —C 1-10 -alkyl, C 3-8 -cycloalkyl, aryl, amino, amino-C 1-8 -alkyl, C 1-3 -acylamino, C 1-3 -acylamino-C 1-8 -alkyl, C 1-6 -alkylamino, C 1-6 -alkylamino C 1-8 alkyl, C 1-6 dialkylamino, C 1-6 dialkylamino C 1-8 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 -alkyl, carboxy-C 1-6 -alkyl, C 1-3 -alkoxycarbonyl, C 1-3 -alkoxycarbonyl-C 1-6 alkyl, carboxy-C 1-6 -alkyloxy, hydroxy, hydroxy-C 1-6 -alkyl, -thio and thio-C 1-6 -alkyl;

each L 1 is independently a leaving group;

A is thienyl optionally substituted with one, two or three substituents independently selected from the group consisting of C 1-6 -alkoxy, C 1-6 -alkyl, C 1-6 -alkylamino, hydroxy, halogen, cyano, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxyl, carbo-C 1-6 -alkoxy and carboxamide;

n is 0, 1, 2, 3 or 4, m is 0, 1, 2 or 3; o is 0, 1, 2, 3 or 4; and the sum of n+m+o is at most 4; and

p is 0, 1, 2, 3 or 4;

comprising the steps of:

(a) acylating the amino group of a compound of formula I with a compound of formula II to produce a compound of formula III as follows:

wherein each L 2, L 3 and L 4 are independently a leaving group;

(b) reacting the compound of formula III, with an amine containing compound IV, to produce a cyclized quinazoline derivative of formula V as follows:

wherein Q is a protecting group;

(c) optionally replacing a group L 1 of formula V, with a group R 1 by reacting the compound of formula R 1 H to provide a compound of formula VIII as follows:

wherein the subscript m is increased and the subscript o is decreased by the number of L 1 groups replaced in VI;

(d) reacting the compound of formula V or VI with a compound of the formula VIII to provide a compound of formula VIII, as follows:

(e) optionally, producing a salt, solvate or hydrate of the compound of formula VIII:

wherein M is selected from the group consisting of Na and K.

2 . The process of claim 1 for preparing compound of formula XVIII:

wherein

R 1 is selected from the group consisting of H, halogen, —OH, —O—C 1-10 -alkyl, amino and C 1-6 -alkylamino;

R 2 is halogen or —O—C 1-10 -alkyl;

X 1 is halogen, and

all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof, comprising the steps of:

(a) acylating the amino group of a compound of formula XI with a compound of formula XII under basic acylation conditions in the presence of an appropriate solvent to produce a compound of formula XIII as follows:

wherein each L 1 , L 2 and L 3 are independently a leaving group; and each R 5 is an electron withdrawing group and the subscript q is 0, 1, 2, 3, or 4;

(b) reacting the compound of formula III, with an amine containing compound XIV, in the presence of a basic catalyst and a solvent at a suitable temperature to produce a cyclized quinazoline derivative of formula XV, as follows:

wherein Q is a protecting group;

(c) replacing the leaving group L 1 of the compound of formula XV with R 1 by reacting the compound of formula R 1 H to provide a compound of formula XVI as follows:

(d) reacting the compound of formula XVI with a compound of the formula XVII to provide a compound of formula XVIII as follows:

(e) and optionally, producing a salt, solvate, or hydrate of the compound of formula XVIII:

wherein M is Na or K.

3 . The process according to claim 2 wherein the amine compound in step (b) is 4-nitro-aniline.

4 . The process according to claim 2 wherein the protecting group Q is selected from the group consisting of Ac, t-BOC and CBZ

5 . The process according to claim 2 wherein step (e) is done with a base selected from the group consisting of potassium carbonate, sodium carbonate, potassium hydroxide and sodium hydroxide.

6 . The process according to claim 2 wherein step (c) further comprises DMSO as a solvent.

7 . The process according to claim 2 wherein step (c) is conducted at a temperature of about 100° C. to about 120° C.

8 . The process according to claim 2 wherein step (d) is conducted at a temperature of about 55° C. to about 75° C.

9 . The process according to claim 2 which is a process for making a compound according to formula XXVIII:

and all pharmaceutically acceptable salt, hydrate and solvate derivatives thereof.

10 . A compound of the formula:

wherein

X 1 is halogen;

wherein each L 1 and L 2 are independently a leaving group; and each R 5 is an electron withdrawing group and the subscript q is 0, 1, 2, 3, or 4.

11 . A compound having the formula:

wherein

X 1 is halogen; and

L 1 is a leaving group.

12 . A compound having the formula:

wherein

R 1 is selected from the group consisting of H, halogen, —OH, —O—C 1-10 -alkyl and C 1-6 -alkylamino; and

X 1 is halogen.

13 . A process for preparing compound of formula XIII comprising acylating the amino group of a compound of formula XI with a compound of formula XII under basic acylation conditions in the presence of an appropriate solvent to produce a compound of formula XIII as follows:

wherein

X 1 is halogen;

wherein each L 1 , L and L 3 are independently a leaving group; and each R 5 is an electron withdrawing group and the subscript q is 0, 1, 2, 3, or 4.

14 . A process for preparing compound of formula XV comprising reacting the compound of formula XIII, with an amine containing compound XIV, to produce a cyclized quinazoline derivative of formula XV as follows:

wherein

X 1 is halogen;

wherein each L 1 and L 2 are independently a leaving group; and each R 5 is an electron withdrawing group and the subscript q is 0, 1, 2, 3, or 4; and

Q is a protecting group.

15 . A process for preparing compound of formula XVI comprising replacing the leaving group L 1 of the compound of formula XV with R 1 by reacting the compound of formula R 1 H to provide a compound of formula XVIII, as follows:

wherein

R 1 is selected from the group consisting of H, halogen, —OH, —O—C 1-10 -alkyl, amino and C 1-6 -alkylamino;

X 1 is halogen; and

L 1 is a leaving group.

16 . A process for preparing compound of formula XVIII comprising reacting the compound of formula XVI with a compound of the formula XVII to provide a compound of formula XVIII as follows:

wherein

R 1 is selected from the group consisting of H, halogen, —OH, —O—C 1-10 -alkyl and C 1-6 -alkylamino;

X 1 is halogen;

wherein L 3 is a leaving group; and

R 2 is halogen or —O—C 1-10 -alkyl.

17 . A process for preparing compound having the formula XIX comprising producing a salt, solvate, hydrate or prodrug of the compound of formula XVIII:

wherein

R 1 is selected from the group consisting of H, halogen, —OH, —O—C 1-10 -alkyl and C 1-6 -alkylamino;

X 1 is halogen;

R 2 is halogen or —O—C 1-10 -alkyl;

M is selected from the group consisting of Na and K.

18 . The process of claim 1 which is a process for making a compound of formula XXVIII:

wherein

R 1 is selected from the group consisting of H, halogen, —OH, —O—C 1-10 -alkyl and C 1-6 -alkylamino;

R 2 is halogen or —O—C 1-10 -alkyl; and

X 1 is halogen

19 . The process of claim 1 which is a process for making a compound of formula XXXVIII:

20 . The process of claim 1 wherein X 1 is —F.

21 . The process of claim 1 wherein R 1 is a member selected from the group consisting of —OH, NH 2 and —NH(—C 1-6 alkyl).

22 . The process of claim 1 wherein R 1 is —NHCH 3 .

23 . The process of claim 1 wherein R 2 is chloro.

24 . The process of claim 1 wherein each leaving group L 1 and L 3 are independently selected from the group consisting of halogen, alkylsulfonate, haloalkylsulfonate and arylsulfonate.

25 . The process of claim 1 wherein each R 5 is independently NO 2 or halogen.

26 . The process of claim 1 wherein the leaving group L 2 is C 1 -C 10 alkoxy.

27 . The compound of claim 10 wherein X 1 is —F.

28 . The compound of claim 10 wherein R 1 is a member selected from the group consisting of —OH, NH 2 and —NH(—C 1-6 alkyl).

29 . The compound of claim 10 wherein R 1 is —NHCH 3 .

30 . The compound according to claim 10 wherein each leaving group L 1 is selected from the group consisting of halogen, alkylsulfonate, haloalkylsulfonate and arylsulfonate.

31 . The compound according to claim 10 wherein each R 5 is selected from the group consisting of NO 2 and halogen.

32 . The compound according to claim 10 wherein the leaving group L 2 is C 1 -C 10 alkoxy.