ES2349170T3 - 4-ANILINOQUINOLINA-3-CARBOXAMIDAS AS INHIBITORS OF THE CSF-1R CINASA. - Google Patents

Abstract

A compound of the formula IA or IB: or one of its pharmaceutically acceptable salts, in which: it is a 3-10 membered heterocycle or heteroaryl, attached by nitrogen; wherein if said heterocycle or heteroaryl contains a -NH- moiety, this nitrogen may be optionally substituted with a group selected from R5; R1 at each occurrence is independently halo, hydroxy, nitro, formyl, cyano, -CO2H, -SH, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy, -OC (O) -alkyl (C1-C6), -C (O) -alkyl (C1-C6), -CO2-alkyl (C1-C6), -NR'R ", - NR'-C (O) -alkyl (C1-C6), alkyl (C1-C6) S (O) a- where a is 0 to 2, -NR'-C (O) -Oalkyl (C1-C6), -NR'-SO2-(C1-C6) alkyl, -NR'-C (O) NR'R ", -SO2-NR'R", -C (O) -NR'R ", carbocyclyl, heterocycle, heteroaryl or oxo; R2 is hydrogen, halo, hydroxy, nitro, formyl, -CO2H, -SH, cyano, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C6) cycloalkyl, -O -C3-C6-cycloalkyl, -OC (O) -C1-C6-alkyl, -C (O) -C1-C6-alkyl, -CO2-(C1-C6) -alkyl, -NR'R ", -NR'-C (O) (C1-C6) alkyl, (C1-C6) alkyl S (O) a- where a is 0 to 2, -NR'-C (O) -O-(C1-C6) alkyl ), -NR'- SO2-(C1-C6) alkyl, -NR'-C (O) NR'R ", -SO2-NR'R", -C (O) -NR'R ", -OC ( O) -NR'R ", carbocyclyl, heterocycle, heteroaryl or (C1-C6) alkoxy; R3 at each occurrence is independently halo, nitro, formyl, cyano, hydroxy, -NR'R", -CO2H, -C (O ) -C1-C6 alkyl, -CO2-C1-C6 alkyl, -C (O) -NR'R ", -NR'-C (O) -C1-C6 alkyl, -NR'- C (O) NR'R ", -NR'-C (O) -O-C1-C6 alkyl, -OC (O) -C1-C6 alkyl, -SH, -SO2-NR'R" , (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) alkyl S (O) a- where a is 0 to 2, -NR '-SO2 (C1-C6) alkyl, carbocyclyl, heterocycle, or heteroaryl, where if said heterocycle or heteroaryl contains a -NH- moiety, this nitrogen may be opc ionically substituted with (C1-C6) alkyl; or two R3 groups on adjacent carbons may optionally form a 5 or 6 membered, saturated, partially unsaturated, unsaturated and / or aromatic ring optionally containing 0, 1, or 2 heteroatoms selected from S, O, or NRa where Ra is absent , is H or (C1-C6) alkyl; R4 is hydrogen or halo; m is 0-3; where the values of R3 can be the same or different; n is 0-3; where the values of R1 can be the same or different; p is independently 1 or 2 at each occurrence; and R5 is selected from (C1-C6) alkyl, (C3-C6) cycloalkyl, -C (O) -C1-C6 alkyl, -S (O) C1-C6 alkyl, -CO2-C1 alkyl -C6), -C (O) -NR'R ", benzyl, benzyloxycarbonyl, benzoyl and phenylsulfonyl; R 'and R" independently at each occurrence are H, optionally substituted (C1-C6) alkyl, or optionally substituted aryl, or considered together with the nitrogen to which they are attached they form a 3-6 membered ring, saturated or partially unsaturated, optionally substituted, containing 0 or 1 additional heteroatom selected from NRa; wherein said optional substituents can be selected from one or more R6; R6 can independently be (C1-C6) alkyl, halo (C1-C6) alkyl, halo, nitro, cyano, hydroxy, (C1-C6) alkoxy, -NR x R y, -COOR x or -CONR x R y; and R x and R y are independently of each other hydrogen or (C1-C6) alkyl; and where each of Ra, R1, R2, R3 and R5 may optionally be substituted on the carbon with one or more formyl groups, -SH, azido, halo, nitro, cyano, hydroxy, trifluoromethoxy, -OC (O) -alkyl (C1-C6), -NR'R ", -CO2H, -C (O) -alkyl (C1-C6), -CO2-alkyl (C1-C6), -C (O) -NR'R", - S-(C1-C6) alkyl, -SOp-(C1-C6) alkyl, -SOpNR'R ", (C1-C6) alkyl, (C3-C6) cycloalkyl, -NR'-C (O) -alkyl ( C1-C6), -NR'-C (O) -O-alkyl (C1-C6), -NR'-SO2-alkyl (C1-C6), -NR'-C (O) NR'R ", alkenyl (C2-C6), (C2-C6) alkynyl, or (C1-C6) alkoxy.

Description

BACKGROUND OF THE INVENTION

The invention relates to chemical compounds, or their pharmaceutically acceptable salts, which have inhibitory activity of the kinase of the colony stimulating factor 1 receptor (CSF-1R) and which are therefore useful for their anti-cancer activity and therefore in Treatment methods of the human or animal body. The invention also relates to processes for the manufacture of said chemical compounds, to pharmaceutical compositions containing them, and to their use in the manufacture of medicaments for use in the production of an anti-cancer effect in a warm-blooded animal such as human being.

The tyrosine kinase receptors (RTK) are a subfamily of protein kinases that play a critical role in cell signaling and are involved in a variety of cancer-related processes that include cell proliferation, survival, angiogenesis, invasion and metastasis. It is believed that there are at least 96 different RTKs including the CSF-1R.

The CSF-1R or c-fms was originally identified as the v-fms oncogene from the feline sarcoma virus. The CSF-1R is a member of the class III RTKs together with the c-Kit, the fms-related tyrosine kinase 3 (Flt3) and the platelet-derived growth factor receptor � and � (PDGFR� and PDGFR� ). All these kinases have been implicated in the tumorigenesis process. CSF-1R is normally expressed as an immature transmembrane protein of 130 kDa and finally results in the mature glycosylated protein, 145-160 kDa, of the cell surface, bound by N. The macrophage colony stimulating factor (M -CSF or CSF-1), the ligand for CSF-1R, binds to the receptor resulting in dimerization, auto-phosphorylation of the receptor and subsequent activation of downward signal transduction cascades (CJ Sherr, Biochim Biophys Acta, 1988, 948: 225-243).

CSF-1R is normally expressed in myeloid cells of the mononuclear phagocytic line and their progenitors in the bone marrow as well as in the epithelial cells of the ducts and alveoli in the breast tissue, but not in the normal breast tissue Resting. The activation of CSF-1R stimulates the proliferation, survival, motility and differentiation of monocyte / macrophage line cells. Mature macrophages play a key role in normal tissue development and immune defense (F.L. Pixley and E.R. Stanley, Trends in Cell Biology, 2004, 14 (11): 628-638). For example, osteoblasts secrete CSF-1 and activate the receptor in osteoclast progenitors resulting in differentiation into mature osteoclasts (S.L. Teitelbaum, Science, 2000,

289: 1504-1508). The CSF-1R axis plays an important role in placental development, embryo implantation, ductal and lobe alveolar development of the mammary gland and lactation (E. Sapi, Exp Biol Med, 2004,229: 1-11).

5 Transfection of CSF-1R with or without CSF-1 induces the transformation and tumorigenicity of NIH3T3 (Rat2 cells and granular cells of the ovaries. Autocrine and / or paracrine signaling mechanisms have been implicated in the activation of CSF- 1R in the tumor epithelium and in the tumor-associated macrophage, aberrant expression and activation of CSF-1R and / or its ligand have been found in

10 Human myeloid leukemia, prostate, breast, ovarian cancer, endometrial cancer and a variety of other cancers. A series of studies have shown that overexpression of CSF-1R is associated with poor prognosis in several of these cancers. In addition, the CSF-1 / CSF-1R axis plays a key role in the regulation of macrophages associated with the tumor, which are assumed to play

15 an important role in angiogenesis, invasion and progression of the tumor (E. Sapi, Exp Biol Med, 2004, 229: 1-11).

SUMMARY AND DETAILED DESCRIPTION OF THE INVENTION

Therefore, the present invention provides a compound of the formula IA or IB:

image 1

or one of its pharmaceutically acceptable salts, in which:

image 1

it is a 3-10 membered heterocycle or heteroaryl, attached by nitrogen; where if said heterocycle or heteroaryl contains a -NH- moiety, this nitrogen may be

5 optionally substituted with a group selected from R5; R1 at each occurrence is independently halo, hydroxy, nitro, formyl, cyano, -CO2H, -SH, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy, -OC (O) -alkyl (C1-C6), -C (O) -alkyl (C1-C6), -CO2-alkyl (C1-C6), -NR'R ", - NR'-C (O) (C1-C6) alkyl, (C1-C6) alkyl S (O) a-where a is 0 to 2, -NR'-C (O) -O-(C1-C6) alkyl , -NR '

10 SO2-(C1-C6) alkyl, -NR'-C (O) NR'R ", -SO2-NR'R", -C (O) -NR'R ", carbocyclyl, heterocycle, heteroaryl or oxo; R2 is hydrogen, halo, hydroxy, nitro, formyl, -CO2H, -SH, cyano, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C6) cycloalkyl, -O -C3-C6 cycloalkyl, -OC (O) (C1-C6) alkyl, -C (O) -C1-C6 alkyl, -CO2-(C1-C6) alkyl, -NR'R ",

15 -NR'-C (O) -alkyl (C1-C6), (C1-C6) alkyl S (O) a-where a is 0 to 2, -NR'-C (O) -Oalkyl (C1-C6) ), -NR'-SO2-(C1-C6) alkyl, -NR'-C (O) NR'R ", -SO2-NR'R", -C (O) -NR'R ", -OC ( O) -NR'R ", carbocyclyl, heterocycle, heteroaryl or (C1-C6) alkoxy; R3 at each occurrence is independently halo, nitro, formyl, cyano, hydroxy, -NR'R ", -CO2H, -C (O) -alkyl (C1-C6), -CO2-alkyl (C1-C6), -C (O) -NR'R ",

20 -NR'-C (O) -alkyl (C1-C6), -N'R'-C (O) NR'R ", -NR'-C (O) -O-(C1-C6) alkyl, -OC (O) (C1-C6) alkyl, -SH, -SO2-NR'R ", (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy , (C1-C6) alkyl S (O) a-where a is 0 to 2, -NR'-SO2-C1-C6 alkyl, carbocyclyl, heterocycle, or heteroaryl, where if said heterocycle or heteroaryl contains a moiety - NH-, this nitrogen may be optionally substituted with (C1-C6) alkyl;

25 or two R3 groups on adjacent carbons may optionally form a 5 or 6 membered ring, saturated, partially unsaturated, unsaturated and / or aromatic optionally containing 0, 1, or 2 heteroatoms selected from S, O, or NRa where Ra is absent, is H or (C1-C6) alkyl;

R4 is hydrogen or halo; m is 0-3; where the values of R3 can be the same or different; n is 0-3; where the values of R1 can be the same or different; p is independently 1 or 2 at each occurrence; and R5 is selected from (C1-C6) alkyl, (C3-C6) cycloalkyl, -C (O) -C1-C6 alkyl, -S (O) C1-C6 alkyl, -CO2-C1 alkyl -C6), -C (O) -NR'R ", benzyl, benzyloxycarbonyl, benzoyl and phenylsulfonyl; R 'and R" independently at each occurrence are H, (C1-C6) alkyl optionally

5 substituted, or optionally substituted aryl, or considered together with the nitrogen to which they are attached form a 3-6 membered ring, saturated or partially unsaturated, optionally substituted, containing 0 or 1 additional heteroatom selected from NRa; wherein said optional substituents may be selected from one or more R6;

R6 may independently be (C1-C6) alkyl, halo (C1-C6) alkyl, halo, nitro, cyano, hydroxy, (C1-C6) alkoxy, -NRxRy, -COORx or -CONRxRy; and Rx and Ry are independently of each other hydrogen or (C1-C6) alkyl; and where each of Ra, R1, R2, R3 and R5 may optionally be substituted on the carbon with one or more formyl groups, -SH, azido, halo, nitro, cyano, hydroxy, trifluoromethoxy,

15 -OC (O) -C1-C6 alkyl, -NR'R ", -CO2H, -C (O) -C1-C6 alkyl, -CO2-C1-C6 alkyl, -C (O ) -NR'R ", -S-(C1-C6) alkyl, -SOp-(C1-C6) alkyl, -SOpNR'R", (C1-C6) alkyl, (C3-C6) cycloalkyl, -NR ' -C (O) -C1-C6 alkyl, -NR'-C (O) -O-C1-C6 alkyl, -NR'-SO2 (C1-C6) alkyl, -NR'-C (O) NR'R ", (C2-C6) alkenyl, (C2-C6) alkynyl, or (C1-C6) alkoxy.

According to a further aspect of the present invention there is provided a compound of the formula IA or IB or a pharmaceutically acceptable salt thereof, in which:

image 1

it is a 3-8 membered heterocycle or heteroaryl; R1 at each occurrence is independently halo, hydroxyl, (C1-C6) alkyl,

Cycloalkyl (C3-C6), alkoxy (C1-C6), -OC (O) -alkyl (C1-C6), -C (O) -alkyl (C1-C6), -CO2-alkyl (C1-C6) , -C (O) -NR'R ", or oxo; R2 is hydrogen, halo, hydroxyl, cyano, (C1-C6) alkyl, cycloalkyl (C3-C6), or (C1-C6) alkoxy; R3 in each appearance is independently halo, nitro, cyano, hydroxy, trifluoromethoxy,

30 NR'R ", CO2H, -C (O) -alkyl (C1-C6), -CO2-alkyl (C1-C6), -C (O) -NR'R", -NR-C (O) alkyl (C1-C6), -NR'-C (O) NR'R ", -NR'-C (O) -O-alkyl (C1-C6), -OC (O) -alkyl (C1-C6), SH, -SO2-NR'R ", (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) alkyl where (O) where a is 0 to 2, -NR'-SO2-(C1-C6) alkyl, (C3-C6) cycloalkyl, heterocycle, or heteroaryl, where if said heterocycle or heteroaryl contains a -NH- moiety, this nitrogen may optionally be substituted with (C1-C6) alkyl; and where if two R3 groups are on adjacent carbons, they can form

5 optionally a 5 or 6-membered, saturated, partially unsaturated or aromatic ring that optionally contains 0, 1, or 2 heteroatoms selected from S, O,

or NRa where Ra is H or (C1-C6) alkyl, S, or O; R4 is hydrogen or halo; m is 0-3;

10 n is 0-3; p is independently 1 or 2 at each occurrence; and R 'and R "independently at each occurrence are H, (C1-C6) alkyl, or aryl, or taken together with the nitrogen to which they are attached form a 3-6 membered ring, saturated or partially unsaturated, optionally substituted, containing 0 or 1 additional heteroatom

15 selected from NRa; and each of Ra, R1, R2, and R3 may optionally be substituted on the carbon with azido, halo, nitro, cyano, hydroxy, trifluoromethoxy, -OC (O) -alkyl (C1-C6), NR'R ", -CO2H; C (O) -C1-C6 alkyl, -CO2-C1-C6 alkyl, -C (O) -NR'R ", S-C1-C6 alkyl, SO-C1-C6 alkyl ), SOpNH-(C1-C6) alkyl, SOpNR'R ", (C2-C6) alkenyl, (C2-C6) alkynyl, or

20 (C1-C6) alkoxy.

According to a further aspect of the present invention there is provided a compound of the formula IA or IB or a pharmaceutically acceptable salt thereof, in which:

image 1

25 is a 3-8 membered heterocycle or heteroaryl, linked by nitrogen; wherein if said heterocycle or heteroaryl contains a -NH- moiety, this nitrogen may be optionally substituted with a group selected from R5; R1 at each occurrence is independently halo, hydroxy, nitro, formyl, cyano, -CO2H, -SH, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy,

30 -OC (O) -C1-C6 alkyl, -C (O) -C1-C6 alkyl, -CO2-C1-C6 alkyl, -NR'R ", -NR'-C (O ) (C1-C6) alkyl, (C1-C6) alkyl S (O) a-where a is 0 to 2, -NR'-C (O) -O-(C1-C6) alkyl, -NR'SO2- (C1-C6) alkyl, -NR'-C (O) NR'R ", -SO2-NR'R", -C (O) -NR'R ", carbocyclyl, heterocycle, heteroaryl or oxo;

R2 is hydrogen, halo, hydroxy, nitro, formyl, -CO2H, -SH, cyano, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C6) cycloalkyl, -O-C3-C6 cycloalkyl, -OC (O) -C1-C6 alkyl, -C (O) -C1-C6 alkyl, -CO2-C1-C6 alkyl, -NR'R ", -NR'-C (O) (C1-C6) alkyl; (C1-C6) alkyl S (O) a-where a is 0 to 2, -NR'-C (O) -O (C1-C6) alkyl, -NR'SO2-alkyl ( C1-C6), -NR'-C (O) NR'R ", -SO2-NR'R", -C (O) -NR'R ", -OC (O) -NR'R", carbocyclyl, heterocycle, heteroaryl or (C1-C6) alkoxy; R3 at each occurrence is independently halo, nitro, formyl, cyano, hydroxy, -NR'R ", -CO2H, -C (O) -C1-C6 alkyl, -CO2-C1-C6 alkyl, -C (O) -NR'R ", -NR'-C (O) -alkyl (C1-C6), -NR'-C (O) NR'R ", -NR'-C (O) -O-(C1-C6) alkyl, -OC ( O) (C1-C6) alkyl, -SH, -SO2-NR'R ", (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) alkyl S (O) a-where a is 0 to 2, -NR'-SO2-(C1-C6) alkyl, carbocyclyl, heterocycle, or heteroaryl, where if said heterocycle or heteroaryl contains a -NH- moiety, this nitrogen may be optionally substituted with (C1-C6) alkyl; or two R3 groups on adjacent carbons may optionally form a ring of 5 or 6 members, saturated, partially unsaturated, unsaturated and / or aromatic that optionally contains 0, 1, or 2 heteroatoms selected from S, O, or NRa where Ra is absent, is H or (C1-C6) alkyl; R4 is hydrogen or halo; m is 0-3; where the values of R3 can be the same or different; n is 0-3; where the values of R1 can be the same or different; p is independently 1 or 2 at each occurrence; Y R5 is selected from (C1-C6) alkyl, cycloalkyl (C3-C6), -C (O) -alkyl (C1-C6), -S (O) p-C1-C6 alkyl, -CO2-C1-C6 alkyl, -C (O) -NR'R ", benzyl, benzyloxycarbonyl, benzoyl and phenylsulfonyl; R 'and R "independently at each occurrence are H, (C1-C6) alkyl optionally substituted, or optionally substituted aryl, or considered together with nitrogen at which are joined form a 3-6 member ring, saturated or partially unsaturated, optionally substituted, containing 0 or 1 additional heteroatom selected from NRa; where said optional substituents can be selected of one or more R6; R6 can independently be (C1-C6) alkyl, halo (C1-C6) alkyl, halo, nitro, cyano, hydroxy, (C1-C6) alkoxy, -NRxRy, -COORx or -CONRxRy; Y Rx and Ry are independently of each other hydrogen or (C1-C6) alkyl; and where

each of Ra, R1, R2, R3 and R5 may optionally be substituted on the carbon with one or more formyl groups, -SH, azido, halo, nitro, cyano, hydroxy, trifluoromethoxy, -OC (O) -alkyl (C1 -C6), -NR'R ", -CO2H, -C (O) -alkyl (C1-C6), -CO2-alkyl (C1-C6), -C (O) NR'R", -S-alkyl (C1-C6), -SOp-(C1-C6) alkyl, -SOpNR'R ", (C1-C6) alkyl, cycloalkyl (C3-C6), -NR'-C (O) -alkyl (C1-C6) ), -NR'-C (O) -O-(C1-C6) alkyl, -NR'-SO2 (C1-C6) alkyl, -NR'-C (O) NR'R ", (C2-C6) alkenyl , (C2-C6) alkynyl, or (C1-C6) alkoxy.

A compound of the formula IA-1 or a pharmaceutically acceptable salt thereof is also provided:

image 1

A compound of the formula IA-2 or a pharmaceutically acceptable salt thereof is also provided:

image 1

wherein Rb at each occurrence is independently H, (C1-C6) alkyl, (C3-C6) cycloalkyl, -C (O) -alkyl (C1-C6), -C (O) -NR'R ", where each Rb can be

15 optionally substituted on carbon with halo, cyano, hydroxy, trifluoromethoxy, OC (O) -alkyl (C1-C6), -NR'R ", -CO2H, -C (O) -alkyl (C1-C6), - CO2-(C1-C6) alkyl, -C (O) -NR'R ", -S-(C1-C6) alkyl, -SOp-(C1-C6) alkyl, -SOpNR'R", (C2-) alkenyl C6), (C2-C6) alkynyl, or (C1-C6) alkoxy, where R ', R ", and p are as defined above. A compound of the formula IA-3 or one of its salts is also provided.

20 pharmaceutically acceptable:

image 1

where R1 and Rb are as defined above; Y X is O, S, SO, SO2, or N-Rc, where Rc is hydrogen, (C1-C6) alkyl, (C3-C6) cycloalkyl, -C (O) -C1-C6 alkyl, -CO2-C1-C6 alkyl, -C (O) -NR'R ", or -SOpNH-C1-C6 alkyl, where Rc may be optionally substituted on the carbon with azido, halo, nitro, cyano, hydroxy, trifluoromethoxy, -OC (O) -alkyl (C1-C6), -NR'R ", -CO2H, -C (O) -C1-C6 alkyl, -CO2-C1-C6 alkyl, -C (O) -NR'R ", -S-C1-C6 alkyl, -SO-C1-C6 alkyl ), -SOpNR'R ", (C2-C6) alkenyl, (C2-C6) alkynyl, or (C1-C6) alkoxy, where R ', R ", and p are as defined before.

A compound of the formula IA-3 or a pharmaceutically acceptable salt thereof is also provided, in which:

R1 and Rb are as defined above; Y X is O, S, SO, SO2, or N-Rc, where Rc is hydrogen, (C1-C6) alkyl, cycloalkyl (C3-C6), alkoxy (C1-C6), -OC (O) -alkyl (C1-C6), -C (O) -alkyl (C1-C6), CO2-alkyl (C1-C6), - C (O) -NR'R ", or SOpNH-(C1-C6) alkyl,

where Rc may be optionally substituted on the carbon with azido, halo, nitro, cyano, hydroxy, trifluoromethoxy, -OC (O) -alkyl (C1-C6), -NR'R ", -CO2H, -C (O) - (C1-C6) alkyl, -CO2-(C1-C6) alkyl, -C (O) -NR'R ", -S-(C1-C6) alkyl, -SOp-(C1-C6) alkyl, -SOpNH - (C1-C6) alkyl, -SOpNR'R ", (C2-C6) alkenyl, (C2-C6) alkynyl, or (C1-C6) alkoxy, where R ', R", and p are as defined above .

The particular values of the variable groups are as follows. Such values may be used when appropriate with any of the definitions, claims or embodiments described hereinbefore or hereinafter.

A compound of the formula IA.

A compound of the formula IB.

image 1

it is a 5-7 membered heterocycle, bound by nitrogen; where if said heterocycle contains a -NH- moiety, this nitrogen may be optionally substituted with a

5 selected group of R5; wherein R5 is selected from (C1-C6) alkyl, (C3-C6) cycloalkyl, -C (O) -C1-C6 alkyl and CO2-(C1-C6) alkyl; and each R5 may be optionally substituted on the carbon with one or more cyano, hydroxy, -OC (O) -C1-C6 alkyl, -NR'R ", cycloalkyl (C3-C6) or alkoxy (C1-C6) groups ); where

R 'and R "independently at each occurrence are (C1-C6) alkyl.

image 1

it is piperazin-1-yl, piperidin-1-yl, morpholino, homopiperazin-1-yl and pyrrolidin-1-yl; wherein said piperazin-1-yl or homopiperazin-1-yl may be optionally substituted on nitrogen with a group selected from R5; where

R5 is selected from methyl, ethyl, isopropyl, cyclopropyl, acetyl, propionyl and tbutoxycarbonyl; and each R5 may be optionally substituted on the carbon with one or more cyano, hydroxy, acetoxy, -NR'R ", cyclopropyl or methoxy groups; where R 'and R" are methyl.

image 1

twenty

it is piperazin-1-yl, N-methylpiperazin-1-yl, N-ethylpiperazin-1-yl, N-isopropylpiperazin-1-yl, N-acetylpiperazin-1-yl, N- (2-hydroxyacetyl) piperazin-1-yl, N- (2-dimethylaminoethyl) piperazin-1-yl, N- (2-methoxyethyl) piperazin-1-yl, N- (2-cyanoethyl) piperazin-1-yl, N- (2-hydroxyethyl) piperazin-1- ilo, 25 N- (cyclopropylmethyl) piperazin-1-yl, N- (cyclopropyl) piperazin-1-yl, N - ((R) -2-hydroxypropionyl) piperazin-1-yl, N - ((S) -2 -hydroxypropionyl) piperazin-1-yl, N- (t-butoxycarbonyl) piperazin-1-yl, N- (acetoxyacetyl) piperazin-1-yl, piperidin-1-yl, morpholino, homopiperazin-1-yl, N-methylhomopiperazin -1-yl, N-ethylhomopiperazin-1-yl,

N-acetylhomopiperazin-1-yl, N-isopropylhomopiperazin-1-yl, Ncyclopropylhomopiperazin-1-yl and pyrrolidin-1-yl.

image 1

it is N-methylpiperazin-1-yl. R1 is hydroxy. R1 at each occurrence is hydroxy, -NR'R "or oxo; where R 'and R"

independently at each occurrence they are (C1-C6) alkyl. R1 at each occurrence is hydroxy, -NMe2 or oxo. n is 0 or 1.

10 n is 0. n is 1. n is 0 or 1 and R1 is hydroxy. n is 0 or 1 and R1 is hydroxy, -NMe2 or oxo. R2 is hydrogen, halo or (C1-C6) alkoxy; where R2 can optionally be

15 substituted on carbon with one or more (C1-C6) alkoxy groups. R2 is hydrogen, halo or (C1-C6) alkoxy; where R2 can optionally be

substituted on carbon with one or more (C1-C6) alkoxy or hydroxy groups. R2 is hydrogen, halo or (C1-C6) alkoxy. R2 is hydrogen, fluoro, methoxy, ethoxy or isopropoxy; where R2 can be

20 optionally substituted on carbon with one or more methoxy groups. R2 is hydrogen, fluoro, methoxy, ethoxy or isopropoxy; where R2 can be

optionally substituted on carbon with one or more methoxy or hydroxy groups. R2 is hydrogen, fluoro, methoxy, ethoxy or isopropoxy. R2 is hydrogen, fluoro, methoxy, ethoxy, 2- (methoxy) ethoxy, 2-hydroxyethoxy or

25 isopropoxy. R2 is hydrogen. R2 is fluoro. R2 is methoxy. R2 is ethoxy.

R2 is isopropoxy. R2 is 2- (methoxy) ethoxy. R2 is 2-hydroxyethoxy.

R3 at each occurrence is independently halo, (C1-C6) alkyl or (C1-C6) alkoxy; where R3 may be optionally substituted on the carbon with halo.

R3 at each occurrence is independently fluoro, chloro, methyl, ethyl or methoxy; 5 where R3 may be optionally substituted on the carbon with fluoro. R3 at each occurrence is independently fluoro, chloro, methyl,

trifluoromethyl, ethyl, methoxy or trifluoromethoxy. m is 1-3; where the values of R3 can be the same or different. m is 1.

10 m is 2; where the values of R3 can be the same or different. m is 3; where the values of R3 can be the same or different. (R3) m and the phenyl to which it is attached form 2,4-difluorophenyl,

2-fluoro-3-chlorophenyl or 2-fluoro-4-methylphenyl. R4 is hydrogen or fluoro.

R4 is hydrogen. R4 is fluoro. Therefore in a further aspect of the invention a compound is provided

of the formula IA or IB (as shown above) in which:

image 1

20 is a 5-7 membered heterocycle, bound by nitrogen; where if said heterocycle contains a -NH- moiety, this nitrogen may be optionally substituted with a group selected from R5; R1 is hydroxy; n is 0 or 1;

R2 is hydrogen, halo or (C1-C6) alkoxy; R3 at each occurrence is independently halo, (C1-C6) alkyl or (C1-C6) alkoxy; where R3 may be optionally substituted on the carbon with halo; m is 1-3; where the values of R3 can be the same or different; R4 is hydrogen or fluoro;

R5 is selected from (C1-C6) alkyl, (C3-C6) cycloalkyl, -C (O) -C1-C6 alkyl and -CO2-(C1-C6) alkyl; where R5 may optionally be substituted on the carbon with one or more cyano, hydroxy, -OC (O) -alkyl (C1-C6), -NR'R ", cycloalkyl (C3-C6) groups

or (C1-C6) alkoxy; Y R 'and R "independently at each occurrence are (C1-C6) alkyl;

or one of its pharmaceutically acceptable salts.

Therefore, in a further aspect of the invention there is provided a compound of the formula IA or IB (as shown above) in which:

image 1

it is a 5-7 membered heterocycle, bound by nitrogen; where if said heterocycle contains a -NH- moiety, this nitrogen may be optionally substituted with a

10 selected group of R5; R1 at each occurrence is hydroxy, -NR'R "or oxo; n is 0 or 1; R2 is hydrogen, halo or (C1-C6) alkoxy; where R2 may be optionally substituted on the carbon with one or more alkoxy groups ( C1-C6) or hydroxy;

R3 at each occurrence is independently halo, (C1-C6) alkyl or (C1-C6) alkoxy; where R3 may be optionally substituted on the carbon with halo; m is 1-3; where the values of R3 can be the same or different; R4 is hydrogen or fluoro; R5 is selected from (C1-C6) alkyl, cycloalkyl (C3-C6), -C (O) -alkyl (C1-C6) and

20 -CO2-(C1-C6) alkyl; where R5 may optionally be substituted on the carbon with one or more cyano, hydroxy, -OC (O) -alkyl (C1-C6), -NR'R ", cycloalkyl (C3-C6) groups

or (C1-C6) alkoxy; Y R 'and R "independently at each occurrence are (C1-C6) alkyl;

or one of its pharmaceutically acceptable salts.

Therefore, in a further aspect of the invention there is provided a compound of the formula IA or IB (as shown above) in which:

image 1

it is piperazin-1-yl, N-methylpiperazin-1-yl, N-ethylpiperazin-1-yl, N-isopropylpiperazin-1-yl, N-acetylpiperazin-1-yl, N- (2-hydroxyacetyl) piperazin-1-yl,

N- (2-dimethylaminoethyl) piperazin-1-yl, N- (2-methoxyethyl) piperazin-1-yl, N- (2-cyanoethyl) piperazin-1-yl, N- (2-hydroxyethyl) piperazin-1- ilo, N- (cyclopropylmethyl) piperazin-1-yl, N- (cyclopropyl) piperazin-1-yl, N - ((R) 2-hydroxypropionyl) piperazin-1-yl, N - ((S) -2-hydroxypropionyl ) piperazin-1-yl,

5 N- (t-butoxycarbonyl) piperazin-1-yl, N- (acetoxyacetyl) piperazin-1-yl, piperidin-1-yl, morpholino, homopiperazin-1-yl, N-methylhomopiperazin-1-yl, N-ethylhomopiperazin -1-yl, N-acetylhomopiperazin-1-yl, N-isopropylhomopiperazin-1-yl, N-cyclopropylhomopiperazin-1-yl and pyrrolidin-1-yl; R1 is hydroxy;

10 n is 0 or 1; R2 is hydrogen, fluoro, methoxy, ethoxy or isopropoxy; R3 at each occurrence is independently fluoro, chloro, methyl, trifluoromethyl, ethyl, methoxy or trifluoromethoxy; m is 1-3; where the values of R3 can be the same or different;

R4 is hydrogen or fluoro;

or one of its pharmaceutically acceptable salts.

Therefore, in a further aspect of the invention there is provided a compound of the formula IA or IB (as shown above) in which:

image 1

20 is piperazin-1-yl, N-methylpiperazin-1-yl, N-ethylpiperazin-1-yl, N-isopropylpiperazin-1-yl, N-acetylpiperazin-1-yl, N- (2-hydroxyacetyl) piperazin-1-yl , N- (2-dimethylaminoethyl) piperazin-1-yl, N- (2-methoxyethyl) piperazin-1-yl, N- (2-cyanoethyl) piperazin-1-yl, N- (2-hydroxyethyl) piperazin-1 -yl, N- (cyclopropylmethyl) piperazin-1-yl, N- (cyclopropyl) piperazin-1-yl,

25 N - ((R) -2-hydroxypropionyl) piperazin-1-yl, N - ((S) -2-hydroxypropionyl) piperazin-1-yl, N- (t-butoxycarbonyl) piperazin-1-yl, N- (acetoxyacetyl) piperazin-1-yl, piperidin-1-yl, morpholino, homopiperazin-1-yl, N-methylhomopiperazin-1-yl, N-ethylhomopiperazin-1-yl, N-acetylhomopiperazin-1-yl, N-isopropylhom -1-yl, N-cyclopropylhomopiperazin-1-yl and pyrrolidin-1-yl;

R1 at each occurrence is hydroxy, -NMe2 or oxo; n is 0 or 1; R2 is hydrogen, fluoro, methoxy, ethoxy, 2- (methoxy) ethoxy, 2-hydroxyethoxy or isopropoxy;

R3 at each occurrence is independently fluoro, chloro, methyl, trifluoromethyl, ethyl, methoxy or trifluoromethoxy; m is 1-3; where the values of R3 can be the same or different; R4 is hydrogen or fluoro;

or one of its pharmaceutically acceptable salts. In another aspect of the invention, the preferred compounds of the invention are any one of the Examples or a pharmaceutically acceptable salt thereof.

In another aspect of the invention, the preferred compounds of the invention are any one of Examples 11, 12, 48, 70, 83, 88, 165, 166, 168 or 172 or a pharmaceutically acceptable salt thereof.

A compound is also provided which is one of the Examples.

A pharmaceutical composition is also provided comprising a compound of the formula IA or IB, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier.

A compound of the formula IA or IB, or a pharmaceutically acceptable salt thereof, is also provided for use as a medicament.

The use of a compound of the formula IA or IB, or a pharmaceutically acceptable salt thereof, is also provided in the manufacture of a medicament for use in the production of a CSF-1R kinase inhibitor effect in a blood animal Hot just like the human being.

The use of a compound of the formula IA or IB, or a pharmaceutically acceptable salt thereof, is also provided in the manufacture of a medicament for use in the production of an anti-cancer effect in a warm-blooded animal such as being human.

The use of a compound of the formula IA or IB, or a pharmaceutically acceptable salt thereof, is also provided in the manufacture of a medicament for use in the treatment of melanoma, papillary thyroid tumors, cholangiocarcinomas, colon cancer, cancer of ovaries, lung cancer, leukemia, malignant lymphoid tumors, carcinomas and sarcomas of the liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumors of the skin, colon, thyroid, lungs and ovaries

The use of a compound of the formula IA or IB, or a pharmaceutically acceptable salt thereof, is also provided in the manufacture of a medicament for use in the treatment of tumors of the breast, ovaries, bladder, cervix, of endometrium, prostate, lung, kidney and pancreatic; hematologic malignancies including myelodysplastic syndrome, acute myelogenous leukemia, chronic myelogenous leukemia, non-Hodgkin lymphoma, Hodgkin's disease, multiple myeloma and chronic lymphocytic leukemia; and glioma, squamous cell carcinoma of the esophagus, uveal melanoma and malignant follicular lymphoma. The use of a compound of the formula IA or IB, or a pharmaceutically acceptable salt thereof, is also provided in the manufacture of a medicament for use in the treatment of osteolysis associated with tumors, osteoporosis including ovariectomy-induced bone loss, failures. of orthopedic implants, autoimmune disorders including systemic lupus erythematosus, arthritis including rheumatoid arthritis, osteoarthritis, renal inflammation and glomerulonephritis; inflammatory bowel disease; transplant rejection including renal and bone marrow allografts and skin xenograft, atherosclerosis, obesity, Alzheimer's disease and Langerhans cell histiocytosis.

The use of a compound of the formula IA or IB, or a pharmaceutically acceptable salt thereof, is also provided in the manufacture of a medicament for use in the treatment of chronic obstructive pulmonary disease, diabetes and chronic skin disorders including psoriasis.

A pharmaceutical composition is also provided comprising a compound of the formula IA or IB, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier, for use in the production of a CSF-kinase inhibitor effect. 1R in a warm-blooded animal such as humans.

A pharmaceutical composition is also provided comprising a compound of the formula IA or IB, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier, for use in the production of an anti-cancer effect in an animal of Warm blood just like the human being.

A pharmaceutical composition is also provided comprising a compound of the formula IA or IB or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier, for use in the treatment of melanoma, papillary thyroid tumors, cholangiocarcinomas, cancer. of colon, ovarian cancer, lung cancer, leukemia, malignant lymphoid tumors, carcinomas and sarcomas of the liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumors of the skin, colon , of thyroid, lungs and ovaries in a warm-blooded animal such as humans.

A pharmaceutical composition is also provided comprising a compound of the formula IA or IB or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier, for use in the treatment of breast, ovarian, bladder tumors, of cervix, endometrium, prostate, lung, kidney and pancreatic; hematologic malignancies including myelodysplastic syndrome, acute myelogenous leukemia, chronic myelogenous leukemia, non-Hodgkin lymphoma, Hodgkin's disease, multiple myeloma and chronic lymphocytic leukemia; and glioma, squamous cell carcinoma of the esophagus, uveal melanoma and malignant follicular lymphoma in a warm-blooded animal such as humans.

A pharmaceutical composition is also provided comprising a compound of the formula IA or IB or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier, for use in the treatment of osteolysis associated with tumors, osteoporosis including bone loss. induced by ovariectomy, orthopedic implant failures, autoimmune disorders including systemic lupus erythematosus, arthritis including rheumatoid arthritis, osteoarthritis, renal inflammation and glomerulonephritis; inflammatory bowel disease; Rejection of transplants including renal and bone marrow allografts and skin xenograft, atherosclerosis, obesity, Alzheimer's disease and Langerhans cell histiocytosis in a warm-blooded animal such as humans.

A pharmaceutical composition is also provided comprising a compound of the formula IA or IB or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier, for use in the treatment of chronic obstructive pulmonary disease, diabetes and disorders. Chronic skin including psoriasis in a warm-blooded animal such as humans.

A process is also provided for preparing a compound of the formula IA or IB or a pharmaceutically acceptable salt thereof, as indicated in Schemes 1 and 2, below.

Definitions

"Alkyl" means a monovalent, saturated linear hydrocarbon radical, and, unless otherwise specified, of one to six carbon atoms or a monovalent, saturated, branched hydrocarbon radical, and, unless otherwise specified, of three at six carbon atoms, eg, methyl, ethyl, propyl, 2-propyl, pentyl, and the like. References to individual alkyl groups such as "propyl" are specific only to the straight chain version and references to individual branched chain alkyl groups such as "isopropyl" are specific to the branched chain version only. For example, "(C1-C6) alkyl" includes methyl, propyl, isopropyl and t-butyl.

The term "halo" refers to fluoro, chloro, bromo and iodo.

"Alkenyl" means a monovalent linear hydrocarbon radical and, unless otherwise specified, of two to six carbon atoms or a monovalent branched hydrocarbon radical and, unless otherwise specified, of three to six carbon atoms, containing at least one double bond, eg, ethenyl, propenyl, and the like. Examples of "(C2-C6) alkenyl" are vinyl, allyl and 1-propenyl.

"Alkynyl" means an alkyl group, as defined above, which has one

or more triple carbon-carbon bonds, eg, ethynyl. Examples of "(C2-C6) alkynyl" are ethynyl, 1-propynyl and 2-propynyl.

"Cycloalkyl" means a saturated monovalent cyclic hydrocarbon radical and, unless otherwise specified, three to six carbons in the ring, eg, cyclopropyl, cyclohexyl, and the like. Examples of "C3-C6 cycloalkyl" include cyclopropyl and cyclohexyl.

"Aryl" means an aromatic or totally unsaturated monovalent monocyclic or bicyclic hydrocarbon radical of 6 to 10 ring atoms.

"Heterocycle" or "heterocycle" means a saturated or partially unsaturated cyclic radical of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from NRa where Ra is as defined above, O, S, SO, or SO2, which may be linked by carbon or nitrogen unless otherwise specified.

"Heteroaryl" means a monovalent monocyclic radical, which is a fully unsaturated and / or aromatic ring of 5 or 6 ring atoms containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining atoms of the C ring, which may be linked by carbon or nitrogen unless otherwise specified. The term "heteroaryl" includes, but is not limited to, pyridyl, pyrrolyl, thienyl, pyrazolyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl and derivatives thereof.

A "carbocyclyl" is a mono or bicyclic carbon ring, saturated, partially saturated or unsaturated, containing 3-12 atoms; in which a CH2-group may be optionally replaced by a -C (O) -. In particular, the "carbocyclyl" is a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms. Suitable values for "carbocyclyl" include cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl. A particular example

5 of "carbocyclyl" is phenyl.

In "Two R3 groups on adjacent carbons may optionally form a 5 or 6 membered ring, saturated, partially unsaturated, unsaturated and / or aromatic optionally containing 0, 1, or 2 heteroatoms selected from S, O,

or NRa where Ra is absent, is H or (C1-C6) alkyl, "said ring forms a ring

10 bicyclic with the phenyl to which it is attached. For the avoidance of doubt, the 5 or 6 ring members include two from the phenyl ring to which it is attached. Suitable examples of two R3 groups on adjacent carbons that form a 5- or 6-membered ring together with the phenyl to which they are attached include naphthyl, indole-6-yl, isoindole-5-yl, benzofuran-4-yl, quinolin-8- ilo and 1H-indazol-7-yl.

R 'and R "" taken together with the nitrogen to which they are attached form a 3-6 membered, saturated or partially unsaturated ring containing 0 or 1 additional heteroatom selected from NRa. "Examples and suitable values of this ring are azetidine. -1-yl, piperidin-1-yl, piperazin-1-yl N-methylpiperazin-1-yl and pyrrolidin-1-yl.

image 1

twenty

it is a 3-10-membered heterocycle or heteroaryl, attached by nitrogen. Said ring can be mono- or bicyclic and / or with a bridge. Examples and suitable values of this ring are azetidin-1-yl, morpholino, piperidin-1-yl, piperazin-1-yl, pyrrolidin-1-yl, thiomorpholino, homopiperazin-1-yl, pyrrole-1-yl, pyrazole- 1-yl, imidazol-1-yl and triazol-1-yl.

25 Additional examples, in which

image 1

It is a bicyclic ring include hexahydropyrrolo [1,2-a] pyrazin-2 (1H) -yl and 3-methyl-5,6-dihydroimidazo [1,2-a] pyrazin-7 (8H) -yl. Additional examples, in which

image 1

It is a bridge ring including 2,5-diazabicyclo [2.2.1] hept-2-yl. Particularly

image 1

it is a 3-8-membered heterocycle or heteroaryl, attached by nitrogen. Examples of

"C1-C6 alkoxy" includes methoxy, ethoxy and isopropoxy. An example of "-OC (O) -C1-C6 alkyl" is acetoxy. "-CO2H" is carboxy. Examples of "-C (O) -C1-C6 alkyl" include propionyl and acetyl. Examples of "-C (O) -NR'R" "where R 'and R" are as defined above include carbamoyl, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl and N-phenyl-N-ethylcarbamoyl. Examples of

10 "-CO2-(C1-C6) alkyl" includes methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl. Examples of "-NR'R" "where R 'and R" are as defined above include amino, methylamino, ethylamino, dimethylamino, diisopropylamino and N-ethyl-N-phenylamino. Examples of "-NR'-C (O) -C1-C6 alkyl" where R 'is as defined above include formamide, acetamide, propionylamino and N-acetyl-N-phenylamino. Examples of

15 "-NR'-C (O) -O-(C1-C6) alkyl" where R 'is as defined above are methoxycarbonylamino and N- (t-butoxycarbonyl) -N-phenylamino. Examples of "-NR'-C (O) NR'R" "where R 'and R" are as defined above include ureido, N, N'-dimethylureido, N-methyl-N'-propylureido, N', N'-diethylureido, N'-methyl-N'-propylureido, N- (methyl) -N'-ethyl-N'-isopropylureido and N-ethyl-N ', N'-diethylureido. Examples of "-NR'-SO2

(C1-C6) alkyl "where R 'is as defined above include mesylamino, N-ethylsulfonyl-N-phenylamino and isopropylsulfonylamino. Examples of" -SO2-NR'R "' 'where R' and R" are as defined above include sulfamoyl, N- (methyl) sulfamoyl, N- (isopropyl) sulfamoyl, N, N- (dimethyl) sulfamoyl and N- (methyl) -N- (phenyl) sulfamoyl. Examples of "-SOp- (C1-C6) alkyl "where p is as defined above include mesyl,

Ethylsulfinyl and isopropylsulfonyl. Examples of "-SOpNR'R" '' where p, R 'and R "are as defined above include amino (oxide) sulfanyl, sulfamoyl, N- (methyl) sulfamoyl, N- (isopropyl) sulfamoyl, N- (isopropyl) amino (oxide) sulfanyl, N, N- (dimethyl) sulfamoyl and N- (methyl) -N- (phenyl) sulfamoyl. Examples of "-S (O) 2-(C1-C6) alkyl" include mesyl, ethylsulfonyl and isopropylsulfonyl. Examples of "-S-(C1-C6) alkyl" include methylthio, ethylthio and isopropylthio. Examples of "(C1-C6) alkyl S (O) a-where a is 0 to 2" include methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl and ethylsulfonyl. Examples of "halo (C1-C6) alkyl" include trifluoromethyl, 1-chloropropyl and 3-bromo-3-methylbutyl. Examples of "-O-cycloalkyl (C3-C6)" include cyclopropyloxy and cyclohexyloxy. Examples of -OC (O) NR'R "include carbamoyloxy, methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy and N-phenyl-N-ethylcarbamoyloxy.

A suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid addition salt of a compound of the invention that is sufficiently basic, for example, an acid addition salt, for example, with an inorganic acid. or organic, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, citric or maleic acid. In addition, a suitable pharmaceutically acceptable salt of a compound of the invention that is sufficiently acidic is an alkali metal salt, for example, a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt. , an ammonium salt or a salt with an organic base that gives a physiologically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) amine.

Some compounds of the formula IA or IB may have chiral centers and / or geometric isomeric centers (E and Z isomers), and it should be understood that the invention encompasses all such optical isomers, diastereoisomers and geometric isomers that possess kinase inhibitory activity of CSF-1R. The invention further relates to any and all tautomeric forms of the compounds of the formula IA or 1B that possess CSF-1R kinase inhibitory activity.

It should also be understood that certain compounds of the formula IA or IB may exist in solvated forms as well as in non-solvated forms such as, for example, hydrated forms. It should be understood that the invention encompasses all these solvated forms that possess CSF-1R kinase inhibitory activity.

Another aspect of the present invention provides a process for preparing a compound of the formula IA or IB or a pharmaceutically acceptable salt thereof, the process of which (the variable groups are, unless otherwise specified, as defined in the formula IA or IB) comprises:

Procedure a) react a compound of the formula IIA or IIB:

image 1

in which L is a movable atom or group; with a compound of formula III:

image 1

or Procedure b) react a compound of the formula IVA or IVB:

image 1

in which L is a movable atom or group; with a compound of the formula V:

image 1

or Procedure c) react a compound of the formula VIA or VIB:

image 1

or one of its activated derivatives; with ammonia; or Procedure d) react a compound of the formula VIIA or VIIB:

image2

wherein R is (C1-C6) alkyl, in particular methyl and ethyl; with formamide and a base; or Procedure e) hydrolysis of a compound of the formula VIIIA or VIIIB:

image3

and then, if necessary:

i) convert a compound of the formula IA or IB into another compound of the formula IA or IB; ii) separate all protecting groups; iii) form a pharmaceutically acceptable salt.

5

L is a movable group, suitable values for L include chlorine, bromine, tosyl and trifluoromethylsulfonyloxy. The specific reaction conditions for the above reactions are as follows:

10

Procedure a) the compounds of the formula IIA or IIB can be reacted with compounds of the formula III by the chemical coupling technique using an appropriate catalyst and ligand such as Pd2 (dba) 3 and BINAP respectively and a suitable base such as tert-butoxide

15 sodium or cesium carbonate. The reaction usually requires thermal conditions in the range of 80 ° C to 100 ° C. The compounds of the formula IIA can be prepared according to the conditions of the

Scheme I:

image4

Scheme 1

The compounds of the formula IIB can be prepared by a modification of the

Scheme 1.

The compounds of the formula IIAa, IIAb and III are commercially available compounds or are compounds described in the literature or are readily prepared by procedures known to those skilled in the art. Procedure b) The compounds of the formula IVA or IVB can be reacted with compounds of the formula V in a solvent such as ethanol or dimethylformamide, usually under thermal conditions often in the range of 70 ° C to 100 ° C, and in some cases catalyzed by the addition of acetic acid. Alternatively, the compounds of the formula IVA or IVB can be reacted with compounds of the formula V by the chemical coupling technique using an appropriate catalyst and ligand such as Pd2 (dba) 3 and BINAP respectively and a suitable base such as tert. -sodium peroxide or cesium carbonate. The reaction usually requires thermal conditions in the range of 80 ° C to 100 ° C. The compounds of the formula IVA and IVB can be prepared by a modification of Scheme 1. The compounds of the formula V are commercially available compounds or are compounds described in the literature or are easily prepared by procedures known to those skilled in the art. Procedure c) The acids of the formula VIA or VIB and ammonia can be coupled together in the presence of a suitable coupling reagent. As suitable coupling reagents, standard peptide coupling reagents known in the art, for example carbonyldiimidazole and dicyclohexyl carbodiimide, may optionally be used in the presence of a catalyst such as dimethylaminopyridine or 4-pyrrolidinopyridine, optionally in the presence of a base per example triethylamine, pyridine, or 2,6-di-alkyl pyridines such as 2,6-lutidine or 2,6-di-tert-butylpyridine. Suitable solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran and dimethylformamide. The coupling reaction can be conveniently carried out at a temperature in the range of -40 to 40 ° C. Suitable activated acid derivatives include acid halides, for example, acid chlorides, and active esters, for example pentafluorophenyl esters. The reaction of these types of compounds with amines is well known in the art, for example, they can be reacted in the presence of a base, such as those described above, and in a suitable solvent, such as those have described above. The reaction can be conveniently carried out at a temperature within the range of -40 to 40 ° C. The compounds of the formula VIA or VIB can be prepared by a modification of Schemes 1, for example by adding a hydrolysis step and the procedure indicated in Procedure a). Procedure d) The esters of the formula VIIA or VIIB can be reacted together with formamide and a base. Preferably this reaction is carried out sequentially, by adding the formamide first, followed by the base. Suitable bases are alkoxide bases, for example methoxide and ethoxide bases, eg sodium methoxide. The reaction is typically carried out at a temperature of 100 ° C in a suitable solvent such as DMF. The compounds of the formula VIIA or VIIB can be prepared by a modification of Scheme 1. Procedure e) The compounds of the formula VIIIA or VIIIB can be hydrolyzed under conventional acidic or basic conditions.

The compounds of the formula VIIIA or VIIIB can be prepared by a modification of Scheme 1.

It will be appreciated that some of the different ring substituents in the compounds of the present invention may be introduced by conventional aromatic substitution reactions or may be generated by modifications of conventional functional groups, before or immediately after the above-mentioned procedures, and as such they are included in the aspect of the processes of the invention. Such reactions and modifications include, for example, the introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. Reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and a Lewis acid (such as aluminum trichloride) under conditions of Friedel Crafts; the introduction of an alkyl group using an alkyl halide and a Lewis acid (such as aluminum trichloride) under Friedel Crafts conditions; and the introduction of a halo group. Particular examples of modifications include the reduction of a nitro group to an amino group, for example, by catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of heating hydrochloric acid; the oxidation of thioalkyl to alkylsulfinyl or alkylsulfonyl.

It should also be appreciated that in some of the reactions mentioned herein it may be necessary / desirable to protect sensitive groups of the compounds. Cases in which protection is necessary or desirable and appropriate procedures for protection are known to those skilled in the art. Conventional protecting groups can be used in accordance with usual practice (for illustration see T.W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if the reaction agents include groups such as amino, carboxy or hydroxy, it may be desirable to protect the group in any of the reactions mentioned herein.

A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example, an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example, a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl, an arylmethoxycarbonyl group, for for example, benzyloxycarbonyl or an aroyl group, for example, benzoyl. The deprotection conditions for the above protective groups necessarily vary with the choice of the protective group. Thus, for example, an acyl group, such as an alkanoyl or alkoxycarbonyl group or an aroyl group, can be separated, for example, by hydrolysis with a suitable base, such as an alkali metal hydroxide, for example, lithium hydroxide or sodium. Alternatively, an acyl group such as a t-butoxycarbonyl group can be separated, for example, by treatment with an appropriate acid such as hydrochloric, sulfuric or phosphoric acid, or trifluoroacetic acid, and an arylmethoxycarbonyl group such as a group Benzyloxycarbonyl can be separated, for example, by hydrogenation on a catalyst such as palladium on carbon, or by treatment with a Lewis acid, for example, boron tris- (trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group, which can be separated by treatment with an alkylamine, for example, dimethylaminopropylamine or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acyl group, for example, an alkanoyl group such as acetyl, an aroyl group, for example, benzoyl or an arylmethyl group, for example, benzyl. The deprotection conditions for the above protective groups will necessarily vary with the choice of the protective group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group can be separated, for example, by hydrolysis with a suitable base, such as an alkali metal hydroxide, for example, lithium or sodium hydroxide. Alternatively, an arylmethyl group, such as a benzyl group, can be separated, for example, by hydrogenation with a catalyst such as palladium on carbon.

A suitable protecting group for a carboxy group is, for example, a group

5 esterifying agent, for example a methyl or ethyl group that can be separated, for example, by hydrolysis with a base such as sodium hydroxide or, for example a t-butyl group that can be separated, for example, by treatment with an acid , for example an organic acid such as trifluoroacetic acid, or for example a benzyl group that can be separated, for example, by hydrogenation with a catalyst such as palladium on

10 coal The protecting groups can be separated at any convenient stage of the synthesis using conventional techniques well known in the chemical art.

Certain intermediates described herein are new and are thus provided as an additional feature of the invention. For example the compounds of the formula VIIA and VIIB are provided as an additional feature of the

invention:

image 1

in which the variable groups are as defined here before. Also the compounds of the formula VIA and VIB are provided as an additional feature of the invention:

image 1

in which the variable groups are as defined here before.

Also, the new compounds of the formula IIA, IIB, VAT, IVB, VIIIA and VIIIB are considered additional features of the invention.

As indicated above, the compounds defined in the present invention have anti-cancer activity that is believed to arise from the CSF-1R kinase inhibitory activity of the compounds. These properties can be evaluated, for example, using the procedure described below.

BIOLOGICAL ACTIVITY

AlphaScreen CSF-1R in vitro assay

The activity of purified CSF-1R was determined in vitro using a homogeneous amplified luminescent proximity (ALPHA) assay (Perkin Elmer), which measures the phosphorylation of the CSF-1R substrate, biotinylated poly-glutamine-tyrosine peptide (pEY-HTRF CisBio 61 GTOBLD), as described below. The His tail kinase domain of CSF-1R (ie, amino acids 568-912, GeneBank ID NM_005211; (see page 25 lines 13-19 of WO 2006/067445 for sequence listing)) was purified from SF + Express insect cells infected by baculovirus (1.4 x 106 cells / ml), lysed in French press and subsequently chromatographed through Qiagen Ni-NTA, Superflow Mono Q HR 10/10, and Superdex 200 SEC columns. The typical yield was 245 µg / l cell pellet with> 95% purity.

The phosphorylation of the CSF-1R substrate was determined in the presence and absence of the compound of interest. In summary, purified 0.57 nM GSF-1R, 5nM pEY substrate, and the compound were pre-incubated in 1x buffer for 30 minutes at 25 ° C. The reactions were started with the addition of 90 µM adenosine triphosphate (ATP) in 1x buffer and incubated at 25 ° C for 60 minutes and the reactions were stopped by adding 5 µl of detection mixture consisting of 136 mM NaCl, ethylenediaminetetraacetic acid 102 mM, 1.65 mg / ml of BSA, 40 ug / ml of streptavidin donor beads (Perkin Elmer 6760002), 40 ug / ml of pTyr100 acceptor beads

5 (Perkin Elmer 6760620). The plates were incubated at 25 ° C for 18 hours in the dark. The phosphorylated substrate was detected by an EnVision plate reader (Perkin Elmer) excitation at 680 nm, emission at 520-620 nm. Data were plotted and IC50 values were calculated using the ExCel Fit program (Microsoft).

When analyzed with the previous in vitro assay, the compounds of the present invention exhibited an activity of less than 30 µM. For example, the following results were obtained:

Example No

IC50 (nM)

3

26

9

2. 3

18

154

Pharmaceutical Formulations According to a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of the formula IA or IB, or a pharmaceutically acceptable salt thereof, as defined herein, in association with a pharmaceutically acceptable diluent or carrier. .

The composition may be in a form suitable for oral administration, for example, in the form of a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or perfusion injection) in the form of a sterile solution, suspension or emulsion. , for topical administration in the form of an ointment or cream or for rectal administration

25 in the form of suppository. In general the above compositions can be prepared in a conventional manner using conventional excipients.

The compound of the formula IA or IB will normally be administered to a warm-blooded animal at a unit dose within the range 1-1000 mg / kg, and this normally provides a therapeutically effective dose. Preferably, a daily dose in the range of 10-100 mg / kg is used. However, the daily dose

It will necessarily vary depending on the patient treated, the particular route of administration and the severity of the disease being treated. Therefore, the optimal dose can be determined by the doctor who is treating a particular patient.

Applications

According to a further aspect of the present invention there is provided a compound of the formula IA or IB, or a pharmaceutically acceptable salt thereof, as defined above, for use in a method of treating the human or animal body by therapy.

It has been found that the compounds defined in the present invention, or a pharmaceutically acceptable salt thereof, are effective anti-cancer agents whose property is believed to arise from their CSF-1R kinase inhibitory properties. Therefore, it is expected that the compounds of the present invention will be useful in the treatment of diseases or medical conditions mediated, only or in part, by the CSF-1R kinase, that is the compounds can be used to produce an inhibitory effect of CSF-1R kinase in a warm-blooded animal that needs such treatment.

Thus, the compounds of the present invention provide a method for treating cancer characterized by the inhibition of CSF-IR kinase, that is, the compounds can be used to produce an anti-cancer mediated effect, only or in part, by CSF-1R kinase inhibition.

Said compound of the invention is expected to have a wide range of anti-cancer properties since aberrant expression of CSF1R and / or CSF1 has been observed in multiple human cancers and derived cell lines, including but not limited to, tumors of breast, ovaries, endometrium, prostate, lung, kidney and pancreatic as well as hematological malignancies including, but not limited to, myelodysplastic syndrome, acute myelogenous leukemia, chronic myelogenous leukemia, non-Hodgkin lymphoma, Hodgkin's disease , multiple myeloma and chronic lymphocytic leukemia. Activating mutations in hematopoietic and lymphoid tissue and in lung cancer have also been described. In addition, macrophages associated with the tumor have been associated with poor prognosis in multiple types of tumors including, but not limited to, breast, endometrial, kidney, lung, bladder and cervical cancers, the glioma, squamous cell carcinoma of the esophagus, uveal melanoma and malignant follicular lymphoma. A compound of the invention is expected to have anti-cancer activity against these cancers through the direct effect on the tumor and / or indirectly through the effect on macrophages associated with the tumor. Alternatively, particular cancers include melanoma, papillary thyroid tumors, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukemia, malignant lymphoid tumors, carcinomas and sarcomas of the liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumors of the skin, colon, thyroid, lungs and ovaries.

In a further aspect of the invention, the compounds of the formula IA or IB may also be valuable in the treatment of certain additional indications. These indications include, but are not limited to, osteolysis associated with tumors, osteoporosis including bone loss induced by ovariectomy, orthopedic implant failures, autoimmune disorders including systemic lupus erythematosus, arthritis including rheumatoid arthritis, osteoarthritis, renal inflammation and glomerulonephritis; inflammatory bowel disease; transplant rejection including renal and bone marrow allografts and skin xenograft, atherosclerosis, obesity, Alzheimer's disease and Langerhans cell histiocytosis. A further aspect of the present invention therefore includes the treatment of one or more of these diseases, particularly arthritis including rheumatoid arthritis and osteoarthritis. These indications also include, but are not limited to, chronic obstructive pulmonary disease, diabetes and chronic skin disorders including psoriasis.

Thus, according to this aspect of the invention there is provided a compound of the formula IA or IB, or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use as a medicament.

According to a further aspect of the invention there is provided the use of a compound of the formula IA or IB, or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the manufacture of a medicament for use in the production of a kinase inhibitor effect of CSF-1R in a warm-blooded animal such as humans.

According to this aspect of the invention there is provided the use of a compound of the formula IA or IB, or a pharmaceutically acceptable salt thereof, as defined above, in the manufacture of a medicament for use in the production of an anti- effect. cancer in a warm-blooded animal such as humans.

According to another feature of the invention, the use of a compound of the formula IA or IB, or a pharmaceutically acceptable salt thereof, as defined above, is provided in the manufacture of a medicament for use in the treatment of melanoma, tumors Thyroid papillary, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukemia, malignant lymphoid tumors, carcinomas and sarcomas of the liver, kidney, bladder, prostate, breast and pancreas, and primary solid tumors and recurring of the skin, colon, thyroid, lungs and ovaries.

According to another feature of the invention, the use of a compound of the formula IA or IB, or a pharmaceutically acceptable salt thereof, as defined hereinbefore, is provided in the manufacture of a medicament for use in the treatment of breast, ovarian, bladder, cervical, endometrial, prostate, lung, kidney and pancreatic tumors; hematologic malignancies including myelodysplastic syndrome, acute myelogenous leukemia, chronic myelogenous leukemia, non-Hodgkin lymphoma, Hodgkin's disease, multiple myeloma and chronic lymphocytic leukemia; and glioma, squamous cell carcinoma of the esophagus, uveal melanoma and malignant follicular lymphoma.

According to another feature of the invention, the use of a compound of the formula IA or IB, or a pharmaceutically acceptable salt thereof, as defined hereinbefore, is provided in the manufacture of a medicament for use in the treatment of osteolysis associated with tumors, osteoporosis including bone loss induced by ovariectomy, orthopedic implant failures, autoimmune disorders including systemic lupus erythematosus, arthritis including rheumatoid arthritis, osteoarthritis, renal inflammation and glomerulonephritis; inflammatory bowel disease; transplant rejection including renal and bone marrow allografts and skin xenograft, atherosclerosis, obesity, Alzheimer's disease, chronic obstructive pulmonary disease, diabetes and chronic skin disorders including psoriasis and Langerhans cell histiocytosis.

According to another feature of this aspect of the invention there is provided a method for producing a CSF-1R kinase inhibitory effect on a warm-blooded animal, such as the human being, in need of such treatment comprising administering to said animal an amount effective of a compound of the formula IA or IB,

or one of its pharmaceutically acceptable salts, as defined above.

According to another feature of this aspect of the invention there is provided a method for producing an anti-cancer effect in a warm-blooded animal, such as the human being, in need of such treatment comprising administering to said animal an effective amount of a compound of Formula IA or IB, or a pharmaceutically acceptable salt thereof, as defined above.

According to an additional feature of this aspect of the invention there is provided a method of treatment of melanoma, papillary thyroid tumors, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukemia, malignant lymphoid tumors, carcinomas and liver sarcomas, of kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumors of the skin, colon, thyroid, lungs and ovaries, in a warm-blooded animal, such as humans, that said treatment needs comprising administering to said animal an effective amount of a compound of the formula IA or IB

or one of its pharmaceutically acceptable salts as defined above.

According to an additional feature of this aspect of the invention there is provided a method of treatment of breast, ovarian, bladder, cervix, endometrial, prostate, lung, kidney and pancreatic tumors; hematologic malignancies including myelodysplastic syndrome, acute myelogenous leukemia, chronic myelogenous leukemia, non-Hodgkin lymphoma, Hodgkin's disease, multiple myeloma and chronic lymphocytic leukemia; and glioma, squamous cell carcinoma of the esophagus, uveal melanoma and malignant follicular lymphoma in a warm-blooded animal, such as humans, in need of such treatment which comprises administering to said animal an effective amount of a compound of the formula IA or IB or one of its pharmaceutically acceptable salts as defined above.

According to an additional feature of this aspect of the invention, a method of treating osteolysis associated with tumors, osteoporosis including bone loss induced by ovariectomy, orthopedic implant failures, autoimmune disorders including systemic lupus erythematosus, arthritis including rheumatoid arthritis, osteoarthritis, is provided. renal inflammation and glomerulonephritis; inflammatory bowel disease; transplant rejection including renal and bone marrow allografts and skin xenograft, atherosclerosis, obesity, Alzheimer's disease, chronic obstructive pulmonary disease, diabetes and chronic skin disorders including psoriasis and histiocytosis of Langerhans cells in a warm-blooded animal, such as the human being, who needs said treatment which comprises administering to said animal an effective amount of a compound of the formula IA or IB or a pharmaceutically acceptable salt thereof as defined above.

In another aspect of the invention there is provided a pharmaceutical composition comprising a compound of the formula IA or IB, or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in association with a pharmaceutically acceptable diluent or carrier, for use in the production of an inhibitory effect of CSF-1R kinase in a warm-blooded animal such as humans.

In another aspect of the invention there is provided a pharmaceutical composition comprising a compound of the formula IA or IB, or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in association with a pharmaceutically acceptable diluent or carrier, for use in the production of an anti-cancer effect in a warm-blooded animal such as humans.

In a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of the formula IA or IB, or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in association with a pharmaceutically acceptable diluent or carrier, for use in the treatment of melanoma, papillary thyroid tumors, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukemias, malignant lymphoid tumors, carcinomas and sarcomas of the liver, kidney, bladder, prostate, breast and of pancreas, and primary and recurrent solid tumors of the skin, colon, thyroid, lungs and ovaries in a warm-blooded animal such as humans.

In a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of the formula IA or IB, or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in association with a pharmaceutically acceptable diluent or carrier, for use in the treatment of breast, ovarian, bladder, cervix, endometrial, prostate, lung, kidney and pancreatic tumors; hematologic malignancies including myelodysplastic syndrome, acute myelogenous leukemia, chronic myelogenous leukemia, non-Hodgkin lymphoma, Hodgkin's disease, multiple myeloma and chronic lymphocytic leukemia; and glioma, squamous cell carcinoma of the esophagus, uveal melanoma and malignant follicular lymphoma in a warm-blooded animal such as humans.

In a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of the formula IA or IB, or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in association with a pharmaceutically acceptable diluent or carrier, for use in the treatment of osteolysis associated with tumors, osteoporosis including bone loss induced by ovariectomy, orthopedic implant failures, autoimmune disorders including systemic lupus erythematosus, arthritis including rheumatoid arthritis, osteoarthritis, renal inflammation and glomerulonephritis; inflammatory bowel disease; transplant rejection including renal and bone marrow allografts and skin xenograft, atherosclerosis, obesity, Alzheimer's disease, chronic obstructive pulmonary disease, diabetes and chronic skin disorders including psoriasis and histiocytosis of Langerhans cells in such a warm-blooded animal Like the human being

According to a further aspect of the invention, the use of a compound of the formula IA or IB, or a pharmaceutically acceptable salt thereof, as defined above, is provided in the production of a CSF-1R kinase inhibitory effect in a warm-blooded animal such as the human being.

According to this aspect of the invention there is provided the use of a compound of the formula IA or IB, or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the production of an anti-cancer effect in an animal of Warm blood just like the human being.

According to a further feature of the invention, the use of a compound of the formula IA or IB, or a pharmaceutically acceptable salt thereof, as defined hereinbefore, is provided in the treatment of melanoma, papillary thyroid tumors, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukemia, malignant lymphoid tumors, carcinomas and sarcomas of the liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumors of the skin , colon, thyroid, lungs and ovaries.

According to a further feature of the invention, the use of a compound of the formula IA or IB, or a pharmaceutically acceptable salt thereof, as defined hereinbefore, is provided in the treatment of breast, ovarian tumors, bladder, cervix, endometrium, prostate, lung, kidney and pancreatic; hematologic malignancies including myelodysplastic syndrome, acute myelogenous leukemia, chronic myelogenous leukemia, non-Hodgkin lymphoma, Hodgkin's disease, multiple myeloma and chronic lymphocytic leukemia; and glioma, squamous cell carcinoma of the esophagus, uveal melanoma and malignant follicular lymphoma.

According to a further feature of the invention, the use of a compound of the formula IA or IB, or a pharmaceutically acceptable salt thereof, as defined hereinbefore, is provided in the treatment of tumor-associated osteolysis, osteoporosis. including ovariectomy-induced bone loss, orthopedic implant failures, autoimmune disorders including systemic lupus erythematosus, arthritis including rheumatoid arthritis, osteoarthritis, renal inflammation and glomerulonephritis; inflammatory bowel disease; transplant rejection including renal and bone marrow allografts and skin xenograft, atherosclerosis, obesity, Alzheimer's disease, chronic obstructive pulmonary disease, diabetes and chronic skin disorders including psoriasis and Langerhans cell histiocytosis.

The CSF-1R kinase inhibitor treatment defined hereinbefore may be applied as a single therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of antitumor agents:

(i)

antiproliferative / antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cisplatin, carboplatin, cyclophosphamide, nitrogen mustards, melphalan, chlorambucil, busulfan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines, for example 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); antitumor antibiotics (for example, anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mitramycin); antimitotic agents (for example vinca alkaloids such as vincristine, vinblastine, vindesine and vinorelbine and taxoids such as taxol and taxotere); and topoisomerase inhibitors (for example epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan and camptothecin);

(ii)

cytostatic agents such as antiestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxifene), negative estrogen receptor regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), antagonists of

LHRH or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazol and exemestane) and S�-reductase inhibitors such as finasteride;

(iii) agents that inhibit the invasion of cancer cells (for example metalloproteinase inhibitors such as marimastat and inhibitors of the function of the receptor of the plasminogen activator urokinase);

(iv)

inhibitors of growth factor function, for example such inhibitors include antibodies against growth factors, antibodies against growth factor receptors (for example the antierbb2 trastuzumab [Herceptin ™] antibody and the anti-erbb1 cetuximab antibody [C225] ), farnesyl transferase inhibitors, MEK inhibitors, tyrosine kinase inhibitors and serine / threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (eg EGFR family tyrosine kinase inhibitors such as N- (3 -chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-amine (gefitinib, AZD1839), N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) quinazolin- 4-amine (erlotinib, OSI-774) and 6-acrylamido-N- (3-chloro-4-fluorophenyl) -7- (3morpholinopropoxy) quinazolin-4-amine (CI 1033)), for example inhibitors of the family of the platelet-derived growth factor and for example inhibitors of the cre factor family hepatocyte foundation;

(v)

antiangiogenic agents such as those that inhibit the effects of vascular endothelial growth factor (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [Avastin ™], compounds such as those described in international patent applications WO 97/22596 , WO 97/30035, WO 97/32856 and WO 98/13354) and compounds that work by other mechanisms (for example linomide, inhibitors of the function of the integrin �v�3 and angiostatin);

(saw)

agents that cause vascular damage, such as combretastatin A4 and the compounds described in international patent applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/0443 and WO 02/08213;

(vii) antisense therapies, for example those directed at the targets listed above, such as ISIS 2503, an anti-ras antisense;

(viii) gene therapy strategies, which include for example strategies to replace abnormal genes such as abnormal p53 or BRCA1 or abnormal BRCA2, GDEPT (gene targeted enzyme prodrug therapy) strategies, such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme, and strategies to increase the patient's tolerance to chemotherapy or radiotherapy, such as multiple drug resistance gene therapy;

(ix)

immunotherapy strategies, including for example ex vivo and in vivo strategies to increase the immunogenicity of the patient's tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, strategies to decrease T cell energy, strategies that employ transfected immune cells such as dendritic cells transfected with cytokines, strategies that use tumor cell lines transfected with cytokines, and strategies that use anti-idiotypic antibodies.

(x)

Cell cycle inhibitors, which include for example CDK inhibitors (eg flavopyridol) and other checkpoint inhibitors of the cell cycle (eg checkpoint kinase); Aurora kinase and other kinase inhibitors involved in the regulation of mitosis and cytokinesis (eg mitotic kinesins); and histone deacetylase inhibitors. Y

(xi)

endothelin antagonists, including endothelin A antagonists, endothelin B antagonists and endothelin A and B antagonists; for example ZD4054 and ZD1611 (WO 96 40681), atrasentan and YM598.

Said joint treatment can be achieved by means of simultaneous, sequential or separate administration of the individual components of the treatment. Such combination products employ the compounds of this invention within the dosage range described above and the other pharmaceutically active agent within its authorized dosage range.

In addition to their use in therapeutic medicine, the compounds of the formula IA or IB and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardization in vitro and in vivo of test systems for the evaluation of the effects of CSF-1R kinase inhibitors in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.

In the other pharmaceutical composition above, the method, method, use and manufacturing properties of the medicament, alternative and preferred embodiments of the compounds of the invention described herein are also applied.

Procedures to perform

The compounds of the formula 1A can be prepared as indicated in Schemes 1 and 2. The routes indicated in the schemes can be easily adapted for the preparation of compounds of the formula IB, by choosing the starting material; that is, by using

image 1

10 as a starting material in Scheme 1 or

image 1

As a starting material in Scheme 2, the compounds of formula IB can be obtained.

Scheme 1

image 1

Scheme 2

image 1

Examples

The invention will be illustrated below by the following non-limiting examples in which, unless otherwise indicated:

(i) temperatures are given in degrees Celsius (° C); operations were carried out at room temperature unless otherwise indicated, that is, at a temperature in the range of 18-25 ° C;

10 (ii) the organic solutions were dried over sodium sulfate, or anhydrous magnesium sulfate; evaporation of the solvent was performed using a rotary evaporator under reduced pressure (600-4000 Pascals; 4.5-30 mm Hg) with a bath temperature of up to 60 ° C;

(iii) in general, the course of the reactions was followed by TLC and the reaction times 15 are given by way of illustration only;

(iv)

the final products had proton nuclear magnetic resonance (NMR) spectra and / or satisfactory mass spectral data;

(v)

yields are given for illustrative purposes only and are not necessarily those

that can be obtained by a thorough development of the process; the preparations were repeated when more material was needed;

(vii) when offered, the NMR data are in the form of delta values for the main diagnostic protons, given in parts per million (ppm) referred to tetramethylsilane (TMS) as internal standard, determined at 400 MHz using perdeuterium dimethylsulfoxide (DMSO-d6) as solvent unless indicated

25 something else;

(vii) chemical symbols have their usual meanings; SI units and symbols are used;

(viii) solvent ratios are given in terms of volume: volume (v / v); Y

(ix) the mass spectra were swept with an electronic energy of 70

30 electron volts in chemical ionization mode (CI) using a direct exposure probe; if indicated, the ionization was effected by electron impact (IE), rapid atom bombardment (FAB) or electrospray (ESP); values are given for m / z; in general, only the ions indicating the main mass are shown and, unless expressed otherwise, the mass ion cited is (MH) +;

(x) when a synthesis is described as analogous to that described in a previous example,

5 the quantities used are the equivalent in millimolar relation to those used in the previous example;

(xi) the following abbreviations have been used:

DMF N, N dimethylformamide; EtOAc ethyl acetate; MeOH methanol; DIEA N, N-Diisopropylethylamine; HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N' hexafluorophosphate

tetramethyluronium; MP-Carbonate of methyl polystyrene-triethylammonium macroporous carbonate; THF tetrahydrofuran; DMSO dimethylsulfoxide;

10 (xii) "ISCO" refers to normal column rapid column chromatography using pre-loaded 12 g and 40 g silica gel cartridges used according to the manufacturer's instructions obtained from ISCO, Inc, 4700 superior street Lincoln, NE, USA. ; Y

(xiii) "Gilson HPLC" refers to a YMC-AQC18 reverse phase HPLC column

15 with dimensions 20 mm / 100 and 50 mm / 250 in water / MeCN with 0.1% TFA as mobile phase.

Example 1

4 - [(2,3-Dichlorophenyl) amino] -7-methoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxamide

To a solution of ethyl 4 - [(2,3-dichlorophenyl) amino] -7-methoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate (Intermediate 1; 117 mg, 0.24 mmol) and formamide (47 µL, 1.2 mmol) in anhydrous DMF under N2 at 100 ° C, a solution of NaOMe in MeOH (0.5 M, 1.44 mL, 0, was added dropwise over 10 minutes. 72 mmol). After 2 hours at 100 ° C, the reaction mixture was cooled and poured into water. It was extracted

The aqueous layer with EtOAc was dried (Na2SO4), filtered, and concentrated to give 38 mg of a solid. 1H NMR (CD3OD): 8.92 (s, 1 H), 7.60 (dd, 1 H), 7.39 (m, 3 H), 7.01 (s, 1 H), 4.07 ( s, 3 H), 3.50 (m, 2 H), 3.38 (m, 2 H), 3.23 (m, 2 H), 2.92 (s, 3 H), 2.73 ( m, 2H); m / z: 460.

Examples 2-173

The following examples were prepared by a method similar to Example 1 using the appropriate starting materials (MP), where purification of the intermediates and final compounds was performed in some cases using an ISCO column chromatography or a Gilson HPLC system.

Ex.

Compound NMR m / z MP

2

4 - [(2,4-Dichlorophenyl) amino] -7methoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxamide CD3OD 8.82 (s, 1 H), 7.52 (d, 1 H), 7.28 (s, 1 H), 7.12 (dd, 1 H), 6.84 (s, 1 H) , 6.71 (d, 1 H), 3.97 (s, 3 H), 2.97 (m, 4 H), 2.86 (m, 4 H), 2.52 (s, 3 H) 460 Intermediate 2

3

4 - [(3,4-Dichlorophenyl) amino] -7methoxy-6- (4-methylpiperazin-1yl) quinolin-3-carboxamide CD3OD 8.79 (s, 1 H), 7.60 (d, 1 H), 7.53 (s, 1 H), 7.44 (d, 2 H), 7.27 (d, 1 H) , 4.1 (s, 3 H), 3.61 (m, 4 H), 3.27 (m, 2 H), 2.98 (m, 5 H) 460 Intermediate 3

4

4 - [(2,4-Difluorophenyl) amino] -7methoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxamide CD3OD 8.81 (s, 1 H), 7.52 (m, 1 H), 7.44 (s, 1H), 7.35 (s, 1H), 7.19 (m, 1 H), 7 , 12 (t, 1 H), 4.09 (s, 3 H), 3.55 (m, 4 H), 3.29 (m, 2 H), 2.96 (s, 3 H), 2 , 90 (m, 2 H) 428 Intermediate 4

5

4 - [(2,3-Dichlorophenyl) amino] -7methoxy-6-morpholin-4-ylquinolin-3carboxamide CD3OD 8.89 (s, 1H), 7.63 (d, 1 H), 7.42 (m, 2 H), 7.27 (s, 1 H), 6.91 (s, 1 H), 4.06 (s, 3 H), 3.70 (m, 4 H), 2.73 (m, 4 H) 447 Intermediate 5

6

4 - [(2,4-Difluorophenyl) amino] -7methoxy-6-morpholin-4-ylquinolin-3carboxamide CD3OD 8.80 (s, 1 H), 7.51 (d, 1 H), 7.31 (s, 1 H), 7.19 (m, 1 H), 7.18 (s, 1 H) , 7.14 (m, 1 H), 4.06 (s, 3 H), 3.74 (m, 4 H), 2.85 (m, 4 H) 415 Intermediate 6

7

4 - [(3,4-Dichlorophenyl) amino] -7methoxy-6-morpholin-4-ylquinolin-3carboxamide CD3OD 8.78 (s, 1 H), 7.62 (d, 1 H), 7.52 (d, 1 H), 7.29 (m, 2 H), 7.20 (s, 1 H) , 4.07 (s, 3 H), 3.76 (m, 4 H), 2.90 (m, 4 H) 447 Intermediate 7

Ex.

Compound NMR m / z MP

8

4 - [(3,4-Dichlorophenyl) amino] -7methoxy-6-piperidin-1-ylquinolin-3carboxamide CD3OD 8.79 (s, 1 H), 7.62 (d, 1 H), 7.51 (d, 1 H), 7.30 (s, 1 H), 7.28 (dd, 1 H) , 7.13 (s, 1 H), 4.05 (s, 3 H), 2.81 (m, 4 H), 1.63 (m; 4 H), 1.55 (m, 2 H) 445 Intermediate 8

9

4 - [(2,3-Dichlorophenyl) amino] -6methoxy-7- (4-methylpiperazin-1yl) quinolin-3-carboxamide CD3OD 8.91 (s, 1 H), 7.78 (s, 1 H), 7.58 (dd, 1 H), 7.41 (m, 3 H), 6.95 (s, 1 H) , 4.08 (m, 2 H), 3.67 (m, 2 H), 3.53 (s, 3 H), 3.33 (m, 4 H), 3.02 (s, 3 H) 460 Intermediate 9

10

4 - [(3,4-Dichlorophenyl) amino] -6methoxy-7- (4-methylpiperazin-1yl) quinolin-3-carboxamide CD3OD 8.74 (s, 1 H), 7.57 (d, 1 H), 7.51 (d, 1 H), 7.37 (s, 1H), 7.34 (s, 1 H), 7.25 (dd, 1 H), 4.03 (m, 2 H), 3.75 (s, 3 H), 3.64 (m, 2 H), 3.30 (m, 4 H), 2.99 (s, 3 H) 460 Intermediate 10

eleven

4 - [(2,4-Difluorophenyl) amino] -7ethoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxamide CD3OD 8.80 (s, 1H), 7.51 (m, 1 H), 7.34 (s, 2 H), 7.20 (m, 1 H), 7.13 (d, 1 H), 4.32 (q, 2 H), 3.54 (m, 4 H), 3.29 (m, 2 H), 2.94 (s, 3 H), 2.85 (m, 2 H), 1.56 (t, 3 H) 441 Intermediate 11

12

4 - [(2,3-Dichlorophenyl) amino] -7ethoxy-6- (4-methylpiperazin-1yl) quinolin-3-carboxamide CD3OD 8.87 (s, 1 H), 7.53 (dd, 1 H), 7.35 (m, 3 H), 6.93 (s, 1 H), 4.27 (q, 2 H) , 3.43 (m, 4 H), 3.20 (m, 2 H), 2.89 (s, 3 H), 2.71 (m, 2 H), 1.49 (t, 3 H) 474 Intermediate 12

13

4 - [(2,4-Difluorophenyl) amino] -7ethoxy-6-morpholin-4-ylquinolin-3carboxamide CD3OD 8.78 (s, 1 H), 7.52 (d, 1 H), 7.24 (m, 3 H), 7.14 (m, 1 H), 4.30 (t, 2 H) , 3.75 (m, 4 H), 2.86 (m, 4 H), 1.52 (t, 3 H) 429 Intermediate 13

14

4 - [(3,4-Dichlorophenyl) amino] -7ethoxy-6-morpholin-4-ylquinolin-3carboxamide CD3OD 8.68 (s, 1 H), 7.53 (d, 1 H), 7.43 (d, 1 H), 7.19 (m, 2 H), 7.10 (s, 1 H) , 4.21 (q, 2 H), 3.65 (m, 4 H), 2.83 (m, 4 H), 1.44 (t, 3 H) 461 Intermediate 14

Ex.

Compound NMR m / z MP

fifteen

4- {3- (Aminocarbonyl) -4 - [(2,3-dichlorophenyl) amino] -7-methoxyquinoline-6-yl} piperazine-1-carboxylic acid tert-butyl ester 10.79 (s, 1 H), 8.94 (s, 1 H), 8.35 (s, 1 H), 7.75 (s, 1 H), 7.34 (s, 1 H), 7.25 (dd, 1 H), 7.14 (1, 1 H), 6.70 (s, 1 H), 6.59 (d, 1 H), 3.95 (s, 3 H), 3.33 (m, 4 H), 2.68 (m, 4 H), 1.39 (s, 9H) 545 Intermediate 15

16

4 - [(2,4-Difluorophenyl) amino] -7fluoro-6- (4-methylpiperazin-1-yl) quinolin-3-carboxamide 10.63 (s, 1 H), 8.86 (s, 1H), 8.29 (s, 1 H), 7.71 (s, 1 H), 7.63 (d, 1 H), 7 , 38 (m, 1 H), 7.11 (m, 3 H), 2.82 (m, 4 H), 2.48 (m, 4 H), 2.26 (s, 3 H) 416 Intermediate 16

17

4 - [(2,3-Dichlorophenyl) amino] -7fluoro-6- (4-methylpiperazin-1yl) quinolin-3-carboxamide 10.84 (s, 1 H), 8.98 (s, 1 H), 8.44 (s, 1H), 7.86 (s, 1 H), 7.70 (d, 1 H), 7 , 32 (d, 1 H), 7.19 (t, 1 H), 6.86 (d, 1 H), 6.69 (d, 1 H), 2.82 (m, 4 H), 2 , 48 (m, 4 H), 2.25 (s, 3 H) 448 Intermediate 17

18

4 - [(2,4-Difluorophenyl) amino] -7fluoro-6-morpholin-4-ylquinolin-3carboxamide CD3OD 8.84 (s, 1 H), 7.66 (d, 1 H), 7.52 (m, 1H), 7.45 (m, 1H), 7.22 (m, 1 H), 7 , 14 (m, 1 H), 3.78 (m, 4 H), 2.95 (m, 4 H) 403 Intermediate 18

19

4 - [(2,3-Dichlorophenyl) amino] -5fluoro-6- (4-methylpiperazin-1-yl) quinolin-3-carboxamide 10.90 (s, 1 H), 8.95 (s, 1 H), 8.46 (s, 1 H), 7.92 (s, 1 H), 7.79 (m, 1 H), 7.64 (t, 1 H), 7.19 (m, 1 H), 7.04 (t, 1 H), 6.47 (d, 1 H), 2.94 (m, 4 H), 2.38 (m, 4 H), 2.18 (s, 3 H) 448 Intermediate 19

twenty

7-Ethoxy-4 - [(4-ethylphenyl) amino] -6- (4methylpiperazin-1-yl) quinolin-3carboxamide 10.78 (s, 1 H), 8.82 (s, 1 H), 8.21 1 (s, 1 H), 7.57 (s, 1 H), 7.17 (s, 1 H) , 7.12 (d, 2 H), 6.89 (d, 2 H), 6.80 (s, 1 H), 4.14 (q, 2 H), 2.63 (s, 4 H) , 2.55 (q, 2 H), 2.30 (s, 4 H), 2.14 (s, 3 H), 1.38 (t, 3 H), 1.13 (t, 3 H) 434 Intermediate 20

twenty-one

4 - [(3-Chloro-4-fluorophenyl) amino] -7ethoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxamide 10.35 (s, 1 H), 8.80 (s, 1 H), 8.17 (s, 1 H), 7.59 (s, 1 H), 7.22-7.34 (m, 2 H), 7.09 (dd, 1 H), 6.85 6.96 (m, 2 H), 4.18 (q, 2 H), 2.81 (s, 4 H), 2.37 (s, 4 H), 2.17 (s, 3 H), 1.40 (t, 3 H) 458 Intermediate 21

Ex.

Compound NMR m / z MP

22

4 - [(3,4-Dichlorophenyl) amino] -7ethoxy-6- (4-methylpiperazin-1yl) quinolin-3-carboxamide 8.78 (s, 1 H), 8.12 (s, 1 H), 7.59 (s, 1 H), 7.44 (d, 1 H), 7.28 (s, 1 H), 7, 09 (d, 1 H), 6.96 (s, 1 H), 6.85 (dd, 1 H), 4.19 (q, 2 H), 2.88 (s, 4 H), 2, 43 (s, 4 H), 2.19 (s, 3 H), 1.41 (t, 3 H) 474 Intermediate 22

2. 3

4 - [(2,3-Dichlorophenyl) amino] -7ethoxy-6- (4-ethylpiperazin-1yl) quinolin-3-carboxamide 10.80 (s, 1 H), 8.91 (s, 1 H), 8.37 (s, 1 H), 7.76 (s, 1 H), 7.29 (s, 1 H), 7.26 (d, 1 H), 7.14 (t, 1 H), 6.64 (s, 1 H), 6.57 (d, 1 H), 4.19 (q, 2 H), 2.75 (s, 4 H), 2.38 (s, 4 H), 2.35 (q, 2 H), 1.40 (t, 3 H), 0.97 (t, 3 H) 488 Intermediate 23

24

4 - [(3-Chloro-2-fluorophenyl) amino] -7ethoxy-6-morpholin-4-ylquinolin-3carboxamide CD2Cl2 10.42 (s, 1 H), 8.77 (s, 1 H), 7.30 (s, 1 H), 7.06 (m, 1 H), 6.88 (m, 2 H) , 6.73 (m, 1 H), 6.05 (br s, 2 H), 4.21 (q, 2 H), 3.72 (m, 4 H), 2.80 (m, 4 H ), 1.50 (t, 3 H) 445 Intermediate 24

25

7-Ethoxy-4 - [(2-fluoro-5methylphenyl) amino] -6-morpholin-4ylquinolin-3-carboxamide CD2Cl2 10.42 (s, 1 H), 8.74 (s, 1 H), 7.26 (s, 1 H), 7.01 (dd, 1 H), 6.95 (s, 1 H) , 6.83 (m, 1 H), 6.77 (dd, 1 H), 6.02 (br s, 2 H), 4.20 (q, 2 H), 3.70 (m, 4 H ), 2.74 (m, 4 H), 2.18 (s, 3H), 1.49 (t, 3H) 426 Intermediate 25

26

4 - [(3-Chloro-4-fluorophenyl) amino] -7ethoxy-6-morpholin-4-ylquinolin-3carboxamide CD2Cl2 10.51 (s, 1H), 8.75 (s, 1 H), 7.27 (s, 1 H), 7.06 (m, 2 H), 6.92 (m, 1H), 6 , 85 (s, 1 H), 6.08 (br s, 2 H), 4.20 (q, 2 H), 3.673 (m, 4 H), 2.79 (m, 4 H), 1, 49 (t, 3 H) 447 Intermediate 26

27

7-Ethoxy-4 - [(4-ethylphenyl) amino] -6morpholin-4-ylquinolin-3carboxamide CD2Cl2 10.60 (s, 1H), 8.69 (s, 1 H), 7.21 (s, 1 H), 7.11 (d, 2 H), 6.97 (d, 2 H), 6.90 (s, 1 H), 5.92 (br s, 2 H), 4.18 (q, 2 H), 3.66 (m, 4 H), 2.67 (m, 4 H) , 2.59 (q, 2 H), 1.47 (t, 3H), 1.18 (t, 3H) 421 Intermediate 27

Ex.

Compound NMR m / z MP

28

4 - [(2,3-Dichlorophenyl) amino] -7ethoxy-6-morpholin-4-ylquinolin-3carboxamide CD2Cl2 10.36 (s, 1 H), 8.80 (s, 1 H), 7.32 (s, 1 H), 7.11 (d, 1 H), 6.97 (dd, 1 H) , 6.79 (s, 1 H), 6.60 (d, 1 H), 6.04 (br s, 2 H), 4.23 (q, 2 H), 3.72 (m, 4 H ), 2.82 (m, 4 H), 1.50 (t, 3 H) 462 Intermediate 28

29

4 - [(2,3-Dichlorophenyl) amino] -7ethoxy-6- (4-isopropylpiperazin-1-yl) quinolin-3-carboxamide 11.10 (s, 1 H), 9.10 (s, 1 H), 8.55 (s, 1 H), 7.95 (s, 1 H), 7.70 (m, 2 H), 7.50 (m, 3 H), 7.36 (s, 1 H), 4.40 (q, 2 H), 3.60 (m, 4 H), 3.30 (m, 1 H), 3.20 (m, 4 H), 1.60 (t, 3 H), 1.50 (d, 6 H) 501 Intermediate 29

30

4 - [(2,3-Dichlorophenyl) amino] -7ethoxy-6- (4-methyl-1,4-diazepan-1yl) quinolin-3-carboxamide 10.69 (s, 1 H), 8.85 (s, 1 H), 8.35 (s, 1 H), 7.74 (s, 1 H), 7.24 (m, 2 H), 7.12 (m, 1 H), 6.54 (m, 2 H), 4.17 (q, 2 H), 3.14 (m, 2 H), 2.99 (m, 2 H), 2.50 (m, 2 H), 2.42 (m, 2 H), 2.19 (s, 3 H), 1.69 (m, 2 H), 1.41 (t, 3 H) 487 Intermediate 30

31

4 - [(2,3-Dichlorophenyl) amino] -7ethoxy-6- (3-hydroxypyrrolidin-1yl) quinolin-3-carboxamide 11.99 (s, 1 H), 8.83 (s, 1 H), 8.40 (s, 1 H), 7.90 (s, 1 H), 7.50 (d, 1 H); 7.33 (m, 1 H), 7.28 (s, 1 H), 7.23 (m, 1 H), 6.35 (s, 1 H), 4.12 (m, 3 H), 3.10 (m, 2 H), 2.90 (m, 2 H), 1.79 (m, 1 H), 1.69 (m, 1 H), 1.39 (t, 3 H) 460 Intermediate 31

32

4 - [(2,3-Dichlorophenyl) amino] -6- {4 [2- (dimethylamino) ethyl] piperazin-1yl} -7-ethoxyquinoline-3-carboxamide 10.80 (s, 1 H), 9.00 (s, 1 H), 8.42 (s, 1 H), 7.75 (s, 1 H), 7.60 (m, 2 H), 7.35 (m, 2 H), 7.20 (s, 1 H), 4.25 (q, 2 H), 3.80-3.00 (m, 12 H), 2.85 (s, 6 H), 1.48 (t, 3 H) 530 Intermediate 32

33

4 - [(2,3-Dichlorophenyl) amino] -7ethoxy-6- [4- (2-methoxyethyl) piperazin1-yl] quinolin-3-carboxamide 11.10 (s, 1 H), 9.00 (s, 1 H), 8.45 (s, 1 H), 7.80 (s, 1 H), 7.60 (m, 2 H), 7.35 (m, 2 H), 7.22 (s, 1 H), 4.20 (q, 2 H), 3.71 (s, 3 H), 3.49-3.10 (m, 10 H), 2.95 (t, 2 H), 1.45 (t, 3 H) 517 Intermediate 33

Ex.

Compound NMR m / z MP

3. 4

4 - [(3,4-Dichlorophenyl) amino] -7 CD2Cl2 10.42 (s, 1 H), 488 Intermediate

ethoxy-6- (4-ethylpiperazin-1

8.75 (s, 1 H), 7.31 (d, 1 3. 4

il) quinolin-3-carboxamide

H), 7.27 (s, 1 H), 7.03 (s, 1 H), 6.86 (s, 1 H), 6.83 (d, 1 H), 6.05 (br s, 2 H), 4.21 (q, 2 H), 2.86 (m, 4 H), 2.48 (m, 4 H), 2.39 (q, 2 H), 1.51 (t, 3 H), 1.05 (t, 3 H)

35

4 - [(2,4-Difluorophenyl) amino] -7 10.72 (s, 1 H), 8.84 (s, 1 456 Intermediate

ethoxy-6- (4-ethylpiperazin-1

H), 8.27 (s, 1 H), 7.64 (s, 35

il) quinolin-3-carboxamide

1 H), 7.36 (m, 1 H), 7.23

(s, 1 H), 7.00 (m, 2 H),

6.79 (s, 1 H), 4.16 (q, 2

H), 2.72 (m, 4 H), 2.38

(m, 4 H), 2.32 (q, 2 H),

1.40 (t, 3 H), 0.97 (t, 3 H)

36

4 - [(3-Chloro-2-fluorophenyl) amino] -7 10.69 (s, 1 H), 8.86 (s, 1 472 Intermediate

ethoxy-6- (4-ethylpiperazin-1

H), 8.30 (s, 1 H), 7.71 (s, 36

il) quinolin-3-carboxamide

1 H), 7.18 -7.29 (m, 2 H), 7.06 (s, 1 H), 6.76 -6.84 (m, 2 H), 4.18 (q, 2 H ), 2.77 (s, 4 H), 2.35 (m, 6 H), 1.40 (t, 3 H), 0.97 (t, 3 H)

37

7-Ethoxy-6- (4-ethylpiperazin-1-yl) -4 [(2-fluoro-5methylphenyl) amino] quinolin-3carboxamide 10.78 (s, 1 H), 8.85 (s, 1 H), 8.29 (s, 1 H), 7.66 (s, 1 H), 7.17 (m, 2 H), 6.87 (m, 2 H), 6.69 (s, 1 H), 4.17 (q, 2 H), 2.71 (m, 4 H), 2.34 (m, 6 H), 2.13 (s, 3 H), 1.40 (t, 3 H), 0.97 (t, 3 H) 452 Intermediate 37

38

4 - [(3-Chloro-4-fluorophenyl) amino] -7 CD2Cl2 10.47 (s, 1 H), 472 Intermediate

ethoxy-6- (4-ethylpiperazin-1

8.74 (s, 1 H), 7.26 (s, 1 38

il) quinolin-3-carboxamide

H), 7.06 (d, 1 H), 7.04 (dd, 1 H), 6.88 (m, 1 H), 6.85 (s, 1 H), 6.08 (br s, 2 H), 4.20 (q, 2 H), 2.82 (m, 4 H), 2.47 (m, 4 H), 2.38 (q, 2 H), 1.50 (t, 3 H), 1.05 (t, 3 H)

39

7-Ethoxy-4 - [(4-ethylphenyl) amino] -6- (4-ethylpiperazin-1-yl) quinolin-3carboxamide CD2Cl2 10.56 (s, 1 H), 8.69 (s, 1 H), 7.19 (s, 1 H), 7.10 (d, 2 H), 6.97 (d, 2 H) , 6.91 (s, 1 H), 6.01 (br s, 2 H), 4.17 (q, 2 H), 2.70 (m, 4 H), 2.60 (q, 2 H ), 2.39 (m, 4 H), 2.36 (q, 2 H), 1.47 (t, 3 H), 1.19 (t, 3 H), 1.04 (t, 3 H ) 448 Intermediate 39

Ex.

Compound NMR m / z MP

40

6- [4- (2-Cyanoethyl) piperazin-1-yl] -4 [(2,3-dichlorophenyl) amino] -7ethoxyquinoline-3-carboxamide 10.80 (s, 1 H), 8.90 (s, 1 H), 8.35 (s, 1 H), 7.72 (s, 1 H), 7.30 (s, 1 H), 7.25 (d, 1 H), 7.15 (t, 1 H), 6.65 (s, 1 H), 6.52 (d, 1 H), 4.20 (q, 2 H), 2,802.45 (m, 12 H), 1.40 (t, 3 H) 512 Intermediate 40

41

4 - [(2,3-Dichlorophenyl) amino] -7ethoxy-6- (4-hydroxypiperidin-1yl) quinolin-3-carboxamide 12.40 (s, 1 H), 9.11 (s, 1 H), 8.68 (s, 1 H), 8.00 (s, 1 H), 7.61 (d, 1 H), 7.50 (s, 1 H), 7.40 (m, 2 H), 6.86 (s, 1 H), 4.20 (q, 2 H), 3.55 (m, 1 H), 3.00 (m, 2 H), 2.45 (m, 2 H), 1.70 (m, 2 H), 1.32 (m, 5 H) 474 Intermediate 41

42

7-Ethoxy-4 - [(4-ethylphenyl) amino] -6- (4methyl-1,4-diazepan-1-yl) quinolin-3carboxamide 10.71 (s, 1 H), 8.77 (s, 1 H), 8.20 (s, 1 H), 7.56 (s, 1 H), 7.14 (s, 1 H), 7.11 (d, 2 H), 6.86 (d, 2 H), 6.72 (s, 1 H), 4.13 (q, 2 H), 3.03 (m, 2 H), 2.86 (m, 2 H), 2.555 (m, 2 H), 2.41 (m, 2 H), 2.18 (s, 3 H), 1.65 (m, 2 H), 1, 39 (t, 3 H), 1.13 (t, 3 H) 448 Intermediate 42

43

4 - [(2,4-Difluorophenyl) amino] -7ethoxy-6- (3-hydroxypyrrolidin-1-yl) quinolin-3-carboxamide 10.60 (s, 1 H), 8.80 (s, 1 H), 8.30 (s, 1 H), 7.69 (s, 1 H), 7.40 (m, 1 H), 7.25 (s, 1 H), 7.05 (m, 1 H), 6.97 (m, 1 H), 6.45 (s, 1 H), 4.87 (d, 1 H), 4.29 (m, 1 H), 4.20 (q, 2 H), 3.45 (m, 1 H), 3.22 (m, 1 H), 3.00 (m, 2 H), 1.90 (m, 1 H), 1.75 (m, 1 H), 1.46 (t, 3 H) 428 Intermediate 43

44

4 - [(2,4-Difluorophenyl) amino] -7ethoxy-6- (4-hydroxypiperidin-1-yl) quinolin-3-carboxamide 10.78 (s, 1 H), 8.90 (s, 1 H), 8.31 (s, 1 H), 7.70 (s, 1 H), 7.43 (m, 1 H), 7.28 (s, 1 H), 7.05 (m, 2 H), 6.88 (s, 1 H), 4.67 (d, 1 H), 4.21 (q, 2 H), 3.55 (m, 1 H), 3.10 (m, 2 H), 2.46 (m, 2 H), 1.75 (m, 2 H), 1.45 (m, 5 H) 442 Intermediate 44

Ex.

Compound NMR m / z MP

Four. Five

4 - [(3,4-Dichlorophenyl) amino] -7 CD3OD 8.79 (s, 1 H), 502 Intermediate

ethoxy-6- (4-isopropylpiperazin-1

7.37 (d, 1 H), 7.26 (s, 1 Four. Five

il) quinolin-3-carboxamide

H), 7.07 (s, 1 H), 7.04 (d, 1 H), 6.88 (dd, 1 H), 4.24 (q, 2 H), 2.96 (m, 4 H), 2.65 (m, 5 H), 1.51 (t, 3 H), 1.10 (d, 6 H)

46

4 - [(2,4-Difluorophenyl) amino] -7 CD3OD 8.76 (s, 1 H), 470 Intermediate

ethoxy-6- (4-isopropylpiperazin-1

7.46 (m, 1 H), 7.36 (s, 1 46

il) quinolin-3-carboxamide

H), 7.34 (s, 1 H), 7.20 (m, 1 H), 7.13 (m, 1 H), 4.30 (q, 2 H), 3.58 (m, 5 H), 3.26 (m, 2 H), 2.95 (m, 2 H), 1.55 (t, 3 H), 1.42 (d, 6 H)

47

4 - [(3-Chloro-2-fluorophenyl) amino] -7 CD3OD 8.81 (s, 1 H), 486 Intermediate

ethoxy-6- (4-isopropylpiperazin-1

7.26 (s, 1 H), 7.16 (m, 1 47

il) quinolin-3-carboxamide

H), 7.04 (m, 1 H), 6.98 (s, 1 H), 6.83 (m, 1 H), 4.24 (q, 2 H), 2.91 (m, 4 H), 2.69 (m, 5 H), 1.51 (1, 3 H), 1.11 (d, 6 H)

48

7-Ethoxy-4 - [(2-fluoro-5methylphenyl) amino] -6- (4isopropylpiperazin-1-yl) quinolin-3carboxamide CD3OD 8.78 (s, 1H), 7.21 (s, 1 H), 7.03 (dd, 1 H), 7.00 (s, 1 H), 6.93 (m, 1 H), 6.78 (dd, 1 H), 4.23 (q, 2 H), 2.83 (m, 4 H), 2.68 (m, 1 H), 2.65 (m, 4 H), 2.19 (s, 3 H), 1.50 (t, 3H), 1.11 (d, 6H) 466 Intermediate 48

49

4 - [(3-Chloro-4-fluorophenyl) amino] -7 CD3OD 8.77 (s, 1 H), 486 Intermediate

ethoxy-6- (4-isopropylpiperazin-1

7.25 (s, 1 H), 7.16 (dd, 1 49

il) quinolin-3-carboxamide

H), 7.07 (d, 1 H), 7.03 (s, 1 H), 6.95 (dd, 1 H), 4.24 (q, 2 H), 2.96 (m, 4 H), 2.77 (m, 1 H), 2.74 (m, 4 H), 1.51 (t, 3 H), 1.13 (d, 6 H)

fifty

4 - [(2,4-Difluorophenyl) amino] -7 10.70 (s, 1 H), 8.85 (s, 1 455 Intermediate

ethoxy-6- (4-methyl-1,4-diazepan-1

H), 8.30 (s, 1 H), 7.61 (s, fifty

il) quinolin-3-carboxamide

1 H), 7.35 (m, 1 H), 7.25 (s, 1 H), 6.89 (m, 2 H), 6.63 (s, 1 H), 4.20 (q, 2 H), 3.20 (m, 2 H), 3.00 (m, 2 H), 2.55 (m, 7 H), 1.80 (m, 2 H), 1.40 (t, 3 H)

Ex.

Compound NMR m / z MP

51

4 - [(2,3-Dichlorophenyl) amino] -6- (4isopropylpiperazin-1-yl) -7methoxyquinoline-3-carboxamide 10.78 (s, 1 H), 8.92 (s, 1 H), 8.35 (s, 1 H), 7.75 (s, 1 H), 7.33 (s, 1 H), 7.26 (m, 1 H), 7.15 (m, 1 H), 6.65 (s, 1 H), 6.58 (d, 1 H), 3.95 (s, 3 H), 2.75 (m, 4 H), 2.60 (m, 1 H), 2.46 (m, 4 H), 0.95 (d, 6 H) 488 Intermediate 51

52

4 - [(2,4-Difluorophenyl) amino] -6- (4isopropylpiperazin-1-yl) -7methoxyquinoline-3-carboxamide 10.72 (s, 1 H), 9.86 (s, 1 H), 8.30 (s, 1 H), 7.67 (s, 1 H), 7.35 (m, 1 H), 7.26 (s, 1 H), 7.01 (m, 2 H), 6.80 (s, 1 H), 3.92 (s, 3 H), 2.70-2.45 (m, 9 H), 0.95 (d, 6 H) 455 Intermediate 52

53

4 - [(2,3-Dichlorophenyl) amino] -7methoxy-6- (4-methyl-1,4-diazepan-1yl) quinolin-3-carboxamide 8.90 (s, 1 H), 8.45 (s, 1 H), 7.75 (s, 1 H), 7.30 (m, 2 H), 7.17 (m, 1 H), 6.63 (s, 1 H), 6.58 (d, 1 H), 3.98 (s, 3 H), 3.20 (m, 2 H), 3.10 (m, 2 H), 2.50 (m, 4 H), 2.25 (s, 3 H), 1.75 (m, 2 H) 474 Intermediate 53

54

4 - [(2,4-Difluorophenyl) amino] -7methoxy-6- (4-methyl-1,4-diazepan-1yl) quinolin-3-carboxamide 10.65 (s, 1 H), 8.80 (s, 1 H), 8.30 (s, 1 H), 7.60 (s, 1 H), 7.32 (m, 1 H), 7.20 (m, 1 H), 6.95 (m, 2 H), 6.75 (m, 1 H), 3.90 (s, 3 H), 3.10 (m, 4 H), 3.00 (m, 4 H), 2.20 (s, 3 H), 1.69 (m, 2 H) 441 Intermediate 54

55

4 - [(2,3-Dichlorophenyl) amino] -6- (4-ethylpiperazin-l-yl) -7-methoxyquinoline-3-carboxamide 10.70 (s, 1 H), 8.85 (s, 1 H), 8.26 (s, 1 H), 7.67 (s, 1 H), 7.35 (m, 1 H), 7.28 (s, 1 H), 7.05 (m, 2 H), 6.80 (s, 1 H), 3.90 (s, 3 H), 2.75 (m, 4 H), 2.55 (m, 6 H), 0.95 (t, 3 H) 474 Intermediate 55

56

4 - [(2,4-Difluorophenyl) amino] -6- (4-ethylpiperazin-1-yl) -7-methoxyquinoline-3-carboxamide 10.80 (s, 1 H), 8.92 (s, 1 H), 8.40 (s, 1 H), 7.80 (s, 1 H), 7.35 (s, 1 H), 7.25 (m, 1 H), 7.15 (m, 1 H), 6.69 (s, 1 H), 6.55 (d, 1 H), 3.95 (s, 3 H), 2.75 (m 4 H), 2.38 (m, 4 H), 2.31 (q, 2 H), 1.00 (t, 3 H) 441 Intermediate 56

Ex.

Compound NMR m / z MP

57

4 - [(3,4-Dichlorophenyl) amino] -6- (4 CDCl3 10.45 (s, 1 H), 474 Intermediate

ethylpiperazin-1-yl) -7

8.74 (s, 1 H), 7.30 (m, 2 57

methoxyquinoline-3-carboxamide

H), 7.03 (d, 1 H), 6.91 (s, 1 H), 6.80 (d, 1 H), 4.00 (s, 3 H), 2.89 (s, 4 H), 2.54 (s, 4 H), 2.44 (q, 2 H), 1.09 (t, 3 H)

58

4 - [(3,4-Dichlorophenyl) amino] -6- (4 10.11 (s, 1 H), 8.80 (s, 1 488 Intermediate

isopropylpiperazin-1-yl) -7

H), 8.13 (s, 1H), 7.60 (s, 58

methoxyquinoline-3-carboxamide

1 H), 7.44 (d, 1 H), 7.31

(s, 1 H), 7.10 (d, 1 H),

6.97 (s, 1 H), 6.84 (d, 1

H), 3.94 (s, 3 H), 2.84 (s,

4 H), 2.63 (s, 1 H), 2.48

(s, 4 H), 0.96 (d, 6 H)

59

4 - [(3,4-Dichlorophenyl) amino] -7 CDCl3 10.40 (s, 1 H), 474 Intermediate

methoxy-6- (4-methyl-1,4-diazepan-1

8.69 (s, 1 H), 7.28 (m, 2 59

il) quinolin-3-carboxamide

H), 7.02 (d, 1 H), 6.80 (m, 2 H), 3.98 (s, 3 H), 3.25 (m, 2 H), 3.08 (m, 2 H), 2.64 (m, 4 H), 2.40 (br s, 3 H), 1.87 (m, 2 H)

60

4 - [(3,4-Dichlorophenyl) amino] -7 CD3OD 8.72 (s, 1 H), 488 Intermediate

ethoxy-6- (4-methyl-1,4-diazepan-1

7.38 (d, 1 H), 7.22 (s, 1 60

il) quinolin-3-carboxamide

H), 7.04 (s, 1 H), 6.86 (m, 2 H), 4.23 (q, 2 H), 3.29 (m, 2 H), 3.11 (m, 2 H), 2.76 (m, 2 H), 2.65 (m, 2 H), 2.36 (s, 3 H), 1.92 (m, 2 H), 1.53 (t, 3 H)

61

7-Ethoxy-4 - [(2-fluoro-5methylphenyl) amino] -6- (4-methyl-1,4diazepan-1-yl) quinolin-3carboxamide CD3OD 8.73 (s, 1 H), 7.19 (s, 1 H), 7.04 (dd, 1 H), 6.89 (m, 2 H), 6.75 (d, 1 H) , 4.21 (q, 2 H), 3.17 (m, 2 H), 2.96 (m, 2 H), 2.73 (m, 2 H), 2.64 (m, 2 H) , 2.35 (s, 3 H), 2.19 (s, 3 H), 1.89 (m, 2 H), 1.52 (t, 3H) 452 Intermediate 61

62

4 - [(3-Chloro-4-fluorophenyl) amino] -7 CD3OD 8.71 (s, 1H), 7.21 472 Intermediate

ethoxy-6- (4-methyl-1,4-diazepan-1

(s, 1 H), 7.15 (m, 1 H), 62

il) quinolin-3-carboxamide

7.04 (m, 1 H), 6.94 (m, 1 H), 6.87 (s, 1 H), 4.23 (q, 2 H), 3.24 (m, 2 H), 3.07 (m, 2 H), 2.78 (m, 2 H), 2.68 (m, 2 H), 2.37 (s, 3 H), 1.94 (m, 2 H), 1.52 (t, 3 H)

Ex.

Compound NMR m / z MP

63

4 - [(2-Fluorophenyl) amino] -7-methoxy6- (4-methylpiperazin-1-yl) quinolin-3carboxamide 10.85 (s, 1 H), 8.71 (s, 1 H), 7.53 (s, 1 H), 7.19 (s, 1 H), 6.68-7.06 (m, 6 H), 3.84 (s, 3 H), 2.65 (s, 4 H), 2.24 (s, 4 H), 2.08 (s, 3 H) 410 Intermediate 63

64

4- {3- (Aminocarbonyl) -4 - [(3-chloro4-fluorophenyl) amino] -7ethoxyquinolin-6-yl} piperazine-1-carboxylic acid tert-butyl ester CD2Cl2 10.42 (s, 1 H), 8.78 (s, 1 H), 7.31 (s, 1 H), 7.08 (m, 1 H), 6.90 (m, 1 H), 6.88 (s, 1 H), 6.72 (m, 1 H), 4.22 (q, 2 H), 3.44 (m, 4 H), 2.76 (m, 4 H), 1.50 (t, 3 H), 1.44 (s, 9 H) 544 Intermediate 64

65

Tert-Butyl 4- {3- (Aminocarbonyl) -7-ethoxy-4 [(2-fluoro-5-methylphenyl) amino] quinolin-6-yl} piperazin-1 carboxylate CD2Cl2 10.50 (s, 1 H), 8.76 (s, 1 H), 7.29 (s, 1 H), 7.02 (m, 1 H), 6.94 (s, 1 H) , 6.88 (m, 1 H), 6.77 (d, 1 H), 4.21 (q, 2 H), 3.42 (m, 4 H), 2.70 (m, 4 H) , 2.18 (s, 3 H), 1.49 (t, 3 H), 1.44 (s, 9 H) 523 Intermediate 65

66

4- {3- (Aminocarbonyl) -4 - [(3-chloro-2-fluorophenyl) amino] -7-ethoxyquinolin-6-yl} piperazine-1-carboxylic acid tert-butyl ester CD2Cl2 10.51 (s, 1 H), 8.75 (s, 1 H), 7.29 (s, 1 H), 7.07 (m, 2 H), 6.85 (m, 2 H), 4.22 (q, 2 H), 3.46 (m, 4 H), 2.76 (m, 4 H), 1.50 (t, 3 H), 1.44 (s, 9 H) 544 Intermediate 66

67

7-Methoxy-4 - [(3-methoxy-2 10.96 (s, 1 H), 8.64 (s, 1 436 Intermediate

methylphenyl) amino] -6- (4

H), 7.44 (s, 1H), 7.10 (s, 67

methylpiperazin-1-yl) quinolin-3

1 H), 6.80-6.85 (m, 1H),

carboxamide

6.72 (s, 1H), 6.70 (s, 1

H), 6.57 (d, 1H), 6.28 (d,

1H), 3.80 (s, 3 H), 3.69

(s, 3 H), 2.54 (s, 4 H),

2.22 (s, 4 H), 2.12 (s, 3

H), 2.08 (s, 3 H)

68

4 - [(4-Chloro-2-methylphenyl) amino] -7 10.73 (s, 1 H), 8.87 (s, 1 440 Intermediate

methoxy-6- (4-methylpiperazin-1

H), 8.30 (s, 1 H), 7.65 (s, 68

il) quinolin-3-carboxamide

1 H), 7.40-7.41 (m, 1H),

7.25 (s, 1 H), 7.10-7.13

(m, 1 H), 6.67 (m, 2 H),

3.89 (s, 3 H), 3.34 (s, 3

H), 2.68 (s, 4H), 2.34 (s,

4 H), 2.17 (s, 3 H)

Ex.

Compound NMR m / z MP

69

4 - [(3-Chloro-2-methylphenyl) amino] -7ethoxy-6- (4-methylpiperazin-1yl) quinolin-3-carboxamide 10.85 (s, 1H), 8.90 (s, 1 Fly, 8.30 (s, 1H), 7.60 (s, 1H), 7.20 (m, 2 H), 7.09 ( t, 1 H), 6.65 (m, 2 H), 4.15 (q, 2 H), 2.65 (m, 4 H), 2.50 (s, 3 H), 2.30 ( m, 4 H), 1.40 (t, 3 H) 453 Intermediate 69

70

4 - [(3-Chloro-2-fluorophenyl) amino] -7ethoxy-6- (4-methylpiperazin-1yl) quinolin-3-carboxamide 10.70 (s, 1 H), 8.85 (s, 1 H), 8.30 (s, 1 H), 7.55 (s, 1 H), 7.20 (m, 2 H), 7.05 (m, 1 H), 6.80 (m, 2 H), 4.20 (q, 2 H), 2.75 (m, 4 H), 2.49 (s, 3 H), 2.30 (m, 4 H), 1.40 (t, 3 H) 457 Intermediate 70

71

7-Ethoxy-4 - [(3-ethylphenyl) amino] -6- (4methylpiperazin-1-yl) quinolin-3carboxamide 10.70 (s, 1 H), 8.85 (s, 1 H), 8.20 (s, 1 H), 7.60 (s, 1 H), 7.20 (m, 2 H), 6,906.70 (m, 4 H), 4.20 (q, 2 H), 2.70 (m, 4 H), 2.50 (m, 5 H), 2.30 (m, 4 H), 1.40 (t, 3 H), 1.10 (t, 3 H) 433 Intermediate 71

72

4 - [(3-Chlorophenyl) amino] -7-ethoxy-6 (4-methylpiperazin-1-yl) quinolin-3carboxamide THF-d8 10.38 (s, 1 H), 8.86 (s, 1 H), 7.60 (s, 1 H), 7.09-7.15 (m, 3 H), 6.74 -6.81 (m, 4 H), 4.07 (q, 2 H), 2.70 (s, 4 H), 2.26 (s, 4 H), 2.09 (s, 3 H) , 1.86 (t, 3 H) 440 Intermediate 72

73

4 - [(2-Chloro-4-fluorophenyl) amino] -7ethoxy-6- (4-methylpiperazin-1yl) quinolin-3-carboxamide 10.85 (s, 1 H), 8.95 (s, 1 H), 8.38 (s, 1 H), 7.75 (s, 1 H), 7.65 (d, 1 H), 7.30 (s, 1 H), 7.15 (m, 1 H), 6.85 (m, 1 H), 6.69 (s, 1 H), 4.22 (q, 2 H), 2.80 (m, 4 H), 2.40 (m, 4 H), 2.21 (s, 3 H), 1.45 (t, 3 H) 457 Intermediate 73

74

4 - [(4-Chloro-2-fluorophenyl) amino] -7ethoxy-6- (4-methylpiperazin-1yl) quinolin-3-carboxamide 10.64 (s, 1 H), 8.85 (s, 1 H), 8.30 (s, 1 H), 7.69 (s, 1 H), 7.50 (d, 1 H), 7.27 (s, 1 H), 7.15 (d, 1 H), 6.89 (m, 1 H), 6.80 (s, 1 H), 4.20 (q, 2 H), 2.80 (m, 4 H), 2.35 (m, 4 H), 2.18 (s, 3 H), 1.40 (t, 3 H) 457 Intermediate 74

Ex.

Compound NMR m / z MP

75

7-Ethoxy-4 - [(3-methylphenyl) amino] -6 (4-methylpiperazin-1-yl) quinolin-3carboxamide 10.70 (s, 1 H), 8.90 (s, 1 H), 8.27 (s, 1 H), 7.65 (s, 1 H), 7.28 (s, 1 H), 7.20 (m, 1 H), 6.93 (m, 2 H), 6.80 (m, 2 H), 4.22 (q, 2 H), 2.75 (m, 4 H), 2.37 (m, 4 H), 2.26 (s, 3 H), 2.20 (s, 3 H), 1.45 (t, 3 H) 419 Intermediate 75

76

4 - [(2-Chloro-3-methylphenyl) amino] -7ethoxy-6- (4-methylpiperazin-1yl) quinolin-3-carboxamide 10.80 (s, 1 H), 8.89 (s, 1 H), 8.32 (s, 1 H), 7.65 (s, 1 H), 7.22 (s, 1 H), 7.00 (m, 2 H), 6.70 (s, 1 H), 6.53 (m, 1 H), 4.18 (q, 2 H), 2.69 (m, 4 H), 2.38 (s, 3 H), 2.30 (m, 4 H), 2.15 (s, 3 H), 1.39 (t, 3 H) 453 Intermediate 76

77

7-Ethoxy-4 - [(3-fluoro-2methylphenyl) amino] -6- (4methylpiperazin-1-yl) quinolin-3carboxamide 10.75 (s, 1 H), 8.86 (s, 1 H), 8.30 (s, 1 H), 7.65 (s, 1 H), 7.20 (s, 1 H), 7.05 (m, 1 H), 6.90 (m, 1 H), 6.66 (s, 1 H), 6.49 (d, 1 H), 4.20 (q, 2 H), 2.70 (m, 4 H), 2.35 (m, 4 H), 2.22 (s, 3 H), 2.15 (s, 3 H), 1.39 (t, 3 H) 437 Intermediate 77

78

4 - [(3,4-Difluorophenyl) amino] -7methoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxamide THF-d8 10.99 (s, 1 H), 8.85 (s, 1 H), 7.70 (s, 1 H), 7.34 (s, 1 H), 7.16 (m, 1 H), 6.99 (s, 1 H), 6.89 (m, 2 H), 6.73 (m, 1 H), 3.99 (s, 3 H), 2.84 (s, 4 H), 2.41 (s, 4 H), 2.23 (s, 3 H) 428 Intermediate 78

79

7-Methoxy-6- (4-methylpiperazin-1-yl) 4 - {[2-methyl-3 (trifluoromethyl) phenyl] amino} quinolin3-carboxamide THF-d8 10.96 (s, 1 H), 8.72 (s, 1 H), 7.67 (s, 1 H), 7.25 (d, 1 H), 7.18 (s, 1 H), 7.02 (t, 1 H), 6.87 (s, 1 H), 6.78 (d, 1 H), 6.64 (s, 1 H), 3.83 (s, 3 H), 2.63 (s, 4 H), 2.45 (s, 3 H), 2.21 (s, 4 H), 2.06 (s, 3 H) 474 Intermediate 79

80

4 - [(4-Chlorophenyl) amino] -7-methoxy6- (4-methylpiperazin-1-yl) quinolin-3carboxamide THF-d8 10.86 (s, 1 H), 8.70 (s, 1 H), 7.62 (s, 1 H), 7.18 (s, 1 H), 7.10 (d, 2 H), 6.78 (m, 4 H), 3.84 (s, 3 H), 2.68 (s, 4 H), 2.25 (s, 4 H), 2.09 (s, 3 H) 426 Intermediate 80

Ex.

Compound NMR m / z MP

81

4 - [(2-Fluoro-4-methylphenyl) amino] -7methoxy-6- (4-methylpiperazin-1yl) quinolin-3-carboxamide THF-d8 10.85 (s, 1 H), 8.67 (s, 1 H), 7.48 (s, 1 H), 7.16 (s, 1 H), 6,646.89 (m, 5 H), 3.82 (s, 3 H), 2.63 (s, 4 H), 2.24 (s, 4 H), 2.18 (s, 3 H), 2.08 (s, 3 H) 424 Intermediate 81

82

7-Methoxy-6- (4-methylpiperazin-1-yl) 4 - {[3- (trifluoromethyl) phenyl] amino} quinolin-3carboxamide THF-d8 10.96 (s, 1 H), 8.79 (s, 1 H), 7.60 (s, 1 H), 7.23 (m, 3 H), 6.89 (m, 4 H), 4.09 (s, 3 H), 2.81 (s, 4 H), 2.37 (s, 4 H), 2.20 (s, 3 H) 460 Intermediate 82

83

7-Ethoxy-4 - [(2-fluoro-5methylphenyl) amino] -6- (4methylpiperazin-1-yl) quinolin-3carboxamide CD2Cl2 10.47 (s, 1 H), 8.76 (s, 1 H), 7.26 (s, 1 H), 7.01 (m, 1 H), 6.95 (s, 1 H) , 6.85 (m, 1 H), 6.76 (d, 1 H), 6.02 (br s, 2 H), 4.20 (q, 2 H), 2.81 (m, 4 H ), 2.48 (m, 4 H), 2.29 (s, 3 H), 2.19 (s, 3 H), 1.49 (t, 3 H) 438 Intermediate 83

84

4 - [(3-Chloro-2-methylphenyl) amino] -7ethoxy-6- (4-ethylpiperazin-1yl) quinolin-3-carboxamide 10.80 (s, 1 H), 8.86 (s, 1 H), 8.30 (s, 1 H), 7.65 (s, 1 H), 7.20 (m, 2 H), 7.06 (m, 1 H), 6.65 (s, 2 H), 4.15 (q, 2 H), 2.66 (m, 4 H), 2.50 (s, 3 H), 2.35 (m, 6 H), 1.40 (t, 3 H), 0.98 (t, 3 H) 467 Intermediate 84

85

4 - [(3-Chloro-2-methylphenyl) amino] -7ethoxy-6- (4-methyl-1,4-diazepan-1yl) quinolin-3-carboxamide CD2Cl2 10.46 (s, 1 H), 8.68 (s, 1 H), 7.19 (s, 1 H), 7.12 (d, 1 H), 6.96 (m, 1 H) , 6.68 (d, 1 H), 6.63 (s, 1 H), 6.05 (br s, 2 H), 4.17 (q, 2 H), 3.08 (m, 2 H ), 2.93 (m, 2 H), 2.52 (m, 4 H), 2.46 (s, 3 H), 2.29 (s, 3 H), 1.68 (m, 2 H ), 1.49 (t, 3 H) 467 Intermediate 85

86

7-Ethoxy-6- (4-ethylpiperazin-1-yl) -4 [(3-fluoro-2-methylphenyl) amino] quinolin-3-carboxamide 10.80 (s, 1 H), 8:90 (s, 1 H), 8.34 (s, 1 H), 7.70 (s, 1 H), 7.30 (s, 1 H), 7.12 (m, 1 H), 6.95 (m, 1 H), 6.75 (s, 1 H), 6.54 (m, 1 H), 4.21 (q, 2 H), 2.66 (m, 4 H), 2.55 (s, 3 H), 2.40 (m, 6 H), 1.45 (t, 3 H), 1.05 (t, 3 H) 451 Intermediate 86

Ex.

Compound NMR m / z MP

87

7-Ethoxy-4 - [(3-fluoro-2methylphenyl) amino] -6- (4-methyl-1,4diazepan-1-yl) quinolin-3carboxamide CD2Cl2 10.30 (s, 1 H), 8.60 (s, 1 H), 7.10 (s, 1 H), 6.85 (m, 1 H), 6.65 (m, 1 H) , 6.56 (s, 1 H), 6.42 (d, 1 H), 4.05 (q, 2 H), 3.00 (m, 2 H), 2.80 (m, 2 H) , 2.49 (m, 2 H), 2.40 (m, 2 H), 2.20 (s, 6 H), 1.69 (m, 2 H), 1.36 (t, 3 H) 451 Intermediate 87

88

7-Ethoxy-4 - [(2-fluoro-4 10.79 (s, 1 H), 8.83 (s, 1 439 Intermediate

methylphenyl) amino] -6- (4

H), 8.26 (s, 1 H), 7.63 (s, 88

methylpiperazin-1-yl) quinolin-3

1 H), 7.20 (s, 1 H), 7.09

carboxamide

(d, 1 H), 6.91 (m, 2 H),

6.80 (s, 1 H), 4.17 (q, 2

H), 2.68 (s, 4 H), 2.32 (s,

4 H), 2.27 (s, 3 H), 2.15

(s, 3 H), 1.39 (t, 3 H)

89

7-Ethoxy-4 - [(3-methoxy-2-methylphenyl) amino] -6- (4-methylpiperazin-1-yl) quinolin-3carboxamide 10.89 (s, 1 H), 8.83 (s, 1 H), 8.28 (s, 1 H), 7.58 (s, 1 H), 7.16 (s, 1 H), 7.05 (m, 1 H), 6.77 (d, 1 H), 6.70 (s, 1 H), 6.38 (d, 1 H), 4.14 (q, 2 H), 3.80 (s, 3 H), 2.59 (s, 4 H), 2.27 (s, 4 H), 2.16 (s, 3 H), 2.14 (s, 3 H), 1.39 (t, 3 H) 450 Intermediate 89

90

4 - [(2,5-Difluorophenyl) amino] -7 CD3OD 8.82 (s, 1 H), 442 Intermediate

ethoxy-6- (4-methylpiperazin-1

7.29 (s, 1 H), 7.19 (m, 1 90

il) quinolin-3-carboxamide

H), 7.03 (s, 1 H), 6.79 (m, 1 H), 6.58 (m, 1 H), 4.25 (q, 2 H), 2.93 (m, 4 H), 2.55 (m, 4 H), 2.30 (s, 3 H), 1.52 (% 3 H)

91

4 - [(2,5-Difluorophenyl) amino] -7 CD3OD 8.82 (s, 1 H), 456 Intermediate

ethoxy-6- (4-ethylpiperazin-1

7.29 (s, 1 H), 7.20 (m, 1 91

il) quinolin-3-carboxamide

H), 7.04 (s, 1 H), 6.79 (m, 1 H), 6.58 (m, 1 H), 4.25 (q, 2 H), 2.95 (m, 4 H), 2.59 (m, 4 H), 2.48 (q, 2 H), 1.52 (t, 3 H), 1.11 (t, 3 H)

Ex.

Compound NMR m / z MP

92

4 - [(2,5-Difluorophenyl) amino] -7ethoxy-6- (4-methyl-1,4-diazepan-1yl) quinolin-3-carboxamide (t, 3H) CD3OD 8.76 (s, 1 H), 7.26 (s, 1 H), 7.17 (m, 1 H), 6.88 (s, 1 H), 6.76 (m, 1 H) , 6.51 (m, 1 H), 4.25 (q, 2 H), 3.29 (m, 2 H), 3.08 (m, 2 H), 2.80 (m, 2 H) , 2.68 (m, 2 H), 2.37 (s, 3 H), 1.93 (m, 2 H), 1.54 456 Intermediate 92

93

7-Ethoxy-6- (4-ethylpiperazin-1-yl) -4 [(2-fluoro-4-methylphenyl) amino] quinolin-3-carboxamide 10.79 (s, 1 H), 8.84 (s, 1 H), 8.27 (s, 1 H), 7.63 (s, 1 H), 7.20 (s, 1 H), 7.13 (d, 1 H), 6.90 (m, 2 H), 6.80 (s, 1 H), 4.16 (q, 2 H), 2.68 (s, 4 H), 2.36 (s, 4 H), 2.31 (s, 2 H), 2.27 (s, 3 H), 1.38 (t, 3 H), 0.97 (t, 3 H) 453 Intermediate 93

94

4 - [(3,4-Dimethylphenyl) amino] -7ethoxy-6- (4-methylpiperazin-1yl) quinolin-3-carboxamide 10.74 (s, 1 H), 8.80 (s, 1 H), 8.18 (s, 1 H), 7.54 (s, 1 H), 7.16 (s, 1 H), 7.03 (d, 1 H), 6.85 (s, 1 H), 6.79 (s, 1 H), 6.72 (d, 1 H), 4.15 (q, 2 H), 2.65 (s, 4 H), 2.29 (s, 4 H), 2.16 (s, 3 H), 2.14 (s, 3 H), 2.13 (s, 3 H), 1.38 (t, 3 H) 435 Intermediate 94

95

4 - [(2,4-Difluorophenyl) amino] -6ethoxy-7- (4-methylpiperazin-1-yl) quinolin-3-carboxamide 10.55 (s, 1 H), 8.83 (s, 1 H), 8.25 (s, 1 H), 7.63 (s, 1 H), 7.35 (m, 1 H), 7.19 (s, 1 H), 6.98 (d, 2 H), 6.80 (s, 1 H), 3.65 (q, 2 H), 3.15 (s, 4 H), 2.48 (s, 4 H), 2.22 (s, 3 H), 1.21 (t, 3 H) 442 Intermediate 95

96

4 - [(2,3-DiClorophenyl) amino] -6ethoxy-7- (4-methylpiperazin-1yl) quinolin-3-carboxamide 10.65 (s, 1 H), 8.91 (s, 1 H), 8.35 (s, 1 H), 7.75 (s, 1 H), 7.25 (s, 1 H), 7.22 (d, 1 H), 7.14 (m, 1 H), 6.66 (s, 1 H), 6.54 (d, 1 H), 3.66 (q, 2 H), 3.17 (s, 4 H), 2.49 (s, 4 H), 2.23 (s, 3 H), 1.21 (t, 3 H) 474 Intermediate 96

Ex.

Compound NMR m / z MP

97

4 - [(2,3-Difluorophenyl) amino] -7ethoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxamide 10.65 (s, 1 H), 8.89 (s, 1 H), 8.30 (s, 1 H), 7.70 (s, 1 H), 7.25 (s, 1 H), 7.05 (m, 2 H), 6.85 (s, 1 H), 6.65 (m, 1 H), 4.16 (q, 2 H), 2.75 (m, 4 H), 2.35 (m, 4 H), 2.15 (s, 3 H), 1.40 (t, 3 H) 441 Intermediate 97

98

4 - [(2,3-Dimethylphenyl) amino] -7ethoxy-6- (4-methylpiperazin-1yl) quinolin-3-carboxamide 10.98 (s, 1 H), 8.85 (s, 1 H), 8.25 (s, 1 H), 7.55 (s, 1 H), 7.16 (s, 1 H), 7.00 (m, 2 H), 6.65 (m, 2 H), 4.15 (q, 2 H), 2.60 (m, 4 H), 2.30 (m, 7 H), 2.20 (s, 3 H), 2.15 (s, 3 H), 1.40 (t, 3 H) 433 Intermediate 98

99

4 - [(4-Chloro-3-fluorophenyl) amino] -7ethoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxamide 10.15 (s, IH), 8.80 (s, 1 H), 8.12 (s, 1 H), 7.60 (s, 1 H), 7.39 (m, 1 H), 7 , 28 (s, 1 H), 6.98-6.90 (m, 2 H), 6.70 (d, 1 H), 4.20 (q, 2 H), 2.90 (m, 4 H), 2.40 (m, 4 H), 1.40 (t, 3 H) 458 Intermediate 99

100

4 - [(2,3-Dichlorophenyl) amino] -6ethoxy-7- (4-ethylpiperazin-1yl) quinolin-3-carboxamide 10.65 (s, 1 H), 8.92 (br s, 1 H), 8.35 (s, 1 H), 7.74 (s, 1 H), 7.23 (d, 2 H) , 7.14 (m, 1 H), 6.66 (s, 1 H), 6.54 (d, 1 H), 3.66 (q, 2 H), 3.18 (s, 4 H) , 2.51 (s, 4 H), 2.37 (q, 2 H), 1.21 (t, 3 H), 1.03 (t, 3 H) 488 Intermediate 100

101

4 - [(2,4-Difluorophenyl) amino] -6ethoxy-7- (4-ethylpiperazin-1-yl) quinolin-3-carboxamide 10.57 (s, 1 H), 8.85 (s, 1 H), 8.27 (s, 1 H), 7.64 (s, 1 H), 7.37 (m, 1 H), 7.21 (s, 1 H), 6.99 (m, 2 H), 6.81 (s, 1 H), 3.66 (q, 2 H), 3.17 (s, 4 H), 2.51 (s, 4 H), 2.39 (q, 2 H), 1.21 (t, 3 H), 1.04 (t, 3 H) 456 Intermediate 101

102

4 - [(3-Chloro-2,4-difluorophenyl) amino] -7-ethoxy-6- (4-ethylpiperazin-1-yl) quinolin-3-carboxamide 10.60 (s, 1 H), 8.85 (s, 1 H), 8.27 (s, 1 H), 7.65 (s, 1 H), 7.25 (m, 2 H), 6.95 (m, 1 H), 6.85 (s, 1 H), 4.20 (q, 2 H), 2.80 (m, 4 H), 2.40 (m, 4 H), 2.31 (m, 2 H), 1.40 (t, 3 H), 1.00 t, 3 H) 489 Intermediate 102

Ex.

Compound NMR m / z MP

103

4 - [(3-Chloro-2,4difluorophenyl) amino] -7-ethoxy-6- (4methylpiperazin-1-yl) quinolin-3carboxamide 10.60 (s, 1 H), 8.83 (s, 1 H), 8.28 (s, 1 H), 7.65 (s, 1 H), 7.25 (m, 2 H), 7.00 (m, 1H), 6.88 (s, 1 H), 4.20 (q, 2 H), 3.80 (m, 4 H), 2.39 (m, 4 H), 2 , 20 (s, 3 H), 1.40 (t, 3 H) 475 Intermediate 103

104

4 - [(3-Chloro-4-fluorophenyl) amino] -6ethoxy-7- (4-methylpiperazin-1-yl) quinolin-3-carboxamide 10.12 (s, 1 H), 8.82 (s, 1 H), 8.15 (s, 1 H), 7.59 (s, 1 H), 7.27 (m, 2 H), 7.14 (d, 1 H), 6.97 (s, 1 H), 6.88 (d, 1 H), 3.81 (q, 2 H), 3.19 (s, 4 H), 2.48 (s, 4 H), 2.25 (s, 3 H), 1.27 (t, 3 H) 458 Intermediate 104

105

4 - [(3-Chloro-4-fluorophenyl) amino] -6ethoxy-7- (4-ethylpiperazin-1-yl) quinolin-3-carboxamide 10.17 (s, 1 H), 8.86 (s, 1 H), 8.19 (s, 1 H), 7.63 (s, 1 H), 7.34 (m, 1 H), 7.29 (s, 1 H), 7.19 (d, 1 H), 7.01 (s, 1 H), 6.92 (d, 1 H), 3.85 (q, 2 H), 3.24 (s, 4 H), 2.61 (s, 4 H), 2.44 (q, 2 H), 1.32 (t, 3 H), 1.10 (t, 3 H) 472 Intermediate 105

106

4 - {[4-Fluoro-2 (trifluoromethyl) phenyl] amino} -7methoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxamide THF-d8 11.14 (s, 1 H), 8.75 (s, 1 H), 7.58 (s, 1 H), 7.42 (m, 1 H), 7.20 (s, 1 H), 7.02 (m, 1 H), 6.88 (s, 1 H), 6.64 (m, 1 H), 6.58 (s, 1 H), 3.83 (s, 3 H), 2.72 (s, 4 H), 2.23 (s, 4 H), 2.08 (s, 3 H) 478 Intermediate 106

107

4 - [(2-Chloro-4-fluorophenyl) amino] -7methoxy-6- (4-methylpiperazin-1yl) quinolin-3-carboxamide 10.95 (s, 1 H), 8.83 (s, 1 H), 7.63 (s, 1 H), 7.32 (m, 1 H), 7.30 (s, 1 H), 6.92 (s, 1 H), 6.87 (m, 1 H), 6.74 (s, 1 H), 6.71 (m, 1 H), 3.95 (s, 3 H), 2.79 (s, 4 H), 2.37 (s, 4 H), 2.19 (s, 3 H) 444 Intermediate 107

108

7-Methoxy-6- (4-methylpiperazin-1-yl) 4 - {[3- (trifluoromethoxy) phenyl] amino} quinolin-3carboxamide 10.37 (s, 1 H), 8.86 (s, 1 H), 8.23 (s, 1 H), 7.65 (s, 1 H), 7.31-7.38 (m, 2 H), 6.85-6.96 (m, 4 H), 3.94 (s, 3 H), 2.76 (s, 4 H), 2.35 (s, 4 H), 2, 16 (s, 3 H) 476 Intermediate 108

Ex.

Compound NMR m / z MP

109

4 - [(2,6-Dimethylphenyl) amino] -7methoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxamide 11.39 (s, 1 H), 8.82 (s, 1 H), 8.21 (s, 1 H), 7.51 (s, 1 H), 7.15-7.20 (m, 4 H), 6.64 (s, 1 H), 3.87 (s, 3 H), 2.44 (s, 4 H), 2.28 (s, 4 H), 2.15 (s, 3 H), 2.06 (s, 6 H) 420 Intermediate 109

110

4 - [(2,4-Difluorophenyl) amino] -7ethoxy-6- (4-ethyl-1,4-diazepan-1yl) quinolin-3-carboxamide 10.55 (s, 1 H), 8.81 (s, 1 H), 8.30 (s, 1 H), 7.80 (s, 1 H), 7.45 (m, 3 H), 7.20 (m, 2 H), 4.25 (m, 2 H), 3.15 (m, 6 H), 2.80 (m, 2 H), 2.30 (m, 2 H), 2.10 (m, 2 H), 1.50 (t, 3 H), 1.25 (t, 3 H) 469 Intermediate 110

111

4 - [(2,3-Dichlorophenyl) amino] -6- (4-ethyl-1,4-diazepan-1-yl) -7methoxyquinoline-3-carboxamide 9.00 (s, 1 H), 8.51 (s, 1 H), 7.95 (s, 1 H), 7.60 (m, 1 H), 7.48 (s, 1 H), 7.40-7.32 (m, 2 H), 6.89 (s, 1 H), 4.00 (s, 3 H), 3.20 (m, 4 H), 2.95 (m, 2 H), 2.70 (m, 2 H), 2.20 (m, 2 H), 2.05 (m, 2 H), 1.29 (t, 3 H) 487 Intermediate 111

112

4 - [(2,3-Dichlorophenyl) amino] -7ethoxy-6- (4-ethyl-1,4-diazepan-1yl) quinolin-3-carboxamide 10.00 (s, 1 H), 8.90 (s, 1 H), 8.40 (s, 1 H), 7.90 (s, 1 H), 7.65 (d, 1 H), 7.30 (m, 3 H), 6.80 (s, 1 H), 4.15 (q, 2 H), 3.15 (m, 4 H), 2.85 (m, 2 H), 2.60 (m, 2 H), 2.15 (m, 2 H), 2.00 (m, 2 H), 1.40 (t, 3 H), 1.15 (t, 3 H) 501 Intermediate 112

113

4 - [(2,4-Difluorophenyl) amino] -7isopropoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxamide 10.74 (s, 1 H), 8.83 (s, 1 H), 8.28 (s, 1 H), 7.65 (s, 1 H), 7.36 (t, 1 H), 7.23 (s, 1 H), 7.02 (in, 2 H), 6.79 (s, 1 H), 4.81 (m, 1 H), 2.71 (s, 4 H), 2.35 (s, 4 H), 2.16 (s, 3 H), 1.34 (d, 6 H) 457 Intermediate 254

114

4 - [(3,4-Dichlorophenyl) amino] -7isopropoxy-6- (4-methylpiperazin-1yl) quinolin-3-carboxamide 10.13 (s, 1 H), 8.78 (s, 1 H), 8.12 (s, 1 H), 7.59 (s, 1 H), 7.46 (d, 1 H), 7.28 (s, 1 H), 7.11 (s, 1 H), 6.96 (s, 1 H), 6.87 (m, 1 H), 4.83 (m, 1 H), 2.86 (s, 4 H), 2.39 (s, 4 H), 2.18 (s, 3 H), 1.36 (d, 6 H) 490 Intermediate 255

Ex.

Compound NMR m / z MP

115

4 - [(3-Chloro-2-fluorophenyl) amino] -7isopropoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxamide 10.66 (s, 1 H), 8.86 (s, 1 H), 8.29 (s, 1 H), 7.69 (s, 1 H), 7.29 (s, 1 H), 7.21 (t, 1 H), 7.07 (t, 1 H), 6.88 (s, 1 H), 6.76 (m, 1 H), 4.85 (m, 1 H), 2,832.50 (m, 8 H), 2.36 (s, 3 H), 1.37 (d, 6 H) 474 Intermediate 256

116

4 - [(2,3-Dichlorophenyl) amino] -7isopropoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxamide 10.83 (s, 1 H), 8.92 (s, 1 H), 8.38 (s, 1 H), 7.77 (s, 1 H), 7.30 (s, 1 H), 7.26 (s, 1 H), 7.16 (m, 1 H), 6.67 (s, 1 H), 6.62 (d, 1 H), 4.85 (m, 1 H), 2.74 (s, 4 H), 2.36 (s, 4 H), 2.17 (s, 3 H), 1.3 7 (d, 6 H) 490 Intermediate 257

117

4 - [(3-Chloro-4-fluorophenyl) amino] -7isopropoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxamide 10.37 (s, 1 H), 8.81 (s, 1 H), 8.18 (s, 1 H), 7.61 (s, 1 H), 7.31 (m, 1 H), 7.27 (s, 1 H), 7.12 (m, 1 H), 6.91 (s, 2 H), 4.86 (m, 1 H), 2.82 (s, 4 H), 2.41 (s, 4 H), 2.20 (s, 3 H), 1.36 (d, 6 H) 474 Intermediate 258

118

4 - [(2,4-Difluorophenyl) amino] -6morpholin-4-ylquinolin-3carboxamide 10.39 (s, 1 H), 8.80 (s, 1 H), 8.26 (s, 1 H), 7.82 (d, 1 H), 7.69 (s, 1 H), 7.59 (d, 1 H), 7.35 (t, 1 H), 7.01 (m, 2 H), 6.86 (s, 1 H), 3.68 (m, 4 H), 2.94 (m, 4 H) 384 Intermediate 259

119

4 - [(3-Chloro-4-fluorophenyl) amino] -61 morpholin-4-ylquinolin-3carboxamide 9.83 (s, 1 H), 8.72 (s, 1 H), 8.09 (s, H), 7.84 (d, 1 H), 7.64 (d, 1 H), 7 , 59 (m, 1 H), 7.28 (t, 1 H), 7.10 (m, 1 H), 7.01 (s, 1 H), 6.86 (m, 1 H), 3 , 71 (m, 4 H), 3.05 (m, 4 H) 401 Intermediate 260

120

4 - [(2,3-Dichlorophenyl) amino] -6morpholin-4-ylquinolin-3carboxamide 10.56 (s, 1 H), 8.91 (s, 1 H), 8.42 (s, 1 H), 7.89 (d, 2 H), 7.65 (m, 1 H), 7.25 (m, 1 H), 7.14 (t, 1 H), 6.66 (s, 1 H), 6.55 (d, 1 H), 3.66 (m, 4 H), 2.94 (m, 4 H) 417 Intermediate 261

Ex.

Compound NMR m / z MP

121

4 - [(2,4-Difluorophenyl) amino] -6- (4methylpiperazin-1-yl) quinolin-3carboxamide 10.40 (s, 1 H), 8.77 (s, 1 H), 8.27 (s, 1 H), 7.77 (s, 1 H), 7.67 (s, 1 H), 7.55 (d, 1 H), 7.33 (t, 1 H), 6.99 (m, 2 H), 6.79 (s, 1 H), 2.94 (m, 4 H), 2.34 (m, 4 H), 2.16 (s, 3 H) 398 Intermediate 262

122

4 - [(2,4-Dichlorophenyl) amino] -6- (4methylpiperazin-1-yl) quinolin-3carboxamide 10.52 (s, 1 H), 8.86 (s, 1 H), 8.37 (s, 1 H), 7.82 (m, 2 H), 7.70 (d, 1 H), 7.60 (m, 1 H), 7.21 (m, 1 H), 6.58 (m, 2 H), 2.96 (m, 4 H), 2.34 (m, 4 H), 2.16 (s, 3 H) 430 Intermediate 263

123

4 - [(3,4-Dichlorophenyl) amino] -6- (4methylpiperazin-1-yl) quinolin-3carboxamide 9.67 (s, 1 H), 8.69 (s, 1 H), 8.05 (s, 1 H), 7.83 (d, 1 H), 7.61 (m, 2 H), 7.43 (d, 1 H), 7.05 (m, 2 H), 6.84 (m, 1 H), 3.16 (m, 4 H), 2.48 (m, 4 H), 2.25 (s, 3 H) 430 Intermediate 264

124

4 - [(2,3-Dichlorophenyl) amino] -6- (4methylpiperazin-1-yl) quinolin-3carboxamide CD3OD 8.83 (s, 1 H), 7.89 (d, 1 H), 7.83 (d, 1 H), 7.55 (d, 1 H), 7.39 (m, 2 H) , 7.08 (d, 1 H), 3.62 (m, 2 H), 3.54 (m, 2 H), 3.21 (m, 2 H), 3.06 (m, 2 H) , 2.90 (s, 3 H) 429 Intermediate 265

125

4- {3- (Aminocarbonyl) -4 - [(2,3-dichlorophenyl) amino] -7-ethoxyquinoline-6-yl} piperazine-1-carboxylic acid tert-butyl ester CD2Cl2 10.20 (s, 1 H), 8.65 (s, 1 H), 7.15 (s, 1 H), 6.95 (d, 1H), 6.80 (m, 1 H), 6.60 (s, 1 H), 6.40 (d, 1 H), 4.05 (q, 2 H), 3.25 (m, 4 H), 2.60 (m, 4 H), 1.32 (t, 3 H), 1.28 (s, 9 H) 560 Intermediate 113

126

4- {3- (Aminocarbonyl) -4 - [(2,4difluorophenyl) amino] -7-methoxyquinolin-6-yl} piperazine-1-carboxylic acid tert-butyl ester 10.60 (s, 1 H), 8.78 (s, 1 H), 8.20 (s, 1 H), 7.60 (s, 1 H), 7.30 (m, 1 H), 7.22 (s, 1 H), 6.98 (m, 2 H), 6.80 (s, 1 H), 3.86 (s, 3 H), 3.25 (m, 4 H), 2.59 (m, 4 H), 1.31 (s, 9 H) 513 Intermediate 114

127

4- {3- (Aminocarbonyl) -4 - [(2,4difluorophenyl) amino] -7-methoxyquinolin-6-yl} -1,4-diazepan1-carboxylic acid tert-butyl ester 527 Intermediate 115

Ex.

Compound NMR m / z MP

128

4- {3- (Aminocarbonyl) -4 - [(2,3-dichlorophenyl) amino] -7-ethoxyquinolin-6-yl} -1,4-diazepan-1-carboxylic acid tert-butyl ester CDCl3 10.63 (s, 1 H), 8.75 (s, 1 H), 8.20 (s, 1 H), 7.88 (s, 1 H), 7.56 (s, 1 H) , 7.30 (m, 1 H), 7.18 (m, 1 H), 6.90 (m, 1 H), 6.70 (m, 1 H), 3.85 (s, 3 H) , 3.20 (m, 4 H), 3.13 (m, 1 H), 3.01 (m, 1 H), 2.95 (m, 2 H), 1.58 (m, 2 H) , 1.25-1.18 (d, 9H) 573 Intermediate 116

129

4- {3- (Aminocarbonyl) -4 - [(2,4difluorophenyl) amino] -7-ethoxyquinoline-6-yl} piperazine-1-carboxylic acid tert-butyl ester CDCl3 10.60 (s, 1 H), 8.85 (s, 1 H), 7.31 (s, 1 H), 6.90 (m, 3 H), 6.75 (m, 1 H) , 4.20 (q, 2 H), 3.50 (m, 4 H), 2.75 (m, 4 H), 1.40 (t, 3 H), 1.38 (s, 9 H) 527 Intermediate 117

130

4- {3- (Aminocarbonyl) -4 - [(2,4-difluorophenyl) amino] -7-ethoxyquinolin-6-yl} -1,4-diazepan-1-carboxylic acid tert-butyl ester 541 Intermediate 118

131

4- {3- (Aminocarbonyl) -4 - [(2,3-dichlorophenyl) amino] -7-methoxyquinolin-6-yl} -1,4-diazepan1-tert-butyl carboxylate 560 Intermediate 119

132

4 - [(2-Fluoro-5-methylphenyl) amino] -7methoxy-6- (4-methylpiperazin-1yl) quinolin-3-carboxamide 10.82 (s, 1 H), 8.88 (s, 1 H), 8.31 (s, 1 H), 7.68 (s, 1 H), 7.27 (s, 1 H), 7.17 (m, 1 H), 6.86 (m, 2 H), 6.72 (m, 1 H), 3.94 (s, 3 H), 2.69 (s, 4 H), 2.34 (s, 4 H), 2.17 (s, 3 H), 2.15 (s, 3 H) 424 Intermediate 120

133

4 - [(2,5-Difluorophenyl) amino] -7methoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxamide 10.68 (s, 1 H), 8.90 (s, 1 H), 8.33 (s, 1 H), 7.73 (s, 1 H), 7.33 (m, 2 H), 6.88 (m, 2 H), 6.64 (m, 1 H), 3.96 (s, 3 H), 2.78 (s, 4 H), 2.38 (s, 4 H), 2.18 (s, 3 H) 428 Intermediate 121

134

4 - [(3-Chloro-2-methylphenyl) amino] -7methoxy-6- (4-methylpiperazin-1yl) quinolin-3-carboxamide 10.86 (s, 1 H), 8.88 (s, 1 H), 8.31 (s, 1 H), 7.66 (s, 1 H), 7.24 (s, 1 H), 7.19 (m, 1 H), 7.08 (m, 1 H), 6.68 (m, 2 H), 3.92 (s, 3 H), 2.64 (s, 4 H), 2.38 (s, 3 H), 2.33 (s, 4 H), 2.17 (s, 3 H) 440 Intermediate 122

Ex.

Compound NMR m / z MP

135

4 - [(2-Chloro-3-methylphenyl) amino] -7 10.81 (s, 1 H), 8.90 (s, 1 440 Intermediate

methoxy-6- (4-methylpiperazin-1

H), 8.32 (s, 1 H), 7.69 (s, 123

il) quinolin-3-carboxamide

1 H), 7.27 (s, 1 H), 7.05

(d, 1 H), 7.03 (s, 1 H),

6.69 (s, 1 H), 6.54 (m, 1

H), 3.92 (s, 3 H), 2.66 (s,

4 H), 2.40 (s, 3 H), 2.33

(s, 4 H), 2.15 (s, 3 H)

136

4 - [(2,4-Difluorophenyl) amino] -6- [3 THF-d8 10.76 (s, 1 H), 442 Intermediate

(dimethylamino) pyrrolidin-1-yl] -7

8.62 (s, 1 H), 7.50 (s, 1 124

methoxy-quinolin-3-carboxamide

H), 7.14 (s, 1 H), 6.93 (m, 1 H), 6.71 (m, 3 H), 6.37 (s, 1 H), 3.82 (s, 3 H), 3.20 (m, 1 H), 3.00 (t, 1 H), 2.89 (t, 1 H), 2.43 (m, 2 H), 2.04 (s, 6 H), 1.85 (m, 1 H), 1.56 (m, 1 H)

137

4 - [(3-Chloro-2-fluorophenyl) amino] -7 10.69 (s, 1 H), 8.87 (s, 1 444 Intermediate

methoxy-6- (4-methylpiperazin-1

H), 8.30 (s, 1 H), 7.71 (s, 125

il) quinolin-3-carboxamide

1 H), 7.30 (s, 1 H), 7.24

(m, 1 H), 7.07 (m, 1 H),

6.85 (s, 1 H), 6.79 (m, 1

H), 3.94 (s, 3 H), 2.74 (s,

4 H), 2.36 (s, 4 H), 2.17

(s, 3 H)

138

4 - [(3-Chloro-5-fluorophenyl) amino] -7 CDCl3 10.37 (s, 1 H), 459 Intermediate

ethoxy-6- (4-methylpiperazin-1

8.75 (s, 1 H), 7.30 (s, 1 126

il) quinolin-3-carboxamide

H), 6.92 (s, 1 H), 6.71 (m, 2 H), 6.51 (d, 1 H), 4.23 (q, 2 H), 2.93 (s, 4 H), 2.53 (s, 4 H), 2.31 (s, 3 H), 1.54 (t, 3 H)

139

7-Ethoxy-6- (4-methylpiperazin-1-yl) -4 CDCl3 10.41 (s, 1 H), 460 Intermediate

[(2,3,4-trifluorophenyl) amino]

8.74 (s, 1 H), 7.28 (s, 1 127

quinolin-3-carboxamide

H), 6.87 (s, 1 H), 6.79 (m, 1 H), 6.61 (m, 1 H), 4.21 (q, 2 H), 2.87 (s, 4 H), 2.52 (s, 4 H), 2.31 (s, 3 H), 1.52 (t, 3 H)

140

4 - [(5-Chloro-2-methylphenyl) amino] -7 CDCl3 10.46 (s, 1 H), 455 Intermediate

ethoxy-6- (4-methylpiperazin-1

8.71 (s, 1 H), 7.26 (s, 1 128

il) quinolin-3-carboxamide

H), 7.16 (d, 1 H), 6.97 (dd, 1 H), 6.79 (m, 2 H), 4.21 (q, 2 H), 2.80 (s, 4 H), 2.49 (s, 4 H), 2.35 (s, 3 H), 2.30 (s, 3 H), 1.52 (t, 3 H)

Ex.

Compound NMR m / z MP

141

7-Ethoxy-4 - [(4-methoxy-CDCl3 2methylphenyl) amino] -H), 7.18 6- (4methylpiperazin-1-6.78 (d, yl) quinolin-3- (br s, 2 carboxamide H ), 2.71 2.29 (s, 3 H) 10.68 (s, 1 H), 8.65 (s, 1 (s, 1 H, 6.89 (m, 2 H), 1 H), 6.62 (dd, 1 H), 5.92 H), 4.15 (q, 2 H), 3.75 (s, 3 (s, 4 H), 2.44 (s, 4 H), 3 H), 2.25 (s, 3 H) , 1.48 (t, 451 Intermediate 129

142

4 - {[2-Chloro-5-CDCl3 (trifluoromethyl) phenyl] H), 7.55 amino} -7-ethoxy-6- (4-7.15 methylpiperazin-1- (s, 1 H), il) quinolin-3-H), 2.86 carboxamide 2.32 (s, 10.43 (s, 1 H), 8.81 (s, 1 (d, 1 H), 7.35 (s, 1 H), (dd, 1 H), 6.88 (s, 1 H) , 6.77 6.00 (br s, 2 H), 4.23 (q, 2 (s, 4 H), 2.50 (s, 4 H), 3 H), 1.53 (t, 3 H) 509 Intermediate 130

143

4 - [(2,4-10,26 Difluorophenyl) amino] - (s, 1 H), 7-ethoxy-6- (4methyl-3-H), 6.95 oxpiperazin-16.53 (s, il) quinolin-3-3.04 (m, carboxamide (s, 2 H), (s, 1 H), 8.50 (s, 1 H), 7.91 7.30 (s, 1 H), 7.01 (t, 1 (s, 1 H), 6.64 (m, 2 H), 1 H), 3.87 (q, 2 H), 2.91-5 H), 2.82 (s, 2 H), 2.16 1.08 (t, 3 H) 474 Intermediate 131

144

4 - [(2,3-10,71 Dichlorophenyl) amino] (s, 1 H), 7- (4-ethylpiperazin-1-yl) H), 7.23 6-methoxyquinoline-3-6.67 (s , carboxamide (m, 4 H), 1.02 (s, 1 H), 8.92 (s, 1 H), 8.36 7.75 (s, 1 H), 7.25 (s, 1 (d, 1 H), 7.15 (m, 1 H), 1 H), 6.57 (d, 1 H), 3.16 H), 2.52 (m, 4 H), 2.37 (q, 2 (t, 3 H) 474 Intermediate 132

145

4 - [(2-Fluoro-5-CD2Cl2 methylphenyl) amino] -6-H), 7.30 methoxy-7- (4-6.87 (m, methylpiperazin-1- (br, 2 il) quinolin-3 -H), 2.55 carboxamide 2.19 (s, 10.37 (s, 1 H), 8.76 (s, 1 (s, 1 H), 7.01 (m, 1 H), 2 H), 6.76 (d, 1 H), 6, 09 H), 3.43 (s, 3 H), 3.22 (s, 4 (s, 4 H), 2.30 (s, 3 H), 3 H) 424 Intermediate 133

146

7- (4-Ethylpiperazin-1-yl) 4 - [(2-fluoro5-methylphenyl) amino] -6-methoxyquinoline-3-carboxamide CD2Cl2 10.36 (s, 1 H), 8.76 (s, 1 H), 7.31 (s, 1 H), 7.01 (m, 1 H), 6.87 (m, 2 H) , 6.77 (d, 1 H), 6.06 (br, 2 H), 3.43 (s, 3 H), 3.23 (s 4 H), 2.60 (s, 4 H), 2.44 (q, 2 H), 2.19 (s, 3 H), 1.09 (t, 3 H) 438 Intermediate 134

147

4 - [(3-Chloro-2-fluorophenyl) amino] -6methoxy-7- (4-methylpiperazin-1yl) quinolin-3-carboxamide CD2Cl2 10.33 (s, 1 H), 8.78 (s, 1 H), 7.34 (s, 1 H), 7.06 (m, 1 H), 6.91 (m, 1 H) , 6.81 (s, 1 H), 6.71 (m, 1 H), 6.04 (br, 2 H), 3.51 (s, 3 H), 3.24 (s, 4 H) , 2.55 (s, 4 H), 2.31 (s, 3 H) 444 Intermediate 135

Ex.

Compound NMR m / z MP

148

4 - [(3-Chloro-2-fluorophenyl) amino] -7 (4-ethylpiperazin-1-yl) -6methoxyquinoline-3-carboxamide CD2Cl2 10.33 (s, 1 H), 8.78 (s, 1 H), 7.34 (s, 1 H), 7.06 (m, 1 H), 6.91 (m, 1 H) , 6.82 (s, 1 H), 6.71 (m, 1 H), 6.02 (br, 2 H), 3.51 (s, 3 H), 3.25 (s, 4 H) , 2.60 (s, 4 H), 2.45 (q, 2 H), 1.09 (1, 3 H) 458 Intermediate 136

149

4 - [(2-Fluoro-5-methylphenyl) amino] -6methoxy-7- (4-methyl-1,4-diazepan-1yl) quinolin-3-carboxamide CD2Cl2 10.35 (s, 1 H), 8.73 (s, 1 H), 7.15 (s, 1 H), 7.01 (m, 1 H), 6.82 (m, 2 H) , 6.77 (d, 1 H), 6.16 (br, 2 H), 3.48 (m, 4 H), 3.40 (s, 3 H), 2.77 (m, 2 H) , 2.64 (m, 2 H), 2.35 (s, 3 H), 2.19 (s, 3 H), 2.03 (m, 2 H) 437 Intermediate 137

150

4 - [(2,4-Difluorophenyl) amino] -6methoxy-7- (4-methyl-1,4-diazepan-1yl) quinolin-3-carboxamide CD2Cl2 10.36 (s, 1 H), 8.70 (s, 1 H), 7.16 (s, 1 H), 6.94 (m, 2 H), 6.79 (m, 1 H) , 6.73 (s, 1 H), 5.91 (br, 2 H), 3.49 (m, 4 H), 3.44 (s, 3 H), 2.76 (m, 2 H) , 2.63 (m, 2 H), 2.35 (s, 3 H), 2.02 (m, 2 H) 441 Intermediate 138

151

4 - [(2-Chloro-3-fluorophenyl) amino] -7ethoxy-6- (4-methylpiperazin-1yl) quinolin-3-carboxamide CD2Cl2 10.39 (s, 1 H), 8.75 (s, 1 H), 7.28 (s, 1 H), 7.24 (m, 1 H), 6.87 (s, 1 H) , 6.71 (m, 2 H), 5.95 (br, 2 H), 4.22 (q, 2 H), 2.86 (s, 4 H), 2.44 (s, 4 H) , 2.26 (s, 3 H), 1.50 (t, 3 H) 458 Intermediate 139

152

4 - [(2-Chloro-3-fluorophenyl) amino] -7ethoxy-6- (4-ethylpiperazin-1-yl) quinolin-3-carboxamide CD2Cl2 10.38 (s, 1 H), 8.75 (s, 1 H) 7.27 (s, 1 H), 7.24 (m, 1 H), 6.87 (s, 1 H), 6.71 (m, 2 H), 6.10 (br, 2 H), 4.21 (q, 2 H), 2.87 (s, 4 H), 2.48 (s, 4 H), 2.39 (q, 2 H), 1.50 (t, 3 H), 1.05 (t, 3 H) 472 Intermediate 140

153

4 - [(2-Chloro-3-fluorophenyl) amino] -7ethoxy-6- (4-isopropylpiperazin-1-yl) quinolin-3-carboxamide CD2Cl2 10.36 (s, 1 H), 8.75 (s, 1 H), 7.28 (s, 1 H), 7.24 (m, 1 H), 6.87 (s, 1 H) , 6.71 (m, 2 H), 5.98 (br, 2 H), 4.22 (q, 2 H), 2.85 (s, 4 H), 2.64 (m, 1 H) , 2.57 (s, 4 H), 1.51 (t, 3 H), 1.03 (d, 6 H) 486 Intermediate 141

Ex.

Compound NMR m / z MP

154

Tert-Butyl 4- {3- (Aminocarbonyl) -7-ethoxy-4 [(2-fluoro-4-methylphenyl) amino] quinolin-6-yl} piperazin-1 carboxylate CD2Cl2 10:61 (s, 1 H), 8.85 (s, 1 H), 7.29 (s, 1 H), 6.99 (d, 1 H), 6.90 (s, 1 H) , 6.79 (m, 2 H), 4.20 (q, 2 H), 3.46 (m, 4 H), 2.71 (m, 4 H), 2.35 (s, 3 H) , 1.51 (t, 3 H), 1.49 (s, 9 H) 524 Intermediate 142

155

4 - [(2,3-Dichlorophenyl) amino] -7ethoxy-6- (3-oxpiperazin-1yl) quinolin-3-carboxamide 10.80 (s, 1 H), 8.93 (s, 1 H), 8.38 (s, 1 H), 7.87 (s, 1 H), 7.76 (s, 1 H), 7.34 (s, 1 H), 7.24 (d, 1 H), 7.14 (m, 1 H), 6.69 (s, 1 H), 6.57 (d, 1 H), 4.22 (q, 2 H), 3.27 (s, 2 H), 3.18 (s, 2 H), 3.11 (s, 2 H), 1.42 (t, 3 H) 474 Intermediate 143

156

7-Ethoxy-4 - [(2-fluoro-5methylphenyl) amino] -6- (3oxpiperazin-1-yl) quinolin-3carboxamide 10.72 (s, 1 H), 8.86 (s, 1H), 8.29 (s, 1H), 7.86 (s, 1 H), 7.64 (s, 1 H), 7, 27 (s, 1H), 7.14 (m, 1H), 6.88 (s, 2 H), 6.73 (d, 1H), 4.20 (q, 2 H), 3.18 (m , 4 H), 3.03 (m, 2 H), 1.41 (t, 3 H) 438 Intermediate 144

157

4 - [(2,4-Difluorophenyl) amino] -7ethoxy-6- (3-oxpiperazin-1yl) quinolin-3-carboxamide MeOD 8.78 (s, 1H), 7.27 (s, 1H), 7.07 (m, 2H), 7.03 (s, 1H), 6.92 (m, 1H), 4.25 (q, 2 H), 3.45 (s, 2 H), 3.34 (m, 2 H), 3.15 (m, 2 H), 1.51 (t, 3 H) 442 Intermediate 145

158

4 - [(2-Chloro-4-methylphenyl) amino] -7ethoxy-6- (4-methylpiperazin-1yl) quinolin-3-carboxamide 10.85 (s, 1 H), 8.90 (s, 1 H), 8.30 (s, 1 H), 7.69 (s, 1 H), 7.38 (s, 1 H), 7, 20 (s, 1 H), 7.00 (d, 1 H), 6.65 (m, 2 H), 4.15 (q, 2 H), 2.69 (s, 4 H), 2, 30 (s, 4 H), 2.20 (s, 3 H), 2.15 (s, 3 H), 1.40 (t, 3 H) 454 Intermediate 146

159

7-Ethoxy-4 - {[2-fluoro-3 (trifluoromethyl) phenyl] amino} -6- (4methylpiperazin-1-yl) quinolin-3carboxamide 10.65 (s, 1H), 8.85 (s, 1H), 8.30 (s, 1H), 7.70 (s, 1 H), 7.40-7.15 (m, 4 H) , 6.85 (s, 1 H), 4.20 (q, 2 H), 2.80 (s, 4 H), 2.35 (s, 4 H), 2.15 (s, 3 H) , 1.40 (t, 3 H) 492 Intermediate 147

Ex.

Compound NMR m / z MP

160

4 - [(2,4-Dimethoxyphenyl) amino] -7ethoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxamide 10.75 (s, 1H), 8.80 (s, 1H), 8.20 (s, 1 H), 7.50 (s, 1H), 7.16 (s, 1 H), 6.85 -6.70 (m, 3 H), 6.50 (d, 1 H), 4.15 (q, 2 H), 3.75 (s, 6H), 2.65 (s, 4 H), 2.30 (s, 4 H), 2.17 (s, 3H), 1.40 (t, 3H) 466 Intermediate 148

161

4 - [(2-Chloro-4-fluoro-5methylphenyl) amino] -7-ethoxy-6- (4methylpiperazin-1-yl) quinolin-3carboxamide 10.95 (s, 1H), 8.96 (s, 1H), 8.40 (s, 1H), 7.75 (s, 1H), 7.55 (d, 1 H), 7.30 ( s, 1 H), 6.80 (d, 1 H), 6.70 (s, 1H), 4.21 (q, 2 H), 2.80 (s, 4 H), 2.35 (s , 4 H), 2.20 (s, 3 H), 2.10 (s, 3 H), 1.45 (t, 3 H) 472 Intermediate 149

162

4 - [(5-Chloro-2-fluorophenyl) amino] -7ethoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxamide 10.70 (s, 1 H), 8.90 (s, 1 H), 8.35 (s, 1H), 7.75 (s, 1H), 7.30 (m, 2 H), 7, 10 (m, 1 H), 6.85 (s, 1 H), 6.80 (d, 1 H), 4.20 (q, 2 H), 3.80 (s, 4 H), 2.35 (s, 4 H), 2.20 (s, 3 H), 1.40 (t, 3 H) 458 Intermediate 150

163

7-Ethoxy-4 - {[2-methoxy-5 (trifluoromethyl) phenyl] amino} -6- (4methylpiperazin-1-yl) quinolin-3carboxamide 10.55 (s, 1 H), 8.90 (s, 1 H), 8.35 (s, 1 H), 7.65 (s, 1 H), 7.30 (m, 3 H), 6, 70 (m, 2 H), 4.21 (q, 2 H), 3.95 (s, 3 H), 2.75 (s, 4 H), 2.30 (s, 4 H), 2, 15 (s, 3 H), 1.40 (t, 3 H) 504 Intermediate 151

164

4 - [(2,3-Dichlorophenyl) amino] -7- (2-methoxyethoxy) -6- (4-methylpiperazin-1-yl) quinolin-3-carboxamide 11.33 (s, 1H), 9.47 (s, 1H), 8.34 (s, 1H), 7.78 (s, 1H), 7.67 (m, 2 H), 7.50 ( s, 1H), 7.23 (s, 1 H), 7.10 (m, 1 H), 4.79 (m, 2 H), 4.32 (m, 2 H), 3.89 (s , 3 H), 3.30 (m, 4 H), 2.86 (m, 4 H), 2.66 (s, 3 H) 506 Intermediate 159

165

4 - [(2,4-Difluorophenyl) amino] -7- (2-methoxyethoxy) -6- (4-methylpiperazin-1-yl) quinolin-3-carboxamide 10.73 (s, 1 H), 8.86 (s, 1 H), 8.28 (s, 1 H), 7.66 (s, 1 H), 7.37 (m, 1 H), 7, 26 (s, 1H), 7.03 (m, 2 H), 6.81 (s, 1H), 4.25 (m, 2 H), 3.73 (m, 2 H), 3.35 ( s, 3 H), 2.75 (s, 4 H), 2.35 (s, 4 H), 2.17 (s, 3 H) 472 Intermediate 160

Ex.

Compound NMR m / z MP

166

4 - [(2-Fluoro-4-methylphenyl) amino] -7 (2-methoxyethoxy) -6- (4methylpiperazin-1-yl) quinolin-3carboxamide 10.80 (s, 1H), 8.85 (s, 1H), 8.28 (s, 1 H), 7.64 (s, 1H), 7.23 (s, 1 H), 7.15 (d, 1H), 6.92 (m, 2 H), 6.82 (s, 1 H), 4.23 (m, 2 H), 3.74 (m, 2 H), 3.31 ( s, 3 H), 2.70 (s, 4 H), 2.32 (s, 4 H), 2.29 (s, 3 H), 2.16 (s, 3H) 468 Intermediate 161

167

4 - [(2-Chloro-3-fluorophenyl) amino] -7 (2-methoxyethoxy) -6- (4methylpiperazin-1-yl) quinolin-3carboxamide 11.14 (s, 1 H), 9.43 (s, 1 H), 8.27 (s, 1 H), 7.84 (m, 1H), 7.76 (s, 1 H), 7 , 42 (s, 1H), 7.36 (s, 1 H), 7.34 (d, 1 H), 7.24 (d, 1H), 4.78 (m, 2 H), 4.29 (m, 2 H), 3.88 (s, 3 H), 3.34 (s, 4 H), 2.88 (s, 4 H), 2.67 (s, 3 H) 488 Intermediate 164

168

4 - [(2-Fluor-5-methylphenyl) amino] -7 (2-methoxyethoxy) -6- (4methylpiperazin-1-yl) quinolin-3carboxamide 11.36 (s, 1 H), 9.41 (s, 1 H), 8.27 (s, 1 H), 7.72 (s, 1 H), 7.56 (m, 1 H), 7 , 39 (m, 3 H), 7.20 (m, 1 H), 4.75 (m, 2 H), 4.28 (m, 2 H), 3.88 (s, 3 H), 3 , 27 (s, 4 H), 2.84 (s, 4 H), 2.65 (s, 3 H), 2.44 (s, 3 H) 468 Intermediate 156

169

4 - [(2,5-Difluorophenyl) amino] -7- (2-methoxyethoxy) -6- (4-methylpiperazin-1-yl) quinolin-3-carboxamide 10.66 (s, 1 H), 8.88 (s, 1 H), 8.32 (s, 1 H), 7.73 (s, 1 H), 7.23 (s, 1 H), 7, 32 (m, 2 H), 6.86 (m, 2 H), 6.62 (m, 1H), 4.27 (m, 2 H), 3.75 (m, 2 H), 3.35 (s, 3H), 2.81 (s, 4 H), 2.37 (s, 4 H), 2.17 (s, 3 H) 472 Intermediate 157

170

4 - [(3-Chloro-2-fluorophenyl) amino] -7 (2-methoxyethoxy) -6- (4methylpiperazin-1-yl) quinolin-3carboxamide 10.70 (s, 1H), 8.84 (s, 1H), 8.40 (s, 1H), 7.60 (s, 1H), 7.24 (s, 1 H), 7.13 ( m, 1 H), 7.03 (m, 1H), 6.85 (s, 1 H), 6.75 (m, 1H), 4.23 (s, 2 H), 3.74 (s, 2 H), 3.33 (s, 3 H), 2.74 (s, 4 H), 2.34 (s, 4 H), 2.15 (s, 3H) 488 Intermediate 158

Ex.

Compound NMR m / z MP

171

4 - [(2-Fluoro-4-methylphenyl) amino] -7 (2-methoxyethoxy) -6-morpholin-4ylquinolin-3-carboxamide 10.82 (s, 1H), 8.86 (s, 1H), 8.29 (s, 1 H), 7.65 (s, 1H), 7.26 (s, 1 H), 7.14 (d, 1H), 6.92 (m, 3 H), 4.24 (m, 2 H), 3.73 (m, 2 H), 3.62 (m, 4 H), 3.36 ( s, 3 H), 2.69 (s, 4 H), 2.27 (s, 3 H) 455 Intermediate 152

172

4 - [(2-Fluoro-4-methylphenyl) amino] -6 (4-isopropylpiperazin-1-yl) -7- (2-methoxyethoxy) quinolin-3carboxamide 10.78 (s, 1 H), 8.83 (s, 1 H), 8.27 (s, 1 H), 7.63 (s, 1 H), 7.22 (s, 1 H), 7, 14 (d, 1H), 6.89 (m, 2 H), 6.79 (s, 1H), 4.23 (m, 2 H), 3.72 (m, 2 H), 3.33 ( s, 3 H), 2.68 (s, 4 H), 2.60 (m, 1H), 2.43 (s, 4 H), 2.27 (s, 3 H), 0.96 (d , 6 H) 496 Intermediate 153

173

4 - [(2-Fluoro-5-methylphenyl) amino] -6 (4-isopropylpiperazin-1-yl) -7- (2-methoxyethoxy) quinolin-3carboxamide 10.75 (s, 1 H), 8.95 (s, 1 H), 8.27 (s, 1 H), 7.64 (s, 1 H), 7.25 (s, 1 H), 7.15 (m, 1 H), 6.89 (m, 1H), 6.83 (s, 1 H), 6.71 (d, 1H), 4.25 (m, 2 H), 3.75 (m , 2 H), 3.34 (s, 3 H), 2.71 (s, 4 H), 2.60 (m, 1H), 2.45 (s, 4 H), 2.13 (s, 3 H), 0.96 (d, 6 H) 496 Intermediate 154

Example 174

4 - [(2,3-Dichlorophenyl) amino] -7-methoxy-6-piperazin-1-ylquinolin-3-carboxamide,

dihydrochloride

To a solution of trifluoroacetic acid / dichloromethane (10 mL, 1: 1) was added 4 {3- (aminocarbonyl) -4 - [(2,3-dichlorophenyl) amino] -7-methoxyquinolin-6-yl} piperazine- 1 tert-butyl carboxylate (Example 15, 250 mg, 0.46 mmol). After 2 hours, the solvent was removed under reduced pressure, the residue was taken up in MeOH (3 mL) and acidified with ethereal HCl. The resulting crystals were collected, washed with Et2O and

10 were dried to give a solid (160 mg). 1H NMR: 11.95 (s, 1 H), 9.28 (s, 2H), 9.00 (s, 1H), 8.45 (s, 1H), 7.86 (s, 1H), 7 , 59 (m, 2 H), 7.37 (m, 2 H), 7.21 (s, 1 H), 4.01 (s, 3H), 3.17 (m, 4 H), 3, 07 (m, 4 H); m / z: 445

Examples 175-185

The following compounds were prepared by a method similar to that of Example

174 using the appropriate starting materials (MP). Some examples were isolated

as hydrochloride salts.

Ex.

Compound NMR m / z MP

175

4 - [(2,3-Dichlorophenyl) amino] -7-ethoxy-6piperazin-1-ylquinolin-3carboxamide 10.78 (s, 1 H), 8.92 (s, 1 H), 8.36 (s, 1 H), 7.76 (s, 1 H), 7.31 (s, 1 H), 7, 24 (d, 1H), 7.13 (m, 1 H), 6.66 (s, 1H), 6.57 (d, 1 H), 4.20 (q, 2 H), 2.86 ( m, 4 H), 2.75 (m, 4 H), 1.41 (t, 3 H) 460 Example 125

176

4 - [(2,4-Difluorophenyl) amino] -7-methoxy-6piperazin-1-ylquinolin-3carboxamide 10.80 (s, 1 H), 8.91 (s, 1H), 8.35 (s, 1 H), 7.70 (s, 1 H), 7.40 (m, 1 H), 7 , 32 (s, 1 H), 7.06 (m, 2 H), 6.85 (s, 1 H), 4.15 (m, 1 H), 3.99 (s, 3 H), 3 , 45 (m, 2 H), 3.20 (m, 2 H), 2.80 (m, 2 H), 2.70 (m, 2 H) 413 Example 126

177

6- (1,4-Diazepan-1-yl) -4 [(2,4-difluorophenyl) amino] -7methoxyquinoline-3-carboxamide 10.60 (s, 1 H), 8.76 (s, 1H), 8.20 (s, 1 H), 7.56 (s, 1H), 7.29 (m, 1H), 7.15 (s, 1 H), 6.90 (m, 2 H), 6.65 (m, 1 H), 3.86 (s, 3 H), 3.70 (m, 1 H), 3.00 ( m, 4 H), 2.65 (m, 4 H), 1.55 (m, 2 H) 427 Example 127

178

4 - [(3-Chloro-4fluorophenyl) amino] -7ethoxy-6-piperazin-1-2 ilquinolin-3carboxamide 4 CD2Cl2 10.41 (s, 1H), 8.77 (s, 1H), 7.28 (s, 1H), 7.07 (m, 1H), 6.87 (m, H), 6.72 ( m, 1 H), 6.14 (br s, 2 H), 4.21 (q, 2 H), 2.89 (m, 4 H), 2.76 (m, H), 1.50 ( t, 3 H) 444 Example 64

179

7-Ethoxy-4 - [(2-fluoro-5methylphenyl) amino] -6piperazin-1-ylquinolin-3H), carboxamide (q, CD2Cl2 10.45 (s, 1 H), 8.75 (s, 1H), 7.26 (s, 1 H), 7.01 (m, 1H), 6.95 (s, 1 6.85 ( m, 1 H), 6.76 (m, 1 H), 4.20 2 H), 2.90 (m, 4 H), 2.73 (m, 4 H), 2.18 (s, 3H ), 1.49 (t, 3H) 424 Example 65

180

4 - [(3-Chloro-2fluorophenyl) amino] -7ethoxy-6-piperazin-1-1 ilquinolin-3carboxamide 4 CD2Cl2 10.51 (s, 1 H), 8.75 (s, 1 H), 7.27 (s, 1 H), 7.06 (m, 2 H), 6.90 (m, H), 6 , 85 (m, 1H), 5.96 (br s, 2 H), 4.20 (q, 2 H), 2.92 (m, 4 H), 2.76 (m, H), 1, 50 (t, 3 H) 444 Example 66

Ex.

Compound NMR m / z MP

181

6- (1,4-Diazepan-1-yl) -4 [(2,3-dichlorophenyl) amino] 7-ethoxyquinoline-3carboxamide 4 10.70 (s, 1 H), 8.85 (s, 1 H), 8.35 (s, 1 H), 7.75 (s, 1 H), 7.26 (m, 2 H), 7, 15 (m, 1H), 6.55 (m, 2 H), 4.20 (q, 2 H), 4.10 (m, 1H), 3.05 (m, 4 H), 2.70 ( m, H), 1.65 (m, 2 H), 1.44 (t, 3 H) 473 Example 128

182

4 - [(2,4-Difluorophenyl) amino] -7-ethoxy-6piperazin-1- (s, ilquinolin-3carboxamide 4 10.71 (s, 1 H), 8.84 (s, 1 H), 8.27 (s, 1 H), 7.64 (s, 1 H), 7.36 (m, 1 H), 7 , 22 1 H), 7.00 (m, 2 H), 6.77 (s, 1 H), 4.16 (q, 2 H), 2.73 (m, 4 H), 2.63 (m , H), 1.39 (t, 3 H) 427 Example 129

183

6- (1,4-Diazepan-1-yl) -4 [(2,4-difluorophenyl) amino] -7- (s, ethoxyquinoline-3-carboxamide 4 10.65 (s, 1 H), 8.80 (s, 1 H), 8.25 (s, 1 H), 7.63 (s, 1 H), 7.35 (m, 1 H), 7.20 1H), 6.95 (m, 2 H), 6.70 (s, 1 H), 4.16 (q, 2 H), 3.05 (m, 4 H), 2.75 (m, H ), 1.61 (m, 2 H), 1.40 (t, 3 H) 441 Example 130

184

6- (1,4-Diazepan-1-yl) -4 [(2,3-dichlorophenyl) amino] 7-methoxyquinoline-3carboxamide 10.79 (s, 1 H), 8.95 (s, 1H), 8.42 (s, 1 H), 7.80 (s, 1 H), 7.32 (m, 2 H), 7 , 20 (m, 1 H), 6.65 (m, 2 H), 4.00 (s, 3 H), 3.85 (m, 1 H), 3.16 (m, 4 H), 2 , 78 (m, 4 H), 1.65 (m, 2H) 460 Example 131

185

7-Ethoxy-4 - [(2-fluoro-4methylphenyl) amino] -6piperazin-1-ylquinolin-3carboxamide CD2Cl2 10.37 (s, 1 H), 8.63 (s, 1H), 7.15 (s, 1H), 6.85 (m, 1H), 6.80 (m, 3 H), 4, 10 (q, 2 H), 2.78 (m, 4 H), 2.60 (m, 4H), 2.22 (s, 3 H), 1.40 (t, 3 H) 424 Example 154

Example 186

2- (4- {3- (Aminocarbonyl) -4 - [(2,3-dichlorophenyl) amino] -7-methoxyquinolin-6-yl} piperazin-1-yl)

2-oxoethyl acetate

5 To a solution of 4 - [(2,3-dichlorophenyl) amino] -7-methoxy-6piperazin-1-ylquinolin-3-carboxamide dihydrochloride (Example 174, 120 mg, 0.23 mmol) and diisopropylethylamine (160 µL , 0.92 mmol) in THF (10 mL) at -10 ° C under N2, a solution of 2-chloro-2-oxoethyl acetate (30 µL, 0.28 mmol) was added dropwise over 10 minutes ) in THF (10 mL). After stirring for 1 hour at -10 ° C, it is

The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and saturated aqueous Na2CO3 solution. The organic layer was dried (Na2SO4), filtered and concentrated, and the residue was crystallized from Et2O / EtOAc to give 100 mg of a solid. NMR: 8.98 (s, 1 H), 8.46 (s, 1H), 7.78 (s, 1 H), 7.37 (s, 1H), 7.25 (d, 1H), 7 , 14 (t, 1H), 6.72 (s, 1H), 6.58 (d, 1 H), 4.77 (s, 2 H), 3.98 (s, 3 H), 3.44 (m, 4 H), 2.78 (m, 4 H), 2.07 (s, 3 H); m / z: 545.

Examples 187-190

The following compounds were prepared by a method similar to that of Example 186 using the appropriate starting materials (MP).

Ex.

Compound NMR m / z MP

187

6- (4-Acetylpiperazin-1-yl) 4 - [(2,3-dichlorophenyl) amino] -7-methoxyquinoline3-carboxamide CD3OD 8.77 (s, 1 H), 7.23 (s, 1H), 7.13 (dd, 1H), 7.00 (t, 1 H), 6.75 (s, 1 H), 6 , 57 (dd, 1H), 3.93 (s, 3 H), 3.50 (m, 4 H), 2.75 (m, 2 H), 2.67 (m, 2 H), 1, 99 (s, 3 H) 487 Example 174

188

6- (4-Acetylpiperazin-1-yl) 4 - [(2,3-dichlorophenyl) amino] -7-ethoxyquinoline-3-carboxamide CD2Cl2 10.42 (s, 1 H), 8.82 (s, 1 H), 7.34 (s, 1 H), 7.13 (d, 1 H), 6.97 (m, 1 H), 6, 79 (s, 1H), 6.60 (d, 1 H), 4.24 (q, 2 H), 3.62 (m, 2 H), 3.50 (m, 2 H), 2.79 (m, 4 H), 2.04 (s, 3 H), 1.51 (t, 3 H) 502 Example 175

189

6- (4-Acetyl-1,4-diazepan1-yl) -4 - [(2,3-dichlorophenyl) amino] -7-ethoxyquinoline-3carboxamide 10.75 (d, 1 H), 8.95 (s, 1 H), 8.42 (s, 1 H), 7.80 (s, 1 H), 7.34 (m, 2 H), 7.20 (m, 1 H), 6.70 (s, 1 H), 6.65 (d, 1 H), 4.28 (q, 2 H), 3,553.12 (m, 11 H), 1.80 (m , 1 H), 1.70 (m, 1 H), 1.50 (t, 3 H) 516 Example 181

190

6- (4-Acetylpiperazin-1-yl) 7-ethoxy-4 - [(2-fluoro-4methylphenyl) amino] quinolin3-carboxamide CD2Cl2 10.49 (s, 1 H), 8.72 (s, 1 H), 7.26 (s, 1H), 6.95 (d, 1 H), 6.91 (s, 1 H), 6.87 (m, 2 H), 5.97 (br, 2 H), 4.20 (q, 2 H), 3.58 (m, 2 H), 3.46 (m, 2H), 2 , 78 (m, 2 H), 2.66 (m, 2 H), 2.32 (s, 3 H), 2.04 (s, 3 H), 1.49 (t, 3 H) 466 Example 185

Example 191

10 4 - [(2,3-Dichlorophenyl) amino] -6- (4-glycolylpiperazin-1-yl) -7-methoxyquinolin-3-carboxamide A mixture of 2- (4- {3- (aminocarbonyl) acetate) - 4 - [(2,3-dichlorophenyl) amino] -7methoxyquinolin-6-yl} piperazin-1-yl) -2-oxoethyl (Example 186, 70 mg, 0.13 mmol), K2CO3 (0.5 g, 3 , 6 mmol), MeOH (5 mL), and water (1 mL) was vigorously stirred for 1 hour. Most of the solvent was removed under reduced pressure, and the residue was subjected to

15 distribution between water (10 mL) and EtOAc (10 mL). The desired product precipitated in the separatory funnel and was collected by filtration. The aqueous layer was then extracted with EtOAc, and the combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure to give an anticipated solid by NMR and LC-MS to the anticipated material. The solids were pooled to give 25 mg. NMR: 10.85 (s, 1 H), 9.01 (s, 1H), 8.43 (s, 1 H), 7.83 (s, 1H), 7.43 (s, 1H), 7 , 33 (dd, 1H), 7.21 (t, 1 H), 6.78 (s, 1 H), 6.65 (d, 1 H), 4.63 (t, 1H), 4.14 (d, 2 H), 4.04 (s, 3 H), 3.57 (m, 2 H), 3.45 (m, 2 H), 2.82 (m, 4 H); m / z: 503.

5

Example 192

4 - [(2,3-Dichlorophenyl) amino] -7-ethoxy-6- [4- (2-hydroxyethyl) piperazin-1-yl] quinolin-3carboxamide A mixture of 4 - [(2,3-dichlorophenyl) amino ] -7-ethoxy-6-piperazin-1-ilquinolin-3

Carboxamide (Example 175, 67 mg, 0.146 mmol) and glycolaldehyde (26 mg, 0.43 mmol) in toluene: MeOH (6 mL, 5: 1) was heated at reflux for 1 hour. The reaction mixture was concentrated and dissolved in THF (15 mL). Sodium triacetoxyborohydride (155 mg, 0.73 mmol) and acetic acid (0.1 mL) were added and the reaction mixture was heated at reflux for 1 hour. Water was added, and the mixture was

15 extracted with EtOAc (4 x 50 mL). The combined organic extracts were dried (MgSO4), filtered, concentrated, and the residue was purified by reverse phase HPLC to give 36 mg of a yellow solid. NMR: 10.50 (s, 1H), 8.95 (s, 1 H), 8.40 (s, 1H), 7.85 (s, 1 H), 7.60 (d, 1H), 7 , 52 (s, 1H), 7.39 (m, 2 H), 7.20 (s, 1 H), 4.25 (q, 2 H), 3.80 (m, 2 H), 3, 50 (m, 4 H), 3.20 (m, 4 H), 2.95 (m, 2 H), 1.43 (t, 3 H); m / z: 503.

twenty

Examples 193-200

The following compounds were prepared by the procedure of Example 192 using the appropriate starting materials (MP).

Ex.

Compound NMR m / z MP

193

4 - [(2,3-Dichlorophenyl) amino] 7-ethoxy-6- (4-isopropyl-1,4diazepan-1-yl) quinolin-3carboxamide 10.69 (s, 1H), 8.85 (s, 1H), 8.33 (s, 1 H), 7.70 (s, 1H), 7.23 (m, 2 H), 7.14 (m, 1 H), 6.65 (m, 2 H), 4.20 (q, 2 H), 3.35 (m, 1 H), 3.10 (m, 4 H), 2,902.55 (m, 4 H), 1.65 (m, 2 H), 1.45 (t, 3 H), 0.92 (m, 6 H) 515 Example 181

194

4 - [(2,4-Difluorophenyl) amino] 7-ethoxy-6- [4- (2-hydroxyethyl) piperazin-1-yl] quinolin-3carboxamide 11.00 (s, 1 H), 8.80 (s, 1 H), 8.20 (s, 1 H), 7.70 (s, 1 H), 7.40-7.10 (m, 5 H), 4.22 (q, 2 H), 3.78 (m, 2 H), 3.55-2.95 (m, 10 H), 1.45 (t, 3 H) 471 Example 182

Ex.

Compound NMR m / z MP

195

6- [4- (Cyclopropylmethyl) piperazin-1-yl] -4 - [(2,4difluorophenyl) amino] -7ethoxyquinoline-3carboxamide 10.10 (s, 1 H), 8.80 (s, 1 H), 8.20 (s, 1 H), 7.70 (s, 1H), 7.45 (m, 4 H), 7 , 15 (m, 1 H), 4.29 (q, 2 H), 3.50 (m, 4 H), 3.15 (m, 4 H), 2.90 (m, 2 H), 1 , 45 (t, 3 H), 1.09 (m, 1 H), 0.65 (m, 2 H), 0.35 (m, 2 H) 481 Example 182

196

4 - [(2,4-Difluorophenyl) amino] 7-ethoxy-6- (4-isopropyl-1,4diazepan-1-yl) quinolin-3carboxamide 10.70 (s, 1H), 8.87 (s, 1H), 8.32 (s, 1 H), 7.70 (s, 1H), 7.40 (m, 1H), 7.26 ( s, 1 H), 7.05 (m, 2 H), 6.75 (s, 1H), 4.22 (q, 2 H), 3.10 (m, 4 H), 2.90 (m , 1H), 2.65 (m, 4 H), 1.75 (m, 2 H), 1.49 (t; 3 H), 1.00 (m, 6 H) 484 Example 183

197

4 - [(2,4-Difluorophenyl) amino] 6- (4-isopropyl-1,4-diazepan1-yl) -7-methoxyquinoline-3-carboxamide 10.55 (s, 1 H), 8.70 (s, 1H), 8.20 (s, 1 H), 7.55 (s, 1 H), 7.25 (m, 1H), 7, 10 (s, 1 H), 6.85 (m, 2 H), 6.62 (s, 1 H), 3.80 (s, 3 H), 3.30 (m, 4 H), 2.95 (m, 4 H), 2.69 (m, 1 H), 1.47 (m, 2 H), 0.80 (d, 6 H) 469 Example 177

198

4 - [(2,4-Difluorophenyl) amino] 6- (4-ethyl-1,4-diazepan-1-yl) 7-methoxyquinoline-3-carboxamide 10.35 (s, 1 H), 8.82 (s, 1 H), 8.33 (s, 1 H), 7.77 (s, 1 H), 7.42 (m, 3 H), 7, 20 (m, 2 H), 4.00 (s, 3 H), 3.50-3.10 (m, 6 H), 2.90 (m, 2 H), 2.28 (m, 2 H ), 2.10 (m, 2 H), 1.28 (t, 3 H) 455 Example 177

199

4 - [(2,3-Dichlorophenyl) amino] 6- (4-isopropyl-1,4-diazepan1-yl) -7-methoxyquinoline-3-carboxamide 10.77 (s, 1 H), 8.92 (s, 1 H), 8.40 (s, 1 H), 7.79 (s, 1 H), 7.30 (m, 2 H), 7, 20 (m, 1 H), 6.70 (s, 1H), 6.60 (d, 1H), 4.00 (s, 3 H), 3.40 (m, 4 H), 3.18 ( m, 4 H), 2.80 (m, 1H), 1.65 (m, 2 H), 0.95 (m, 6 H) 502 Example 184

200

7-Ethoxy-4 - [(2-ffuoro-4methylphenyl) amino] -6- [4- (2-hydroxyethyl) piperazin-1-yl] quinolin-3-carboxamide CD2Cl2 10.44 (s, 1 H), 8.70 (s, 1 H), 7.23 (s, 1 H), 6.94 (d, 1 H), 6.91 (s, 1 H), 6, 86 (m, 2 H), 5.97 (br, 2 H), 4.19 (q, 2 H), 3.56 (t, 2 H), 2.78 (s, 4 H), 2, 53 (m, 6H), 2.31 (s, 3 H), 1.48 (t, 3 H) 468 Example 185

Example 201

4 - [(2,3-Dichlorophenyl) amino] -7-ethoxy-6- (4-glycolylpiperazin-1-yl) quinolin-3-carboxamide

A mixture of 4 - [(2,3-dichlorophenyl) amino] -7-ethoxy-6-piperazin-1ylquinolin-3-carboxamide hydrochloride (Example 175, 80 mg, 0.14 mmol), glycolic acid (38 mg, 0.5 mmol), HATU (106 mg, 0.28 mmol) and DIEA (72 mg, 0.56 mmol) in anhydrous DMF (3 mL) was stirred at room temperature for 5 hours. The crude mixture was purified by reverse phase HPLC to give 30 mg of a yellow solid. NMR: 12.10 (s, 1 H), 8.98 (s, 1 H), 8.46 (s, 1 H), 7.95 (s, 1 H), 7.65 (d, 1 H), 7.42 (m, 2 H), 7.35 (d, 1H), 6.96 (s, 1 H), 4.25 (q, 2 H), 4.09 (s, 2 H), 3 , 60 (m, 4 H), 2.80 (m, 2 H), 2.70 (m, 2 H), 1.25 (t, 3H); m / z: 518.

Examples 202-206

The following compounds were prepared by a method similar to that of Example 201 using the appropriate starting materials (MP).

Ex.

Compound NMR m / z MP

202

4 - [(2,3-Dichlorophenyl) amino] -7-ethoxy-6- {4 - [(2S) 1 2-hydroxypropanoyl] piperazin-1-yl} quinolin-3carboxamide 4 12.15 (s, 1H), 8.96 (s, 1H), 8.45 (s, H), 7.95 (s, 1H), 7.65 (d, 1 H), 7.40 ( m, 3 H), 6.99 (s, 1 H), 4.40 (m, 1 H), 4.26 (q, 2 H), 3.55 (m, 4 H), 2.80 (m , H), 1.48 (t, 3 H), 1.15 (d, 3 H) 532 Example 175

203

4 - [(2,3-Dichlorophenyl) amino] -7-ethoxy-6- {4 - [(2R) 1 2-hydroxypropanoyl] (s, piperazin-1-yl} quinolin-3carboxamide 4 12.29 (s, 1 H), 9.05 (s, 1 H), 8.57 (s, H), 7.96 (s, 1H), 7.65 (d, 1 H), 7, 50 1 H), 7.40 (m, 2 H), 6.98 (s, 1 H), 4.42 (m, 1H), 4.25 (q, 2 H), 3.60 (m, H), 2.80 (m, 4 H), 1.45 (t, 3 H), 1.20 (d, 3 H) 532 Example 175

204

7-Ethoxy-4 - [(2-fluoro-4methylphenyl) amino] -6- (4-glycolylpiperazin-1-yl) quinolin-3-carboxamide CD2Cl2 10.48 (s, 1H), 8.73 (s, 1H), 7.26 (s, 1H), 6.95 (d, 1H), 6.92 (s, 1 H), 6.86 (m, 2 H), 5.97 (br, 2 H), 4.20 (q, 2 H), 4.11 (s, 2 H), 3.66 (m, 2 H), 3.27 (m, 2 H), 2.78 (m, 2 H), 2.71 (m, 2 H), 2.32 (s, 3 H), 1.49 (% 3 H) 481 Example 185

205

7-Ethoxy-4 - [(2-fluoro-4methylphenyl) amino] -6- {4 [(2S) -2-hydroxypropanoyl] piperazin-1-yl} quinolin-3carboxamide 2 CD2Cl2 10.47 (s, 1H), 8.72 (s, 1H), 7.26 (s, 1H), 6.95 (d, 1 H), 6.92 (s, 1 H), 6, 87 (m, 2 H), 5.96 (br, 2H), 4.41 (q, 1H), 4.20 (q, 2 H), 3.66 (m, 2 H), 3.42 ( m, 2 H), 2.79 (m, 2 H), 2.72 (m, H), 2.32 (s, 3 H), 1.49 (t, 3 H), 1.27 (d , 3 H) 496 Example 185

206

7-Ethoxy-4 - [(2-fluoro-4methylphenyl) amino] -6- {4 [(2R) -2-hydroxypropanoyl] piperazin-1-yl} quinolin-3carboxamide 2 (d, CD2Cl2 10.47 (s, 1H), 8.72 (s, 1H), 7.26 (s, 1H), 6.95 (d, 1H), 6.92 (s, 1 H), 6.87 (m, 2 H), 5.96 (br, 2H), 4.41 (q, 1 H), 4.21 (q, 2 H), 3.66 (m, 2 H), 3.42 ( m, 2 H), 2.79 (m, 2 H), 2.73 (m, H), 2.32 (s, 3 H), 1.49 (t, 3 H), 1.27 3 H ) 496 Example 185

Example 207

6- (4-Cyclopropyl-1,4-diazepan-1-yl) -4 - [(2,4-difluorophenyl) amino] -7-ethoxyquinoline-3carboxamide To a solution of 6- (1,4-diazepan-1 -il) -4 - [(2,4-difluorophenyl) amino] -7

5 ethoxyquinoline-3-carboxamide (Example 183, 100 mg, 0.227 mmol) in MeOH (10 mL) [(1-ethoxycyclopropyl) oxy] trimethyl silane (237 mg, 1.36 mmol), acetic acid (136 mg) were added , 2.27 mmol), 4Å molecular sieves (2 g) and sodium cyanoborohydride (291 mg, 4.54 mmol). The resulting reaction mixture was stirred at reflux overnight. Water was added, the mixture was extracted with EtOAc (3 x 30 mL), and the extracts

The combined organics were dried (Na2SO4), concentrated and the residue was purified with an ISCO chromatography system to give 100 mg of a light yellow solid. NMR: 10.66 (s, 1 H), 8.89 (s, 1 H), 8.25 (s, 1 H), 7.65 (s, 1 H), 7.35 (m, 1 H ), 7.20 (s, 1H), 6.95 (m, 2H), 6.68 (s, 1H), 4.17 (q, 2 H), 3.03 (m, 4 H), 2 , 73 (m, 4 H), 1.86 (m, 1 H), 1.70 (m, 2 H), 1.42 (t, 3 H), 0.41 (m, 2 H), 0 , 27 (m, 2 H); m / z: 482.

fifteen

Examples 208-215

The following compounds were prepared by a method similar to that of Example 207 using the appropriate starting materials (MP)

Ex.

Compound NMR m / z MP

208

6- (4-Cyclopropylpiperazin-1-yl) -4 - [(2,4-difluorophenyl) amino] -7-ethoxyquinoline-3-carboxamide 10.79 (s, 1H), 8.90 (s, 1H), 8.31 (s, 1 H), 7.70 (s, 1H), 7.40 (m, 1H), 7.30 ( s, 1 H), 7.09 (m, 2 H), 6.86 (s, 1 H), 4.25 (q, 2 H), 2.79 (m, 8 H), 2.65 ( m, 1 H), 1.46 (t, 3 H), 0.71 (m, 2 H), 0.63 (m, 2 H) 467 Example 182

209

6- (4-Cyclopropylpiperazin-1-yl) -4 - [(2,4-difluorophenyl) amino] -7-methoxyquinoline-3-carboxamide 10.65 (s, 1H), 8.91 (s, 1H), 8.30 (s, 1 H), 7.68 (s, 1 H), 7.38 (m, 1H), 7.30 (s, 1 H), 7.06 (m, 2 H), 6.86 (s, 1 H), 3.95 (s, 3 H), 2.70 (m, 4 H), 2.56 (m, 4 H), 1.65 (m, 1H), 0.41 (m, 2 H), 0.30 (m, 2 H) 453 Example 176

210

6- (4-Cyclopropylpiperazin-1-yl) -4 - [(2,3-dichlorophenyl) amino] -7-methoxyquinoline-3-carboxamide 10.80 (s, 1H), 8.95 (s, 1H), 8.40 (s, 1 H), 7.79 (s, 1H), 7.35 (s, 1H), 7.28 ( d, 1 H), 7.15 (m, 1H), 6.69 (s, 1H), 6.60 (d, 1H), 3.98 (s, 3 H), 2.71 (m, 4 H), 2.56 (m, 4 H), 1.65 (m, 1 H), 0.40 (m, 2 H), 0.20 (m, 2 H) 486 Example 174

211

6- (4-Cyclopropyl-1,4 10.69 (s, 1 H), 8.80 (s, 1 H), 467 Example

diazepan-1-il) -4 - [(2,4

8.28 (s, 1 H), 7.65 (s, 1 H), 177

difluorophenyl) amino] -7

7.36 (m, 1 H), 7.24 (s, 1 H),

methoxyquinoline-3

6.97 (m, 2 H), 6.70 (s, 1H),

carboxamide

3.91 (s, 3H), 3.05 (m, 4 H),

2.70 (m, 4 H), 1.82 (m, 1H),

1.67 (m, 2 H), 0.40 (m, 2 H),

0.27 (m, 2 H)

212

6- (4-Cyclopropyl-1,4 10.70 (s, 1H), 8.89 (s, 1H), 500 Example

diazepan-1-il) -4 - [(2,3

8.35 (s, 1 H), 7.63 (s, 1 H), 184

dichlorophenyl) amino] -7

7.25 (m, 2 H), 7.12 (m, 1H),

methoxyquinoline-3

6.55 (m, 2 H), 3.95 (s, 3 H),

carboxamide

3.12 (m, 2 H), 3.07 (m, 2 H),

2.65 (m, 4 H), 1.85 (m, 1 H),

1.65 (m, 2 H), 0.42 (m, 2 H),

0.26 (m, 2 H)

213

4 - [(3-Chloro-4-fluorophenyl) amino] -6- (4-cyclopropyl piperazin-1-yl) -7ethoxyquinoline-3carboxamide CD3OD 8.81 (s, 1H), 7.26 (s, 1H), 7.20 (m, 1H), 7.03 (m, 1H), 7.00 (s, 1 H), 6.90 (m, 1 H), 4.25 (q, 2 H), 2.88 (m, 4 H), 2.79 (m, 4 H), 1.84 (m, 1 H), 1.52 (t, 3 H), 0.55 (m, 2 H), 0.48 (m, 2 H) 484 Example 178

214

6- (4-Cyclopropylpiperazin-1-yl) -7-ethoxy-4 - [(2-fluoro-5-methylphenyl) amino] quinolin-3-carboxamide CD3OD 8.78 (s, 1H), 7.23 (s, 1H), 7.06 (dd, 1H), 7.01 (s, 1 H), 6.94 (m, 1 H), 6, 79 (d, 1 H), 4.23 (q, 2 H), 2.80 (m 4 H), 2.69 (m, 4 H), 2.20 (s, 3H), 1.69 ( m, 1H), 1.51 (t, 3H), 0.50 (m, 2 H), 0.42 (m, 2 H) 464 Example 179

215

4 - [(3-Chloro-2-fluorophenyl) amino] -6- (4-cyclopropylpiperazin-1-yl) -7ethoxyquinoline-3carboxamide CD3OD 8.76 (s, 1H), 7.25 (s, 1H), 7.17 (dd, 1H), 7.06 (d, 1H), 7.02 (s, 1 H), 6.95 (m, 1H), 4.24 (q, 2 H), 2.88 (m, 4 H), 2.72 (m, 4 H), 1.70 (m, 1 H), 1.52 ( t, 3 H), 0.50 (m, 2 H), 0.43 (m, 2 H) 484 Example 180

Example 216

4 - [(2,4-Difluorophenyl) amino] -7- (2-hydroxyethoxy) -6- (4-methylpiperazin-1-yl) quinolin-3

carboxamide

5 To a solution of 7- (2 - {[tert-butyl (dimethyl) silyl) oxy} ethoxy) -4 - [(2,4-difluorophenyl) amino] -6- (4-methylpiperazin-1-yl) quinolin -3-ethyl carboxylate (Intermediate 162, 0.200 g, 0.33 mmol) and formamide (0.132 mL, 3.33 mmol) in DMF (5 mL), heated at 100 ° C for 30 minutes, a methoxide solution was added of sodium in MeOH (0.5 M, 0.85 mL, 0.43 mmol). After 16 hours, the reaction was cooled, water was added

10 (50 mL), and the reaction mixture was extracted with EtOAc (3 x 50 mL). The combined organic extracts were concentrated and a solution of tetrabutylammonium fluoride (1.0 M in THF, 1 mL) was added. The mixture was allowed to stand for 1 hour. Water (10 mL) was added and the mixture was extracted with EtOAc (3 x 10 mL). The combined organic extracts were concentrated and the residue was purified by reverse phase HPLC.

5 The product (hexane / acetone) was recrystallized to give 85 mg (56%) of a yellow solid. 1 H NMR: 10.73 (s, 1 H), 8.85 (s, 1 H), 8.29 (s, 1 H), 7.66 (s, 1 H), 7.37 (t, 1 H) , 7.26 (s, 1 H), 7.03 (m, 2 H), 6.80 (s, 1H), 4.87 (t, 1H), 4.16 (m, 2 H), 3 , 79 (m, 2 H), 2.76 (s, 4 H), 2.37 (s, 4 H), 2.18 (s, 3 H); m / z: 458.

Example 217 The following compound was prepared by a method similar to that of Example 216 using the appropriate starting material (MP).

Ex.

Compound NMR m / z MP

217

4 - [(3-Chloro-2-fluorophenyl) amino] -7- (2-hydroxyethoxy) 6- (4-methylpiperazin-1-yl) quinolin-3-carboxamide 10.69 (s, 1 H), 8.88 (s, 1H), 8.31 (s, 1 H), 7.70 (s, 1 H), 7.30 (s, 1 H), 7 , 23 (t, 1 H), 7.08 (s, 1H), 6.84 (m, 2 H), 4.87 (t, 1H), 4.18 (m, 2 H), 3.80 (m, 2 H), 2.81 (s, 4 H), 2.37 (s, 4 H), 2.18 (s, 3 H) 474 Intermediate 163

15 Preparation of starting materials

Intermediate 1

Ethyl 4 - [(2,3-Dichlorophenyl) amino] -7-methoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate

A mixture of ethyl 6-bromo-4 - [(2,3-dichlorophenyl) amino] -7-methoxyquinoline-3-carboxylate (Intermediate 155; 400 mg, 0.82 mmol), tris (dibenzylidenacetone) dipaladium (0 ) (60 mg, 0.066 mmol), (R, S) -2,2'-bis (diphenylphosphino) 1,1'-binaphthyl (124 mg, 0.20 mmol), Cs2CO3 (390 mg, 1.2 mmol) , and N-methylpiperazine (227 µL, 2.05 mmol) in anhydrous toluene under N2, was heated at 100 ° C for 18 hours.

The reaction mixture was filtered and concentrated, and the crude oil was purified by reverse phase HPLC to give 117 mg of a solid; m / z: 489.

Intermediates 2-154

The following compounds were prepared by a method similar to Intermediate 1 using the appropriate starting materials (MP).

Int.

Compound M / z / NMR MP

2

Ethyl 4 - [(2,4-Dichlorophenyl) amino] -7-methoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate Intermediate 165

3

Ethyl 4 - [(3,4-Dichlorophenyl) amino] -7-methoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate Intermediate 166

4

Ethyl 4 - [(2,4-Difluorophenyl) amino] -7-methoxy-6 (4-methylpiperazin-1-yl) quinolin-3-carboxylate 458 Intermediate 167

5

Ethyl 4 - [(2,3-Dichlorophenyl) amino] -7-methoxy-6morpholin-4-ylquinolin-3-carboxylate Intermediate 155

6

Ethyl 4 - [(2,4-Difluorophenyl) amino] -7-methoxy-6morpholin-4-ylquinolin-3-carboxylate Intermediate 167

7

Ethyl 4 - [(3,4-Dichlorophenyl) amino] -7-methoxy-6morpholin-4-ylquinolin-3-carboxylate Intermediate 166

8

Ethyl 4 - [(3,4-Dichlorophenyl) amino] -7-methoxy-6piperidin-1-ylquinolin-3-carboxylate Intermediate 166

9

Ethyl 4 - [(2,3-Dichlorophenyl) amino] -6-methoxy-7- (4-methylpiperazin-1-yl) quinolin-3-carboxylate Intermediate 168

10

Ethyl 4 - [(3,4-Dichlorophenyl) amino] -6-methoxy-7- (4-methylpiperazin-1-yl) quinolin-3-carboxylate Intermediate 169

eleven

4 - [(2,4-Difluorophenyl) amino] -7-ethoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate ethyl 471 Intermediate 170

12

Ethyl 4 - [(2,3-Dichlorophenyl) amino] -7-ethoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate 504 Intermediate 171

13

Ethyl 4 - [(2,4-Difluorophenyl) amino] -7-ethoxy-6morpholin-4-ylquinolin-3-carboxylate Intermediate 170

14

Ethyl 4 - [(3,4-Dichlorophenyl) amino] -7-ethoxy-6morpholin-4-ylquinolin-3-carboxylate Intermediate 172

fifteen

6- [4- (tert-Butoxycarbonyl) piperazin-1-yl] -4 [(2,3-dichlorophenyl) amino] -7-methoxyquinoline-3-carboxylate ethyl 575 Intermediate 155

16

4 - [(2,4-Difluorophenyl) amino] -7-fluoro-6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate ethyl 445 Intermediate 173

17

Ethyl 4 - [(2,3-Dichlorophenyl) amino] -7-fluoro-6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate Intermediate 174

Int.

Compound M / z / NMR MP

18

Ethyl 4 - [(2,4-Difluorophenyl) amino] -7-fluoro-6morpholin-4-ylquinolin-3-carboxylate Intermediate 173

19

Ethyl 4 - [(2,3-Dichlorophenyl) amino] -5-fluoro-6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate Intermediate 175

twenty

Ethyl 7-Ethoxy-4 - [(4-ethylphenyl) amino] -6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate 463 Intermediate 176

twenty-one

Ethyl 4 - [(3-Chloro-4-fluorophenyl) amino] -7-ethoxy-6 (4-methylpiperazin-1-yl) quinoline-3-carboxylate 487 Intermediate 177

22

Ethyl 4 - [(3,4-Dichlorophenyl) amino] -7-ethoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate 503 Intermediate 172

2. 3

Ethyl 4 - [(2,3-Dichlorophenyl) amino] -7-ethoxy-6- (4-ethylpiperazin-1-yl) quinolin-3-carboxylate 517 Intermediate 171

24

Ethyl 4 - [(3-Chloro-2-fluorophenyl) amino] -7-ethoxy-6morpholin-4-ylquinolin-3-carboxylate 474 Intermediate 178

25

Ethyl 7-Ethoxy-4 - [(2-fluoro-5-methylphenyl) amino] -6morpholin-4-ylquinolin-3-carboxylate 454 Intermediate 179

26

Ethyl 4 - [(3-Chloro-4-fluorophenyl) amino] -7-ethoxy-6morpholin-4-ylquinolin-3-carboxylate 454 Intermediate 177

27

Ethyl 7-Ethoxy-4 - [(4-ethylphenyl) amino] -6-morpholin-4ylquinolin-3-carboxylate 450 Intermediate 176

28

Ethyl 4 - [(2,3-Dichlorophenyl) amino] -7-ethoxy-6morpholin-4-ylquinolin-3-carboxylate 490 Intermediate 171

29

Ethyl 4 - [(2,3-Dichlorophenyl) amino] -7-ethoxy-6- (4isopropylpiperazin-1-yl) quinoline-3-carboxylate 530 Intermediate 171

30

Ethyl 4 - [(2,3-Dichlorophenyl) amino] -7-ethoxy-6- (4-methyl-1,4-diazepan-1-yl) quinolin-3-carboxylate 516 Intermediate 171

31

Ethyl 4 - [(2,3-Dichlorophenyl) amino] -7-ethoxy-6- (3-hydroxypyrrolidin-1-yl) quinolin-3-carboxylate 489 Intermediate 171

32

Ethyl 4 - [(2,3-Dichlorophenyl) amino] -6- {4- [2 (dimethylamino) ethyl] piperazin-1-yl} -7ethoxyquinoline-3-carboxylate 559 Intermediate 171

33

Ethyl 4 - [(2,3-Dichlorophenyl) amino] -7-ethoxy-6- [4 (2-methoxyethyl) piperazin-1-yl] quinolin-3-carboxylate 546 Intermediate 171

Int.

Compound M / z / NMR MP

3. 4

Ethyl 4 - [(3,4-Dichlorophenyl) amino] -7-ethoxy-6- (4-ethylpiperazin-1-yl) quinolin-3-carboxylate 517 Intermediate 172

35

4 - [(2,4-Difluorophenyl) amino] -7-ethoxy-6- (4-ethylpiperazin-1-yl) quinolin-3-carboxylate ethyl 485 Intermediate 170

36

Ethyl 4 - [(3-Chloro-2-fluorophenyl) amino] -7-ethoxy-6 (4-ethylpiperazin-1-yl) quinolin-3-carboxylate 501 Intermediate 178

37

Ethyl 7-Ethoxy-6- (4-ethylpiperazin-1-yl) -4 - [(2fluoro-5-methylphenyl) amino] quinoline-3-carboxylate 481 Intermediate 179

38

Ethyl 4 - [(3-Chloro-4-fluorophenyl) amino] -7-ethoxy-6 (4-ethylpiperazin-1-yl) quinolin-3-carboxylate 501 Intermediate 177

39

Ethyl 7-Ethoxy-4 - [(4-ethylphenyl) amino] -6- (4-ethylpiperazin-1-yl) quinolin-3-carboxylate 477 Intermediate 176

40

6- [4- (2-Cyanoethyl) piperazin-1-yl] -4 - [(2,3-dichlorophenyl) amino] -7-ethoxyquinoline-3-carboxylate ethyl 541 Intermediate 171

41

Ethyl 4 - [(2,3-Dichlorophenyl) amino] -7-ethoxy-6- (4-hydroxypiperidin-1-yl) quinolin-3-carboxylate 503 Intermediate 171

42

Ethyl 7-Ethoxy-4 - [(4-ethylphenyl) amino] -6- (4-methyl1,4-diazepan-1-yl) quinolin-3-carboxylate 477 Intermediate 176

43

Ethyl 4 - [(2,4-Difluorophenyl) amino] -7-ethoxy-6- (3-hydroxypyrrolidin-1-yl) quinolin-3-carboxylate 457 Intermediate 170

44

Ethyl 4 - [(2,4-Difluorophenyl) amino] -7-ethoxy-6- (4-hydroxypiperidin-1-yl) quinolin-3-carboxylate 471 Intermediate 170

Four. Five

Ethyl 4 - [(3,4-Dichlorophenyl) amino] -7-ethoxy-6- (4isopropylpiperazin-1-yl) quinoline-3-carboxylate 531 Intermediate 172

46

Ethyl 4 - [(2,4-Difluorophenyl) amino] -7-ethoxy-6- (4isopropylpiperazin-1-yl) quinoline-3-carboxylate 499 Intermediate 170

47

Ethyl 4 - [(3-Chloro-2-fluorophenyl) amino] -7-ethoxy-6 (4-isopropylpiperazin-1-yl) quinoline-3-carboxylate 515 Intermediate 178

Int.

Compound M / z / NMR MP

48

Ethyl 7-Ethoxy-4 - [(2-fluoro-5-methylphenyl) amino] -6 (4-isopropylpiperazin-1-yl) quinoline-3-carboxylate 515 Intermediate 179

49

Ethyl 4 - [(3-Chloro-4-fluorophenyl) amino] -7-ethoxy-6 (4-isopropylpiperazin-1-yl) quinoline-3-carboxylate 491 Intermediate 177

fifty

Ethyl 4 - [(2,4-Difluorophenyl) amino] -7-ethoxy-6- (4-methyl-1,4-diazepan-1-yl) quinoline-3-carboxylate 484 Intermediate 170

51

Ethyl 4 - [(2,3-Dichlorophenyl) amino] -6- (4isopropylpiperazin-1-yl) -7-methoxyquinoline-3-carboxylate 517 Intermediate 155

52

Ethyl 4 - [(2,4-Difluorophenyl) amino] -6- (4isopropylpiperazin-1-yl) -7-methoxyquinoline-3-carboxylate 484 Intermediate 167

53

Ethyl 4 - [(2,3-Dichlorophenyl) amino] -7-methoxy-6- (4-methyl-1,4-diazepan-1-yl) quinolin-3-carboxylate 503 Intermediate 155

54

Ethyl 4 - [(2,4-Difluorophenyl) amino] -7-methoxy-6 (4-methyl-1,4-diazepan-1-yl) quinoline-3-carboxylate 470 Intermediate 167

55

Ethyl 4 - [(2,3-Dichlorophenyl) amino] -6- (4-ethylpiperazin-1-yl) -7-methoxyquinoline-3-carboxylate 503 Intermediate 155

56

Ethyl 4 - [(2,4-Difluorophenyl) amino] -6- (4-ethylpiperazin-1-yl) -7-methoxyquinoline-3-carboxylate 470 Intermediate 167

57

Ethyl 4 - [(3,4-Dichlorophenyl) amino] -6- (4-ethylpiperazin-1-yl) -7-methoxyquinoline-3-carboxylate 503 Intermediate 166

58

Ethyl 4 - [(3,4-Dichlorophenyl) amino] -6- (4isopropylpiperazin-1-yl) -7-methoxyquinoline-3-carboxylate 517 Intermediate 166

59

Ethyl 4 - [(3,4-Dichlorophenyl) amino] -7-methoxy-6- (4methyl-1,4-diazepan-1-yl) quinolin-3-carboxylate 503 Intermediate 166

60

Ethyl 4 - [(3,4-Dichlorophenyl) amino] -7-ethoxy-6- (4-methyl-1,4-diazepan-1-yl) quinolin-3-carboxylate 517 Intermediate 172

61

Ethyl 7-Ethoxy-4 - [(2-fluoro-5-methylphenyl) amino] -6 (4-methyl-1,4-diazepan-1-yl) quinoline-3-carboxylate 481 Intermediate 179

Int.

Compound M / z / NMR MP

62

Ethyl 4 - [(3-Chloro-4-fluorophenyl) amino] -7-ethoxy-6 (4-methyl-1,4-diazepan-1-yl) quinoline-3-carboxylate 487 Intermediate 177

63

Ethyl 4 - [(2-Fluorophenyl) amino] -7-methoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate Intermediate 180

64

6- [4- (tert-Butoxycarbonyl) piperazin-1-yl] -4 [(3-chloro-4-fluorophenyl) amino] -7-ethoxyquinoline-3-carboxylate ethyl 573 Intermediate 177

65

6- [4- (tert-Butoxycarbonyl) piperazin-1-yl] -7ethoxy-4 - [(2-fluoro-5-methylphenyl) amino] quinolin-3-carboxylate ethyl 553 Intermediate 179

66

6- [4- (tert-Butoxycarbonyl) piperazin-1-yl] -4 [(3-chloro-2-fluorophenyl) amino] -7-ethoxyquinoline-3-carboxylate ethyl 573 Intermediate 178

67

Ethyl 7-Methoxy-4 - [(3-methoxy-2-methylphenyl) amino] 6- (4-methylpiperazin-1-yl) quinoline-3-carboxylate 465 Intermediate 181

68

Ethyl 4 - [(4-Chloro-2-methylphenyl) amino] -7-methoxy6- (4-methylpiperazin-1-yl) quinoline-3-carboxylate 469 Intermediate 182

69

Ethyl 4 - [(3-Chloro-2-methylphenyl) amino] -7-ethoxy-6 (4-methylpiperazin-1-yl) quinoline-3-carboxylate 463 Intermediate 183

70

Ethyl 4 - [(3-Chloro-2-fluorophenyl) amino] -7-ethoxy-6 (4-methylpiperazin-1-yl) quinoline-3-carboxylate 486 Intermediate 178

71

Ethyl 7-Ethoxy-4 - [(3-ethylphenyl) amino] -6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate 462 Intermediate 184

72

Ethyl 4 - [(3-Chlorophenyl) amino] -7-ethoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate 469 Intermediate 185

73

Ethyl 4 - [(2-Chloro-4-fluorophenyl) amino] -7-ethoxy-6 (4-methylpiperazin-1-yl) quinoline-3-carboxylate 486 Intermediate 186

74

Ethyl 4 - [(4-Chloro-2-fluorophenyl) amino] -7-ethoxy-6 (4-methylpiperazin-1-yl) quinoline-3-carboxylate 486 Intermediate 187

75

Ethyl 7-Ethoxy-4 - [(3-methylphenyl) amino] -6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate 448 Intermediate 188

Int.

Compound M / z / NMR MP

76

Ethyl 4 - [(2-Chloro-3-methylphenyl) amino] -7-ethoxy-6 (4-methylpipemzin-1-yl) quinoline-3-carboxylate 482 Intermediate 189

77

Ethyl 7-Ethoxy-4 - [(3-fluoro-2-methylphenyl) amino] -6 (4-methylpiperazin-1-yl) quinoline-3-carboxylate 466 Intermediate 190

78

Ethyl 4 - [(3,4-Difluorophenyl) amino] -7-methoxy-6 (4-methylpiperazin-1-yl) quinolin-3-carboxylate 457 Intermediate 191

79

7-Methoxy-6- (4-methylpiperazin-1-yl) -4 - {[2methyl-3- (trifluoromethyl) phenyl] amino} quinolin3-ethyl carboxylate Intermediate 192

80

Ethyl 4 - [(4-Chlorophenyl) amino] -7-methoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate 455 Intermediate 193

81

Ethyl 4 - [(2-Fluoro-4-methylphenyl) amino] -7-methoxy6- (4-methylpiperazin-1-yl) quinoline-3-carboxylate 453 Intermediate 194

82

7-Methoxy-6- (4-methylpiperazin-1-yl) -4 - {[3 (trifluoromethyl) phenyl] amino} quinolin-3-carboxylate ethyl 489 Intermediate 195

83

Ethyl 7-Ethoxy-4 - [(2-fluoro-5-methylphenyl) amino] -6 (4-methylpiperazin-1-yl) quinoline-3-carboxylate 467 Intermediate 179

84

Ethyl 4 - [(3-Chloro-2-methylphenyl) amino] -7-ethoxy-6 (4-ethylpiperazin-1-yl) quinolin-3-carboxylate 496 Intermediate 183

85

Ethyl 4 - [(3-Chloro-2-methylphenyl) amino] -7-ethoxy-6 (4-methyl-1,4-diazepan-1-yl) quinoline-3-carboxylate 496 Intermediate 183

86

Ethyl 7-Ethoxy-6- (4-ethylpiperazin-1-yl) -4 - [(3fluoro-2-methylphenyl) amino] quinoline-3-carboxylate 480 Intermediate 190

87

Ethyl 7-Ethoxy-4 - [(3-fluoro-2-methylphenyl) amino] -6 (4-methyl-1,4-diazepan-1-yl) quinoline-3-carboxylate 480 Intermediate 190

88

Ethyl 7-Ethoxy-4 - [(2-fluoro-4-methylphenyl) amino] -6 (4-methylpiperazin-1-yl) quinoline-3-carboxylate 467 Intermediate 196

89

Ethyl 7-Ethoxy-4 - [(3-methoxy-2-methylphenyl) amino] 6- (4-methylpiperazin-1-yl) quinoline-3-carboxylate 479 Intermediate 197

Int.

Compound M / z / NMR MP

90

4 - [(2,5-Difluorophenyl) amino] -7-ethoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate ethyl 471 Intermediate 198

91

4 - [(2,5-Difluorophenyl) amino] -7-ethoxy-6- (4-ethylpiperazin-1-yl) quinolin-3-carboxylate ethyl 485 Intermediate 198

92

Ethyl 4 - [(2,5-Difluorophenyl) amino] -7-ethoxy-6- (4-methyl-1,4-diazepan-1-yl) quinoline-3-carboxylate 485 Intermediate 198

93

Ethyl 7-Ethoxy-6- (4-ethylpiperazin-1-yl) -4 - [(2fluoro4-methylphenyl) amino] quinolin-3-carboxylate 481 Intermediate 196

94

Ethyl 4 - [(3,4-Dimethylphenyl) amino] -7-ethoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate 463 Intermediate 199

95

4 - [(2,4-Difluorophenyl) amino] -6-ethoxy-7- (4-methylpiperazin-1-yl) quinolin-3-carboxylate ethyl 471 Intermediate 200

96

Ethyl 4 - [(2,3-Dichlorophenyl) amino] -6-ethoxy-7- (4-methylpiperazin-1-yl) quinolin-3-carboxylate 503 Intermediate 201

97

4 - [(2,3-Difluorophenyl) amino] -7-ethoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate ethyl 471 Intermediate 202

98

Ethyl 4 - [(2,3-Dimethylphenyl) amino] -7-ethoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate 463 Intermediate 203

99

Ethyl 4 - [(4-Chloro-3-fluorophenyl) amino] -7-ethoxy-6 (4-methylpiperazin-1-yl) quinoline-3-carboxylate 488 Intermediate 204

100

Ethyl 4 - [(2,3-Dichlorophenyl) amino] -6-ethoxy-7- (4-ethylpiperazin-1-yl) quinolin-3-carboxylate 517 Intermediate 201

101

4 - [(2,4-Difluorophenyl) amino] -6-ethoxy-7- (4-ethylpiperazin-1-yl) quinolin-3-carboxylate ethyl 485 Intermediate 200

102

Ethyl 4 - [(3-Chloro-2,4-difluorophenyl) amino] -7ethoxy-6- (4-ethylpiperazin-1-yl) quinoline-3-carboxylate 518 Intermediate 205

103

Ethyl 4 - [(3-Chloro-2,4-difluorophenyl) amino] -7ethoxy-6- (4-methylpiperazin-1-yl) quinoline-3-carboxylate 504 Intermediate 205

Int.

Compound M / z / NMR MP

104

Ethyl 4 - [(3-Chloro-4-fluorophenyl) amino] -6-ethoxy-7 (4-methylpiperazin-1-yl) quinoline-3-carboxylate 487 Intermediate 206

105

Ethyl 4 - [(3-Chloro-4-fluorophenyl) amino] -6-ethoxy-7 (4-ethylpiperazin-1-yl) quinolin-3-carboxylate 501 Intermediate 206

106

4 - {[4-Fluoro-2- (trifluoromethyl) phenyl] amino} 7-methoxy-6- (4-methylpiperazin-1-yl) quinolin3-ethyl carboxylate Intermediate 207

107

Ethyl 4 - [(2-Chloro-4-fluorophenyl) amino] -7methoxy-6- (4-methylpiperazin-1-yl) quinoline-3-carboxylate 473 Intermediate 208

108

7-Methoxy-6- (4-methylpiperazin-1-yl) -4 - {[3 (trifluoromethoxy) phenyl] amino} quinolin-3-carboxylate ethyl 505 Intermediate 209

109

Ethyl 4 - [(2,6-Dimethylphenyl) amino] -7-methoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate 449 Intermediate 210

110

Ethyl 4 - [(2,4-Difluorophenyl) amino] -7-ethoxy-6- (4-ethyl-1,4-diazepan-1-yl) quinoline-3-carboxylate 498 Intermediate 170 and Intermediate 252

111

Ethyl 4 - [(2,3-Dichlorophenyl) amino] -6- (4-ethyl-1,4diazepan-1-yl) -7-methoxyquinoline-3-carboxylate 516 Intermediate 155 and Intermediate 252

112

Ethyl 4 - [(2,3-Dichlorophenyl) amino] -7-ethoxy-6- (4-ethyl-1,4-diazepan-1-yl) quinolin-3-carboxylate 530 Intermediate 171 and Intermediate 252

113

6- [4- (tert-Butoxycarbonyl) piperazin-1-yl] -4 [(2,3-dichlorophenyl) amino] -7-ethoxyquinoline-3-carboxylate ethyl 589 Intermediate 171

114

6- [4- (tert-Butoxycarbonyl) piperazin-1-yl] -4 [(2,4-difluorophenyl) amino] -7-methoxyquinoline-3-carboxylate ethyl 542 Intermediate 167

115

6- [4- (tert-Butoxycarbonyl) -1,4-diazepan-1yl] -4 - [(2,4-difluorophenyl) amino] -7-methoxyquinoline-3-carboxylate ethyl 556 Intermediate 167

116

6- [4- (tert-Butoxycarbonyl) -1,4-diazepan-1il] -4 - [(2,3-dichlorophenyl) amino] -7-ethoxyquinoline-3-carboxylate ethyl 602 Intermediate 171

117

6- [4- (tert-Butoxycarbonyl) piperazin-1-yl] -4 [(2,4-difluorophenyl) amino] -7-ethoxyquinoline-3-carboxylate ethyl 556 Intermediate 170

Int.

Compound M / z / NMR MP

118

6- [4- (tert-Butoxycarbonyl) -1,4-diazepan-1yl] -4 - [(2,4-difluorophenyl) amino] -7-ethoxyquinoline-3-carboxylate ethyl 570 Intermediate 170

119

6- [4- (tert-Butoxycarbonyl) -1,4-diazepan-1il] -4 - [(2,3-dichlorophenyl) amino] -7-ethylmethoxyquinoline-3-carboxylate 589 Intermediate 155

120

Ethyl 4 - [(2-Fluoro-5-methylphenyl) amino] -7-methoxy6- (4-methylpiperazin-1-yl) quinoline-3-carboxylate 453 Intermediate 211

121

4 - [(2,5-Difluorophenyl) amino] -7-methoxy-6 (4-methylpiperazin-1-yl) quinolin-3-carboxylate ethyl 457 Intermediate 212

122

Ethyl 4 - [(3-Chloro-2-methylphenyl) amino] -7-methoxy6- (4-methylpiperazin-1-yl) quinoline-3-carboxylate 470 Intermediate 213

123

Ethyl 4 - [(2-Chloro-3-methylphenyl) amino] -7-methoxy6- (4-methylpiperazin-1-yl) quinoline-3-carboxylate 469 Intermediate 214

124

Ethyl 4 - [(2,4-Difluorophenyl) amino] -6- [3 (dimethylamino) pyrrolidin-1-yl] -7methoxyquinoline-3-carboxylate 471 Intermediate 167

125

Ethyl 4 - [(3-Chloro-2-fluorophenyl) amino] -7-methoxy6- (4-methylpiperazin-1-yl) quinoline-3-carboxylate 473 Intermediate 215

126

Ethyl 4 - [(3-Chloro-5-fluorophenyl) amino] -7-ethoxy-6 (4-methylpiperazin-1-yl) quinoline-3-carboxylate 488 Intermediate 216

127

Ethyl 7-Ethoxy-6- (4-methylpiperazin-1-yl) -4 - [(2,3,4trifluorophenyl) amino] quinolin-3-carboxylate 489 Intermediate 217

128

Ethyl 4 - [(5-Chloro-2-methylphenyl) amino] -7-ethoxy-6 (4-methylpiperazin-1-yl) quinoline-3-carboxylate 484 Intermediate 218

129

Ethyl 7-Ethoxy-4 - [(4-methoxy-2-methylphenyl) amino] 6- (4-methylpiperazin-1-yl) quinoline-3-carboxylate 479 Intermediate 219

130

Ethyl 4 - {[2-Chloro-5- (trifluoromethyl) phenyl] amino} 7-ethoxy-6- (4-methylpiperazin-1-yl) quinoline-3-carboxylate 538 Intermediate 220

131

Ethyl 4 - [(2,4-Difluorophenyl) amino] -7-ethoxy-6- (4-methyl-3-oxpiperazin-1-yl) quinoline-3-carboxylate 485 Intermediate 170

Int.

Compound M / z / NMR MP

132

Ethyl 4 - [(2,3-Dichlorophenyl) amino] -7- (4-ethylpiperazin-1-yl) -6-methoxyquinoline-3-carboxylate 474 Intermediate 168

133

Ethyl 4 - [(2-Fluoro-5-methylphenyl) amino] -6-methoxy7- (4-methylpiperazin-1-yl) quinoline-3-carboxylate 454 Intermediate 221

134

Ethyl 7- (4-Ethylpiperazin-1-yl) -4 - [(2-fluoro-5-methylphenyl) amino] -6-methoxyquinoline-3-carboxylate 467 Intermediate 221

135

Ethyl 4 - [(3-Chloro-2-fluorophenyl) amino] -6-methoxy7- (4-methylpiperazin-1-yl) quinoline-3-carboxylate 473 Intermediate 222

136

Ethyl 4 - [(3-Chloro-2-fluorophenyl) amino] -7- (4-ethylpiperazin-1-yl) -6-methoxyquinoline-3-carboxylate 487 Intermediate 222

137

Ethyl 4 - [(2-Fluoro-5-methylphenyl) amino] -6-methoxy7- (4-methyl-1,4-diazepan-1-yl) quinolin-3-carboxylate 467 Intermediate 221

138

Ethyl 4 - [(2,4-Difluorophenyl) amino] -6-methoxy-7 (4-methyl-1,4-diazepan-1-yl) quinolin-3-carboxylate 471 Intermediate 223

139

Ethyl 4 - [(2-Chloro-3-fluorophenyl) amino] -7-ethoxy-6 (4-methylpiperazin-1-yl) quinoline-3-carboxylate 487 Intermediate 224

140

Ethyl 4 - [(2-Chloro-3-fluorophenyl) amino] -7-ethoxy-6 (4-ethylpiperazin-1-yl) quinolin-3-carboxylate 501 Intermediate 224

141

Ethyl 4 - [(2-Chloro-3-fluorophenyl) amino] -7-ethoxy-6 (4-isopropylpiperazin-1-yl) quinoline-3-carboxylate Intermediate 224

142

6- [4- (tert-Butoxycarbonyl) piperazin-1-yl] -7ethoxy-4 - [(2-fluoro-4-methylphenyl) amino] quinolin-3-carboxylate ethyl 553 Intermediate 196

143

Ethyl 4 - [(2,3-Dichlorophenyl) amino] -7-ethoxy-6- (3oxpiperazin-1-yl) quinolin-3-carboxylate 504 Intermediate 171

144

Ethyl 7-Ethoxy-4 - [(2-fluoro-5-methylphenyl) amino] -6 (3-oxpiperazin-1-yl) quinolin-3-carboxylate 467 Intermediate 179

145

4 - [(2,4-Difluorophenyl) amino] -7-ethoxy-6- (3oxpiperazin-1-yl) quinolin-3-carboxylate ethyl 471 Intermediate 170

Int.

Compound M / z / NMR MP

146

Ethyl 4 - [(2-Chloro-4-methylphenyl) amino] -7-ethoxy-6 (4-methylpiperazin-1-yl) quinoline-3-carboxylate 9.98 (s, 1H), 8.99 (s, 1 H), 7.50 (s, 1 H), 7.30 (s, 1H), 7.10 (d, 1H), 6.90 (d, 1H), 6.77 (s, 1 H), 4.35 (q, 2 H), 4.20 (q, 2 H), 2.70 (s, 4 H), 2.40 ( s, 4 H), 2.30 (s, 3 H), 2.20 (s, 3 H), 1.40 (m, 6 H) Intermediate 225

147

Ethyl 7-Ethoxy-4 - {[2-fluoro-3- (trifluoromethyl) phenyl] amino} -6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate 9.55 (s, 1 H), 8.87 (s, 1H), 7.45-7.15 (m, 5 H), 4.28 (q, 2 H), 4.12 (q, 2 H), 3.90 (s, 4 H), 2.42 (s, 4 H), 2.22 (s, 3 H), 1.45 (t, 3 H), 1.21 (t, 3 H) Intermediate 226

148

4 - [(2,4-Dimethoxyphenyl) amino] -7-ethoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate ethyl 9.98 (s, 1H), 8.90 (s, 1 H), 7.20 (s, 1 H), 7.00 (m, 1 H), 6.91 (s, 1H), 6, 70 (s, 1H), 6.52 (t, 1 H), 4.35 (q, 2 H), 4.19 (q, 2 H), 3.80 (s, 3 H), 3.75 (s, 3 H), 2.68 (s, 4 H), 2.35 (s, 4 H), 2.20 (s, 3H), 2.35 (m, 6 H) Intermediate 227

149

Ethyl 4 - [(2-Chloro-4-fluoro-5-methylphenyl) amino] -7ethoxy-6- (4-methylpiperazin-1-yl) quinoline-3-carboxylate 9.89 (s, 1 H), 8.91 (s, 1 H), 7.57 (d, 1 H), 7.29 (s, 1H), 7.00 (d, 1 H), 6 , 75 (s, 1H), 4.32 (q, 2 H), 4.20 (q, 2 H), 2.75 (s, 4 H), 2.40 (s, 4 H), 2, 21 (s, 3 H), 2.10 (s, 3 H), 1.45 (t, 3 H), 1.37 (t, 3 H) Intermediate 228

150

Ethyl 4 - [(5-Chloro-2-fluorophenyl) amino] -7-ethoxy-6 (4-methylpiperazin-1-yl) quinoline-3-carboxylate 9.60 (s, 1H), 8.89 (s, 1H), 7.35 (m, 2 H), 7.15-7.05 (m, 3 H), 4.20 (q, 4 H ), 2.90 (s, 4 H), 2.42 (s, 4 H), 2.20 (s, 3 H), 1.40 (t, 3 H), 1.25 (t, 3 H ) Intermediate 229

Int.

Compound M / z / NMR MP

151

Ethyl 7-Ethoxy-4 - {[2-methoxy-5- (trifluoromethyl) phenyl] amino} -6- (4-methylpiperazin-1yl) quinolin-3-carboxylate 9.85 (s, 1 H), 8.90 (s, 1 H), 7.40 (m, 1 H), 7.30 (m, 2 H), 6.95 (s, 1 H), 6, 85 (s, 1H), 4.30 (q, 2 H), 4.20 (q, 2 H), 3.90 (s, 3 H), 2.80 (s, 4 H), 2.40 (s, 4 H), 2.20 (s, 3 H), 1.40 (t, 3 H), 1.30 (t, 3H) Intermediate 230

152

Ethyl 4 - [(2-Fluoro-4-methylphenyl) amino] -7- (2-methoxyethoxy) -6-morpholin-4-ylquinolin-3-carboxylate 484 Intermediate 231

153

4 - [(2-Fluoro-4-methylphenyl) amino] -6- (4isopropylpiperazin-1-yl) -7- (2-methoxyethoxy) quinolin-3-carboxylate ethyl 525 Intermediate 231

154

4 - [(2-Fluoro-5-methylphenyl) amino] -6- (4isopropylpiperazin-1-yl) -7- (2-methoxyethoxy) quinolin-3-carboxylate ethyl 525 Intermediate 232

Intermediate 155

Ethyl 6-Bromo-4 - [(2,3-dichlorophenyl) amino] -7-methoxyquinoline-3-carboxylate A mixture of ethyl 6-bromo-4-chloro-7-methoxyquinoline-3-carboxylate

5 (Intermediate 233; 1.0 g, 2.9 mmol), 2,3-dichloroaniline (535 mg, 3.2 mmol), acetic acid (900 µL) and DMF (8 mL) was heated at 100 ° C for 2 hours. The reaction mixture was poured onto ice water, the pH was adjusted to 9 with 0.1 N NaOH and the resulting precipitate was filtered to give 900 mg of a solid; m / z: 471.

10 Intermediates 156-232 The following compounds were prepared by a method similar to that of Intermediate 155 using the appropriate starting materials (MP).

Int.

Compound M / z / NMR MP

156

4 - [(2-Fluoro-5-methylphenyl) amino] -7- (2-methoxyethoxy) -6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate ethyl 497 Intermediate 277

157

4 - [(2,5-Difluorophenyl) amino] -7- (2-methoxyethoxy) -6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate ethyl 501 Intermediate 277

Int.

Compound M / z / NMR MP

158

Ethyl 4 - [(3-Chloro-2-fluorophenyl) amino] -7- (2-methoxyethoxy) -6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate 517 Intermediate 277

159

Ethyl 4 - [(2,3-Dichlorophenyl) amino] -7- (2-methoxyethoxy) -6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate 534 Intermediate 277

160

Ethyl 4 - [(2,4-Difluorophenyl) amino] -7- (2-methoxyethoxy) -6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate 501 Intermediate 277

161

4 - [(2-Fluoro-4-methylphenyl) amino] -7- (2-methoxyethoxy) -6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate ethyl 497 Intermediate 277

162

7- (2 - {[tert-Butyl (dimethyl) silyl] oxy} ethoxy) -4 [(2,4-difluorophenyl) amino] -6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate ethyl 601 Intermediate 284

163

7- (2 - {[tert-Butyl (dimethyl) silyl] oxy} ethoxy) -4 - [(3-chloro-2-fluorophenyl) amino] -6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate ethyl 617 Intermediate 284

164

4 - [(2-Chloro-3-fluorophenyl) amino] -7- (2-methoxyethoxy) -6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate ethyl 517 Intermediate 277

165

Ethyl 6-Bromo-4 - [(2,4-dichlorophenyl) amino] -7-methoxyquinoline-3-carboxylate Intermediate 233

166

Ethyl 6-Bromo-4 - [(3,4-dichlorophenyl) amino] -7methoxyquinoline-3-carboxylate Intermediate 233

167

Ethyl 6-Bromo-4 - [(2,4-difluorophenyl) amino] -7-methoxyquinoline-3-carboxylate 438 Intermediate 233

168

Ethyl 7-Bromo-4 - [(2,3-dichlorophenyl) amino] -6-methoxyquinoline-3-carboxylate Intermediate 236

169

Ethyl 7-Bromo-4 - [(3,4-dichlorophenyl) amino] -6-methoxyquinoline-3-carboxylate Intermediate 236

170

Ethyl 6-Bromo-4 - [(2,4-difluorophenyl) amino] -7ethoxyquinoline-3-carboxylate 452 Intermediate 240

171

Ethyl 6-Bromo-4 - [(2,3-dichlorophenyl) amino] -7ethoxyquinoline-3-carboxylate 485 Intermediate 240

172

Ethyl 6-Bromo-4 - [(3,4-dichlorophenyl) amino] -7ethoxyquinoline-3-carboxylate Intermediate 240

173

Ethyl 6-Bromo-4 - [(2,4-difluorophenyl) amino] -7fluoroquinolin-3-carboxylate Intermediate 243

Int.

Compound M / z / NMR MP

174

Ethyl 6-Bromo-4 - [(2,3-dichlorophenyl) amino] -7fluoroquinolin-3-carboxylate Intermediate 243

175

Ethyl 6-Bromo-4 - [(2,3-dichlorophenyl) amino] -5fluoroquinolin-3-carboxylate Intermediate 243

176

Ethyl 6-Bromo-7-ethoxy-4 - [(4-ethylphenyl) amino] quinolin-3-carboxylate 445 Intermediate 240

177

Ethyl 6-Bromo-4 - [(3-chloro-4-fluorophenyl) amino] -7-ethoxyquinoline-3-carboxylate Intermediate 240

178

Ethyl 6-Bromo-4 - [(3-chloro-2-fluorophenyl) amino] -7-ethoxyquinoline-3-carboxylate 469 Intermediate 240

179

Ethyl 6-Bromo-7-ethoxy-4 - [(2-fluoro-5-methylphenyl) amino] quinolin-3-carboxylate 449 Intermediate 240

180

Ethyl 6-Bromo-4 - [(2-fluorophenyl) amino] -7-methoxyquinoline-3-carboxylate 420 Intermediate 233

181

Ethyl 6-Bromo-7-methoxy-4 - [(3-methoxy-2-methylphenyl) amino] quinolin-3-carboxylate 445 Intermediate 233

182

Ethyl 6-Bromo-4 - [(4-chloro-2-methylphenyl) amino] -7-methoxyquinoline-3-carboxylate 449 Intermediate 233

183

Ethyl 6-Bromo-4 - [(3-chloro-2-methylphenyl) amino] -7-ethoxyquinoline-3-carboxylate 463 Intermediate 240

184

Ethyl 6-Bromo-7-ethoxy-4 - [(3-ethylphenyl) amino] quinolin-3-carboxylate 443 Intermediate 240

185

Ethyl 6-Bromo-4 - [(3-chlorophenyl) amino] -7ethoxyquinoline-3-carboxylate 449 Intermediate 240

186

Ethyl 6-Bromo-4 - [(2-chloro-4-fluorophenyl) amino] -7-ethoxyquinoline-3-carboxylate 467 Intermediate 240

187

Ethyl 6-Bromo-4 - [(4-chloro-2-fluorophenyl) amino] -7-ethoxyquinoline-3-carboxylate 467 Intermediate 240

188

Ethyl 6-Bromo-7-ethoxy-4 - [(3-methylphenyl) amino] quinolin-3-carboxylate 429 Intermediate 240

189

Ethyl 6-Bromo-4 - [(2-chloro-3-methylphenyl) amino] -7-ethoxyquinoline-3-carboxylate 463 Intermediate 240

190

Ethyl 6-Bromo-7-ethoxy-4 - [(3-fluoro-2-methylphenyl) amino] quinolin-3-carboxylate 447 Intermediate 240

191

Ethyl 6-Bromo-4 - [(3,4-difluorophenyl) amino] -7-methoxyquinoline-3-carboxylate 437 Intermediate 233

192

Ethyl 6-Bromo-7-methoxy-4 - {[2-methyl-3 (trifluoromethyl) phenyl] amino} quinolin-3-carboxylate 484 Intermediate 233

Int.

Compound M / z / NMR MP

193

Ethyl 6-Bromo-4 - [(4-chlorophenyl) amino] -7-methoxyquinoline-3-carboxylate 435 Intermediate 233

194

Ethyl 6-Bromo-4 - [(2-fluoro-4-methylphenyl) amino] -7-methoxyquinoline-3-carboxylate 434 Intermediate 233

195

Ethyl 6-Bromo-7-methoxy-4 - {[3- (trifluoromethyl) phenyl] amino} quinolin-3-carboxylate 469 Intermediate 233

196

Ethyl 6-Bromo-7-ethoxy-4 - [(2-fluoro-4-methylphenyl) amino] quinolin-3-carboxylate 447 Intermediate 240

197

Ethyl 6-Bromo-7-ethoxy-4 - [(3-methoxy-2-methylphenyl) amino] quinolin-3-carboxylate 459 Intermediate 240

198

Ethyl 6-Bromo-4 - [(2,5-difluorophenyl) amino] -7ethoxyquinoline-3-carboxylate 454 Intermediate 240

199

Ethyl 6-Bromo-4 - [(3,4-dimethylphenyl) amino] -7ethoxyquinoline-3-carboxylate 444 Intermediate 240

200

Ethyl 7-Bromo-4 - [(2,4-difluorophenyl) amino] -6ethoxyquinoline-3-carboxylate 453 Intermediate 246

201

Ethyl 7-Bromo-4 - [(2,3-dichlorophenyl) amino] -6ethoxyquinoline-3-carboxylate 485 Intermediate 246

202

Ethyl 6-Bromo-4 - [(2,3-difluorophenyl) amino] -7ethoxyquinoline-3-carboxylate 452 Intermediate 240

203

Ethyl 6-Bromo-4 - [(2,3-dimethylphenyl) amino] -7-ethoxyquinoline-3-carboxylate 444 Intermediate 240

204

Ethyl 6-Bromo-4 - [(4-chloro-3-fluorophenyl) amino] -7-ethoxyquinoline-3-carboxylate 468 Intermediate 240

205

Ethyl 6-Bromo-4 - [(3-chloro-2,4-difluorophenyl) amino] -7-ethoxyquinoline-3-carboxylate 485 Intermediate 240

206

Ethyl 7-Bromo-4 - [(3-chloro-4-fluorophenyl) amino] -6ethoxyquinoline-3-carboxylate 467 Intermediate 246

207

Ethyl 6-Bromo-4 - {[4-fluoro-2- (trifluoromethyl) phenyl] amino} -7-methoxyquinoline-3-carboxylate 487 Intermediate 233

208

Ethyl 6-Bromo-4 - [(2-chloro-4-fluorophenyl) amino] -7-methoxyquinoline-3-carboxylate 453 Intermediate 233

209

Ethyl 6-Bromo-7-methoxy-4 - {[3- (trifluoromethoxy) phenyl] amino} quinolin-3-carboxylate 485 Intermediate 233

210

Ethyl 6-Bromo-4 - [(2,6-dimethylphenyl) amino] -7-methoxyquinoline-3-carboxylate 429 Intermediate 233

211

Ethyl 6-Bromo-4 - [(2-fluoro-5-methylphenyl) amino] -7-methoxyquinoline-3-carboxylate 433 Intermediate 233

Int.

Compound M / z / NMR MP

212

Ethyl 6-Bromo-4 - [(2,5-difluorophenyl) amino] -7-methoxyquinoline-3-carboxylate 437 Intermediate 233

213

Ethyl 6-Bromo-4 - [(3-chloro-2-methylphenyl) amino] -7-methoxyquinoline-3-carboxylate 449 Intermediate 233

214

Ethyl 6-Bromo-4 - [(2-chloro-3-methylphenyl) amino] -7-methoxyquinoline-3-carboxylate 450 Intermediate 233

215

Ethyl 6-Bromo-4 - [(3-chloro-2-fluorophenyl) amino] -7-methoxyquinoline-3-carboxylate 453 Intermediate 233

216

Ethyl 6-Bromo-4 - [(3-chloro-5-fluorophenyl) amino] -7-ethoxyquinoline-3-carboxylate 469 Intermediate 240

217

Ethyl 6-Bromo-7-ethoxy-4 - [(2,3,4-trifluorophenyl) amino] quinolin-3-carboxylate 470 Intermediate 240

218

Ethyl 6-Bromo-4 - [(5-chloro-2-methylphenyl) amino] -7-ethoxyquinoline-3-carboxylate 465 Intermediate 240

219

Ethyl 6-Bromo-7-ethoxy-4 - [(4-methoxy-2-methylphenyl) amino] quinolin-3-carboxylate 460 Intermediate 240

220

Ethyl 6-Bromo-4 - {[2-chloro-5- (trifluoromethyl) phenyl] amino} -7-ethoxyquinoline-3-carboxylate 519 Intermediate 240

221

Ethyl 7-Bromo-4 - [(2-fluoro-5-methylphenyl) amino] -6-methoxyquinoline-3-carboxylate 435 Intermediate 236

222

Ethyl 7-Bromo-4 - [(3-chloro-2-fluorophenyl) amino] -6-methoxyquinoline-3-carboxylate 455 Intermediate 236

223

Ethyl 7-Bromo-4 - [(2,4-difluorophenyl) amino] -6-methoxyquinoline-3-carboxylate 439 Intermediate 236

224

Ethyl 6-Bromo-4 - [(2-chloro-3-fluorophenyl) amino] -7-ethoxyquinoline-3-carboxylate 469 Intermediate 240

225

Ethyl 6-Bromo-4 - [(2-chloro-4-methylphenyl) amino] -7-ethoxyquinoline-3-carboxylate 9.90 (s, 1H), 9.00 (s, 1 H), 7.92 (s, 1 H), 7.40 (m, 2 H), 7.10 (m, 1H), 7, 00 (m, 1 H), 4.29 (q, 2 H), 4.20 (q, 2 H), 2.31 (s, 3 H), 1.40 (t, 3 H), 1, 30 (t, 3 H) Intermediate 240

226

Ethyl 6-Bromo-7-ethoxy-4 - {[2-fluoro-3 (trifluoromethyl) phenyl] amino} quinolin-3-carboxylate 9.56 (s, 1H), 8.88 (s, 1H), 8.51 (s, 1 H), 7.50-7.30 (m, 4 H), 4.31 (q, 2 H ), 3.91 (q, 2 H), 1.32 (t, 3 H), 1.10 (t, 3 H) Intermediate 240

Int.

Compound M / z / NMR MP

227

Ethyl 6-Bromo-4 - [(2,4-dimethoxyphenyl) amino] -7ethoxyquinoline-3-carboxylate 10.05 (s, 1 H), 8.92 (s, 1 H), 7.89 (s, 1 H), 7.32 (s, 1 H), 7.05 (d, 1 H), 6 , 71 (s, 1H), 6.52 (d, 1 H), 4.21 (q, 4 H), 3.79 (s, 3 H), 3.70 (s, 3 H), 1, 40 (t, 3 H), 1.30 (t, 3 H) Intermediate 240

228

Ethyl 6-Bromo-4 - [(2-chloro-4-fluoro-5methylphenyl) amino] -7-ethoxyquinoline-3-carboxylate 9.80 (s, 1 H), 8.95 (s, 1 H), 8.05 (s, 1 H), 7.55 (m, 1 H), 7.45 (s, 1 H), 7, 15 (m, 1H), 4.30 (q, 2 H), 4.18 (q, 2 H), 2.15 (s, 3 H), 1.45 (t, 3 H), 1.28 (t, 3 H) Intermediate 240

229

Ethyl 6-Bromo-4 - [(5-chloro-2-fluorophenyl) amino] -7-ethoxyquinoline-3-carboxylate 9.55 (s, 1 H), 8.87 (s, 1H), 8.45 (s, 1 H), 7.50 (s, 1H), 7.35 (m, 1 H), 7, 17 (m, 2H), 4.32 (q, 2 H), 4.00 (q, 2 H), 1.46 (t, 3 H), 1.19 (t, 3 H) Intermediate 240

230

Ethyl 6-Bromo-7-ethoxy-4 - {[2-methoxy-5 (trifluoromethyl) phenyl] amino} quinolin-3-carboxylate 9.80 (s, 1H), 8.96 (s, 1H), 8.15 (s, 1 H), 7.45 (m, 2 H), 7.30 (m, 1H), 7.18 (s, 1 H), 4.30 (q, 2 H), 4.10 (q, 2 H), 3.85 (s, 3 H), 1.40 (t, 3 H), 1.20 (t, 3 H) Intermediate 240

231

Ethyl 6-Chloro-4 - [(2-fluoro-4-methylphenyl) amino] -7 (2-methoxyethoxy) quinolin-3-carboxylate 433 Intermediate 281

232

Ethyl 6-Chloro-4 - [(2-fluoro-5-methylphenyl) amino] -7 (2-methoxyethoxy) quinolin-3-carboxylate 433 Intermediate 281

Intermediate 233

Ethyl 6-Bromo-4-chloro-7-methoxyquinoline-3-carboxylate

This compound was described in WO 2002092571, and was prepared

in accordance with the procedures described in Burke T.R. et al., J. Med. Chem., 36

(1993) 425-432.

A solution of ethyl 6-bromo-7-methoxy-4-oxo-1,4-dihydroquinolin-3-carboxylate (Intermediate 234; 8.0 g, 0.025) in phosphorus oxychloride (100 mL) was heated to reflux during the night. After cooling, the solution was carefully poured onto ~ 400 mL of ice water with stirring. The resulting mixture was basified with 2N NaOH and extracted with EtOAc. The organic layer was washed with water, dried (Na2SO4), and concentrated under reduced pressure to give 8.0 g (93%) of a white solid. 1H NMR: 9.14 (s, 1 H), 8.55 (s, 1 H), 7.66 (s, 1 H), 4.42 (d, 2 H), 4.09 (s, 3 H), 1.38 (t, 3 H); m / z: 344.

Intermediate 234

Ethyl 6-Bromo-7-methoxy-4-oxo-1,4-dihydroquinolin-3-carboxylate

A solution of diethyl {[(4-bromo-3-methoxyphenyl) amino] methylene} malonate (Intermediate 235; 11 g, 0.029 mol) in hot diphenyl ether (20 mL) was added dropwise over 15 minutes to diphenyl ether at reflux (180 mL). After 3 hours, the solution was cooled, diluted with hexane (200 mL), and the resulting precipitate was collected to give 8.9 g (93%) of a white solid.

Intermediate 235

Diethyl {[(4-Bromo-3-methoxyphenyl) amino] methylene} malonate

To a solution of 4-bromo-3-methoxyaniline (25 g, 0.12 mol) in CH3CN (150 mL) was added diethylene ethoxymethylene malonate (27 mL, 0.13 mol). After 20 hours, the solvent was removed under reduced pressure and the residue was dissolved in EtOAc. Hexane was added, and the resulting precipitate was collected to give 37 g (80%) of almost white solid. 1H NMR: 10.68 (d, 1H), 8.38 (d, 1 H), 7.52 (d, 1 H), 7.20 (d, 1 H), 6.91 (dd, 1 H ), 4.20 (q, 2 H), 4.11 (q, 2 H), 3.86 (s, 3 H), 1.23 (m, 6 H); m / z: 372.

Intermediate 236

Ethyl 7-Bromo-4-chloro-6-methoxyquinolin-3-carboxylate

A mixture of ethyl 7-bromo-6-methoxy-4-oxo-1,4-dihydroquinolin-3-carboxylate (Intermediate 237; 4.0 g, 11.6 mmol) and phosphorus oxychloride (80 mL) was heated at reflux for 2.5 hours. The solution was cooled, and carefully poured onto ice (800 g) with stirring. The mixture was carefully neutralized with 2N NaOH, and the resulting precipitate was filtered, washed with water and dried to give 3.8 g of white solid. 1 H NMR (CDCl 3): 9.00 (s, 1 H), 8.32 (s, 1 H), 7.54 (s, 1 H), 4.43 (q, 2 H), 4.02 (s , 3 H), 1.39 (t, 3H).

Intermediate 237

Ethyl 7-Bromo-6-methoxy-4-oxo-1,4-dihydroquinolin-3-carboxylate

A solution of diethyl {[(3-bromo-4-methoxyphenyl) amino] methylene} malonate (Intermediate 238; 10 g, 0.027 mol) in hot diphenyl ether (100 mL) was added dropwise over 15 minutes to diphenyl ether at reflux (100 mL). After 3 hours, the reaction mixture was cooled, and petroleum ether (120 mL) was added to the solid material, which was filtered and washed with hexane to give 8 g of white solid. 1 H NMR: 8.54 (s, 1 H), 7.92 (s, 1 H), 7.65 (s, 1 H), 4.22 (q, 2 H), 3.95 (s, 3 H) , 1.28 (t, 3 H). Intermediate 238 {[(3-Bromo-4-methoxyphenyl) amino] methylene} diethyl malonate

A solution of 3-bromo-4-methoxyaniline (Intermediate 239; 8.3 g, 40.9 mmol) and diethyl ethoxymethylenemalonate (8.85 mL, 44.2 mmol) in CH3CN (60 mL) was stirred for 2 hours . The solvent was removed under reduced pressure. By recrystallization of the residue in hexane, 11 g of white solid were obtained. 1H NMR (CDCl3): 10.98 (d, 1H), 8.40 (d, 1H), 7.40 (d, 1H), 7.08 (dd, 1 H), 6.91 (d, 1 H), 4.29 (m, 4 H), 3.91 (s, 3 H), 1.37 (m, 6 H).

Intermediate 239

3-Bromo-4-methoxyaniline

The title compound was prepared according to the procedure of Liu Y.-Y. and Munich, M., J. Label Compd Radiophann., 18 (1981), 791-797.

Intermediate 240

Ethyl 6-Bromo-4-chloro-7-ethoxyquinoline-3-carboxylate

Preparation a)

A mixture of ethyl 6-bromo-7-ethoxy-4-oxo-1,4-dihydroquinolin-3-carboxylate (Intermediate 241; 16.8 g, 49 mmol) and phosphorus oxychloride (40 mL) was heated to reflux for 16 hours The solution was cooled, and carefully poured onto ice water (~ 500 mL) with stirring. The resulting solid was filtered, washed with water and dried to give 17.1 g of a slightly brown solid. 1 H NMR: 9.13 (s, 1 H), 8.54 (s, 1 H), 7.63 (s, 1 H), 4.39 (m, 4 H), 1.46 (t, 3 H), 1.38 (t, 3 H).

Alternative preparation b)

To a solution of diethyl {[(4-bromo-3-ethoxyphenyl) amino] methyl} malonate (Intermediate 242; 52.9 g, 0.137 mol) in toluene (125 ml) was added POCl3 (209.9 g, 125 mL, 1.37 mol). The reaction mixture was stirred at 110 ° C for 48 hours, cooled and concentrated under reduced pressure. The residue was carefully treated with saturated NaHCO3 solution until no more gas evolved, and the resulting solid was filtered, washed with saturated NaHCO3 and water, and then mixed in hot MeOH (~ 200 mL), cooled and filtered to give 42 g of an orange solid.

Alternative preparation c)

Triethylamine (12.8 kg, 126 mol) was added to a suspension of 4-bromo-3-ethoxyaniline hydrochloride (29.94 kg, 118 mol) in toluene (119 L) and water (60 L) at room temperature. The suspension was stirred until a solution was obtained. The biphasic mixture was filtered through diatomaceous earth (4 kg) by washing the cake with toluene (10 L) and the aqueous layer was separated and discarded. Toluene (13 L) was distilled off to dry the mixture. Diethylene ethoxymethylene malonate (25.60 kg, 118 mol) was added slowly to the toluene solution at 70-80 ° C, at a rate that gently maintained reflux. Toluene and ethanol (70 L) were distilled off under reduced pressure (400 mbar, 85 ° C). The reaction temperature was reduced to 60 ° C and the reaction was analyzed by HPLC. Phosphorus oxychloride (45.6 kg, 297 mol) was added over 45 minutes. The reaction was heated at 110 ° C over 2 hours and maintained for at least 5 hours. The reaction was cooled to 70 ° C and analyzed by HPLC. Phosphorus oxychloride and toluene (50 L) were distilled off under reduced pressure (100-150 mbar, 50-67 ° C). Toluene (40 L) was added and the mixture was distilled again (40 L of distillate collected). Tetrahydrofuran (THF) (36 L) was added and the resulting mixture was cooled to 20-25 ° C. The resulting red solution was added slowly (over -50 minutes to control the evolution of gas) to a mixture of potassium bicarbonate (99 kg, 989 mol) in water (296 L) at room temperature. The reaction mixture was washed with more THF (3.6 L). The resulting suspension was stirred for 1 hour before separating in a centrifuge. The wet product was suspended in ethanol (119 L) and heated to 70 ° C. The suspension was cooled to room temperature and the product collected by centrifugation, washed with ethanol (40 L) and dried under reduced pressure (30 ° C at 2 mbar) to give the title compound (30.8 kg, 86 mol, 73%)

Intermediate 241

Ethyl 6-Bromo-7-ethoxy-4-oxo-1,4-dihydroquinolin-3-carboxylate

A solution of diethyl {[(4-bromo-3-ethoxyphenyl) amino] methyl} malonate (Intermediate 242; 25 g, 64 mmol) in hot diphenyl ether (150 mL) was added dropwise over 15 minutes to diphenyl ether at reflux (~ 250 mL). After 3 hours the reaction mixture was cooled, and hexane (~ 250 mL) was added to the solid, which was filtered to give 16.8 g of a white crystalline solid that was used without further purification.

Intermediate 242

Diethyl {[(4-Bromo-3-ethoxyphenyl) amino] methyl} malonate

A solution of 4-bromo-3-ethoxyaniline (21 g, 0.1 mol) and diethyl ethoxymethylenemalonate (19 mL, 0.1 mol) in CH3CN (150 mL) was stirred for 2 hours and then heated to 75 ° C for 16 hours The solvent was removed under reduced pressure and the residue was recrystallized from hexane to give 25 g of a white solid, which was used without further purification.

Intermediate 243

Ethyl 6-Bromo-4-chloro-7-fluoroquinolin-3-carboxylate and ethyl 6-bromo-4-chloro-5-fluoroquinolin-3-carboxylate

A mixture of ethyl 6-bromo-7-fluoro-4-hydroxyquinolin-3-carboxylate and 6-bromo-5-fluoro-4-hydroxyquinolin-3-carboxylate ethyl (Intermediate 244; 3.2 g, 10.19 mmol) was stirred in phosphorus oxychloride at reflux (4.6 ml, 50.96 mmol) for 3 hours. After cooling, the mixture was concentrated under reduced pressure, and CH3CN (10 mL) was added. The mixture was poured slowly over NaHCO3 solution and the resulting suspension was extracted with EtOAc. The organic layer was dried (MgSO4), filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (EtOAc / hexane gradient) to give 0.15 g (4.7%) of 6-bromine Ethyl -4-chloro-5fluoroquinolin-3-carboxylate. 1 H NMR: 9.17 (s, 1 H), 8.64 (d, 1 H), 8.12 (d, 1 H), 4.48 (q, 2 H), 1.40 (t, 3 H ); m / z: 334, and 1.4 g (44%) of ethyl 6-bromo-7-fluoro-4-hydroxyquinolin-3-carboxylate 1 H NMR: 9.11 (s, 1 H), 8.22 (t, 1 H), 7.96 (d, 1 H), 4.48 (q, 2 H), 1.40 (t, 3 H); m / z: 334.,

Intermediate 244

Ethyl 6-Bromo-7-fluoro-4-hydroxyquinolin-3-carboxylate and ethyl 6-bromo-5-fluoro-4-hydroxyquinoline-3-carboxylate

A solution of diethyl {[(4-bromo-3-fluorophenyl) amino] methylene} malonate (Intermediate 245; 6.00 g, 16.66 mmol) and diphenyl ether (10 mL) was heated at 250 ° C for 40 minutes . After cooling, hexane (10 mL) was added, and the resulting precipitate was filtered and washed with acetone (20 mL), to give 3.2 g (61%) of a slightly brown solid, an insoluble mixture of isomers.

Intermediate 245

{[(4-Bromo-3-fluorophenyl) amino] methylene} diethyl malonate

A solution of 4-bromo-3-fluoroaniline (5.00 g, 28.3 mmol) and diethyl ethoxymethylenemalonate (5.7 mL, 28.4 mmol) in CH3CN (15 mL) was stirred for 6 days. The reaction mixture was filtered to give 6.2 grams (65%) of a white solid. 1H NMR: 10.65 (d, 1 H), 8.36 (d, 1 H), 7.67 (t, 1 H), 7.59 (dd, 1 H), 7.24 (d, 1 H), 4.18 (m, 4 H), 1.29 (m, 6 H).

Intermediate 246

Ethyl 7-Bromo-4-chloro-6-ethoxyquinoline-3-carboxylate

A suspension of ethyl 7-bromo-6-ethoxy-4-oxo-1,4-dihydroquinolin-3-carboxylate (Intermediate 247; 21 g, 0.06 mol) in phosphorus oxychloride was heated at reflux for 2.5 hours. After cooling, the reaction mixture was carefully poured onto 2 L of ice water and neutralized with concentrated aqueous ammonia. The precipitate was collected, washed with water, dried, and recrystallized from EtOAc to give 17 g of an almost white solid. 1H NMR: 9.01 (s, 1 H), 8.45 (s, 1 H), 7.63 (s, 1 H), 4.43 (q, 2 H), 4.34 (q, 2 H), 1.48 (t, 3 H), 1.38 (t, 3 H); m / z: 359.

Intermediate 247

Ethyl 7-Bromo-6-ethoxy-4-oxo-1,4-dihydroquinolin-3-carboxylate

A solution of diethyl {[(3-bromo-4-ethoxyphenyl) amino] methylene} malonate (Intermediate 248; 33 g, 0.085 mol) in hot diphenyl ether (200 mL) was added dropwise over 30 minutes to diphenyl ether at reflux (400 mL). After 3 hours at reflux, the reaction was cooled. To the resulting gelatinous solid hexane, cyclohexane, and petroleum ether (~ 150 mL each) were added and the mixture was filtered. The crude material was triturated with hot hexane for 20 minutes to give 21 g of a solid. 1H NMR: 12.26 (s, 1H), 8.52 (s, 1 H), 7.91 (s, 1 H), 7.62 (s, 1 H), 4.21 (m, 4 H ), 1.41 (t, 3 H), 1.28 (t, 3 H); m / z: 342.

Intermediate 248

{[(3-Bromo-4-ethoxyphenyl) amino] methylene} diethyl malonate

A solution of (3-bromo-4-ethoxyphenyl) amine (Intermediate 249; 22 g, 0.1 mol) and diethylethoxymethylene malonate (23 mL, 0.11 mol) in acetonitrile (150 mL) was stirred for 2 hours . The precipitate was collected and recrystallized / triturated with hexane to give 33 g of a solid, used without further purification. 1 H NMR (MeOD): 8.42 (s, 1 H), 7.51 (d, 1 H), 7.20 (m, 1 H), 7.05 (d, 1 H), 4.29 ( q, 2 H), 4.22 (q, 2 H), 4.11 (q, 2 H), 1.44 (t, 3 H), 1.34 (m, 6 H); m / z: 384.

Intermediate 249

(3-Bromo-4-ethoxyphenyl) amine

To a stirring suspension of 2-bromo-1-ethoxy-4-nitrobenzene (Intermediate 250; 27 g, 0.11 mol), iron powder (50 g, 0.89 mol), and 50% aqueous ethanol ( 200 mL), a solution of concentrated HCl (2 mL) in 50% aqueous ethanol (20 mL) was added dropwise over 30 minutes. Heat was applied after adding half of the acid solution to start the reaction. Then, the reaction mixture was refluxed by adjusting the rate of acid addition. Reflux was maintained for 1.5 hours after the addition of the acid by an external heating blanket. The reaction mixture was filtered hot through a bed of diatomaceous earth. After cooling, the aqueous filtrate was extracted with chloroform (2 x 300 mL) and EtOAc (2 x 300 mL). The organic extracts were combined, dried (Na2SO4), and concentrated under reduced pressure to give 22 g of a solid. 1H NMR: 6.82 (m, 1 H), 6.53 (d, 1 H), 6.51 (s, 1 H), 3.91 (q, 2 H), 1.28 (t, 3 H); m / z: 216.

Intermediate 250

2-Bromo-1-ethoxy-4-nitrobenzene

A mixture of iodoethane, (22.2 mL, 0.28 mol), 2-bromo-4-nitrophenol (Intermediate 251; 24 g, 0.11 mol) and potassium carbonate (30.6 g, 0.22 mol ) in DMF (200 mL) was stirred for 18 hours. The reaction mixture was poured onto ice water (2 L) and extracted with EtOAc (3 x 300 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure to give 27.1 g of a solid, used without further purification. 1H NMR: 8.42 (d, 1 H), 8.25 (d, 1 H), 7.31 (d, 1 H), 4.28 (q, 2 H), 1.41 (t, 3 H).

Intermediate 251

2-Bromo-4-nitrophenol

A mixture of 4-nitrophenol (50 g, 0.36 mol), acetic acid (400 mL), and bromine (27 mL, 0.52 mol) was stirred for 18 hours. The excess solvent was removed under reduced pressure and the residue was crystallized from dichloromethane / hexane to give 60 g of a solid, used without further purification. 1 H NMR (MeOD): 8.40 (d, 1 H), 8.12 (dd, 1 H), 7.02 (d, 1 H); m / z: 216.

Intermediate 252

1-Ethyl-1,4-diazepan

A mixture of tert-butyl 4-ethyl-1,4-diazepan-1-carboxylate (Intermediate 253; 700 mg, 3.07 mmol) in 2M HCl in ether (10 mL) was stirred at room temperature for 2 hours . The white solid was filtered and washed with diethyl ether. The solid was dissolved in 20 ml of MeOH, approximately 2 g of MP-carbonate (3.1 mmol / g) was added to the solution. The resulting mixture was stirred at room temperature for 30 minutes, filtered, washed with MeOH, and the filtrate was concentrated to give 390 mg of a light yellow oil. 1H NMR (CD2Cl2): 3.00 (m, 6H), 2.75 (m, 2 H), 2.62 (m, 2 H), 1.90 (m, 2 H), 1.10 (t , 3 H); m / z: 128.

Intermediate 253

Tert-Butyl 4-Ethyl-1,4-diazepan-1-carboxylate

A mixture of tert-butyl 1,4-diazepan-1-carboxylate (3 g, 15 mmol), iodoethane (3.51 g, 22.5 mmol) and potassium carbonate (4.14 g, 30 mmol) in Acetonitrile (15 ml), heated at reflux for 20 hours. The reaction mixture was cooled and filtered, washing with dichloromethane. The filtrate was concentrated and the residue was purified with an ISCO chromatography system to give 700 mg of an oil. 1 H NMR (CD 2 Cl 2): 3.60 (m, 4 H), 2.70 (m, 6 H), 1.95 (m, 2 H), 1.61 (s, 9 H), 1.20 ( t, 3 H); m / z: 228.

Intermediate 254

Ethyl 4 - [(2,4-Difluorophenyl) amino] -7-isopropoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate

A solution of ethyl 4-chloro-7-isopropoxy-6- (4-methylpiperazin-1-yl) quinoline-3-carboxylate (Intermediate 266; 0.25 g, 0.64 mmol), 2,4-difluoroaniline (0, 22 mL, 1.91 mmol), and glacial acetic acid (0.1 mL) in EtOAc (5 mL), was heated at 77 ° C for 16 hours. The reaction mixture was cooled, NaHCO3 solution (3 mL) was added, and the mixture was extracted with EtOAc (3 x 3 mL). The combined organic extracts were concentrated, and the residue was purified by column chromatography (hexane / EtOAc) to give 80 mg (53%) of a yellow solid. 1H NMR: 9.69 (s, 1 H), 8.84 (s, 1 H), 7.39 (m, 1 H), 7.26 (s, 1 H), 7.19 (m, 1 H), 7.07 (m, 1 H), 6.96 (s, 1 H), 4.83 (m, 1 H), 4.39

5 (q, 2 H), 2.75 (s, 4 H), 2.37 (s, 4 H), 2.17 (s, 3 H), 1.34 (d, 6 H), 1, 28 (t, 3 H); m / z: 485.

Intermediates 255-265

The following compounds were prepared by a method similar to that of Intermediate 254

10

Int.

Compound m / z MP

255

Ethyl 4 - [(3,4-Dichlorophenyl) amino] -7-isopropoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate 517 Intermediate 266

256

Ethyl 4 - [(3-Chloro-2-fluorophenyl) amino] -7-isopropoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate 501 Intermediate 266

257

Ethyl 4 - [(2,3-Dichlorophenyl) amino] -7-isopropoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate 517 Intermediate 266

258

Ethyl 4 - [(3-Chloro-4-fluorophenyl) amino] -7-isopropoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate 501 Intermediate 266

259

Ethyl 4 - [(2,4-Difluorophenyl) amino] -6-morpholin-4-ylquinolin-3-carboxylate 415 Intermediate 271

260

Ethyl 4 - [(3-Chloro-4-fluorophenyl) amino] -6-morpholin-4ylquinolin-3-carboxylate 432 Intermediate 271

261

Ethyl 4 - [(2,3-Dichlorophenyl) amino] -6-morpholin-4-ylquinolin-3-carboxylate 446 Intermediate 271

262

Ethyl 4 - [(2,4-Difluorophenyl) amino] -6- (4-methylpiperazin1yl) quinolin-3-carboxylate 427 Intermediate 274

263

Ethyl 4 - [(2,4-Dichlorophenyl) amino] -6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate Intermediate 274

264

Ethyl 4 - [(3,4-Dichlorophenyl) amino] -6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate Intermediate 274

265

Ethyl 4 - [(2,3-Dichlorophenyl) amino] -6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate Intermediate 274

Intermediate 266

Ethyl 4-Chloro-7-isopropoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate

A mixture of diethyl ({[3-isopropoxy-4- (4-methylpiperazin-1-yl) phenyl] amino} methylene) malonate (Intermediate 267; 5.7 g, 13.6 mmol) and phosphorus oxychloride (12 , 4 g, 20.8 mmol), was heated at 108 ° C for 16 hours. The reaction mixture was cooled and concentrated under reduced pressure. The resulting dark oil was diluted with acetonitrile (20 mL), added to a stirring solution of NaHCO3, and extracted with EtOAc (3 x 100 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. Hexane (30 mL) was added and after 15 minutes of sonication, the mixture was filtered to give 3.1 g (58%) of a brown solid. 1H NMR: 8.89 (s, 1 H), 7.45 (s, 1 H), 7.42 (s, 1 H), 4.91 (m, 1 H), 4.39 (q, 2 H), 3.16 (s, 4 H), 2.50 (s, 4 H), 2.23 (s, 3 H), 1.37 (m, 9 H); m / z: 392.

Intermediate 267

({[3-Isopropoxy-4- (4-methylpiperazin-1-yl) phenyl] amino} methylene) diethyl malonate

A solution of [3-isopropoxy-4- (4-methylpiperazin-1-yl) phenyl] amine (Intermediate 268; 5.0 g, 21.5 mmol) and diethyl ethoxymethylenemalonate (4.65 mL, 23.24 mL ) in acetonitrile (20 mL), stirred for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (hexane / EtOAc) to give 6.7 g (74%) of a viscous dark oil. 1H NMR: 10.68 (d, 1 H), 8.23 (d, 1 H), 6.99 (s, 1 H), 6.84 (s, 2 H), 4.65 (m, 1 H), 4.21-4.00 (m, 4 H), 2.93 (s, 4 H), 2.42 (s, 4 H), 1.27-1.16 (m, 12 H) .

Intermediate 268

[3-Isopropoxy-4- (4-methylpiperazin-1-yl) phenyl] amine

It was stirred under hydrogen gas (344.8 kPa) for 1 hour, 1- (2-isopropoxy-4-nitrophenyl) -4-methylpiperazine (Intermediate 269; 6.0 g, 21.5 mmol) and 10% palladium on carbon ( 0.6 g) in MeOH (30 ml) and then filtered through a bed of diatomaceous earth. The filtrate was concentrated under reduced pressure to give 5.01 g (94%) of a brown oil. 1H NMR: 6.59 (d, 1 H), 6.18 (d, 1 H), 6.08 (dd, 1 H), 4.65 (s, 2 H), 4.45 (m, 1 H), 2.79 (s, 4 H), 2.39 (s, 4 H), 2.17 (s, 3 H), 1.21 (d, 6 H).

Intermediate 269

1- (2-Isopropoxy-4-nitrophenyl) -4-methylpiperazine

A mixture of 1-chloro-2-isopropoxy-4-nitrobenzene (Intermediate 270; 5.0 g, 23.2 mmol), 1-methylpiperazine (3.09 mL, 27.82 mmol), and potassium carbonate (3 , 99 g, 23.19 mmol) in DMF (10 mL), was heated at 135 ° C for 16 hours. The reaction mixture was cooled, added to water (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure to give 6.0 grams (93%) of a red solid. 1 H NMR: 7.80 (dd, 1 H), 7.65 (d, 1 H), 7.0 (d, 1 H), 4.71 (m, 1 H), 3.20 (m, 4 H), 2.44 (m, 4 H), 2.21 (s, 3 H), 1.32 (d, 6 H); m / z: 280.

Intermediate 270

1-Chloro-2-isopropoxy-4-nitrobenzene

A mixture of 2-chloro-5-nitrophenol (10.0 g, 57.6 mmol), 2-iodopropane (6.79 mL, 69.1 mmol), cesium carbonate (1.87 g, 5.76 mmol ), and potassium carbonate (9.93 g, 57.6 mmol) in DMF (50 mL), was heated at 35 ° C for 24 hours. The reaction mixture was cooled, added to water (200 mL) and extracted with EtOAc (3 x 25 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure to give 12.1 grams (97%) of a red solid. 1H NMR: 7.88 (d, 1 H), 7.80 (dd, 1 H), 7.72 (d, 1 H), 4.87 (m, 1 H), 1.32 (d, 6 H).

Intermediate 271

Ethyl 4-Chloro-6-morpholinoquinolin-3-carboxylate

Ethyl 4-hydroxy-6-morpholin-4-ylquinolin-3-carboxylate (Intermediate 272; 2.2 g, 7.28 mmol) was stirred in reflux phosphorus oxychloride (6.6 mL, 72.8 mmol) during 3 hours. After cooling, the mixture was concentrated under reduced pressure, and CH3CN (20 mL) was added. This mixture was poured slowly over NaHCO3 solution (150 mL) and the resulting suspension was extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and concentrated, and the residue was purified by column chromatography (EtOAc / hexane gradient) to give 1.8 g (77%) of a white solid. 1H NMR: 8.86 (s, 1 H), 8.00 (d, 1 H), 7.87 (d, 1 H), 7.38 (s, 1 H), 4.45 (q, 2 H), 3.82 (s, 4 H), 3.38 (s, 4 H), 1.38 (t, 3H); m / z: 321.

Intermediate 272

Ethyl 4-Hydroxy-6-morpholin-4-ylquinolin-3-carboxylate

A solution of diethyl {[(4-morpholin-4-ylphenyl) amino] methylene} malonate (Intermediate 273; 5.00 g, 14.35 mmol) in diphenyl ether (30 mL) was heated at 250 ° C for 2 hours . After cooling, hexane (20 mL) was added, and the resulting precipitate was filtered and washed with acetone (20 mL) to give 2.4 g (55%) of a slightly brown solid. 1H NMR: 12.21 (s, 1 H), 8.45 (s, 1 H), 7.50 (m, 3 H), 4.21 (m, 2 H), 3.78 (s, 4 H), 3.17 (s, 4 H), 1.27 (t, 3 H); m / z: 303.

Intermediate 273

{[(4-Morpholin-4-ylphenyl) amino] methylene} diethyl malonate

A solution of 4- (4-aminophenyl) morpholine (5.00 g, 28.1 mmol) and diethyl ethoxymethylenemalonate (6.1 mL, 30.5 mmol) in CH3CN (10 mL) was stirred for 24 hours. The reaction mixture was added to EtOAc (50 mL), washed with brine, dried (MgSO4), filtered, and concentrated. Hexane (50 ml) was added to the residue and after 30 minutes of sonication, the resulting suspension was filtered to give 7.2 g (74%) of a brown solid. 1H NMR: 10.75 (d, 1 H), 8.35 (d, 1 H), 7.27 (d, 2 H), 6.98 (d, 2 H), 4.22 (m, 4 H), 3.73 (s, 4 H), 3.08 (s, 4 H), 1.25 (m, 6 H).

Intermediate 274

Ethyl 4-Chloro-6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate

Ethyl 4-hydroxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate (Intermediate 275; 0.5 g, 1.5 mmol) was stirred in reflux phosphorus oxychloride (1.5 ml, 15.9 mmol) for 3 hours. After cooling, the mixture was concentrated under reduced pressure, and dichloromethane (10 mL) was added. This mixture was poured slowly over NaHCO3 solution (50 mL) and the resulting suspension was extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and concentrated, and the residue was taken up in hexane and filtered to give 0.4 g (76%) of a black solid. 1H NMR: 8.84 (s, 1 H), 7.97 (d, 1 H), 7.85 (d, 1 H), 7.35 (s, 1 H), 4.45 (q, 2 H), 3.40 (m, 4 H), 2.47 (m, 4 H), 2.25 (s, 3 H), 1.38 (t, 3 H); m / z: 334.

Intermediate 275

Ethyl 4-Hydroxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate

A solution of diethyl ({[4- (4-methylpiperazin-1-yl) phenyl] amino} methylene) malonate (Intermediate 276; 5.00 g, 13.8 mmol) in diphenyl ether (30 mL) was heated to 250 ° C for 2 hours. After cooling, hexane (20 mL) was added, and the resulting precipitate was filtered and washed with acetone (20 mL) to give 0.52 g (10%) of a slightly brown solid. 1H NMR: 12.19 (s, 1 H), 8.43 (s, 1 H), 7.50 (m, 3 H), 4.23 (m, 2 H), 3.19 (m, 4 H), 2.47 (m, 4 H), 2.23 (s, 3 H), 1.27 (t, 3 H).

Intermediate 276

({[4- (4-Methylpiperazin-1-yl) phenyl] amino} methylene) diethyl malonate

A solution of 4- (4-methylpiperazino) aniline (3.0 g, 15.7 mmol) and diethyl ethoxymethylenemalonate (3.4 mL, 16.9 mmol) in CH3CN (10 mL) was stirred for 24 hours. The reaction mixture was concentrated under reduced pressure, hexane (30 ml) was added to the residue, and the resulting suspension was filtered to give 5.0 g (88%) of a brown solid. 1H NMR: 10.74 (d, 1 H), 8.34 (d, 1 H), 7.24 (d, 2 H), 6.97 (d, 2 H), 4.14 (m, 4 H), 3.11 (m, 4 H), 2.44 (m, 4 H), 2.21 (s, 3 H), 1.25 (m, 6 H).

Intermediate 277

Ethyl 4-Chloro-7- (2-methoxvetoxy) -6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate

A mixture of diethyl ({[3- (2-methoxyethoxy) -4- (4-methylpiperazin-1-yl) phenyl] amino} methylene) malonate (Intermediate 278; 6.6 g, 15.15 mmol) and oxychloride phosphorus (23.24 g, 151.5 mmol) was heated at 110 ° C for 16 hours. The reaction mixture was cooled and concentrated under reduced pressure. The resulting dark oil was diluted with CH3CN (20 mL) and added to a stirring solution of NaHCO3. The resulting mixture was extracted with dichloromethane (3 x 25 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting oil was purified by chromatography on silica (EtOAc) to give 1.25 g (20%) of a pale yellow powder. 1 H NMR: 8.92 (s, 1 H), 7.48 (s, 2 H), 4.41 (q, 2 H), 4.39 (q, 2 H), 4.34 (m, 2 H), 3.78 (m, 2 H), 3.37 (s, 3 H), 3.22 (m, 4 H), 2.53 (s, 4 H), 2.26 (s, 3 H), 1.37 (t, 3 H); m / z: 408.

Intermediate 278

({[3- (2-Methoxyethoxy) -4- (4-methylpiperazin-1-yl) phenyl] amino} methylene) diethyl malonate

1- [2- (2-Methoxyethoxy) -4-nitrophenyl] -4-methylpiperazine (Intermediate 279; 7.0 g, 23.70 mmol), 10% palladium on carbon (0.7 g), and MeOH (20 ml) under a nitrogen atmosphere. The nitrogen atmosphere was removed and 344.8 KPa of hydrogen gas pressure was applied for 1 hour while the reaction vessel was stirred. The hydrogen gas was separated, and replaced with nitrogen gas. Diethyl ethoxymethylenemalonate (4.84 mL, 24.18 mmol) was added, and the resulting mixture was allowed to stand for 16 hours. The resulting black suspension was filtered through a bed of diatomaceous earth, and the filtrate was concentrated under reduced pressure. The resulting oil was purified by chromatography on silica (EtOAc) to give 6.6 grams (64%) of a yellow oil. 1H NMR: 6.59 (d, 1 H), 6.18 (d, 1 H), 6.08 (dd, 1 H), 4.65 (s, 2 H), (s, 2 H), 4.45 (m, 1 H), 2.79 (s, 4 H), 2.39 (s, 4 H), 2.17 (s, 3 H), 1.22 (s, 3 H), 1.20 (s, 3 H); m / z: 436.

Intermediate 279

1- [2- (2-Methoxyethoxy) -4-nitrophenyl] -4-methylpiperazine

To a solution of 1-chloro-2- (2-methoxyethoxy) -4-nitrobenzene (Intermediate 280; 5.0 g, 23.19 mmol) in DMF (10 mL) at 60 ° C, N-methylpiperazine (3 , 09 mL, 27.82 mmol). After heating at 130 ° C for 26 hours, the reaction mixture was cooled and added to a solution of NaHCO3 (50 mL). The mixture was extracted with EtOAc (3 x 100 mL), and the combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure to give 6.1 grams (92.6%) of a red solid. 1 H NMR: 7.80 (dd, 1 H), 7.69 (d, 1 H), 7.0 (d, 1 H), 4.21 (m, 2 H), 3.71 (m, 2 H), 3.34 (s, 3 H), 3.24 (m, 4 H), 2.44 (m, 4 H), 2.22 (s, 3 H); m / z: 296.

Intermediate 280

1-Chloro-2- (2-methoxyethoxy) -4-nitrobenzene

A solution of 2-chloro-5-nitrophenol (10.0 g, 57.62 mmol), 1-bromo-2methoxyethane (8.4 mL, 69.14 mmol), and potassium carbonate (11.92 g, 69 , 14 mmol) in DMF (40 mL), heated at 40 ° C for 48 hours. The reaction mixture was cooled and added to a solution of NaHCO3 (100 mL) and dichloromethane (100 mL). The resulting mixture was extracted with dichloromethane (3 x 100 mL). The combined organic extracts were dried with (Na2SO4), filtered, and concentrated under reduced pressure to give a red solid. The red solid was filtered through a bed of silica gel, eluting with a 9: 1 ratio of hexane: EtOAc. The filtrate was concentrated to give 10.3 g (77%) of a reddish orange crystalline solid. 1H NMR: 7.92 (d, 1 H), 7.85 (dd, 1 H), 7.75 (d, 1 H), 4.35 (m, 2 H), 3.73 (m, 2 H), 3.34 (s, 3 H).

Intermediate 281

Ethyl 4,6-Dichloro-7- (2-methoxyethoxy) quinolin-3-carboxylate

A solution of ethyl 6-chloro-4-hydroxy-7- (2-methoxyethoxy) quinolin-3-carboxylate (Intermediate 282; 6.7 g, 20.56 mmol), thionyl chloride (4.5 mL, 61 , 69 mmol), and DMF (1 drop) in CH3CN (25 mL), was heated at 60 ° C for 2 hours. The reaction mixture was cooled and slowly added to a solution of NaHCO3 (100 mL). The resulting suspension was extracted with EtOAc (3 x 100 mL) and the organic extracts were combined and dried (Na2SO4). Purification of the residue by silica chromatography (gradient of hexane / EtOAc) gave 5.5 g (78%) of a white solid. 1H NMR: 9.10 (s, 1 H), 8.34 (s, 1 H), 7.69 (s, 1 H), 4.44 (m, 4 H), 3.81 (m, 2 H), 3.37 (s, 3 H), 1.38 (t, 3 H).

Intermediate 282

Ethyl 6-Chloro-4-hydroxy-7- (2-methoxyethoxy) quinolin-3-carboxylate

To a solution of Dowtherm A (25 mL) at 250 ° C, diethyl ({[4-chloro-3- (2-methoxyethoxy) phenyl] amino} methylene) malonate (Intermediate 283; 12.7 g, 34.16 mmol ) and heating continued for 1 hour. The reaction vessel was cooled, hexane (100 mL) was added and the resulting suspension was filtered and dried to give 10.5 g (94%) of an insoluble gray solid.

Intermediate 283

({[4-Chloro-3- (2-methoxyethoxy) phenyl] amino} methylene) diethyl malonate

A mixture of 1-chloro-2- (2-methoxyethoxy) -4-nitrobenzene (Intermediate 280; 10.3 g, 44.47 mmol), 5% platinum on carbon (1.0 g), and zinc iodide (II) (2.84 g, 8.89 mmol) in EtOAc (40 ml) under nitrogen was evacuated to hydrogen (1 atm) and stirred for 24 hours. Hydrogen was replaced by nitrogen, and diethyl ethoxymethylenemalonate (9.07 mL, 24.18 mmol) and Na2SO4 (1 g) were added. After 16 hours, the resulting black suspension was filtered through a bed of diatomaceous earth, and the filtrate was concentrated under reduced pressure. The resulting oil was purified by silica chromatography (hexane / EtOAc gradient) to give 12.7 grams (77%) of an almost white powder. 1H NMR: 10.70 (d, 1 H), 8.40 (d, 1 H), 7.40 (d, 1 H), 7.26 (s, 1 H), 6.98 (d, 1 H), 4.24 (m, 6 H), 3.72 (m, 2 H), 3.34 (s, 3 H), 1.28 (m, 6 H); m / z: 372.

Intermediate 284

7- (2 - {[tert-Butyl (dimethyl) silyl] oxy} ethoxy) -4-chloro-6- (4-methylpiperazin-1-yl) quinolin-3-carboxylate ethyl

A solution of diethyl ({[3- (2 - {[tert-butyl (dimethyl) silyl) oxy} ethoxy) -4- (4-methylpiperazin-1-yl) phenyl] amino} methyl) malonate (Intermediate 285; 2, 0 g, 3.73 mmol), triethylamine (9.05 g, 89.59 mmol) and phosphorus oxychloride (1.14 g, 7.47 mmol) in toluene (10 mL), heated at 100 ° C for 24 hours. The reaction mixture was cooled, acetonitrile (10 mL) was added, and the resulting mixture was added to a NaHCO3 solution. The mixture was extracted with EtOAc (3 x 100 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting oil was purified by chromatography on silica (gradient of EtOAc / MeOH) to give 0.545 g (29%) of a pale yellow solid. 1H NMR: 8.84 (s, 1 H), 7.40 (s, 2 H), 4.32 (q, 2 H), 4.22 (m, 2 H), 3.94 (m, 2 H), 3.16 (s, 4 H), 2.45 (s, 4 H), 1.28 (t, 3 H), 0.79 (s, 9 H), 0.00 (s, 6 H); m / z: 508.

Intermediate 285

({[3- (2 - {[tert-Butyl (dimethyl) silyl) oxy} ethoxy) -4- (4-methylpiperazin-1-yl) phenyl] amino} methylene) diethyl malonate

A mixture of 1- [2- (2 - {[tert-butyl (dimethyl) silyl] oxy} ethoxy) -4-nitrophenyl] -4-methylpiperazine (Intermediate 286; 1.5 g, 3.79 mmol) and palladium 10% on carbon (0.4 g) in EtOAc (10 ml) under nitrogen was evacuated to hydrogen (1 atm) and stirred for 16 hours. The hydrogen gas was separated, and replaced with nitrogen gas. Diethyl ethoxymethylenemalonate (0.774 mL, 3.87 mmol) was added, and after stirring for 24 hours, the resulting black suspension was filtered through a bed of diatomaceous earth. The filtrate was concentrated under reduced pressure to give 2.0 g (99%) of a white solid. 1H NMR: 10.72 (d, 1 H), 8.37 (d, 1 H), 7.02 (s, 1 H), 6.86 (s, 2 H), 4.23-4.10 (m, 6 H), 3.92 (m, 2 H), 2.97 (m, 4 H), 2.43 (m, 4 H), 2.20 (s, 3 H), 1.25 (m, 6 H), 0.86 (s, 9 H), 0.07 (s, 6 H); m / z: 536,

Intermediate 286

1- [2- (2 - {[tert-Butyl (dimethyl) silyl] oxy} ethoxy) -4-nitrophenyl] -4-methylpiperazine

A solution of tert-butyl [2- (2-chloro-5-nitrophenoxy) ethoxy] dimethylsilane (Intermediate 287; 6.0 g, 18.08 mmol) and N-methylpiperazine (4.41 mL, 39.77 mmol) in DMF (10 mL), it was heated at 100 ° C for 3 days. After cooling, water (20 mL) was added and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated, and the residue was purified by chromatography on silica (hexane / EtOAc gradient) to give 5.0 g (70%) of a yellow solid. 1H NMR: 7.84 (dd, 1 H), 7.70 (d, 1 H), 7.02 (d, 1 H), 4.17 (m, 2 H), 3.96 (m, 2 H), 3.26 (m, 4 H), 2.45 (m, 4 H), 2.21 (s, 3 H), 0.86 (s, 9 H), 0.07 (s, 6 H); m / z: 396.

Intermediate 287

tert-Butyl [2- (2-chloro-5-nitrophenoxy) ethoxy] dimethylsilane

A mixture of 2-chloro-5-nitrophenol (6.0 g, 34.57 mmol), (2-bromoethoxy) -tercbutyldimethylsilane (8.6 mL, 41.5 mmol) and potassium carbonate (7.15 g, 41.5 mmol), in DMF (40 mL), was heated at 40 ° C for 4 days. The reaction mixture was filtered. Brine (200 mL) was added, and the mixture was extracted with EtOAc (3x 50 mL). The combined organic extracts were concentrated, and the residue was purified by chromatography on silica (hexane / EtOAc gradient) to give 6.5 g (57%) of a white solid. 1H NMR: 7.94 (s, 1 H), 7.84 (dd, 1 H), 7.74 (d, 1 H), 4.325 (m, 2 H), 3.96 (m, 2 H) , 0.82 (s, 9 H), 0.04 (s, 6 H).

Claims (15)

1. A compound of the formula IA or IB: image 1 or one of its pharmaceutically acceptable salts, in which: image 1 it is a 3-10 membered heterocycle or heteroaryl, attached by nitrogen; where if said heterocycle or heteroaryl contains a -NH- moiety, this nitrogen may be 10 optionally substituted with a group selected from R5; R1 at each occurrence is independently halo, hydroxy, nitro, formyl, cyano, -CO2H, -SH, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy, -OC (O) -alkyl (C1-C6), -C (O) -alkyl (C1-C6), -CO2-alkyl (C1-C6), -NR'R ", - NR'-C (O) -alkyl (C1-C6), (C1-C6) alkyl S (O) a-where a is 0 to 2, -NR'-C (O) -O (C1-C6) alkyl, -NR'-SO2-(C1-C6) alkyl, -NR'-C (O) NR'R ", -SO2-NR'R", -C (O) -NR ' R ", carbocyclyl, heterocycle, heteroaryl or oxo; R2 is hydrogen, halo, hydroxy, nitro, formyl, -CO2H, -SH, cyano, (C1-C6) alkyl, alkenyl (C2-C6), alkynyl (C2-C6 ), cycloalkyl (C3-C6), -O-cycloalkyl (C3-C6), -OC (O) -alkyl (C1-C6), -C (O) -alkyl (C1-C6), -CO2-alkyl ( C1-C6), -NR'R ", -NR'-C (O) (C1-C6) alkyl, (C1-C6) alkyl S (O) a-where a is 0 to 2, -NR'-C (O) -O-(C1-C6) alkyl, -NR'SO2- (C1-C6) alkyl, -NR'-C (O) NR'R ", -SO2-NR'R", -C (O) -NR'R ", -OC (O) -NR'R", carbocyclyl, heterocycle, heteroaryl or (C1-C6) alkoxy; R3 at each occurrence is independently halo, nitro, formyl, cyano, hydroxy, -NR'R ", -CO2H, -C (O) -alkyl (C1-C6), -CO2-alkyl (C1-C6), -C (O) -NR'R ", -NR'-C (O) -alkyl (C1-C6), -NR'-C (O) NR'R", -NR'-C (O) -O-alkyl (C1-C6), -OC (O) -alkyl (C1-C6), -SH, -SO2-NR'R ", (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl , (C1-C6) alkoxy, (C1-C6) alkyl S (O) a-where a is 0 to 2, -NR'-SO2 (C1-C6) alkyl, carbocyclyl, heterocycle, or heteroaryl, where said heterocycle or heteroaryl contains a -NH- moiety, this nitrogen may be optionally substituted with (C1-C6) alkyl; or two R3 groups on adjacent carbons may optionally form a 5 or 6 membered, saturated, partially unsaturated, unsaturated and / or aromatic ring optionally containing 0, 1, or 2 heteroatoms selected from S, O, or NRa where Ra is absent , is H or (C1-C6) alkyl; R4 is hydrogen or halo; m is 0-3; where the values of R3 can be the same or different; n is 0-3; where the values of R1 can be the same or different; p is independently 1 or 2 at each occurrence; and R5 is selected from (C1-C6) alkyl, (C3-C6) cycloalkyl, -C (O) -C1-C6 alkyl, -S (O) C1-C6 alkyl, -CO2-C1 alkyl -C6), -C (O) -NR'R ", benzyl, benzyloxycarbonyl, benzoyl and phenylsulfonyl; R 'and R" independently at each occurrence are H, optionally substituted (C1-C6) alkyl, or optionally substituted aryl, or considered together with the nitrogen to which they are attached they form a 3-6 membered ring, saturated or partially unsaturated, optionally substituted, containing 0 or 1 additional heteroatom selected from NRa; wherein said optional substituents can be selected from one or more R6; R6 can independently be (C1-C6) alkyl, halo (C1-C6) alkyl, halo, nitro, cyano, hydroxy, (C1-C6) alkoxy, -NRxRy, -COORx or -CONRxRy; and Rx and Ry are independently of each other hydrogen or (C1-C6) alkyl; and where each of Ra, R1, R2, R3 and R5 may optionally be substituted on the carbon with one or more formyl groups, -SH, azido, halo, nitro, cyano, hydroxy, trifluoromethoxy, OC (O) -alkyl ( C1-C6), -NR'R ", -CO2H, -C (O) -alkyl (C1-C6), -CO2-alkyl (C1-C6), -C (O) -NR'R", -S -C1-C6 alkyl, -SOp-C1-C6 alkyl, -SOpNR'R ", (C1-C6) alkyl, C3-C6 cycloalkyl, -NR'-C (O) -C1 alkyl -C6), -NR'-C (O) -O-(C1-C6) alkyl, -NR'-SO2-(C1-C6) alkyl, -NR'-C (O) NR'R ", alkenyl ( C2-C6), (C2-C6) alkynyl, or (C1-C6) alkoxy. 2. A compound of the formula IA according to claim 1, or one of its 5 pharmaceutically acceptable salts. 3. A compound of the formula IB according to claim 1, or a pharmaceutically acceptable salt thereof. A compound of the formula IA or IB or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein: image 1 it is a 5-7 membered heterocycle, bound by nitrogen; where if said heterocycle 15 contains a moiety -NH-, this nitrogen may be optionally substituted with a group selected from R5; where R5 is selected from (C1-C6) alkyl, (C3-C6) cycloalkyl, -C (O) -C1-C6 alkyl and -CO2-(C1-C6) alkyl; and each R5 may be optionally substituted on carbon with one or more groups Cyan, hydroxy, -OC (O) -C1-C6 alkyl, -NR'R ", C3-C6 cycloalkyl or (C1-C6) alkoxy; where R 'and R" independently at each occurrence are alkyl (C1-C6). 5. A compound of the formula IA or IB or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, in the That R1 in each occurrence is hydroxy, -NR'R "or oxo; where R 'and R" independently in each occurrence are (C1-C6) alkyl. 6. A compound of the formula IA or IB or one of its salts Pharmaceutically acceptable according to any one of claims 1-5, wherein n is 0 or 1. 7. A compound of the formula IA or IB or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, wherein R2 is hydrogen, halo or (C1-C6) alkoxy; where R2 may be optionally substituted on the carbon with one or more (C1-C6) alkoxy or hydroxy groups. 8. A compound of the formula IA or IB or one of its salts 5 pharmaceutically acceptable according to any one of claims 1-7, wherein R3 at each occurrence is independently halo, (C1-C6) alkyl or (C1-C6) alkoxy; where R3 may be optionally substituted on the carbon with halo. 9. A compound of the formula IA or IB or one of its salts Pharmaceutically acceptable according to any one of claims 1-8, wherein m is 1-3; where the values of R3 can be the same or different. 10. A compound of the formula IA or IB or one of its salts Pharmaceutically acceptable according to any one of claims 1-9, wherein R4 is hydrogen or fluoro. 11. A compound of the formula IA or IB: image 1 20 in which: image 1 it is piperazin-1-yl, N-methylpiperazin-1-yl, N-ethylpiperazin-1-yl, N-isopropylpiperazin-1-yl, N-acetylpiperazin-1-yl, N- (2-hydroxyacetyl) piperazin-1- ilo, N- (2-dimethylaminoethyl) piperazin-1-yl, N- (2-methoxyethyl) piperazin-1-yl, 5 N- (2-cyanoethyl) piperazin-1-yl, N- (2-hydroxyethyl) piperazin -1-yl, N- (cyclopropylmethyl) piperazin-1-yl, N- (cyclopropyl) piperazin-1-yl, N - ((R) -2-hydroxypropionyl) piperazin-1-yl, N - ((S) -2-hydroxypropionyl) piperazin-1-yl, N- (t-butoxycarbonyl) piperazin-1-yl, N- (acetoxyacetyl) piperazin-1-yl, piperidin-1-yl, morpholino, homopiperazin-1-yl, N -methylhomopiperazin-1-yl, N-ethylhomopiperazin-1-yl, N-acetylhomopiperazin-1-yl, N-isopropylhomopiperazin-1-yl, N-cyclopropylhomopiperazin-1-yl and pyrrolidin-1-yl; R1 at each occurrence is hydroxy, -NMe2 or oxo; n is 0 or 1; R2 is hydrogen, fluoro, methoxy, ethoxy, 2- (methoxy) ethoxy, 2-hydroxyethoxy or isopropoxy; R3 at each occurrence is independently fluoro, chloro, methyl, trifluoromethyl, ethyl, methoxy or trifluoromethoxy; m is 1-3; where the values of R3 can be the same or different; R4 is hydrogen or fluoro; or one of its pharmaceutically acceptable salts. twenty 12. A compound of the formula IA or IB: image 1 image 1 selected from: 4 - [(2,4-difluorophenyl) amino] -7-ethoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxamide; 4 - [(2,3-dichlorophenyl) amino] -7-ethoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxamide; 7-ethoxy-4 - [(2-fluoro-5-methylphenyl) amino] -6- (4-isopropylpiperazin-1-yl) quinolin-3-carboxamide; 4 - [(3-Chloro-2-fluorophenyl) amino] -7-ethoxy-6- (4-methylpiperazin-1-yl) quinolin-3-carboxamide; 7-ethoxy-4 - [(2-fluoro-5-methylphenyl) amino] -6- (4-methylpiperazin-1-yl) quinolin-3-carboxamide; 7-ethoxy-4 - [(2-fluoro-4-methylphenyl) amino] -6- (4-methylpiperazin-1-yl) quinolin-3-carboxamide; 4 - [(2,4-difluorophenyl) amino] -7- (2-methoxyethoxy) -6- (4-methylpiperazin-1-yl) quinolin-3-carboxamide; 4 - [(2-Fluoro-4-methylphenyl) amino] -7- (2-methoxyethoxy) -6- (4-methylpiperazin-1-yl) quinolin-3carboxamide; 4 - [(2-Fluoro-5-methylphenyl) amino] -7- (2-methoxyethoxy) -6- (4-methylpiperazin-1-yl) quinolin-3carboxamide; and 4 - [(2-fluoro-4-methylphenyl) amino] -6- (4-isopropylpiperazin-1-yl) -7- (2-methoxyethoxy) quinolin-3-carboxamide.

13.

A compound of the formula IA or IB according to claim 12, wherein the compound is 4 - [(2,4-difluorophenyl) amino] -7-ethoxy-6- (4-methylpiperazin-1-yl) quinolin-3 -carboxamide.

14.

A process for preparing a compound of the formula IA or IB or a pharmaceutically acceptable salt thereof, according to claim 1, whose

method, wherein the variable groups are, unless otherwise specified, as defined in claim 1, comprises: Procedure a) react a compound of the formula IIA or IIB: image2 in which L is a movable atom or group; with a compound of formula III: image 1 or Procedure b) react a compound of the formula IVA or IVB: image 1 in which L is a movable atom or group; with a compound of the formula V: image 1 or Procedure c) react a compound of the formula VIA or VIB: image 1 or one of its activated derivatives; with ammonia; or Procedure d) react a compound of the formula VIIA or VIIB: image 1 image 1 wherein R is (C1-C6) alkyl, in particular methyl and ethyl; with formamide and a base; or Procedure e) hydrolysis of a compound of the formula VIIIA or VIIIB: image 1 and then, if necessary: i) convert a compound of the formula IA or IB into another compound of the formula IA or IB; 10 ii) separate all protective groups; iii) form a pharmaceutically acceptable salt. 15. A pharmaceutical composition comprising a compound of the formula IA or IB, or a pharmaceutically acceptable salt thereof, according to a Any one of claims 1-13, in association with a pharmaceutically acceptable diluent or carrier. 16. A compound of the formula IA or IB, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-13, for use as a medicament.