SA07280179B1 - Anilinoquinoline -3 –Carboxamides as CSF 1R Kinase Inhibitors - Google Patents

Abstract

Anilinoquinoline-3-carboxamides as CSF-1R Kinase Inhibitors Abstract The present invention relates to chemical compounds having the formula IA or IB:IAIB or pharmaceutically acceptable salts thereof having inhibitory activity of the CSF-1R receptor ) kinase, and thus useful for its anti‑cancer activity, and therefore, useful in methods of treating the human or animal body. Also, the invention relates to processes for the manufacture of the said chemical compounds, and to pharmaceutical compositions containing them, and to their use in the manufacture of drugs for use in producing an anti-cancer effect in warm-blooded organisms, such as humans.

Description

Y — — Anilinoquinoline -7-carboxamides as CSF-1R Kinase Inhibitors 057-11 Anilinoquinoline -3 —Carboxamides as CSF-1R Kinase Inhibitors Full Description

background of the invention

The invention relates to chemical compounds; or pharmaceutically acceptable salts thereof that have receptor-inhibiting activity

Lg's anti-cancer and thus beneficial anticancer activity ¢ (CSF-1R) kinase

Hence; They are useful in methods of treating the human or animal body. like that; The invention relates to 0 processes for the manufacture of said chemical compounds; and pharmaceutical formulations containing it; And using it in

manufacture of drugs for use in producing an anti-cancer effect in warm-blooded organisms; like:

human.

Receptor tyrosine kinases (RTK's) are a subfamily of protein kinase enzymes.

Which play an influential role in cells sending signals; They are involved in many cancer-related processes0 including cellular AS; her survival; Special vessels are born

Baha, conquest and spread. It is believed that there are at least 96 different species out of 871,678 incl

.CSF-1R

081-118 or 205-" was primarily identified as 805-"_ of an oncogene from a sarcoma virus.

tyrosine with RTK's coenzyme III is a member of the feline CSF-IR class. The sarcoma virus and platelet-derived growth factor receptor 8 ofims gy-associated (FIt3) kinase 3 Vo

(PDGFRB PDGFRa) All of these kinase enzymes have been indicated in the process of formation

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__As —

Oncology. Normal JSS 057-11 is transgenically expressed as an immature transmembrane protein

of the 130 kDa type and thus leads to a glycosylated protein bound at N to a surface

A cell weighing from Vo to 10 kDa. The receptor correlates with macrophage colony stimulation

The large M-CSF (or CSF-1) ligand complex of the “CSF-1R receptor dimerizes; self-phosphorylation of the receptor and subsequent activation of the following signal transgene sequences:

(C.J.

Sherr, Biochim Biophys Acta, 1988, 948: 225-243).

087-18 is normally transgenically expressed in myeloid cells of the phagocytic lineage

Mononuclear cells producing their own bone marrow as well as ductal epithelial cells

the alveoli in the breast tissue for lactation; But it's normal. Activation of 0 082-18 stimulates proliferation of cells of the macrophage/monocyte lineage; her survival;

and move it; and distinguish between them. Mature macrophages play a major role in tissue development

Natural and immune defense:

(F.L.

Pixley and E.R.

Stanley, Trends in Cell Biology, 2004, 14(11): 628-638.

example; Osteoblasts secrete 6517-1 and activate the receptor on osteoclast-producing 10 cells, leading to differentiation of mature osteoblasts:

Teitelbaum, Science, 2000, 289: 1504-1 508 (5.1). Alaa 057-11 plays an important role in

development of the chorionic membrane; local implantation; and the development of the lobe alveoli and gland ducts

-(E.

Sapi, Exp Biol Med, 2004, 229:1-11: Mammals and Lactation

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_— $ — Transfection with 087-18 with or without 0587-1 causes transmembrane formation and tumorigenesis in the organism of L10171373 (rat cells? and ovarian granulosa cells). Signal transduction mechanisms specific to endocrine and/or paraendocrine have been implicated in the activation of CSF-IR in tumor-specific epithelium and tumor-associated macrophages. Incorrect genoexpression and activation of 687-18 and/or its ligand complex were found in human myeloid leukemia, prostate prostate, breast and ovaries, and endometrial cancer. endometrial and various other types of cancer. A number of studies have shown that transgenic overexpression of 087-18 is associated with a poor prognostic sign in many cancer cases. in addition to; The CSF-1/CSF-IR0 axis plays a key role in the regulation of tumor-associated macrophages; Presumed to play an influential role in the development and proliferation of tumour-producing cells: (E.

Sapi, Exp Biol Med, 2004, 229:1-11) General description of the invention ely on that; The present invention provides a compound of formula TA or IB (Ry), R | HN 0 4 60 00 N NH, > 7 Vo R, N IA Yéov

oO -_— — Ra), R, 7 HN 0 R Xr” ON, ? 7 (R 1 In N N IB or a pharmaceutically acceptable salt dla where: g is a heterocyclic or aryl heterocyclic”; attached — nitrogen ; to which 0 to 01 atoms, whereby if said heterocyclic or said aryl heterocyclic has a -1011- moiety, nitrogen can be optionally substituted by a selection of (Rs:8) at each occurrence of formation separately : halo, hydroxy, nitro, formyl, cyano, -CO,H, -SH, (C;-Ce)alkyl, (C,-Ce)alkenyl, (Ca-Cy)alkynyl, (C3-Ce) cycloalkyl, (C,-Cg)alkoxy, -OC(O)-(C;-Ce)alkyl, -C(0)-(Cy-Cg)alkyl, -CO2(C;-Cg)alkyl, - NR'R”, -NR'-C(0)-(C,-Cg)alkyl, 01 (C1-Ce)alkylS(O)a- where e is from zero to or -NR' -C(0)-0(C;-Ce)alkyl, -NR'-SO,-(C,-Cg)alkyl, -NR'-C(O)NR'R", -S0,-NR 'R",-C(0)-NR'R", carbocyclyl, heterocyclo, heteroaryl or oxo; Yéov

: to form hydrogen, halo, hydroxy, nitro, formyl, -CO,H, -SH, cyano, (C,-C¢)alkyl, (C2-Cg)alkenyl, (Co-Ce)alkynyl, (C3) -Ce)cycloalkyl, -O-(C3-Cg)cycloalkyl, -0C(0)-(C,-Cg)alkyl, -C(0)-(C;-Cg)alkyl, -CO(C;-Ce )alkyl, -NR'R", -NR'-C(0)-(C-Cg)alkyl, (C;-Ce)alkylS(O),- ° : or 1 is from zero to a where by (from-)0-(0 )0 - we reduce - -NR'-SO,-(C-Cg)alkyl, -NR'-C(O)NR'R”, -SO,- NR'R”, -C(O)-NR’R”, -OC(O)-NR’R”, carbocyclyl, heterocyclo, heteroaryl or (C;-Cg)alkoxy; Ry halo, nitro, formyl, cyano, hydroxy, -NR'R”, -CO,H, -0)0(-)0 mmlo- x -CO,y (C-Cgalkyl, -C(0)-NR'R", -NR'-C(0)-(C;-Cg)alkyl, -NR'-C(O)NR'R", -NR'- C(0)-O(C;-Ce)alkyl, -O-C(0)-(C;-Cq)alkyl, -SH, -SO,-NR'R”, (C,-Cg)alkyl, (Co -Ce)alkenyl, (Co-Ce)alkynyl, (C;-Ce)alkoxy, (Ci-C)alkylS(O),- or 17 where 8 is from zero to where if the compound is -NR'-SO,-(Ci-Cg)alkyl, carbocyclyl, heterocyclo, or heteroaryl d-nitrogen The -NH- heterocyclic containing the aryl heterocyclic moiety can be replaced by + or ; or (C1-Co)alkyl optionally by

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Optionally two Ry groups on two adjacent carbon atoms can form a saturated, partially unsaturated and/or unsaturated aromatic ring of 0 or 76 atoms optionally including a yellow or 1; or “a selected heteroatom of 8 or ©; or Cus NRy C18 does not exist or SH(C)-Ce)alkyl C is halo 0 hydrogen ¢ “be from zero to where Ry values can be the same or different; be from zero to ?; where Ry values can be the same or different; they are set to 1 saa or ? at each occurrence; and they are not selected from: ve (and 0-:0)m (5)0- ,enolalo- )-(0)©- (C3-Ce)cycloalkyl, papaldo©-:©) -CO,(C;-Ce)alkyl, -C(O)-NR' R”, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; Optional with “aryl” or form with a nitrogen atom to which they are attached to a ring consisting of 1 of ? to + optionally substituted atoms that are saturated or partially unsaturated containing 0 or 1 additional heterotom selected from NR , where the mentioned optional substitution groups are selected from one or more Rg m separately selected from: YéoV

{ — A —_ (C1-Ce)alkyl, halo(C;-Cg)alkyl, halo, nitro, cyano, hydroxy, (Ci-Cs)alkoxy, -NR*R?, —

COOR* or —CONRR'; 3 Where ¢ (C-Celalkyl or hydrogen) can form independently of each other RY 5 RY : having an optional substitution on the carbon with one or more Rss Rss Rog «Ris Ro » be © formyl, -SH, 22100, halo, nitro, cyano, hydroxy, trifluoromethoxy, -OC(O)-(C;-C¢)alkyl, -NR'R”, -CO,H, -C(0)-(C; -C¢)alkyl, -CO,(C;-Cg)alkyl, -C(O)-NR'R”, -S-(C;-Cg¢)alkyl, -SOp-(Ci-Ce)alkyl, -SONR'R”, (C;-Cg)alkyl, (C3-Ce)cycloalkyl, -NR'-C(0)-(C,-Cg)alkyl, -NR'-C(0)-O(C ;-Cg)alkyl, -NR'-SO,-(C;-Cg)alkyl, -NR'-C(O)NR'R?”, (C,-Cg)alkenyl, (C2-Cg)alkynyl, or (C;-Ce)alkoxy. from ? to 8 atoms; aryl forms a heterocyclic 0): at each occurrence each separately forms 8, 1 halo, hydroxyl, (C,-Ce)alkyl, (C3-Cg)cycloalkyl, ( C;-Cg)alkoxy, -OC(O)-(C,-Ce)alkyl, -C(0)-(C;-Ce)alkyl, -CO,(C-Cg)alkyl, -C(O) -NR'R", or oxo;

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C 9 _ Ry is : (C3-C¢)cycloalkyl, or (C,-Cg)alkoxy; Occurring: ‎halo, nitro, cyano, hydroxy, trifluoromethoxy, NR'R", CO,H, -C(O)-(C,-Cs)alkyl, -COy(C;-Celalkyl) , -C(O)-NR'R", -NR-C(0)-(C;-Cg)alkyl, -NR'-C(O)NR'R", ° -NR'-C( O)-0(C-Ce)alkyl, -O-C(O)-(C,-Cg)alkyl, SH, -SO,-NR'R”, (C;-Cg)alkyl, (C3-Ce )alkenyl, (C,-Co)alkynyl, (C;-Cg)alkoxy, (Ci-Ce)alkylS(O), where a is from zero to ; or heterocyclo, or heteroaryl in and is 0 and 0) - , initial (0-,0)-14187-502- Cus that if 0 is the heterocyclic compound; or aryl heterocyclic containing an NH moiety: nitrogen can be optionally substituted by 1 and the yl(f-,©); and optionally two Ry groups on adjacent carbon atoms may form a saturated, partially unsaturated and/or unsaturated aromatic ring composed of © or + atoms including optionally a yellow, 11 or “hetero-atom selected from 8”; or ©0; or NR, where .8 is non-Basse or oH is 0 (0 for blood-©) » or 8 or 0; Ry is halo of hydrogen ¢ m is from zero to ?; « be from zero to ??; Yéov

= and 1 - p are 1 or 1 apart for each occurrence; And R and 87 are each separately at each occurrence of cH or (C-Collalkyl “or b-caryl) or they are with the nitrogen atom to which they are attached to a ring consisting of ? to 1 substituent atoms Optional is saturated or molecularly unsaturated Containing zero or 1 additional heteroatom Selected from oo 3 can be “Ris (Ry) and with 5 Rss Ry has an optional substitution on the carbon by : NR'R “, Balollagro-©0)-(00)0- halo, nitro, cyano, hydroxy, trifluoromethoxy, 22100 , -COzH, C(O)-(C,-Cg)alkyl, -CO,(C ,-Cg)alkyl, -C(0)-NR'R", S(C;-Cg), SOp(Cy-Celalkyl, SO,NH(C,-Cg)alkyl, SO,NR'R” , (C,-Cg)alkenyl, (C,-Ce)alkynyl, or -Cg)alkoxy .1 0 According to another aspect of the present invention, a compound of formula IA or IB or an acceptable salt is provided Pharmacologically, die where: (©) is a heterocyclic or aryl heterocyclic; bound to nitrogen; have from ¥ to A atoms; Whereas, if said heterocyclic or said aryl heterocyclic \o contains a “-NH- moiety the nitrogen can optionally be substituted by a selection of 8 Rs’ at each occurrence of each formation separately : halo, hydroxy, nitro, formyl, cyano, -CO,H, -SH, (C, -Ce)alkyl, (Co-Cg)alkenyl, (C2-Ce)alkynyl, (C5-Cs )cycloalkyl, (C;-Co)alkoxy, -OC(0)-(C;-Cg)alkyl, m

-NR'R”, -NR'-C(0)-(C,-Cg)alkyl, unyld0-r0 )n-alloldzo -, 0)-(0)n- -f(5)0 aboldron-r0 ) where a is from zero to 1 or: -NR'-C(0)-O(C;-Ce)alkyl, -NR'-S0,-(C;-Cg)alkyl, -NR '-C(O)NR'R", -SO,-NR'R", -C(O)-NR'R", carbocyclyl, heterocyclo, heteroaryl or oxo; ° Ry is : hydrogen, halo, hydroxy, nitro, formyl, -CO,H, -SH, cyano, (C;-Cs)alkyl, (C2-Ce)alkenyl, (C,-Ce )alkynyl, (C3-Ce)cycloalkyl, -O-(C;-Ce)cycloalkyl, -0C(0)-(Ci-Cg)alkyl, -C(O)-(C-Cg)alkyl, - CO,(C,-Cg)alkyl, -NR'R", -NR'-C(0O)-(C;-Cg)alkyl, (C;-Ce)alkylS(O),- 01 where 8 is from zero to 1 or

-NR'-C(0)-O(C;-Cg)alkyl, -NR'-SO,-(C,-Cg)alkyl, -NR'-C(O)NR'R”, -SO, -NR'R”, -C(0)-NR’R”, -OC(O)-NR’R”, carbocyclyl, heterocyclo, heteroaryl or (C;-Cg)alkoxy;

Ry halo, nitro, formyl, cyano, hydroxy, -NR'R”, -CO,H, -C(0)-(C,;-C¢)alkyl, at each time of occurrence: Vo -COy(C-Ce)alkyl, -C(O)-NR'R", -NR'-C(0)-(C;-Cg)alkyl, -NR'-C(O)NR'R” , -NR'-C(0)-0O(C;-Ce)alkyl, -O-C(0)-(Ci-Ce)alkyl, -SH, -SO,-NR'R”, (C;-Cg) alkyl, (C2-Cg)alkenyl, (Cp-Cg)alkynyl, (C;-Ce)alkoxy, (C-Ce)alkylS(O),-

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where e is from zero to SY -NR'-80,-(C,-Ce)alkyl ' or heterocyclic ' or aryl heterocyclic ' where if the heterocyclic compound or aryl Heterocyclic contains an NH moiety Nitrogen can be optionally replaced by (C1-Calkyl; or m) Two Ry groups on two adjacent carbon atoms can optionally form a saturated, partially unsaturated and/or unsaturated aromatic ring Saturated made up of © or + atoms optionally including a yellow or 11 or “heteroatom selected from 8; or ©0; or NR, where 8 is not present; or SH Waldron-0) ¢ Ry is hydrogen or halo ¢ 0 “is from zero to” where the Ry values can be the same or different; “is from zero to , where the Ry values can be the same or different m is separately 1 or ? at each occurrence; and is selected from: (C1-Cealkyl, (Cs-Ce)cycloalkyl, -C(0)-(C;-Ce)alkyl, -S (0)p(C;-Cg)alkyl, -CO4(C,-Co)alkyl, -C(O)-NR'R”, benzyl, benzyloxycarbonyl, benzoyl and Vo phenylsulphonyl JS R74 R separately on each occurrence of 1]; or optionally substituted with (C1-Collalkyl; or optionally substituted with aryl ; Or they form with a nitrogen atom to which they are attached a ring forming a Yé¢ov

of JY + optionally substituted atoms that are saturated or partially unsaturated containing 0 or 1 additional heteroatom selected from NR, wherein said optional (Jan WY) groups are selected from one or more Re ,8 to be separately selected from : halo(C,-Cg)alkyl, halo, nitro, cyano, hydroxy, (C1-Ce)alkoxy, -NR*RY, — °panol (un-r)) COOR* or —CONR*R; 3 RY and 87 are independently of each other hydrogen or (C-Collalkyl ; where Rss (Ras «Ras (Ris «Ry) can have an optional substitution on the carbon with one or more of : formyl, -SH, 82100, halo, nitro, cyano, hydroxy, trifluoromethoxy, -OC(0)-(C;-Cg)alkyl, 01 -CO,(C,-Ce )alkyl, -C(0)-NR'R", -S-(C;-Cg)alkyl, ,alldo0- 0)-(0)0- -NR'R", -CO;H, -SOp-(Cy-Ce)alkyl, -SO,NR'R”, (C,-Cg)alkyl, (C3-Cg)cycloalkyl, -NR'-C(O)-(C;-Ce )alkyl, -NR'-C(0)-O(C;-Cg)alkyl, -NR'-SO,-(C;-Cg)alkyl, -NR'-C(O)NR'R” , (C,-Cg)alkenyl, (C,-Ce)alkynyl, or (C 1-Ce)alkoxy.ae What is supplied is a compound of formula 1-18 or a pharmaceutically acceptable salt thereof: (Ry) 0 a m" N NH, 8 pe Ry N IA-1 Yiov

{ — $ \ — What is supplied is a compound of formula 18-2 or a pharmaceutically acceptable salt thereof: Ryn, HN 0 Ry, N IAN NH, NF R,0 IA- 2 Ry Cua when each occurrence is individually 11; or -C(O)-NR'R", ollazo0- 0)-(0)0- (C-Cyalkyl, (C3-Ce)cycloalkyl, + where each Rp is substituent Optional on carbon by : halo, cyano, hydroxy, trifluoromethoxy, -0C(0)-(Cy-Cg)alkyl, -NR'R”, -CO,H, -C(0)-(Cy-Ce )alkyl, -CO,(C,-Cg)alkyl, -C(O)-NR'R", -S(Ci-Ce)alkyl, -SO,(C;-Ch)alkyl, -SO, NR'R”, (C,-Cg)alkenyl, (Ca-Ce)alkynyl, or (C;-Cg)alkoxy, where R75 RY and (is as shown before. ys. What is done To provide it is a compound of formula 18-3 or a pharmaceutically acceptable salt thereof: m XT 17 0 N NS NH, having R1 — R,0 N IA-3 L

— m3 _ where: Ry and m8a are as shown before; and *be©; or 8” or 50; or ,80; or Cus NR, which is: hydrogen, (C;-Ce)alkyl, (C3-Ce)cycloalkyl, -C(O)-(Cy-Ce)alkyl, -CO4(C;-Cg)alkyl, -C(O)-NR'R", or -SO,NH(C,-Cg)alkyl, ° where R, can have an optional substitution on carbon by : halo, nitro, cyano, hydroxy, trifluoromethoxy, -OC(0)-(C; -Ce)alkyl, -NR'R”, ,22100 -COxH, -C(0)-(C1-Ce)alkyl, -CO(C,- Ce)alkyl, -C(O)-NR'R", -S(C;-Cy)alkyl, -S0p(Ci-Cealkyl, -SO,NR'R", (C,-Cg)alkenyl, (C,-Ce)alkynyl, or (C;-Cg)alkoxy, 00 where RGR and m are as shown above. What is provided is a compound of formula 1-3 or a pharmaceutically acceptable salt thereof where: Ry Ry is as shown before; and # is ©; or 8; or SO or “SO; or NR, where Re is: hydrogen, (C,-Ce)alkyl , (C3-Cg)cycloalkyl, (C-Cg)alkoxy, -OC(0)-(C;-Cg)alkyl, -C(0)-(Cy-Celalkyl, -CO»(C,-Cg) )alkyl, -C(0)-NR'R", or SO,NH(C;-Cg)alkyl, Vo where R, can have an optional substitution on the carbon by : L 1

22100, halo, nitro, cyano, hydroxy, trifluoromethoxy, -OC(0O)-(C,-Cg¢)alkyl, NR'R”, - ,11o00 C(0)-(C;-Ce)alkyl, -CO,(C;-Ce)alkyl, -C(O)-NR'R”, S(C;-Cy),

SO,(Ci-Ce)alkyl, SO,NH(C;-Ce)alkyl, SO,NR'R”, (C,-Cs)alkenyl, (C,-Ce)alkynyl, or (C-Ce)alkoxy As shown before .py RPGR where © The values defined for variable sets are as follows. Such values may be used wherever they fit into any of the definitions; or safeguards; Or the forms shown in this application above or below

JA is a compound of the formula

IB is a compound with the formula > © atoms; where 1 has from © to “nitrogen — form a heterocycle; Nitrogen related that if said heterocycle contains slit -111-; where: (Rs can optionally be substituted by a selection of : be selected from Rs and (Ci-Cealkyl, (C53-Cg)cycloalkyl, -C(0)-(Cy-Cg)alkyl and -CO,(C,-Cg)alkyl; Vo : have an optional substitution on the carbon with one or more Sas Ry cyano, hydroxy, -OC(0)-(C;-Ce)alkyl, -NR' R”, (C3-Cg)cycloalkyl or (C;-Cg)alkoxy;

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: Cus + (C1-Collalkyl and “107” are separately at each occurrence of R (> piperazin-1-yl, piperidin-1-yl, morpholino, homopiperazin-1-yl and) and are the aforementioned substituents piperazin-1-yl or homopiperazin-1-yl is Cua pyrrolidin-1-yl; where: (Rs by selection of selective nitrogen over 0 : be selected from Rs methyl, ethyl, isopropyl, cyclopropyl, acetyl, propionyl and #-butoxycarbonyl; : have an optional substitution on the carbon by one or more Rs that can be each; where: cyano, hydroxy, acetoxy, -NR'R”, cyclopropyl or methoxy .methyl and 87 Ry.© forms : 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)piperazine-1-yl, N-(2-methoxyethyl)piperazine-1-yl,

N-(2-cyanoethyl)piperazine-1-yl, N-(2-hydroxyethyl)piperazine-1-yl, Vo

N-(cyclopropylmethyl)piperazine-1-yl, N-(cyclopropyl)piperazine-1-yl,

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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. ° be -.N-methylpiperazin-1-yl R; be hydroxy . R, is at JS the occurrence of hydroxy " or "-NR'R" or 0x0 ; Where 8 and 1287 are each separately at each occurrence of OOLADRU-R). 0 : 8 is at JS the occurrence of <NR'R “Jf ” hydroxy or 0x0 . 11 is zero or A “ is zero. “be .1” be zero or 1; Ris is hydroxy . 0 " is zero or 0 and b is hydroxy " or 1807 or 0x0 . R, is hydrogen ; or halo” or (C-Celalkoxy ¢) where R; has an optional substitution on the carbon with one or SSI of (Cr-Colalkoxy . L 1

- 1 =

R, is hydrogen “that halo” or (Cr-Clalkoxy ; where Ry is an optionally substituted

on carbon by one or more of its ? (aldo-0:0) hydroxy 4d .

(C1-C)alkoxy “halo” i.e. “hydrogen” and be

be hydrogen, fluoro, methoxy, ethoxy or isopropoxy; Where they have an arbitrary substitution on the carbon with one or more methoxy.

ya [to be:

hydrogen, fluoro, methoxy, ethoxy, 2-(methoxy)ethoxy, 2-hydroxyethoxy or isopropoxy.

hydrogen, fluoro, methoxy, ethoxy or isopropoxy. M be

: Ry hydrogen, fluoro, methoxy, ethoxy, 2-(methoxy)ethoxy, 2-hydroxyethoxy or 1SOpropoxy. 0 0

Dhaka is hydrogen.

may be fluoro.

d be methoxy .

,. ethoxy is R; . 1Sopropoxy is 82 0

It could be 2-(methoxy)ethoxy.

1 stay

Ry is 2-hydroxyethoxy Ry at each occurrence of a halo, (C1-Clalkyl or (C-Cglalkoxy) ¢ where it can be selectively substituted on the carbon by a halo . Ry is at each occurrence of fluoro, chloro, methyl, ethyl or methoxy , where © can be optionally substituted on carbon by 000:0 . Ry is at each occurrence Separately: fluoro, chloro, methyl, trifluoromethyl, ethyl, methoxy or trifluoromethoxy. “Be from 1 to “; where the values of y) can be the same or different. 8 be 1. 0 “Be Where Ry values can be the same or different. Kim , where Ry values can be the same or different. Phenyl s (Ram) has two conjugates: -2,4-difluorophenyl, 2-fluoro-3-chlorophenyl or 2-fluoro-4-methylphenyl.Ry is hydrogen or fluoro.Vo if hydrogen.Ry is fluoro.shiny

{Therefore, in another aspect of the present invention; Provide a compound of formula IB (IA or LS) shown by) where: > is a heterocyclic; bonded to nitrogen; has ∼ to 1 atoms; where as if the heterocyclic These contain the -NH- moiety. The nitrogen can be optionally replaced by a selection of the R) hydroxy moieties; 11 be zero or \ s be hydrogen ¢ i.e. (C1-Ce)alkoxy sl « halo ; Ry at each occurrence is separately chalo, (Cj-Ce)alkyl or (C)-Celalkoxy; and ¢ where 0 can be an optionally substituted on the carbon by halo ; «« be from 1 to ; where the values of Ry can be the same or different; Ry be hydrogen or fluoro ¢ Rs are selected from: palolemo©- 0 (d0-) and yl(0-0)-(0)0- (C3-Cg)cycloalkyl, 0-0) where ve can have an optional substitution on the carbon with one or more: -NR'R”, (C3-Cg)cycloalkyl or (C-Cg)alkoxy; pabolol0-0) -(00)0- cyano, hydroxy, ; and Yeov

R and 1087 are each separately at each occurrence of (C1-Cglalkyl ¢ or a pharmaceutically acceptable salt thereof. Therefore in another aspect of the present invention a compound of the formula IA or LS) IB is shown before) where: >(° is a heterocyclic ring; linked to - nitrogen; it has from * to VY atoms; since if the mentioned heterocyclic contains an NH- moiety, nitrogen can be substituted Optionally by a selection of s[; at each occurrence of hydroxy ¢ or “-NR'R” or 0X0 ; 11 is zero or 1 0 162 is hydrogen » or chalo or else «mkladzha-r]); Where Ry can have an optional substitution on carbon aal or more than (C1-Collalkoxy i.e. hydroxy ¢ Ry) at each occurrence of each formation on halo, (Ci-Ce)alkyl or ( Cj-Cg)alkoxy sas where Ry can be optionally substituted on carbon by halo ; “ be from 1 to ?; where Ry values can be the same or different; 1 s is hydrogen or fluoro ; Rs be selected from: Yéov

{ (C-Cealkyl, (C3-Ce)cycloalkyl, -C(0)-(C,-Ce)alkyl and -CO»(C;-Ce)alkyl; where Rs can be optionally substituted on the carbon with one or more of: -NR'R", (C3-Cg)cycloalkyl or (C;-Cg)alkoxy; chloro-0)-(00)0- cyano, hydroxy, and 87 are each on Acuity at each occurrence of (Ci-Celalkyl ¢ ee 0 is a pharmaceutically acceptable salt thereof. Therefore, in another aspect of the present invention, a compound of the formula IB (TA or LS) is provided above) where: © They are : 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, 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, Vo 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; YsoVv

{ ( be hydroxy ¢ be hydrogen, fluoro, methoxy, ethoxy or isopropoxy ¢ Ry be at each occurrence separately : fluoro, chloro, methyl, trifluoromethyl, ethyl, methoxy or trifluoromethoxy; 0 be from 1 to 6 where the values of Ry can be the same or different. Ry is hydrogen “¢ or a fluoro; or a pharmaceutically acceptable salt thereof. Therefore it is on the AT side of The present invention provides a compound of formula IB (IA or WS) described before) where: <1 is: -piperazin-1-yl, N-methylpiperazin-1-yl, N-ethylpiperazin -1-yl, N-isopropyl piperazin-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, Vo ‎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, Y¢ov

Yo — - 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; R, when each occurrence of “hydroxy and non-3 0x0 ¢ 0” is zero or 1; x[ is: hydrogen, fluoro, methoxy, ethoxy, 2-(methoxy)ethoxy, 2-hydroxyethoxy or 1SOpropoxy; trifluoromethoxy; 01 « is from 1 to ; Where Ry values can be the same or different. Ry is 0 hydrogen or 0:000 ; or a pharmaceutically acceptable salt thereof. In another aspect of the invention; The preferred compounds of the invention are one of the examples or 1 pharmaceutically acceptable salt thereof. L 1

In another aspect of the invention; The preferred compounds of the invention are one of the examples (EA) SY) (OY) i.e. (V1) S010) (A) SAY) (Ye) VIA or ) 1 or acceptable salt Because of it. Provided Lad is a compound being one example. M. Also supplied is a pharmaceutical composition comprising a compound of formula TA or IB or a pharmaceutically acceptable salt thereof; with a pharmaceutically acceptable carrier or diluent. What is supplied Lad is a compound of formula TA or (IB or Pharmaceutical Acceptable Salt ie for use as a drug. What is provided Gad is the use of a compound of formula IA or 8]; or Pharmaceutical Acceptable Salt ie in the manufacture of Jie for use in obtaining on an inhibitory effect of the CSF-1R kinase enzyme in a warm-blooded animal such as: human. on an anti-cancer effect in a warm-blooded animal” such as: human What is also provided is the use of a compound of formula IA or IB or a pharmaceutically acceptable salt thereof in the manufacture of a drug for use in the treatment of melanoma papillary thyroid tumors, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, types of leukemia, and malignant lymphomas. Lymphoid malignancies ¢, types of cancer, and sarcomas in the liver, bladder, and prostate agglutinin 1

! xy - prostate ¢ and breast; Pancreas 0200:6868 and Primary Solid Tumors; primary and recurrent solid tumors of the skin and colon; the thyroid gland; And lungs ¢ and ovaries ovaries.

What is provided Lad is the use of a compound having dye IA or JIB a pharmaceutically acceptable salt aie in the bladder, bladder ¢ ovaries and ovaries ¢ breast gi Manufacture of a drug for use in the treatment of oo “lung and reindeer tumors prostate; endometrial prostate; cervical and haematological endometriosis; malignant tumors related to the blood, pancreas, scrotum, kidneys, leukemia, myelodysplastic syndrome, including myelodysplastic syndrome; and chronic myelogenous leukemia

chronic myelogenous leukemia 0; and lymphoma of a disease other than Hodgkin's disease, lymphoma 0:5 ag 1100 non; Hodgkin's disease, multiple myeloma, chronic lymphocytic leukemia, and glioma; squamous cell carcinoma of the esophagus; and malignant uveal melanoma

uveal melanoma ve; And follicular lymphoma. What is provided Lad is the use of a compound of formula E1 or 18 or a pharmaceutically acceptable salt thereof; in the manufacture of a drug for use

In the manufacture of a drug for use in the treatment of mor ‎Lay associated osteolysis, osteoporosis including ovarian ovariectomy induced bone loss ¢ and orthopedic implant failure

orthopedic implant failure 0 ¢ and autoimmune disorders including systemic lupus erythematosus ¢ and arthritis including

Yi{oV

[

YA - rheumatoid arthritis ¢ and osteoarthritis; inflammation of the kidneys, glomerulonephritis, and inflammatory bowel disease; rejection of transplants, including renal and bone marrow allografts; And the graft ° xenograft specific to the skin, skin xenograft, atherosclerosis, obesity, Alzheimer's disease, proliferation of langerhans cells. cell histiocytosis in ie UN ana or acceptable salt IB is the use of a compound with formula 18 or La What is provided Manufacturing a drug for use in the manufacture of a drug for use in the treatment of chronic obstructive pulmonary disease obstructive pulmonary 01568868 0 Ansmat” and diabetes; Chronic skin disorders, including psoriasis. What is provided Load is a method to obtain an inhibitory effect of the enzyme 087-118 kinase in a warm-blooded animal such as: human; is in need of treatment comprising administration of said animal an effective amount of a compound of the formula TA or IB or a pharmaceutically acceptable salt thereof. Those with lad blood, such as: humans, are in need of treatment that includes giving the aforementioned animal an effective amount of a compound of the formula TA or dB, or a pharmaceutically acceptable salt thereof. What is provided Lind is a method for treating melanoma melanoma, papillary thyroid tumors, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, and types of leukemia.

A - leukemia ¢ and malignant lymphomas, lymphoid malignancies, and types of cancer and sarcomas in the liver and bladder; the prostate, the breast, and the pancreas; primary solid tumors; and frequent occurrence of primary and crecurrent solid tumors of the skin and colon; 077010, thyroid gland, lungs, lungs, and ovaries in a warm-blooded animal - such as a human - in need of treatment that includes giving the said animal an effective amount of a compound of formula 18 or IB or a pharmaceutically acceptable salt Ade what is provided Lad is a method for treating tumors of the breast gal ¢ and ovaries ; Bladder bladder, cervical cervix, endometrial lining, prostate, lung Jung, and kidneys; pancreas ¢ and malignant blood-related tumors die oie haematological malignancies myelodysplastic syndrome syndrome and acute myelogenous leukemia s and chronic myelogenous leukemia Lind chronic myelogenous leukemia » and private lymphoma non Hodgkin's lymphoma » and Hodgkin's disease 00:5 a.m. 1100 Vo, multiple myeloma and chronic lymphocytic leukemia; glioma ¢ and squamous cell carcinoma of the esophagus; And malignant uveal melanoma – malignant uveal melanoma – and follicular lymphoma “follicular lymphoma” in a warm-blooded animal - such as: a human - is in need of treatment that includes giving x. the said animal an effective amount of a compound has the formula 18 or 13; or a pharmaceutically acceptable salt thereof. L 1

Also provided is a modality for the treatment of tumor associated osteolysis, osteoporosis including ovarian ovariectomy induced bone loss; orthopedic implant failure ¢ and autoimmune disorders dc lial including systemic lupus erythematosus ¢ and arthritis including rheumatoid arthritis » and osteoarthritis 05 » and inflammation renal inflammation » and glomerulonephritis; inflammatory bowel disease; rejection of transplants, including renal and bone marrow allografts; and yo graft yo Lind skin xenograft ¢ and atherosclerosis ¢ and obesity ; And Alzheimer's disease is the proliferation of Langerhans cell histiocytosis ¢ in a warm-blooded animal - such as a human - in need of treatment that includes giving the aforementioned animal an effective amount of a compound of formula IA or 18 or a pharmaceutically acceptable salt thereof. ho What is provided Ua is a method for the treatment of chronic obstructive pulmonary disease 20170735 and diabetes mellitus; Chronic skin disorders, including psoriasis, in a warm-blooded animal - such as a human - in need of treatment include giving the aforementioned animal an effective amount of a compound of the formula TA or IB. or a pharmaceutically acceptable salt thereof. glossy a

Also supplied is a pharmaceutical composition comprising a compound of formula 18 or IB a pharmaceutically acceptable salt se with a pharmaceutically acceptable diluent or carrier for use in achieving an inhibitory effect of kinase 081-118 in a blood animal Warm is like: human. Also supplied is a pharmaceutical composition comprising a compound of formula IA or dB or a pharmaceutically acceptable salt die with a pharmaceutically acceptable diluent or carrier for use in obtaining an anticancer effect in a warm-blooded animal. Ex: human. Also provided is a pharmaceutical formulation comprising a compound of formula Bf TA a pharmaceutically acceptable salt thereof; With a pharmaceutically acceptable diluent or carrier for use in the treatment of melanoma, papillary thyroid tumors, cholangiocarcinomas, and colon cancer; Ovarian cancer, boil ge lung cancer, leukemia, lymphoid malignancies, types of cancer and sarcomas in the liver, bladder and prostate. prostate; breast, pancreas, primary and recurrent solid tumors of the skin, csolid tumors of the skin, colon, thyroid, lungs and ovaries In a warm-blooded animal, such as a human. Provided Lin is a pharmaceutical formulation comprising a compound of formula 18 or 18 or a pharmaceutically acceptable die salt with a pharmaceutically acceptable diluent or carrier for use in the treatment of breast ¢ and ovarian tumors; the bladder; and cervical cervical; and the endometrial lining 00 ¢ and the prostate 0 prostate and the lung Jung and the kidneys kidney; And the pancreas ¢ Yéov

ARS - and haematological malignancies including myelodysplastic syndrome, acute myelogenous leukemia, chronic myelogenous leukemia, and lymphoma of non-Hodgkin's disease. Hodgkin's lymphoma and Hodgkin's disease 0; multiple melanoma; chronic lymphocytic leukemia; glioma ¢ and squamous cell carcinoma of the esophagus and malignant uveal melanoma; And follicular lymphoma »in a warm-blooded animal such as: human. Also provided is a pharmaceutical formulation comprising a compound of formula 18, IB, or a pharmaceutically acceptable die salt with a pharmaceutically acceptable diluent or carrier for use in the treatment of tumor associated osteolysis, osteoporosis including JL afi ovarian ovariectomy induced bone loss ¢ orthopedic implant failure ¢ and autoimmune disorders \o including systemic lupus erythematosus ¢ arthritis including rheumatoid arthritis, osteoarthritis, nephritis + and glomerulonephritis; inflammatory bowel disease; rejection of transplants, including renal and bone marrow allografts 0; skin xenograft, atherosclerosis, obesity + Alzheimer's disease 21226100675; recurrences

1 lam

_b_— langerhans cell histiocytosis; In a warm-blooded animal, such as a human. Also supplied is a pharmaceutical composition comprising a compound of formula TA or IB or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable diluent or carrier for use in the treatment of chronic obstructive pulmonary disease. Diabetes and chronic skin disorders, including psoriasis, in a warm-blooded animal, such as a human. What is also provided is a process for preparing a compound of formula E1 or (IB) or salt pharmaceutically acceptable cia as shown in diagrams (1) and (1); shown Lad follows. 1 carbon or a monovalent saturated, branched hydrocarbon moiety, unless otherwise stated; from ? to + carbon atoms” such as methyl, ethyl, propyl, 2-propyl, pentyl, and the like. And references to alkyl groups Odd like propyl is for straight chain only and the 1 signs for odd branched chain alkyl groups like isopropyl' are for branched chain only. For example 1-6 La ¢ alkyl C in that: -methyl, propyl , isopropyl and t-butyl and the term “halo” refers to bromo chloro fluoro and 1000.

Y $ — _ means alkenyl! straight monovalent hydrocarbon radical unless otherwise stated; of TY carbon atoms or a branched monovalent hydrocarbon moiety unless otherwise stated; Consists of ? to 7 carbon atoms »; contain at least one double bond; For example ethenyl Ls propenyl s the like. It is an analogue of phenyl allys » alkenyl Cy and -1-propenyl meaning 'alkynyl' ' ' alkyl ¢ group as defined before; having one or more carbon-carbon triple bonds; such as ethynyl Examples of alkynyl Cog are: ethynyl, 1-propynyl and -2-propynyl means cycloalkyl! is a saturated monovalent cyclohydrocarbon moiety from ? to + carbon atoms except when mentioning other than eld for example cyclohexyl s “cyclopropyl” etc. and from Lhd cyclohexyl s cyclopropyl “cycloalkyl C3-C¢ 1.” Aryl! means a monocyclic, divalent, dicyclic aromatic or fully unsaturated hydrocarbon moiety of + to 10 cyclic carbon atoms. “Heterocyclic” or “heterocyclic” means a partially unsaturated or saturated cyclic moiety of Y A) one led cyclic atoms or ? of the cyclic atoms are unsaturated atoms Homogeneous is yo chosen from NR, where Ra is prefixed 0, 8, 80, or 50 which can be carbon-bonded or nitrogen-bonded unless otherwise stated. aryl' means heterocyclic. Fully unsaturated monovalent monocyclic moiety and/or aromatic ring of © or 1 cyclic atoms containing 1 or ? or * heteroatoms to be chosen from JN 0 or 5 ; where the remaining loop is ©; which could be carbon R nitrogen L 1

vo —_ — related unless otherwise specified. The term aryl' heterocyclic includes, but is not limited to: pyridyl, pyrrolyl, thienyl, pyrazolyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl and derivatives thereof. Partially saturated or unsaturated of a mono- or double carbon ring containing a © - VY atom; where the group CH, optionally can be replaced by C(O)Je to be precise; then 'carbocyclyl' is a monocyclic ring containing 0 or + atoms or a binary ring containing ? or 01 atoms. A suitable value for dala b “carbocyclyl” is: cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, 01 cyclohexenyl, phenyl, naphthyl, tetralinyl, indany! or 1-oxoindanyl.

and the specific example of phenyl sa carbocyclyl . Two Ry groups on adjacent carbon atoms can form an aromatic, saturated, partially saturated and/or unsaturated ring containing 0, 1, or ? Of the heteroatoms in which 1 is selected from 8, O or M188 Cum M18 is absent; The 11 or (alkyl Cig) ring forms a double ring with the phenyl bonded to it. For the avoidance of doubt, a ring consisting of * or 1 atoms has 7 lati pall phenyl ring in it. A suitable example of the two groups of Rs is the neighboring carbon atoms forming © or + atoms of the ring with the phenyl attached to it where

Include :

naphthyl, indol-6-yl, isoindole-5-yl, benzofuran-4-yl, quinolin-8-yl and 1H-indazol-7-yl. and 18" are taken together with their attached nitrogen To form an Ade or partially saturated ring of =F6 atoms containing zero or 1 additional hetero-atom is Loa bos) of NR, ". Examples and suitable values for this ring are: azetidin-1-yl, piperidin-1-yl, piperazin-1-yl, N-methylpiperazin-1-yl and pyrrolidin-1-yl. © 3) is a heterocyclic or aryl heterocyclic consisting of 10 - Fe atoms; bonded to nitrogen and said ring can be monomeric, binary and/or transitive. Examples of suitable values for this ring are those for include : azetidin-1-yl, morpholino, piperidin-1-yl, piperazin-1-yl, pyrrolidin-1-yl, thiomorpholino, homopiperazin-1-yl, pyrrol-1-yl, pyrazol-1 yl, imidazole-1-yl and 01 triazol-1-yl. Some additional examples in which g includes a double ring of : hexahydropyrrolo{1,2-a|pyrazin-2(1H)-yl and 3 -methyl-5,6-dihydroimidazo[1,2- alpyrazin-7(8 H)-yl.

specifically le 5.2 5-diazabicyclo[2.2.1Thept-2-yl; Consisting of ? - “HA bonded to nitrogen ¢ or heterocyclic or aryl heterocyclic. Examples of C1-6 "alkoxy" are those that include methoxy, ethoxy, and isopropoxy. An example is “-OC(0) (C;-Cealkyl is acetoxy . and -0011 is carboxy . and from itd© m0m©-©)-(0)©- alkyl includes propionyl acetyls. Examples of R' Cus -C(0)-NR'R” and 87 are as specified above and include carbamoyl, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl and N-phenyl-N-ethylcarbamoyl and i hd -COy(C-Cg) those comprising: 0 methoxycarbonyl, ethoxycarbonyl, 7- and f-butoxycarbonyl Examples of -NR'R are those with 0 RGR as defined above and include They contain: amino, methylamino, ethylamino, dimethylamino, diisopropylamino and N-ethyl-N-phenylamino. Among the alkyl -NR-C(0)-(C-Ce) molecules, where: 8 is as follows specified before and include formamido, acetamide, propionylamino and N-acetyl-N-phenylamino and examples of alkyl -NR'-C(0)-0O(C1-Cq) | where 82 is as defined before is methoxycarbonylamino and N-(f-butoxycarbonyl)-N-phenylamino . i hd “NR'-C(O)NR’R™ wherein 18 R75” is as specified above; and includes on : glossy 1 ureido, NV, 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. They are as specified above and include R where “alkyl -NR’-80,-(C1-Co) and from examples of . mesylamino, N-ethylsulphonyl-N-phenylamino and isopropylsulphonylamino 0 : as specified above and to include GR" RGus -SO,-NR'R examples sulphamoyl, N-(methyl)sulphamoyl, N-(isopropyl) sulphamoyl,

N,N-(dimethyl)sulphamoyl and N-(methyl)-N-(phenyl)sulphamoyl. Examples: as specified before and include pled which is alkyl (m©-,0)-m50- sR 5p led which is -SONR'R and examples are mesyl, ethylsulphinyl and isopropylsulphonyl 0 : shall be as specified above and shall include 7 amino(oxido)sulfanyl, sulphamoyl, N-(methyl)sulphamoyl, N-(isopropyl)sulphamoyl,

N-(isopropyl)amino(oxido)sulfanyl, N,N-(dimethyl)sulphamoyl and

N-(methyl)-N-(phenyl)sulphamoyl. : It includes “S(0),(Cr-Colalkyl” from vo acids that include S-(C)-Cealkyl and examples are mesyl, ethylsulphonyl and isopropylsulphonyl, where p is “( C-Co)alkylS(0),- examples of -methylthio, ethylthio and isopropylthio: include Y to 0 from Yéov

v q — — methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl + and halo(C)-Ce)alkyl Aid that includes: trifluoromethyl, 1-chloropropyl and 3-bromo-3-methylbutyl Examples: O-(C3-Ce)eycloalkyl, those containing cyclopropyloxy and cyclohexyloxy. Examples of -0(00)-”11887 include: carbamoyloxy, methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy and N-phenyl-N-ethylcarbamoyloxy. An appropriate pharmaceutically acceptable salt of the compound of the present invention is for example an acidic salt An addition of the compound of the present invention is sufficiently basic, for example as a salt, adding 0 acidic, for example, with an organic or non-Jaan (Spas, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, citric or maleic acid. alkaline earth metal salt ¢ e.g. calcium \o salt i.e. magnesium » or ammonium salt or salt with an organic base providing an acceptable cation Lage ud on Ju Like salt with methylamine "i.e. de dimethylamine trimethylamine ¢ or piperidine; or morpholine or tris (2 hydroxyethyl)amine Some compounds of formula 1A or of formula IB can have chiral centers Geometric isomeric centers and or geometric isomeric centers (Zs E isomeric luminaries 1)

= .$$ — It can be understood that the present invention includes all the diastercoisomers 4a 53 yall or geometric isomers having kinase inhibitory activity 087-118. The present invention also relates to any or all tautomeric isomers of compounds of formula 18 or 18 that have stretching activity for the -CSF-1R kinase enzyme.

0 It is also evident that certain compounds of formula TA or formula IB can exist in soluble as well as insoluble forms eg in aqueous forms. It is also understood that the present invention includes all solutes that have CSF-1R kinase inhibitory activity. The AT aspect of the present invention provides a process for preparing a compound of formula IA, 13, or

- a pharmaceutically acceptable salt Logie, in which process A) in which the different group is as defined in Formulas E or IB unless otherwise stated) includes: Process A) a complex reaction of Formula IIA or 118 : Ry), (Ry) Rm L , HN 0 *' WH Pr + R, L ~N NH, NH, = ~ L N R, N IIB IIA when L is is a displaced atom or group; With a compound of formula TIT l

_ \ — (R, hn

NH

178 : 11 or IVA or process b) a complex reaction with the formula

R,

R, L © and ( LQ R,

N A NH, ~ NH, _ — e N N

R, N

IVA IVB

TV, where a is a displaced atom or group; with a compound of the formula

Ry),

HN. 7

VIB or VIA process c) a complex reaction with the formula

Ryn 0 (Ry),

R, R, 3

R)), € HN they i

R

N ~X OH 2 ~ OH = R N NT

R, N Ro

VIA VIB

¢ ammonia or active derivative terminated with :17113 or VIIA or process d) complex reaction of formula 0

Yeov

Crown Crown R, for R (R), £ ' HN 0 : HN 0 : 2 2 N > 0 _R > 0 N NT Crown = R, N VIIA VIIB where 1 being 01-06 alkyl ¢ and specifically formamideas ¢ ethyl 3 methyl and base; or process e) decomposition of a compound of formula VIIA or 171118: Ry) b Rm a } Bey 8 4 (R, In HN R, > CN N > CN — Ry dn N N b R, N VIIA VIIIB I) and then, if necessary: ((convert a compound of formula TA or 13 to another of formula IA or AB") removing any groups protect;") Pharmaceutical acceptable salt composition. a is a displacement group; And the appropriate values for Jaa BL on bromo chloro tosyls trifluoromethylsulphonyloxys 0 . The specific reaction conditions for the above interactions are as follows: Yéov

y _ $ _ process a) compounds of formula TA or 118 can be reacted with compounds of formula [11] through coupling chemistry using an appropriate catalyst and BINAP 5 Pdy(dba) bond group; Jie, respectively, and a suitable base of sodium tert-butoxide Jie or caesium carbonate. The reaction usually requires thermal conditions between A and 100 °C. ° Compounds of formula ITA Laka la can be prepared under the conditions shown in Scheme 1: CO,Et R, 20 00 R, 0 0 Rmo 510 R, 0 tm L OL 250°C L 08 CH,CN | PhO R, NH, R, N R, N l1Aa NAc POCI,, IIAd®R,), Toluene, A POC, ° nl Re R, ca o Conditions of HN 0 Conditions of 3 A Process d) L Xn OE: Process b) L > OF: v 27 and 7 R, N R, N HAf Hae Scheme 1 and compounds of formula 118 (Sa) prepared by modifying Scheme 1. Compounds of formula TAD 5 TA and 111 are commercially available compounds, compounds in the art, or can be readily prepared by processes known to those skilled in the art Process b) Compounds of formula IVA or 1713 can be reacted with compounds of formula (AV Die solvent, dimethylformamide ethanol Ve ¢, usually in thermal conditions usually ranging from Ve ° C to 100 ° C; in some cases it is catalyzed by the addition of acetic acid.

— $ $ _— instead; compounds of formula IVA or 1713 can be reacted with compounds of formula Vo using coupling chemistry and using the appropriate catalyst and binder group such as BINAP 5 Pdy(dba); respectively; The appropriate base is sodium tert-butoxide (ie caesium carbonate). The reaction usually requires thermal conditions ranging from 880 ° C to 0 100 ° C. Compounds of formula 17/8 TVB can be prepared by modifying the scheme. 1. The compounds of formula V are commercially available, or they can be compounds mentioned in books related to this field, or they can be prepared easily through processes known to those skilled in this field. They are coupled to each other in the presence of a suitable coupling agent 0. Suitable peptide couplings recognized in the art can be employed as suitable coupling agents, eg, dicyclohexyl-5 “carbonyldiimidazole carbodiimide” and optionally in the presence of a catalyst such as : dimethylaminopyridine or 4-pyrrolidinopyridine; optionally in the presence of a base eg triethylamine » or : \o -2,6-01-161 has triethylamine, pyridine, or 2,6-di-alkyl-pyridines such as 2,6-lutidine butylpyridine. Suitable solvents include: dimethylacetamide, dichloromethane, benzene, tetrahydrofuran and dimethylformamide.

— Mg ¢ — Suitable coupling reactions can be suitably prepared in the temperature range of — Ev °C to 560 °C. Suitable active acid derivatives include acid halides, eg acid chlorides, active s esters; Such as pentafluorophenyl esters. interactions of these types

M compounds with amines are well known in this field; For example they can interact in the presence of a base; such as those mentioned before; in a suitable solvent; Like that mentioned before. The reaction can also be carried out suitably in the temperature range of -460 to 500°C. Compounds of formula VIA or VIB can be prepared by modifying Scheme 1 eg by adding a hydrolysis step and the procedure specified in Process a).

formamide or 8 can be reacted with each other with formula VIIA esters process d) 0 first then followed by formamide and base. Preferably, this reaction should occur sequentially; Where “ethoxide 5 methoxide” for example “alkoxide” is added as a base. The appropriate bases are 100 degree bases. The reaction is typically carried out at a temperature of . sodium methoxide Jie or 7118 can be prepared from VIIA and compounds of formula DMF C in a suitable solvent such as

1. During the modification of Scheme 1 process e) Compounds of formula 71118 or 71118 can be hydrolyzed under suitable acidic or basic conditions.

lah l

— $7 - It should be understood that some of the different cyclic substituent groups in the compounds of the present invention may be introduced through standard aromatic substitution reactions or generated through modifications of the appropriate functional groups either before or immediately after the process mentioned before. including the process aspect of the present invention. Such reactions and modifications include, for example, the introduction of a substituent group and the oxidation of substituent groups. The agents and reaction conditions of these procedures are well known to those skilled in the field of chemistry. Specific examples of aromatic substitution reactions are those involving the placement of a nitro group using concentrated nitric acid; rendering acyl de same using, for example, acyl halide and Lewis acid (as aluminum trichloride) in Friedel Crafts conditions; rendering of an alkyl group using alkyl halide 0 and aluminum trichloride (Jie (Lewis acid) in a Friedel Crafts envelope; rendering of a halo group. Specific examples are those of modifications involving reduction of a nitro group to a group Amino for example hydrogenation catalyst with a nickel catalyst or iron treatment in the presence of hydrochloric acid with heating and oxidation of alkylthio to alkylsulphinyl i.e. alkylsulphonyl oe vo realizing that some reactions Listed herein may be necessary/required to protect any sensitive groups in vehicles.Examples for which protection is necessary or required and appropriate methods of protection are well known to those skilled in the art.Conventional protection groups may be used according to standard procedure (for an explanation see T.W.

Green, Protective (Groups in Organic Synthesis, John Wiley and Sons, 1991) and then if 0 reactants contain this amino », carboxy or hydroxy 438 it may be required Protection of the group in some of the interactions mentioned here

sy - The appropriate protecting group of an amino or amino alkyl group would be for example an “acyl group eg acetyl Jie ¢ alkanoyl group; or “alkoxycarbonyl group eg: methoxycarbonyl” or ethoxycarbonyl or I-butoxycarbonyl “or arylmethoxycarbonyl m ¢ eg benzyloxycarbonyl Jia) or aroyl ¢ group on methyl benzoyl . The specific protection removal conditions cle sana the previous protection which must be varied with the protection group options. Hence for example an acyl group such as an alkanoyl or an alkoxycarbonyl or an aroyl group may be removed for example by hydrolysis with a suitable base metal hydroxy Jie 558" for example lithium or sodium hydroxide 0 Instead, an acyl group such as -butoxycarbonyl group can be removed, for example, by treatment with a suitable acid such as: hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl benzyloxycarbonyl (Jie). They can be removed for example by hydrogenation 1 on a palladium Jie catalyst on carbon, or by treatment with Lewis acid eg boron tris(trifluoroacetate). The basic amino, for example, is a phthaloyl group, which can be removed by treatment with an alkylamine «for example, dimethylaminopropylamine» i.e. -hydrazine, and from the appropriate protective groups of the hydroxy ¢ group, for example, the group « acyl 0 eg acetyl Jie alkanoyl group and aroyl group ; for example benzoyl or the aryl methyl group; For example benzyl . Circumstances of special removal of protection z ‎Yéov

With the previous protection group it is necessary to vary with the choice of protection group. lg for example; The alkanoyl Jie acyl or aroyl group can be removed for example by hydrolysis using a suitable base alkali metal hydroxide Jie© such as lithium sodium hydroxide. Alternatively an arylmethyl group such as a benzoyl group 0 can be removed for example through hydrolysis with sodium hydroxide base Jie¢ or for example a group of ; Butyl which can be removed for example through treatment aang such as trifluoroacetic organic acid Jie or for example a benzyl group can be removed for example through hydrogenation on a palladium Jw catalyst on carbon. The protective groups can be removed at any suitable stage in the synthesis using appropriate Vo techniques known in the field of chemistry. Some of the specific intermediates mentioned herein are novel and are therefore provided as an additional property of the present invention. for example; The compounds of Formula VIIA and 7115 are provided as an additional property of the present invention: The following are: A HN and N WOT CG VIIB VIIA ve While variable groups are defined as described above. And

—_— 4 $ _- Similarly, the compounds of the formula VIA and VIB are provided as an additional property of the present invention: Lee and Leake R 8 r h r, * HN 1 b la 6 m 000 N 2 > OH OH ~ B N ( 6 .8 ) R, N VIA VIB © while the variable groups are as specified before.

For example, new compounds of the formula TTA R115 5 17 VIB VIIA IVB have other additional properties of the present invention.

As mentioned before; The compounds identified in the present invention have anticancer activity that is believed to emerge from the compounds' CSF-IR enzyme inhibitory activity. maybe

. Evaluate these properties ¢ using the procedure described below ye

In vitro alphascreen biological experiments for testing 0517 -- IR

The activity of purified 057-118 was determined in the laboratory using the test:

1 lam

- oe «(Perkin Elmer) (ALPHA) Amplified Luminescent Proximity Homogeneous Assay by alla poly-glutamine-tyrosine peptide 5 «CSF - 1R which measures the phosphorylation of the kinase as mentioned below. Biotinylated coenzyme domain (Pey — HTRF CisBio 6 1GTOBLD)

Gene Bank ID “AVY — 074 amino acids (i.e., CSF — 1 R —J His with ISPM 19-1” lines from Yo (see page NM005211 labeled with SF + Express (_for sequences)) purified from insect cells (115 00 cells/mL); issued in French and for which a chromatogram was made (baculovirus 3 011 014

Superdex 200 SEC and Qiagen Ni-NTA columns, Superflow Mono Q HR 10/10 from PH. The typical yield was YEO μg/mL of cell pellet at more than 7 426 purity. 0 Phosphorylation of ACSF-IR and the presence and absence of the compound of interest were determined. Brief 1.517 nm of “CSF — IR© 5 nmolar of pEY and the compound were initially incubated in 1 x buffer for Te min at YO °C. The reactions were started by adding 900 μM of adenosine triphosphate (ATP) in XV buffer and incubated at Yo °C for 0 min and stopped by adding ∼μL of the detection mixture consisting of VF do Vo M of NaCl » and 0.11 mM of ethylenediamine tetraacetic acid ¢ 1.10 mg/mL of 500 µg/mL (BSA; Perkin Elmer donor) Streptavidin 6760002 (£4 μg [mL] pellets of 100 Perkin Elmer receptor (pTyr 0?..) plates were incubated at YO °C for VA 1 hour in the dark. Phosphorylated treated material was detected with a reader (Perkin Elmer) EnVision dishes with a YL stimulus of 1 nm TAL and an emission of 171 - 571 nm A plot was made from the data and a calculation was made using the Excel Fit (Microsoft) suite, 10 d.

— \ m and when tested in the previous laboratory experiment; The compounds of the present invention exhibited a Ji activity of 00 micromolar. For example, the following results were obtained: In 1 Pharmaceutical formulations In accordance with the aT aspect of the present invention, a pharmaceutical composition comprising a compound of formula HA or 158 or a pharmaceutically acceptable salt thereof as specified herein is provided in connection with the diluent diluent or a pharmaceutically acceptable carrier. The formulation may be in a form suitable for oral administration; for example as tablets or capsules; For external injection (including intravenous ¢, subcutaneous 00, into muscle, intramuscular, intravascular, or by infusion as a sterile solution ¢, suspension, or emulsion “for external administration as an ointment or cream, or for rectal administration as a suppository – in general, the above formulations can be prepared in the traditional way using conventional excipients. 10 _ The compound of formula TA or 18 can be administered normally By administration to a warm-blooded animal or a dose unit of 101.1.—1 mg/kg ¢ that is naturally provided by Yéiov

Y — m therapeutically effective dose. Preferably, the daily dose ranges from 100-100 mg / kg. However, the daily dose will need to be varied based on the host to be administered, the specific route of administration, and the severity of the disease to be treated. Accordingly, the optimal dose is determined by the practitioner treating a particular patient. ° Uses According to a specific aspect of the invention no compound of formula 1A or 18 or a pharmaceutically acceptable salt terminated as specified above is provided; To be used in a specific way to treat a person or an animal. We have discovered that the compounds identified in the present invention or the pharmaceutically accepted supplement terminated are potent anti-cancer agents and their related properties are expected to emerge from the properties of 0 inhibition of the enzyme CSF - IR kinase and accordingly; The compounds of the present invention are expected to be useful in the treatment of diseases or medical conditions mediated by the CSF-IR enzyme alone or Wa, which compounds could be useful for producing an inhibitory effect of the CSF-IR kinase in organisms. Warm-blooded need this treatment. Therefore, the compounds included in the present invention provide a special way to treat cancer characterized by 1 inhibition of the CSF-IR kinase, meaning that the compounds can be used to produce an anti-cancer effect that mediates alone or partially in the inhibition of the CSF IR KINASE enzyme. Such a compound of the present invention is expected to possess many anticancer properties such as different expression of 68718 and/or 6871 observed in several human cancers and derived cell lines; Ly in that Yéov

— Sjren

For example, but not limited to, breast, ovarian, endometrial, prostate, lung, kidney, and pancreas, in addition to haematological malignancies 4; sell including de stromal tumors gla, wy myelodysplastic syndrome blood el al acute acute

This is myelogenous leukemia, chronic myelogenous leukemia, “non Hodgkin’s lymphoma,” Hodgkin’s disease, various tumors, and chronic lymphocytic leukemia. And he has

Activating mutations appeared in antigens of blood, lymphoid tissue, and lung cancer. In addition, large tumor-associated cells were associated with poorer prognosis

0 Multiple types of tumors including but not limited to breast, endometrial, kidney, kidney, lung, lung, bladder, cervical cancers, glioma, and LAN cancer Squamous cell carcinoma of the esophagus - malignant uveal melanoma and follicular lymphoma. It is expected to composite

1_ The present invention would have anti-cancer activity in these types of cancer by directly affecting the tumor and/or indirectly on tumor associated macrophages. And instead

than that; Some types of cancer include melanoma; papillary thyroid tumors and cholangiocarcinomas

Colon cancer, ovarian cancer, and lung cancer

lymphoid malignancies malignant lymphatic diseases ¢ leukemias blood cancers cancer 0 bladder kidney liver sarcomas cancers and sarcomas

1 am

Bladder, prostate, breast, pancreas ¢, primary and recurrent solid tumors of the skin, colon, thyroid, lung, and ovaries . In another aspect of the present invention; The compounds of formula TA and 13 may also be of value 0 in the treatment of some other conditions. These conditions include, but are not limited to, tumor-associated osteolysis, osteoporosis, including bone loss due to ovariectomy, bone transplant failure, and autoimmune disorders, including systemic lupus erythematosus. systemic lupus erythematosus + and arthritis including rheumatoid arthritis 0 ¢, alae arthritis, renal inflammation, and kidney inflammation Kidney | glomerulonephritis and inflammatory bowel disease; He refused transplantation, including transplanted parts of the kidney related to bone marrow, skin, atherosclerosis, obesity, Alzheimer's disease, 2126101678 disease, and Langerhans cell histiocytosis. Another aspect ve_ of the present invention involves the treatment of one or more of these diseases; Especially arthritis, especially rheumatoid arthritis, and osteoarthritis. These cases include, but are not limited to, chronic obstructive pulmonary disease. Diabetes and chronic skin disorders, including psoriasis. Yéov

DOH - THEREFORE AND pursuant to this aspect of the present invention a compound of formula 18 or 18 or a pharmaceutically acceptable salt thereof is provided as specified above; for use in treatment. According to another aspect of the present invention the use of a compound of Formula IA or dB or a pharmaceutically acceptable salt thereof as specified above is provided; In the manufacture of a drug to be used in the production of an inhibitory effect of the enzyme IR kinase 057 in warm-blooded human Jie organisms. In accordance with this aspect of the present invention, the use of a compound of formula 18 or 13 or a pharmaceutically acceptable salt thereof as specified earlier in the manufacture of a drug for use in producing an anti-cancer effect in warm-blooded organisms such as humans is provided. According to another aspect of the invention; Use of a compound of formula TA or 13 or an acceptable salt of 0 Pharmaceutical Assignment as previously specified is provided in the manufacture of a drug for use in the treatment of melanoma, papillary thyroid tumors, or ductal carcinoma cholangiocarcinomas or colon cancer ovarian cancer ovarian cancer or lung cancer slung cancer leukemia or malignant lymphatic diseases “lymphoid malignancies” or cancers and sarcomas in the liver liver | 0 Kidneys, bladder, prostate, breast, pancreas, primary and recurrent solid tumors of the skin, colon, and thyroid gland Lung and ovaries. According to another aspect of the invention; Use of a compound of Formula IA or 13 or a Pharmaceutical Acceptable Salt of them as specified prior to the manufacture of a drug is provided for use in the treatment of tumors of the breast Y.61, ovarian, bladder, cervix, endometrium, and prostate Yeov

Dah - lung Jung, kidney and pancreas; and haematological malignancies, including myelodysplastic syndrome, acute myeloid cancer, chronic myelogenous leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, and multiple myeloma. Myeloma, chronic lymphocytic leukemia, glioma, glioma, squamous cell carcinoma, malignant uveal melanoma, and follicular lymphoma. According to another aspect of the invention; Compound use of Formula 18, 13, or an acceptable salt is provided as specified prior to manufacture of a drug for use in the treatment of tumor-associated osteolysis and osteoporosis including bone loss. Due to oophorectomy “078:8_ Bone graft failure and autoimmune disorders including systemic lupus erythematosus 5+, arthritis including rheumatoid arthritis ¢ and osteoarthritis renal inflammation, kidney inflammation, glomerulonephritis, inflammatory bowel disease, refusal of transplantation, including kidney and bone marrow transplants, atherosclerosis, obesity Alzheimer's disease, chronic obstructive pulmonary disease, diabetes mellitus, and chronic skin disorders, including psoriasis, WA Langerhans cell histiocytosis. la jai Yéov

ov — - According to another aspect of the present invention, a special method is provided for producing an inhibitory effect of the CSF IR enzyme in warm-blooded organisms; like a human being; in need of such treatment which includes administration of said organism an effective amount of compound of formula 18 or 13 or a pharmaceutically acceptable salt terminated as specified above.

According to the AT answer of the present invention, a special method is provided to produce an anti-cancer effect in blood organisms “lad” such as humans that need this treatment, which includes giving the aforementioned animal an effective amount of a compound of the formula TA or ( IB or a pharmaceutically acceptable salt terminated as specified above.In accordance with another aspect of the invention a method is provided for producing an anti-cancer effect in organisms

0 _ the blood is all like a human being; This is needed for a treatment which includes administering said organism an effective amount of a compound of Formula 1A or IB or a pharmaceutically acceptable salt terminated as specified above. According to an additional aspect of this aspect of the present invention; A special method is provided for the treatment of melanoma, papillary thyroid tumors, cholangiocarcinomas, and colon cancer.

leukemias, blood cancers, lung cancer, ovarian cancer, ovarian cancer1, carcinomas, lymphoid malignancies, and malignant lymphatic diseases

gly prostate prostate bladder bladder kidney kidney liver sarcomas

1, pancreas ¢ and primary and recurrent tumors of the skin, colon, and adrenal glands

thyroid, kidney kidneys, and ovaries in blood organisms “Jal, like the human being who blamed 1

oA - - requires such treatment which includes administering said organism an effective amount of a compound of Formula 1A or IB or a pharmaceutically acceptable salt thereof as specified above. According to an additional aspect of this aspect of the present invention; A special method is provided for the treatment of breast, ovarian, bladder, neck, endometrium, lung 45,05 prostate, kidney, pancreas, as well as haematological malignancies including syndrome myelodysplastic syndrome ¢ and acute myelogenous leukemia and chronic myelogenous leukemia; Non Hodgkin's lymphoma ©, Hodgkin's disease, various tumors, chronic lymphocytic leukemia, glioma, and squamous cell carcinoma of the esophagus - And malignant uveal melanoma malignant uveal melanoma and follicular lymphoma in human blood Jie lal organisms that need this treatment that includes giving the aforementioned organism an adequate amount of compound formula 18 or 13 or salt Pharmacologically acceptable ones as ho specified before. lis for an additional aspect of this aspect of the present invention; A special method is provided for the treatment of tumor-associated osteolysis, osteoporosis including bone loss, Cu ovarian resection, bone transplant failure, and autoimmune disorders including lupus. systemic lupus erythematosus”; Leyarthritis, including rheumatoid arthritis L1

Duh - rheumatoid arthritis, renal inflammation, kidney inflammation, glomerulonephritis, inflammatory bowel disease; refusal of transplantation, including kidney and bone marrow transplants, atherosclerosis, obesity, Alzheimer's disease, and chronic obstructive pulmonary disease; Diabetes Diabetes and chronic skin disorders Ly chronic skin disorders Including psoriasis 481 all WIA tissue decomposition Langerhans cell histiocytosis ia In warm-blooded organisms such as humans in need of this treatment, which includes giving the aforementioned organism an amount An effect of a compound of formula TA or 13 or a pharmaceutically acceptable salt thereof as specified herein. 0 In a further aspect of the present invention a pharmaceutical composition comprising a compound of formula IA or IB or a pharmaceutically acceptable salt thereof as defined herein in combination with a pharmaceutically acceptable diluent or carrier is provided for use in producing a CSF IR inhibitory effect kinase in warm-blooded organisms such as humans. In other cals of the invention a pharmaceutical composition comprising a compound of formula 18 or oe 13 or a pharmaceutically acceptable salt terminated as specified herein is provided in combination with a pharmaceutically acceptable diluent or dela for use in producing an anticancer effect in an organism Warm-blooded human Jie. In another aspect of the invention a pharmaceutical composition comprising a compound of Formula 14 or 3 or a pharmaceutically acceptable salt terminated as specified herein is provided in combination with a pharmaceutically acceptable dilute or carrier for use in the treatment of melanoma and thyroid papillomas. colon, cholangiocarcinomas, and thyroid tumors

Yeov

20+ - cancer, ovarian cancer, lung cancer, leukemias, malignant lymphoid diseases, cancers, and sarcomas of the liver, kidneys, and bladder The prostate, breast, pancreas ¢, primary and recurrent solid tumors of the skin 0, colon, thyroid gland, lung, and ovaries in warm-blooded organisms such as Human. In another aspect of the invention a pharmaceutical composition comprising a compound of Formula 18 or IB or a pharmaceutically acceptable salt terminated as specified herein is provided in combination with a pharmaceutically acceptable diluent or carrier for use in the treatment of breast, ovarian and bladder cancer bladder | 0, neck, endometrium, prostate, lung, lung, kidney, and pancreas, in addition to haematological malignancies, including myelodysplastic syndrome; Acute myelogenous leukemia chronic myelogenous leukemia non Hodgkin's lymphoma ¢ Hodgkins disease Vo and various tumors chronic lymphocytic leukemia and glioma glioma, squamous cell carcinoma of the esophagus, malignant uveal melanoma, and follicular lymphoma in warm-blooded organisms such as humans. In the AT aspect of the invention a pharmaceutical composition is provided comprising a compound of Formula 14 or JIB 0 a pharmaceutically acceptable salt terminated as specified above in combination with an acceptable diluent of L 1

- +1

Pharmacist or carrier for use in the treatment of tumor-associated bone degeneration

osteolysis ¢ and osteoporosis La osteoporosis in that bone loss due to Jatin Ovary

JS ovarian Bone transplantation and autoimmune disorders Lo autoimmune disorders In it

disease) 453 systemic lupus erythematosus » and arthritis Sle oo that rheumatoid arthritis; and renal osteoarthritis

inflammation, kidney infection (ASH), glomerulonephritis, and

inflammatory bowel disease; Refuse cultivation, including the transplanted parts

renal, bone marrow and skin; Atherosclerosis and obesity

Alzheimer's disease 812161016375 and chronic obstructive pulmonary disease 0; Diabetes and chronic skin disorders

Including psoriasis psoriasis and tissue decomposition of 5 a cells not transduced by Langerhans cell

8 In blood creatures, lal, such as the human being.

In another aspect of the invention a pharmaceutical composition comprising a compound of Formula 18 or

3 or a pharmaceutically acceptable salt terminated as specified above to produce a kinase inhibitory effect vo 87-18 in a warm-blooded organism such as a human.

In the AT aspect of the invention a pharmaceutical composition comprising a compound of formula SIA is provided

3 or a pharmaceutically acceptable salt terminated as previously specified to produce an anti-cancer effect in

A warm-blooded being like a human.

In another aspect of the invention a pharmaceutical composition comprising a compound of Formula 18 or 13 0 or a pharmaceutically acceptable salt terminated as specified herein is provided prior to the treatment of melanomas or tumors

Yeov

~My — papillary thyroid tumors ¢ cholangiocarcinomas colon cancer ovarian cancer slung cancer leukemia or lymphoid malignant diseases malignancies ¢ or cancers and sarcomas in the liver liver, kidneys, kidney, bladder, prostate, breast, pancreas, and primary and recurrent solid tumors of the skin skin, colon, thyroid, lung, lung and ovaries. In the AT aspect of the invention a pharmaceutical composition is provided comprising a compound of formula 14 or 8 or a pharmaceutically acceptable salt terminated as specified before In combination with an acceptable diluent 0 Pharmaceutical or pregnant to be used in the treatment of breast cancer 41, ovarian, bladder, neck, endometrium, prostate, lung, lung, kidney, pancreas, in addition to blood malignant diseases haematological malignancies, including myelodysplastic syndrome, acute myelogenous leukemia, chronic myelogenous leukemia, non-Hodgkin's lymphoma, and Hodgkin's disease. disease, various tumors, chronic lymphocytic leukemia, glioma, LOAN squamous cell carcinoma of the esophagus - and sal melanoma malignant uveal melanoma and tumor Follicular lymphoma. L 1

Also, in another aspect of the invention, the use of a compound of Formula 18 or 13 or a pharmaceutically acceptable salt terminated as specified above in combination with a pharmaceutically acceptable diluent or carrier is provided for use in the treatment of tumor-associated osteolysis and osteoporosis. including bone loss due to ovarian resection, bone transplant failure, and autoimmune disorders, including systemic lupus erythematosus; Lyarthritis Including rheumatoid arthritis ¢ Renal inflammation Kidney nephritis Glomerulonephritis Bowel disease 101270712100 Transplant rejection including renal transplants 0 for bone marrow and skin; Atherosclerosis, obesity, Alzheimer's disease, chronic obstructive pulmonary disease, diabetes, and chronic skin disorders, including psoriasis and tissue degeneration. WA Langer Islands 0 Langerhans cell histiocytosis js The previously specified CSF 18 kinase inhibitory therapy can be applied as a single therapy or may be combined 1 in addition to the compound of the present invention to conventional surgery, radiotherapy or chemotherapy. Such chemotherapy includes one or more of the following classes of anticancer agents: 1- antiproliferative / antineoplastic drugs and combinations thereof; According to use in the treatment of oncology; such as alkylating agents (eg cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, 0 Yéov

“(busulphan and nitrosoureas and anti-metabolites Jie) antimetabolites antifolate cantifolates such as fluoropyrimidines such as: 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea © and antitumor antibiotics antitumor antibiotics, for example: similar anthracyclines: adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, Jal sell ) dactinomycin and mithramycin anti-cell death (for example) vinca alkaloids » such as: taxotere staxol Jie vincristine, vinblastine, vindesine and vinorelbine and taxoids 01 (') and topoisomerase inhibitors (eg Jie epipodophyllotoxins: (etoposide and teniposide, amsacrine, topotecan and camptothecin ¢ —Y cytostatic agents such as Jie) antioestrogens: tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfen 1 and Vo-reduced regulators of the oestrogen receptor (such as (fulvestrant) antiandrogens eg bicalutamide, flutamide, nilutamide and cyproterone acetate and LHRH antagonists or LHRH cofactors (eg (goserelin, leuprorelin and buserelin and ie) “progestogens eg 0” (megestrol acetate and antagonists Ic) aromatase pathway Yéov

- Yo — eg anastrozole, letrozole, vorazole and exemestane ( and -5-a inhibitors such as finasteride ¢©”- agents that inhibit the proliferation of cancer cells (such as metalloproteinase inhibitors such as 41 and inhibitors of activator receptor function” urokinase plasminogen M + - inhibitors of growth factor function eg inhibitors that include antibodies to growth factor and growth factor receptor Jee antibodies eg anti-erbb2 antibody trastuzumab [Herceptin™] and the anti-erbbl antibody cetuximab ([C225], farnesyl transferase ¢ inhibitors, MEK inhibitors; tyrosine kinase inhibitors : Jie EGFR Bla tyrosine kinase inhibitors (eg.

N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine 01 (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-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)), Jie-specific inhibitors eg inhibitors of the hepatocyte-derived growth factor family 1 family of hepatocytes; E - Antiangiogenic agents such as those that inhibit the effects of endothelial growth factor (Jie) anti-angiogenic endothelial growth factor antibody bevacizumab [Avastin™] and compounds such as those disclosed in IPRs: 58/177084 and AY TYAS AND GLITTER 1

- +1 -

997/3 and 97/7595) and compounds with other mechanisms (eg linomide

integrin inhibitors of angiostatin s avB3 function);

+ - Combretastatin Ad Jie vessel destroying agents and ca SSW compounds reported in

International applications: 46 47 9 0, YYYE 4/ 1, 1213294 / .., 574 / ., 1307 5 45, and “1AM./A..

- anti-anxiety therapies such as those directed at the targets mentioned above; ISIS Jie

2203 and anticonvulsants for R. Sense.

gene therapy methods; Including representative methods for the replacement of dysregulated genes

Such as 53m dysregulated or uh or BRCA2 dysregulated or GDEPT (preliminary drug treatment 0l genetically directed enzyme) Jie that is done using cytosine deaminase any thymidine

0 And methods for increasing the patient's potential for chemotherapy, nitroreductase or enzyme kinase

radiotherapy such as multidrug-resistant gene therapy;

4- Immunotherapy methods; Such as the methods performed before entry into the body of living PE and in vivo

ella organism to increase the immunogenicity of tumor cells in patients; Methyltransfection with cytokines such as 4 interleukin 2, interleukin or macrophage colony stimulating factor

granular Methods for decreasing oT cell energy, and methods for using immune cells that

The infection was transmitted to it, such as the infectious dendritic LAY, “cytokine” and methods that use strains

Gastrointestinal tumor cytokinesis and methods using different types of antibodies

subjectivity;

1 2 Ah

—Y cell cycle inhibitors including for example CDK inhibitors (such as flavopiridol ( and other cell cycle checkpoint inhibitors ala Jie) assay kinase 1, inhibitors of aurora kinase and other kinase enzymes In mitosis and regulation of the generation of cytokinesis (mitotic kinesins Ji) and inhibitors of histone deacetylase ¢ M-11 endothelin antagonists including Jaf sll anti-endothelin «antagonists A and endothelin 5 endothelin antagonists B and 3 such as ZD1611 5 ZD4054 (IP No. 341 37/4) - (YM598 5 atrasentan). Such combination therapy can be achieved by using triggers or separate dosing of the individual components of the treatment. Such combination products use compounds of the present invention 0 within the dosage range indicated above and the pharmaceutically active agent AY within the approved dosage range.In addition to their use in therapeutic drugs, the compounds of Formula [E] or IB and pharmaceutically acceptable salts These are also useful as AYN tools in the development and calibration of experimental systems in the laboratory and in vivo for evaluating the effects of kinase inhibitors Vo 1 ho in laboratory animals Jie cats, dogs, mice, monkeys, rats and vertebrates as part of the research dal gall The new therapeutic. In the pharmaceutical composition, process, method, use, and manufacturing properties of dal the alternative and preferred forms of compounds of the present invention mentioned herein have been applied. Yéov

Processes for manufacturing Formula HA compounds can be prepared as shown in the drawings or LY The paths used in the drawings can be easily configured to prepare the compounds of formula IB by selecting the starting materials; Which by using RO as a starting material in the scheme (Ryn Oy NH, 1) or RO as a starting material in the oF scheme, compounds of formula IB can be obtained, scheme 1 CO,Et 0 Sublim Se DOT ed bala ____ and cd l RbO NH, CH,CN RbO N Ph,0 RbO 1 83 cl 0 y “N A REO Ni DMF, 100°C RbO NT R3 R3 LL :5 (Ryn N (Rn N) ser cog HCONH,, NaOMe 5 con, 0 = Pd,(dba),, BINAP _ MeOH, 100°C Cs,CO,, Tol, 100 °C RbO N RbO Nid Yeov

a — a" _ chart? R3 oy mS ge our fun TL i) 250°C, PhO Open iv) NH, RbO Nl i Pocha Reo NF v) HCONH,, NaOMe gy 1 will Now the clarification of this invention in the following non-restrictive examples which led except when otherwise stated: - (1) Temperatures are provided in degrees Celsius, and operations were carried out at room temperature or ambient temperature, except when otherwise stated. That; at a temperature ranging from YO - VA °C; (7) the organic solutions were dried on anhydrous sodium sulphate (magnesium sulphate ¢) and the solvent was evaporated using a rotary evaporator at low pressure (Ter) - m Pa + 0.7 mm Hg) with a bath of To °C; (v) cole face following TLC reaction and reaction times shown for illustration only; Ve (8) Products (9) Results are presented for illustrative purposes only and do not have to be those obtained through the elaborate process; preparations were repeated if needed On to more material; Lad 1

= f

(vii) NMR data when provided are differential values of large diagnostic protons; provided in parts per million for tetramethylsilane (TMS) as an internal standard; set at 4000 MHz using perdeuterio dimethyl

sulphoxide (DMSO-dg) as solvent unless otherwise stated; (v) ° chemical symbols have the usual meanings; ST unit and symbols are used;

¢ Solvent ratios then set by volume (V/V) (A)

(4) The mass spectrometer was operated with an electronic energy of 71 KeV in ionization mode

chemiluminescence (CI) using the live exposure tool; where the indicated ionizations were efficiencies by electron effect 0 (EI), fast atomic bombardment (FAB) or electrophoresis Ve (©1887); The mlz values for the ole face are also shown. The ions that indicated the original mass are reported unless otherwise stated; the mass ion in question is (MH) (V+) When describing the synthesis as corresponding to that in the previous example the quantities used are relative milliolar equivalents to those used in the previous example \o () The following abbreviations are Use: N,N-dimethylformamide DMF ¢ ethyl acetate EtOAc ¢ Yéiov

¢ methanol MeOH

N, N-diisopropylethylamine; DIEA

O-(7-azabenzotriazol-1-yl)-N,N,N’,N-tetramethyluronium HATU hexafluorophosphate; macroporous; triethylammonium methylpolystyrene carbonate MP-carbonate 0 ¢ tetrahydrofuran THF ¢ dimethylsulphoxide DMSO g ¢ 0 g and 1 Y to normal phase flash column chromatography using “ISCO” indicates previously packaged according to user silicad) obtained from gel packs of 1500? Inc, 4700 superior street Lincoln, NE, USA from 0 1/0 dimensions YMC-AQCIS for reverse phase HPLC to column Gilson HPLC indicated with (178.7+) as mobile phase. MeCN/ in YOu water [ala*1 and 001 fale (1) example 4-[(2,3-Dichlorophenyl)amino]-7 -methoxy-6-(4-methylpiperazin-1 -yl)quinoline-3- carboxamide Vo : to a solution of

ethyl 4-[(2,3-dichlorophenyl)amino}-7-methoxy-6-(4-methylpiperazin-1 -yl)quinoline-3- carboxylate (intermediate compound (1)); 174 aan 111 mmol (£V) formamide μl; 011 mmol) in SY DMF in an Np atmosphere at 100 °C; A solution of ENaOMe in 0 5 (MeOH mol VY cde 01 mmol) was added drop by drop over the course of 10 minutes. After 1 hour at a temperature of 1 001 » the reaction mixture was cooled and poured into water. The aqueous layer was extracted with EtOAc and dried (E048250; filtered and concentrated to yield YA mg solid. 'H NMR (CD;OD): 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, 2 H); m/z: 460 Ve Examples (Y) to (VY) The following examples have been prepared in a manner similar to that of Example ) 1) using suitable Al materials where the process of denaturation of intermediates and final compounds was carried out in some cases using ISCO column chromatograph or Gilson HPLC system and

Compound 460 | 010:01( 8.82 (s, 1 H), 7.52 | 4-[(2,4-Dichlorophenyl) y (d, 1 H), 7.28 (s, 1 H), 7.12 | amino]-7-methoxy-6 -(4-

Y median (dd, 1 H), 6.84 (s, 1 H), | methylpiperazine-1- 6.71 (d, 1 H), 3.97 (s, 3 H), | yl)quinoline-3-carboxamide 2.97 (m, 4 H), 2.86 (m, 4

H), 2.52 (s, 3 H) Compound 460 | CDsOD 8.79 (s, 1 H), 7.60 | 4-[(3,4-Dichlorophenyl) v 1 )0 1 H), 7.53 (s, 1 H), 7.44 | amino]-7-methoxy-6-(4-median? (d, 2H), 7.27 (d, 1H), 4.11 | methylpiperazin-1- (s, 3H), 3.61 (m, 4H) ), 3.27 |yl)quinoline-3-carboxamide (m, 2 H), 2.98 (m, 5 H) Compound 428 | CD;OD 8.81 (s, 1 H), 7.52 | 4-[(2,4-Difluorophenyl) ¢ 1 (m, 1 H), 7.44 (s, 1 H), 7.35 | amino]-7-methoxy-6-(4- 4 median (s, 1 H), 7.19 (m, 1 H), 7.12 | methylpiperazin-1- (t, 1 H), 4.09 (s, 3 H) Compound 447 | 010010 8.89 (s, 1 H), 7.63 | 4-[(2,3-Dichlorophenyl) 1 (d, 1 H), 7.42 (m, 2 H), 7.27 | amino]-7-methoxy-6-© median (s, 1 H), 6.91 (s, 1 H), 4.06 | morpholin-4-ylquinoline-3- (s, 3H), 3.70 (m, 4H), 2.73 | carboxamide (m, 4 H) compound 415 | CD;OD 8.80 (s, 1 H), 7.51 | 4-[(2,4-Difluorophenyl) + 1 (d, 1 H), 7.31 (s, 1 H), 7.19 | amino]-7-methoxy-6- > median (m, 1 H), 7.18 (s, 1 H), 7.14 | morpholin-4-ylquinoline-3- (m, 1H), 4.06 (s, 3H), 3.74 | carboxamide (m, 4 H), 2.85 (m, 4 H) Compound 447 | CD;0D 8.78 (s, 1 H), 7.62 | 4-[(3,4-Dichloropheny)) 7 1 (d, 1 H), 7.52 (d, 1 H), 7.29 | amino]-7-methoxy-6-

V Median (m, 2 H), 7.20 (s, 1 H), 4.07 | morpholin-4-ylquinoline-3- (s, 3H), 3.76 (m, 4H), 2.90 | carboxamide (m, 4 H) compound 445 | CD30D 8.79 (s, 1 H), 7.62 | 4-[(3,4-Dichlorophenyl) A 1 (d, 1 H), 7.51 (d, 1 H), 7.30 | amino]-7-methoxy-6-

A median (s, 1 H), 7.28 (dd, 1 H), | piperidin-1-ylquinoline-3- 7.13 (s, 1H), 4.05 (s, 3H), | carboxamide 2.81 (m, 4 H), 1.63 (m, 4

H), 1.55 (m, 2 H) Composite 460 010:01 8.91 (s, 1 H), 7.78 | 4-[(2,3-Dichlorophenyl) q 1 (s, 1 H), 7.58 (dd, 1 H), | amino]-6-methoxy-7-(4- 4 median 7.41 (m, 3 H), 6.95 (s, 1 H), | methylpiperazin-1- 4.08 (m, 2 H), 3.67 (m, 2 |yl)quinoline-3-carboxamide

H), 3.53 (s, 3 H), 3.33 (m, 4

Y¢ov i 1 | 10302310 [TT Composite 460 | CD;0D 8.74 (s, 1 H), 7.57 | 4-[(3,4-Dichlorophenyl) 1 1 (d, 1 H), 7.51 (d, 1 H), 7.37 | amino]-6-methoxy-7-(4- 01 median (s, 1 H), 7.34 (s, 1 H), 7.25 | methylpiperazin-1- (dd, 1 H), 4.03 (m, 2 H) ), |yl)quinoline-3-carboxamide 3.75 (s, 3 H), 3.64 (m, 2 H), 3.30 (m, 4 H), 2.99 (s, 3 H) Compound 441 | 010:0 8.80 (s, 1 H), 7.51 | 4-[(2,4-Difluorophenyl) 11 1 (m, 1 H), 7.34 (s, 2 H), 7.20 | amino]-7-ethoxy-6-(4- 11 median (m, 1 H), 7.13 (d, 1 H), 4.32 | methylpiperazin-1- (q, 2 H), 3.54 (m, 4 H) Compound 474 | CD;OD 8.87 (s, 1 H), 7.53 | 4-[(2,3-Dichlorophenyl) yy 1 (dd, 1 H), 7.35 (m, 3 H), | amino]-7-ethoxy-6-(4-

VY Median 6.93 (s, 1 H), 4.27 (q, 2 H), | methylpiperazin-1- 3.43 (m, 4 H), 3.20 (m, 2 | yl)quinoline-3-carboxamide

H), 2.89 (s, 3 H), 2.71 (m, 2

H), 1.49 (t, 3 H) compound | 429 | 0:00 8.78 (s, 1 H), 7.52 | 4-[(2,4-Difluorophenyl) - (d, 1 H), 7.24 (m, 3 H), 7.14 | amino]-7-ethoxy-6-

VY Median (m, 1 H), 4.30 (t, 2 H), 3.75 | morpholin-4-ylquinoline-3- (m, 4H), 2.86 (m, 4H), | carboxamide 1.52 (t, 3 H), compound 461 | CD;OD 8.68 (s, 1 H), 7.53 4-[(3,4-Dichlorophenyl) \¢ (d, 1 H), 7.43 (d, 1 H), 7.19 | amino]-7-ethoxy-6- 1 4 intermediate (m, 2 H), 7.10 (s, 1 H), 4.21 | morpholin-4-ylquinoline-3- (9, 2H), 3.65 (m, 4H), 2.83 | carboxamide (m, 4 H), 1.44 (t, 3 H) cv 5451 10.79 (s, 1 H), 8.94 (s, 1 H), tert-Butyl 4-{3- yo ' 8.35 (s, 1 H), 7.75 (s, 1 H), | (aminocarbonyl)-4-[(2,3-

Yo median 7.34 (s, 1 H), 7.25 (dd, 1 | dichlorophenyl)amino]-7-

H), 7.14 (t, 1 H), 6.70 (s, 1 methoxyquinolin-6-

H), 6.59 (d, 1 H), 3.95 (s, 3 | yl}piperazine-1 -carboxylate

H), 3.33 (m, 4 H), 2.68 (m, 4 H), 1.39 (s, 9H) Compound 416 | 10.63 (s, 1 H), 8.86 (s, 1 H), 4-[(2,4-Difluorophenyl) to ' 8.29 (s, 1 H), 7.71 (s, 1 H), amino]- 7-fluoro-6-(4-11 median 7.63 (d, 1 H), 7.38 (m, 1 H), |methylpiperazin-1- 7.11 (m, 3 H), 2.82 (m, 4 | yl) quinoline-3-carboxamide : H), 2.48 (m, 4H), 2.26 (s, 3

H) Composite 10.84 (s, 1 H), 8.98 (s, 1 H), | 4-[(2,3-Dichlorophenyl) Vy 1 8.44 (s, 1 H), 7.86 (s, 1 H), amino ]-7-fluoro-6-(4- 7.70 (d, 1 H), 7.32 ( d, 1 H), methylpiperazin-1-1 lustrous

— Vo — 11 Median 7.19 (t, 1 H), 6.86 (d, 1 H), | yl)quinoline-3-carboxamide i 6.69 (d, 1 H), 2.82 (m, 4 H), 2.48 (m, 4 H), 2.25 (s, 3 H) Compound 403 | CDs;OD 8.84 (s, 1 H), 7.66 | 4-[(2,4-Difluorophenyl) vA 1 (d, 1 H), 7.52 (m, 1 H), 7.45 | amino]-7-fluoro-6-

YA Median (m, 1 H), 7.22 (m, 1 H), | morpholin-4-ylquinoline-3- 7.14 (m, 1H), 3.78 (m, 4 | carboxamide

H), 2.95 (m, 4 H) 7.92 (s, 1 H), | amino]-5-fluoro-6-(4-

V4 Median 7.79 (m, 1 H), 7.64 (t, 1 H), | methylpiperazine-1- 7.19 (m, 1 H), 7.04 (t, 1 H), | yDquinoline-3-carboxamide 6.47 (d, 1 H), 2.94 (m, 4 H), 2.38 (m, 4 H), 2.18 (s, 3 H) Compound 434 | 10.78 (s, 1 H), 8.82 (s, 1 H), | 7-Ethoxy-4-[(4- Y. 1 8.21 (s, 1 H), 7.57 (s, 1 H), | ethylphenyl)amino]-6-(4- 01 median 7.17 (s, 1 H) ), 7.12 (d, 2 H), |methylpiperazin-1- 6.89 (d, 2 H), 6.80 (s, 1 H), |yl)quinoline-3-carboxamide 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) Compound 458 | 10.35 (s, 1 H), 8.80 (s, 1 H), | 4-[(3-Chloro-4- 71 8.17 (s, 1 H), 7.59 (s, 1 H), |fluorophenyl)amino]-7-

YY Median 7.22 - 7.34 (m, 2 H), 7.09 | ethoxy-6-(4- (dd, 1 H), 6.85 - 6.96 (m, 2 | methylpiperazin-1-

H), 4.18 (q, 2 H), 2.81 (s, 4 | yl)quinoline-3-carboxamide

H), 2.37 (s, 4 H), 2.17 (s, 3

H), 1.40 (t, 3 H) 474 1 8.78 (s, 1 H), 8.12 (s, 1 H), 4-[(3,4-Dichlorophenyl) YY 7.59 (s, 1 H), 7.44 (d, 1H), | amino]-7-ethoxy-6-(4-

YY Median 7.28 (s, 1 H), 7.09 (d, 1 H), | methylpiperazin-1- 6.96 (s, 1 H), 6.85 (dd, 1 | yl)quinoline-3-carboxamide : 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) compound 488 | 10.80 (s, 1 H), 8.91 (s, 1 H), | 4-[(2,3-Dichlorophenyl) yy 8.37 (s, 1 H), 7.76 (s, 1 H), n01-7-ctoxv-6-(4-

YY Median 7.29 (s, 1 H), 7.26 (d, 1 H), | 2mino]-7-ethoxy-6-( 7.14 ) 1H), 6.64 (s, 1H), | ethylpiperazin-1- ot B Ho hv & : 0 yl)quinoline-3-carboxamide 2.35 (q, 2 H), 1.40 ) 3 H), 0.97 (t, 3 H) Compound 445 | CDCl, 10.42 (s, 1 H), 8.77 | 4-[(3-Chloro-2- Y¢ ' (s, 1 H), 7.30 (s, 1 H), 7.06 | fluorophenyl)amino]-7- 17 4 Median (m, 1 H), 6.88 (m, 2H), | ethoxy-6-morpholin-4- 6.73 (m, 1H), 6.05 (br s, 2 | ylquinoline-3-carboxamide

Yeov

H), 4.21 (q, 2 H), 3.72 (m, 4

H), 2.80 (m, 4 H), 1.50 (t, 3

H) Compound 426 | CDCl, 10.42 (s, 1 H), 8.74 )6 7-Ethoxy-4-[(2-fluoro-5- Yo 1H), 7.26 (s, 1 H), 7.01 (dd, 1 methylphenyl)amino]-6 -

Yo median H), 6.95 (s, 1 H), 6.83 (m, 1 morpholin-4-ylquinoline-3-

H), 6.77 (dd, 1 H), 6.02 (brs, | carboxamide 2 H), 4.20 (q, 2 H), 3.70 4

H), 2.74 (m, 4 H), 2.18 (s, 3

HH), 1.49(t, 3H) compound 447 | 010202 10.51 (s, 1 H), 8.75 | 4-[(3-Chloro-4- v1 1 (s, 1 H), 7.27 (s, 1 H), 7.06 fluorophenyl)amino]-7- 7 median (m, 2 H), 692 (m, 1 H), ethoxy-6-morpholin-4- 6.85 (s, 1 H), 6.08 (br s, 2 | ylquinoline-3-carboxamide

H), 4.20 (q, 2 H), 3.673 (m, 4 H), 2.79 (m, 4 H), 1.49 (t, 3 H) 0,0 | 421 Compound 10.60 (s, 1 H), 8.69 7-Ethoxy-4-[(4- vy (s, 1 H), 7.21 (s, 1 H), 7.11 ethylphenyl)amino]-6

YV median (d, 2 H), 6.97 (d, 2 H), 6.90 morpholin-4-ylquinoline-3- (s, 1 H), 5.92 (br s, 2 H), | carboxamide 4.18 (q, 2H), 3.66 (m, 4H), 2.67 (m, 4H), 2.59 (q, 2H), 1.47 (t,3H), 1.18 (t, 3H) 462 | 010:01: 10.36 (s, 1 H), 8.80 (s, 4-[(2,3-Dichlorophenyl) Compound 1 1100.732 )5. 1110, 7.11 (d, 1 | amino]-7-ethoxy-6- A

YA median Fl), 6.97 (dd, 1 H), 6.79 (s, 1 | morpholin-4-ylquinoline-3-

H), 6.60 (d, 1 H), 6.04 (brs, 2 carboxamide)

H), 4.23 (q, 2 H), 3.72 (m, 4

H), 2.82 (m, 4 H), 1.50 (¢, 3 H) Composite 501 | 11.10 (s, 1 H), 9.10 (s, 1 H), 4-[(2,3-Dichlorophenyl) Yq 1 8.55 (s, 1 H), 7.95 (s, 1 H), amino]-7-ethoxy -6-(4-

Ya median 7.70 (m, 2 H), 7.50 (m, 3 | isopropylpiperazin-1-

H), 7.36 (s, 1 H), 4.40 (q, 2 | yl)quinoline-3-carboxamide

H), 3.60 (m, 4 H), 3.30 (m, 1 H), 3.20 (m, 4 H), 1.60 (t, 3H), 1.50 (d, 6 H) Composite 487 | 10.69 (s, 1 H), 8.85 (s, 1 H), 4-[(2,3-Dichloropheny!) v. 8.35 (s, 1H), 7.74 (s, 1H), amino]-7-ethoxy-6-(4-01 median 7.24 (m, 2H), 7.12 (m, 1 methyl-1,4 -diazepan-1-

H), 6.54 (m, 2 H), 4.17 (q, 2 | yl)quinoline-3-carboxamide

H), 3.14 (m, 2H), 2.99 (m, 2H), 2.50 (m, 2H), 2.42 (m, 2H), 2.19 (s, 3H), 1.69 (m, 2H) , 1.41 (t, 3 H) compound 460 | 11.99 (s, 1 H), 8.83 (s, 1 H), 4-[(2,3-Dichlorophenyl) vy 8.40 (s, 1 H), 7.90 (s, 1 H), amino]-7-ethoxy- 6-(3- 01 median 7.50 (d, 1 H), 7.33 (m, 1 H), hydroxypyrrolidin-1- 7.28 (s, 1 H), 7.23 (m, 1 H), yl)quinoline-3 -carboxamide 6.35 (s, 1 H), 4.12 (m, 3 H),

YeioV

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) Composite 530 | 10.80 (s, 1 H), 9.00 (s, 1 H), 4-[(2,3-Dichlorophenyl) vy 8.42 (s, 1 H), 7.75 (s, 1 H), | amino]-6-{4-[2- 17 median 7.60 (m, 2 H), 7.35 (m, 2 | (dimethylamino)ethyl]

H), 7.20 (s, 1 H), 4.25 (q, 2 | piperazin-1-yl}-7-

H), 3.80-3.00 (m, 12 H), | ethoxyquinoline-3- 2.85 (s,6 H), 1.48 (t, 3H) carboxamide compound 517 | 11.10 (s, 1 H), 9.00 (s, 1 H), 4-[(2,3-Dichlorophenyl) wy 8.45 (s, 1 H), 7.80 (s, 1 H), | amino]-7-ethoxy-6-[4-(2-

Median FY 7.60 (m, 2 H), 7.35 (m, 2 | methoxyethyl)piperazin-1-

H), 7.22 (s, 1 H), 4.20 (q, 2 | yl]quinoline-3-carboxamide

H), 3.71 (s, 3 H), 3.49-3.10 (m, 10 H), 2.95 (t, 2 H), 1.45 (t, 3 H) Compound 488 | 010201 10.42 (s, 1 H), 8.75 4-[(3,4-Dichlorophenyl) ve (s, 1 H), 7.31 (d, 1 H), 7.27 | amino]-7-ethoxy-6-(4-

Ve Median (s, 1 H), 7.03 (s, | H), 6.86 | ethylpiperazine-1- (s, 1 H), 6.83 (d, 1 H), 6.05 | y)quinoline-3-carboxamide (br s, 2H), 421 (q, 2H), 2.86 (m, 4H), 2.48 (m, 4

H), 2.39 (q, 2H), 1.51 3

H), 1.05 (t, 3 H) Compound 456 | 10.72 (s, 1 H), 8.84 (s, 1 H), 4-[(2,4-Difluorophenyl) vo 8.27 (s, 1 H), 7.64 (s, 1 H), | amino]-7-ethoxy-6-(4-

Yo Median 7.36 (m, 1 H), 7.23 (s, 1 H), | ethylpiperazine-1- 7.00 (m, 2 H), 6.79 (s, 1 H), | yl)quinoline-3-carboxamide 4.16 (q, 2H), 2.72 (m, 4H), 2.38 (m, 4H), 2.32 (q, 2H), 1.40 (t, 3H), 0.97 (t) , 3 H) Compound 472 110.69 (s, 1 H), 8.86 (s, 1 H), | 4-[(3-Chloro-2- vi 8.30 (s, 1 H), 7.71 (s, 1 H), | fluorophenyl)amino]-7- 1 median 7.18 - 7.29 (m, 2 H), 7.06 | ethoxy-6-(4-chylpiperazin- (s, 1H), 6.76 - 6.84 (m, 2 | 1-yl)quinoline-3-

H), 4.18 (q, 2H), 2.77 (s, 4 | carboxamide

H), 2.35 (m, 6 H), 1.40 (t, 3

H), 0.97 (t, 3 H) Compound 452 | 10.78 (s, 1 H), 8.85 (s, 1 H), 7-Ethoxy-6-(4- ay 8.29 (s, 1 H), 7.66 (s, 1 H), | ethylpiperazin-1-yl)- 4-[(2-

YY Median 7.17 (m, 2 H), 6.87 (m, 2 | fluoro-5-

H), 6.69 (s, 1 H), 4.17 (q, 2 | methylphenyl)amino]quinol

H), 2.71 (m, 4 H), 2.34 (m, |ine-3-carboxamide 6 H), 2.13 (s, 3 H), 1.40 (t,

Ysov

(310097630|AA CDCl; 10.47 (s, 1 H), 8.74 | 4-[(3-Chloro-4- YA | 472 Compound (s, 1 H), 7.26 (s, 1 H), 7.06 | fluorophenyl)amino]-7- (d, 1 H), 7.04 (dd, 1 H), | ethoxy-6-(4-ethylpiperazin- intermediate YA (m, 1 H), 6.85 (s) , I H), |1-yl)quinoline-3- 6.88 (br s, 2 H), 4.20 (q, 2 | carboxamide 6.08 H), 2.82 (m, 4 H), 2.47 (m, H), 2.38 (q, 2 H), 1.50 (t, 4 H), 1.05 (t, 3 H) 3 (s, 1 H), 8.69 7-Ethoxy-4-[(4- vq 10.56 0,0 |448 Compound (s, 1H), 7.19 (s, 1 H), 7.10 ethylphenyl)amino]-6-(4- (d, 2 H), 6.97 (d, 2 H), 6.91 |ethylpiperazin-1-intermediate va (s, 1 H), 6.01 (br s, 2 H), |yl)quinoline-3-carboxamide (q, 2 H), 2.70 (m, 4 H), 4.17 (q, 2 H), 2.39 (m, 4 H), 2.60 (q, 2 H), 1.47 (t, 3 H), 2.36 (t, 3 H), 1.04 (t, 3 H) 1.19 (s, 1 H), 8.90 (s, 1 H), |6-[4-(2-Cyanoethyl) ' 110.80 512 Compound 1 8.35 (s, 1 H), 7.72 (s, 1 H), |piperazin-1-yl]-4-[(2,3- (s, 1 H), 7.25 (d, 1 H), |dichlorophenyl)amino]-7 7.30 Median 00 (t, 1 H), 6.65 (s, 1 H), |ethoxyquinoline-3- 7.15 (d, 1 H), 4.20 (q, 2 H), | carboxamide 6.52 (m, 12 H), 1.40 (t, 2.80-2.45 H) 3 (s, 1 H), 9.11 (s, 1 H), 4-[(2,3-Dichlorophenyl) 1 112.40 474 Compound 1 8.68 (s, 1 H), 8.00 (s, 1 H), amino]-7-ethoxy-6-(4- (d, 1 H), 7.50 (s, 1 H) ), |hydroxypiperidin-1- 7.61 median 41 (m, 2 H), 6.86 (s, 1 H), yDquinoline-3-carboxamide 7.40 (q, 2 H), 3.55 (m, 1 H), 4.20 (m, 2 H), 2.45 (m, 2 H), 3.00 (m, 2 H), 1.32 (m, 5 H), 1.70 (s, 1 H), 8.77 (s, 1 H), 7-Ethoxy-4-[(4- 110.71 448 (s, 1 H), 7.56 (5, 1 11: | ethylphonyDamino]-6-(4- | 5 820) nN “ 2 Hy methyl-1,4-diazepan-1- 0 y 0 Je: median £Y (s.i a : 6.72 , ) } (q.2H), 3.03 00.2 1D, yDquinoline-3 -carboxamide 413 (m, 2 H), 2.555 (m, 2 H), 2.86 (m, 2 H), 2.18 (s, 3 H), 2.41 (m, 2 H), 1.39 ( t, 3 H), 1.65 (t, 3 H) 1.13 (s, 1 H), 8.80 (s, 1 H), 4-[(2,4-Difluorophenyl) 10.60 | 428 H) , 7.69 (6 1 H), |amino]-7-cthoxy.6-(3.2 1 ,5) 830 Compound J o> hydroxypyrrolidin-1-0 !b bis intermediate 47 : 2 limit : 5 m, , 0. m, . (s, 1 H), 487 (d. 1 H), yl)quinoline-3-carboxamide 645 (m, 1 H), 4.20 (q, 2 H), 4.29 (m, 1 H), 3.22 (m, 1 H), 3.45 (m, 2 H), 1.90 (m, 1 H), 3.00 (m, 1 H), 1.46 (t, 3 H) 1.75 Yéov

4 4 Median 8.31 (s, 1 H), 7.70 (s, 1 H), | amino]-7-ethoxy-6-(4- ' 7.43 (m, 1 H), 7.28 (s, 1 H), | hydroxypiperidin-1- 7.05 (m, 2 H), 6.88 (s, 1 H), |yl)quinoline-3-carboxamide 4.67 (d, 1H), 4.21 (q, 2H), 3.55 (m, 1H), 3.10 (m, 2

H), 2.46 (m, 2 H), 1.75 (m, 2 H), 1.45 (m, 5 H) Composite 502 | CD;OD 8.79 (s, 1 H), 7.37 4-[(3,4-Dichlorophenyl) ‘0 1 (d, 1 H), 7.26 (s, 1 H), 7.07 | amino]-7-ethoxy-6-(4- to intermediate (s, 1 H), 7.04 (d, 1 H), 6.88 | isopropylpiperazin-1- (dd, 1 H), 4.24 (q, 2 H) ), |yDquinoline-3-carboxamide 2.96 (m, 4 H), 2.65 (m, 5

H), 1.51 (t, 3 H), 1.10 (d, 6

H) Compound 470 | CD3OD 8.76 (s, 1 H), 7.46 4-[(2,4-Difluorophenyl) 8 (m, 1 H), 7.36 (s, 1 H), 7.34 | amino]-7-ethoxy-6-(4-£1 median (s, 1 H), 7.20 (m, 1 H), 7.13 | isopropylpiperazin-1- (m, 1 H), 4.30 (q, 2 H), 3.58 |yl)quinoline-3-carboxamide (m, 5H), 3.26 (m, 2H), 2.95 (m, 2H), 1.55 (t, 3H), 1.42 (d, 6H) Compound 486 | CD;OD 8.81 (s, 1 H), 7.26 | 4-[(3-Chloro-2- cy ' (s, 1 H), 7.16 (m, 1 H), 7.04 | fluorophenyl)amino]-7- 49 median (m, 1 H), 6.98 (s , 1 H), 6.83 | ethoxy-6-(4- (m, 1H), 4.24 (q, 2H), 2.91 |isopropylpiperazin-1- (m, 4H), 2.69 (m, 5H), |yl)quinoline-3- carboxamide 1.51 (t,3H), 1.11 (d, 6H), compound 466 | CD3;OD 8.78 (s, 1 H), 7.21 7-Ethoxy-4-[(2-fluoro-5-$A (s, 1 H), 7.03 (dd, 1 H), | methylphenyl)amino]-6 -(4-

EA Median 7.00 (s, 1 H), 6.93 (m, 1 H), | isopropylpiperazin-1- 6.78 (dd, 1 H), 4.23 (q, 2 | yl)quinoline-3-carboxamide

H), 2.83 (m, 4 H), 2.68 (m, 1 H), 2.65 (m, 4 H), 2.19 (s, 3 H), 1.50 (t, 3 H), 1.11 (d, 6 H) Compound 486 | 00:00 8.77 (s, 1 H), 7.25 (s, | 4-[(3-Chloro-4- 0 1H), 7.16 (dd, 1 H), 7.07 (d, 1 | fluorophenyl)amino]-7 - £4 median H), 7.03 (s, 1 H), 6.95 (dd, 1 | ethoxy-6-(4-

H), 4.24 (q, 2 H), 2.96 ) 4 | isopropylpiperazine-1-

H), 2.77 (m, 1 H), 2.74 (m, 4 yl)quinoline-3-carboxamide

H), 1.51 (t, 3 H), 1.13 (d, 6

H) Compound 455 1 10.70 (s, 1 H), 8.85 (s, 1 H), | 4-[(2,4-Difluorophenyl)1 8.30 (s, 1 H), 7.61 (s, 1 H), | amino]-7-ethoxy-6-(4- 50 median 7.35 (m, 1 H), 7.25 (s, 1 H), | methyl-1,4-diazepan-1- no Ca

- .m — 6.89 (m, 2 H), 6.63 (s, 1 H), | yl)quinoline-3-carboxamide 4.20 (q, 2H), 3.20 (m, 2H), 3.00 (m, 2H), 2.55 (m, 7

H), 1.80 (m, 2 H), 1.40 (t, 3

H) Compound 488 | 10.78 (s, 1 H), 8.92 (s, 1 H), | 4-[(2,3-Dichlorophenyl) 0 1 8.35 (s, 1 H), 7.75 (s, 1 H), | amino]-6-(4- 51 median 7.33 (s, 1 H), 7.26 (m, 1 H), | isopropylpiperazin-1-yl)-7- 7.15 (m, 1 H), 6.65 (s, 1 H), | methoxyquinoline-3- 6.58 (d, 1 H), 3.95 (s, 3 H), | carboxamide 2.75 (m, 4 H), 2.60 (m, 1

H), 2.46 (m, 4 H), 0.95 (d, 6

H) 455 110.72 (s, 1 H), 9.86 (s, 1 H), 4-[(2,4-Difluorophenyl) ov 8.30 (s, 1 H), 7.67 (s, 1 H) , | amino]-6-(4-oY median 7.35 (m, 1 H), 7.26 (s, 1 H), | isopropylpiperazin-1-y})-7- 7.01 (m, 2 H), 6.80 (s , 1 H), | methoxyquinoline-3- 3.92 (s, 3 H), 2.70-2.45 (m, | carboxamide 9H), 0.95 (d, 6 H) Compound 474 | 8.90 (s, 1 H), 8.45 (s, 1 H), | 4-[(2,3-Dichlorophenyl) oy 7.75 (s, 1 H), 7.30 (m, 2 H), | amino]-7-methoxy-6-(4- ov median 7.17 (m, 1 H), 6.63 (s, 1 H), | methyl-1,4-diazepan-1- 6.58 (d, 1 H) , 3.98 (s, 3 H), |yl)quinoline-3-carboxamide 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) Compound 441 | 10.65 (s, 1 H), 8.80 (s, 1 H), 4-[(2,4-Difluorophenyl) of 8.30 (s, 1 H), 7.60 (s, 1 H), | amino]-7-methoxy-6-(4- 4 median 7.32 (m, 1 H), 7.20 (m, 1 | methyl-1,4-diazepan-1-

H), 6.95 (m, 2H), 6.75 (m, |yl)quinoline-3-carboxamide 1H), 3.90 (s, 3H), 3.10 (m, 4H), 3.00 (m, 4H) , 2.20 (s, 3 H), 1.69 (m, 2 H) Composite 474 110.70 (s, 1 H), 8.85 (s, 1 H), | 4-[(2,3-Dichlorophenyl)1 8.26 (s, 1 H), 7.67 (s, 1 H), | amino}-6-(4-ethylpiperazin- 00 median 7.35 (m, 1 H), 7.28 (s, 1 H), | 1-yl)-7-methoxyquinoline- 7.05 (m, 2 H), 6.80 ( s, 1 H), | 3-carboxamide 3.90 (s, 3 H), 2.75 (m, 4 H), 2.55 (m, 6 H), 0.95 (t, 3 H) Compound 441 | 10.80 (s, 1 H), 8.92 (s, 1 H), 4-[(2,4-Difluorophenyl) on 8.40 (s, 1 H), 7.80 (s, 1 H), | amino]-6-(4-ethylpiperazin- 57 median 7.35 (s, 1 H), 7.25 (m, 1 H), | 1-yl)-7-methoxyquinoline- : 7.15 (m, 1 H), 6.69 (s, 1H), | 3-carboxamide 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) 1 Stay

CDCl; 10.45 (s, 1 H), 8.74 4-[(3,4-Dichlorophenyl) ov | 474 Compound 1 (s, 1 H), 7.30 (m, 2 H), 7.03 amino]-6-(4-ethylpiperazin- (d, 1 H), 6.91 (s, 1 H), 6.80 1- yl)-7-methoxyquinoline- median oV (d, 1 H), 4.00 (s, 3 H), 2.89 | 3-carboxamide (s, 4 H), 2.54 (s, 4 H), 2.44 H), 1.09 (t, 3 H) 9,2( (s, 1 H), 8.80 (s, 1 H), 4-[(3,4-Dichlorophenyl) oA 10.11 |488 Compound 1 8.13 (s, 1 H), 7.60 (s, 1 H), | amino]-6-(4- ( d, 1 H), 7.31 (s, 1 H), | isopropylpiperazin-1-yl)-7- 7.44 median oA (d, 1 H), 6.97 (s, 1 H), | methoxyquinoline-3 - 7.10 (d, 1 H), 3.94 (s, 3 H), carboxamide 6.84 (s, 4 H), 2.63 (s, 1 H), 2.84 (s,4 H), 0.96 (d, 6 H) 2.48 CDCI 1040 (5, 1 H), 869 (s, | 4-[(3,4-Dichlorophenyl) 04 | 474 | compound H), 7.28 (m, 2 H) , 7.02 (d, | | amino]-7-methoxy-6-(4- 1 H), 6.80 (m, 2H), 3.98 (s, 3 methyl-1,4-diazepan-1- intermediate 09 H), 3.25 (m, 2 H), 3.08 (m, 2 yDquinoline-3-carboxamide H), 2.64 (m, 4 H), 2.40 (br s, 3 H), 1.87 (m , 2 H) (s, 1 H), 7.38 (d, 4-[(3,4-Dichlorophenyl) 0 8.72 0.00 | 488 H), 722 (s, 1 H), 7.04 (s, 1 amino]-7-ethoxy-6-(4- 1 H), 6.86 (m, 2 H), 4.23 (q, 2 | methyl-1,4-diazepan-1- intermediate +1 H), 3.29 (m, 2 H), 3.11 (m, 2 yl)quinoline-3-carboxamide 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) (s, 1 H), 7.19 (s, 7-Ethoxy-4-[(2-fluoro-5- +11) 8.73 00:00 | 452 compound H), 7.04 (dd, 1 H), 6.89 (m, methylphenyl)amino]-6-(4- 1 H), 6.75 (d, 1 H), 4.21 (q, 2 methyl-1 ,4-diazepan-1-2 intermediate TY H), 3.17 (m, 2 H), 2.96 (m, 2 yl)quinoline-3-carboxamide H), 2.73 (m, 2 H), 2.64 (m, 2 H), 2.35 (5, 3 H), 2.19 (s, 3 H), (m, 2 H), 1.52 (t, 3 H) 1.89 b CD;0D 8.71 (s, 1 H), 7.21 | 4-[(3-Chloro-4- | 472 compound (s, 1 H), 7.15 (m, 1 H), 7.04 fluorophenyl)amino]-7- (m, 1 H), 6.94 (m , 1 H), ethoxy-6-(4-methyl-1,4- intermediate TY (s, 1 H), 4.23 (q, 2 H), |diazepan-1 -yl)quinoline-3- 6.87 (m, 2 H), 3.07 (m, 2 | carboxamide 3.24 H), 2.78 (m, 2 H), 2.68 (m, H), 2.37 (s, 3H), 1.94 (m , 2 H), 1.52 (t, 3 H) 2 (s, 1 H), 8.71 (s, 1 H), 4-[(2-Fluorophenyl) amino]- Ty 10.85 | 410 Compound (s, 1 H), 7.19 (s, 1 H), 7-methoxy-6-(4- 7.53 (m, 6 H), 3.84 | methylpiperazin-1- 7.06 - 6.68 Intermediate 67 (s, 3 H), 2.65 (s, 4 H), 2.24 |yl)quinoline-3-carboxamide (s,4H),2.08 (s,3 H) Yéov

CDCl, 10.42 (s, 1 H), 8.78 | tert-Butyl 4-{3- + | 544 Compound 1 (s, 1 H), 7.31 (s, 1 H), 7.08 (aminocarbonyl)-4-[(3- (m, 1 H), 6.90 (m, 1 H), chloro-4 -fluorophenyl) intermediate 64+ (s, 1 H), 6.72 (m, 1 H), amino]-7-ethoxy quinolin-6- 6.88 (q, 2 H), 3.44 (m, 4 H) , | yl} piperazine-1 -carboxylate 4.22 (m, 4 H), 1.50 ) 3 H), 2.76 (s, 9 H), 1.44 (s, 1 H), 8.76 | tert-Butyl 4-{3- “6 10.50 : 01and10 | 523 Compound 1 (s, 1 H), 7.29 (s, 1 H), 7.02 (aminocarbonyl)-7-ethoxy- (m, 1 H), 6.94 (s, 1 H), 6.88 | 4-[(2-fluoro-5- median To (m, 1 H), 6.77 (d, 1 H), 4.21 methylphenyl)amino] (q, 2 H), 3.42 (m, 4 H), 2.70 quinolin-6-yl} piperazine-1- (m, 4 H), 2.18 (s, 3 H), 1.49 | carboxylate (t, 3H), 1.44 (6, 9 H) CD,Cl, 10.51 (s, 1 H), 8.75 (s, | tert-Butyl 4-{3- | 544 H), 7.29 (s, 1 H), 7.07 (m, 2 | (aminocarbonyl)-4-[(3- 1 1 FD), 6.85 (m, 2 H), 422 (q, 2 | chloro-2- fluorophenyl) intermediate 66 H), 3.46 (m, 4 H), 2.76 (m, 4 amino|-7-ethoxy quinolin-6- H), 1.50(t, 3 H), 1.44 (5, 9 H) yl} piperazine-1-carboxylate ‎(s, 1 H), 8.64 (s, 1 H), 7-Methoxy-4-[(3-methoxy- +7 10.96 | 436 Compound 1 7.44 (s) , 1 H), 7.10 (s, 1 H), 2-methylphenyl)amino]-6- (m, 1 H), 6.72 (s, 1 (4-methylpiperazin-1- 6.80-6.85) Intermediate TY M), 6.70 (s, 1 H), 6.57 (d, 1 yhquinoline-3-carboxamide H), 6.28 (d, 1 H), 3.80 (s, 3 H), 3.69 (s, 3 H), 2.54 (s, 4 H), (s, 4 H), 2.12 (s, 3 H), 2.22 (s, 3 H), 2.08 (s, 1 H), 8.87 ( s, 1 H), |4-[(4-Chloro-2- TA 10.73 | 440 Compound 1 8.30 (s, 1 H), 7.65 (s, 1 H), methylphenyl)amino]-7 (m, 1 H), 7.25 (s, | methoxy-6-(4- 7.40-7.41 median TA H), 7.10-7.13 (m, 1 H), | methylpiperazin-1-1 ( m, 2 H), 3.89 (s, 3 H), |yl)quinoline-3-carboxamide 6.67 (s, 3 H), 2.68 (s, 4 H), 3.34 (s,4 H), 2.17 (s, 3 H) 2.34 110.85 )8, 1 H), 8.90 (s, 1 H), | 4-[(3-Chloro-2- +4 453 Compound 1 8.30 (s, 1 H), 7.60 (s, 1 H), methylphenyl)amino]-7- (m, 2 H), 7.09 (t, 1H), | ethoxy-6-(4- 7.20 median 19 (m, 2 H), 4.15 (q, 2 H), methylpiperazin-1- 6.65 (m, 4 H), 2.50 (s, 3 H), | yl)quinoline-3-carboxamide 2.65 (m, 4 H), 1.40 (t, 3 H) 2.30 (s, 1 H), 8.85 (s, 1 H), 4-[(3-Chloro- 2- .10.70 |457 (s, 1 H), 7.55 (s, 1 H), fluorophenyl)amino]-7- Y 8.30 compound (m, 2 H), 7.05 (m, 1 H), | ethoxy-6-(4- 7.20 intermediate Ve (m, 2H), 4.20 (q.2H), methylpiperazin-1 _ 6.80 on oi YR H), yl)quinoline-3-carboxamide H), 8.85 (5, 1 H), | 7-Ethoxy-4-[(3- 2 1 ) 10.70[ 433 | Compound 1 8.20 (s, 1 H), 7.60 (s, 1 H), ethylphenyl)amino]-6-(4- methylpiperazin-1- ;l 0 0 fs intermediate VY m, : : 7 : with q, .and H), 2.50 (m, 5 H). 2.30 (m.4 yl)quinoline-3-carboxamide Yeov

Compound 440 | 1111-08 10.38 (s, 1 H), 8.86 | 4-[(3-Chlorophenyl) VY 1 (s, 1 H), 7.60 (s, 1 H), 7.09- | amino]-7-ethoxy-6-(4-

YY median 7.15 (m, 3 H), 6.74-6.81 (m, | methylpiperazin-1- 4 H), 4.07 (q, 2 H), 2.70 (s, | yDquinoline-3-carboxamide 4 H), 2.26 (s, 4 H), 2.09 (s, 3H), 1.86 (t,3H) Compound 457 | 10.85 (s, 1 H), 8.95 (s, 1 H), | 4-[(2-Chloro-4- VY 1 8.38 (s, 1 H), 7.75 (s, 1 H), |fluorophenyl)amino]-7-

VY Median 7.65 (d, 1 H), 7.30 (s, 1 H), | ethoxy-6-(4- 7.15 (m, 1H), 6.85 (m, 1 | methylpiperazin-1-

H), 6.69 (s, 1 H), 4.22 (q, 2 | yl)quinoline-3-carboxamide

H), 2.80 (m, 4 H), 2.40 (m, 4 H), 2.21 (s, 3 H), 1.45 (4, 3 H) Composite 457 110.64 (s, 1 H), 8.85 (s, 1 H), | 4-[(4-Chloro-2- 7 1 8.30 (s, 1 H), 7.69 (s, 1 H), |fluorophenyl)amino]-7-

Ve Median 7.50 (d, 1 H), 7.27 (s, 1 H), | ethoxy-6-(4- 7.15 (d, 1H), 6.89 (m, 1H), | methylpiperazine-1- 6.80 (s, 1H), 4.20 (q, 2H), |yD)quinoline-3 -carboxamide 2.80 (m, 4 H), 2.35 (m, 4

H), 2.18 (s, 3 H), 1.40 (t, 3

H) Al-Markab 419 | 10.70 (s, 1 H), 8.90 (s, 1 H), | 7-Ethoxy-4-[(3- Vo ‘ 8.27 (s, 1 H), 7.65 (s, 1 H), | methylphenyl)amino]-6-(4-

Vo Median 7.28 (s, 1 H), 7.20 (m, 1 H), | methylpiperazin-1- 6.93 (m, 2 H), 6.80 (m, 2 | yl)quinoline-3-carboxamide

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 ) 3

H) Compound 453 110.80 (8, 1 H), 8.89 (s, 1 H), | 4-[(2-Chloro-3- 71 1 8.32 (s, 1 H), 7.65 (s, 1 H), | methylphenyl)amino]-7- 1776 Median 7.22 (s, 1 H), 7.00 ( m, 2H), | ethoxy-6-(4- 6.70 (s, 1 H), 6.53 (m, 1 H), | methylpiperazine-1- 4.18 (q, 2 H), 2.69 (m, 4 H), |yl)quinoline-3 -carboxamide 2.38 (s, 3 H), 2.30 (m, 4 H), 2.15 6,3 H), 1.39 (t, 3 H) Compound 437 | 10.75 (s, 1 H), 8.86 (s, 1 H), | 7-Ethoxy-4-[(3-fluoro-2- BAL' 8.30 (s, 1 H), 7.65 (s, 1 H), | methylphenyl)amino]-6-(4-

VY Median 7.20 (s, 1 H), 7.05 (m, 1 H), | methylpiperazine-1- 6.90 (m, 1 H), 6.66 (s, 1 H), | yDquinoline-3-carboxamide 6.49 (d, 1H), 4.20 (q, 2H), 2.70 (m, 4H), 2.35 (m, 4

H), 2.22 (s, 3 H), 2.15 3

H), 1.39 (t, 3 H) 1 (s, 1 H), 7.70 (s, 1 H), 7.34 | Difluorophenyl)amino]-7- Ram »Al

VA median (s, 1 H), 7.16 (m, 1 H), 6.99 methoxy-6-(4- ' (s, 1 H), 6.89 (m, 2 H), 6.73 |methylpiperazin-1- ( m, 1 H), 3.99 (s, 3 H), 2.84 |yl)quinoline-3-carboxamide (s, 4 H), 2.41 (s, 4 H), 2.23 (s, 3 H) Compound 474 | THF-d8 10.96 (s, 1 H), 8.72 7-Methoxy-6-(4- va (s, 1 H), 7.67 (s, 1 H), 7.25 |methylpiperazin-1 -yl)-4-

Va Median (d, 1 H), 7.18 (s, 1 H), 7.02 | {[2-methyl-3- (t, 1 H), 6.87 (s, 1 H), 6.78 (trifluoromethyl)phenyl]ami (d, 1 H), 6.64 (s, 1 H), 3.83 | no}quinoline-3- (s, 3 H), 2.63 (s, 4 H), 2.45 | carboxamide (s, 3H), 2.21 (s, 4H), 2.06 (s, 3H) Compound 426 | THF-d8 10.86 (s, 1 H), 8.70 4-[(4-Chlorophenyl) A 1 (s, 1 H),7.62(s,1H),7.18 amino]-7-methoxy-6-(4-

Av Median (s, 1 H), 7.10 (d, 2 H), 6.78 | methylpiperazine-1- (m, 4 H), 3.84 (s, 3 H), 2.68 | yl)quinoline-3-carboxamide (s,4 H), 2.25 (s, 4 H), 2.09 (s, 3 H) Compound 424 | THF-d8 10.85 (s, 1 H), 8.67 | 4-[(2-Fluoro-4- A (s, 1 H), 7.48 (s, 1 H), 7.16 methylphenyl)amino]-7-

AY (s, 1 H), 6.64-6.89 (m, 5 H), methoxy-6-(4-methyl 3.82 (s, 3 H), 2.63 (s, 4 H), | piperazin-1 - yl)quinoline-3- 2.24 (s, 4 H), 2.18 (s, 3 H), | carboxamide 2.08 (s, 3 H), compound 460 | THF-d8 10.96 (s, 1 H), 8.79 7-Methoxy-6-(4- AY (s, 1 H), 7.60 (s, 1 H), 7.23 |methylpiperazin-1 -yl)-4-

AY median (m, 3 H), 6.89 (m, 4 H), {[3-(trifluoromethyl) 4.09 (s, 3 H), 2.81 (s, 4 H), phenyl]amino}quinoline-3- 2.37 (s,4H),2.20(s,3H) | compound carboxamide 438 | 00:01 10.47 (s, 1 H), 8.76 7-Ethoxy-4-[(2-fluoro-5- AV (s, 1 H), 7.26 (s, 1 H), 7.01 methylphenyl)amino]-6 (4-

AY median (m, 1 H), 6.95 (s, 1 H), 6.85 methylpiperazin-1- (m, 1 H), 6.76 (d, 1 H), 6.02 yDquinoline-3-carboxamide (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 ) 3 H) Compound 467 110.80 (s, 1 H), 8.86 (s, 1 H), | 4-[(3-Chloro-2- At 1 8.30 (s, 1 H), 7.65 (s, 1 H), methylphenyl)amino]-7-

Median Af 7.20 (m, 2H), 7.06 (m, 1 ethoxy-6-(4-ethyl piperazin-

H), 6.65 (s, 2H), 4.15 (q, 2 | 1-yl)quinoline-3-

H), 2.66 (m, 4 H), 2.50 (s, 3 | carboxamide

H), 2.35 (m, 6 H), 1.40 (t, 3

H), 0.98 (t, 3 H) Compound 467 | 0:0 10.46 (s, 1 H), 8.68 | 4-[(3-Chloro-2- AO (s, 1 H), 7.19 (s, 1 H), 7.12 methylphenyl)amino]-7-

Ao median (d, 1 H), 6.96 (m, 1 H), 6.68 ethoxy-6-(4-methyl-1,4-

Ysov

- mm — (d, 1 H), 6.63 (s, 1 H), 6.05 | diazepan-1-yl)quinoline-3- (br s, 2 H), 4.17 (q, 2 H), | carboxamide 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) Compound 451 | 10.80 (s, 1 H), 8.90 (s, 1 H), 7-Ethoxy-6-(4- AR 8.34 (s, 1 H), 7.70 (s, 1 H), | ethylpiperazin-1-y1)- 4-[(3-

AT Median 7.30 (s, 1 H), 7.12 (m, 1 H), | fluoro-2- 6.95 (m, 1 H), 6.75 (s, 1 H), | methylphenyl)amino] 6.54 (m, 1H), 4.21 (q, 2H), | quinoline-3-carboxamide 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) Compound | 451 | CD:CL 10.30 (s, 1H), 8.60 (s, | 7-Ethoxy-4-[(3-fluoro-2- AV 1 H), 7.10 (s, 1H), 6.85 (m, 1 | methylphenyl) amino]-6-(4-

AY median H), 6.65 (m, 1 H), 6.56 (s, 1 | methyl-1,4-diazepan-1-

H), 6.42 (d, 1 H), 4.05 (q, 2 yl)quinoline-3-carboxamide

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) 439 | 10.79 (s, 1 H), 8.83 (s, I H), | 7-Ethoxy-4-[(2-fluoro-4- compound 8.26 (s. 1 H), 7.63 (5, 1 H), | methylphenybamino] 16-4

AA Median 7.20 (s, 1 H), 7.09 (d, 1 H), | methylpiperazin-1- 6.91 (m, 2H), 6.80 (s, 1H), yl)quinoline-3-carboxamide 4.17 (q, 2H), 2.68 (s, 4H), 232 (s, 4H) Compound 450 110.89 (s, 1 H), 8.83 (s, 1 H), 7-Ethoxy- 4-[(3-methoxy-2- AS 8.28 (s, 1 H), 7.58 (s, 1 H), | methylphenyl)amino]-6-(4-

Median 7.16 (s, 1 H), 7.05 (m, 1 H), | methylpiperazine-1- 6.77 (d, 1 H), 6.70 (s, 1 H), | yl)quinoline-3-carboxamide 6.38 (d, 1H), 4.14 (q, 2H), 3.80 (s, 3H), 2.59 (s, 4H), 2.27 (s, 4H), 2.16 (s , 3 H), 2.14 (s,3 H), 1.39 (t, 3H) Compound 442 | CDs;OD 8.82 (s, 1 H), 7.29 4-[(2,5-Difluorophenyl)q. (s, 1H), 7.19 (m, 1H), 7.03 | amino]-7-ethoxy-6-(4- 960 median (s, I H), 6.79 (m, 1 H), 6.58 | methylpiperazin-1- (m, 1 H), 4.25 (q, 2 H) Compound 456 | CDs;OD 8.82 (s, 1 H), 7.29 4-[(2,5-Difluorophenyl) 91 (s, 1 H), 7.20 (m, 1 H), 7.04 | amino]-7-ethoxy-6-(4- 911 median (s, 1 H), 6.79 (m, 1 H), 6.58 | ethylpiperazin-1- (m, 1 H), 4.25 (q, 2 H) ), 2.95 |yl)quinoline-3-carboxamide (m, 4H), 2.59 (m, 4H), 2.48 (q, 2H), 1.52 (t, 3H), 1.11 (t, 3H)

Ye¢ov

CDs;OD 8.76 (s, 1 H), 7.26 4-[(2,5-Difluorophenyl) qv | 456 Compound (s, I H), 7.17 (m, 1 H), 6.88 | amino]-7-ethoxy-6-(4- (s, 1 H), 6.76 (m, 1 H), 6.51 | methyl-1,4-diazepan-1- intermediate Y (m, 1 H), 4.25 (q, 2 H), 3.29 |yl)quinoline-3-carboxamide (m, 2 H), 3.08 (m, 2 H), (m, 2 H), 2.68 (m , 2 2.80 H), 2.37 (s, 3 H), 1.93 (m, 2 H), 1.54 (t, 3 H) (s, 1 H), 8.84 (s, 1 H), 7-Ethoxy-6-(4- qv 110.79 453 Compound (s, 1 H), 7.63 (s, 1 H), | ethylpiperazin-1-yl)-4-[(2- 8.27 (s, 1 H), 7.13 (d, 1 H), |fluoro-4- 7.20 median 97 (m, 2 H), 6.80 (s, 1 H), | methylphenyl)amino] 6.90 (q, 2 H ), 2.68 (s, 4 H), | quinoline-3-carboxamide 4.16 (s, 4 H), 2.31 (s, 2 H), 2.36 (s, 3 H), 1.38 ( 3 H), 2.27 (t, 3 H) 0.97 110.74 (s, 1 H), 8.80 (s, 1 H), 4-[(3,4-Dimethylpheny!) q¢ 435 (s, 1 H), 7.54 (s, 1 H) , | amino]-7-ethoxy-6-(4- 8.18 (s, 1 H), 7.03 (d, 1 H), | methylpiperazin-1- 7.16 intermediate 94 (s, 1 H), 6.79 (s) , 1 H), |yl)quinoline-3-carboxamide 6.85 (d, 1 H), 4.15 (q, 2 H), 6.72 (s, 4 H), 2.29 (s, 4 H), 2.65 (s, 3 H), 2.14 (s, 3 H), 2.16 (s,3 H), 1.38 (t, 3 H) 2.13 110.55 (s, 1 H), 8.83 (s , 1 H), 4-[(2,4-Difluorophenyl) q0 442 (s, 1 H), 7.63 (s, 1 H), | amino]-6-ethoxy-7-(4- 8.25 (m, 1 H), 7.19 (s, 1 H), | methylpiperazin-1- 7.35 median q0 (d, 2 H), 6.80 (s, 1 H), |yl)quinoline-3-carboxamide 6.98 (q, 2 H), 3.15 (s, 4 H), 3.65 (s, 4 H), 2.22 (s, 3 H) , 2.48 (t, 3 H) 1.21 (s, 1 H), 8.91 (s, 1 H), 4-[(2,3-Dichlorophenyl) qv 10.65 1 474 (s, 1 H) ), 7.75 (s, 1 H), | amino]-6-ethoxy-7-(4- 8.35 725(s, 1 H), 7.22 (d, 1 H), methylpiperazin-1- intermediate 97 (m, 1 H), 6.66 (s, 1 H), |yl)quinoline-3-carboxamide 7.14 (d, 1 H), 3.66 (q, 2 H), 6.54 (s, 4 H), 2.49 (s, 4 H), 3.17 (s,3 H), 1.21 (1, 3H) 2.23 (s, 1 H), 8.89 (s, 1 H), 4-[(2,3-Difluorophenyl) qy 10.65 | 441 Compound (s, 1 H), 7.70 (s, 1 H), amino |-7-ethoxy-6-(4- 8.30 (s, 1 H), 7.05 (m, 2 H), | methylpiperazin -1- 7.25 median VY (s, 1 H), 6.65 (m, 1 H), |yl)quinoline-3-carboxamide 6.85 (q, 2 H), 2.75 (m, 4 H) , 4.16 (m, 4 H), 2.15 (s, 3 H), 2.35 (t, 3 H) 1.40 L 1

(s, 1 H), 8.85 (s, 1 H), 4-[(2,3-Dimethylphenyl) aA 10.98 | 433 Compound 1 8.25 (s, 1 H), 7.55 (s, 1 H), amino]-7-ethoxy-6-(4- (s, 1 H), 7.00 (m, 2 H), | methylpiperazin-1- 7.16 intermediate AA (m, 2 H), 4.15 (q, 2 H), |yl)quinoline-3-carboxamide 6.65 (m, 4 H), 2.30 (m, 7 2.60 H), 2.20 (s, 3H), 2.15 (s, 3 H), 1.40 (t, 3 H), 8.80 (s, 1 H), | 4-[(4-Chloro-3- 49 1 ,8) 10.15 | 458 Compound (s, 1 H), 7.60 (s, 1 H), fluorophenyl)amino]-7- 8.12 (m, 1 H), 7.28 (s, 1 H), | ethoxy-6-(4- 7.39 median 99 (m, 2 H), 6.70 (d, | methylpiperazin-1- 6.98-6.90 H), 4.20 (q, 2 H), 2.90 (m, | yl )quinoline-3-carboxamide 1 H), 2.40 (m, 4 H), 1.40 (t, 4 3H) (s, 1 H), 8.92 (brs, 1 4-[(2,3) -Dichlorophenyl) ya 10.65 | 488 compound 1 H), 8.35 (s, 1 H), 7.74 (s, 1 amino]-6-ethoxy-7-(4- H), 7.23 (d, 2 H) ), 7.14 (m, 1 | ethylpiperazin-1-median H), 6.66 (s, 1 H), 6.54 (d, 1 | yl)quinoline-3-carboxamide Yeo 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 3 H) (s, 1H), 8.85 (s, 1H), | 4-[(2,4-Difluorophenyl) Yo 10.57 | 456 | Compound 1 8.27 (s, 1 H), 7.64 (s, 1 H), amino]-6-ethoxy-7-(4- (m, 1 H), 7.21 (s, 1 H), | ethylpiperazin -1- 7.37 intermediate (m, 2 H), 6.81 (s, 1 H), |yl)quinoline-3-carboxamide 6.99 011 3.66 (q, 2 H), 3.17 (s, 4 H), (s, 4 H), 2.39 (q, 2 H), 2.51 (t,3 H), 1.04 (t, 3 H), 1.21 (s, 1 H), 8.85 (s, 1 H ), 4-[(3-Chloro-2,4- yy 10.60 | 489 (s, 1 H), 7.65 (s, 1 H), difluorophenyl)amino]-7- 8.27 ' (m, 2 H), 6.95 (m, 1 ethoxy-6-(4-ethyl piperazin- 7.25 intermediate H), 6.85 (s, 1 H), 4.20 (q, 2 | 1-yl)quinoline-3- 01 H), 2.80 (m, 4 H), 2.40 (m, | carboxamide H), 2.31 (m, 2 H), 1.40 (1, 4 3H), 1.00¢, 3 H) ( s, 1 H), 8.83 (s, 1 H), 4-[(3-Chloro-2,4- yoy 10.60 | 475 (s, 1 H), 7.65 (s, 1 H), difluorophenyl) amino]-7- 8.28 ' (m, 2 H), 7.00 (m, 1 | ethoxy-6-(4- 7.25 intermediate H), 6.88 (s, 1 H), 4.20 (q, 2 methylpiperazin -1- 0 H), 3.80 (m, 4 H), 2.39 (m, |yl)quinoline-3-carboxamide H), 2.20 (s, 3 H), 1.40 (1, 4 3H ) (s, 1 H), 8.82 (s, 1 H), | 4-[(3-Chloro-4- yg 10.12 | 458 Compound 1 8.15 (s, 1 H), 7.59 (s, 1 H), fluorophenyl)amino]-6- (m, 2 H), 7.14 (d, 1H), | ethoxy-7-(4- 7.27 median (s, 1 H), 6.88 (d, 1 H), methylpiperazin-1- 6.97 Yéov yo 3.81 (q, 2 H), 3.19 (s, 4 H) ), |yl)quinoline-3-carboxamide 2.48 (s, 4 H), 2.25 (s, 3 H), 1.27 (t, 3 H) Compound 472 10.17 (s, 1 H), 8.86 (s, 1 H), | 4-[(3-Chloro-4- 1.1 8.19 (s, 1 H), 7.63 (s, 1 H), |fluorophenyl)amino]-6- median 7.34 (m, 1 H), 7.29 ( s, 1 H), | ethoxy-7-(4-ethylpiperazin- 7.19 (d, 1H), 7.01 (s, 1H), |1-yD)quinoline-3-

Yeo 6.92 (d, 1 H), 3.85 (q, 2 H), | carboxamide 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) Compound 478 | 1111-08 11.14 (s, 1 H), 8.75 4-{[4-Fluoro-2- yen (s, 1 H), 7.58 (s, 1 H), 7.42 | (trifluoromethyl)phenyl]ami intermediate (m, 1 H), 7.20 (s, 1 H), 7.02 | no}-7-methoxy-6-(4- (m, 1 H), 6.88 (s, 1 H), 6.64 | methylpiperazin-1- 1 (m, 1 H), 6.58 (s, 1 H), 3.83 | yhquinoline-3-carboxamide (s, 3 H), 2.72 (s, 4 H), 2.23 (s, 4 H), 2.08 (s, 3 H) Compound 444 | 10.95 (s, 1 H), 8.83 (s, 1 H), | 4-[(2-Chloro-4- yoy 7.63 (s, 1 H), 7.32 (m, 1 H), | fluorophenyl)amino]-7- median 7.30 (s, 1 H), 6.92 (s, 1 H), | methoxy-6-(4- 6.87 (m, 1 H), 6.74 (s, 1 H), | methylpiperazin-1- 07 6.71 (m, 1 H), 3.95 (s, 3 H), |y)quinoline-3-carboxamide 2.79 (s, 4 H), 2.37 (s, 4 H), 2.19 (s, 3 H) Compound 476 | 10.37 (s, 1 H) ), 8.86 (s, 1 H), 7-Methoxy-6-(4- 1 8.23 (s, 1 H), 7.65 (s, 1 H), | methylpiperazin-1-yl)-4- median 7.31 -7.38 (m, 2H), 6.85- |{[3-(trifluoromethoxy) 6.96 (m, 4H), 3.94 (s, 3H), |phenyl]amino}quinoline-3- 01 2.76 (s, 4 H), 2.35 (s, 4 H), | carboxamide 2.16 (s,3 H) 420 [11.39 (s, 1 H), 8.82 (5, 1 H), | 4-[(2,6- compound) 821 (5, 1 H), 751 (5, 1 H), |DimethylphenyDamino]-7- |© median 7.15-7.20 (m, 4 H), 6.64 )5.1 | methoxy-6-(4-

H), 3.87(s,3H). 2.44 (5, 4H), | 1 peihy iniperazin-1-

Ved 228 Sen? 2.15 (s, 3 H), yDquinoline-3-carboxamide compound 469 | 10.55 (s, 1 H), 8.81 (s, 1 H), 4-[(2,4-Difluorophenyl) VY. 8.30 (s, 1 H), 7.80 (s, 1 H), | amino]-7-ethoxy-6-(4-ethyl- intermediate 7.45 (m, 3 H), 7.20 (m, 2 H), |1 ,4-diazepan-1- 4.25 (m, 2 H), 3.15 (m, 6 H), yl)quinoline-3-carboxamide 1 L

A No 2.10 (m, 2 H), 1.50 ( 3 H), 1.25 3 H) 487 | 9.00 (s, 1 H), 8.51 (s, 1 H), 4-[(2,3-Dichlorophenyl) compound 7.95 (5, 1 H), 7.60 (m, 1 H), | amino]-6-(4-ctyl-1 4.1 median 748 (s, 1 H), 740-732 (m, 2 | diazepan-1-y1)-7- ' 350 5 3 05 ¢ (s , J 0 methoxyquinoline-3- 11.m, , 2.m, , 2.70 (m, 2H), 2.20 (m, 2H), CArboxamide 2.05 (m, 2H), 1.29 (t, 3H) ) Compound 501 | 10.00 (s, 1 H), 8.90 (s, 1 H), 4-[(2,3-Dichlorophenyl) 111 1 8.40 (s, 1 H), 7.90 (s, 1 H), amino]-7-ethoxy-6-(4-ethyl- intermediate 7.65 (d, 1 H), 7.30 (m, 3 H), 1,4-diazepan-1- ' 6.80 (s, 1 H), 4.15 (q, 2H), yDquinoline-3-carboxamide

YY 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 (1, 3 H), 1.15 (t, 3 H) 457 [10.74 (s, 1 H), 8.83 (s, | H), | 4-[(2,4-Difluorophenyl) yyy compound 8.28 (s, 1 H), 7.65 (s, 1 H), | amino]-7-isopropoxy-6-(4- ' 7.36 ) 1 H), 7.23 (s, 1 H), methylpiperazin-1- median 7.02 (m, 2 H), 6.79 (s, 1 H), yl)quinoline-3-carboxamide 4.81 (m, 1H), 2.71 (s, 4H),

Yo 2.35 (s, 4 H), 2.16 (s, 3 H), 1.34 (d, 6 H) Compound 490 | 10.13 (s, 1 H), 8.78 (s, 1 H), | 4-[(3,4-Dichlorophenyl) VY ¢ 1 8.12 (s, 1 H), 7.59 (s, 1 H), amino}-7-isopropoxy-6-(4- median 7.46 (d, 1 H) ), 7.28 (s, 1 H), |methylpiperazin-1- 7.11 (s, 1 H), 6.96 (s, 1 H), |yl)quinoline-3-carboxamide

Yoo 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) Compound 474 110.66 (s, 1 H), 8.86 (s, 1 H), | 4-[(3-Chloro-2- \Vo 1 8.29 (s, 1 H), 7.69 (s, 1 H), fluorophenyl)amino]-7- median 7.29 (s, 1 H), 7.21 (t , 1 H), | isopropoxy-6-(4- 7.07 (t, 1 H), 6.88 (s, 1 H), | methylpiperazin-1-

Yel 6.76 (m, 1 H), 4.85 (m, 1 | yl)quinoline-3-carboxamide

H), 2.83-2.50 (m, 8 H), 2.36 (s, 3 H), 1.37 (d, 6 H) Composite 490 | 10.83 (s, 1 H), 8.92 (s, 1 H), 4-[(2,3-Dichlorophenyl) 71 1 8.38 (s, 1 H), 7.77 (s, 1 H), amino]-7-isopropoxy -6-(4- median 7.30 (s, 1 H), 7.26 (s, 1 H), methylpiperazin-1- 7.16 (m, 1 H), 6.67 (s, 1 H), |yl)quinoline- 3-carboxamide

Yov 6.62 (d, 1 H), 4.85 (m, 1 H), 2.74 (s, 4 H), 2.36 (s, 4 H), 2.17(s,3H), 1.37(d, 6 H) Composite | 474 [1037 (5, 1H), 881 (5, TH), | 4-[3-Chloro-4-_">8.18 (s, 1 H), 7.61 (s, 1 H), fluorophenyl)amino]-7- median 7.31 (m, 1 H), 7.27 (s, 1 H), isopropoxy-6-(4- 7.12 (m, 1 H), 6.91 (s, 2 H), methylpiperazine-1-

Yeov

A 4.86 (m, 1 H), 2.82 (s, 4 H), | yl)quinoline-3-carboxamide B 2.41 (s, 4 H), 2.20 (s, 3 H), 1.36 (d, 6 H) Compound 384 110.39 (85, 1 H), 8.80 (s, 1 H), 4-[(2,4-Difluorophenyl) 117 8.26 (s, 1 H), 7.82 (d, 1 H), amino]-6-morpholin-4- intermediate 7.69 (s, 1 H), 7.59 (d, 1 H), | ylquinoline-3-carboxamide 7.35 (t, 1 H), 7.01 (m, 2 H), ved 6.86 (s, 1 H), 3.68 (m, 4 H), 2.94 (m, 4 H) Compound 401 | 9.83 (s, 1 H), 8.72 (s, 1 H), | 4-[(3-Chloro-4- 111 8.09 (s, 1 H), 7.84 (d, 1 H), fluorophenyl)amino}-6- median 7.64 (d, 1 H), 7.59 (m, 1 H), | morpholin-4-ylquinoline-3- 7.28 (1, 1H), 7.10 (m, 1H), | carboxamide vi. 7.01 (s, 1 H), 6.86 (m, 1 H), 3.71 (m, 4 H), 3.05 (m, 4 H) Composite 417 | 10.56 (s, 1 H), 8.91 (8, 1 H), 4-[(2,3-Dichlorophenyl) \Y. 8.42 (s, 1 H), 7.89 (d, 2 H), amino|-6-morpholin-4- median 7.65 (m, 1 H), 7.25 (m, 1 | ylquinoline-3-carboxamide

H), 7.14 (t, 1 H), 6.66 (s, 1 7.5 H), 6.55 (d, 1 H), 3.66 (m, 4

H), 2.94 (m, 4 H) 398 110.40 (s, 1 H), 8.77 (s, 1 H), 4-[(2,4-Difluorophenyl) yY 8.27 (s, 1 H), 7.77 (s, 1H), | amino]-6-(4- median 7.67 (s, 1 H), 7.55 (d, 1 H), | methylpiperazin-1- 7.33 (t, 1 H), 6.99 (m, 2 H), | yl )quinoline-3-carboxamide vay 6.79 (s, 1 H), 2.94 (m, 4 H), 2.34 (m, 4 H), 2.16 (s, 3 H) Compound 430 110.52 (s, 1 H) ), 8.86 (s, 1 H), 4-[(2,4-Dichlorophenyl) YY Y 8.37 (s, 1 H), 7.82 (m, 2 H), | amino]-6-(4- median 7.70 (d, 1 H), 7.60 (m, 1 H), |methylpiperazin-1- 7.21 (m, 1 H), 6.58 (m, 2 |yl)quinoline- 3-carboxamide vay H), 2.96 (m, 4 H), 2.34 (m, 4 H), 2.16 (s, 3 H) Compound 430 | 9.67 (s, 1 H), 8.69 (s, 1 H), 4-[(3,4-Dichlorophenyl) yyy 8.05 (s, 1 H), 7.83 (d, 1 H), | amino]-6-(4- median 7.61 (m, 2 H), 7.43 (d, 1 H), | methylpiperazin-1- 7.05 (m, 2 H), 6.84 (m, 1 | yDquinoline-3- carboxamide vie H), 3.16 (m, 4 H), 2.48 (m, 4 H), 2.25 (s, 3 H) compound |429 |00300 8.83 (s,1 H), 7.89 |4-[(2 ,3-Dichlorophenyl) YY g (d, 1 H), 7.83 (d, 1 H), 7.55 | amino]-6-(4- intermediate (d, 1 H), 7.39 (m, 2 H), 7.08 |methylpiperazine-1- (d, 1 H), 3.62 (m, 2 H), 3.54 |yl)quinoline-3-carboxamide

Vie (m, 2 H), 321 (m, 2 H), 3.06 (m, 2 H), 2.90 (s, 3 H) Composite 560 | CD2CI2 10.20 (s, 1 H), 8.65 tert-Butyl 4-{3- \Yo (s, 1 H), 7.15 (s, 1 H), 6.95 (aminocarbonyl)-4-[(2,3- median) ‎ (d, 1 H), 6.80 (m, 1 H), 6.60 dichlorophenyl)amino]-7-

Yé¢ov yyw (s, 1 H), 6.40 (d, 1 H), 4.05 | ethoxyquinolin-6- (9, 2 H), 3.25 (m, 4 H), 2.60 | yl} piperazine-1-carboxylate (m, 4 H), 1.32 (t, 3 H), 1.28 (s, 9H) Compound 513 110.60 (s, 1 H), 8.78 (s, 1 H), tert-Butyl 4-{3- XT 8.20 (s, 1 H), 7.60 (s, 1 H), | (aminocarbonyl)-4-[(2,4- median 7.30 (m, 1 H), 7.22 (s, 1 H), | difluorophenyl)amino]-7- 6.98 (m, 2 H), 6.80 (s , 1 H), | methoxyquinolin-6- 101 3.86 (s, 3 H), 3.25 (m, 4 H), | yl} piperazine-1-carboxylate 2.59 (m, 4 H), 1.31 (s, 9 H) 527 tert-Butyl 4-{3- (aminocarbonyl)-4-[(2,4- TY) intermediate difluorophenyl)amino]-7-methoxyquinolin-6-yl}-1,4-

We diazepane-1-carboxylate compound 573 | CDCI3 10.63 (s, 1 H), 8.75 tert-Butyl 4-{3-YYA (s, 1 H), 8.20 (s, 1 H), 7.88 | (aminocarbonyl)-4-[(2,3- median (s, 1 H), 7.56 (s, 1 H), 7.30 | dichlorophenyl)amino]-7- (m, 1 H), 7.18 (m, 1 H), | ethoxyquinolin-6-yl}-1,4-111 6.90 (m, 1 H), 6.70 (m, 1 | diazepane-1-carboxylate

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, 9 H) Composite 527 | CDCI3 10.60 (s, 1 H), 8.85 tert-Butyl 4-{3- 17 (s, 1 H), 7.31 (s, 1 H), 6.90 | (aminocarbonyl)-4-[(2,4- median (m, 3 H), 675 (m, 1 H), | difluorophenyl)amino]-7- 4.20 (q, 2 H), 3.50 (m, 4 H), | ethoxyquinolin-6- ny 2.75 (m, 4 H), 1.40 (t, 3 H), | yl} piperazine-1-carboxylate 1.38 (s, 9 H) compound 541 tert-Butyl 4-{3- Vv. (aminocarbonyl)-4-[(2,4- intermediate difluorophenyl)amino]-7- ethoxyquinolin-6-yl}-1,4-

VIA diazepane-1-carboxylate Compound 560 tert-Butyl 4- {3- 11 (aminocarbonyl)-4-[(2,3- intermediate dichlorophenyl)amino]-7- methoxyquinolin-6-yl}-1, 4- 11 diazepane-1-carboxylate 424 | 10.82 (s, 1 H), 8.88 (s, 1 H), | 4-[(2-Fluoro-5- compound 8.31 (s, 1 H), 7.68 (s, 1 H), | methylphenyl)amino]-7- d median 7.27 (s, 1 H) , 7.17 (m, 1 H), methoxy-6-(4- 6.86 (m, 2 H), 6.72 (m, 1 H), | methviniperazin-1- 00 2 3 ; Hy 20 5 ; 0 yl)quinoline 3-carboxamide 2.15 (s, 3 H) 428 [10.68 (s, 1 H), 8.90 (s, 1 H), | 4-[(2,5- Alak [ER EL] by Germoussamah 11

Yeov

(m, 2 H), 6.88 (m, 2 H), methoxy-6-(4- 7.33 median i 6.64 (m, 1 H), 3.96 (s, 3 H), | methylpiperazin-1- 171 ore on 2.38 (s, 4 H), | y])quinoline-3-carboxamide (s, 18 (s, 1 H), 8.88 (s, 1 H), | 4-[(3) -Chloro-2- 10.86 | 440 (s, 1 H), 7.66 (s, 1 H), | methylphenyl)amino]-7- 've 8.31 Compound Lo dl 7.24 (5, 1 H), 7.19 (m, 1 H), | methoxv-6.(4. (m, 1 H), 6.68 (m, 2 H), eta 1.7.08 lucid 11 < > ; i 2 5 ; yl)quinoline -3-carboxamide (s, 3H) 217 (s, 1 H), 8.90 (s, 1 H), 4-[(2-Chloro-3- 10.81 | 440 (s, 1 H) , 7.69 (s, 1 H), |methylphenyl)amino]-7- ve 8.32 compound (s, 1 H), 7.05 (d, 1 H), methoxy-6-(4- 7.27 intermediate 1H) , 6.69 (s.1 H), |methorsiverazin.1- ,5( 7.03 1, 0-5 1 ty ) 7 ; i yl)quinoline-3-carboxamide (s, 4 H), 2.15 ( s, 3 H) 2.33 THF-dg 10.76 (s, 1 H), 8.62 (s, | 4-[(2.,4-Difluorophenyl) | 442 I H), 7.50 (s, 1 H), 7.14 (s, 1 amino]-6-[3- "1 H), 6.93 (m, 1 H), 6.71 (m, 3 | (dimethylamino)pyrrolidin- intermediate Vy 330 on 5 0 y 0 1-yl]-7-methoxy quinoline- Je > 3 - 1 and m, . H), 2.43 (m. 2 H), | > carboxamide 1 ,1( 2.89 (s, 6 H), 1.85 (m, 1 H), 2.04 (m, 1 H), 1.56 (s, 1 H), 8.87 (s, 1 H) , |4-[(3-Chloro-2- 10.69[ 444 (s, 1 H), 7.71 (s, 1 H), |fluorophenyl)amino]-7- TY 8.30 (s, 1 H) ), 7.24 (m, 1 H), methoxy-6-(4-7.30 intermediate (im, 1H), 6.85 (5, 1 H), |prepoisinerazin |. 7.07 yl)quinoline-3-carboxamide ; 5 m 0 1" 0 on A (s, 3 H) 2.17 CDCl; 10.37 (s, 1 H), 8.75 (s, | 4-|(3-Chloro-5- | 459 H), 7.30 (s, 1 H), 692 (s, 1 | fluorophenyl)amino]-7- YA 1 on (m, 2 H), 6.51 (d, 1 ethoxy-6-(4-methyl) 0 Intermediate Si piperazin-1-yl)quinoline-3- 0 b a 0 1 carboxamide | > b H) 3 01 1.54 [CDCl 10.41 (5, 1 H), 8.74 | 7 -Ethoxy-6-(4- yr 460 | compound 1 (s, 1 H), 7.28 (s, 1 H), 6.87 | methylpiperazin-1-yl)-4- (s, 1 H), 6.79 (m, 1 H), 6.61 | [(2,3,4-trifluorophenyl) intermediate (m, 1 H), 4.21 (q, 2 H), 2.87 | amino]quinoline-3- YY ( s, 4 H), 2.52 (s, 4 H), 2.31 |carboxamide (s,3 H), 1.52 (t, 3 H) CDCl; 10.46 (s, 1 H), 8.71 (s, | 4-[(5-Chloro-2- ve. | 455 | compound I H), 7.26 (s, 1 H), 7.16 (d, 1 | methylphenyl)amino]-7-H), 6.97 (dd, 1 H), 679 (m, 2 | ethoxy-6-( 4- Intermediate methylpiperazin-1- 5 0 9 0 2 b (s a 1 2 0 0 / yl)quinoline-3-carboxamide M2 VYA b | CDCl; 1068 (5, 1 H ), 8.65 | 7-Ethoxy-4-[(4-methoxy2- 451 | compound 1 (s, 1 H), 7.18 (s, 1 H), 6.89 | methylphenyl)amino]-6-(4- Yeov

— qv B median (m, 2 H), 678 (d, 1 H), 6.62 methylpiperazin-1- (dd, 1 H), 5.92 (br s, 2 H), | yl)quinoline-3-carboxamide 1 4.15 (q, 2H), 3.75 (s, 3H), 2.71 (s, 4H), 2.44 (s, 4H), 2.29 (s, 3H), 2.25 ( s, 3 H), 1.48 (t, 3 H) Compound 509 | CDCl; 10.43 (s, 1 H), 8.81 (s, 4-{[2-Chloro-5- VEY 1 H), 7.55 (d, 1 H), 7.35 (s, 1 (trifluoromethyl)phenyl] intermediate H) , 7.15 (dd, 1 H), 6.88 (s, 1 amino }-7-ethoxy-6-(4-

H), 6.77 (s, 1 H), 6.00 (brs, 2 methylpiperazin- 1- 000 0 0 Si yl)quinoline-3-carboxamide 1.53 (t, 3 H) 474 [10.26 (s, 1 H) , 8.50 (s, 1 H), | 4[(2.4- compound 7.91 (s, 1 H), 7.30 (s, 1 H), Difluorophenyl)amino]-7- VET intermediate 7.01 ( 1 H), 6.95 (s, 1 H), ethoxy -6-(4-methyl-3- 6.64 (m, 2 H), 6.53 (s, 1 H), oxopiperazin-1- 01 x wo 0 0 oy yl)quinoline-3-carboxamide 1.08 (t, 3 H) Compound 474 | 10.71 (s, 1 H), 8.92 (s, 1 H), 4-])2,3- E: vy 8.36 (s, 1 H), 7.75 (s, 1 H), Dichlorophenyl)amino]- 7- Median 7.25 (s, 1 H), 7.23 (d, 1 H), (4-ethylpiperazin-1-yl)-6- 7.15 (m, 1 H), 6.67 (s, 1 H), methoxyquinoline -3- "9 6.57 (d, 1 H), 3.16 (m, 4 H), | carboxamide 2.52 (m, 4 H), 2.37 (q, 2 H), 1.02 (t, 3 H) Compound 424 | 0102012 10.37 (s, 1 H), 8.76 | 4-[(2-Fluoro-5- yéo (s, 1 H), 7.30 (s, 1 H), 7.01 methylphenyl)amino]-6- intermediate ( m, 1 H), 6.87 (m, 2 H), | methoxy-7-(4- 6.76 (d, 1 H), 6.09 (br, 2 H), methylpiperazin-1- yy 3.43 (s, 3 H) , 3.22 (s, 4 H), |yl)quinoline-3-carboxamide 2.55 (s, 4 H), 2.30 (s, 3 H), 2.19 (s, 3 H) Compound 438 | 010:0 10.36 ( s, 1 H), 8.76 7-(4-Ethylpiperazin-1-yl)-4- y £1 (s, 1 H), 7.31 (5, 1 H), 7.01 | [(2-fluoro-5- Median (m, 1 H), 6.87 (m, 2 H), methylphenyl)amino]-6- 6.77 (d, 1 H), 6.06 (br, 2 H), |methoxyquinoline-3- 0 3.43 (s, 3 11(, 3.23 (s, 4 H), | carboxamide 2.60 (s, 4 H), 2.44 (q, 2 H), 2.19 (s, 3H), 1.09 (t, 3 H)

SD | 444 | CD, Cl, 10.33 (s, 1 H), 8.78 | 4-[(3-Chloro-2- | LV (s, 1 H), 7.34 (s, 1 H), 7.06 fluorophenyl)amino]-6- intermediate (m, 1 H), 691 (m, 1 H), methoxy-7-(4- 6.81 (s, 1 H), 6.71 (m, 1 H), methylpiperazin-1- 1" 6.04 (br, 2 H), 3.51 (s, 3 H), yl) quinoline-3-carboxamide 3.24 (s, 4H), 2.55 (s, 4H), 2.31 (s, 3H) (s, 1H), 7.34 (s, 1H), 7.06 fluorophenyl)amino]-7- (4-

Yeov

Median (m, 1 H), 691 (m, 1 H), | ethylpiperazin-1-yl)-6- ’ 6.82 (s, 1 H), 6.71 (m, 1 H), | methoxyquinoline-3- 7 6.02 (br, 2H), 3.51 (s, 3H), | carboxamide 3.25 (s, 4 H), 2.60 (s, 4 H), 2.45 (q, 2 H), 1.09 (t, 3 H) Compound 437 | 1001 10.35 (s, 1 H), 8.73 | 4-[(2-Fluoro-5- 4 1 (s, 1 H), 7.15 (s, 1 H), 7.01 | methylphenyl)amino]-6- intermediate (m, 1 H), 6.82 (m, 2 H), | methoxy-7-(4-methyl-1,4- 6.77 (d, 1H), 6.16 (br, 2H), | diazepan-1-yl)quinoline-3- 7 3.48 (m, 4H), 3.40 (s, 3H), | carboxamide 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) Compound 441 | 01201 10.36 (s, 1 H), 8.70 | 4-[(2,4- Vo. 1 (s, 1 H), 7.16 (s, 1 H), 6.94 | Difluorophenyl)amino]-6- Median (m, 2 H), 679 (m, 1 H), | methoxy-7-(4-methyl-1,4- 6.73 (s, 1H), 5.91 (br, 2H), |diazepan-1-yl)quinoline-3-0 3.49 (m, 4H), 3.44 (s, 3H), | carboxamide 2.76 (m, 2 H), 2.63 (m, 2

H), 2.35 (s, 3 H), 2.02 (m, 2

H) Compound 458 | 0.0 9 1 H), 8.75 (s, 4-[(2-Chloro-3- yoo 1 1 H), 7.28 (s, 1 H), 7.24 (m, 1 | fluorophenyl)amino]-7- median H), 6.87 (s, 1 H), 6.71 (m, 2 | ethoxy-6-(4-

H), 5.95 (br, 2 H), 4.22 (4, 2 | methylpiperazin-1- 'va 1 b Si 150 © mn yDquinoline-3-carboxamide compound 472 | CDCl, 10.38 (s, 1 H) , 8.75 (s, | 4-[(2-Chloro-3- 1 M 1 1H), 7.27 (s, 1 H), 7.24 (m, 1 | fluorophenyl)amino]-7- median H), 6.87 (s, 1 H), 6.71 ) 2 | ethoxy-6-(4-ethylpiperazin- pean ae imine 239 (q, 2 H), 1.50 (1, 3 H), | Carooxamide 1.05 (t, 3 H) 486 | CDCl, 10.36 (s, 1 H), 8.75 (s, | 4-[(2-Chloro-3- compound 1 11( 7.28 (s, 1 H), 7.24 (m, 1 | fluorophenyl)amino]-7- ver intermediate H), 6.87 E) 1 H), 6.71 (m, 2 | ethoxy-6-(4-

H), 5.98 (br, 2 H), 4.22 (a, 2 | isopropylpiperazine-1-

Ye) i 25 So eh yl)quinoline-3-carboxamide 1.03 (d, 6 H) Compound 524 | CDCl, 10.61 (s, 1 H), 8.85 | 77-51 4-{3- Vos 1 (s, 1 H), 7.29 (s, 1 H), 6.99 | (aminocarbonyl)-7-ethoxy-median (d, 1 H), 6.90 (s, 1 H), 6.79 | 4-[(2-fluoro-4- (m, 2H), 4.20 (q, 2H), 3.46 | methylphenyl)amino]quinol

VEY (m, 4 H), 2.71 (m, 4 H), | in-6-yl}piperazine-1- 2.35 (s, 3H), 1.51 (t, 3H), | carboxylate 1.49 (s, 9 H) 10.80 (s, 1 H), 8.93 (s, 1 H), | 4-[(2,3- 1 8.38 (s, 1 H), 7.87 (s, 1 H), | Dichlorophenyl)amino]-7- 1.76 (s, 1 H), 7.34 (s, 1 H), | ethoxy-6-(3-oxopiperazin-1-

Yeov

Median 7.24 (d, 1 H), 7.14 (m, 1 H), | yh)quinoline-3-carboxamide ’ 6.69 (s, 1 H), 6.57 (d, 1 H),

VEY 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) Compound 438 | 10.72 (s, 1 H), 8.86 (s, 1 H), | 7-Ethoxy-4-[(2-fluoro-5- yor ' 8.29 (s, 1 H), 7.86 (s, 1 H), methylphenyl)amino]-6-(3- median 7.64 (s, 1 H), 7.27 (s, 1 H), |oxopiperazin-1- 7.14 (m, 1 H), 6.88 (s, 2 H), |yl)quinoline-3-carboxamide

Vet 6.73 (d, 1H), 4.20 (q, 2H), 3.18 (m, 4H), 3.03 (m, 2

H), 1.41 (t,3H) the compound 442 | MeOD 8.78 (s, 1 H), 7.27 4-[(2,4-Difluorophenyl) Voy 1 (s, 1 H), 7.07 (m, 2 H), 7.03 amino]-7-ethoxy-6-(3- Median (s, 1 H), 6.92 (m, 1 H), 4.25 |oxopiperazin-1- (q, 2 H), 3.45 (s, 2 H), 3.34 |yl)quinoline-3-carboxamide

Vio (m, 2 H), 3.15 (m, 2 H), 1.51 (t, 3 H) Composite 454 | 10.85 (s, 1 H), 8.90 (s, 1 H), | 4-[(2-Chloro-4- \ oA 1 8.30 (s, 1 H), 7.69 (s, 1 H), methylphenyl)amino]-7- median 7.38 (s, 1 H), 7.20 (s , 1 H), ethoxy-6-(4- 7.00 (d, 1 H), 6.65 (m, 2 H), methylpiperazine-1-

Ye 4.15 (q, 2H), 2.69 (s, 4H), yDquinoline-3-carboxamide 230 (s, 4H), 2.20 (s, 3H), 2.15 (s, 3H), 1.40 (t, 3 H) Al-Markab 492 | 10.65 (s, 1 H), 8.85 (8, 1 H), 7-Ethoxy-4-{[2-fluoro-3- 1 1 8.30 (s, 1 H), 7.70 (s, 1 H), (trifluoromethyl) )phenyl] median 7.40-7.15 (m, 4 H), 6.85 (s, | amino}-6-(4-methyl 1 H), 4.20 (q, 2 H), 2.80 (s, | piperazin-1 -yl)quinoline-3-

V&V 4 H), 2.35 (s, 4 H), 2.15 (s, | carboxamide 3H), 1.40 (t, 3 H) compound | 466 [10.75 (s, 1 H), 8.80 (s, 1 H), | 4-[(2,4-Dimethoxy - : 8.20 (s, 1 H), 7.50 (s, 1 H), phenyl)amino}-7-ethoxy-6- intermediate i Pr a py ; (4-methylpiperazine-1-

VEN H), 3.75 (s.6 H). 2.65 (a 411 yhquinoline-3-carboxamide 2.30 (s, 4 H), 2.17 (s, 3 H), 1.40 (t, 3 H) 472 | 10.95 (s, 1 H), 8.96 (s, | H), | 4-[(2-Chloro-4-fluoro-5- compound 8.40 (s, 1 H), 7.75 (s, 1 H), methylphenyl)amino]-7- 11 median 7.55 (d, 1 H), 7.30 (s, 1 H), ethoxy-6-(4-methyl yea B 0 0 L 5 A piperazin-1-yl)quinoline-3- 235 ) 4 Hy 220 E 3 H), | carboxamide 2.10 (s, 3 H), 1.45 (1, 3 H) 458 | 10.70 (s, 1 H), 8.90 (s, 1 H), 4-[(5-Chloro-2- 8.35 (s, 1 H), 7.75 (s, 1 H), fluorophenyl)amino]- 7- VY median 7.30 (m, 2 H), 7.10 (m, 1 H), ethoxy-6-(4-methyl

Vo. o8 5 ْ 0 b © ; ID piperazin-1 -yl)quinoline-3- 235 (s, 4H), 220 (s, 3H), | CarPoxamide 1 LAD P.O

A || _ 14030 1 Compound 504 10.55 (s, 1 H), 8.90 (s, 1 H), 7-Ethoxy-4-{[2-methoxy-5- "MY 8.35 (s, 1 H), 7.65 (s) , 1 H), | (trifluoromethyl)pheny!] median 7.30 (m, 3 H), 6.70 (m, 2 H), amino} -6-(4-methyl 4.21 (q, 2 H), 3.95 ( 5, 3 H), piperazin-1-yl)quinoline-3- yoy 2.75 (5, 4 H), 230 (5, 4 H), cpp oo 2.15 (s,3 H), 1.40 (t, 3 H) ) 506 | 11.33 (s, 1 H), 9.47 (s, 1 H), | 4-[(2,3-Dichlorophenyl) Compound 146: Lmr 8.34 (s, 1 H), 7.78 (s, 1 H), amino]-7-(2- median 7.67 (m, 2 H), 7.50 (s, 1 H), methoxyethoxy)-6-(4- oq fio 0 : bdl on ; 2 methylpiperazin-1-yl) M.m, , G4.m, 0 : Meo 1 3.89 (s, 3 H), 3.30 (m, 4 H), quinoline-3-carboxamide 2.86 (m, 4 H) , 2.66 (s, 3 H) 472 110.73 (s, 1 H), 8.86 (s, 1 H), |4-[(2,4-Difluorophenyl) 1m1 8.28 (s, 1 H), 7.66 (s, 1 H), | amino]-7-(2- median 7.37 (m, 1 H), 7.26 (s, 1 H), | methoxyethoxy)-6-(4- 7.03 (m, 2) H), 6.81 (s, 1 H), |methylpiperazin-1-yl) 0 4.25 (m, 2 H), 3.73 (m, 2 | quinoline-3-carboxamide

H), 3.35 (s, 3 H), 2.75 (s, 4

H), 2.35 (s, 4 H), 2.17 (s, 3

H) the compound | 468 | 1080 (5, 1H), 8.85 (s, 1H), | 4-[(2-Fluoro-4- _ 5 1 8.28 (s, 1 H), 7.64 (s, 1 H), methylphenyl)amino]-7-(2- intermediate 7.23 (s, 1 H), 7.15 (d, 1 H), | methoxyethoxy)-6-(4- 6.92 (m, 2 H), 6.82 (s, 1 H), | methylpiperazin-1- 11 4.23 (m, 2 H), 3.74 ) 2 | yl)quinoline-3-carboxamide

H), 3.31 (s, 3 H), 2.70 (s, 4

H), 2.32 (s, 4 H), 2.29 (s, 3

H), 2.16 (s, 3 H) compound | 488 [11.14 (5, 1H), 9.43 (5, 1H), | 4-[(2-Chloro-3- yey 1 8.27 (s, 1 H), 7.84 (m, 1 H), | fluorophenyl)amino]-7-(2- median 7.76 (s, 1 H), 7.42 (s, 1 H), | methoxyethoxy)-6-(4- 7.36 (s, 1 H), 7.34 (d, 1 H), | methylpiperazin-1-

Vit 7.24 (d, 1 H), 4.78 (m, 2 H), | yl)quinoline-3-carboxamide 4.29 (m, 2H), 3.88 (s, 3H), 3.34 (s, 4H), 2.88 (s, 4H), 2.67 (s,3H) 468 | 11.36 (s, 1 H), 9.41 (s, 1 H), 4-[(2-Fluoro-5- YA) for MRCD 8.27 (s, 1 H), 7.72 (s, 1 H), | methylphenyl )amino]-7-(2- Methoxyethoxy)-6-(4-

I.fe on ; wn I ow : 0 methylpiperazin-1- 0 28 (m, , 3.88 (s, \ la . 327 (s, 4H), 2.84 (s, 4II) yl)quinoline-3-carboxamide 2.65 (s,3H) ), 2.44 (s, 3 H) 472 | 10.66 (s, 1 H), 8.88 (s, 1 H), | 4-[(2,5-compound > 1 for MRCD 8.32 (s, 1 H) ), 7.73 (s, 1 H), Difluorophenyl)amino]-7- median 7:23 (s, 1 H), 7.32 (m, 2 H), | )2-060«760:00-6 )4- Shi (m, 2 o 8.92 (m, ; H), methylpiperazin-1- oy 27 (m, 2 H), 3.75 (m, 2 H), yl)quinoline-3-carboxamide 1 ,

A for (s, 4 H), 2.17 (s, 3 H) 2.37 (s, 1 H), 8.84 (s, 1 H), | 4-[(3-Chloro-2- \V. 10.70 | 488 Compound 1 8.40 (s, 1 H), 7.60 (s, 1 H), |fluorophenyl)amino]-7-(2- ( s, 1 H), 7.13 (m, 1 H), | methoxyethoxy)-6-(4- 7.24 median (m, 1 H), 6.85 (s, 1 H), | methylpiperazin-1- 7.03 018 6.75 (m, 1 H), 4.23 (s, 2 H), |yl)quinoline-3-carboxamide (s, 2 H), 3.33 (s, 3 H), 3.74 (s, 4 H) ), 2.34 (s, 4 H), 2.74 H) 2.15(,3 110.82 (s, 1 H), 8.86 (s, 1 H), | 4-[(2-Fluoro-4- 1171 455 Compound 1 8.29 (s, 1 H), 7.65 (s, 1 H), |methylphenyl)amino]-7-(2- (s, 1 H), 7.14 (d, 1 H), | methoxyethoxy)-6- 7.26 median (m, 3 H), 4.24 (m, 2 | morpholin-4-ylquinoline-3- 6.92 0" H), 3.73 (m, 2 H), 3.62 (m , |carboxamide H), 3.36 (s, 3 H), 2.69 (s, 4 H), 2.27 (s, 3 H) 4 (s, 1 H), 8.83 (s, 1 H) , |4-[(2-Fluoro-4- \VY 10.78 | 496 Compound 1 8.27 (s, 1 H), 7.63 (s, 1 H), | methylphenyl)amino]-6-(4- (s, 1 H), 7.14 (d, 1 H), | isopropylpiperazin-1-yl)-7- 7.22 median (m, 2 H), 6.79 (s, 1 H), | (2-methoxyethoxy) 6.89 yor 4.23 (m, 2 H), 3.72 (m, 2 | quinoline-3-carboxamide H), 3.33 (s, 3 H), 2.68 (s, 4 H), 2.60 (m, 1 H), 2.43 (s, 4 H), 2.27 (s, 3 H), 0.96 (d, 6 H) b (s, 1 H), 8.95 (s, 1 H), | 4-[(2-Fluoro-5- 110.75 496 Compound 1 8.27 (s, 1 H), 7.64 (s, 1 H), | methylphenyl)amino]-6-(4- (s, 1 H) ), 7.15 (m, 1 H), |isopropylpiperazin-1-yl)-7- 7.25 median (m, 1 H), 6.83 (s, 1 H), | (2-methoxyethoxy) 6.89 yot 6.71 (d, 1 H), 4.25 (m, 2 H), | quinoline-3-carboxamide (m, 2 H), 3.34 (s, 3 H), 3.75 (s, 4 H), 2.60 (m, 1 H), 2.71 (s, 4 H), 2.13 (s, 3 H), 2.45 (d, 6 H) 0.96

( yV¢ ) Example 4-[(2,3-Dichlorophenyl)amino]-7-methoxy-6-piperazin-1-ylquinoline-3-carboxamide dihydrochloride

: (Vi)oda 01( trifluoracetic acid/dichloromethane) was added to a solution of © tert-butyl 4-{3-(aminocarbonyl)-4-[(2,3 -dichlorophenyl)amino]-7-methoxyquinolin- 6- yl}piperazine-1-carboxylate h; the solvent was removed under pressure Y and after 0 mmol) “81 cada You 1 1 °) (eg ethereal (? ml) and acidic using low MeOH” and the residue was drawn off and dried to obtain a solid Et,O and then collected the resulting crystals; washed with HCl (0 mg) Ye. )

'H NMR: 11.95 (s, 1 H), 9.28 (s, 2 H), 9.00 (s, 1 H), 8.45 (s, 1 H), 7.86 (s, 1 H), 7.59 (m, 2H) , 7.37 (m, 2H), 7.21 (s, 1H), 4.01 (s, 3H), 3.17 (m, 4H), 3.07 (m, 4H); m/z: 445

(1085): to (Ave) Examples from 0 The following compounds were prepared in a manner similar to that followed in Example (a) using starting materials

Convenience. Some examples have been isolated as hydrochloride salts

_ a 8 — Example 460 [10.78 (s, 1H), 8.92 (5, | 4-]2,3- Vo 1 H), 836 (s, 1 H),| _ ( VY 0) 7.76 (s, 1 H), 7.31 (s, 1 Dichlorophenyl)amino]-7-

H), 7.24 (d, 1 H), 7.13 ethoxy-6-piperazin-1- (m, 1 H), 6.66 (s, 1 H), 6.57 (d, 1 H), 4.20 (q, 2 | ylquinoline -3-carboxamide

H), 2.86 (m, 4 H), 2.75 (m, 4 H), 1.41 (t, 3 H) \ 413 | 10.80 (s, 1 H), 8.91 (s, | 4-[(2,4- 1 ex. 1 H), 835 (s, 1 H), .. VY ( y YA 7.70 (s, 1 H) , 7.40 (m, Difluorophenyl)amino]-7-

LH), 732 (s, 1 H). | methoxy-6-piperazin-1- 7.06 (m, 2 H), 6.85 (s, 1 H), 4.15 (m, 1 H), | ylquinoline-3-carboxamide 3.99 (s, 3H), 3.45 (m, 2H), 3.20 (m, 2H), 2.80 (m, 2H), 2.70 (m, 2H) 2 427 | 10.60 (s, 1 H), 8.76 (s, | 6-(1,4-Diazepan-1-yl)-4-[(2,4-ex. 1 H), 820 (s, 1 H), | .. VY ( VY v) 7.56 (s, 1 H), 7.29 (m, | difluorophenyl)amino]-7-

IH), 7.15 (s, 1 H), | methoxyquinoline-3- 6.90 (m, 2 H), 6.65 (m, 1 H), 3.86 (s, 3 H), | carboxamide 3.70 (m, 1 H), 3.00 (m, 4 H), 2.65 (m, 4 H), 1.55 (m, 2 H) 444 | 00:01: 10.41 (s, 1 H), | 4-[(3-Chloro-4- (14)) Example 8.77 (s, 1 H), 7.28 (s, 1 VA

H), 7.07 (m, 1 H), 6.87 fluorophenyl)amino}-7-ethoxy- 0 2 we “i 6-piperazin-1-ylquinoline-3- 4.21 (gq, 2 H), 2.89 (m, | carboxamide 4 H), 2.76 (m, 4 H), 1.50 (t, 3 H) - 424 | CDCl, 10.45 (s, 1 H), | 7-Ethoxy-4-[(2-fluoro-5- (Te) eg 8.75 (s, 1 H), 7.26 (s, 1 AS)

H), 7.01 (m, 1 H), 6.95 methylphenyl)amino]-6- B or 8 20 © piperazin-1-ylquinoline-3- 2 H), 2.90 (m, 4 H), | carboxamide 2.73 (m, 4 H), 2.18 (s, 3 H), 1.49 (t, 3 H). 444 | 10.51 (s, 1 H), | 4-[(3-Chloro-2- (V1) e.g. 8.75 (s, 1 H), 7.27 (s, 1 VA)

H), 7.06 (m, 2 H), 6.90 fluorophenyl)amino]-7-ethoxy- (m, 1 H), 6.85 (m, 1!1 g_p; a1 a H), 5.96 (br 5. 2H). piperazin-1-ylquinoline-3 4.20 (q, 2H), 2.92 (m, | carboxamide

Ysov

.w for H), 2.76 (m, 4 H), 4 (t, 3 H), 1.50 (s, 1 H), 8.85 (s, | 6-(1,4-Diazepan-1- y1)-4-[(2,3- YAY 10.70 | 473 example H), 835 (5, 1 H),|1 1 VY A) 7.75 (s, 1 H), 7.26 (m, | dichlorophenyl)amino]-7- H), 7.15 (m, 1 H), ethoxyquinoline-3- 2 (m, 2 H), 4.20 (q, 6.55 H), 4.10 (m, 1 H) ), | carboxamide 2 (m, 4 H), 2.70 (m, 3.05 H), 1.65 (m, 2 H), 4 (t, 3 H), 1.44 (s, 1 H), 8.84 ( s, | 4-[(2,4- 10.71[ . 427 H), 827 (s, 1 H), .. VAY 1 ex. \Y 1) 7.64 (s, 1 H), 7.36 (m , Difluorophenyl)amino]-7- ( IH), 722 (5, 1 H), ethoxy-6-piperazin-1- (m, 2 H), 6.77 (s, 7.00 H), 4.16 (q, 2H), | ylquinoline-3-carboxamide 1 (m, 4 H), 2.63 (m, 2.73 H), 1.39 (t, 3 H) 4 (s, 1 H), 8.80 (s, |6-( 1,4-Diazepan-1-yl)-4-[(2,4- 10.65 | 441 . H), 8.25 (s, 1 H),|_VAY 1 Ex. YY. 7.63 (s, 1 H), 7.35 (m, | difluorophenyl)amino]-7- ( IH), 720 (s, 1 H), |ethoxyquinoline-3- (m, 2 H), 6.70 (s, 6.95 H), 4.16 (q, 2 H), |carboxamide 1 (m, 4 H), 2.75 (m, 3.05 H), 1.61 (m, 2 H), 4 H) 1 , 3 ( 1.40 (s, 1 H), 8.95 (s, | 6-(1,4-Diazepan-1-yl)-4-[(2,3- 10.79 | 460 2 H), 842 (s, 1 H), | _.. VA 1 Ex (s, 1 H), 7.32 (m, dichlorophenyl)amino]-7- 7.80 \ ( (m, 1 H), methoxyquinoline-3- 7.20 , (11 2 (m, 2 H), 4.00 (s, 6.65 H), 3.85 (m, 1 H), | carboxamide 3 (m, 4 H), 2.78 (m, 3.16 H) , 1.65 (m, 2 H) 4 blood CD,Cl, 10.37 (s, 1 H), 7-Ethoxy-4-[(2-fluoro-4- | 424 eg (s, 1 H), 7.15 (s, 1 8.63 Vos ) H), 6.85 (m, 1 H), 6.80 methylphenyl)amino]-6- ( na 1h) (4 2 oy piperazin-1-ylquinoline-3- H ), 2.22 (s, 3 H), |carboxamide 4 (t, 3 H) 1.40

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

to a solution of : 4-[(2,3-dichlorophenyl)amino]-7-methoxy-6-piperazin-1-ylquinoline-3-carboxamide dihydrochloride ° Y¥ cana 011 ((VVE) Jb) + mmol (YT) diisopropylethylamine s μl "0 mL (Use in (Je 01) THF at a temperature of -10 C in an atmosphere of 80 A solution of (1) 2-chloro-2 was added -oxoethyl acetate μl YA + mmol) in (Je 10) THF drop by drop over 10 minutes. After stirring for 1 hour at a temperature of -10 C; The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and a saturated aqueous Na,CO3 solution. The organic layer “(NapSO;) was dried, filtered and concentrated; the residue was crystallized from EtOAc/ERO to obtain 001 mg solid. NMR: 8.96 (s, 1 H), 8.46 (s, 1 H), 7.78 (s, l H), 7.37 (8,111), 7.25 (d, 1 H), 7.14 ( t, 1 H), 6.72 (s, 1 H), 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), (s, 3 H); m/z: 545 \o 2.07 Examples from (V4) (VAY) Then prepare the following compounds in a manner similar to that in the (VA) example using Appropriate starting materials. Yé?ov

— 11. - 487 | CDsOD 8.77 (s, 1 H), | 6-(4-Acetylpiperazin-1-yl)-4- YAY Example fe Coe i (dd, [(2,3-dichlorophenyl)amino]- 6.75 (s, 1 H), 6.57 (dd, | 7- 3-methoxyquinoline

VE 1'H),3.93 Gs, 3 H, carboxamide 3.50 (m, 4 H), 2.75 (m, 2 H), 2.67 (m, 2 H), 1.99 (s, 3 H) Example 502 | 010:0 10.42 (s, 1 H), | 6-(4-Acetylpiperazin-1-yl)-4- \ AA 8.82 (s, 1 H), 7.34 (s, 1 . : 7 H) a 3d ; H) > [(2,3-dichloropheny!)amino]- (m, 1 H), 6.79 (s, 1 H), | 7-ethoxyquinoline-3- om Cs Sa carboxamide 3.50 (m, 2 H), 2.79 (m, 4 H), 2.04 (s, 3 H), 1.51 (t, 3 H) Example 516 | 10.75 (d, 1 H), 8.95 (s, | 6-(4-Acetyl-1,4-diazepan-1- yA 1 H), 8.42 (s, 1 H), 181 7.80 (s, 1 H), 7.34 (m, 714-123 2 H), 7.20 (m, 1 H), dichlorophenyl)amino]-7- 6.70 (s, 1 H), 6.65 (d, 1 So

H), 4.28 (q, 2 H), 3.55- ethoxyquinoline-3- 3.12 (m, 11 H), 1.80 carboxamide (m, 1 H), 1.70 (m, 1

H), 1.50 (t, 3 H) Ex. 466 | 102:01 10.49 (s, 1 H), | 6-(4-Acetylpiperazin-1-yl)-7- Yq. 8.72 (s, 1 H), 7.26 (s, 1 mm H), 6.95 (d, 1 H), 6.91 | Ethoxy-4-[(2-fluoro-4- (s, 1 H), 6.87 (m, 2 H), | methylphenyl)amino] th or. : b >i @ quinoline-3-carboxamide 3.46 (m, 2 H), 2.78 (m, 2 H), 2.66 (m, 2 H), 2.32 (5,3 H), 2.04 (s,3

H), 1.49 (t, 3 H) (Ya)) is an example

{ A VY = — 4-[(2,3-Dichlorophenyl)amino]-6-(4-glycoloylpiperazin-1-yl)-7-methoxyquinoline-3- carboxamide A mixture of: 2-(4-{3-(aminocarbonyl)-4-[(2,3-dichlorophenyl)amino]-7-methoxyquinolin-6- yl} piperazin-1-yl)-2-oxoethyl acetate ° (example Vo (VAT) mg; and 1 ml of water vigorously for 1 hour. Most of the solvent was removed under reduced pressure; and partitioning of the residue among water (01) EtOAc (Je 01 (ml). The required product was deposited in a separation funnel; B. Mogdah) and filtered it 3 and concentrated it cial low pressure to obtain an identical solid by NMR and LC-MS for the previous material. The solids were collected to obtain YO mg. NMR: 10.85 (s, 1 H) , 9.01 (s, 1 H), 8.43 (s, 1 H), 7.83 (8, 1 H), 7.43 (s, 1 H), 7.33 (dd, 1 H), 7.21 (t, 1 H) , 6.78 (s, 1 H), 6.65 (d, 1 H), 4.63 (t, 1 H), 4.14 (d, 2 H), 4.04 (s, 3 H), (m, 2 H), 3.45 (m, 2H), 2.82 (m, 4H); m/z: 503 Vo 3.57 Example (7) L1

- 1,6 — 4-[(2,3-Dichlorophenyl)amino]-7-ethoxy-6-[4-(2-hydroxycthyl)piperazin-1- yl}jquinoline-3-carboxamide

A mixture of: 4-[(2,3-dichlorophenyl)amino]-7-ethoxy-6-piperazin-1-ylquinoline-3-carboxamide was heated (eg TV (WV) 1043 mmol) YT) glycolaldehydes mg; 6.47 mmol) in (Yio) MeOH:toluene for 1 hour reflux. The reaction mixture was concentrated and dissolved in (Je Yo) THF. VY cana (YOO) Sodium triacetoxyborohydride + mmol) (Je +.Y) acetic acids was added and the reaction mixture was heated for reflux for 1 h. water added; and extract the mixture with EtOAc (; 50 X ml). The combined organic extract 0 (NaySOy) was dried, filtered 6, concentrated ¢, and the residue purified using reverse-phase HPLC to yield 19 mg of a yellow solid. NMR: 10.50 (s, 1 H), 8.95 (s, 1 H), 8.40 (s, 1 H), 7.85 (6, 1 H), 7.60 (d, 1 H), 7.52 (s, 1 H), 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 ve Examples (VAY) to :(001) The following compounds were prepared in a manner similar to that in Example (7) 1 using appropriate starting materials. L 1

_ \ «0 — Ex. (m, Dichlorophenyl)amino]-7 2H), 7.14 (m, 1 H), ethoxy-6-(4-isopropyl-1,4- 6.65 (m, 2 11), 420 (q, | .. a a 2H) ), 3.35 (m.1H), diazepan-1-yl)quinoline-3 3.10 (m, 4H), 2.90- carboxamide 2.55 (m, 4H), 1.65 (m, 2H), 1.45 (t, 3 H), 0.92 (m, 6 H) A 471 Example Te 0 A A (s, 1 4-[(2,4-Difluorophenyl) ya 7 . S, , ”

YAY 7.70 (s, 1 H), 7.40-7.10 | &mino]-7-ethoxy-6-[4-(2- (m, 5 H), 4.22 (q, 2 H), | hydroxyethyl) piperazin-1- 3.78 (m, 2 H), 3.55- I]quinoline -3-carboxamide 2.95 (m, 10 H), 1.45 ben 8 3 H) a 481 ex jo 0 0 a (s, | 6-[4-(Cyclopropylmethyl) yao , 8.20 (s, , ::

VAY 7.70 (s, 1 H), 7.45 (m, |Pperazin-l-yl]-4-[(2,4- 4 H), 7.15 (m, 1 H), difluorophenyl)amino]-7- 4.29 ( q, 2 H), 3.50 (m, Co 4 H), 3.15 (m, 4 H), ethoxyquinoline-3- 2.90 (m, 2 H), 1.45 (t, 3 | carboxamide

H), 1.09 (m, 1 H), 0.65 (m, 2 H), 0.35 (m, 2 H) . 484 1 10.70 (s, 1 H), 8.87 (s, 1 | 4-[(2,4-Difluorophenyl) eg H), 8.32 (s, 1 H), 7.70 (s, 51 A 1 H) ), 7.40 (m, 1H), 7.26 amino]-7-ethoxy-6-(4- (s, 1H), 7.05 (m, 2H), isopropyl-1,4-diazepan-1- 6.75 ( s, 1 H), 4.22 (q, 2

H), 3.10 (m, 4H), 2.90 yl)quinoline-3-carboxamide (m, 1H), 2.65 (m, 4H), 1.75 (m, 2H), 1.49 (t, 3

H), 1.00 (m, 6H) . 469 | 10.55 (s, 1 H), 8.70 (s, 1 | 4-[(2,4-Difluorophenyl) e.g. H), 8.20 (s, 1 H), 7.55 (s, .. VAY by 1 H) ), 7.25 (m, 1 H), 7.10 amino]-6-(4-isopropyl-1,4- (s, 1 H), 6.85 (m, 2 H), : oul 6.62 (s, 1 H), 3.80 (s, 3 diazepan-1-y1)-7

H), 3.30 (m, 4H), 2.95 methoxyquinoline-3- (m, 4H), 2.69 (m, 1H), 1.47 (m, 2H), 0.80 (d, 6 | carboxamide

H) ex. 4

VY 7.77 (s, 1H), 7.42 (m, |2mino]-6-(4-ethyl-1.4- 3H), 7.20 (m, 2H), diazepan-1-yl)-7- 4.00 (s , 3 H), 3.50-3.10 th inoline.3 (m, 6 H), 2.90 (m, 2 methoxyquinoline-3-

Yeov

- 11.1 =

H), 2.28 (m, 2 H), 2.10 | carboxamide ne (m, 2 H), 1.28 (1, 3 H) ex. 502 py 0 he in (s, | 4-[(2,3-Dichlorophenyl) 4 , 8.40 (s, , : :

VAS 7.79 (s. 1 H), 7.30 (m, amino }-6-(4-isopropyl-1,4- 2 H), 7.20 (m, 1 H), diazepan-1-yl)-7- 6.70 ( s, 1 H), 6.60 (d, 1 oo

H), 4.00 (s, 3 H), 3.40 methoxyquinoline-3- (m, 4 H), 3.18 (im, 4 carboxamide

H), 2.80 (m, 1 H), 1.65 (m, 2 H), 0.95 (m, 6 H) Example 468 | 00201 10.44 (s, 1 H), | 7-Ethoxy-4-[(2-fluoro-4- Ya. 8.70 (s, 1 H), 7.23 (s, 1 : \ Ao 11, 6.94 (d, 1 H), 6.91 methylphenyl)amino]-6 [4- (s, 1 H), 6.86 (m, 2 H), | (2-hydroxyethyl) piperazin- 5.97 (br, 2 H), 4.19 (q, oo 2H), 3.56 (t, 2 H), 2.78 ||-Yl]quinoline-3- (s,4 H), 2.53 (m, 6 H), |carboxamide 2.31 (s,3H), 1.48 (1,3

H) (Y 11 ) Example 4-[(2,3-Dichlorophenyl)amino]-7-ethoxy-6-(4-glycoloylpiperazin-1-yl)quinoline-3- carboxamide ht then 18% stir 3 A mixture of : 4-[(2,3-dichlorophenyl)amino]-7-ethoxy-6-piperazin-1-ylquinoline-3-carboxamide hydrochloride (eg (5 no 0 o) mg 0 .204 mmol); YA) glycolic acids mg 0.09 mmol); V+) HATU mg; TA (+ mmol) and 0158 0107 cane VY (mmol) in anhydrous DMF

- VV —

HPLC for © hours. The crude mixture was purified using 28 all at a temperature (Ja 1) mg of solid zero | P. Ye for reverse phase to obtain

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, 1 H), 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, 2H), 1.25 (t, 3H); m/z: 518 o:) 0011( to (YY) Examples from Using starting materials (710) The following compounds have been prepared in a manner similar to that in the maltama example. Example 532 12.15) 5, 1 H), 8.96 (s, 1 4-[(2,3-Dichlorophenyl) YoY

H), 8.45 (s, 1 H), 7.95 (s, 1 \Vo H), 7.65 (d, 1 H), 7.40 (m, amino|-7-ethoxy-6-{4-[(2S)- 2- ony ty A360 h jy hydroxypropanoyl] piperazin- 3.55 (m, 4 H), 2.80 4 1-yl}quinoline-3-carboxamide

H), 1.48 (t, 3H), 3

H) ex. 53212.29 (6, 1 H), 9.05 (s, 1 4-[(2,3-Dichlorophenyl) Y.v

H), 8.57 (s, 1 H), 7.96 (s, 1 \vo H), 7.65 (d, 1 H), 7.50 (s, 1 | amino]-7-ethoxy-6-{4-[(2R) )-2-

HD, do to TH 28” hydroxypropanoyl] piperazin- (q, 2 H), 3.60 (m, 4 H), 1-yl}quinoline-3-carboxamide 2.80 (m, 4 H), 1.45 (t, 3

H), 1.20(d, 3 H) Ex. 481 | 010201 10.48 (s, 1 H), 7-Ethoxy-4-[(2-fluoro-4- Ys 8.73 (s, 1 H), 7.26 (5, 1 H), M 6.95 (d, 1 H) , 6.92 (s, 1 H), methylphenyl)amino]-6-(4- trot 2h 4 re 2 glycoloylpiperazin-1-

H), 3.66 (m, 2H), 3.27 (m, |yl)quinoline-3-carboxamide

— \ 0 A — 2 H), 2.78 (m, 2 H), 2.71 (m, 2 H), 2.32 (s, 3 H), 1.49 (t, 3 H) CD,Cl; 10.47 (s, 1 H), 7-Ethoxy-4-[(2-fluoro-4- Y.o | 496 e.g. (s, 1 H), 7.26 (s, 1 H), 8.72 YAO 6.95 (d , 1 H), 6.92 (s, 1 H), methylphenyl)amino]-6- {4- 6.87 (m, 2H), 5.96 (br, 2 | 129)-2-hvd

H), 4.41 (q, 1 H), 4.20 (q, | [(2>)-2hydroxypropanoyl] 2H), 3.66 (m,2 H), 3.42 | piperazin-1-yl}quinoline-3- (m, 2H), 2.79 (m, 2H), 2.72 (m, 2H), 2.32(s,3 | carboxamide

H), 1.49 (t, 3 H), 1.27 (d, 3

H) CDCl, 10.47 (s, 1 H), 7-Ethoxy-4-[(2-fluoro-4- Yn | 496 ex. (s, 1 H), 7.26 (5, 1 H), 8.72 \Ao 6.95 (d, 1 H), 6.92 (s, 1 H), methylphenyl)amino]-6- {4- 6.87 (m, 2 H), 5.96 (br, 2 5

HY, 4.41 (q, 1H), 421 (a, [(2R)-2-hydroxypropanoyl] 2H),3.66 (m,2H), 3.42 | piperazin-1-yl}quinoline-3- (m, 2H), 2.79 (m, 2H), : 2.73 (m, 2H), 232(s,3 | carboxamide

H), 1.49 (t, 3 H), 1.27 3

H) (Y 0 Ex (No) 6-(4-Cyclopropyl-1,4-diazepan-1-yl)-4-[(2,4-difluorophenyl)amino]-7-ethoxyquinoline- 3-carboxamide to a solution of : 6-(1,4-diazepan-1-yl)-4-[(2,4-difluorophenyl)amino]-7-ethoxyquinoline-3-carboxamide (ex. 1 AY) for 0 mg; f mmol) ' and molecular sieves ¢ Angbstrom (Y g) sodium cana (YA) cyanoborohydride 0 .08 mmol) 0 The resulting reaction mixture was stirred upon reflux

1.9 - - All night long. celal was added and the mixture extracted with EtOAc (?1 X ml); The combined organic extract (NaySO4) was dried, concentrated, and the residue purified using an ISCO chromatography system to yield Yoo mg 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), 720)6.10 0 H), 6.95 (m, 2 H), 6.68 (s, 1 H), 4.17 ( 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, 2H), 0.27 (m, 2H); m/z: 482 Examples (YA) to (YY) The following compounds were prepared in a manner similar to that of the (Yo) example using Ady starting materials

_ \ \ . — example, 467 | 10.79 (s, 1 H), 8.90 (s, 1 | 6-(4-Cyclopropyl piperazin-1- YA)

H), 8.31 (s, 1 H), 7.70 1)-4-[(2.4-

VAY (s, 1H), 7.40 m, 1H), |” 7.30(s, 1 H), 7.09 (m, 2 | difluorophenyl)amino]-7-

EN or py Ti, ethoxyquinoline-3- 2.65 (m, 1H), 1.46 (t,3 | carboxamide

H), 0.71 (m, 2 H), 0.63 (m, 2 H) Ex. 453 110.65 (s, 1 H), 8.91 (s, 1 | 6-(4-Cyclopropyl piperazin-1- |), b q

H), 8.30 (s, 1 H), 7.68 yI)-4-[(2.4-

A (s, 1 H), 7.38 (m, 1 H), ’ 7.30 (s, 1 H), 7.06 (m, 2 | difluorophenyl)amino]-7-

H), 6.86 (s, 1 H), 3.95 methoxyquinoline-3- (s, 3 H), 2.70 (m, 4 H), Yq 2.56 (m, 4 H), 1.65 (m, 1 | carboxamide

H), 0.41 (m, 2 H), 0.30 (m, 2 H) Example 486 0 in rs 1 | 6-(4-Cyclopropyl piperazin-1- YY. , 8.40 (s, , 7.

Vy (s, 1H), 735s, 110), | YD-4123- 7.28 (d, 1 H), 7.15 (m, 1 | dichlorophenyl)amino]-7-

H), 6.69 (s, 1 H), 6.60 methoxyquinoline-3- (d, 1 H), 3.98 (s, 3 H), 2.71 (m, 4 H), 2.56 (m, 4 | carboxamide

H), 1.65 (m, 1 H), 0.40 (m, 2 H), 0.20 (m, 2 H) Example 467 es 1 11 8 1 | 6-(4-Cyclopropyl-1,4- YY wy oi H), 5 0 y |diazepan-l-yl-4-[(2,4- 7.24 (s, 1 H), 6.97 (m, 2) difluorophenyl)amino]-7-

H), 6.70 (s, 1 H), 3.91 oo (s. 3 H), 3.05 (m, 4 1), methoxyquinoline-3- 2.70 (m, 4 H), 1.82 (m, 1 | carboxamide

H), 1.67 (m, 2 H), 0.40 (m,2 H), 0.27 (m, 2 H) Example 500 Re 1 De 1 | 6-(4-Cyclopropyl-1,4- L Om7 H), os or oq, | diazepan-l-yD-4-[(2.3- 7.12 (m, 1 H), 6.55 (m, 2 | dichlorophenyl)amino]-7-

H), 3.95 (s, 3H), 3.12 methoxvauinoline-3- (m, 2H), 3.07 (m, 2H), yqunotne 2.65 (m, 4H), 1.85 (m, 1 | carboxamide

H), 1.65 (m, 2 H), 0.42 (m, 2 H), 0.26 (m, 2 H). 7 0 7 on i, wm fluoropheny!l)amino]-6-(4- (s, 1 H), 6.90 (m, 1 H),

- 11 - 4.25, (2 H), 2.88 (m, 4 |cyclopropyl piperazin-1-yl)-7-

FD), 2.79 (m, 4 H), 1.84 ethoxyquinoline-3- (m, 1 H), 1.52 ) 3 H), Ya 0.55 (m, 2 H), 0.48 (m, 2 | carboxamide

H) Example 464 | CD;0D 8.78 (s, 1 H), 6-(4-Cyclopropyl piperazin-1- | yy 7.23 (s, 1 H), 7.06 (dd, 1 7 1), 7.01 (s, 1 H), 6.94 yl )-7-ethoxy-4-[(2-fluoro-5- (m, 1 H),6.79(d, 1 H), | methylphenyl)amino] 4.23 (q,2H),2.80 (m4 oo : 110. 2.69 (m, 4 H), 2.20 quinoline-3-carboxamide (s, 3 H), 1.69 (m, 1 H), 1.51 (t,3 H), 0.50 (m, 2

H), 0.42 (m, 2 H) Ex. 484 | 0:00 8.76 (s, 1 H), 7.25 | 4-[(3-Chloro-2- Yio (s, 1 H), 7.17 (dd, 1 H),

VA 7.06 (d, 1 H), 7.02 (s, 1 H), fluorophenyl)amino]-6-(4- 6.95 (m, 1 H), 4.24 (q, 2 I oi -1-717-7- and H), 2.88 (m, 4 H), 2.72 (m, | 0 A) Pipetazin-i-y ) 4 H), 1.70 (m, 1 H), 1.52 ethoxyquinoline-3- A) 3 H), 0.50 (m, 2 H), 1 y 0.43 (m, 2 H) carboxamide (Y 1 ) Example 4-[(2,4-Difluorophenyl)amino]-7-(2-hydroxyethoxy)- 6-(4-methylpiperazin-1- yDquinoline-3-carboxamide : to a solution of ethyl 7-(2-{[zert-butyl(dimethyl)silylJoxy ( ethoxy)-4-[(2,4-difluorophenyl) )amino]-6-(4- methylpiperazin-1-yl)quinoline-3-carboxylate 791 ml; Add Ve m for 001 heated at a temperature (Je©) DMF mmol) in mmol). and after 147 cde 1880 mol 4.0) MeOH sodium methoxide a solution of 0

! - WY - ml); The reaction mixture was extracted using 00) ele h; The mixture was cooled” and 1 was added, then the combined organic extracts were concentrated and a solution was added. (Ja 0 + X 9 EtOAc 1 mL). The mixture was allowed to stand for 1 M in 1117; 1(tetrabutylammonium fluoride 01 XV) EtOAc mL); And the reaction mixture was extracted using (0) h. Then, water was added for the HPLC phase, the combined organic extracts were concentrated, and the residue was purified by (0 mg (£07) of Ae to obtain) hexanes/ The resulting acetone (compounds Js reversed. Reverted yellow solid. “HNMR: 10.73 (s, 1 H), 8.85 (s, 1 H), 8.29 (s, 1 H), 7.66 (s , 1 H), 7.37 ( 1 H), 7.26 (s, 1 H), 7.03 (m, 2 H), 6.80 (s, 1 IT), 4.87 (t, 1 H), 4.16 (m, 2 H) Example: , 3.79 (m, 2 H), 2.76 (s, 4 H), 2.37 (s, 4 H), 2.18 (s, 3 H); Using the precursor (YY) the following compound was prepared in a manner similar to that followed in the matching example. Z 4741 10.69 (s, 1 H), 8.88 (s, 1 L 2-4 -3)) - Alm Cb Zero Lamrkd (s, 110), 7.70 1810-2-4 Intermediate (s, 1 H), 7.30 (s, 1 H), fluorophenyl)amino]-7-(2- 7.23 ( t,1 H), 7.08 (5,1 | hydroxyethoxy)-6-(4- iy H), 6.84 (m, 2 H), 4.87 methylpiperazin- 1- (t, 1 H), 4.18 (m, 2 H) ), yl)quinoline-3-carboxamide 3.80 (m, 2 H), 2.81 (s, 4

H), 2.37 (s, 4H), 2.18 (s, 3H)

117 - - Preparation of Starting Materials Intermediate Compound (1) Ethyl 4-[(2,3-dichlorophenyl)amino}-7-methoxy-6-(4-methylpiperazin-1-yl)quinoline-3- carboxylate o, then 3 heating a mixture of: ethyl 6-bromo-4-[(2,3-dichlorophenyl)amino]-7-methoxyquinoline-3-carboxylate (intermediate compound (5 Yo); in mg LAY mmol); ane ) tris(dibenzylideneacetone) dipalladium(0) to mmol) and 17 4((R,S)-2,2'-bis(diphenylphosphino)-1,1' -binaphthy!mg (1.01 mmol) 011 cana (¥34) Cs;CO35 (0 mmol) and (YYV) N-methylpiperazine μl; 0.06 mmol) in aqueous toluene in an atmosphere of Np at a temperature of 100 C YA Bad h. The reaction mixture was filtered and concentrated.; reverse-phase HPLC purification of crude oil to yield 1117 mg of solid; 489:10/2. Intermediates (1) to (Vet) 1 The following compounds were prepared in a manner similar to that for intermediate (1) using appropriate starting materials. SM M/z/NMR intermediate complex

- 114 - Ethyl 4-])2,4- Y 111 Intermediate dichlorophenyl)amino]-7- methoxy-6-(4- methylpiperazin-1- Ethyl 4-])3,4- ' 116 Intermediate dichlorophenyl)amino]-7- methoxy-6-(4- methylpiperazin-1- Compound 458 | Ethyl 4-[(2,4- 1117 difluorophenyl)amino]-7- methoxy- 6-(4- methylpiperazin-1- yl)quinoline-3-carboxylate Ethyl 4-[(2,3-)

Yoo intermediate dichlorophenyl)amino]-7- methoxy-6-morpholin-4- compound Ethyl 4-[(2,4- 1117 difluorophenyl)amino]-7- methoxy-6-morpholin-4- Compound Ethyl 4-[(3,4- 7 1011 intermediate dichlorophenyl)amino]-7- methoxy-6-morpholin-4- Compound Ethyl 4-[(3,4- 1 111 intermediate dichlorophenyl )amino]-7-methoxy-6-piperidin-1-

A 11 - - Ethyl 4-])2,3- 9 dichlorophenyl)amino]-6- intermediate 1168 methoxy-7-(4- methylpiperazin-1- yl) quinoline-3-carboxylate ‎Ethyl 4-])3,4- 0 dichlorophenyl)amino}-6- intermediate 119 methoxy-7-(4- methylpiperazin-1- yl) quinoline-3-carboxylate ethyl 4-[(2,4- 1 | 471 difluorophenyl)amino]-7- intermediate 1171 ethoxy-6-(4-methylpiperazin- 1-yl) quinoline-3-carboxylate ethyl 4-[(2,3- \Y | 504 dichlorophenyl)amino]-7- intermediate 111 ethoxy-6-(4-methylpiperazin- 1-yl )quinoline-3-carboxylate ‎Ethyl 4-])2,4- Ww compound difluorophenyl)amino]-7- intermediate 1171 ethoxy-6-morpholin-4- ylquinoline-3-carboxylate Ethyl 4-[(3,4- \¢ dichlorophenyl)amino]-7- intermediate 111 ethoxy-6-morpholin-4- ylquinoline-3-carboxylate Ethyl 6-{4 -(tert- \o | 575 butoxycarbonyl)piperazin-1- intermediate yoo yil-4-[(2,3- i

A dichlorophenyl)amino]-7- methoxyquinoline-3- carboxylate compound 445 | Ethyl 4-[(2,4- V4 117 intermediate difluorophenyl)amino]-7- fluoro-6-(4-methylpiperazin- compound Ethyl 4-])2,3- 7 114 dichlorophenyl)amino ]-7-fluoro-6-(4-methylpiperazin- compound Ethyl 4-[(2,4- VA 117 intermediate difluorophenyl)amino]-7- fluoro-6-morpholin-4- compound Ethyl 4 -[(2,3- \4 11H median dichlorophenyl)amino}-5- fluoro-6-(4-methylpiperazin- compound 463 | Ethyl 7-ethoxy-4-[(4- Y. 116 median) ‎ ethylphenyl)amino}-6-(4- methylpiperazin-1- compound 487 | Ethyl 4-[(3-chloro-4- Y 1117) intermediate fluorophenyl)amino|-7- ethoxy-6-(4- methylpiperazin- 117 intermediate dichlorophenyl)amino]-7- ethoxy-6-(4-methylpiperazin-

NY

i a MWY - - Tie | of Ethyl 4-[(2,3- vy | 517 dichlorophenyl)amino]-7- intermediate 111 ethoxy-6-(4- ethylpiperazin-1- EN Ethyl 4-[(3-chloro-2- Ys | 474 fluorophenyl)amino]-7- intermediate 11778 ethoxy-6-morpholin-4- Ethyl 7-ethoxy-4-[(2-fluoro-5- Yo | 545 compound methylphenyl)amino]-6- intermediate 116 morpholin-4-ylquinoline-3- Ethyl 4-[(3- chloro-4- YH |545 fluorophenyl)amino}-7- intermediate YWY ethoxy-6-morpholin-4- Ethyl 7-ethoxy-4-[(4- vy | 450) ethylphenyl)amino]-6- intermediate 11776 morpholin-4-ylquinoline-3- ethyl 4-[(2,3- YA compound dichlorophenyl)amino}-7- intermediate 1171 ethoxy -6-morpholin-4- Ethyl 4-[(2,3- Yq | 530 dichlorophenyl)amino]-7- intermediate 1171 ethoxy-6-(4- isopropylpiperazin-1- yl)quinoline-3-carboxylate dichlorophenyl)amino}-7- intermediate 1171 ethoxy-6-(4-methyl-1,4- YsoV

:- YA-diazepan-1-yl)quinoline-3-

Cm compound 489 | Ethyl 4-])2,3- 1 111 is the intermediate dichlorophenyl)amino]-7- ethoxy-6-(3- hydroxypyrrolidin-1-) of the compound Ethyl 4-[(2,3- vy 111) the intermediate dichlorophenyl)amino]-6-{4-[2- (dimethylamino)ethyl]piperaz in-1-yl}-7-ethoxyquinoline-3- carboxylate Compound 546 | Ethyl 4-])2,3- vy 111 The intermediate dichlorophenyl)amino]-7- ethoxy-6-[4-(2- methoxyethyl)piperazin-1- yl]quinoline-3-carboxylate with the compound | Ethyl 4-[(3,4- ve 117 intermediate dichlorophenyl)amino}-7- ethoxy-6-(4-ethylpiperazin-1- compound 485 | Ethyl 4-[(2,4- vo 111 intermediate) ‎ difluorophenyl)amino]-7- ethoxy-6-(4-ethylpiperazin-1- compound 501 | Ethyl 4-[(3-chloro-2- ve 1178 intermediate fluorophenyl)amino]-7- ethoxy-6 -(4-ethylpiperazine-1-an

YsoV

= 1189 -

VV Intermediate ethylpiperazin-1-yl)-4-[(2- fluoro-5- methylphenyl)amino]quinolin e-3-carboxylate Ethyl 4-[(3-chloro-4- *A | 501) Compound 1117 intermediate fluorophenyl)amino}-7- ethoxy-6-(4-ethylpiperazin-1- compound 477 | Ethyl 7-ethoxy-4-[(4- va 1176 ethylphenyl)amino intermediate]- 6-(4- ethylpiperazin-1-yl)quinoline- compound 541 | Ethyl 6-[4-(2- 111 intermediate cyanoethyl)piperazin-1-yl}-4-[(2,3- dichlorophenyl)amino]- 7-ethoxyquinoline-3- carboxylate ‎Ethyl 4-[(2,3- 2 | 503 compound 111 intermediate dichlorophenyl)amino]-7- ethoxy-6-(4- hydroxypiperidin-1- yl)quinoline-3-carboxylate ‎Ethyl 7-ethoxy-4-[(4- $Y | 477 compound 179 intermediate ethylphenyl)amino]-6-(4- methyl-1,4-diazepan-1 Compound 457 | Ethyl 4-])2,4- $y 111 Intermediate difluorophenyl)amino]-7- ethoxy-6-(3- YéoV

—_ \ Y . — Compound 471 | Ethyl 4-[(2,4-111 intermediate difluorophenyl)amino]-7- ethoxy-6-(4- hydroxypiperidin-1- yl) quinoline-3-carboxylate Compound 531 | Ethyl 4-[(3,4- '0 117 intermediate dichlorophenyl)amino]-7- ethoxy-6-(4- isopropylpiperazin-1- yhquinoline-3-carboxylate) Compound Ethyl 4-[(2,4- $n 1171 Intermediate difluorophenyl)amino]-7- ' ethoxy-6-(4- isopropylpiperazin-1- yl)quinoline-3-carboxylate Compound 515 | Ethyl 4-[(3-chloro-2- 1 1178) The intermediate fluorophenyl)amino]-7- ethoxy-6-(4- isopropylpiperazin-1- yl)quinoline-3-carboxylate Compound 515 | Ethyl 7-ethoxy-4-[(2-fluoro-5- | M 1146 Intermediate methylphenyl)amino]-6-(4- isopropylpiperazin-1- ybDquinoline-3-carboxylate Compound 491 | Ethyl 4-[(3-chloro-4- x 111 fluorophenyl)amino intermediate ]-7- ethoxy-6-(4- isopropylpiperazin-1- yDquinoline-3-carboxylate 1 L

- YN - AA Compound 484 | Ethyl 4-[(2,4-

1171 intermediate difluorophenyl)amino}-7- ethoxy-6-(4-methyl-1,4- diazepan-1-yl)quinoline-3- carboxylate

Ethyl 4-[(2,3- 2 | 517 Compound

100 Intermediate dichlorophenyl)amino}-6-(4-isopropylpiperazin-1-yl)-7-methoxyquinoline-3-carboxylate

Ethyl 4-[(2,4- oy | 484) Compound

111 intermediate difluorophenyl)amino]-6-(4-isopropylpiperazin-1-yl)-7-methoxyquinoline-3-carboxylate

Ethyl 4-])2,3- oy | 503 Compound

Yoo intermediate dichlorophenyl)amino]-7- methoxy-6-(4-methyl-1,4- diazepan-1-yl)quinoline-3- carboxylate

Ethyl 4-[(2,4- | 470 Compound

111 intermediate difluorophenyl)amino}-7- methoxy-6-(4-methyl-1,4- diazepan-1-yl)quinoline-3- carboxylate

Ethyl 4-[(2,3- | 503 Compound

yoo intermediate dichlorophenyl)amino]-6-(4- ethylpiperazin-1-yl)-7- methoxyquinoline-3- carboxylate

Lah 76

' - 1117 - Al-Markab 470 | Ethyl 4-[(2,4-on

VAY Intermediate difluorophenyl)amino}-6-(4- ethylpiperazin-1-yl)-7- methoxyquinoline-3- carboxylate Compound 503 | Ethyl 4-[(3,4- ov 111 intermediate dichlorophenyl)amino]-6-(4- ethylpiperazin-1-yl)-7- methoxyquinoline-3- carboxylate compound 517 | Ethyl 4-[(3,4- oh 111 intermediate dichlorophenyl)amino]-6-(4- isopropylpiperazin-1-yl)-7- methoxyquinoline-3- carboxylate compound 503 | Ethyl 4-[(3,4- 04 111 intermediate dichlorophenyl)amino]-7- methoxy-6-(4-methyl-1,4- diazepan-1-yl)quinoline-3- compound 517 | Ethyl 4-[(3,4- “1 117 intermediate dichlorophenyl)amino]-7- ethoxy-6-(4-methyl-1,4- diazepan-1-yl)quinoline-3- 2 B= compound ‎ Ethyl 7-ethoxy-4-[(2-fluoro-5- 1 115 intermediate methylphenyl)amino}-6-(4- methyl-1,4-diazepan-1-

EE

No a

; - YY - 1117 intermediate fluorophenyl)amino]-7- ethoxy-6-(4-methyl-1,4- diazepan-1-yl)quinoline-3- carboxylate B-2)]-4 Ethyl compound

VA intermediate fluorophenyl)amino]-7- methoxy-6-(4- methylpiperazin-1- Ethyl 6-[4-(tert- + | 573 compound 179 butoxycarbonyl)piperazin-1- yl] -4-[(3-chloro-4- fluorophenyl)amino]-7- ethoxyquinoline-3- carboxylate ‎Ethyl 6-[4-(tert- “0 | 553 compound 116 intermediate butoxycarbonyl)piperazin-1- yl]-7-ethoxy-4-[(2-fluoro-5- methylphenyl)amino]quinolin e-3-carboxylate ‎Ethyl 6-[4-(tert- “1 | 573 compound 11778 intermediate butoxycarbonyl) piperazin-1- yl]-4-[(3-chloro-2- fluorophenyl)amino}-7- ethoxyquinoline-3- carboxylate ‎Ethyl 7-methoxy-4-[(3- wy | 465) compound ‎methoxy-2 - Intermediate 181 methylphenyl)amino]-6-(4- methylpiperazin-1- yl)quinoline-3-carboxylate Cl el methylphenyl)amino]-7-lam

- 174 -

VAY intermediate methoxy-6-(4- methylpiperazin-1- ml ylquinoline-3-carboxylate Compound 463 | Ethyl 4-[(3-chloro-2- “4

VAY intermediate methylphenyl)amino]-7- ethoxy-6-(4-methylpiperazin- 2 1-yl)quinoline-3-carboxylate a compound 486 | Ethyl 4-[(3-chloro-2- V. 118 intermediate fluorophenyl)amino]-7- ethoxy-6-(4-methylpiperazin- compound 462 | Ethyl 7-ethoxy-4-[(3- vy) 184 Intermediate ethylphenyl)amino]-6-(4- methylpiperazin-1- compound Ethyl 4-])3- vy

VAS intermediate chlorophenyl)amino]-7- ethoxy-6-(4-methylpiperazin- Compound 486 | Ethyl 4-[(2-chloro-4- VY)

YAY intermediate fluorophenyl)amino]-7- ethoxy-6-(4-methylpiperazin- compound 486 | Ethyl 4-[(4-chloro-2- 7)

VAY intermediate fluorophenyl)amino]-7- ethoxy-6-(4-methylpiperazin- compound 448 | Ethyl 7-ethoxy-4-[(3- vo 18/8 methylphenyl)amino]-6 (4- methylpiperazin-1- so no

[ — \Yo —

VAS intermediate methylphenyl)amino}]-7- ethoxy-6-(4-methylpiperazin- ne 1-yl)quinoline-3-carboxylate 0 compound Ethyl 7-ethoxy-4-[(3-fluoro-2-) VY 190 intermediate methylphenyl)amino]-6-(4- methylpiperazin-1-b yl)quinoline-3-carboxylate a compound 457 | Ethyl 4-[(3,4- VA 191 intermediate difluorophenyl)amino]-7- methoxy-6-(4- methylpiperazin-1- yl)quinoline-3-carboxylate compound Ethyl 7-methoxy-6-( 4- va 197 intermediate methylpiperazin-1-yl)-4-{[2- methyl-3- (trifluoromethyl)phenyljamin o}quinoline-3-carboxylate compound 455 | Ethyl 4-])4-m VAY intermediate chlorophenyl)amino]-7- methoxy-6-(4- methylpiperazin-1- yl)quinoline-3-carboxylate compound 453 | Ethyl 4-[(2-fluoro-4- A

V4 ¢ intermediate methylphenyl)amino}-7- methoxy-6-(4- methylpiperazin-1- yl)quinoline-3-carboxylate compound 489 | Ethyl 7-methoxy-6-(4- AY 140 intermediate methylpiperazin-1-yl)-4-{[3- (trifluoromethyl)phenyljamin) to Lachme B

A - 171 - methylphenyl)amino]-6-(4- intermediate 119 methylpiperazin-1- Ethyl 4-[(3-chloro-2- At methylphenyl)amino]-7 Intermediate VAY ethoxy-6-(4-ethylpiperazin-1- Ethyl 4-[(3-chloro-2- Ao methylphenyl)amino]-7- intermediate VAY ethoxy-6- (4-methyl-1,4- diazepan-1-yl)quinoline-3- carboxylate Ethyl 7-ethoxy-6-(4- AY | 480 compound ethylpiperazin-1-yl)-4 -[(3- intermediate 110 fluoro-2- methylphenyl)amino]quinolin e-3-carboxylate pam | Ethyl 7-ethoxy-4-[(3-fluoro-2- |480 Compound methylphenyl)amino]-6-(4- intermediate 110 methyl-1,4-diazepan-1- Ethyl 7-ethoxy-4-[(2-fluoro-4- AA) | 467 methylphenyl)amino]-6-(4- intermediate 1976 methylpiperazin-1- Ethyl 7-ethoxy-4-[(3-methoxy-2- AS | 479 methylphenyl)amino] -6-(4-VAY intermediate methylpiperazin-1-yl)quinoline- L

- \YV -

1178 intermediate difluorophenyl)amino]-7-ethoxy- 6-(4-methylpiperazin-1- yl)quinoline-3-carboxylate

Ethyl 4-]2,5-ay | 485 "difluorophenyl)amino]-7-ethoxy- |"

1678 intermediate phenyl)] 7 6-(4-ethylpiperazin-1- yh)quinoline-3-carboxylate

Ethyl 4-[(2,5- 9 485 Compound

1978 intermediate difluorophenyl)amino]-7- ethoxy-6-(4-methyl-1,4- diazepan-1-yl)quinoline-3- carboxylate

Ethyl 7-ethoxy-6-(4- qv | 481 Compound

197 Intermediate ethylpiperazin-1-yl)-4-[(2- fluoro-4- methylphenyl)amino]quinolin e-3-carboxylate

Ethyl 4-[(3,4- q¢ | 463 dimethylphenyl)amino]-7- intermediate 144 ethoxy-6-(4-methylpiperazin- 1-yl)quinoline-3-carboxylate Ethyl 4-[(2,4- 40 | 471 difluorophenyl)amino]-6 intermediate 0? ethoxy-7-(4-methylpiperazin- 1-yl)quinoline-3-carboxylate Ethyl 4-[(2,3- 5 | 503 dichlorophenyl)amino]-6- intermediate 110 ? ethoxy-7-(4-methylpiperazin- 1-yl)quinoline-3-carboxylate Ethyl 4-[(2,3- 9 | 471 difluorophenyl)amino]-7- intermediate 27? ethoxy-6-(4-methylpiperazin- 1-yl)quinoline-3-carboxylate Ysonv i - 18 - compound 463 | Ethyl 4-[(2,3-aA

Yor intermediate dimethylphenyl)amino]-7- ethoxy-6-(4-methylpiperazin- 2“ 1-yl)quinoline-3-carboxylate 0 Compound 488 | Ethyl 4-[(4-chloro-3- qq ?14 intermediate fluorophenyl)amino]-7- ethoxy-6-(4-methylpiperazin- Compound 517 | Ethyl 4-[(2,3- A) .

Intermediate Yo dichlorophenyl)amino]-6- ethoxy-7-(4-ethylpiperazin-1- Compound 485 | Ethyl 4-[(2,4- 111)

Yoo Intermediate difluorophenyl)amino]-6- ethoxy-7-(4-ethylpiperazin-1- Compound 518 | Ethyl 4-[(3-chloro-2,4- Voy

Yoo intermediate difluorophenyl)amino}-7- ethoxy-6-(4-ethylpiperazin-1- compound 504 | Ethyl 4-[(3-chloro-2,4- yoy ?16) difluorophenyl intermediate) aminoj-7- ethoxy-6-(4-methylpiperazin- compound 487 | Ethyl 4-[(3-chloro-4- 0.4)

Yo mediator fluorophenyl)aminol]-6- ethoxy-7-(4-methylpiperazin- mediator 6?fluorophenyl)amino]-6- ethoxy-7-(4-ethylpiperazin-1-

YéoVv

A 1"9 - - Ethyl 4-{{4-fluoro-2-1 compound (trifluoromethyl)phenyljamino}- intermediate 0117 7-methoxy-6-(4- methylpiperazin- 1-yl)quinoline- 3-carboxylate Ethyl 4-[(2-chloro-4- Voy | 473 fluorophenyl)amino]-7- intermediate YA methoxy-6-(4- methylpiperazin-1-yDquinoline-3-carboxylate Ethyl 7-methoxy-6-(4- 0 | 505 compound methylpiperazin-1-yl)-4-{[3-intermediate Yd] (trifluoromethoxy)phenyl]ami no}quinoline-3-carboxylate Ethyl 4-[(2,6- 4 dimethylphenyl)amino]-7- intermediate 101?methoxy-6-(4 - methylpiperazin-1- yl)quinoline-3-carboxylate Ethyl 4-])2,4- \Y | 498 compound difluorophenyl)amino]-7- intermediate 1171 ethoxy-6 -(4-ethyl-1,4- y-6-(4-ethy) and diazepan-1-yl)quinoline-3- intermediate YoY carboxylate 7 Ethyl 4-[( 2,3-111|516 dichlorophenyl)amino]-6-(4-intermediate 100 ethyl-1,4-diazepan-1-yl)-7-pan-1-yl) in haler and the compound methoxyquinoline-3- intermediate Yoy carboxylate : Ethyl 4-[(2,3- VY | 530 dichlorophenyl)amino]-7- intermediate 111 ethoxy-6-(4 -ethyl-1,4- y-6-(4-ethy) and the compound lag-la

Al-Sah S A Ss carboxylate compound 589 | Ethyl 6-[4-(tert- yyy 111 intermediate butoxycarbonyl)piperazin-1- yl]-4-1(2,3- dichlorophenyl)amino]-7- ethoxyquinoline-3- carboxylate compound 542 | Ethyl 6-[4-(tert- \ yg 111 intermediate butoxycarbonyl)piperazin-1- 11[-4-])2,4- difluorophenyl)amino]-7- methoxyquinoline-3- carboxylate Compound 556 | Ethyl 6-[4-(tert- 'yo 1117 intermediate butoxycarbonyl)-1,4- diazepan-1-yl]-4-[(2,4- difluorophenyl)amino]-7- methoxyquinoline-3- carboxylate Compound 602 | Ethyl 6-[4-(tert- 111 111 intermediate butoxycarbonyl)-1,4- diazepan-1-yl}-4-[(2,3- dichlorophenyl)amino}-7- ethoxyquinoline-3- carboxylate compound 556 | Ethyl 6-[4-(tert- NY "Wo intermediate butoxycarbonyl)piperazin-1- yil-4-[(2,4- difluorophenyl)amino]-7- ethoxyquinoline-3- carboxylate 2 uhh

AA “1 - - Ethyl 6-[4-(tert- VA | 570) butoxycarbonyl)-1,4- intermediate 1171 diazepan-1-yl}-4-[(2, 4- difluorophenyl)amino]-7- ethoxyquinoline-3- carboxylate Ethyl 6-[4-(tert- 14 | 589) butoxycarbonyl)-1,4- intermediate 101 diazepan-1-yl}-4-[(2,3- dichlorophenyl)amino]|-7- methoxyquinoline-3- carboxylate Ethyl 4-[(2-fluoro-5- 7 | 453 Compound [methylphenyl)amino]-7- Median 11? methoxy-6-(4- methylpiperazin-1- yl)quinoline-3-carboxylate Ethyl 4-])2,5- 111 | 457 difluorophenyl)amino]-7- intermediate YAY methoxy-6-(4- methylpiperazin-1- yD) quinoline-3-carboxylate Ethyl 4-[(3-chloro-2) - \ YY |470 Compound methylphenyl)amino]-7- intermediate YAY methoxy-6-(4- methylpiperazin-1- yl)quinoline-3-carboxylate Ethyl 4-[( 2-chloro-3- YY compound [methylphenyl)amino]-7- intermediate 16 methoxy-6-(4- methylpiperazin-1- yhquinoline-3-carboxylate YsoV

[ - 117 -

111 intermediate difluorophenyl)amino]-6-|3- (dimethylamino)pyrrolidin-1- carboxylate

Ethyl 4-[(3-chloro-2- \ Yo | 473 Compound "|Tet 6-(4-methylpiperazin-1- yl)quinoline-3-carboxylate Ethyl 4-[(3-chloro) -5- \ va | 488 fluorophenyl)amino]-7-ethoxy-6- ER yDquinoline-3-carboxylate Ethyl 7-ethoxy-6-(4- yyy | 489 methylpiperazine -1-yl)-4-[(2,3,4- WE|“ -3-carboxylate Ethyl 4-[(5-chloro-2- VY A | 484 Compound

YAA intermediate methylphenyl)amino]-7-

ethoxy-6-(4-methylpiperazin- compound 479 | Ethyl 7-ethoxy-4-[(4-methoxy- 11)

?11 intermediate 2-methylphenyl)amino]-6-(4-

methylpiperazine-1- compound 538 | Ethyl 4-1]2-01010-5-VY.

YY. The intermediate (trifluoromethyl)phenyljamin o0}-7-ethoxy-6-(4- methylpiperazin-1- ylhquinoline-3-carboxylate

Ethyl 4-])2,4- \ VA compound

1171 intermediate difluorophenyl)amino]-7- ethoxy-6-(4-methyl-3-

L

A 1 B "-2,3([-4 Ethyl|474 dichlorophenyl)amino]-7-(4-intermediate 118 ethylpiperazin-1-yl)-6- methoxyquinoline-3- carboxylate ethyl 4-[(2-fluoro-5- YY | 454 methylphenyl)amino]-6- intermediate YY methoxy-7-(4- methylpiperazin- 1- yDquinoline-3-carboxylate Ethyl 7-(4-ethylpiperazin-1- \ v4 | 467 yl)-4-[(2-fluoro-5- intermediate YY methylphenyl)amino ]-6- methoxyquinoline-3- carboxylate Ethyl 4-[(3-chloro-2- \Vo | 473 fluorophenyl)amino}-6- intermediate YYY methoxy-7- (4- methylpiperazin-1- yl)quinoline-3-carboxylate Ethyl 4-[(3-chloro-2- Xa | 487 fluorophenyl)amino]-7-(4- intermediate) YYY ethylpiperazin-1-yl)-6- methoxyquinoline-3- carboxylate Ba-Ethyl 4-[(2-fluoro-5- 1 | 467 methylphenyl)amino]-6 Mediator 1?? methoxy-7-(4-methyl-1,4- diazepan-1-yl)quinoline-3- carboxylate YeoV

A 17 4 - -

YY intermediate difluorophenyl)amino]-6- methoxy-7-(4-methyl-1,4- diazepan-1-yl)quinoline-3- carboxylate Ethyl 4-[(2-chloroe-3- XT | 487 Compound ‎fluorophenyl)amino}-7- Mediator 4?? ethoxy-6-(4-methylpiperazin- 1-yl)quinoline-3-carboxylate .tt "Ethyl 4-[(2-chloro-3- | 501 fluorophenyl)amino]-7- Intermediate 4 ethoxy-6-(4-ethylpiperazin-1- yl)quinoline-3-carboxylate Ethyl 4-[(2-chloro-3- 1 compound YY 4 fluorophenyl intermediate) amino]-7- ethoxy-6-(4- isopropylpiperazin-1- yl)quinoline-3-carboxylate Ethyl 6-[4-(tert- \ $Y | 553 compound 17-intermediate butoxycarbonyl)piperazin-1 - yl}-7-ethoxy-4-[(2-fluoro-4- methylphenyl)amino]quinolin e-3-carboxylate ‎Ethyl 4-[(2,3- \¢y | 504 compound 111 intermediate dichlorophenyl)amino]-7- ethoxy-6-(3-oxopiperazin-1- yl)quinoline-3-carboxylate ‎Ethyl 7-ethoxy-4-[(2-fluoro-5- 4 | 467 compound 1179 intermediate methylphenyl)amino]-6-(3-oxopiperazin-1-yl)quinoline- 3-carboxylate i 4 um

- \Yo-

1171 intermediate difluorophenyl)amino]-7- ethoxy-6-(3-oxopiperazin-1- yl)quinoline-3-carboxylate

(s, 1 H), 8.99 (s, 1 H), | Ethyl 4-[(2-chloro-4- \ $Y 9.98 compound (s, 1 H), 7.30 (s, 1 H), thylphenyl)amino]-7 7.50 ' (d, 1 H), 6.90 (a, 1 | methylphenyhaminol-7- 7.10 | intermediate YY0 H), 6.77 (s, 1 H), 4.35 (q, 2 | ethoxy-6-(4-methylpiperazin- 1-yl) quinoline-3-carboxylate hands per mm 1 H), 2.20 (s, 3 H), 1.40 (m, H), 6 (s, 1 H), 8.87 (s, 1 H), | Ethyl 7-ethoxy-4-{|2-fluoro-3- \ $V 9.55 Compound 1 7.45-7.15 (m, 5 H), 4.28 . (g,2 H), 4.12 (q, 2 H), (trifluoromethyl)phenylj]amin | Median YY (s, 4 H), 2.42 (s, 4 H), | 0}-6-(4-methylpiperazin-1- 3.90 a Ph ; 0 1.45 )53 H), yl)quinoline-3-carboxylate (s, 1 H), 8.90 (s, 1 H), | Ethyl 4-[(2,4- EA 9.98 Compound 1 7.20 (s, 1 H), 7.00 (m, 1 .H), 6.91 (s, 1H), 6.70 (s, 1 | imethoxyphenyljamino ]-7- | median YYV H), 6.52 (t, 1 H), 4.35 (q, 2 | ethoxy-6-(4-methylpiperazin- os 268 > J 1-yl)quinoline-3 -carboxylate A 0 Te 9 Le 3 H), 2.35 (s, 4 H), 2.20 (s, 3 H), 2.35 (m, 6 H) (s, 1 H) , 8.91 (s, 1 H), |Ethyl 4-[(2-chloro-4-fluoro-5- \ 49 9.89 Compound 1 7.57 (d, 1 H), 7.29 (s, 1 H), methylphenyl) amino]-7 (d, 1 H), 6.75 (s, 1 H), | Tey 0313 60012010 7.00 | intermediate Y YA (q, 2 H), 4.20 (q, 2 ethoxy-6- (4-methylpiperazin- 4.32 o ; = i o ; 1-yl)quinoline-3-carboxylate 7 1 H), 1.45 (t,3 H), 1.37 (t, 3 H) (s , 1 H), 8.89 (s, 1 H), | Ethyl 4-[(5-chloro-2- Vo. 9.60 Compound 1 7.35 (m, 2 H), 7.15-7.05 8 henvDaminol-7 ( m, 3 H), 4.20 (q, 4 H), uorophenylamino}-7- | intermediate YY4 (s, 4 H), 2.42 (s, 4 H), | ethoxy-6-(4-methylpiperazin - 2.90 Hn 1.40 (t, 3 H), 1-yl)quinoline-3-carboxylate D 58 1 (s, 1 H), 8.90 (s, 1 H), |Ethyl 7-ethoxy-4- {|2- 161 9.85 compound 1 7.40 (m, 1 H), 7.30 (m, 2 th 5 H), 6.95 (s, 1 H), 6.85 (s, 1 | cox" | median YY. H), 4.30 (q, 2 H), 4.20 (q, | (trifluoromethyl)phenyljamin H), 3.90 (s, 3 H), 2.80 (s, . . 2 0}-6-(4-methylpiperazin-1- - 220 1 4 - 2.40 4 H), 1.40 (t, 3 H), 1.30 (t, |yl)quinoline-3-carboxylate 3 3H ) Ahh 2 7

A 19 - - Ethyl 4-[(2-fluoro-4- Voy | 484 methylphenyl)amino]-7-(2-intermediate YEN methoxyethoxy)-6-morpholin- 4 -ylquinoline-3-carboxylate Ethyl 4-[(2-fluoro-4- Voy | 525 methylphenyl)amino]-6-(4-intermediate YY isopropylpiperazin-1-yl)-7- (2- methoxyethoxy)quinoline-3- carboxylate ethyl 4-[(2-fluoro-5- vot | 525 methylphenyl)amino]-6-(4-YY intermediate isopropylpiperazin -1-yl)-7-(2- methoxyethoxy)quinoline-3- carboxylate Intermediate compound (Yoo) Ethyl 6-bromo-4-[(2,3-dichlorophenyl)amino}- 7-methoxyquinoline-3-carboxylate M A mixture of ethyl 6-bromo-4-chloro-7-methoxyquinoline-3-carboxylate (intermediate compound 1 16 vv) g 7.9 mmol) was heated; 4 vo) 2,3-dichloroaniline © mg; 5.7 mmol); acetic acid s (+9 μl) (A) DMF ml) at a temperature of 100 C for 1 hour. The reaction mixture was poured over ice water; The pH was adjusted to be 4 using 1 00 M and filtered the resulting precipitate to yield 000 mg of sale solid; Ve 1:2 Lt. Yéov

- H - Intermediates from (V0) (7.7): The following compounds were prepared in a manner similar to that of the intermediate (Yoo) using appropriate starting materials. SM M/z / NMR intermediate complex Ethyl 4-[(2-fluoro-5- you | 497 methylphenyl)amino}]-7-(2-methoxyethoxy intermediate)-6-(4-yy yethoxy)-6-( methylpiperazin-1 -yl)quinoline-3-carboxylate

Ethyl 4-|(2,5- 11 | 501 difluorophenyl)amino]-7-(2-methoxyethoxy)-6-(4-)

(Vy yethoxy)-6-( methylpiperazin-1-yl)quinoline-3-carboxylate

Ethyl 4-[(3-chloro-2- 1 | 517 fluorophenyl)amino)-7-(2- methoxyethoxy intermediate)-6-(4- YéoV

- 1m-1 methylpiperazin-1-yl)quinoline-3-

Ct ae compound 534 | Ethyl 4-[(2,3- 64 intermediate dichlorophenyl)amino]-7-(2-

Vy methoxyethoxy)-6-(4- methylpiperazin-1-yl)quinoline-3- compound 501 | Ethyl 4-[(2,4-p-difluorophenyl)amino}-7-(2-b methoxyethoxy)-6-(4- methylpiperazin-1-yl)quinoline-3- Compound 497 | Ethyl 4-[(2-fluoro-4- 14 intermediate methylphenyl)amino]-7-(2-

Vy methoxyethoxy)-6-(4- methylpiperazin-1-yl)quinoline-3- compound 601 | Ethyl 7-(2-{[tert- \ vy intermediate butyl(dimethyl)silyl]oxy}ethoxy)-4-

YA [(2,4-difluorophenyl)amino]-6-(4- methylpiperazin-1-yl)quinoline-3- compound 617 | Ethyl 7-(2-{[tert-VY intermediate butyl(dimethyl)silyljoxy}ethoxy)-4-

YA [(3-chloro-2-fluorophenyl)amino]-6- (4-methylpiperazin-1-yl)quinoline- compound 517 | Ethyl 4-[(2-chloro-3- Vv ¢ intermediate fluorophenyl)amino]-7-(2- yy methoxyethoxy)-6-(4- methylpiperazin-1-yl)quinoline-3- ea eee

Yesnav

- 119 - the mediator dichlorophenyl)amino]-7- yy methoxyquinoline-3-carboxylate the compound Ethyl 6-bromo-4-[(3,4- XE . inol-7- the mediator dichlorophenyl)amino] methoxyquinoline- 3-carboxylate yy compound 438 | Ethyl 6-bromo-4-[(2,4- VY intermediate difluorophenyl)amino}-7- methoxyquinoline-3-carboxylate yyy Compound Ethyl 7-bromo-4-[(2,3- 1A intermediate) dichlorophenyl)amino}-6-

Yen methoxyquinoline-3-carboxylate Ethyl 7-bromo-4-[(3,4- 154 intermediate dichlorophenyl)amino]-6-oo. compound methoxyquinoline-3-carboxylate 452 | Ethyl 6-bromo-4-[(2,4- VY. intermediate difluorophenyl)amino}-7- ve ethoxyquinoline-3-carboxylate compound 485 | Ethyl 6-bromo-4-|(2,3- 11 dichlorophenyl)amino]-7- » ethoxyquinoline-3-carboxylate compound Ethyl 6-bromo-4-[(3,4- VY intermediate) dichlorophenyl)amino}-7-

Ye ethoxyquinoline-3-carboxylate Ethyl 6-bromo-4-[(2,4- \VY intermediate difluorophenyl)amino]-7- fluoroquinoline-3-carboxylate vey Ethyl 6-bromo-4- [(2,3-VV intermediate dichlorophenyl)amino]-7-fluoroquinoline-3-carboxylate

Yev

YAN

- Ng. Compound Ethyl 6-bromo-4-[(2,3- "Wo intermediate dichlorophenyl)amino]-5- - fluoroquinoline-3-carboxylate Compound 445 | Ethyl 6-bromo-7-ethoxy-4- [(4- VV intermediate ethylphenyl)amino]quinoline-3- 1 carboxylate compound Ethyl 6-bromo-4-[(3-chloro-4- \ VY intermediate fluorophenyl)amino]-7- ' ethoxyquinoline -3-carboxylate Ethyl 6-bromo-4-[(3-chloro-2- AWA intermediate fluorophenyl)amino]-7- 1 ethoxyquinoline-3-carboxylate Ethyl 6-bromo-7-ethoxy -4-[(2- 15 intermediate fluoro-5- d-methylphenyl)amino]quinoline-3- carboxylate compound 420 | Ethyl 6-bromo-4-](2- VA intermediate fluorophenyl)amino ]-7- ry methoxyquinoline-3-carboxylate Compound 445 | Ethyl 6-bromo-7-methoxy-4-[(3- VAY intermediate methoxy-2- .vy methylphenyl)amino]quinoline-3- carboxylate Compound Ethyl 6-bromo-4-[(4-chloro-2- VAY intermediate methylphenyl)amino]-7- vy methoxyquinoline-3-carboxylate Compound 463 | Ethyl 6-bromo-4-[(3) -chloro-2- VAY methylphenyl)amino]-7- Lamek

- Vey -

ethoxyquinoline-3-carboxylate intermediate

Yéo the compound 443 | Ethyl 6-bromo-7-ethoxy-4-[(3- VAS intermediate ethylphenyl)amino]quinoline-3-

1 carboxylate compound Ethyl 6-1-01110-4-])3- mm intermediate chlorophenyl)amino]-7-

1 ethoxyquinoline-3-carboxylate compound 467 | Ethyl 6-bromo-4-[(2-chloro-4- \ AR intermediate fluorophenyl)amino}-7-

1 ethoxyquinoline-3-carboxylate compound 467 | Ethyl 6-bromo-4-[(4-chloro-2- VAY intermediate fluorophenyl)amino]-7-

,. . Compound ethoxyquinoline-3-carboxylate 429 | Ethyl 6-bromo-7-ethoxy-4-[(3- VAA intermediate methylphenyl)amino]quinoline-3-

1 carboxylate compound 463 | Ethyl 6-bromo-4-[(2-chloro-3- YAS intermediate methylphenyl)amino]-7-

‎; Compound ethoxyquinoline-3-carboxylate 447 | Ethyl 6-bromo-7-ethoxy-4-[(3- 9 intermediate fluoro-2-

1 methylphenyl)amino]quinoline-3-

carboxylate

Ethyl 6-bromo-4-|(3,4- 111 | 437 difluorophenyl)amino]-7- intermediate

ry methoxyquinoline-3-carboxylate compound 484 | Ethyl 6-bromo-7-methoxy-4-{[2- Vay intermediate methyl-3-

Yéav

[ - 457 - yyy (trifluoromethyl)phenyljamino}quin oline-3-carboxylate Compound 435 Ethyl 6-bromo-4-[(4- 14Yy intermediate chlorophenyl)amino]-7- 1b methoxyquinoline-3- compound carboxylate 434 | Ethyl 6-bromo-4-[(2-fluoro-4- V9 ¢ intermediate methylphenyl)amino]-7- 1b methoxyquinoline-3-carboxylate compound Ethyl 6-bromo-7-methoxy-4- {[3- \ 40 intermediate (trifluoromethyl)phenyljamino}quin 1 vy oline-3-carboxylate compound 447 | Ethyl 6-bromo-7-ethoxy-4-[(2- ya intermediate fluoro-4- .methylphenyl)amino]quinoline-3- carboxylate compound 459 | Ethyl 6-bromo-7-ethoxy-4-[(3- 111 intermediate methoxy-2-

J ‘ methylphenyl)amino]quinoline-3- carboxylate compound 454 | Ethyl 6-bromo-4-[(2,5- V4 A intermediate difluorophenyl)amino}-7- d ethoxyquinoline-3-carboxylate Compound Ethyl 6-bromo-4-[(3,4- 144) Intermediate dimethylphenyl)amino]-7- 7 ethoxyquinoline-3-carboxylate Compound 453 | Ethyl 7-bromo-4-[(2,4- Y.o. intermediate difluorophenyl)amino]-6- 1 0 ethoxyquinoline-3-carboxylate LAM

intermediate dichlorophenyl)amino}-6-

Yen ethoxyquinoline-3-carboxylate compound 452 | Ethyl 6-bromo-4-{(2,3- Y.Y intermediate difluorophenyl)amino]-7-

Ys ethoxyquinoline-3-carboxylate compound 444 | Ethyl 6-bromo-4-{(2,3-voy intermediate dimethylphenyl)amino}-7-

Ye ethoxyquinoline-3-carboxylate compound 468 | Ethyl 6-bromo-4-{(4-chloro-3- vos mediator) 111101011161171(21721120[-7-

Ys ethoxyquinoline-3-carboxylate compound 485 | Ethyl 6-1-01110-4-])3-211010-2,4- Y.o Intermediate difluorophenyl)amino]-7- » ethoxyquinoline-3-carboxylate Compound 467 | Ethyl 7-bromo-4-[(3-chloro-4- You intermediate fluorophenyl)amino]-6-

Yen ethoxyquinoline-3-carboxylate compound 487 | Ethyl 6-bromo-4-{[4-fluoro-2- NY intermediate (trifluoromethyl)phenyljamino}-7- methoxyquinoline-3-carboxylate yyy Yd y compound 453 | Ethyl 6-bromo-4-[(2-chloro-4- YA intermediate fluorophenyl)amino}-7- methoxyquinoline-3-carboxylate yyy compound 485 | Ethyl 6-bromo-7-methoxy-4-{[3- Y.4q intermediate (trifluoromethoxy)phenyljamino}qu inoline-3-carboxylate

Yyy 7 lam

- 166 - intermediate dimethylphenyl)amino]-7- yyy methoxyquinoline-3-carboxylate compound 433 | Ethyl 6-bromo-4-[(2-fluoro-5- 911 intermediate methylphenyl)amino]-7- methoxyquinoline-3-carboxylate

Yvy Compound 437 | Ethyl 6-bromo-4-[(2,5- YY intermediate difluorophenyl)amino]-7- methoxyquinoline-3-carboxylate yyy ya y The compound Ethyl 6-bromo-4-[(3-chloro-2-) YY intermediate methylphenyl)amino]-7- methoxyquinoline-3-carboxylate vy Yd y compound 450 | Ethyl 6-bromo-4-[(2-chloro-3- xy intermediate methylphenyl)amino]-7- methoxyquinoline-3-carboxylate ry compound 453 | Ethyl 6-bromo-4-[(3-chloro-2- Vo intermediate fluorophenyl)amino|-7- methoxyquinoline-3-carboxylate

Yvy Ethyl 6-bromo-4-[(3-chloro-5- 71 fluorophenyl)amino intermediate]-7

Ye ethoxyquinoline-3-carboxylate compound 470 | Ethyl 6-bromo-7-ethoxy-4-[(2,3,4- YY intermediate trifluorophenyl)amino]quinoline-3- carboxylate

Yio the compound 465 | Ethyl 6-bromo-4-[(5-chloro-2- YA the intermediate methylphenyl)amino]-7- » ethoxyquinoline-3-carboxylate so no

[ — \ 4 o — median methoxy-2-

Ys methylphenyl)amino]quinoline-3- carboxylate compound 519 | Ethyl 6-bromo-4-{[2-chloro-5-YY. . tomo intermediate (trifluoromethyl)phenyljamino}

Ye ethoxyquinoline-3-carboxylate compound 435 | Ethyl 7-bromo-4-[(2-fluoro-5- YY intermediate methylphenyl)amino]-6- yu methoxyquinoline-3-carboxylate compound 455 | Ethyl 7-bromo-4-[(3-chloro-2-b" intermediate fluorophenyl)amino]-6-

Yeu methoxyquinoline-3-carboxylate compound 439 | Ethyl 7-bromo-4-[(2,4- yyy intermediate difluorophenyl)amino]-6- methoxyquinoline-3-carboxylate ya Compound Ethyl 6-bromo-4-[(2-chloro-3- YY¢ Intermediate fluorophenyl)amino]-7- » ethoxyquinoline-3-carboxylate Compound 9.90 (s, 1 H), 9.00 (s, | Ethyl 6-bromo-4-[(2-chloro-4- Yvye 1H) , 7.92(s, 1H), 1 og Inhenyl)amino]-7- Median | 7.40 (m, 2H), 7.10 yipheny (m, 1H), 7.00 (m, 1 ethoxyquinoline-3-carboxylate 01H), 4.29 (q,2H), 4.20 (q, 2H), 2.31 (s , 3 H), 1.40 (t,3 H), 1.30 (¢, 3

H) compound 9.56 (s, 1 H), 8.88 (s, | Ethyl 6-bromo-7-ethoxy-4-{[2- YYu 1 H), 8.51 (s, 1 H), fluoro-3 mediator | 7.50-7.30 (m, 4H), 4.31 (q, 2H), 3.91 (q, | (trifluoromethyl)phenyl]amino}quin 2H), 1.32 (1, 3H), oline-3-carboxylate 1.10 ( t, 3 H) oxylate the compound 10.05 (s, 1 H), 8.92 (s, | Ethyl 6-bromo-4-[(2,4- yyy 1 H), 7.89 (s, 1 H), dimeth henvDaminol -7 median | 7.32 (s, 1 H), 7.05 (@, | 00600 )amino]-7- 1 H), 6.71 (s, 1 H), ethoxyquinoline-3-carboxylate

YéoVv

- Ven ys. | 6.52(d, 1H), 4.21(q, 4H), 3.79 (s, 3H), 3.70 (s, 3H), 1.40 (t, 3H), 1.30 (t, 3H) Compound 9.80 ( s, 1 H), 8.95 (s, | Ethyl 6-bromo-4-[(2-chloro-4- YYA 1 1 H), 8.05 (s, 1 H), 8 hvlphenyNaminol-7 intermediate | 7.55 ( m, 1 H), 7.45 Gs, uoro-5-methylphenyl)amino}-7- 1 H), 7.15 (m, 1 H), ethoxyquinoline-3-carboxylate

Y¢+14.30(q,2H),4.18(q,2H), 2.15(s,3H), 1.45(t,3H), 1.28(¢,3

H) 9.55 (s, 1 H), 8.87 (s, | Ethyl 6-bromo-4-[(5-chloro-2- compound y 49 1 1 H), 8.45 (s, 1 H), . Median | 7.50 (s, 1 H), 7.35 (m, fluorophenyl)amino]-7- 1 H), 7.17 (m, 2 H), ethoxyquinoline-3-carboxylate 01 432(q,2 H), 4.00 ( q, 2 H), 1.46 (t, 3 H), 1.19 (t,3 H) 9.80 (s, 1 H), 8.96 (s, | Ethyl 6-bromo-7-ethoxy-4-{[ 2- YY.1 1 H), 8.15 (s, 1 H), methoxv-S- median | 7.45 (m, 2 0 y (m, 1H), 7.18 (s, 1 (trifluoromethyl)phenyljamino}quin 01|), 4.30 (q,2 H),4.10 |1 (q, 2H), 3.85 (s, 3 H), oline-3-carboxylate 1.40 (t, 3 H), 1.20 (t, 3

H) 433 | Ethyl 6-chloro-4-[(2-fluoro-4- compound YY intermediate methylphenyl)amino}-7-(2- 1 A methoxyethoxy)quinoline-3- carboxylate compound 433 | Ethyl 6-chloro-4-[(2-fluoro-5- vy intermediate methylphenyl)amino]-7-(2-

A methoxyethoxy)quinoline-3- carboxylate (YFY) Intermediate compound This compound is described as Ethyl 6-bromo-4-chloro-7-methoxyquinoline-3-carboxylate

YsoV

[ 1197 - - International Application No. 000780478901; and tig was prepared for the procedure described in: Burke T.R. etal, J.Med. Chem, 36 (1993) 425-432 A solution of: ethyl 6-bromo-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (intermediate compound (; 71)) was heated + g (...701 in 001 (phosphorous oxychloride ml) under regeneration all night 0. After cooling the solution was carefully poured into −10 ml of ice water by stirring. The resulting mixture was made basic with ¥ N NaOH and extracted with EtOAc washing the organic layer with water; dried (048250), and concentrated under reduced pressure to yield A g (797) of sale white solid. 11 111/2:9.14 (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 3

H); m/z: 344 \ The intermediate (4??) Ethyl 6-bromo-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate is the addition of a solution of diethyl {[(4-bromo- 3-methoxyphenyl)amino]methylene} malonate 0 (intermediate compound 0.074 cpa 11 (YO) mol) in warm diphenyl ether () + (Je Y) drop by drop over the course of Vo min to return YAY) diphenyl ether ml). After hours; the solution has been cooled; diluted with 001 (hexane mL); The resulting precipitate was collected to obtain 8.9 g (797) of a solid. And

VEN - - intermediate (Y70) diethyl {[(4-bromo-3-methoxyphenyl)amino]methylene}malonate to a solution of VY aa ¥©) 4-bromo-3-methoxyaniline + mol ) in Yo) CH3CN ml); VY cde YY) diethylethoxymethylene malonate mol was added. and after 10 hours; © The solvent was removed under reduced pressure and the residue dissolved in P281088. Hexane was added and the resulting precipitate was collected to obtain YY g (7280) of an off-white solid. 'THNMR:10.68 (d, 1 H), 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 (5, 3 H), 1.23 (m, 6 H); m/z: 372 Soa 0 Mediator (YY) Ethyl 7-bromo-4-chloro-6-methoxyquinoline-3-carboxylate A mixture of: ethyl 7-bromo-6-methoxy-4 was heated -oxo-1,4-dihydroquinoline-3-carboxylate (intermediate compound (779); 4,116 mmol) and (Ja A+) phosphorous oxychloride at reflux of 0. \o hour. then cool the mixture; Pour it carefully over ice (Ava gm) while stirring. Then carefully neutralize the mixture using NaOH? standard; filtering of the resulting precipitate; It was washed with water and dried to obtain Y.A. g of a white solid. NMR (CDCls): 9.00 (s, 1 H), 8.32 (s, 1 H), 7.54 (s, 1 H), 4.43 (4 2 H), 4.02 (s, 3 H), 1 (t , 3 H) 1.39 Lm

1689 - - intermediate compound (377) Ethyl 7-bromo-6-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate A solution of diethyl {[(3-bromo-4-methoxyphenyl) was added (amino]methylene} malonate (intermediate compound (774); 01 g 0.079 mol) in warm diphenyl ether (Ja 001) 0 drop by drop over Vo min to return diphenyl ether (001) mL After ?hours, the reaction mixture was cooled; (de VY +) petroleum ether was added to the filtered solid and washed with hexane to yield A g of a white solid.'H NMR:8.54 ( s, 1 H), 7.92 (s, 1 H), 7.65 (s, 1 H), 4.22 (s, 1 H), 4.22 (s, 3 H), 3.95 (s,3 H), 1.28 3 H).Vo is the intermediate compound (YYA) diethyl {[(3-bromo-4-methoxyphenyl)amino]methylene} malonate A solution of 3-bromo-4-methoxyaniline (intermediate compound ALY (YY) G £0.9 m) was stirred mol) and diethylethoxymethylene malonate m fill 0.7 mmol) 8 CH;CN (Ja 10) for ? hour. The solvent was removed under reduced pressure. The remaining \o hexane was recrystallized to yield 11 g of a white solid. 'H NMR (CDCl): 10.98 (d, 1 H), 8.40 (d, 1 H), 7.40 (d, 1 H), 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 compound (174) -Bromo-4-methoxyaniline (m)

[Vo. = — the title compound was prepared according to the procedure described in: Liu Y.-Y. and 18 Munich, M., J. (1981), 791-797 (1981).

Label Compd Radiopharm., . Intermediate compound (Ye) Ethyl 6-bromo-4-chloro-7-ethoxyquinoline-3-carboxylate oo Method of preparation { A mixture of ethyl 6-bromo-7-ethoxy-4-oxo-1 was heated ,4-dihydroquinoline-3-carboxylate (intermediate compound (41?); YT.A g £9 mmol) phosphorous oxychloride s (+£ ml) on reflux for VT h. the mixture has cooled; Carefully pour it over ice water (- 500ml) and stir. The resulting mixture was filtered; and washed with water and dried to obtain 17101 g of a light brown solid 0. (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, 9.13 11111187 H) 3 Alternative method of preparation b) 10 to a solution of diethyl {[(4-bromo-3-ethoxyphenyl)amino]methyl} malonate (intermediate compound (747); 07.4 g VY + mol) in ( Js V YO) toluene POCI (9- 70 g; 0117 de YO mol) added. The reaction mixture was stirred at 110°C for 48 hours; It is cooled, condensed and concentrated under reduced pressure. The dial was carefully treated with a saturated NaHCO solution until the gas no longer evolved; The solid was filtered out

[1e - resulting; and washed with 180,1100 saturates and water; then slurry in hot MeOH-001 (mL); and cooled and filtered to yield £Y g of an orange solid. Alternative method of preparation c) triethylamine (17.8) kg; (Use 177) was added to a suspension of: 4-bromo-3-ethoxyaniline hydrochloride 0 (54 kg; 118 mol) in 119) toluene liter) and water (16_ liter) at ambient temperature. The suspension was stirred until a solution was obtained. Then the two-phase mixture was filtered through diatomaceous earth (; kg) and the dough was washed using 10 (toluene liter) and the aqueous layer was separated and discarded. (VY) toluene was distilled to dry the mixture. Diethylethoxymethylene malonate (159.50 kg; (Use 118) was added slowly to 0 toluene solution at a temperature of Ve to Ar m at a rate maintaining a moderate yield. 1010 liter ethanol toluene was distilled ) under reduced pressure 4060 mbar AS 0 m the reaction temperature was reduced to 61 °C and the mixture was analyzed by HPLC phosphorous oxychloride (£0.71 kg) was added; YAY Mall) on © ae; minute. The reaction mixture was heated to a temperature of 101a over ¥ hours and held for at least ¥ hours. The reaction mixture was cooled to a temperature of VO m and analyzed by HPLC (e+) toluencs phosphorous oxychloride (l) was removed by distillation at reduced pressure (100 to 0 mbar; © to 17 °C) . Toluene (£4 L) was added and the reaction mixture Ee (from the combined distillate) was re-distilled. Y1) Tetrahydrofuran (THF) was added and the resulting mixture was cooled to a temperature of 10 to YO C. The resulting red solution -0 was added slowly (over -00 minutes to control gas evolution) to a mixture of potassium bicarbonate (99 kg; GAY mol) in water (797 L) at ambient temperature. The reaction mixture was washed to a wash

7m11 - using more THF (.6? litres). The resulting suspension was stirred for 1 hour before isolation on a centrifuge. The wet product was slurryed in ethanol (119 L) and heated to a temperature of Ve m. The slurry was cooled to ambient temperature and the product was collected by centrifugation; It was washed with ethanol (£0 litre) and dried under low pressure 170 m at ? mbar) to obtain the title compound Fela as the AT moiety (IVY) intermediate compound (49 7) ethyl 6-bromo-7-ethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate A solution of diethyl {[(4-bromo-3-ethoxyphenyl)amino]methyl malonate (intermediate TE can YO ¢(Y£Y) mmol) in Yor) diphenyl ether mL) was added Drop by drop on ade ja to return (de YOu -) diphenyl ether after ? hours; the “Je lal” mixture was cooled and (Je You ~) hexane added to the solid; which was filtered to yield 4 g of A white solid le 3 was used without further purification.The intermediate compound (Y£Y) Diethyl {[(4-bromo-3-ethoxyphenyl)amino]methyl malonate 0 Y solution was stirred) 4-bromo-3-ethoxyaniline g 010 mol) 5 diethylethoxymethylene (V4) malonate mL (Use 110 in (Je 1001) CHRON for ? hour; then heat to VO 4 VT for 1 h. A) Solvent was made under reduced pressure and residual hexane recrystallized to yield YO g white solid; used without YsoV purification

— name of the intermediate compound (¥ ¢ ) Ethyl 6-bromo-4-chloro-7-fluoroquinoline-3-carboxylate and ethyl 6-bromo-4-chloro-5- fluoroquinoline-3-carboxylate The mixture was stirred Of : ethyl 6-bromo-7-fluoro-4-hydroxyquinoline-3-carboxylate 0 (intermediate compound (441); 0.7 0010 mmol g) in phosphorous oxychloride of reduction (7) .£ Jw 56.556 mmol) for a period of ? hours. After cay pall the mixture was concentrated under reduced pressure” and 11:01 01 (ml) was added. The mixture was slowly decanted into a NaHCO solution; the resulting slurry was extracted with EtOAc The organic layer 0 (MgSOy) was dried, filtered, concentrated under low dakia, and the residue purified by column chromatography (graded amount of EtOAC / Compounds (hexane to obtain 00069 g (/74.97) of : ¢thyl 6-bromo-4-chloro-5-fluoroquinoline-3-carboxylate "HNMR: 9.17 (s, 1 H), 8.64 (d, 1 H), 8.12 (d, 1 H), 4.48 ( 2 H), 1.40 (t, 3 H); m/z: .334 Vo and 4.0 g (¢¢”) of ethyl 6-bromo-7-fluoro-4-hydroxyquinoline-3-carboxylate ), 1.40 (t, 3 H); m/z: 334 intermediate compound (YE¢) YéoV

Voi — Ethyl 6-bromo-7-fluoro-4-hydroxyquinoline-3-carboxylate and ethyl 6-bromo-5-fluoro- 4-hydroxyquinoline-3-carboxylate and then heating a solution of diethyl { [(4-bromo-3-fluorophenyl)amino]methylene} malonate (intermediate compound (745); 6.00 11.33 μm) (Je V+) diphenyl ethers to 0 at 790 °C for ?00 minutes. after cay yal 01 (hexane mL) was added; The precipitate was filtered and washed with acetone (Ja YH) to yield YY g (7251) of a light brown solid; A mixture of insoluble isomers. Intermediate compound (Y£2) Diethyl {[(4-bromo-3-fluorophenyl)amino]methylene} malonate 01 solution of 4-bromo-3-fluoroaniline (©)YAY body was stirred mmol (©.V) diethylethoxymethylene malonate 5 ml » 18.4 mmol (8 (Je 01) CH3CN) for + days. The reaction mixture was filtered to yield TY g (£710) of a white solid. H NMR: 10.65 (d, 1 H), 8.36 (d, 1 H), 7.67 ( ) 1 H, 7.59 (dd, 1 H), 7.24 (d, 1 H), 4.18 (m, 4 H) , 1.29 (m, 6 H) Vo intermediate (Y€7) ethyl 7-bromo-4-chloro-6-ethoxyquinoline-3-carboxylate A suspension of ethyl 7-bromo-6-ethoxy was heated -4-oxo-1,4-dihydroquinoline-3-carboxylate (intermediate compound (7 497); 71 005 aa mol) in phosphorous oxychloride under reflux a)

— g - for 8 hours. After capil the resulting mixture was carefully poured onto the ? liters of ice water and neutralize it with concentrated aqueous ammonia. The precipitate was collected using water; drying it; and re-coloured from EtOAC to yield 117 g of an off-white solid. B 1.48 “HI 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), H ), 1.38 (t, 3 H); m/z: 359 ° 3 Intermediate compound (Y£V) Ethyl 7-bromo-6-cthoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate A solution of dicthyl {[(3-bromo-4-ethoxyphenyl)amino]methylene} malonate (intermediate compound 0.088 can TY (YEA) mol) in warm diphenyl ether (001 mL) was added ) 0 drop by drop over 0 ?min to return (Je £40) diphenyl ether after ¥ hours on reflux; the mixture was cooled. 151 - (ml each) and filter the mixture. The raw material was pulverized with hot hexane for 0 min to yield VY g solid.’” H NMR:12.26 (s, 1 H) , 8.52 (s, 1 H), 7.91 (s, 1 H), 7.62 (5, 1 H), 4.21 (m, 4 H), 1.41 (t, \o 3H), 1.28 (t, 3 H ); m/z: 342 Intermediate compound (YEA) Diethyl {[(3-bromo-4-ethoxyphenyl)amino]methylene} malonate A solution of (3-bromo-4-ethoxyphenyl)amine (compound) was stirred The median (aa YY ¢ (Y69) is not p g lg a

1,1-diethylethoxymethylene malonate 5 (Js + .) (¥" filling 16.11 mol) in acetonitrile (Ja V0) for ¥ h. The precipitate was collected and re-oko/pulverized with hexane To obtain FY g of solid, used without further purification. 4 1 H), 4.29 (q, 2 H), (q,2 H), 4.11 (q, 2 H), 1.44 (t, 3 H), 1.34 (m, 6 H); m/z: 384 ° 4.22 intermediate (Y£9) (3-Bromo-4-ethoxyphenyl)amine to a suspension of 2-bromo-1-ethoxy-4-nitrobenzene (intermediate 71 (Yor) g 0.11 mol); iron powder (00 g 6.84 mol) and 0.01 (Sle ethanol 7801 ml); 0.0 solution of concentrated HCl (Y ml) were added in 7280 (de Yo) Sle ethanol drop by drop over 10 min. Heating was used after half of the acid solution was added to start the reaction. Thereafter, the reaction mixture was kept in reflux by adjusting the acid addition rate. The reflux was maintained for 160 hours after adding the acid through an external heating burner.The reaction mixture was filtered while hot through a layer of diatomaceous earth.After cooling; The aqueous filtrate was extracted using (Yor XY) EtOAc (Je 001 XY) chloroform ml). The organic extracts were pooled; And dry it “(Na;SOq) and concentrate it under low pressure to get YY g of solid. m/z: 216 0 Intermediate (Yo!) 2-Bromo-1-ethoxy-4-nitrobenzene Meat 7

o 7 — \ _— then stir 13 Jar of 1011 (¢ iodoethane ma mol) and 2-bromo-4-nitrophenol (intermediate compound) YE ( 11 vol. 0211 mol) potassium carbonate s (17 J YY mol) in 1 A 3 dal (Ja Y ve ) DMF h. Then, the reaction mixture was poured into ice water (Y liter) and extracted using (de 001 “” ¥) EtOAc °, then the product was dried. For organic extraction (Bug Yua 1, filtration 3 and concentration under reduced pressure to obtain 1.1 g of solid sale was used without further purification. 'H NMR: 8.42 (d, 1 H), 8.25 (4, 1 H) ), 7.31 (d, 1 H), 4.28 (q, 2 H), 1.41 (, 3 H) intermediate compound (Yo) 2-Bromo-4-nitrophenol 7 A mixture of A con was stirred Oa ) 4-nitrophenol mol); acetic acid ) mm ml) and bromine YY) ml; 7*<1_mol) for YA h. The excess solvent was removed under reduced pressure and the remaining dichloromethane/hexane i was processed to yield 01 g of a solid which was used without further purification. 'H NMR (MeOD):8.40 ) 1H), 8.12 (dd, 1H), 7.02 (d, 1H); m/z: 1 6 intermediate compound (YoY) 1-ethyl-1,4-diazepane A mixture of oS all) rers-butyl 4-ethyl-1,4-diazepane-1 was stirred Intermediate carboxylate (YoY) in mg and mmol) in 1 HCI molar (Yo ml) at room temperature for Y hours. white solid filtration; and washed with diethyl ether. Substance YsoV dissolved

o A — 0 _ solid in 100 mL of (MeOH) and about ¥ a> of MP-carbonate mR (p> [J sa] was added to the solution. Then the resulting mixture was stirred at room temperature for Ye min; filtered; washed with “MeOH” and concentrated the filtrate to yield (va. mg of Cu) of a light yellow colour. ’”H NMR (CD,Cly): 3.00 (m, 6 H), 2.75 (m, 2 H), 2.62 (m, 2 H), 1.90 (m, 2 H), 1.10 3 ° H) m/z: 128 intermediate (Yor) tert-Butyl 4-ethyl-1,4-diazepane-1-carboxylate A mixture of tert-butyl 1,4-diazepane-1-carboxylate was heated (¥ g VO mmol); can ¥.0V) jodoethaney 0 7.5 mmol) § potassium carbonate (€1.£ g YO mmol) in (Je 1 0) acetonitrile to return Then the reaction mixture was cooled and filtered, washed with dichloromethane, the filtrate was concentrated and the residue was purified using the ISCO chromatograph to obtain Yao mg of oil.’H NMR (CD,CL): 3.60 (m, 4 H), 2.70 (m, 6 H), 1.95 (m, 2 H), 1.61 (s, 9 H), 1.20 (1, 3 H); m/z: 228 \o Intermediate Voi Ethyl 4-[(2,4-difluorophenyl)amino]-7-isopropoxy-6-(4-methylpiperazin-1- yl)quinoline-3-carboxylate A solution of: M "the

- 19 - (compound ethyl 4-chloro-7-isopropoxy-6-(4-methylpiperazin-1-yl)quinoline-3-carboxylate m 011 Je 1 ) 2,4-difluoroaniline s « (Use m m » UE of medium (11) 4 0 g 101 for 1 VV at a temperature of (Je©) EtOAc A (Je++) (aD acetic acids mol); the mixture was extracted ' (Ja ¥ ) NaHCO; h. Then cool the reaction mixture; add solution, ml). The combined extracts were concentrated; And purify the residue (YX OY) EtOAC using (757) mg of Av material to obtain (EtOAc / hexane) column chromatography (compounds yellow solid 'H 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, 1H), 4.39 (q, 2H), 2.75 (s, 4H), 2.37 (s, 4H), 2.17 (s, 3H), 1.34 (d, 6H), 1.28 (t , 3 H); m/z: 485 1 (Ye) to (Yoo) Intermediates from ( Yo¢ ) The following compounds were prepared in a manner similar to that used for the intermediate compound Los Co. Compound 517 Ethyl 4-[(3,4-dichlorophenyl)amino]-7- Yoo

YA Intermediate isopropoxy-6-(4-methylpiperazin-1- ylquinoline-3-carboxylate) Compound 501 | Ethyl 4-[(3-chloro-2-fluorophenyl)amino]-7- Yor

YA mediator isopropoxy-6-(4-methylpiperazin-1-

Y$Av

- 11.0

I AAA 3006386 000000 Compound 517 Ethyl 4-[(2,3-dichlorophenyl)amino]-7- Yoy a EEE yl)quinoline-3-carboxylate Compound 501 | Ethyl 4-[(3-chloro-4-fluorophenyl)amino}-7- YoA

Rc “yl)quinoline-3-carboxylate Compound 415 Ethyl 4-[(2,4-difluorophenyl)amino]-6- Yo4

Eri Al-Markab 432 | Ethyl 4-[(3-chloro-4-fluorophenyl)amino]-6- Yl. compound ene 446 Ethyl 4-[(2,3-dichlorophenyl)amino]-6- YT)

Eri Compound 427 Ethyl 4-[(2,4-difluorophenyl)amino]-6-(4- YY BPA carboxylate

Cm YVE intermediate methylpiperazin-1-yl)quinoline-3- carboxylate n compound Ethyl 4-[(3,4-dichlorophenyl)amino]-6-(4- ni me © carboxylate compound Ethyl 4-[(2,3-dichlorophenyl)amino]-6-(4- Yio lite © carboxylate intermediate compound (75?)

Ethyl 4-chloro-7-isopropoxy-6-(4-methylpiperazin-1-yl)quinoline-3-carboxylate : A mixture of (7) meat was heated

111 - - diethyl ({[3-isopropoxy-4-(4-methylpiperazin-1-yl)phenyl]amino } methylene)malonate (intermediate compound (YTV) 8.7 g; 1.5 mM) VY.£) phosphorous oxychloride s (J s—e g; 018 mmol) at #01 C for VV hr. The reaction mixture was cooled and concentrated under reduced pressure. The resulting dark oil was diluted with “(Ja 01 (acetonitrile) and added to the NaHCO solution; stirred and extracted with EtOAc (XY 001 mL). The combined extracts (Na;SOy) were dried, filtered and concentrated under reduced pressure. (Je?1) hexane compounds were added after 11 minutes of exposure to sonic waves; the mixture was filtered to yield YoY (g OA) % (brown solid (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, 8.89 s 4H), 2.50 (s, 4 H ), 2.23 (s, 3 H), 1.37 (m, 9 H); m/z: 10 392 Intermediate (Y3Y) Diethyl ({[3-isopropoxy-4-(4-methylpiperazin-1-) yl)phenyl Jamino } methylene)malonate then stir J olan of [3-isopropoxy-4-(4-methylpiperazin-1-yl)phenyllamine (intermediate compound A) ); 0 7010 can m (J 17 5) diethylethoxymethylene malonate 5 (Js) (Ja 72.74 vo in 01 (acetonitrile mL) for 10 hours. The reaction mixture was concentrated under reduced pressure and purified through a column chromatograph (EtOAc/ hexane to obtain LY g (AVE) from a dark viscous oil.” HNMR: 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 - (m, 4 H), 2.93 (s,4 H), 2.42 (s, 4 H), 1.27-1.16 (m, 12 H) 4.00 AHA

117 - - Intermediate compound (YTA) [3-Isopropoxy-4-(4-methylpiperazin-1-yl)phenyl]amine 1-(2-Isopropoxy-4-nitrophenyl)-4 was stirred -methylpiperazine (intermediate compound (7765); 6 70159 aa mmol) and 10/palladium on carbon) +1 (p> in 0 (MeOH ml) in 0 atmosphere of gas 51 hydrogen ( psi) for 1 hour; then filtered through a layer of diatomaceous earth. The filtrate was concentrated under reduced pressure to yield 59.01 g (794) of brown oil.” HNMR: 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, 4H), 2.39 (s ,4H),2.17 (s, 3 H), 1.21 (d, 6 H) 0 The intermediate compound (Y19) 1-(2-Isopropoxy-4-nitrophenyl)-4-methylpiperazine heated A mixture of 1-chloro-2-isopropoxy-4-nitrobenzene (intermediate (7760); ©g; YY.Y mmol) and YV.AY (J 0.4) I-methyl piperazine from me mol) t potassium can ¥.44) carbonate 77219 mmol) in 01 DMF (ml) at 170 °C for 11 ve h. The reaction mixture was cooled and added to Jo Yor water ) and extracted with EtOAc (XY 001 ml). The combined extract (NaSOy) was dried, filtered, and concentrated under reduced pressure to yield 4 g (9 q%) of a red solid.

110 - - (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 7.80 : 1111 /4 (m, 4 H), 2.21 (s, 3 H), 1.32 (d, 6 H); m/z: 280 intermediate compound (YV+) 1-Chloro-2-isopropoxy-4-nitrobenzene m A mixture of 2-chloro-5-nitrophenol (0) g (6 mmol) was heated + f 2-iodopropane (Ja 1.1 1) 19.1 mmol) 5 V.AY) caesium carbonate g 9.76 mmol); ‎potassium carbonate )¥ 4 g; 07.56 mmol) in (Je 04) DMF at YO C for YE hours. The reaction mixture was cooled” and added to Yor water (ml) and extracted with (Je Yo x ¥) EtOAc . The combined extracts (,048250; 0) were dried, filtered and concentrated under reduced pressure to yield 17.11 g (7997) of a red solid.” HNMR: 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 compound (YY1) Ethyl 4-chloro-6-morpholinoquinoline-3-carboxylate Stirring Ethyl 4-hydroxy-6-morpholin-4-ylquinoline-3-carboxylate (intermediate compound 10 (777); aa 01 1.786 mmol) into phosphorous oxychloride of reflux (1.1 fill 7.8 mmol) ) for 2 hours. After cooling, the mixture was concentrated under reduced pressure, and 01:08 01 (01 mL) was added. This mixture was slowly poured into a solution of (Je) 0+) NaHCO; and the resulting slurry was extracted with EtOAc Yiov

116 - - Then the organic layer “(MgS0y) was dried, filtered ¢, concentrated” and the residue was purified by column chromatography (gradual amount of EtOAc / (hexane) compounds to obtain 1.8 g (£vY) of material White solid. s, H), 3.38 (s, 4 H), 1.38 (t, 3 H); m/z: 321 ° 4 intermediate compound (YVY) Ethyl 4-hydroxy-6-morpholin-4- ylquinoline-3-carboxylate (pad) was dissolved from diethyl {[(4-morpholin-4-ylphenyl)amino]methylene} malonate (intermediate compound (7977); © 14.78 con mmol) in (da "01( diphenyl ether) to reach oy.You temperature m for ? hour. After cay yal was added (Yo) hexane ml); the resulting precipitate was filtered and washed with (Y+) acetone mL) to yield 7.4 g (£00) of a light brown solid. (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 11112.21 yr (s,4 H), 1.27 ) 3 H); m/z: 303 \o intermediate compound (177) YéoVv

155 - - Diethyl {[(4-morpholin-4-ylphenyl)amino]methylene}malonate A solution of 4-(4-aminophenyl)morpholine )© g; YAY mM (Js—11 ) diethylethoxymethylene malonate s mL; 000 mmol) in (Je 01(CH3CN) for ? h. The reaction mixture was added to (Je 04) EtOAc and washed with brine; 0 (50g01) dried; filtered; concentrated. Compounds were added. (Je 0 ) hexane to the residue and after 0 min exposure to acoustic waves; the resulting slurry was filtered to yield 1.7 g (774) of a brown solid.” HNMR: 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) 0 intermediate compound (YVE) Ethyl 4-chloro-6-(4-methylpiperazin-1-yl)quinoline-3-carboxylate then stirred Ethyl 4-hydroxy -6-(4-methylpiperazin-1-yl)quinoline-3-carboxylate (intermediate precipitate CAN 18 ¢(YVO) 1.0 mM (Us in phosphorous oxychloride of reflux ©01) (mL; 15.9 mL (Use for “? hours. After cay al the mixture was concentrated under reduced pressure; addition of (V+) dichloromethane mL). The mixture was slowly poured into a NaHCO solution (50 mL) and extracted The resulting slurry with EtOAc organic layer (04,50g) was dried, filtered, concentrated under reduced pressure” and the residue drawn in hexane to yield 6.4 g (/7177) of a black solid. L 1

- 111 - “HNMR: 8.84 (s, 1 H), 7.97 (d, 1 II), 7.85 (d, 1 H), 7.35 (s, 1 H), 4.45 (4 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 (YV2) intermediate compound

Ethyl 4-hydroxy-6-(4-methylpiperazin-1-yl)quinoline-3-carboxylate : Then heating a solution of 0 (diethyl ({[4-(4-methylpiperazin-1-yl)phenyl] amino}methylene)malonate

You at a temperature of (Je Yr) diphenyl ether mmol) in 1.8 can ©¢ (YV) median mL); The precipitate was filtered and washed with (10) M hexane for 7 hours. After cooling, a light brown solid (70) 1.87 g was added to obtain (Je Yo) with acetone. HNMR: 12.19 (s, 1 H), 8.43 (s, 1 H), 7.50 (mn, 3 H), 4.23 (m, 2 H), 3.19 (m, 4 H), 2.47 1 (YY) intermediate compound

Diethyl ({[4-(4-methylpiperazin-1-yl)phenyl]amino}methylene)malonate «Ja Y'.£) diethylethoxymethylene malonate 5 mmol) 15.7 can ¥) A solution of hour. The reaction mixture was cooled and concentrated under YE for (Je 01 (CH3CN mmol) in 4 to the residue; the resulting slurry was filtered to obtain (JeY.) hexane at low pressure; and \o of Brown solid. (AAA) on © g "HNMR: 10.74 (d, 1 H), 8.34 (d, 1 H), 7.24 (d, 2H), 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) 7 2 uh

179 - - Intermediate compound (YY) Ethyl 4-chloro-7-(2-methoxyethoxy)-6-(4-methylpiperazin-1-yl)quinoline-3-carboxylate A mixture of: amino was heated } diethyl ({[3-(2-methoxyethoxy)-4-(4-methylpiperazin-1-yl)phenyl] methylene)malonate ° (intermediate compound) can 1.5 ¢ (YVA) 10.10 mM Y¥. Y¢) phosphorous oxychloride s (J se g; 15016 mmol) at a temperature of 110 . for 10 hours. The reaction mixture was cooled; concentration under reduced pressure. The resulting dark oil was diluted with 01 (CHRON ml); and added to the NaHCO solution; it was stirred. The resulting mixture was extracted using (YO XY) dichloromethane 0 mL). The combined extract ((N2;S04) was dried, filtered and concentrated under reduced pressure. The resulting oil was purified by a J seanlilica (EtOAc) chromatogram on 017*g (XY) of colored powder Pale yellow. '"H NMR: 8.92 (s, 1 H), 7.48 (s, 2 H), 4.41 (q, 2 H), 4.39 (4 2 H), 4.34 (m, 2 H), 3.78 m/ z: 408 1 _ intermediate (YYA) Diethyl ({{3-(2-methoxyethoxy)-4-(4-methylpiperazin-1 yl)phenyl]amino} methylene)malonate Yeov ‏

18 - [2-(2-Methoxyethoxy)-4-nitrophenyl]-4-methylpiperazine 1 (intermediate compound) 1a) has been assembled; 7 1 1 fax millimoles); and palladium / Yo on carbon (no * g) in MeOH (01 da) in a nitrogen atmosphere. The nitrogen atmosphere was removed and 50 lb [square inch] of hydrogen gas was used for 1 hour while shaking the reaction vessel. Then the hydrogen gas “0” was removed and replaced with nitrogen gas. Diethylethoxymethylene malonate 64 was added (7.18 mol), and the resulting mixture was allowed to stand for 11 hours. It was filtered The resulting black slurry was filtered through a layer of diatomaceous earth, and the filtrate was concentrated under reduced pressure. 6.59 (4, 1 H), 6.18 (d, 1 H), 6.08 (dd, 1 H), 4.65 (s, 2 H), (s, 2 H), 4.45 (m, 1 Ve 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 compound ( YV3) 1-[2-(2-Methoxyethoxy)-4-nitrophenyl]-4-methylpiperazine to a solution of 1-chloro-2-(2-methoxyethoxy)-4-nitrobenzene (the intermediate compound ¢ (YA4) © Vo g.7 mmol) in (Je 0 ) DMF at Te 1 + then the addition of: 0.0 (1) N-methyl piperazine filling 77.87 mmol). After heating at 1 001°C for Y hours; The reaction mixture was cooled and added to solution 1 (NaHCO; ©mL). The mixture was extracted with EtOAc (XY 001 mL); The organic extracts “(NayS04) f

114 - - filtered and concentrated under low pressure to obtain 6.1 g (797.71) of a red solid. '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 M intermediate compound (YA) 1-Chloro-2-(2-methoxyethoxy)-4-nitrobenzene A solution of (2-chloro-5-nitrophenol) (01) was heated; 51.767 mmol); 5 1-bromo-2- A.£) methoxyethane 19.14 mmol) and its potassium adeoxide (57 g; 04 mmol) in DMF (4 lb) at 50 °C for £A hour. The 0 reaction mixture was cooled and added to a solution of 001 (NaHCO; ml) 001 ( dichloromethane s ml). The resulting mixture was extracted using (100 XY) dichloromethane ml). The combined organic extracts using “(Na,SOy) were dried, filtered ¢ and concentrated under low pressure cual to obtain a red solid. The red solid was filtered through a silica gel layer; With eluting using a 5 : 1 ratio of EtOAc : hexane compounds .vo the filtrate was concentrated to give 0.17 g (AVY) of a red-orange crystalline solid. 'H NMR: 2 (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 , 3H) YsoV

- 117. (YAY) intermediate compound

Ethyl 4,6-dichloro-7-(2-methoxyethoxy)quinoline-3-carboxylate : A solution of (the intermediate compound ethyl 6-chloro-4-hydroxy-7-(2-methoxyethoxy)quinoline-3) was heated -carboxylate mmol); 1.34 “Ja £.0) thionyl chloride s mmol); 0011 g TY (YAY) 0 m for 7 h. The mixture of 01 was cooled at (Je YO) CHRON drop)_ in 1 (DMF ml). The resulting slurry was extracted with NaHCO;3001 and slowly added to a solution (Je lin) and the organic extracts were collected and dried (E 0.1850). The residue (EtOAc) was purified to yield hexane compounds [ EtOAc (graded amount of silica obtained by chromatography of a white solid. (AYA) #.e g 0 "HNMR: 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, 3H), 1.38(t,3 H) (YAY) intermediate compound

Ethyl 6-chloro-4-hydroxy-7-(2-methoxyethoxy)quinoline-3-carboxylate : Added > Yo. ian temperature at (Je Yo ) Dowtherm A to a solution of Vo (diethyl ({[4-chloro-3-(2-methoxyethoxy)phenyl]amino }methylene)malonate 1 hour. Then cooling bowl 1 ); and gm 9.1 mmol) and heating continued for AY) mediator NO 2 NO

- except = interaction. addition of 001 compounds (hexane mL); The resulting slurry was filtered and dried to yield 00 g (794) of an insoluble gray solid. Intermediate compound (YAY) Diethyl ({[4-chloro-3-(2-methoxyethoxy)phenyl]amino } methylene)malonate 0 A mixture of 1-chloro-2-(2-methoxyethoxy) was discharged -4-nitrobenzene (intermediate compound ¢(YA+) can 01 44.497 mmol) 705 platinum on carbon (g) Y.At) zinc(Iiodide s AT eA con mmol) in (Je £1) EtOAc in an atmosphere of nitrogen to (V) hydrogen atmospheric pressure) and stirred for YE hours. Then hydrogen was replaced by nitrogen; 01.cde/(diethylethoxymethylene malonate) 1014 mM (Use and 0.118250 (1 g) was added. After VT 1 hour, the resulting black slurry was filtered through a layer of diatomaceous earth; the filtrate was concentrated under pressure The resulting oil was purified through a silica graded (AS) chromatography of (EtOAc / hexane) compounds to obtain 1117 g (AVY) of an off-white powder. 1 H), 8.40 (d, 1 H), 7.40 (d, 1 H), 7.26 (s, 1 H), 6.98 (d, 1 H), 4 (m, 6 H), 3.72 (m, 2 H), 3.34 (s, 3 H), 1.28 (m, 6 H); m/z: 372 \o Intermediate (YAEL) Ethyl 7-(2-{[tert-butyl(dimethyl) silylJoxy ( ethoxy)-4-chloro-6-(4-methylpiperazin-1- yhquinoline-3-carboxylate no no

- 177 - Then heating a solution of: diethyl ({[3-(2-{[rert-butyl(dimethyl)silylJoxy}ethoxy)-4-(4-methylpiperazin-1- yl)phenyl]amino }methylene) malonate (intermediate compound (85?); ¥ can 7.27 mmol); triethylamine y (4.40 G A4.09 °M 0114) phosphorous oxychloride 5 (Use 47 g .No mmol) in 1 toluene ml) at 1 001 for YE hour. The reaction mixture was cooled” and V+ } = acetonitrile was added (; the resulting mixture was then added to the NaHCO solution; the mixture was extracted with EtOAc (XY 001 mL). The combined organic extracts (NaS) were dried, filtered, and concentrated under reduced pressure. The resulting oil AED was through a silica chromatography (0 graded amount) of MeOH / EtOAc to yield 1.545 g (779) of a pale yellow solid. 'H NMR: 8.84 (s, 1 H), 7.40 (s, 2 H), 4.32 (q, 2 H), 4.22 (m, 2 H), 3.94 (m, 2.11, 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 (YA) intermediate compound

Diethyl ({[3-(2-{[tert-butyl(dimethyl)silyl]oxy } ethoxy)-4-(4-methylpiperazin-1- yDphenyljamino}methylene)malonate \o a mixture of: 1-[2] was discharged -(2-{[tert-butyl(dimethyl)silylJoxy ( ethoxy)-4-nitrophenyl]-4-methylpiperazine L-No

unless -

(intermediate compound) 0 7 q Cox 1 .0 oY AR mmol) and palladium/ Ye. on carbon (0 ¢” (a> in 0 ) EtOAc mL) in an atmosphere of nitrogen to 1 hydrogen (atmospheric pressure) and stirred for 1 hour VT. Then allan uly hydrogen was removed with nitrogen gas. “Ja +.VVE) diethylethoxymethylene malonate 7.87 mmol) was added and after stirring for 0 h; The resulting black slurry was filtered through a layer of diatomaceous earth. The product was concentrated

Filtration under reduced pressure to obtain ¥ (799) g of a white solid. HNMR: 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), (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), 3.92 (s , 6 H); m/z: 536 0.07

(YAT) intermediate compound 0 1-[2-(2-{[tert-Butyl(dimethyl)silyl]oxy } ethoxy)-4-nitrophenyl]-4-methylpiperazine tert-butyl[2-(2-chloro-) 5-nitrophenoxy)ethoxy]dimethylsilane of J sas heated ml £.%Y) N-methylpiperazine 5(Js—s mMYA. +A g 11 ¢(YAV) (compound The medium was capillary m for days, and after 001 at a temperature of (01 Ja) DMF in (Use mM WAVY ml). EtOAc (XY) products were dried (50 ml); And extract the mixture using Vi) adding water 1 and filtering and concentrating it and purifying the remaining material from the combined organic extraction (NapSOy) E0 to obtain (EtOAc / hexane) (a graded amount of silica compounds) through a chromatogram Of a yellow solid. (ZY 0 ) g lam

- 1186 - !]1111/1:7.84 (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 (YAY) intermediate tert-Butyl[2-(2-chloro-5-nitrophenoxy)ethoxyJdimethylsilane (2-bromoethoxy)- and «(Use? m 4.51 can 1) 2- A mixture of chloro-5-nitrophenol heated g; potassium carbonate V.10 (5 ml 41.6 mmol) A.) tert-butyldimethylsilane; days. The mixture of sad 1 40 was filtered at (Je £4) DMF mmol); at 8

XY) EtOAc mL); and extract the mixture using Yoo) reaction. Then, ml of saline was added. The combined organic extracts were concentrated; and purify the residue with 0 to yield 1.0 g EtOAc/hexane (gradient amount of silica chromatography 0 (£0V) from a white solid. "HNMR: 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), (s, 9 H), 0.04 (s, 6 H) 0.82 L no

Claims (1)

\Vo Claims 1-1 A compound of the formula ma or 'IB (Ry), R, m HN £ ,))® N NH, Y 2 N IA m (Ry), R, HN 0 R, > NH, . = (R 1 hn N N IB); or a pharmaceutically acceptable die salt where : o N be heterocyclic or aryl homologous; bonded to nitrogen > having from ? to 10 atoms; Cus that if said heterocyclic or aryl is non The said congener contains an NH moiety - Lo lial nitrogen A can be replaced by a mo ic medium selected from 8,9 R's at each occurrence of each formation separately: halo, hydroxy, nitro , formyl, cyano, - 00211, -SH, (C,-Ce)alkyl, (C>-Cs)alkenyl, Ya lag A Vv (C,-Ce)alkynyl, (C3-Ce)eycloalkyl, (Ci-Ce)alkoxy, -OC(0)~(C1-Ce)alkyl, 1 -©)0(-)0© ,allola(and- -CO»(C,-Cg)alkyl, -NR'R”, -NR'-C(O)-(C;-Ce)alkyl, 'Y (C1-CealkylS(0),- 'Y das 4 is from zero to SY -NR’-C(0)-O(C;-Cg)alkyl, -NR’-SO,-(C;-Cg)alkyl, -NR’-C(O)NR’R”, yo -S0,-NR’R”,-C(O)-NR’R”, carbocyclyl, 4 11 or a heterocyclic compound; or hetero aryl” or e*”e ; : w1 be YA hydrogen, halo, hydroxy, nitro, formyl, -CO,H, -SH, cyano, (C;-Cs)alkyl, 41 (C,-Cg)alkynyl, (C3-Cg)cycloalkyl, -O-(Cs-Cg)cycloalkyl, vs super(and-and) -OC(0)-(C,-Cg)alkyl, -C(0)-(C-Cg)alkyl, -CO»(C;-Ce)alkyl, -NR’R”, 8 1112 Pan(O-:0)-(0)0- (C1-Cg)alkylS(O)- 7" : from zero to? or gia where YY -NR’-C(0)-O(C,-Cg)alkyl, -NR’-SO,-(C;-Cg)alkyl, -NR’-C(O)NR’R”, Y ¢ -SO,-NR’R”, -C(0)-NR’R”, -OC(O)-NR’R”, carbocyclyl, Yo 7 or a heterocyclic or aryl heterocyclic compound; or (C1-Coalkoxy; : When each occurrence is Ry YY halo, nitro, formyl, cyano, hydroxy, -NR'R”, -CO,H, -C(0O)-(C;-Ce)alkyl, YA -CO,(C,-Co)alkyl, -C (O)-NR'R", -NR'-C(0)-(C;-Ce)alkyl, -NR'-C(O)NR'R", ya -NR’-C(0)-O(C,-Ce)alkyl, -O-C(0)-(C;-Cg)alkyl, -SH, -SO,-NR’R”, ¥. (Ci-Cglalkyl, (Cy-Ce)alkenyl, (C,-Cg)alkynyl, (C;-Cg)alkoxy, (C,-Ce)alkylS(O).- 7 AV the i \VY PY e is from zero to Gas YY aryl, first m (0-,©)-2187-507-; or heterocyclic compound” or carbocyelyl —Y¥ heterocyclic aryl congener; Whereas, if the heterocyclic compound or YE; or alkyl (C1-Ce) optionally by nitrogen substitution (Say NH-containing YO moiety on two adjacent carbon atoms aromatic ring Ry _can optionally form 2 groups © atoms include 1 saturated and/or partially unsaturated and/or unsaturated composed of * or 7 R, where NR, a hetero-atom selected from 8; or ©; or optionally Y yellow or 1 or © ; alkyl (C1-Cq) All R of not exist 4 ¢ i.e. hydrogen tweezers 6 are the same or different; Ry where values of OF can be from zero to « 8 ) are the same or different; Ry af is from zero to ; where « EY can be at each occurrence; and 1 or 1m are separately EY: and are selected from £8 pola (and 0-© (C3-Cg)cycloalkyl, -C(0)-(C1-Cg)alkyl, -S(0),(C,-Ce)alkyl, te -CO,(C,-Ce)alkyl, -C(O)-NR'R”, benzyl, benzyloxycarbonyl, benzoyl and 1 phenylsulphonyl; 3 or with optionally substituted with cH and 27 are each separately at each occurrence of 8:4 which nitrogen is with an aryl atom or has optionally substituted with an alkyl (>-n)4; attached to a ring consisting of © to + optionally substituted atoms are saturated or non© where NR, additional heteroatom selected from 1 partially saturated containing 0 (or ©) Re mentioned optionally substituent groups are selected from one or more OY YsoV what : selected separately from SOR OF (C,-Cy)alkyl, halo(C;-Ce)alkyl, halo, nitro, cyano, hydroxy, (C,-C¢)alkoxy, of -NR*R’, —COOR* or —CONR*RY; °° ¢ alkyl (C;-Cq) or hydrogen inserts that form independently of each other 87 having an optional substitution on carbon Rss Ris Ros Ris (Ry) and where the OV can be: with one or more of ‎ OA formyl, -SH, azido, halo, nitro, cyano, hydroxy, trifluoromethoxy, °4 -0OC(0)-(C;-Cg)alkyl, -NR'R”, -CO,H, -C(0O) )-(C;-Cg)alkyl, -CO,(C;-Ce)alkyl, 1 -C(0)-NR'R”, -S-(C;-Cg)alkyl, -SO,-(C ;-Cs)alkyl, -SO,NR'R", (C;-Cs)alkyl, 1 (C3-Ce)cycloalkyl, -NR'-C(0)-(C;-Ce)alkyl, -NR' -C(0)-O(C,-Ce)alkyl, 1 -NR'-S0,-(C-Cg)alkyl, -NR'-C(O)NR'R”, (C,-Cg)alkenyl , (C,-Cg)alkynyl, or 17 (Cy-Cg)alkoxy.1s or a pharmaceutically acceptable salt thereof.1 according to claim TA ?- a compound of formula 1 =F) a compound of formula 18 according to claim 1 or a pharmaceutically acceptable salt thereof. 1 or a pharmaceutically acceptable salt thereof in accordance with the claims of IB or TA a compound of formula 4-1 to ? Where: laz form a heterogeneous ring; bonded to “nitrogen” has from © to 1 atoms; ; where af is if said heterocycle contains a -1111 split; (Say replace Y$oav Qa nitrogen © optionally by de gana selected from (Rs) where: alkyl f (0-0)-(0)0- + cycloalkyl (C3-Cg) 5 ¢ alkyl be selected from f (0-6) Rs 1; and alkyl F (M002)0-0-06 No : y can have an optional substitution on the carbon with one or more A's cyano, hydroxy, -OC(0)-(C;-Ce)alkyl, -NR’R”, (C3-Cg)cycloalkyl or 1 “mald(0-0) 01 : where 11 . alkyl separately on each occurrence of (m©-0) HORRY 1 or a pharmaceutically acceptable salt thereof in accordance with the claims of 13 SIA, a compound of the formula “1 8 -#”; where oxo or 11818 or hydroxy to ; Where 8 is present, each time it is Y. alkyl and 8 are independently when each time they are (0,0-m6)FY 1 or a pharmaceutically acceptable salt thereof pursuant to IB or IA claims, a compound of formula 1-1.1, where is “be zero or © JY 1 according to the claims of dia or a pharmaceutically acceptable salt IB or 1A compound of formula 7-1 having a Ry substitution; where hydrogen, halo or (Ci-Cg)alkoxy is Rp to © where . (C1-Cg)alkoxy or hydroxy is optional on carbon with one or more Y 1 or 13 or a pharmaceutically acceptable salt thereof in accordance with the claims of IA (a compound having the formula =A): at each occurrence separately SR "to 7 where slept 2 b leachate or (C;-Cg)alkoxy 7 enlodzone (0-R0) halo, ; where Ry can have an optional substitution of ¢ on carbon by halo . 1 4- A compound having the formula TA or IB or a pharmaceutically acceptable salt thereof according to claims from 1 "to A where F is - 1 am and where Ry values can be the same 1-01 a compound having the formula TA or 13 or a pharmaceutically acceptable salt thereof according to claims 1 to A where Ry is hydrogen or 0:000. A compound of formula IA or AB and R, HY 0 € ,)® N Y NH, > ~ R, N IA Ry), net R, They are HN R NH, y > 2 ~ [R)), N N IB ; 0 where: uh :7 aha>(be: piperazin-1-yl, N-methylpiperazine-1-yl, N-ethylpiperazine-1-yl, 1 N-isopropylpiperazine-1-yl, N-acetylpiperazin-1-yl, 7 N-(2-hydroxyacetyl)piperazine-1-yl, N-(2-dimethylaminoethyl)piperazine-1-yl, A N-(2-methoxyethyl)piperazin-1-yl, N-(2-cyanoethyl)piperazin-1-yl, q N-(2-hydroxyethyl)piperazin-1-yl, N-(cyclopropylmethyl)piperazin-1-yl , \ N-(cyclopropyl)piperazin-1-yl, N-(((R)-2-hydroxypropionyl)piperazin-1-yl, 11 N-((S)-2-hydroxypropionyl)piperazin-1-yl, N- (t-butoxycarbonyl)piperazin-1-yl, VY N-(acetoxyacetyl)piperazin-1-yl, piperidin-1-yl, morpholino, homopiperazin-1 -yl, 01“ N-methythomopiperazin-1-yl, N-ethylhomopiperazin -1-yl, y¢ N-acetylhomopiperazin-1-yl, N-isopropylhomopiperazin-1-yl, yo N-cyclopropylhomopiperazin-1-yl and pyrrolidin-1-yl; aa; 0x0 or «NMe, or » hydroxy be at each occurrence of Ry 7 ; be 0 or < yy, : 2s be 4 hydrogen, fluoro, methoxy, ethoxy , 2-(methoxy)ethoxy, 2-hydroxyethoxy or 70 iSOpropoxy; s : at each occurrence separately SSR; yy fluoro, chloro, methyl, trifluoromethyl, ethyl, methoxy or trifluoromethoxy; YY is the same or different. Ry to ; where 1 can be a value of "+". ¢ fluoro or “hydrogen be Ry 9) lm VAY or a pharmaceutically acceptable salt thereof. Yo Yi IB Compound of formula Ha or -1 1 Ry) Rm M R), £ N ~~ NH, Y 7 R, N IA (Ry Im R, HN 0 R, NN NH, 7 ®R), N N IB where: i Y 4-[(2,4-difluorophenyl)amino]-7-ethoxy-6- (4-methylpiperazin-1-yl)quinoline-3 carboxamide; 4-[(2,3-dichlorophenyl)amino] -7-ethoxy-6-(4-methylpiperazin-1-yl)quinoline-3- ¢ carboxamide; 8 7-ethoxy-4-[(2-fluoro-5-methylphenyl)amino] -6-(4-isopropylpiperazin-1- 1 yl)quinoline-3-carboxamide; For 4-[(3-chloro-2-fluorophenyl)amino]-7-ethoxy-6 -(4-methylpiperazin-1- A meat l VAY yl)quinoline-3-carboxamide; 1 7-ethoxy-4-[(2-fluoro-5-methylphenyl)amino]-6-(4-methylpiperazin-1- 01 yDquinoline-3-carboxamide; 1 7-ethoxy-4-[(2-fluoro-4) -methylphenyl)amino]-6-(4-methylpiperazin-1- VY yl)quinoline-3-carboxamide; Ww 4-[(2,4-difluorophenyl)amino]-7-(2-methoxyethoxy)-6-(4 -methylpiperazin-1- yl)quinoline-3-carboxamide; Ye 4-[(2-fluoro-4-methylphenyl)amino]-7-(2-methoxyethoxy)-6-(4-methylpiperazin- 1 1 -yl)quinoline-3-carboxamide;1 4-[(2-fluoro-5-methylphenyl)amino]-7-(2-methoxyethoxy)-6-(4-methylpiperazin- YA 1-yl)quinoline-3-carboxamide ; and 5 4-[(2-fluoro-4-methylphenyl)amino]-6-(4-isopropylpiperazin-1-yl)-7-(2- ve methoxyethoxy)quinoline-3-carboxamide.7 YY yy Y¢ 1-1” A process for preparing a compound of formula TA or 13 or a pharmaceutically acceptable salt Y of which this operation includes (in which the different set is as defined YF in SIA Formats 18 unless otherwise noted) at: ; Process A) a complex reaction of formula TIA or 113: 1 2 AH VAL Ry) Rm 0 0 L Hm Qe + HNO © L R Xr” TNH, ' Xr” “NH, M ~ R, N L N IA 18 :11] is a displacement atom or group; with a compound It has the formula L when (R Vn NH Vv 11 VB or IVA or Process B) a complex reaction of formula R, R, LO A Rn £ L 9 R, Xr” “NH N xn 2 NH, _ and for N N R, N q IVA IVB AV where a. is a displacement atom or group; With a compound of formula A (Ry) HN wv LAN Maha Vv 11 Process c) A complex reaction of formula VIA or VIB YY (Ra) Ry), as they are R ' HN 1 M lyr + 60 (0) N XX OH OH > ~~ nl R)), € N = R, N VIA VIB or active derivative terminated with ammonia ¢ c 3 ba £ or process d complex reaction of formula VIIA or VIIB: 1 25 nor guardian SD of R, HN © (R 1 on £ HN 9 R, > _R p (R,), 2 N = to R , N VIIA VIIB R Cus be alkyl C1-C6 ¢ and specifically formamidea— ¢ ethyl 3 methyl VY and several? Format VIIA or 171113: 49 7 YsoV VAR Ry) (Ry), for , 8 R, HN AN R, CN 6 N > CN 7, 7 D N N M _ R, N YY VIIA VIIIB YY and then, if necessary: Yt : - : -1 to convert a compound of formula 1A or IB into an OA compound of formula IA or IB . Y Remove any protection groups. * - Pharmacologically acceptable salt composition. -140-1 A pharmaceutical composition comprising a compound of formula IA or 13 or a pharmaceutically acceptable salt de die Y of claims 1 to OY in combination with a pharmaceutically acceptable diluent or carrier. -1#1 A compound of formula HA or IB or a pharmaceutically acceptable salt thereof under Claims 1 Y to NY for therapeutic use. 11-1 Use of a compound of formula HA or 3 or a pharmaceutically acceptable salt thereof in accordance with items “protection from 1 to NY” in the manufacture of a drug to be used in the production of the inhibitory effect of the enzyme kinase * 087-18 in warm-blooded organisms such as Human - 117 1 Using a compound with the formula IB SIA or a pharmaceutically acceptable salt die according to Bled 1 to BOY manufacturing a drug for use in producing an anti-cancer effect in warm-blooded organisms such as humans. the YA) the use of a compound having the formula TA or IB or a pharmaceutically acceptable salt thereof in accordance with Amser Y Protection 1 to 01 in the manufacture of a drug for use in the production of a drug for use in the treatment of “melanoma 2061200108 papillary thyroid tumors, gall pug, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukemia3 and lymphoid malignancies And sarcomas in liver, kidney, kidney, bladder, prostate, breast, pancreas 08007688, primary and recurrent solid tumors of the skin ~~ 4, and colon colon, thyroid gland, lung, and ovaries. 11-1 Using a compound having the formula TA or 13 or a pharmaceutically acceptable salt thereof according to protection elements from 1 to AY Manufacturing a drug for use in the production of a drug for use in treating tumors of the chest, ovarian, bladder and neck the endometrium; the prostate, lung, kidney, and pancreas; and haematological malignancies including Ao Pe myelodysplasia, acute myeloid cancer, chronic myelogenous leukemia 1, non Hodgkin's lymphoma, and Hodgkin's disease A g all multiple myeloma, chronic lymphocytic leukemia, glioma, and 0 squamous cell carcinoma of the esophagus; And melanoma uveal malignant uveal wall Lah Ka Ehh . follicular lymphoma lb jus melanoma 1 alia] or 18 or a pharmaceutically acceptable salt thereof according to TA The use of a compound having the formula 710-1 in the manufacture of a drug for use in the production of a drug for use in the treatment of 0 to 1 1 Protection from “osteoporosis” tumor-associated osteolysis tumor-associated bone decomposition ¥ Jad ovarian transplantation including bone loss due to ovarian resection Ly osteoporosis ¢ lupus Ley autoimmune disorders bone and autoimmune disorders © including arthritis; systemic lupus erythematosus + systemic lupus erythematosus; rheumatoid arthritis such as rheumatoid arthritis1, kidney and renal inflammation 4 He refused “inflammatory bowel disease and glomerulonephritis” 4 “Transplantation, including transplanted parts of the kidney, bone marrow and skin”; Ys alzheimer’s, obesity, atherosclerosis and atherosclerosis 11 “chronic obstructive pulmonary disease And chronic obstructive rheumatoid disease VY including chronic skin disorders and chronic skin disorders diabetes and diabetes histiocytosis 0 -71 1 Use of a compound of formula TA or IB or a pharmaceutically acceptable salt thereof according to protective factors Y 1 to OY in combination with a pharmaceutically acceptable diluent or carrier for use in ¥ to produce an inhibitory effect CSF IR kinase in human warm-blooded organisms Jie. =YY 1 Use a compound of the formula TA or IB or a pharmaceutically acceptable salt thereof according to YsoVv E how much XY Protection from 1 to OY in combination with a pharmaceutically acceptable diluent or carrier for use in Y produce an anticancer effect in warm-blooded human Jie. 1 79- Using a compound having the formula TA or 13 or a pharmaceutically acceptable salt thereof according to the “protection elements from 1 to AY” in combination with a pharmaceutically acceptable diluent or dela to be used in the treatment of melanoma and papillomas of the thyroid gland papillary thyroid tumors and cancer; - cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, Jung cancer, blood cancers dJeukemias 3, lymphoid malignancies, carcinoid diseases, and sarcomas Sarcomas of liver, kidney, kidney, bladder A, prostate, chest, and pancreas; primary and recurrent solid tumors of the skin and colon 0, the thyroid gland, the lung Tung, and the ovaries A ovaries warm-blooded organisms such as 1 human. alia) or 13 or a pharmaceutically acceptable salt thereof pursuant to 1A 4; bladder, ovarian bladder, ovaries, breast, breast cancer treatment, pancreas, pancreas, kidney, lung, lung, prostate, uterus, and prostate including Lu haematological malignancies, in addition to blood malignant diseases oe and cancer Acute myelogenous leukemia “myelodysplastic syndrome 1 chronic” chronic eal and leukemia “non Hodgkin’s lymphoma 1” disease “myelogenous leukemia ~~ A” and various tumors and lymphocytic leukemia Chronic Hodgkin's disease 8 Why not Va. chronic lymphocytic leukemia 0, glioma and squamous cell carcinoma 111 in the esophagus squamous cell carcinoma of the esophagus - and cell melanoma VY malignant uveal melanoma and follicular lymphoma 0 in Jad blood creatures like humans. liad, 13, or a pharmaceutically acceptable salt thereof according to TA Use of a compound of formula Yo 1 — in combination with a pharmaceutically acceptable diluent or carrier for use in OY to 1 protection against “ and osteoporosis ¢ tumor- associated osteolysis treatment of tumor-related bone degeneration ¥ ovarian transplant failure including bone loss due to oophorectomy le osteoporosis ¢ including lupus ley autoimmune disorders bone and autoimmune disorders © in loarthritis and inflammation Arthritis ¢ systemic lupus erythematosus 1 and systemic erythema 1 and osteoarthritis ¢ rheumatoid arthritis 1 and rheumatoid arthritis 1 and glomerulonephritis renal inflammation A rejected inflammatory bowel disease and inflammatory bowel disease Bowel glomerulonephritis 4 Transplantation including renal, bone marrow and skin transplants 0 alzheimer's aia 3 obesity atherosclerosis 11 “chronic obstructive pulmonary disease 5.0 disease VY Including chronic skin disorders die yall, diabetes 01856168, skin disorders VY Langerhans cell la ya, tissue decomposition of Gesner cells, psoriasis 4, human. Jie, in warm-blooded organisms, histiocytosis 0 1 + 7- Using a compound with the formula TA or 13 or a pharmaceutically acceptable salt thereof according to elements “protection from 1 to 01 in the production of an inhibitory effect of the enzyme CSF - IR kinase in blood organisms The hot i 01 m is like a human being. Y lial or a pharmaceutically acceptable salt thereof according to IB or TA Using a compound having the formula (YY) Jia Producing an anti-cancer effect in warm blood organisms BOY to 1 Protection from “human. Or a pharmaceutically acceptable salt thereof according to IB or TA properties Using a compound having the formula (YA) papillary Treatment of melanoma or papillary thyroid tumors SOY to 1 Protection from or cholangiocarcinomas; or thyroid tumors ¥ lung, ovarian cancer, or colon cancer; colon ¢ lymphoid malignancies or leukemia or lymphatic malignancies cancer and bladder kidney and liver sarcomas or cancers and sarcomas 1; And solid tumors, pancreas, breast, pancreas, prostate, bladder 1, and colon primary and recurrent solid tumors of the skin that are chronic and originating in the skin A. ovaries, ovaries, lung, thyroid 48 all, colon 8 alia] or 13 or a pharmaceutically acceptable salt thereof according to TA Use of a compound of the formula - 79 1, ovarian bladder, ovary, breast Treatment of breast cancer BAY to 1 protection against “kidney, kidney, lung, lung, prostate, neck, endometrium, prostate, bladder ¥ haematological, in addition to malignant blood diseases, pancreas; myelodysplastic syndrome, including anaplastic syndrome La malignancies acute myelogenous leukemia 1 non Hodgkin's ¢ chronic myelogenous leukemia 1 and various tumors and leukemia Hodgkin's disease + lymphoma A YS Av [vay 4 Chronic lymphocytic leukemia, glioma and 0 squamous cell carcinoma of the esophagus - and 11 malignant uveal melanoma and VY lymphoma Follicular lymphoma. 1 > © - the use of a compound of formula 18 or 13 or a pharmaceutically acceptable salt thereof in accordance with the elements of the MSSR Protection 1 to BY Treatment of tumor-associated osteolysis ¢ and osteoporosis Lay osteoporosis including bone loss due to resection ; Ovarian ovarian Bone transplantation failure Cll ja al autoimmunity Autoimmune Loy disorders | © Including systemic lupus erythematosus lea gc + joint arthritis including rheumatoid arthritis 1 ¢, renal inflammation, and kidney inflammation Kidney A glomerulonephritis and inflammatory bowel disease (4) and refusal of transplantation, including transplanted renal and fifth parts, 0 with bone and skin marrow; atherosclerosis, obesity, Alzheimer's disease 11, chronic obstructive pulmonary disease VY; Diabetes and chronic skin disorders Lay disorders VY including psoriasis and tissue decomposition of the islets of Langerhans cells Langerhans cell histiocytosis 1 . 'VIIB 5 VIIA is a compound with the formula — ¥Y 1 1 lam Yay Ry), (Ry), 3 R for Y (R 1 )h € ! HN 0 8 R, AN 0 _R > 0 a _ ss and N N R, N VIIA VIIB 7 -_stay and« and shall be as defined in any of Rese Nola C-Ce where 8 is AY to 1; the protections of FY) - compound of formula VIA and 713: Crown nb the Rs HN 0 7 b x x Np on for “OH _ > N 2 and for R, N VIA VIB yp where RyRy and “ and » was as defined in any of the claims 1 ¢ to AY for no