NZ621436B2 - Bicyclic heterocycle derivatives for the treatment of pulmonary arterial hypertension - Google Patents
Bicyclic heterocycle derivatives for the treatment of pulmonary arterial hypertension Download PDFInfo
- Publication number
- NZ621436B2 NZ621436B2 NZ621436A NZ62143612A NZ621436B2 NZ 621436 B2 NZ621436 B2 NZ 621436B2 NZ 621436 A NZ621436 A NZ 621436A NZ 62143612 A NZ62143612 A NZ 62143612A NZ 621436 B2 NZ621436 B2 NZ 621436B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- alkyl
- optionally substituted
- alkoxy
- imidazo
- pyridine
- Prior art date
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- 206010064911 Pulmonary arterial hypertension Diseases 0.000 title claims abstract description 14
- 125000002618 bicyclic heterocycle group Chemical group 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 292
- -1 pyrazolopyridine derivative compounds Chemical class 0.000 claims abstract description 141
- 125000000217 alkyl group Chemical group 0.000 claims description 242
- 125000000623 heterocyclic group Chemical group 0.000 claims description 189
- 239000000203 mixture Substances 0.000 claims description 173
- 229910052736 halogen Inorganic materials 0.000 claims description 168
- 150000002367 halogens Chemical class 0.000 claims description 157
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 131
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 129
- 125000003545 alkoxy group Chemical group 0.000 claims description 88
- 239000011780 sodium chloride Substances 0.000 claims description 77
- 150000003839 salts Chemical class 0.000 claims description 76
- ZMBYQTGAXZOMOO-UHFFFAOYSA-N imidazo[1,2-a]pyridine-3-carboxamide Chemical compound C1=CC=CN2C(C(=O)N)=CN=C21 ZMBYQTGAXZOMOO-UHFFFAOYSA-N 0.000 claims description 75
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 73
- 125000001188 haloalkyl group Chemical group 0.000 claims description 72
- 125000001424 substituent group Chemical group 0.000 claims description 71
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 claims description 58
- 125000003118 aryl group Chemical group 0.000 claims description 56
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 51
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 50
- 201000010099 disease Diseases 0.000 claims description 49
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 43
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 37
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 37
- 229910052739 hydrogen Inorganic materials 0.000 claims description 36
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 32
- 239000003795 chemical substances by application Substances 0.000 claims description 31
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 31
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- 125000004122 cyclic group Chemical group 0.000 claims description 25
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- 125000004076 pyridyl group Chemical group 0.000 claims description 23
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- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 21
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- 239000011570 nicotinamide Substances 0.000 claims description 15
- JVOGPCAZHXALIS-UHFFFAOYSA-N pyrazolo[1,5-a]pyridine-3-carboxamide Chemical compound C1=CC=CC2=C(C(=O)N)C=NN21 JVOGPCAZHXALIS-UHFFFAOYSA-N 0.000 claims description 15
- 229910052717 sulfur Inorganic materials 0.000 claims description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 11
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- TZRQZPMQUXEZMC-UHFFFAOYSA-N tert-butyl N-(2-bromoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCBr TZRQZPMQUXEZMC-UHFFFAOYSA-N 0.000 description 1
- BMCSSROYAYPYAX-NSHDSACASA-N tert-butyl N-[2-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]ethyl]carbamate Chemical compound COC[C@@H]1CCCN1CCNC(=O)OC(C)(C)C BMCSSROYAYPYAX-NSHDSACASA-N 0.000 description 1
- 125000006318 tert-butyl amino group Chemical group [H]N(*)C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YPWFISCTZQNZAU-UHFFFAOYSA-N tetrahydro-2H-thiopyran Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran THF Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 102000004217 thyroid hormone receptors Human genes 0.000 description 1
- 108090000721 thyroid hormone receptors Proteins 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 239000012443 tonicity enhancing agent Substances 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- CDMIYIVDILNBIJ-UHFFFAOYSA-N triazinane-4,5,6-trithione Chemical compound SC1=NN=NC(S)=C1S CDMIYIVDILNBIJ-UHFFFAOYSA-N 0.000 description 1
- BSUNTQCMCCQSQH-UHFFFAOYSA-N triazine Chemical compound C1=CN=NN=C1.C1=CN=NN=C1 BSUNTQCMCCQSQH-UHFFFAOYSA-N 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- YTJUCJAUJCXFTN-UHFFFAOYSA-O tritert-butylphosphanium;tetrafluoroborate Chemical compound F[B-](F)(F)F.CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C YTJUCJAUJCXFTN-UHFFFAOYSA-O 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 229960002381 vardenafil Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
Provided are imidazopyridine and pyrazolopyridine derivative compounds of the general formula (I), wherein the variables are as defined in the specification. Examples of the compounds include N-(2-Fluoro-5-(2-(4-methylpiperazin-1-yl)benzylcarbamoyl)phenyl)-7-(1-methyl-1H-pyrazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamide and N-(5-((2-(2,2-dimethylpyrrolidin-1-yl)ethyl)carbamoyl)-2-methylpyridin-3-yl)-6-( 1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyridine-3-carboxamide. The compounds are inhibitors of PDGFR kinase. The compounds may be useful in the treatment of pulmonary arterial hypertension. yridine-3-carboxamide and N-(5-((2-(2,2-dimethylpyrrolidin-1-yl)ethyl)carbamoyl)-2-methylpyridin-3-yl)-6-( 1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyridine-3-carboxamide. The compounds are inhibitors of PDGFR kinase. The compounds may be useful in the treatment of pulmonary arterial hypertension.
Description
ic Heterocycle Derivatives for the Treatment of Pulmonary Arterial
Hypertension
FIELD OF THE INVENTION
The present invention relates to bicyclic heterocycle derivatives, their preparation,
their use as pharmaceuticals and ceutical compositions ning them.
More particularly the present invention relates to their use in inhibiting PDGF receptor
mediated biological activity.
BACKGROUND
Protein kinases (PK) are a large set of urally related phosphoryl transferases
having highly conserved structures and catalytic functions. Protein kinases are
enzymatic components of the signal transduction pathways which catalyze the
transfer of the terminal phosphate from ATP to the hydroxy group of tyrosine, serine
and/or threonine residues of proteins, and are ore categorized into families by
the substrates they orylate: Protein Tyrosine Kinases (PTK), and Protein
Serine/Threonine Kinases.
n kinases play a al role in the control of cell growth and differentiation and
are responsible for the control of a wide y of cellular signal transduction
processes, wherein protein kinases are key ors of cellular signals leading to
the production of growth factors and cytokines. The overexpression or inappropriate
expression of normal or mutant n kinases plays a significant role in the
development of many diseases and disorders including, central nervous system
disorders such as mer's, inflammatory disorders such as arthritis, bone
diseases such as osteoporosis, metabolic disorders such as diabetes, blood vessel
proliferative disorders such as angiogenesis, mune diseases such as
rheumatoid arthritis, ocular diseases, cardiovascular disease, atherosclerosis,
cancer, thrombosis, psoriasis, restenosis, schizophrenia, pain sensation, transplant
rejection and infectious diseases such as viral, and fungal infections.
The agents of the invention act as inhibitors of PDGFR kinase, c-Kit kinase and
related receptor and non-receptor tyrosine kinases. PDGFR is activated by binding of
the growth factor PDGF to the extracellular portion of the receptor. Upon activation
PDGFR phosphorylates many substrate proteins and controls a wide variety of
cellular functions including eration and migration. PDGFR mediates these
effects on multiple cell types including those of the mesenchymal lineage, fibroblasts,
vascular smooth muscles cells and pericytes.
PDGFR kinase inhibition is ed to be a useful target for the treatment of various
cardiovascular, ary, tissue remodelling and hypertrophic disorders, many
cancers and other indications in which PDGF driven onal responses contribute
to pathology, including PAH. PDGFR, PDGFR ligands and activated, phosphorylated
PDGFR is found in the proliferating smooth muscle cells that comprise the lesions in
the pulmonary vasculature of PAH patients and animal models of PAH. Furthermore,
the tyrosine kinase inhibitor Gieevec® has been shown to be ious in the
treatment of PAH clinically and in pre-clinical PAH models. Other targets inhibited by
the agents of the invention may contribute to the efficacy of the agents in PAH,
asthma and other indications. For example, c—kit inhibition contributes to the
ion of mast cells and is cial in the treatment of preclinical models of
asthma.
SUMMARY OF THE INVENTION
In a first aspect of the invention, Embodiment 1, we provide a compound of formula
(I);
or a pharmaceutically acceptable salt thereof,
wherein,
A is R3
PCT/IBZOIZIOS4501
R1 is C1—C4 alkyl; C1-C4 alkoxy optionally substituted by one or more halogen atoms;
ON; or halogen;
R16‘ is H, halogen, C1-C4 alkyl or C1-C4 haloalkyl;
X is N or CH;
R2 is H; C1—C3 alkyl optionally substituted by one or more OH, -NR9R11 or C1—C4
alkoxy; C1—C3 haloalkyl; C2-Cg alkynyl tuted by one or more halogen, OH, —
NRQR11 or C1-C4 alkoxy; C3-C10 cycloalkyl; -(C1-C4 alkyl)~C3-Cg cycloalkyl; 01—03
alkoxy optionally substituted by one or more halogen, -NR9R11 or OH; OH; CN;
halogen; -(Co—C4 alkyl)—NR9R“; -(co-<:4 alkyi)—C02R15; -(c:o-c4 alkyl)—C(O)NR9R“; -
1O (Co-C4 —Cs—C14 aryl; or 4 —3 to 14 membered heterocyclyl; wherein the
cycioalkyl, -(Co-C4 alkyl)—C6-C14 aryl and -(Co-C4 alkyl)~3 to 14 heterocyclyl are each
optionally substituted by one or more Za substituents;
R3 is H; C1-C8 alkyl optionally substituted by one or more OH, -NR9R11 or C1-C4
alkoxy; C1—Cg haloalkyl; C2-Cg alkynyl tuted by one or more n, OH, ~
NRQR“, or 01-04 alkoxy; 03-010 cycloalkyl; -(c:1—c4 alkyl)—Cs-Cg lkyi; 01-03
alkoxy optionally substituted by one or more halogen, -NR5‘R11 or OH; OH; CN;
halogen; -(Co-C4 —NR9R“; -(Co-C4 alkyl)—COZR15; -(Co-C4 alkyi)~C(O)NR9R“; -
(Co-C4 —Ca—C14 aryl; or 4 alkyi)—3 to 14 membered heterocyclyl; wherein the
cycloalkyl, -(Co-C4 alkyl)-Cs-C14 aryl and -(Co—C4 alkyl)—3 to 14 heterocyclyl are each
ally substituted by one or more Za substituents;
each Z3 is ndently OH; —(Co~C4 alkyl)—C5 aryl; ~O—Cs aryl; C1-C4 alkyl optionally
substituted by one or more OH, ON or —NR193R213; C1-C4 haloalkyl; C1-C4 alkoxy
optionally tuted by one or more OH, 98, -NR19"‘R21a or C1-C4 alkoxy; -
NR1BaC(O)R21a; —C(O)NR193R21a; _NR18aC(O)NR19aR21a; _NR193R213; —(Co-C4 alkyl)-
C(O)OR183; —(Co-C4 alkyl)—C(O)R193; 0x0; CN; N02; halogen or -(oo-c4 alkyl)—4 to 6
membered heterocyclyl; wherein the aryl and heterocyclyl are each optionally
substituted by halogen, C1—C4 alkyl, C1—C4 haloalkyl or C1-C4 alkoxy optionally
substituted by one or more halogens;
R4 is H, C1—C4 alkyl or C1-C4 haloalkyl;
R5 is H, 01—04 alkyl or C1-C4 haloalkyl;
R6 is selected from C1—C3 alkyl optionally substituted by one or more C1-C4 alkoxy;
01-08 haloalkyl; —(Co-C4alkyl)—C3-Cgcycloalkyl; C1-Cgalkoxy optionally substituted by
one or more halogen atoms; —NR‘9R21; ~(Co—C4 alkyl)—Ce—C14aryl; —(Co—C4 alkyl)—3 to 14
membered heterocyclyl; and -(Co-C4 alkyl)—COZR15; wherein the —(Co—C4a|kyl)-Cs-
Cgcycloaikyl, -(Co-C4 alkyl)—Cs-C14ary| and -(Co-C4 alkyl)-3 to 14 heterocyclyl are each
optionally substituted by one or more Z substituents;
each Z is independently selected from OH; (Co-C4 alkyi)—Ca aryl; O—Cs aryl; 01-05
alkyl ally substituted by one or more OH, ON or —NR19R21; C1-Ce haloalkyl; C1—
06 alkoxy optionally substituted by one or more OH, —COZR18, -NF<’19R21 or C1-C4
alkoxy; (O)R‘9; -C(O)NR‘3R21; -NR‘BC(O)NR19R2‘; -NR‘9R2‘; (co-c4 -
C(O)OR19; (co-c4 alkyI)—C(O)R19; oxo; CN; N02; halogen and (co-c4 aikyl)—4 to 6
membered heterocyclyl; and wherein the aryl and heterocyciyi are each optionally
substituted by one or more halogen, 01-05 aikyi, 01—06 haloalkyl and 01—05 alkoxy
optionally substituted by one or more halogens;
R9 and R" are each ndently selected from H; 01-05 alkyl ally substituted
by one or more C1—C4 alkoxy or OH; (31—05 haloalkyl; 1aikyl)~Cg—C5 cycloalkyl;
(Co-C4 alkyl)- (36-014aryl optionally substituted by one or more groups selected from
C1—C6 alkyl, C1~Ca alkoxy and halogen; and (Co-C4 alkyl)— 3- to 14-membered
heterocyclyl optionally substituted by one or more groups seiected from halogen,
oxo, C1—Ce alkyl and —Ca alkyl; or
R9 and R11 together with the nitrogen atom to which they are attached form a 5- to
-membered heterocyclyl, which heterocyclyl inciudes O to 3 further heteroatoms
selected from N, O and S, the heterocyclyl being ally substituted by one or
more substituents selected from OH; n; phenyl, 5— to iO-membered
heterocyclyl; C1-Cs aikyi; C1-C5 haloalkyl; 01—05 alkoxy optionally substituted by one
or more OH or 01-04 alkoxy; and C(O)OC1-Csaikyl; wherein the phenyl and
heterocyclyl substituent groups are themselves optionally substituted by 01—05 alkyl,
C1-C5 haloalkyl or 01—05 alkoxy;
R15 is selected from H; 01—08 alkyl; C1—Cs haloalkyl; Cg-Cm lkyl; (—C1—C4alkyl)-
Cg-Ca cycloalkyl; —(Co—C4 alkyi)~Cs-C14aryi and -(Co-C4 aikyl)-3 to 14 membered
heterocyclyl group; wherein the lkyl, aryl and heterocyclyl groups are each
optionally substituted by one or more Z substituents;
R183 is independently H or 61-05 alkyl;
R193 and R218 are each independently H; (31-05 alkyl optionally substituted by one or
more C1—C4 alkoxy or OH; C1-C6 haloalkyl; —(CO-C1alkyl)—C3~Cacycloa|kyl; (Co-C4 alkyl)-
05-014aryl optionally substituted by one or more groups seiected from 01-06 alkyi, C1-
06 alkoxy and halogen; or (Co-C4 alkyl)— 3— to 14—membered heterocyclyl optionally
substituted by one or more groups seiected from halogen, oxo, 01-06 alkyl and
C(O)C1—CG alkyl; or
R198‘ and R213 together with the nitrogen atom to which they attached form a 5- to 10-
membered heterocyclyl, which cyclyl includes 0 to 3 further heteroatoms
selected from N, O and S, the heterocyclyl being optionally substituted by one or
more tuents selected from OH; halogen; ; 5— to ‘lO-membered
heterocyclyl; C1-Cs alkyl; C1-C5 haloalkyl; C1—C5 alkoxy optionally substituted by one
or more OH or C1—C4 alkoxy; and C(O)OC1-C5alkyl; wherein the phenyl and
heterocyclyl substituent groups are themselves optionally substituted by C1-C6 alkyl,
01-05 haloalkyl or C1—Ce alkoxy;
R18 is independently H or C1—C5 alkyl;
R19 and R21 are each independently H; 01-05 alkyl optionally substituted by one or
more C1—C4 alkoxy or OH; C1-Ce kyl; ~(Co-C1alkyl)—C3—Cscycloalkyl; (C0—C4 alkyl)—
Ce-Cmaryl optionally substituted by one or more groups selected from 01—05 alkyl, C1-
Ce alkoxy and halogen; or (Co—C4 alkyl)- 3- to 14—membered heterocyclyl, optionally
1O substituted by one or more groups selected from halogen, oxo. C1-Cs alkyl and
C(O)C1—Cs alkyl; or
R19 and R21 together with the nitrogen atom to which they attached form a 5— to 10—
membered cyclyl, which heterocyclyl includes 0 to 3 further heteroatoms
selected from N, O and S, the heterocyclyl being optionally substituted by one or
more substituents selected from OH; halogen; ; 5— to 10-membered
heterocyclyl; C1—C5 alkyl; 01-06 haloalkyl; 01-05 alkoxy optionally substituted by one
or more OH or C1-C4 alkoxy and C(O)OC1-Csalkyl; wherein the phenyl and
heterocyclyl substituent groups are themselves optionally substituted by a substituent
selected from C1-Cs alkyl, 01-05 kyl and C1—05 .
DEFINITIONS
For purposes of reting this specification, the following definitions will apply and
whenever appropriate, terms used in the singular will also include the plural and vice
versa.
As used herein, the term “alkyl” refers to a fully saturated ed or unbranched
hydrocarbon moiety having up to 20 carbon atoms. Unless othenNise provided, alkyl
refers to hydrocarbon moieties having 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1
to 4 carbon atoms. Representative examples of alkyl include, but are not limited to,
, ethyl, n-propyl, opyl, l, sec—butyl, iso-butyl, tent-butyl, n-pentyl,
isopentyl, neopentyl, n—hexyl, 3-methylhexyl, 2,2— dimethylpentyl, methylpentyl,
n—heptyl, or n—octyl.
As used herein, the term “alkoxy” refers to alkyl-O-, wherein alkyl is defined herein
above. Representative examples of alkoxy include, but are not limited to, methoxy,
ethoxy, propoxy, 2-propoxy, , tert—butoxy, pentyloxy, hexyloxy, cyclopropyloxy—
, cyclohexyloxy— and the like. Typically, alkoxy groups have about 1~6, more
preferably about 1—4 carbons.
As used herein, the term ”haloalkyl” refers to an alkyl as defined herein that is
substituted by one or more halo groups as defined . The haloalkyl can be
monohaloalkyl, dihaloalkyl or polyhaloalkyl including oalkyl. A loalkyl
can have one iodo, bromo, chloro or fluoro within the alkyl group. Dihaloalky and
polyhaloalkyl groups can have two or more of the same halo atoms or a combination
of different halo groups within the alkyl. Typically the polyhaloalkyl contains up to 12,
or 10, or 8, or 6, or 5, or 4, or 3, or 2 halo groups. Non—limiting examples of haloalkyl
e fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,
dichlorofluoromethyl, roethyl, difluoropropyl, dichloroethyl and dichloropropyl. A
perhaloalkyl refers to an alkyl having all hydrogen atoms replaced with halo atoms.
As used , the term "cycloalkyl" refers to saturated or unsaturated monocyclic,
bicyclic or tricyclic hydrocarbon groups of 3-10 carbon atoms. Unless othen/vise
provided, cycloalkyl refers to cyclic hydrocarbon groups having between 3 and 10
ring carbon atoms or between 3 and 8 ring carbon atoms. Exemplary monocyclic
hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl,
cyclopentyl, cyclopentenyl, exyl or cyclohexenyl. Exemplary bicyclic
hydrocarbon groups include bornyl, indyl, hexahydroindyl, tetrahydronaphthyl,
decahydronaphthyl, bicyclo[2.‘l.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl,
6,6—dimethylbicyclo[3.1.1]heptyl, trimethylbicyclo[3.i .1]heptyl, or
bicyclo[2.2.2]octyl.
The term “02-8 alkynyl” as used herein refers to a linear or branched saturated
hydrocarbon group containing from 2 to 8 carbon atoms that contains at least one
carbon to carbon triple bond. Examples of such groups include l, propynyl,
butynyl and yl.
The term "aryl" refers to an aromatic hydrocarbon group having 6-14 carbon atoms in
the ring portion. Typically, aryl is monocyclic or bicyclic aryl having 6—14 carbon
atoms and includes one aromatic ring fused to one non-aromatic hydrocarbon ring.
miting examples include phenyl, indane, naphthyl or tetrahydronaphthyl.
As used herein, the term “aryloxy” refers to both an --O-aryl and an --O—heteroaryl
group, wherein aryl and heteroaryl are defined herein.
As used herein, the term “4- to 8-Membered cyclyl”, “5— to 6- membered
heterocyclyl”, “3— to 10-membered heterocyclyl”, “3— to 14-membered heterocyclyl”,
“4- to 14—membered heterocyclyl” and “5- to 14-membered heterocyclyl”, refers,
respectively, to 4- to 8—membered, 5- to 6—membered, 3- to lO—membered, 3— to 14—
membered, 4- to 14—membered and 5- to 14-membered heterocyclic rings containing
at least one ring heteroatom selected from the group consisting of nitrogen, oxygen
’IO and sulphur, which may be saturated, partially saturated or unsaturated (aromatic).
The heterocyclyl es single ring groups, fused ring groups and bridged groups.
es of such heterocyclyl include, but are not limited to, furan, pyrrole,
pyrrolidine, pyrazole, imidazole, triazole, isotriazole, tetrazole, thiadiazole,
azole, oxadiazole, pyridine, piperidine, pyrazine, oxazole, isoxazole, pyrazine.,
pyridazine, pyrimidine, piperazine, pyrrolidine, pyrrolidinone, morpholine, triazine,
oxazine, yrofuran, ydrothiophene, tetrahydrothiopyran, tetrahydropyran,
1,4-dioxane, athiane, indazole, ine, indazole, indole, 8~aza-
bicyclo[3.2.1]octane, 2,3-dihydrobenzofuran or thiazole.
"Heteroaryl" is a subset of heterocyclyl, wherein "heteroaryl" are completely
unsaturated (aromatic). Examples of such groups are pyridine and pyrazine.
As used herein, the term “halogen” or “halo” refers to fluoro, chloro, bromo, and iodo.
s ments of the invention are described herein. lt will be ized that
features specified in each embodiment may be combined with other specified
features to provide further embodiments.
Embodiment 2: A compound of formula (I);
WO 30802 PCT/182012/054501
or a pharmaceutically acceptable salt f,
wherein,
A is R3
R1 is C1-C4 alkyl; C1-C4 alkoxy optionally substituted by one or more halogen atoms;
ON; or halogen;
R1a is H, halogen, C1-C4 alkyl or C1-C4 haloalkyl;
X is N or CH;
R2 is H; C1-Cg alkyl optionally substituted by one or more OH, ~NR9R“ or C1—C4
alkoxy; C1~Cg haloalkyl; Cz'Cg alkynyl substituted by one or more halogen, OH, —
NRS’R11 or C1-C4 alkoxy; 03-010 cycloalkyl; -(C1—C4 aikyl)—Cg—Cg cycioalkyl; C1-Cg
alkoxy optionally substituted by one or more halogen, —NR9R11 or OH; OH; CN;
halogen; ~(Co-C4 alkyl)—N RQR”; -(co-c4 awn-0021215; «co-c:4 alkyl)-C(O)NR9R“; -
(Co-C4 alkyl)-Ca-C14 aryl; or —(Co—C4 alkyl)—3 to 14 membered cyclyl; wherein the
cycloalkyl, 4 -CG-C14 aryl and -(Co-C4 alkyl)~3 to 14 heterocyclyl are each
optionally substituted by one or more Za substituents;
R3 is H; 01-08 alkyl optionally substituted by one or more OH, -NR9R11 or C1-C4
alkoxy; C1-C3 haloalkyl; C2-03 l substituted by one or more halogen, OH, -
NRQR“, or C1-C4 alkoxy; C3-C10 cycloalkyl; ~(C1-C4 alkyi)-C3-Ca cycloalkyl; C1-C8
alkoxy optionally substituted by one or more halogen, 1 or OH; OH; CN;
n; -(Co-C4 alkyl)—NR9R”; ~(Co—C4 alkyl)—COZR15; -(CO-C4 alkyl)-C(O)NR9R“; -
(Co—C4 alkyl)—Cs—C14 aryl; or -(Co—C4 alkyl)—3 to 14 membered heterocyolyl; wherein the
cycloalkyl, -(Co—C4 —Ca-C14 aryl and -(Co—C4 alkyl)~3 to 14 heterocyclyl are each
optionally substituted by one or more Za substituents;
each Z3 is independently OH; (Co—C4 alkyl)—C5 aryl; O-Ca aryl; C1—C4 alkyl optionally
substituted by one or more OH, ON or —NR193R213; C1-C4 haloalkyl; 01-04 alkoxy
optionally substituted by one or more OH, 'COQR193, -NR19E‘R21a or C1—C4 ; —
NR18aC(O)R21a; —C(O)NR198R213; _NR18aC(O)NR1QaR21a; _NR193R21a; —(Co—C4 alkyl)-
13‘“; -(co—c4 alkyl)-C(0)R‘9a; oxo; CN; N02; halogen; «co—cl, alkyl)-4 to 6
membered cyclyl; or —O-(4 to 6 membered heterocyclyl); wherein the (Co-C4
—Co aryl, O-Cs aryl, -(Co—C4 alkyl)—4 to 6 membered heterocyclyl and —O—(4 to 6
membered heterocyclyl) are each optionally substituted by OH, halogen, C1-C4 alkyl,
C1—C4 haloalkyl or C1-C4 alkoxy optionally substituted by one or more halogens;
R4 is H;
R5 is H, C1-C4 alkyl or C1—C4 haloalkyl;
R6 is selected from C1-C8 alkyl optionally substituted by one or more C1—C4 alkoxy or
—NR19R21; c1-c8 haloalkyl; ~(Co-C4alkyl)—C3-CecycloaIkyl; C1-Cgalkoxy optionally
tuted by one or more halogen atoms; 21; —(Co—C4 alkyt)—Ce-C14aryl; and —
(Co-C4 alkyI)-3 to 14 membered cyclyl; wherein the —(Co-C4a|kyl)-C3-
Cgcycloalkyl, —(Co-C4 alkyl)—Ce-C14ary| and -(Co—C4 alkyl)—3 to 14 heterocyclyl are each
optionally substituted by one or more Z substituents;
2O each Z is independently ed from (Co—C4 -Cs aryl; O-Cs aryl; Cl-C5 alkyl
optionally substituted by one or more 01-05 alkoxy, ON or -NR19R21; 01—05 kyl;
C1~C5 alkoxy optionally substituted by one or more -NR19R21 or C1-C4 alkoxy; -
NR‘QRZ‘; (co-c4 alkyl)—C(O)R19; CN; halogen and (co-c:4 alkyl)—4 to 6 membered
cyclyl; and wherein the aryl and heterocyclyl are each optionally substituted by
one or more halogen, 01-05 alkyl, 01—06 haloalkyl and 01-05 alkoxy optionally
substituted by one or more ns;
R9 and R" are each independently selected from H; 01—05 alkyl optionally substituted
by one or more C1-C4 alkoxy or OH; 01-06 haloalkyl; -(Co-C1a|kyl)—C3-Cs lkyl;
(C0-C4 alkyl)- C6-C14aryl optionally substituted by one or more groups selected from
C1-C6 alkyl, C1-Cs alkoxy and halogen; and (Co-C4 alkyl)- 3- to 14—membered
heterocyclyl optionally substituted by one or more groups selected from halogen,
oxo, C1-C5 alkyl and C(O)Cl~C5 alkyl; or
R9 and R“ together with the nitrogen atom to which they are attached form a 5- to
-membered heterocyclyl, which heterocyclyl includes 0 to 3 further heteroatoms
selected from N, O and S, the heterocyclyl being optionally substituted by one or
more substituents selected from OH; halogen; phenyl, 5- to 10—membered
heterocyclyl; C1~Cs alkyl; C1—C5 haloalkyl; 01-05 alkoxy optionally substituted by one
or more OH or C1-C4 alkoxy; and C(O)OC1-Caalkyl; wherein the phenyl and
heterocyclyl substituent groups are themselves optionally substituted by 01-05 alkyl,
C1-Cs haloalkyl or C1-C5 alkoxy;
R15 is selected from H; C1-Cs alkyl; C1-Cs haloalkyl; 03-010 cycloalkyl; (C4alkyl)-
Cg'Cg cycloalkyl; -(Co-C4 alkyl)-C5-C14aryl and -(Cg-C4 alkyl)—3 to 14 membered
heterocyclyl group; wherein the C3—C10 cycloalkyl, (-C1-C4alkyl)—Ca~Cg cycloalkyl, -(Co-
C4 alkyl)—Ca—C14aryl and —(Co—C4 alkyl)—3 to 14 membered heterocyclyl groups are
each optionally substituted by one or more Z substituents;
R183 is independently H or 01—05 alkyl;
R193 and R21a are each independently H; C1-C5 alkyl optionally substituted by one or
more C1-C4 alkoxy,— NR22R23‘, or OH; c1-c6 haloalkyl; —(Co-C1alkyl)-Cg~Cscycloalkyl; -
(Co-C4 alkyl)— C5—C14aryl optionally substituted by one or more groups selected from
C1-C5 alkyl, 01—05 alkoxy and halogen; or -(Co-C4 alkyl)~ 3- to 14-membered
heterocyclyl optionally substituted by one or more groups ed from halogen,
oxo, 01-06 alkyl and C(O)C1~Cs alkyl; or
R19‘1 and R213 together with the nitrogen atom to which they attached form a 5- to 10-
membered cyclyl, which heterocyclyl es 0 to 3 further heteroatoms
selected from N, O and S, the heterocyclyl being optionally substituted by one or
more substituents selected from OH; halogen; phenyl; 5- to 10-membered
heterocyclyl; 01-05 alkyl; C1—Ce haloalkyl; C1-C6 alkoxy optionally tuted by one
or more OH or C1—C4 alkoxy; and C(O)OC1-Cealkyl; wherein the phenyl and
heterocyclyl tuent groups are themselves optionally substituted by C1—Ce alkyl,
C1-Cs haloalkyl or C1-C5 ;
R18 is ndently H or C1-C5 alkyl;
R19 and R21 are each independently C1—Ce alkyl ally substituted by one or
more
C1-C4 alkoxy; C1—Cs haloalkyl; ~(Co-C1alkyI)-Cg-Cscycloalkyl;- (Co-C4 —CG-C14aryl
optionally substituted by one or more groups selected from C1—C6 alkyl, 01—05 alkoxy
and halogen; or -(Co-C4 — 3- to 14—membered heterocyclyl, ally substituted
by one or more groups selected from halogen, 01-06 alkyl and -C(O)C1—C6 alkyl; or
R19 and R21 together with the nitrogen atom to which they attached form a 5- to 10—
membered heterocyclyl, which heterocyclyl includes 0 to 3 further heteroatoms
selected from N, O and S, the heterocyclyl being optionally tuted by one or
more substituents ed from halogen; phenyl; 5— to 10—membered heterocyclyl;
01-05 alkyl; 01-06 haloalkyl; 01-05 alkoxy optionally substituted by one or more C1-C4
alkoxy and C(O)OC1-Cealkyl; wherein the phenyl and heterocyclyl substituent groups
are themselves optionally substituted by a substituent selected from C1-C5 alkyl, C1—
Cs haloalkyl and C1-Ce alkoxy; and
R22 and R23 are each independently H or C1—C6 alkyl.
Embodiment 3: A compound of formula (I), according to Embodiment 1 or
Embodiment2, n R1 is C1-C4 alkyl, C1-C4 alkoxy, ON or n.
Embodiment 4: A compound of formula (1), according to any preceding Embodiment,
wherein R1 is C1-C4 alkyl or halogen.
ment 5: A compound of formula (l), ing to any preceding Embodiment.
1O wherein R1 is methyl or halogen.
Embodiment 6: A compound of formula (l), according to any preceding Embodiment,
wherein R1 is methyl or F.
Embodiment 7: A compound of formula (I), according to any preceding Embodiment,
wherein R13 is H, methyl or F; particularly R1a is H.
ment 8: A compound of formula (I), according to any preceding Embodiment,
wherein X is N.
Embodiment 9: A compound of formula (I), according to any one of Embodiments 1
to 7, wherein X is CH.
Embodiment 10: A compound of formula (I), according to any preceding
Embodiment, n R2 is H; C1~Cs alkyl optionally substituted by one or more OH, ~
NR9R1‘or C1-C4 alkoxy; 01—06 haloalkyl; (32—06 alkynyl tuted by one or more
halogen, OH, -NRQR11 or C1-C4 alkoxy; Cg'CB cycloalkyl; -(C1—C4 alkyl)—Ca-Cs
cycloalkyl; C1-C5 alkoxy optionally substituted by one or more halogen, ~NR9R‘1 or
OH; OH; CN; halogen; -(Co-C4 -NR9R“; 4 alkyl}COzR15; -(C0—C4 alkyl)-
C(O)NR19R21; -(co-c4 alkyl)—Cs~C14aryl; or -(cO—c4 alkyl)—3 to 14 membered
heterocyclyl; wherein the Cs-Cecycloalkyl, -(CO-C4 alkyl)—C6-C14aryl and -(Co-C4 alkyl)-
3 to 14 heterocyclyl are each optionally substituted by one or more Za substituents.
ment 11: A compound of formula (I), according to any ing
Embodiment, wherein R2 is H; C1-C4 alkyl optionally substituted by one or more OH, -
NR9R11or C1-C4 alkoxy; C1-C4 haloalkyl; C2-C5 alkynyl tuted by one or more
halogen, OH, -NR9R“, or c1-c4 alkoxy; 03-05 cycloalkyl; —(c1-c4 alkyl)—Cg-Ce
cycioalkyi; 01—05 alkoxy optionally substituted by one or more halogen, -NRQR11 or
OH; OH; CN; halogen; —(c0—c4 alkyl)—NR9R“; -(co-c4 alkyi}COzR15; —(Co—C4 alkyl)—
C(O)NR19R“; -(Co-C4 alkyl)-C5—C14aryi; or —(Co-C4 aikyi)-3 to 14 membered
heterocyclyi; wherein the C3-Cscycloalkyi, -(Co-C4 -Ce-C14aryl and —(Co-C4 alkyl}
3 to 14 cyclyi are each optionally substituted by one or more Za substituents.
ment 12: A compound of formula (l ), according to any preceding
Embodiment, wherein R2 is H; C1—C4 alkyi ally tuted by one or more OH
or ~NR9R“; Cl—C4 haioalkyl; C1-C4 alkoxy optionally substituted by one or more
halogen, -NR9R11 or OH; OH; CN; halogen; —(c0-c4 alkyI)-NR9R”; ~(Co—C4 alkyl)—
C(O)NR9R"; phenyl; or -(Co—C4 alkyl)—5 to 6 membered heterocyclyi; wherein the
phenyl and -(Co—C4 aikyl)—5 to 6 heterocyclyi are each optionally substituted by one or
more Za substituents.
Embodiment 13: A nd of formula (1), according to any preceding
ment,wherein R2 is H; C1—C4 alkyl optionally substituted by one or more OH or
-NH2; C1-C4 alkoxy ally substituted by one or more -NR9RH or OH; F; Br; —(C1-
CZ alkyl)—NR9R“; —C(O)NR9R“; phenyl; or —(Co—C4 aikyi)—5 to 6 ed
heterocyclyl; wherein the phenyl and —(Co-C4 alkyl)—5 to 6 heterocyclyl are each
optionally substituted by one or more 2" substituents.
Embodiment 14: A compound of formula (I), according to any preceding
Embodiment,wherein R2 is H; C1—C4 alkyl optionally substituted by one or more OH or
-NH2; C1—C4 alkoxy optionally substituted by -NR9R”; F; Br; 2 aikyl)—NR9R"; —
C(O)NR9R“; phenyl; or -(Co—C4 aiky|)-5 to 6 membered heterocyclyi; wherein the
phenyl and —(Co—C4 alkyI)—5 to 6 heterocyclyi are each optionally substituted by one or
more Za substituents.
Embodiment 15: A compound of formula (1), according to any preceding
Embodiment,wherein R2 is H; C1-C4 alkyl optionally substituted by one or more OH;
C1-C4 alkoxy optionally substituted by -NR9R11; F; Br; HR“; phenyl; or -(Co-C4
—5 to 6 membered heterocyclyi; wherein the phenyl and -(Co-C4 —5 to 6
membered heterocyclyi are each optionally substituted by one or more Za
substituents.
Embodiment 16: A compound of formula (I), according to any preceding
Embodiment, n R2 is phenyl or -(Co—C4 alkyl)—5 to 6 membered heterocyclyl,
each optionally substituted by one, two or three Za substituents.
Embodiment 17: A compound of a (I), according to any preceding
Embodiment, wherein R2 is phenyl or 5- or 6-membered heterocyclyl, each ally
substituted by one, two or three Za substituents.
Embodiment ‘18: A compound of formula (I), according to any one of Embodiments 1
to 15, wherein R2 is H, F, Br,
/‘<\/Q\\ OH 1‘
F C F O
l [Elm/OH
;t\\ , gtifiYkH/k/DH“a.
H 6*“H ;‘\\\ /“\“
/ /——/
urn Na—N/J N\N
Vt kl.
' 5? g2/ /‘
Embodiment 19: A compound of formula (l), according to any preceding
Embodiment, wherein R3 is H; C1—C4 alkyl optionally substituted by one or more OH, -
NRgRflor C1-C4alkoxy; C1—C4 haloalkyl; C2-C5 alkynyl substituted by one or more
halogen, OH, -NRQR11 or lkoxy; 03-06 cycloalkyl; -(C1-C4 alkyl)-Cg-Cg
cycloalkyl; -C1—C4alkoxy optionally substituted by one or more halogen, -NR9R11 or
OH; OH; CN; halogen; —(Co-C4 alkyl)-NR9R“; -(cQ-c4 alkyl)—C02R15;-(Co-C4 alkyl)-
C(0)NR9R“; —(co-c4 -Cearyl; or {co-ca, alkyl)-5 to 6 ed heterocyclyl;
wherein the 03-05 cycloalkyi, -(Co—C4 alkyl)-Caaryl and ~(Co-C4 alkyl)—5 to 6
heterocyclyl are each optionally tuted by one or more Za substituents.
Embodiment 20: A compound of formula (I), according to any preceding
Embodiment, wherein R3 is H; C1—C4 alkyl optionally substituted by one or more OH
or —NR9R“; C1-C4 haloalkyl; 03-05 cycioalkyl; C1-C4alkoxy optionally substituted by
one or more halogen or ~NR9R“; OH; CN; halogen; —(Co-C4 alkyl)—C(O)NR19R21;
phenyl; or -5 to 6 ed cyclyl, wherein the Cst lkyl, phenyl and 5
to 6 cyclyl are each optionally substituted by one or more Za substituents.
Embodiment 21: A compound of formula (I), according to any preceding
Embodiment, wherein R3 is H; C1-C4 alkyl; -C1—C4alkoxy; OH; CN; halogen; -
C(O)NR9R“; phenyl or -5 to 6 ed heterocyclyl; wherein the phenyl and 5 to 6
heterocyclyl are each optionally substituted by one or more 22‘1 substituents.
Embodiment 22: A compound of formula (l), according to any preceding
Embodiment, n R3 is H; C1—C4 alkyl; -C1-C4 alkoxy; halogen or —C(O)NR9R”.
PCT/IBZOIZ/054501
Embodiment 23: A compound of a (I), according to any preceding
ment, wherein R3 is H.
Embodiment 24: A compound of formula (I), according to any preceding
Embodiment, wherein R4 is H.
Embodiment 25: A nd of a (l), according to any ing
Embodiment, wherein R5 is H, C1—C4 alkyl or C1-C4 haloalkyl.
Embodiment 26: A compound of formula (1), according to any preceding
Embodiment, wherein R5 is H or methyl.
Embodiment 27: A compound of a (l), according to any preceding
Embodiment, wherein R5 is H.
Embodiment 28: A compound of formula (I), according to any preceding
Embodiment, wherein R4 is H and R5 is H.
Embodiment 29: A compound of formula (l), according to any preceding
Embodiment, wherein R6 is 01-05 alkyl ally substituted by C1—C4 alkoxy; C1-Ce
haloalkyl; ~(Co—C4alkyl)—Cg—Cs cycloalkyl; Ci-C4 alkoxy optionally substituted by one or
more halogen atoms; —NR19R21; -(Co—C4 alkyl)—Cs-C14aryl or —(Co~C4 alkyl)-3 to 14
membered heterocyclyl; wherein the cycloalkyl, -(Co-C4 alkyl)—Ce—C14 aryl and -(Co-C4
alkyl)—3 to 14 heterocyclyl are each optionally substituted by one or more Z
substituents.
Embodiment 30: A compound of formula (l), according to any preceding
Embodiment, wherein R6 is 01-05 alkyl optionally substituted by one or more C1-C4
3O alkoxy; C1-C6 haloalkyl; alkyl)—Ca-Cscycloalkyl; C1—C4 alkoxy optionally
substituted by one or more halogen atoms; —NR19R21; 4 alkyl)—Cs—C1oaryl or -(Co-
C4 alkyl)-5 to 6 membered heterocyclyl; wherein the —(Co-C1alkyl)-Cs-Cecycloalkyl, -
(CO-C4 alkyl)-C5—C14aryl and ~(Co—C4 alkyl)—5 to 6 membered heterocyclyl are each
optionally tuted by one or more Z tuents.
Embodiment 31: A nd of formula (I), according to any preceding
Embodiment, wherein R6 is 01—05 alkyl optionally substituted by C1—C4 alkoxy; -(Co—
Czalkyl)—Cg-Cecycloalkyl; C1-C4alkoxy; -Ca~C1oaryl or -(CO-Cz alkyl)—5 to 6 membered
heterocyclyl; wherein the —(Co—Czalkyl)-C3—Cecycloalkyl, —(CO-02 alkyl)-Ce—C1oaryl and —
(Co-Czalkyl)-5 to 6 membered heterocyclyl are each optionally substituted by one or
more Z substituents.
Embodiment 32: A nd of formula (l), according to any preceding
Embodiment, wherein R6 is C1-Ca alkyl optionally substituted by C1-C4 ; —(Co—
C1alkyl)-cyclohexyl; phenyl or 1 alkyl)-5 to 6 membered heterocyclyl; wherein
the -(Co~C1alkyl)—cyclohexyl, phenyl and -(Co-C1 ~5 to 6 membered heterocyclyl
are each optionally substituted by one or more Z substituents.
Embodiment 33: A compound of formula (I), according to any one of Embodiments 1
to 30,wherein R6 is C1-C4 alkyl ally substituted by one or more C1-C4 alkoxy;
phenyl; C1-C4 haloalkyl; tetrahydrofuran; pyrrolidine, yrrolidine or -CH2-
piperidine; wherein phenyl, tetrahydrofuran, pyrrolidine, -CH2—pyrrolidine and -CH2-
piperidine are each optionally substituted by one or more Z substituents.
Embodiment 34: A compound of formula (l), according to any one of Embodiments 1
to 30, wherein R5 is -(Co-C2 alkyl)—5 to 6 membered heterocyclyl, optionally
substituted by one, two or three Z substituents.
Embodiment 35: A compound of formula (l), according to any one of Embodiments 1
to 30, wherein R6 is
ZOlZ/054501
" F -..I-_
N >,. o
I I !
" \—0
or \<.
Embodiment 36: A compound of formula (1), according to any one of Embodiments ‘l
to 30, wherein R6 is
Embodiment 37: A nd of formula (l), according to any preceding
ment, wherein each Z3 is independently OH; ~(Co-C4 alkyl)—C5 aryl; -O—Ca aryl;
C1—C4 alkyl optionally substituted by one or more OH, ON or ~NR193R213; Ci-C4
haloalkyl; C1—C4 alkoxy optionally substituted by one or more OH, —COZR193, -
NR1QaR21a or 01-04 alkoxy; -NR1BQC(O)R213; ~C(O)NR193R213; -NR18aC(O)NR‘QaR21a; —
NR193R213; -(c0-c4 alkyl)—C(O)OR188; -(co—c4 —C(O)R1Qa; oxo; CN; N02; halogen
or ~(Co—C4 alkyl)-4 to 6 membered cyclyl; wherein the -(Co-C4 alkyl)—Ce aryl, -O-
06 aryl and -(Co-C4 alkyl)—4 to 6 membered heterocyclyl are each optionally
substituted by halogen, C1-C4 alkyl, C1-C4 haloalkyl or C1—C4 alkoxy optionally
substituted by one or more halogens.
2O Embodiment 38: A compound of formula (I), according to any preceding
Embodiment, n each Z8 is independently OH; C1—C4 alkyl optionally substituted
by one or more OH or ~NR‘93R213; C1-C4 haloalkyl; C1-C4 alkoxy optionally substituted
by one or more OH, C1—C4 alkoxy or —NR‘93R213; —C(O)NR‘93R213; CN; halogen or —(Co~
C4 alkyl)—4 to 6 membered cyclyl; wherein the -(Co-C4 alkyl)—4 to 6 membered
heterocyclyl are each optionally substituted by halogen, C1—C4 haloalkyl, or C1—C4
alkoxy optionally substituted by one or more halogens.
Embodiment 39: A compound of formula (I), according to any preceding
Embodiment, wherein each Z3 is independently C1~C4 alkyl optionally substituted by
one or more OH or ~NR193R213; C1-C4 haloalkyl; C1-C4 alkoxy optionally substituted by
one or more OH, C1—C4 alkoxy or -NR193R213; -C(O)N R193R21a; halogen or ~(Co—C4
alkyl)~4 to 6 membered heterocyclyl; n the —(Co-C4 alkyl)—4 to 6 ed
heterocyclyl is optionally substituted by halogen, C1-C4 alkyl or C1-C4 haloalkyl.
Embodiment 40: A compound of formula (l), according to any preceding
Embodiment, wherein each 2a is independently C1—C4 alkyl ally substituted by
one or more OH or -NR193R21a.
Embodiment 41: A compound of formula (l), according to any one of Embodiments 1
to 39, wherein each Z3 is independently fluorine, bromine, chlorine, , y,
N .,
-CH2NH2, ‘ H '. V
, , ,
1 or |\/O.
Embodiment 42: A compound of formula (I), according to any ing
Embodiment, wherein each Z is independently -(Co-C4 alkyl)-Cs aryl; -O-Ce aryl; C1-
04 alkyl optionally substituted by one or more ON or —NR19R21; C1-C4 haloalkyl; C1-C4
alkoxy optionally substituted by one or more ~NR19R21 or C1-C4 ; ~NR‘9R21; -
(Co-C4 —C(O)R19; CN; n or -(Co—C4 alkyl)-4 to 6 membered heterocyclyl;
wherein the -(C0—C4 alkyl)—Cs aryl, —O—Ce aryl and —(Co—C4 alky|)-4 to 6 membered
cyclyl are each optionally substituted by halogen, C1—C4 alkyl, C1-C4 haloalkyl
or C1-C4 alkoxy optionally substituted by one or more halogens.
Embodiment 43: A compound of formula (l), according to any preceding
Embodiment, wherein each 2 is independently C1-C4 alkyl optionally substituted by
one or more NHZ; C1-C4 kyl; C1-C4 alkoxy optionally substituted by one or more
C1-C4 alkoxy or —NR19R2‘; CN; halogen or -(Co-C4 alkyl)—4 to 6 membered
heterocyclyl; wherein the ~(Co-C4 alkyl)—4 to 6 membered heterocyclyl is optionally
substituted by n, C1-C4 alkyl, C1-C4 haloalkyl, or C1—C4 alkoxy optionally
substituted by one or more halogens.
Embodiment 44: A compound of formula (I), according to any preceding Embodiment
n each Z is independently C1—C4 alkoxy, halogen, C1—C4 alkyl or C1-C4
kyl.
Embodiment 45: A compound of formula (l), ing to any preceding
Embodiment, wherein R9 and R11 are each independently H; 01-05 alkyl optionally
substituted by C1-C4 alkoxy or OH; 01—05 haloalkyl; -(Co-C1alkyl)-Ca-Cscycloalkyl; (Co-
C4 alkyl)- Ca—C14aryl optionally substituted by one or more groups selected from 01-06
alkyl, C1—Ce alkoxy and halogen; or ~(Co—C4 alkyl)— 5- to 6-membered cyclyl
optionally substituted by one or more groups selected from halogen, 0x0, C1—C5 alkyl
and C(O)C1-Ce alkyl.
Embodiment 46: A compound of formula (I), according to any one of ments 1
to 44, wherein R9 and R“ together with the nitrogen atom to which they attached
form a 5- to 6-membered heterocyclyl, the heterocyclyl including 0 to 3 further
heteroatoms selected from N, O and S, the heterocyclyl being optionally substituted
by one or more substituents selected from OH; n; phenyl; 5- to 10-membered
heterocyclyl; C1—C5 alkyl; 01—06 haloalkyl; 01—05 alkoxy optionally substituted by one
or more OH or C1-C4 alkoxy; and C(O)OC1—Cfia|kyl; wherein the phenyl and
heterocyclyl tuent groups are themselves optionally substituted by C1—C6 alkyl,
01—05 kyl or C1-C5 alkoxy.
Embodiment 47: A compound of formula (I), according to any preceding
Embodiment, wherein R15 is H; C1-C4 alkyl; c1-c4 haloalkyl; cs-c10 cycloalkyl; +01—
C4alkyl)-Cg-C8 cycloalkyi; -(Co~C4 alkyl)—Ce—C14aryi or 4 alkyl)—3 to 14 membered
heterocyclyl group; wherein the 03—010 cycioalkyl, —(—C1—C4alkyI)-C3-Ca cycloalkyl, -
(Co—C4 alkyl)—C6—C14aryl and -(Co-C4 -3 to 14 membered heterocyclyl groups are
each optionally substituted by one or more Z substituents.
Embodiment 48: A compound of formula (i), according to any preceding
Embodiment, wherein R15 is H or C1-C4 alkyl.
Embodiment 49: A nd of a (l), according to any preceding
Embodiment, wherein R18 is independently H or C1-C4 alkyl.
ment 50: A compound of formula (l), according to any preceding
Embodiment, wherein R19 and Ft21 are each independently C1-Cs alkyl optionally
substituted by one or more C1—C4 alkoxy; C1—Ce haloalkyl; -(Co-C1a|kyl)-Cg-
Cscycloalkyl; (C0-C4 alkyl)-aryl optionally substituted by one or more groups selected
from 01-06 alkyl, C1-05 alkoxy and halogen; or (Co—C4 alkyl)— 5- to 6-membered
heterocyclyl optionally substituted by one or more groups selected from halogen, C1-
C6 alkyl and -Cs alkyl.
Embodiment 51: A compound of formula (I), according to any one of Embodiments 1
to 49, wherein R19 and R21 together with the nitrogen atom to which they are attached
form a 5— to 6—membered heterocyclyl, which heterocyclyl includes 0 to 3 further
heteroatoms selected from N, O and S, the heterocyclyl being optionally substituted
by one or more substituents selected from halogen; phenyl; 5- to 10~membered
heterocyclyl; C1—C4 alkyl; C1-C4 haloalkyl; C1-Cs alkoxy optionally tuted by one
or more OH or C1-C4 alkoxy and C(O)OC1-C6alkyl; wherein the phenyi and
heterocyclyl tuent groups are themselves optionally tuted by 01-06 alkyl,
C1~Cs haloaikyl or 01-05 alkoxy.
3O Embodiment 52: A compound of formula (i), according to any preceding
Embodiment, wherein R18a is independently H or C1-C4 alkyl.
Embodiment 53: A compound of formula (l), according to any ing
Embodiment, n R193 and R213 are each independently H; 01-05 alkyl optionally
substituted by C1-C4 alkoxy or OH; C1-C5 haloalkyl; -(Co-C1alkyl)-Cg-Cscycloalkyl; (C0-
C4 alkyl)~aryl optionally substituted by one or more groups selected from 01—05 alkyl,
01-05 alkoxy and halogen; or (Co—C4 alkyl)— 5- to ered cyclyl optionally
PCT/IBZOIZ/054501
substituted by one or more groups ed from halogen, oxo, C1-C6 alkyl and
C(O)C1-Ce alkyl.
ment 54: A compound of formula (I), according to any one of Embodiments 1
to 52, wherein R1961 and R215‘ together with the nitrogen atom to which they attached
form a 5- to 6—membered cyclyl which heterocyclyl includes 0 to 3 further
atoms selected from N, O and S, the heterocyclyl being optionally substituted
by one or more substituents selected from OH; halogen; phenyl; 5— to 10—membered
heterocyclyl; C1-C4 alkyl; C1-C4 haloalkyl; C1-C6 alkoxy optionally substituted by one
or more OH or C1—C4 ; and C(O)OC1-Cealkyl; wherein the phenyl and
heterocyclyl substituent groups are themselves optionally substituted by C1—C5 alkyl,
01-06 haloalkyl or 01-05 alkoxy.
Embodiment 55: A compound of formula (l), according to any preceding
Embodiment, wherein the compounds are represented by a II:
35qu "H. [3“].([1
R13? . LE... )5ng
Jf, W
RS ,-
(ll).
Embodiment 56: A compound of formula (II), or a pharmaceutically acceptable salt
thereof:
(II)
wherein
R1 is C1-C4 alkyl, C1-C4 , ON or halogen;
R12‘ is H, halogen, C1—C4 alkyl or C1-C4 haloalkyl;
X is N or CH;
R2 is H; C1-C4 alkyl optionally substituted by one or more OH, -NR$’R11 or C1-C4
alkoxy; C1—C4 haloalkyl; 02—05 alkynyl substituted by one or more halogen, OH, -
NRQR“ or C1—C4 alkoxy; 03-05 cycloalkyl; —(C1-C4 alkyl)—Cg-Cs cycloalkyl; 01-06 alkoxy
optionally substituted by one or more halogen, —NR9R11 or OH; OH; CN; halogen; -
(co-c4 alkyl)—NR9R”; —(Cg—C4 alky|)—COQR15; -(Co—C4 alkyl)—C(O)NR9R”; -(c:o-c4 alkyl)-
Cs-C14aryl; or 4 alkyl)—3 to 14 membered heterocyclyl; wherein the Cg-
Cecycloalkyl, -(Co-C4 alkyl)—C5—Ci4aryl and -(Co—C4 —3 to 14 heterocyclyl are each
optionally substituted by one or more Za substituents;
R6 is 01-06 alkyl optionally substituted by one or more C1-C4 alkoxy; C1—C5 haloalkyl; -
(Co-C1alkyl)-Cg~Cecycloalkyl; C1-Ca alkoxy optionally substituted by one or more
halogen atoms; ~NR‘9R21; {Co-C4 alkyl)—C5-C1oaryl; or ~(C0-C4 alkyi)—5 to 6 membered
heterocyclyl; wherein the ~(Co—C1alky|)—Cg-Cecycloalkyl, ~(Co-C4 alkyl)-Ce—C14aryl and —
(Co-C4 alkyl)-3 to 14 heterocyclyl are each optionally tuted by one or more Z
substituents.
each Z21 is independently OH; C1—C4 alkyl optionally tuted by one or more OH or
N H2; C1-C4 haloalkyl; C1-C4 alkoxy ally substituted by one or more OH, 01-04
alkoxy or -NR193R213; -C(O)NR193R213; CN; halogen or 4 alkyl)-4 to 6 membered
heterocyclyl; wherein the — heterocyclyl is optionally substituted by halogen, C1—C4
alkyl optionally substituted by one or more halogen atoms, or C1—C4 alkoxy optionally
substituted by one or more halogens;
each Z is independently C1—C4 alkyl optionally substituted by one or more NH2; C1-C4
haloalkyl; C1-C4 alkoxy ally substituted by one or more C1-C4 alkoxy or —
NR19R2‘; CN; halogen or 4 alkyl)—4 to 6 membered heterocyclyl; wherein the
heterocyclyl contains at least one heteroatom selected from N, O and S, wherein the
heterocyclyl is optionally substituted by n, C1—C4 alkyl, C1-C4 haloalkyl or 01—04
alkoxy optionally substituted by one or more halogens;
R9 and R“ are each ndently H; 01-05 alkyl optionally substituted by one or
more C1-C4 alkoxy or OH; 01-05 haloalkyl; -(Co—C1alkyl)—C3-Csoycioalkyl; -(Co-C4
alky|)- 06—014aryl optionally substituted by one or more groups selected from 01-06
alkyl, 01—06 alkoxy and halogen; or -(CO—C4 — 5- to 6—membered cyclyl
optionally substituted by one or more groups ed from halogen, oxo, 01-05 alkyl
and -C(O)C1-Ce alkyl;
R15 is H or C1—C4 alkyl;
PCT/IBZOIZ/054501
R19 and R21 are each independently 01-06 alkyl optionally substituted by one or more
C1—C4 alkoxy; 01-05 haloalkyi; -(C0—C1aIkyl)—Cg—Cscycloalkyl; —(C0-C4 — aryl
optionally substituted by one or more groups selected from 01-05 alkyl, C1-Cs alkoxy
and halogen; or —(Co-C4 alkyl)— 5- to 6—membered heterocyclyl optionally substituted
by one or more groups selected from halogen, C1-C5 alkyl and —C(O)C1—Ce alkyl;
R193 and R21:11 are each ndently H; C1-Ce alkyl optionally substituted by one or
more C1—C4 alkoxy or OH; 01—05 haloalkyl; -(Co-C1alkyl)—03~Cecycloaikyl; (Co—C4 alkyl)—
aryl optionally substituted by one or more groups selected from 01-05 alkyl, C1-Ce
alkoxy and halogen; or (Co-C4 alkyl)— 5- to 6—membered heterocyclyl optionally
substituted by one or more groups selected from halogen, oxo, C1'Cs alkyl and
C(O)C1—Cs alkyl.
Embodiment 57: A compound of formula (1), according to any one of Embodiments 1
to 54, wherein the compounds are represented by formula (Ht):
(ill).
ment 58: A compound of a (til), or a pharmaceuticaily acceptable salt
thereof:
H [gN‘t N Ex. ’N
Fiat-ilk;”r' HI-fl/ Ill]
D L R2
(Ill)
wherein
R1 is C1-C4 alkyl, C1-C4 alkoxy, ON or halogen;
R16 is H, halogen, Ci—C4 alkyl or C1-C4 kyl;
X is N or CH;
R2 is H; C1-C4 alkyl optionally substituted by one or more OH, -N RQR11 or C1-C4
alkoxy; C1—C4 haloalkyl; Cz-Cs l substituted by one or more halogen, OH, -
NRQR11 or C1—C4 alkoxy; Cs—Ce cycloalkyl; -(C1-C4 alkyl)—Cs-Ca cycloalkyl; C1—C4 alkoxy
optionally substituted by one or more halogen, -N RQR11 or OH; OH; CN; halogen; -
(co-c4 alkyI)-NR9R“; ~(co-c4 alkyl)—COZR15; -(c0-c4 alkyl)—C(O)NR9R“; 4 —
aryl; or —(Co—C4 alkyl)-3 to 14 membered heterocyclyl; wherein the Cg-
Cecycloalkyl, 4 —C6-C14aryl and ~(Co-C4 alkyl)—3 to 14 heterocyclyl are each
optionally substituted by one or more Za substituents;
R6 is 01-06 alkyl ally substituted by one or more 01-04 alkoxy; C1-C4 haloalkyl; —
(C0—C1alkyl)—Cg-Cecycloalkyl; C1-C4 alkoxy optionally substituted by one or more
halogen atoms; -N R19R21; -(C0-C4 alkyl)-Ce-C10aryl or -(Co-C4 alkyl)—5 to 6 membered
heterocyclyl; wherein the —(Co—C1alkyl)—C3—Cacycloalkyl, —(Co—C4 alkyl)—Cs-C1oaryl and -
(Co-C4 alkyl)—5 to 6 ed cyclyl are each optionally substituted by one or
more Z substituents;
each Z6‘ is independently OH; C1—C4 alkyl optionally substituted by one or more OH or
NH2; C1-C4 alkyl; C1-C4 haloalkyl; C1—C4 alkoxy optionally substituted by one or more
OH, c,-c4 alkoxy or -NR193R213; —C(0)NR193R213; CN; halogen or -(Co-C4 alkyl)—4 to 6
membered heterocyclyl; n the heterocyclyl is optionally substituted by halogen,
C1—C4 alkyl, C1—C4 haloalkyl or C1-C4 alkoxy optionally substituted by one or more
halogens;
each Z is independently C1-C4 alkyl optionally substituted by one or more NHZ; C1—C4
alkyl; C1-C4 haloalkyl; C1-C4 alkoxy optionally substituted by one or more C1—C4
alkoxy or —NR’9R21; CN, halogen or 4 alkyl)-4 to 6 membered heterocyclyl;
wherein the heterocyclyl is optionally substituted by halogen, C1—C4 alkyl, C1~C4
haloalkyl or C1-C4 alkoxy optionally substituted by one or more halogens;
R9 and R11 are each independently H; C1-Cs alkyl optionally substituted by one or
more C1—C4 alkoxy or OH; C1-C5 haloalkyl; -(CO—C1alkyl)-C3-Cecycloalkyl; -(Co—C4
alkyl)— Ce-C14aryl optionally substituted by one or more groups selected from C1-C5
alkyl, (31-06 alkoxy and halogen; or -(Co-C4 alkyl)— 5— to 6-membered heterocyclyl
optionally substituted by one or more groups selected from halogen, oxo, C1-C6 alkyl
and 1-Cb- alkyl;
R15 is H or C1—C4 alkyl;
R19 and R21 are each independently 01-05 alkyl optionally substituted by one or more
C1—C4 alkoxy; C1—Ce haloalkyl; —(Co-C1alkyl)—Cg-Cacycloalkyl; —(Co-C4 alkyl)— Ce~C14aryl
optionally substituted by one or more groups selected from 01—05 alkyl, (31—05 alkoxy
and halogen; or ~(Co-C4 alkyl)— 5- to ered cyclyl optionally substituted
by one or more groups selected from halogen, C1—Ce alkyl and —C(O)C1—06 alkyl;
R193 and R218 are each independently H; C1-C5 alkyl ally substituted by one or
more C1—C4 alkoxy or OH; 01-05 haloalkyl; -(Co-C1atkyl)—Cg-Cacycloalkyl; (Co-C4 alkyl)—
aryl optionally substituted by one or more groups selected from C1—Ce alkyl, 01—05
alkoxy and halogen; or (Co-C4 alkyl)— 5- to 6-membered heterocyclyl optionally
substituted by one or more groups selected from halogen, oxo, (31—05 alkyl and
C(O)Ci-C5 alkyl.
1O Embodiment 59: A compound of formula (I), (I) or (III), according to any preceding
Embodiment, wherein x, R1, R13, R2, R3, R4, R5, R6, 2, 2a R15, R18, R19 and R19 are
those defined by the Embodiments above or by the Examples section below.
Embodiment 60: A compound of formuia (l), which is ed from:
N—(2-Fluoro(2—(4-methylpiperazin~1-yl)benzylcarbamoyl)phenyI)—7-(1-methyl-1H—
pyrazolyl)imidazo[1,2—a]pyridinecarboxamide;
7-(3-Fluoro(2-hydroxyethylcarbamoyl)phenyl)-N-(2-fluoro(2-(4-methylpiperazin-
1—y|)benzylcarbamoyi)phenyi)imidazo[1,2-alpyridine-S—carboxamide;
o-N-(2-methyl(2—(4-methylpiperazin-1—
y|)benzylcarbamoyl)phenyi)imidazo[1,2-a]pyridinecarboxamide;
7-(1 ~MethyI-1 H—pyrazoI—S—yl)—N-(2-methyl~5-(2—(4—methylpiperazin-1 ~
yl)benzylcarbamoyl) phenyl)imidazo[1,2—a]pyridine—3-carboxamide;
N-(2-Fluoro(2-(4—methylpiperazin-t -yl)benzylcarbamoyl)phenyl)-7—(pyridine~3-
yl)imidazo[1,2—a]pyridinecarboxamide;
N-(2—Flu0r0(2-(4—methyipiperazinyl)benzylcarbamoyl)phenyl)~7-(1~methyl-1 H—
pyrazolyl)imidazo[1,2-a]pyridine—3-carboxamide;
N-(5-(3,4—difluorobenzylcarbamoyl)—2—tluorophenyl)(1-methyl-1H-pyrazolyl)
imidazo [1,2—a]pyridine -3—carboxamide;
N—(5-(benzylcarba moyi)—2-fluoropheny|)—6—(1~methyI-1H-pyrazoly|)imid azo[1,2-
a]pyridinecarboxamide;
N-(4-fluoro—2—methyi—5-(2—(4-methyl piperazinyl) benzylcarbamoyl)phenyl)—7—
(pyridineyl)imidazo[1,2-a]pyr idinecarboxamide;
N-(5-(3,4—difluorobenzylcarbamoyl)—2—f|uorophenyI)—7—(6-(3-(dimethyl amino) propoxy)
pyridineyi)imid 2-a]pyridinecarboxamide;
N-(5-(2-(2.6-cis-dimethylpiperidin—t-yl)ethyicarbamoyl)—2-fluorophenyl)—7-(1-methyl-
1 H-pyrazol-S—yl)imidazo[1,2-a]pyridine-3—carboxamide;
WO 30802
7-(4—(aminomethyl) )-N—(2-fluoro—5—(2—(4-methylpiperazin-1 -
yl)benzy|carbamoyl) phenyl)imidazo[1,2-a]pyridine-3—carboxamide;
N—(5-(2-tert—butoxyethyloarbamoyl)—2—fluorophenyl)—7—(1—(2-morpholinoethyl)—1 H—
pyrazolyl)imidazo[1,2-a]pyridine—3—carboxamide;
N-(5-((5,5—dimethyltetrahyd rofuran—Z—yl)methyl ca rbamoy!)~2—fluorophenyl )—7—(1 -(2~
morpholinoethyI)-1H-pyrazol-4—yl)imidazo [1 ,2-a]pyridineca rboxamide; N—(2—fl uoro—
-(2~(4-methy}piperazinyl)benzylcarbamoyl)phenyl)(6—methoxy ne
yl)imidazo [1,2-a]pyridine—3-carboxamide;
N—(2~fluoro—5—(2-(4-methylpiperazinyl)benzylcarbamoy!)pheny!)-6~(1—methyl—1 H—
pyrazol—5—yl)pyrazolo[1,5-8]pyridinecarb0xamide;
1-(2—(4-fluoro(7~(pyridine~3-yl)imidazo [1,2—a]pyridine~3—
carboxamido)benzamido)ethyi)-2,6-cis-dimethyl piperidine;
N-(5-(2-tert-butoxyethylcarbamoyl)—2—fluorophenyl)—6-(6—(3—(dimethylamino)
propoxy)pyridine—3-y|)pyrazolo[1,5-a]pyridine-3—carboxamide;
N-(2~methyl(2—(4-methylpiperazin-1—yl)benzylcarbamoyl)phenyl)-7—(pyridine
yl)imidazo[1 yridine—3-carboxamide;
1-methyI(2-((6-methyl(7-(1-methyl -1 H-pyrazolyl)imidazo[1,2—a]pyridine—3-
carbox amido)nicotina mido)methy|)pheny!)piperazine;
7—(1—Methyl-1 H-pyrazol-4—yl)—imidazo[1,2—a]pyridine—3-carboxylic acid {5-[2—(2,6—ois-
dimethyI-piperidin-1 thy|carbam oyl ]—2-fluoro—phenyl}-amid e;
N—(5-(2—tert-Butoxyethylcarbamoyl)—2—fiuorophenyl)—7—(6-(3-(dimethylamino)propoxy)
pyridin—S—yl)imidazo[1,2-a]pyridine-3—carboxamide;
N-(5—(3,4—DifluorobenzylcarbamoyI)—2-fl uorophenyl)~7-(6-(2—(pyrrolidin~1—yl)ethoxy)
pyridin-S-yl)imidazo[1,2-a]pyridine—S-carboxamide;
6—(1—MethyI-1 H-pyrazol-5—yl)—N-(2—methyl-5—(2—(4—methyipiperazin-1—
yl)benzylcarbamoy!) phenyi)pyrazolo[1,5-a]pyridine—3—carboxamide;
N-(2-Bromo—5-(2~(4—methylpiperazinyl)benzylcarbamoyl)pheny|)imidazo[1,2-
a]pyridine—3—carboxamide;
N—(2-Bromo(2-(4-methylpiperazin-1~yl)benzylcarbamoyl)phenyl)pyrazolo[1,5-
a]pyridinecarboxamide;
N-(5-(3,4-Difluorobenzylcarbamoyl)—2—fluor0phenyl )(3—hyd roxy—S-methyl
butyl)imidazo[1,2—a]pyridine—3—carboxamide;
N~(5-(3,4—Difluorobenzylcarbamoyl)—2—fl uorophenyl)—7—(3—f|uoro—4—(2—(piperidin—1—
ylcarbamoyl)phenyl)imidazo[1,2-a]pyridinecarboxamide;
N-(5-(3,4-Difluorobenzylcarbamoy!)fluorophenyl)(3-f|uoro—4-(2-(tetrahyd ro-2H—
pyran-4—yl)ethy|carbamoyl )phenyl)imidazo[1 ,2—a]pyridine—3—carboxamid e;
WO 30802
N-(5-(3,4-Diflu0robenzylcarbamoyI)-2~fluorophenyl)—7—(3-fluoro-4—(3-morpholino
propylcarbamoyl)phenyl)imidazo[1,2-a}pyridinecarboxamide;
6-(1—MethyI-1H—pyrazoIy|)-N-(2-methyl(2—(4—methylpiperazin
y|)benzy|carbamoyl)pyridinyl)pyrazolo[1,5-a]pyridine—3-carboxamide;
N—(5—((5,5—Dimethyltetrahydrofuran-Z—yl )methylca rbamoyl)fluorophenyE)-7—(6-(4—
methylpiperazin-1—y|)pyridinyl)imidazo[1,2—a]pyridine—3-carboxamide;
3,4-Difluorobenzylcarbamoyl)—2—fluorophenyl)—7-(1-(3—(dimethy| amino)propyl)-
1 H-pyrazol-4—yl)imidazo[1,2-a]pyridine—3-carboxamide;
N-(5—((5,5—Dimethyltetra hyd rofuran—Z—yl )methylcarbamoyl)f|uor0pheny|)—7—(5-
1O ((tetrahydro-2H—pyranylamin0)methyl)pyridinyl)imidazo[1,2—a]pyridine—3—
carboxamide;
(S)—N-(5-(((5,5-Dimethyltetrahydrofuranyl)methyl) carbamoyl)—2~fluorophenyl)—7-(5—
(((2-fluoroethyl) amino)methy!)pyridin—3-yl)imidazo[1,2-a]pyridine-3—carboxamide ;
(R)—N~(5—(((5,5—dimethyltetrahydrofura n-2—yl)methyl) oyl)f|uorophenyl)—7-(5—
ethoxyethyl) (methyl)amino)methyl)pyridinyl) imidazo[1,2—a] pyridine
carboxamide ;
(R)—7-(5—((tert—butylamino)methy| )pyridin—S-yl)-N—(5-(((5, 5-dimethyltetrahydrofuran
yl)methyl)carbamoyI)—2~fluorophenyl) imidazoh,2—a]pyridine-3—carboxamide ;
N-(5-(3,4-Difluorobenzylcarbamoyl)fluorophenyl)—7-(6-(2—(pyrrolidiny!)ethoxy)
pyridinyl)imidazo[1,2-a]pyridine—3-carboxamide;
N~(5-((2—(tert—Butoxy) ethyl)carbamoyl)—2—fluoro phenyl)—7-(8-(2—(pyrrolidin~1—yl)
ethoxy)pyridin~3-yl) imidazo[1,2-a] ne-S—carboxamide ;
N-(5—(((5,5-dimethyl tetrahydrofuran—Z—yl)methyi)carbamoyI)—2~fluorophenyl)(6-((1 -
methyl piperidin-4—yl)oxy) pyridinyl)imidazo[1,2-a]pyridine—3-carboxamide ;
6-(1-Methyl~1 H-pyrazol-S-yl)-N-(2—methyl(2—(4—methyipiperazin-1 -
yl)benzylcarbamoyl) )pyrazolo[1,5—a]pyridine—3-carboxamide;
N—(Z-Bromo—5—(2—(4-methylpiperazin—1~yl)benzylcarbamoyl)phenyl)imidazo[1 ,2-
a]pyridinecarboxamide;
N-(Z-Bromo-S-(Z-(4—m ethylpiperazin-1 -yl)benzylcarbamoyl)phenyl)pyrazolo[1 ,5-
a]pyridinecarboxamide;
N—(5~(3,4-Difluorobenzylcarbamoyl)—2—fluorophenyl )—7—(3-hyd roxymethyl
butyl)imidazo[1,2—a]pyridine—3-carboxamide;
N—(5—(3,4—DifluorobenzylcarbamoyI)—2—fl uorophenyl)—7~(3-fluoro—4-(2—(piperidin—1—
yl)ethylcarbamoyl)phenyl)imidazo[1,2-a1pyridine—3-carboxamide;
N-(5-(3,4-DifluorobenzylcarbamoyI)fl uorophenyl)(3—fluoro—4-(2-(tetrahyd ro-2H-
pyran-4—yl)ethyioarbamoyl)pheny|)imidazo[1,2—a]pyridine—3-carboxamide;
N-(S-((2-(2,2—Dimethylpyrrolidin-1~yl)ethy1)carbamoyl)f|uorophenyl)—7-(1~methyl—
1 H-pyrazol-4—yl)imidazo{1,2-3]pyridine-S—carboxamide;
N-(5-(2-(2,2-Dimethylpyrrolidiny|)ethylcarbamoyl)—2—fluorophenyl)—7-(3-fluoro
((1 R,2R)—2—hyd roxycyclohexylcarbamoyl)phenyl)imidazo[1 ,2—a]pyridine—3-
carboxamide;
N—(5—(2-(2,2-Dimethylpyrrolidin-1~yl)ethylcarbamoyl)—2-fl uorophenyl)—7—(3-fluoro(1 -
hydroxy—Z-methylpropanylcarbamoyl)phenyl)imidazo[1,2—a]pyridine—3—
carboxamide;
N—(5-(2—(2,2—Dimethylpyrrolidiny|)ethyicarbamoyl)-2~methylpyridinyl)—6-(3—fluoro~
1O 4—(1»hydroxy~2—methylpropan—Z—ylcarbamoyl)phenyl)pyrazolo[1,5—a]pyridine~3—
carboxamide;
N—(5—(3,4-Difluorobenzylcarbamoyi)-2—fluorophenyl)(3~fluoro—4-(3-morpholino
propylcarbamoyl)phenyl)imidazo[1,2—3]pyridine—3-carboxamide;
2—(2,6-cis-Dimethylpiperidin-1—y!)ethylcarbamoyl)—2-fluoropheny|)—7-(3-fluoro
(1 —hydroxy~2—methylpropa n—2-ylca rbamoyl)ph enyl)imidazo[1 ,2-a]pyridine
carboxamide;
7—(3—F1uoro—4-(2-fluoroethylcarbamoyi )phenyl)—N-(2-f|uoro—5—(2—(4—methylpiperazin-1 —
zylcarbamoyl)phenyl)imidazo[1,2—a]pyridine—3—carboxamide;
N-(2-Fluoro(2-(4-methylpiperazin—1-yl)benzylcarbamoyl)phenyl)(3-fluoro(2-
hydroxy ethylcarbamoyl )ph enyl)imid azo[1 ,2—a]pyridine—3-carboxamide;
N-(5-(2—(2.2-dimethylpyrrolidin-1—y1)ethylcarbamoyl)methylpyridin—3-yl)—6-(1 -
methyl-1 H-pyrazoI—4-yl)pyrazolo[1 ,5-a]pyridine—3~carboxamid e;
(S)~N-(2—Fluoro(2-(2—(methoxy methyl) pyrrolidin~1~yl)ethyl oyl)phenyI)—7—
(1-methyl—1H—pyrazolyl)imidazo[1,2—a]pyridine—S-Carboxamide;
N—(2—Fluor0((2—(3-propylpyrrolidinyl)ethyl)carbamoyl)phenyI)—7-(1-methyl—1 H—
pyrazolyl)imidazo [1 yridinecarboxamide;
(R)-N-(2—F|uoro-5—((2—(2-(methoxymethyl) pyrrolidin—1-yl)ethyl) carbamoyl)phenyl)-7—
(1-methyI-1 zol—4-yl)imidazo[1,2-a]pyridine—3-carboxamide;
N~(5-((2-(3,5-Dimethylpiperidin—1-y1)ethyl)carbamoyl)—2-fluoropheny|)—7-(1—methyl—1 H-
pyrazolyl)imidazo[1,2—a]pyridinecarboxamide;
N-(2—fiuoro((2-(2,2,6,6-tetra methylpiperidin—1-yl)ethyl)carba moyl)phenyl)—7-(1 -
methyl-1 H-pyrazoIy1)imidazo[1,2—3]pyridinecarboxamide;
N—(5—((2—(tert—buty1(methyl)amino)ethy1 )carbamoy1)a2-fluorophenyl)(1~methyl—1 H—
pyrazol-S-yl)imidazo[1,2-a]pyridinecarboxamide;
(2-(2,2-dimethylpyrrolidin—1 -y1)ethyl)carba moyl)-2—methy|pyridinyl)(1 -
methyl-1 H—pyrazoI-S-y|)pyrazo|o[1,5—a]pyridine—3-carboxamide;
N—(5-((2—(butyl (ethyl)amino)ethyl)carbamoyl)~2-fluoro )—7-(3-fluoro-4~((2—
hydroxy ethyl)carb amoyl)phenyl)imidazo[1,2—a]pyridine—S—carboxamide;
uoro-4—((1-hydroxymethylpropanyl)oarbamoyl)phenyl)-N-(2-fluoro-5—((2—
(3-propylpyrrolidinyl)ethy!)oarbamoyl)phenyl)imidazo[1,2—a]pyridine
carboxamide;
N-(5-((2—(3,3—dimethylmorpholino)ethyl)carbamoyl)fluorophenyl)—7-(3—fluoro-4—((1—
hydroxy-Z—methylpropanyl)oarbamoyl)phenyl)imidazo[1 ,2—a]pyridine
carboxamide;
(R)—7-(3—fluoro—4—((1-hydroxy-2—methylpropan-Z-yl)carbamoyl)phenyl)—N—(2—fluoro-5—
1O ((2—(2—(methoxymethyl)pyrrolidin—1—yl)ethyl) carbamoyl)phenyl)imidazo[1,2—a]pyridine—
3—carboxamide;
N-(5-((3,4-Difluorobenzyl)oarbamoyl)fluorophenyl)—7—(6—((2—
(dimethylamino)ethyl)carbamoyl)pyridin-3—yl)imidazo[1,2—a]pyridine—B-carboxamide;
N—(5-((2-(2,2-Dimethylpiperidin-1~y!)ethyl)oarbamoy|)-2—methylpyridinyl)—6—(1-
methyl-1 H~pyrazo|—4—yl)pyrazolo[1,5—a]pyridine—3-carboxamide;
N—(5—((2—(2,6—cis-Dimethyipiperidinyl)ethyl)carbamoyl}2—methylpyridinyl)—6—(1-
methyl-1 H-pyrazoI—4—y|)pyrazolo{1,5-a]pyridine-S-oarboxamide;
(2—((28,3R)—2,3—diethylazetidiny|)ethyl) oyl)—2-fluorophenyl)—7—(1—
methyl-1 H—pyrazoIyl)imidazo[1,2—a]pyridine-S-oarboxamide;
N-(5-(3,4-Difluorobenzylcarbamoyl)-2—f|uorophenyl)(6-(((2-hydroxyethyl)
(methyl)amino)methyl)pyridin—3—y!)imidazo[1,2-a]pyridineoarboxamide;
N—(5—((3,4—difluorobenzyl)carbamoyI)—2-fluorophenyl)—7—(6—((methyl
(phenethyl)amino)methy|)pyridinyl)imidazo[1,2—a]pyridinecarboxamide;
N—(5-((3,4—Difluoro benzyl)carbamoy!)—2—fluorophenyl)—7-(6—
yl(phenethyl)amino)methyl)pyridinyl)imidazo[1,2—a]pyridine—3-carboxamide;
N—(5~((3,4-Difluoro benzyl)carbamoyi)—2—fluorophenyl)(5-((methylamino)
methyl)pyridin—3-yl)imidazo[1,2—a]pyridinecarboxamide;
7~(5-((Cyclohexyl amino)methyl)pyridin-B-yl)-N-(5~((3,4-difiuoroben2yl) carba moyl)—2-
fluoro ) imidazo[1,2-a]pyrid inecarboxamide; and
3O N-(5-((3,4-Difluoro benzyl)carbamoyl)fluorophenyl)(5—(((2-methoxyethyl)
(methyl)amino)methyl)pyridinyl)imid azo[1,2—a]pyridine-3—oarboxamide;
or a pharmaceutically acceptable salt thereof.
Embodiment 61: A compound of formula (I), which is selected from: N—(5-((2-(2,2—
Dimethylpyrrolidinyl)ethyl)carbamoyl)—2—fluorophenyl)—7-(1-methyl-1H-pyrazoI-4—
yl)imidazo[1,2—a]pyridine~3-carboxamide;
N-(5-(2-(2,6-cis-Dimethylpiperidinyl)ethylcarbamoyl)fluorophenyl)—7-(1-methyl-
1 H—pyrazol—5-y|)imidazo[1,2-a]pyridinecarboxamide;
N-(5-(2—(2,2-dimethylpyrrolidin—1-yl)ethylcarbamoyl)-2—methylpyridinyl)(1 -
methyl-1 H—pyrazol—4—yl)pyrazolo[1,5-a]pyridinecarboxamide;
7-(1-Methyl-1 H—pyrazol-4—yl)-imidazo[1,2—aipyridinecarboxylic acid {5—[2—(2,6—cisdimethyl
—piperidin-1—yl)-ethylcarbamoyl ]-2—fluoro—phenyl}—amide; and
N—(5-(2—(2.6—cis-Dimethylpiperidin—1-yl)ethylcarbamoyl)fluorophenyl)~7-(3—tluoro-4—
(1-hydroxy—2—methylpropan—2—ylcarbamoyl)phenyl)imidazo[1,2—alpyridine-3—
carboxamide;
1O or a ceutically acceptable salt f.
in another embodiment, the individual nds according to the invention are
those listed in the es section below, as the free base or as a pharmaceutically
acceptable salt thereof.
As used herein, the term “an optical isomer” or “a stereoisomer” refers to any of the
various stereo isomeric configurations which may exist for a given compound of the
present invention and includes geometric isomers. It is understood that a substituent
may be attached at a chiral center of a carbon atom. The term "chiral“ refers to
molecules which have the property of non-superimposability on their mirror image
partner, while the term "achiral" refers to molecules which are superimposable on
their mirror image partner. Therefore, the invention includes enantiomers,
reomers or racemates of the compound. iomers” are a pair of
stereoisomers that are non-superimposable mirror images of each other. A 1:1
mixture of a pair of enantiomers is a "racemic” mixture. The term is used to
designate a racemic mixture where appropriate. "Diastereoisomers” are
stereoisomers that have at least two asymmetric atoms, but which are not mirror-
images of each other. The absolute chemistry is specified according to the
Cahn~ lngold- Prelog R-S system. When a compound is a pure enantiomer the
chemistry at each chiral carbon may be ied by either R or 8. Resolved
nds whose absolute configuration is unknown can be designated (+) or (-)
depending on the direction (dextro— or levorotatory) which they rotate plane polarized
light at the wavelength of the sodium D line. Certain compounds described herein
contain one or more asymmetric centers or axes and may thus give rise to
enantiomers, reomers, and other stereoisomerlc forms that may be defined, in
terms of absolute stereochemistry, as (R)— or (S)-.
Depending on the choice of the starting materials and procedures, the compounds
can be present in the form of one of the possible isomers or as mixtures thereof, for
example as pure optical isomers, or as isomer mixtures, such as racemates and
diastereoisomer es, depending on the number of asymmetric carbon atoms.
The present invention is meant to include all such possible isomers, including
racemic es, diasteriomeric mixtures and optically pure forms. Optically active
(R)— and (S)— isomers may be prepared using chiral synthons or chiral ts, or
ed using conventional techniques. if the compound contains a double bond,
the substituent may be E or Z configuration. If the compound contains a
disubstituted cycloalkyl, the cycloalkyl substituent may have a cis— or trans—
configuration. All tautomeric forms are also intended to be included.
As used herein, the terms “salt” or “salts” refers to an acid on or base addition
salt of a compound of the ion. “Salts” include in particular “pharmaceutical
acceptable salts”. The term aceutically acceptable salts” refers to salts that
retain the biological effectiveness and properties of the compounds of this invention
and, which typically are not biologically or otherwise undesirable. In many cases, the
compounds of the present invention are capable of forming acid and/or base salts by
virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
Pharmaceutically acceptable acid addition salts can be formed with inorganic acids
and organic acids, e.g., acetate, aspartate, benzoate, besylate,
bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate,
chloride/hydrochloride, chlortheophyllonate, citrate, isulfonate, fumarate,
tate, gluconate, onate, ate, hydroiodide/iodide, isethionate,
lactate, lactobionate, laurylsulfate, , maleate, malonate, mandelate, mesylate,
methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate,
oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate,
polygalacturonate, propionate, stearate, succinate, sulfosalicylate, te, tosylate
and trifluoroacetate salts.
lnorganic acids from which salts can be derived include, for example, hydrochloric
acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
Organic acids from which salts can be derived inciude, for example, acetic acid,
propionic acid, giycolic acid, oxalic acid, malic acid, maleic acid, malonic acid,
succinic acid, fumaric acid, L-tartaric acid, citric acid, c acid, 4—hydroxybenzoic
acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p—toluenesulfonic
acid, sulfosalicylio acid, L—glutamic acid, hippuric acid, nicotinic acid, adipic acid,
saccharin and the like. Pharmaceutically acceptable base on salts can be
formed with inorganic and organic bases.
Inorganic bases from which salts can be derived include, for example, ammonium
salts and metals from columns l to XII of the periodic table. In certain embodiments,
the salts are d from sodium, potassium, ammonium, m, magnesium, iron,
silver, zinc, and copper; ularly suitable salts include ammonium, potassium,
sodium, calcium and magnesium salts.
Organic bases from which salts can be d include, for example, primary,
ary, and tertiary amines, substituted amines including naturally occurring
substituted , cyclic amines, basic ion exchange resins, and the like. Certain
organic amines include isopropylamine, benzathine, cholinate, diethanolamine,
diethylamine, lysine, meglumine, piperazine and tromethamine.
The pharmaceutically acceptable salts of the present invention can be sized
from a basic or acidic moiety, by conventional chemical methods. Generally, such
salts can be prepared by reacting free acid forms of these nds with a
stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide,
carbonate, bicarbonate or the like), or by reacting free base forms of these
compounds with a stoichiometric amount of the appropriate acid. Such reactions are
lly carried out in water or in an organic solvent. or in a mixture of the two.
Generally, use of non—aqueous media like ether, ethyl acetate, ethanol, isopropanol,
or acetonitrile is desirable, where cable. Lists of additional le salts can be
found, e.g., in ”Remington's Pharmaceutical Sciences”, 20th ed., Mack Publishing
Company, Easton, Pa., ; and in “Handbook of Pharmaceutical Salts:
Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim,
Germany, 2002).
Any formula given herein is also intended to represent unlabeled forms as well as
isotopically labeled forms of the compounds. lsotopically labeled compounds have
structures depicted by the formulas given herein except that one or more atoms are
replaced by an atom having a selected atomic mass or mass number. Examples of
isotopes that can be orated into compounds of the invention include isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2H,
2012/054501
3H, “C, 13C, 14C, 15N, 18F ”Cl, 1251 tively. The invention includes various
isotopically d compounds as defined herein, for e those into which
radioactive isotopes, such as 3H and 14C, or those into which non-radioactive
isotopes, such as 2H and 13C are present. Such isotopically labelled compounds are
useful in metabolic studies (with 14C), reaction kinetic studies (with, for example 2H or
3H), detection or imaging techniques, such as positron emission tomography (PET) or
single—photon emission computed tomography (SPECT) including drug or ate
tissue distribution assays, or in radioactive treatment of patients. in particular, an 18F
or labeled compound may be particularly desirable for PET or SPECT studies.
isotopically-labeled compounds of formula (i) can generally be ed by
conventional techniques known to those skilled in the art or by processes analogous
to those described in the accompanying Examples and Preparations using an
appropriate isotopically-labeled reagents in place of the non-labeled t
previously employed.
Further, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D) may
afford certain eutic advantages resulting from greater metabolic stability, for
example sed in vivo ife or reduced dosage requirements or an
improvement in therapeutic index. it is understood that deuterium in this t is
ed as a substituent of a compound of the formula (I). The concentration of
such a heavier isotope, specifically deuterium, may be defined by the isotopic
enrichment factor. The term "isotopic enrichment factor" as used herein means the
ratio between the isotopic abundance and the natural abundance of a specified
isotope. If a substituent in a compound of this invention is denoted deuterium, such
compound has an isotopic enrichment factor for each ated deuterium atom of
at least 3500 (52.5% deuterium incorporation at each ated deuterium atom), at
least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium
oration), at least 5000 (75% deuterium incorporation), at least 5500 (82.5%
deuterium incorporation), at least 6000 (90% deuterium oration), at least
6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium
incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3
(99.5% deuterium incorporation).
Pharmaceutically acceptable solvates in accordance with the invention include those
wherein the solvent of crystallization may be isotopically substituted, e.g. D20, d5-
acetone, de-DMSO.
Compounds of the invention, i.e. compounds of formula (i), (ll) or (III) that contain
groups capable of acting as donors and/or acceptors for hydrogen bonds may be
capable of g co—crystals with suitable co—crystal formers. These co-crystals
may be ed from compounds of formula (i), (ll) or (III) by known co-crystal
forming procedures. Such procedures include grinding, heating, co-subliming, co-
melting, or contacting in solution compounds of a (l), (ll) or (Ill) with the cocrystal
former under crystallization conditions and ing co-crystals thereby
formed. Suitable co-crystal formers include those described in .
Hence the invention further provides co-crystals comprising a compound of formula
1O (I), (ll) or (in).
As used herein, the term "pharmaceutically able r" includes any and all
solvents, dispersion media, coatings, tants, antioxidants, preservatives (e.g.,
antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents,
salts, preservatives, drug stabilizers, binders, excipients, disintegration agents,
lubricants, sweetening agents, ng agents, dyes, and the like and combinations
thereof, as would be known to those skilled in the art (see, for example, Remington's
Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329).
Except insofar as any conventional carrier is incompatible with the active ingredient,
its use in the therapeutic or pharmaceutical compositions is contemplated.
The term "a therapeutically effective amount" of a compound of the present invention
refers to an amount of the compound of the present invention that will elicit the
ical or medical response of a subject, for example, reduction or tion of an
enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or
delay disease ssion, or prevent a disease, etc. in one non—limiting
embodiment, the term “a therapeutically effective amount” refers to the amount of the
compound of the present ion that, when administered to a t, is effective
to (1) at least partially alleviating, ting, preventing and/or ameliorating a
condition, or a disorder or a disease (i) mediated by PDGFR or (ii) associated with
PDGFR activity, or (iii) characterized by activity (normal or abnormal) of PDGFR; or
(2) ng or inhibiting the activity of PDGFR. in another non-limiting embodiment,
the term “a therapeutically ive amount” refers to the amount of the compound of
the present invention that, when stered to a cell, or a tissue, or a non-cellular
biological material, or a medium, is effective to at least partially reducing or inhibiting
the activity of PDGFR.
As used herein, the term “subject” refers to an animal. Typically the animal is a
mammal. A subject also refers to for example, primates (e.g., humans, male or
female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and
the like. in certain embodiments, the subject is a primate. In yet other embodiments,
the subject is a human.
As used herein, the term it”, “inhibition" or “inhibiting” refers to the reduction or
suppression of a given ion, symptom, or disorder, or disease, or a significant
decrease in the baseline activity of a biological activity or process.
As used herein, the term ”treat”, “treating" or "treatment" of any disease or er
refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or
arresting or reducing the development of the disease or at least one of the clinical
symptoms f). In another embodiment “treat", "treating" or "treatment" refers to
alleviating or ameliorating at least one physical parameter ing those which may
not be nible by the patient. in yet another embodiment, “treat", "treating" or
"treatment" refers to modulating the disease or disorder, either physically, (e.g.,
stabilization of a discernible symptom), logically, (e.g., stabilization of a
physical parameter), or both. in yet another embodiment, “treat”, "treating" or
"treatment" refers to preventing or delaying the onset or development or progression
of the e or disorder.
As used herein, a subject is “in need of” a treatment if such subject would benefit
biologically, medically or in quality of life from such treatment.
As used herein, the term "a,” "an,” "the” and similar terms used in the context of the
present invention (especially in the context of the claims) are to be construed to
cover both the singular and plural unless otherwise indicated herein or clearly
dicted by the t.
All methods described herein can be performed in any suitable order unless
otherwise ted herein or ise y contradicted by context. The use of
any and all examples, or exemplary language (e.g. "such as”) provided herein is
intended merely to better illuminate the invention and does not pose a limitation on
the scope of the invention otherwise claimed.
Any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present
invention can be present in racemic or enantiomerically enriched, for example the
(R)-, (S)— or (R,S)— configuration. In certain embodiments, each asymmetric atom
has at least 50 % enantiomeric excess, at least 60 % enantiomeric excess, at least
70 % omeric excess, at least 80 % enantiomeric excess, at least 90 %
enantiomeric excess, at least 95 % omeric excess, or at least 99 %
enantiomeric excess in the (R)— or (S)— configuration. Substituents at atoms with
unsaturated double bonds may, if possible, be present in cis- (Z)— or trans— (E)— form.
Accordingly, as used herein a compound of the t invention can be in the form
of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures
thereof, for example, as substantially pure geometric (cis or trans) isomers,
diastereomers, l s (antipodes), racemates or mixtures thereof.
Any resulting mixtures of s can be separated on the basis of the
physicochemical differences of the constituents, into the pure or substantially pure
geometric or optical isomers, diastereomers, racemates, for example, by
chromatography and/or onal crystallization.
2O Any resulting racemates of final products or intermediates can be resolved into the
l antipodes by known methods, e.g., by separation of the diastereomeric salts
thereof, obtained with an optically active acid or base, and liberating the optically
active acidic or basic compound. in particular, a basic moiety may thus be ed
to resolve the compounds of the present invention into their optical antipodes,
e.g.,
by fractional crystallization of a salt formed with an optically active acid, 6.9., tartaric
acid, dibenzoyl tartaric acid, diacetyl ic acid, di-0,0’—p-toluoy| tartaric acid,
mandelic acid, malic acid or camphor—1 O-sulfonic acid. Racemic ts can also
be resolved by chiral chromatography, e.g., high pressure liquid chromotography
(HPLC) using a chiral adsorbent.
Furthermore, the compounds of the present invention, including their salts, can also
be obtained in the form of their hydrates, or include other solvents used for their
crystallization. The compounds of the present ion may ntly or by design
form solvates with pharmaceutically acceptable solvents (including water); therefore,
it is intended that the invention embrace both solvated and unsolvated forms. The
term "solvate" refers to a molecular x of a compound of the present invention
(including pharmaceutically acceptable salts thereof) with one or more solvent
WO 30802
molecules. Such solvent molecules are those commonly used in the pharmaceutical
art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the
like. The term "hydrate" refers to the complex where the solvent molecule is water.
General Synthetic Schemes
The nds of the invention may be synthesized by the general synthetic routes
below, specific examples of which are described in more detail in the Examples.
Scheme 1. Method A and A1
F21 F5“
Arm-i2 )ng
>1 \
Rilaff R15
lirleth [ti Al Method A/ HOAO\Ef
Cl) KO
\x /
HM" “*0
1O Ra/EOR‘}
In scheme, the formation of the amide bond is shown using either Method A
or Method A1. Method A is an amide coupling. Methedo A1 is a TBD coupling. This
amide ion uces the R5 moeity. X, R1, R13, R4, R5 and R6 are as defined
herein.
Scheme 2. lmidazopyridines
Method 81
Method BE
1 W
- “
R” \f -1’11~11 \
R" FY a 1/
M‘KN a“ NH
Cl) 0 , LE?
11111111111110 Kl x“ 1’2
Riakf
HM” weo
R41” ‘95
In scheme 2, the formation of the amide bond at the aniline nitrogen is shown
using Method 81 and Method 82. Method Bl and Method B2 are e amide
couplings using acid chlorides. ln on, scheme 2 depicts the formation of an
amide bond to introduce the R6 moiety using Method A2, which is an amide coupling.
One on and Y2 is a halogen, such as bromine, and one on and Y2 is hydrogen. X,
R1, R13, R4, R5 and R6 are as defined herein.
Scheme 3.
'3 “y
R1 N\_}‘Y
“(IN H
XI \ Ear-'2
—ll‘~l 1
Fit.
Q5 .5
Method D / ‘\ Method 0
F!1 is not Br \Q‘ B rict Br
Nit fill
R 1 if)» R2
C L \1,
11—; R1
‘ 't HL‘X‘RZ-__
R1 3 /k“4/"
HM 0
Wk] HM 0
P‘ 7k4
”"“K F:E
R5 FEB
In scheme 3, the introduciton of R2 and/or R3 is depicted as a substitution
reaction at Y or Y2 using Method C or Method D. Method C is a Suzuki reaction to
couple aryl group at R2 or R3. Method D is a Negishi reaction to couple an alkyl
group at R2 or R3. R1 cannot be bromine for this reaction. One on and Y2 is a
halogen, such as e, and one on and Y2 is hydrogen. X, R1, R13, R2, R3, R4,
R5 and R6 are as defined herein.
Scheme 4. Pyrazolopyridines
2012/054501
NH 1
2 R
l NH2
R13 xl \
O O
HN O
R6A\H
Method 81
Method 82
O \ \
R1 Y
X \ y2 /N\
l N
/ O \
R13 \
R1 Y
(I) 0
Method A2 >i \ Y2
HN O
H R6
In scheme 4, the formation of the amide bond at the aniline nitrogen is shown
using Method Bi and Method 82. Method Bi and Method BZ are aniline amide
couplings using acid chlorides. In addition, scheme 2 depicts the formation of an
amide bond to introduce the R6 moiety using Method A2, which is an amide coupling.
One of Y and Y2 is a halogen, such as bromine, and one on and Y2 is hydrogen. X,
R1, R”, R4, R5 and R6 are as defined herein.
’10 Scheme 5.
/N\N
O \ \
R1 Y
XI \ Y2
HN 0
R49\
R5 R6
Method D Memo" C
R1 is not Br R1 is not Br
/ \N N
/ \N
O \ \
R1 R2 O \ \
\_ R1 R2
NH \
XI \ R3 NH
/ X] \
R13 /
R41 0
HN o
R >j\4
R5 R6
R5 R6
ln scheme 5, the introduciton of R2 and/or R3 is depicted as a substitution
reaction at Y or Y2 using Method C or Method D. Method C is a Suzuki reaction to
couple aryl group at R2 or R3. Method D is a Negishi reaction to couple an alkyl
group at R2 or R3. R1 cannot be bromine for this reaction. One of Y and Y2 is a
n, such as bromine, and one on and Y2 is hydrogen. X, R1, R“, R2, R3, R4,
R5 and R6 are as defined herein.
Scheme 6
| N\ N
N \ l
R1 0
o MeMgl N \
x R1
NH ———> -
/O Method E
HN O
kRG HN O
in scheme 6, the introduciton of alkyi group alpha to an ester group is
ed using Method E, a Grignard addition, to form tertiary alcohol. R1 and R6 are
as defined herein.
Scheme 7
l \ F
N N \ 0
NH R1
/ N
—————>
HN 0 Method F
kR6 TBD or h droiysis ”N 0
then HATSIJ k
in scheme 7, the introduciton of amide bond from an ester group is depicted
using Method F. Method F is a TBD reaction. R1, R6, and R21 are as defined herein.
Scheme 8
I N\ N
o “N \
N \ I
F O N K
CI N \
\ \ / F
NH - \ / OR'
Method G
HN 0
K NaH HN O
In scheme 8, the introduciton of alkoxy moiety is depicted using methog G. Method
G is a nucleophilic cement of a halide. R’ is C1—C4 alkoxy optionally tuted
by one or more OH, -COZR1B, -NR19F€21 or C1—C4 alkoxy. R1, R6, R18, R1g and R21 are
as defined herein.
The invention further es any variant of the present processes, in which an
intermediate product obtainable at any stage thereof is used as starting material and
the remaining steps are carried out, or in which the starting materials are formed in
situ under the reaction conditions, or in which the reaction components are used in
1O the form of their salts or iiy pure material.
Compounds of the invention and intermediates can also be converted into each other
according to methods generally known to those skilled in the art.
Within the scope of this text. only a readily removable group that is not a constituent
of the particular desired end product of the compounds of the present invention is
designated a "protecting group", unless the context indicates othen/vise. The
tion of functional groups by such protecting groups, the protecting groups
themselves, and their cleavage reactions are described for example in standard
reference works, such as J. F. W. McOmie, "Protective Groups in Organic
Chemistry", Plenum Press, London and New York 1973, in T. W. Greene and P. G.
M. Wuts, "Protective Groups in c Synthesis", Third edition, Wiley, New York
1999, in "The Peptides"; Voiume 3 (editors: E. Gross and J. Meienhofer), Academic
Press, London and New York 1981, in "Methoden der organischen Chemie"
(Methods of Organic Chemistry), Houben Weyi, 4th edition, Volume 15/l. Georg
Thieme Verlag, art 1974, in H.-D. Jakubke and H. eit. "Aminosauren,
Peptide, Proteine” (Amino acids, Peptides, Proteins), Verlag Chemie, Weinheim,
Deerfield Beach, and Basel 1982, and in Jochen Lehmann, "Chemie der
hydrate: Monosaccharide und Derivate" (Chemistry of Carbohydrates:
Monosaccharides and Derivatives), Georg Thieme Verlag, Stuttgart 1974. A
characteristic of protecting groups is that they can be removed readily (Le. without
the occurrence of undesired secondary ons) for example by ysis,
reduction, photolysis or alternatively under physiological ions (9.9. by
enzymatic cleavage).
Salts of compounds of the t invention having at least one salt—forming group
may be prepared in a manner known to those skilled in the art. For example, salts of
compounds of the present invention having acid groups may be formed, for example,
by ng the compounds with metal compounds, such as alkali metal salts of
suitable organic carboxylic acids, e.g. the sodium salt of 2-ethylhexanoic acid, with
organic alkali metal or alkaline earth metal compounds, such as the corresponding
hydroxides, carbonates or hydrogen carbonates, such as sodium or potassium
hydroxide, carbonate or hydrogen ate, with corresponding calcium compounds
or with ammonia or a suitable organic amine, stoichiometric amounts or only a small
excess of the salt-forming agent ably being used. Acid addition salts of
compounds of the present ion are obtained in customary manner, e.g. by
treating the compounds with an acid or a suitable anion ge reagent. Internal
salts of compounds of the present ion containing acid and basic salt-forming
groups, e.g. a free carboxy group and a free amino group, may be formed, e.g. by
the neutralisation of salts, such as acid addition salts, to the isoelectric point, e.g.
with weak bases, or by treatment with ion exchangers.
Salts can be converted into the free compounds in accordance with methods known
to those skilled in the art. Metal and ammonium salts can be converted, for example,
by treatment with suitable acids, and acid addition salts, for example, by treatment
with a suitable basic agent.
Mixtures of isomers obtainabie according to the invention can be separated in a
manner known to those skilled in the art into the individuai isomers; reoisomers
can be separated, for example, by partitioning between polyphasic solvent mixtures,
recrystallisation and/or chromatographic separation, for example over silica gel or by
e.g. medium pressure liquid chromatography over a reversed phase column, and
racemates can be separated, for example, by the formation of salts with optically
pure salt-forming reagents and tion of the mixture of diastereoisomers so
obtainable, for example by means of fractionai crystallisation, or by chromatography
over optically active column ais.
ediates and final products can be worked up and/or purified ing to
standard methods, e.g. using chromatographic methods, bution methods, (re-
)crystallization, and the iike.
The following applies in general to all processes mentioned herein before and
hereinafter.
All the above-mentioned process steps can be d out under reaction ions
that are known to those skilled in the art, including those mentioned specifically, in
the e or, customarily, in the presence of solvents or diluents, including, for
e, solvents or diluents that are inert s the reagents used and dissolve
them, in the e or ce of catalysts, condensation or neutralizing ,
for example ion exchangers, such as cation exchangers, 9.9. in the H+ form,
depending on the nature of the reaction and/or of the reactants at reduced, normal or
elevated temperature, for example in a temperature range of from about —100 °C to
about 190 °C, ing, for example, from imately -80 °C to approximately
‘IO 150 °C, for example at from -80 to -60 °C, at room temperature, at from -20 to 40 °C
or at reflux temperature, under atmospheric pressure or in a closed vessel, where
appropriate under pressure, and/or in an inert atmosphere, for example under an
argon or nitrogen atmosphere.
At all stages of the reactions, mixtures of isomers that are formed can be ted
into the dual isomers, for example diastereoisomers or enantiomers, or into
desired mixtures of isomers, for example racemates or mixtures of diastereoisomers,
for example ously to the methods described under "Additional process steps".
The solvents from which those solvents that are suitable for any particular reaction
may be selected include those mentioned specifically or, for example, water, esters,
such as lower alkyl—lower alkanoates, for example ethyl acetate, ethers, such as
aliphatic ethers, for example diethyl ether, or cyclic ethers, for example
tetrahydrofuran or dioxane, liquid aromatic hydrocarbons, such as benzene or
toluene, alcohols, such as methanol, ethanol or i- or 2—propanol, nitriles, such as
acetonitrile, halogenated hydrocarbons, such as methylene chloride or chloroform,
acid amides, such as dimethylformamide or dimethyl acetamide, bases, such as
heterocyclic nitrogen bases, for example pyridine or N-methylpyrrolidin-2—one,
carboxylic acid anhydrides, such as lower alkanoic acid anhydrides, for example
acetic anhydride, cyclic, linear or branched hydrocarbons, such as cyclohexane,
hexane or isopentane, methycyclohexane, or mixtures of those solvents, for example
aqueous solutions, unless othenivise indicated in the ption of the processes.
Such solvent mixtures may also be used in working up, for e by
chromatography or partitioning.
The compounds, including their salts, may also be obtained in the form of hydrates,
or their crystals may, for example, include the solvent used for crystallization.
Different crystalline forms may be present.
The invention relates also to those forms of the process in which a nd
obtainable as an intermediate at any stage of the process is used as ng material
and the remaining process steps are d out, or in which a starting material is
formed under the reaction conditions or is used in the form of a derivative, for
example in a protected form or in the form of a salt, or a compound obtainable by the
process according to the invention is produced under the process conditions and
processed further in situ.
All starting als, building blocks, reagents, acids, bases, dehydrating agents,
solvents and catalysts utilized to synthesize the compounds of the present invention
are either commercially available or can be produced by organic synthesis methods
known to one of ordinary skill in the art (Houben-Weyl 4th Ed. 1952, Methods of
Organic Synthesis, Thieme, Volume 21).
In another aspect, the present invention provides a pharmaceutical composition
comprising a compound of the present invention and a pharmaceutically able
r. The pharmaceutical composition can be formulated for particular routes of
stration such as oral administration, parenterai administration, and rectal
administration, etc. in addition, the pharmaceutical compositions of the present
invention can be made up in a solid form (including without limitation capsules,
tablets, pills, granules, powders or suppositories), or in a liquid form (including
without limitation ons, suspensions or emulsions). The pharmaceutical
itions can be subjected to conventional pharmaceutical operations such as
sterilization and/or can contain conventional inert diluents, lubricating agents, or
buffering agents, as well as nts, such as preservatives, stabilizers, wetting
agents, emulsifers and buffers, etc.
Typically, the pharmaceutical compositions are tablets or n capsules comprising
the active ingredient together with
a) diluents, e,g., lactose, dextrose, e, mannitol, sorbitol, cellulose
and/or glycine;
b) lubricants, e.g., silica, talcum, c acid, its magnesium or calcium salt
and/or polyethyleneglycol; for tablets also
c) s, 6.9., magnesium aluminum silicate, starch paste, gelatin,
tragacanth, methylcellulose, sodium carboxymethylcellulose and/or
polyvinylpyrrolidone; if desired
d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or
effervescent es; and/or
e) absorbents, colorants, flavors and sweeteners.
Tablets may be either film coated or enteric coated ing to methods known in
the art.
Suitable compositions for oral administration include an effective amount of a
compound of the invention in the form of tablets, lozenges, aqueous or oily
suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or
syrups or elixirs. Compositions ed for oral use are prepared according to any
method known in the art for the manufacture of ceutical itions and
such compositions can contain one or more agents ed from the
group
consisting of ning agents, flavoring agents, coloring agents and preserving
agents in order to provide pharmaceutically elegant and palatable preparations.
Tablets may contain the active ingredient in a mixture with nontoxic pharmaceutically
acceptable excipients which are suitable for the manufacture of tablets. These
excipients are, for example, inert diluents, such as calcium carbonate, sodium
carbonate, lactose, calcium phosphate or sodium phosphate; granulating and
disintegrating agents, for e, corn , or alginic acid; binding agents, for
example, starch, gelatin or acacia; and lubricating agents, for example magnesium
stearate, stearic acid or talc. The tablets are uncoated or coated by known
techniques to delay disintegration and absorption in the gastrointestinal tract and
thereby provide a sustained action over a longer . For example, a time delay
material such as glyceryl monostearate or glyceryl distearate can be employed.
ations for oral use can be presented as hard gelatin capsules wherein the
3O active ingredient is mixed with an inert solid diluent, for example, calcium carbonate,
calcium phosphate or , or as soft gelatin capsules wherein the active ingredient
is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive
oil.
Certain able compositions are s isotonic solutions or suspensions, and
suppositories are advantageously prepared from fatty emulsions or suspensions.
Said compositions may be sterilized and/or contain adiuvants, such as preserving,
stabilizing, g or fying agents, solution promoters, salts for regulating the
osmotic re and/or buffers. in addition, they may also contain other
therapeutically valuable substances. Said compositions are prepared according to
conventional mixing, granulating or coating methods, respectively, and contain about
01—75%, or contain about 1-50%, of the active ingredient.
Suitable compositions for transdermal application include an effective amount of a
compound of the invention with a suitabie r. Carriers suitable for transdermai
delivery include absorbable pharmacologically acceptable solvents to assist passage
through the skin of the host. For example, transdermal devices are in the form of a
bandage comprising a backing member, a reservoir containing the compound
optionally with carriers, ally a rate controlling barrier to deiiver the compound of
the skin of the host at a controlled and ermined rate over a prolonged period of
time, and means to secure the device to the skin.
Suitable compositions for topical application, e.g., to the skin and eyes, e
aqueous solutions, suspensions, ointments, creams, gels or sprayabie formulations,
e.g., for delivery by l or the like. Such topical delivery systems will in particuiar
be appropriate for dermal application, e.g., for the treatment of skin cancer,
e.g., for
2O prophylactic use in sun creams, lotions, sprays and the like. They are thus
particularly suited for use in topical, including ic, formulations well—known in
the art. Such may contain soiubiiizers, izers, tonicity enhancing agents, buffers
and preservatives.
As used herein a topical application may also n to an inhalation or to an
intranasal application. They may be conveniently delivered in the form of a dry
powder (either atone, as a mixture, for example a dry blend with lactose, or a mixed
component particle, for example with phosphoiipids) from a dry powder r or an
aerosol spray presentation from a pressurised container, pump, spray, atomizer or
nebuliser, with or without the use of a suitable propellant.
Where the inhalable form of the active ingredient is an aerosol ition, the
tion device may be an aerosol vial provided with a valve adapted to deliver a
metered dose, such as 10 to 100 at, e.g. 25 to 50 pl, of the composition, Le. a device
known as a metered dose inhaler. Suitable such l vials and procedures for
containing within them l compositions under pressure are well known to those
skilled in the art of inhalation therapy. For example, an aerosol composition
may be
administered from a coated can, for example as described in EP-A—0642992. Where
the inhalable form of the active ingredient is a nebulizabie aqueous, c or
aqueous/organic dispersion, the inhalation device may be a known nebulizer, for
example a conventional tic nebulizer such as an airjet nebulizer, or an
ultrasonic nebulizer, which may contain, for example, from 1 to 50 ml, commonly 1 to
ml, of the dispersion; or a hand—held nebulizer, sometimes referred to as a soft
mist or soft spray inhaler, for example an electronically controlled device such as an
AERX (Aradigm, US) or Aerodose (Aerogen), or a mechanical device such as a
AT (Boehringer ingelheim) nebulizer which allows much smaller nebulized
volumes, e.g. 10 to 100 pl, than conventional nebulizers. Where the inhalable form of
the active ingredient is the finely d particulate form, the inhalation device
be, for example, a dry powder inhalation device adapted to deliver dry powder from a
capsule or blister containing a dry powder comprising a dosage unit of (A) and/or (B)
or a multidose dry powder inhalation (MDPl) device adapted to deliver, for example,
3—25 mg of dry powder comprising a dosage unit of (A) andlor (B) per actuation. The
dry powder composition ably contains a diluent or r, such as lactose, and
a compound that helps to protect against product performance deterioration due to
moisture e.g. ium stearate. Suitable such dry powder inhalation devices
include s sed in US 3991761 (including the AEROLIZERTM device), WO
042, WO 97/20589 ding the CERTIHALERTM device), WO 97/30743
(including the ALERTM device) and WO 05/37353 (including the
LERTM device).
The invention also includes (A) an agent of the invention in free form, or a
pharmaceutically acceptable sait or soivate thereof, in ble form; (B) an
inhalable medicament comprising such a compound in inhatable form together with a
pharmaceutically acceptable carrier in inhalable form; (C) a pharmaceutical product
comprising such a compound in inhalable form in association with an inhalation
device; and (D) an inhalation device containing such a compound in inhalable form.
Dosages of agents of the invention ed in practising the present invention wilt
of course vary depending, for example, on the particular condition to be treated, the
effect desired and the mode of administration. tn general, suitable daily dosages for
administration by inhalation are of the order of 0.0001 to 30 mg/kg, typically 0.01 to
10 mg per patient, while for oral administration suitable daily doses are of the order of
0.01 to 100 mg/kg.
PCT/1B2012/054501
The present invention further provides anhydrous ceutical compositions and
dosage forms comprising the compounds of the present invention as active
ingredients, since water may tate the degradation of certain compounds.
Anhydrous pharmaceutical compositions and dosage forms of the invention can be
prepared using anhydrous or low moisture ning ingredients and low moisture or
low humidity conditions. An anhydrous pharmaceutical ition may be
prepared and stored such that its anhydrous nature is maintained. Accordingly,
anhydrous compositions are packaged using materials known to prevent exposure to
‘IO water such that they can be included in suitable formulary kits. Examples of suitable
packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose
containers (e. g., vials), blister packs, and strip packs.
The invention further provides pharmaceutical compositions and dosage forms that
comprise one or more agents that reduce the rate by which the compound of the
t invention as an active ingredient will ose. Such agents, which are
referred to herein as "stabilizers,” include, but are not limited to, antioxidants such as
ascorbic acid, pH buffers, or salt buffers, etc.
The compound of the present invention may be administered either simultaneously
with, or before or after, one or more other therapeutic agent. The compound of the
present ion may be administered separately, by the same or different route of
administration, or together in the same ceutical composition as the other
agents.
Another aspect of this invention relates to the fact that the compounds of formula (I),
(II) or (III) and their pharmaceutically acceptable salts have beneficial
pharmacological activity and, therefore, are useful as pharmaceuticals.
ore, according to a further aspect of the invention a compound of formula (I),
(ll) or (III) is before described as a medicament. The use of compounds of
formula (I), (II) or (III) in inhibiting PDGF receptor mediated biological ty is novel
per se. Therefore, a nd of formula (l), (II) or (III) or pharmaceuticall
able salt thereof is an inhibitor of PDGF receptor mediated ical activity.
We particularly provide a compound of formula (I), (II) or (III) or a pharmaceuticallly
acceptable salt thereof for the treatment of a respiratory disorder.
According to a further aspect of the invention the use of a compound of formula (I) is
hereinbefore described in the manufacture of a medicament. More ularly, the
use is hereinbefore described in the manufacture of a medicament for inhibiting
PDGF receptor mediated biological activity. Another aspect of the invention is the
use of a compound of formula (I) in the cture of a medicament for the
treatment of a respiratory disorder.
Another aspect provided herein are pharmaceutical itions that include a
therapeutically effective amount of a compound of Formula (I), (II), or (III), or a
pharmaceutical salt thereof and a pharmaceutically acceptable r. in certain
embodiments of such pharmaceutical compositions, the pharmaceutical ition
is formulated for intravenous administration, intravitrial administration, intramuscular
administration, oral administration, rectal administration, transdermal administration,
ary administration, inhalation administration, nasal administration, topical
administration, ophthalmic administration or otic administration. In other
embodiments, the pharmaceutical compositions are in the form of a tablet, a pill, a
capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a solution, an
emulsion, an ointment, eye drop or ear drop. In other embodiments, such
pharmaceutical compositions further include one or more additional therapeutic
agents.
Use and Method of ng
Another aspect provided herein is the use of the compound of Formula (I), (II) or (III)
or a ceutically acceptable salt thereof for the treatment of a disorder or
disease in a subject by inhibiting c—kit and/or PDGFR kinase activity, and such suc
use e a therapeutically effective amount of the compound of a (I), (II) or
(III).
r aspect provided herein is the use of the compound of Formula (I), (II) or (Ill)
3O or a pharmaceutically able salt thereof for the treatment of a disorder or
disease in a subject by inhibiting c-kit and/or PDGFR kinase activity, and such suc
use include a therapeutically effective amount of the compound of Formula (I), (II) or
(III), wherein the disease or disorder is a mast-cell associated disease, a respiratory
disease, an inflammatory disorder, irritable bowel syndrome (IBS), inflammatory
bowel disease (I BD), an autoimmune er, a metabolic disease, a fibrosis
disease, a dermatological disease, cariac hypertrophy, cancers of the lung or other
tissues in which a PDGFR isoform is mutated, pressed or activiated,
012/054501
pulmonary arterial ension (PAH) or primary pulmonary hypertension (PPH). In
other embodiments of this aspect, the disease is asthma, allergic rhinitis, pulmonary
al hypertension (PAH), pulmonary fibrosis, hepatic fibrosis, cardiac fibrosis,
derma, irritable bowel syndrome (IBS), inflammatory bowel disease (lBD),
ia, dermatosis, type I diabetes or type II diabetes.
r aspect provided herein are uses for treating a disease mediated by a kinase
in a patient in need therof, and such uses include a therapeutically effective amount
of a compound of Formula (l), (II) or (III), the kinase is selected from c-kit, c,
’10 PDGFRB, p38, BCR—abl and c-FMS and the disease is a mast-cell associated
disease, a respiratory disease, an inflammatory disorder, irritable bowel syndrome
(IBS), inflammatory bowel disease (lBD), an autoimmune disorder, a metabolic
disease, a fibrosis disease, a dermatological disease, pulmonary arterial
hypertension (PAH) or primary pulmonary hypertension (PPH).
In certain embodiments of this aspect, the disease is asthma, allergic rhinitis,
pulmonary arterial hypertension (PAH), pulmonary fibrosis, c fibrosis, cardiac
fibrosis, cardiac hypertrophy, scleroderma, irritable bowel syndrome (IBS).
inflammatory bowel disease (lBD), uticaria, dermatosis, type I diabetes or type II
diabetes.
Another aspect ed herein is the use ofa compound of a (I), (II) or (III), in
the manufacture of a medicament for treating a disease or disorder in a t where
modulation of a c—kit and/or PDGFR kinase is implicated.
Another aspect provided herein includes methods for treating a disease or disorder
where modulation of c—kit and/or PDGFR kinase is implicated, wherein the method
includes administering to a system or subject in need of such treatment an effective
amount of a compound of Formula (I), (II) or (III), or pharmaceutically acceptable
salts or pharmaceutical compositions thereof, y treating the disease or
er. In such s, the compound of Formula (I), (II) or (III), is an inhibitor of
c-kit and/or PDGFR kinases. In certain embodiments of such s, the methods
e administering the compound to a cell or tissue system or to a human or
animal subject. In certain embodiments of such methods, the disease or condition is
a metabolic disease, a fibrotic e, cardiac hypertrophy, a respiratory disease, an
inflammatory disease or disorder, a dermatological disease or an autoimmune
disease. In certain embodiments of such s, the disease or condition is
asthma, allergic rhinitis, irritable bowel syndrome (188), inflammatory bowel disease
(lBD), pulmonary arterial hypertension (PAH), pulmonary fibrosis, liver fibrosis,
cardiac fibrosis, scleroderma, urticaria, dermatoses, atopic itis, type I diabetes
or type II diabetes.
In another embodiment the disease is selected from a a respiratory disease, an
inflammatory er, irritable bowel syndrome (188), matory bowel disease
(IBD), aa fibrosis disease, pulmonary arterial ension (PAH) and y
pulmonary hypertension (PPH). in other embodiments the es is asthma,
pulmonary arterial hypertension (PAH), pulmonary fibrosis, hepatic fibrosis, cardiac
fibrosis, or cardiac hypertrophy.
Pharmaceutical Composition and Combinations
The pharmaceutical composition or combination of the present invention can be in
unit dosage of about 1 -1000 mg of active ingredient(s) for a subject of about 50-70
kg, or about 1—500 mg or about 1-250 mg or about 1-150 mg or about 0.5-100 mg, or
about 1-50 mg of active ingredients. The therapeutically effective dosage of a
compound, the pharmaceutical composition, or the combinations thereof. is
dependent on the species of the t, the body weight, age and individual
condition, the er or disease or the severity thereof being treated. A physician,
clinician or veterinarian of ordinary skill can readily determine the effective amount of
each of the active ingredients necessary to prevent, treat or inhibit the progress of
the er or disease.
The above-cited dosage properties are demonstrable in vitro and in vivo tests using
advantageously mammals, 9.9., mice, rats, dogs, monkeys or isolated organs,
tissues and ations thereof. The compounds of the present invention can be
applied in vitro in the form of solutions, e.g., aqueous ons, and in vivo either
3O enterally, parenterally, advantageously intravenously, e.g., as a suspension or in
aqueous solution. The dosage in vitro may range between about 10‘3 molar and 10'9
molar concentrations. A therapeutically ive amount in vivo may
range
depending on the route of administration, between about 01—500 mg/kg, or between
about 1-100 mg/kg.
The activity of a compound ing to the present invention can be assessed by
the following in vitro & in vivo methods.
Pharmaceutical Use and Assay
Compounds of a (l), (ll) or (III) provided herein were assayed to measure their
capacity to t PDGFR kinases using the appropriate assay described below:
PDGFR inhibition was evaluated using the Rat A10 cell proliferation.
Rat A10 cell proliferation assay
Rat A10 cells (ATCC) were resuspended in DMEM mented with 1% FBS and
ng/mL recombinant rat PDGF-BB at 20,000 cells/mL. The cells were ted
into 384 well plates at 50 pL/well and incubated for 4 hours at 37°C. 0.5 uL of test
compound 3-fold serially diluted in DMSO was added to each well. The plates were
returned to the incubator for a further 68 hours. 25 pL of CellTiter—Glo (Promega)
was added to each well and the plates were incubated on the bench for 15 minutes.
Luminescence was then read using a CLIPR CCD camera (Molecular Devices).
Data were analysed using non—linear regression fitted to sigmoidal ble slope)
curves using a four parameter logistic equation to generate |C50 values for each
compound.
Compounds of the examples, herein below, generally have PDGFR Kb values in the
Rat A10 cell based assay below 10pM. Table A provides a list of representative
compounds with their |C50 values.
Table A.
PDGFR RAT(A10) leo luM
0.009
0.040
—'*0.010
40.004
0.011
PDGFR inhibtors, including the compounds of formula (l), (ll) or (ill) are also useful
as co-therapeutic agents for use in ation with second agents, such as organic
nitrates and NO-donors, such as sodium nitroprusside, nitroglycerin, isosorbide
mononitrate, isosorbide dinitrate, molsidomine or SlN—i, and lnhalational NO;
compounds that inhibit the ation of cyclic guanosine monophosphate (cGMP)
and/or cyclic adenosine monophosphate , such as inhibitors of
phosphodiesterases (PDE) 1, 2, 3, 4 and/or 5, especially PDE 5 inhibitors such as
sildenafil, vardenafil and tadalafil; NO—independent, but haem-dependent stimulators
of guanylate cyclas'e, such as in particular the compounds described in WO
00/06568, WO 00/06569, WO 02/42301 and WO 03/095451; NO- and haem-
independent activators of guanylate cyclase, such as in particular the nds
described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO
02/070462 and WO 02/070510; compounds which inhibit human philic
se, such as sivelestat or DX-890 (Reltran); compounds inhibiting the signal
uction cascade, such as tyrosine kinase and/or serine/threonine kinase
inhibitors, in particular imatinib, ib, erlotinib, sorafenib and sunitinib;
compounds influencing the energy metabolism of the heart, for example and
preferably etomoxir, dichloroacetate, ranolazine or trimetazidine; antithrombotic
agents, for example and preferably from the group comprising platelet aggregation
inhibitors, anticoagulants or profibrinolytic substances; active nces for lowering
blood pressure, for example and ably from the group comprising calcium
antagonists, angiotensin ll nists, ACE inhibitors, endothelin nists, renin
inhibitors, aldosterone synthase inhibitors, alpha receptor blockers, beta receptor
blockers, locorticoid or antagonists, Rho-kinase inhibitors and diuretics;
and/or active nces that modify lipid metabolism, for example and preferably
from the group comprising thyroid receptor ts, inhibitors of cholesterol
synthesis, for example and preferably HMG-CoA—reductase inhibitors or inhibitors of
ne synthesis, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR—alpha,
PPAR-gamma and/or PPAR—delta agonists, cholesterol absorption inhibitors, lipase
inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors and
lipoprotein(a) antagonists, particulariy in the treatment of PAH or diseases and
ers such as those mentioned hereinbefore, e.g., as potentiators of therapeutic
activity of such drugs or as a means of reducing required dosaging or potential side
effects of such drugs.
In particular, an embodiment of this invention is a pharmaceutical combination
comprising the compounds of formula (i), (ll) or (Ill) and a second agent wherein the
second agent is a PDEV inhibitor or neutral endopeptidase inhibitor.
The compounds of formula (I), (ll) or (III) may be mixed with a second agent in a
fixed pharmaceutical composition or it may be administered tely, ,
simultaneously with or after the other drug substance.
Other useful combinations of PDGFR inhibitorwith anti—inflammatory drugs are those
with antagonists of ine receptors, e.g., OCR-1, OCR-2, OCR-3, CCR-4, COR—
, COR-6, OCR-7, OCR-8, COR-9 and CCR10, CXCR1, CXCRZ, CXCR3, CXCR4,
CXCRS, particularly OCR-5 antagonists, such as Schering-Plough antagonists SC—
351125, SCH-55700 and SCH-D; Takeda antagonists, such as N-[[4-[[[6,7-dihydro
hyl-phenyl)-5H—benzo-cycloheptenyl]carbonyl]amino]phenyi}-
methyl]tetrahydro—N,N-dimethyl—2H—pyran-4—amin—ium chloride (TAK—770); and COR—
antagonists described in USP 6,166,037 (particularly claims 18 and 19), WO
00/66558 (particularly claim 8), WO 00/66559 (particularly claim 9), W0 04/018425
and W0 04/026873.
Suitable anti-inflammatory drugs include steroids, in ular, glucocorticosteroids,
such as budesonide, beclamethasone dipropionate, fluticasone propionate,
onide or mometasone e, or steroids described in W0 02/88167, W0
02/12266, WO 02/100879, WO 02/00679 (especially those of Examples 3, 11, 14,
17, 19, 26, 34, 37, 39, 51, 60, 67, 72, 73, 90, 99 and 101), WO 03/35668, WO
81, W0 03/62259, W0 03/64445, W0 03/72592, WO 27 and WO
04/66920; non—steroidal glucocorticoid or agonists, such as those described in
DE 10261874, WO 00/00531, WO 02/10143, W0 03/82280, WO 03/82787, WO
03/86294, WO 03/104195, W0 03/101932, WO 04/05229, W0 04/18429, WO
1O 04/19935 and WO 04/26248; LTD4 antagonists, such as montelukast and zafirlukast;
PDE4 inhibitors, such as cilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk
Gulden),V—11294A (Napp), BAY19—8004 (Bayer), SCH—351591 (Schering-Plough),
Arofylline (Almirall Prodesfarma), PD189659/PD168787 (Parke-Davis), AWD—12—281
(Asta ), CDC-801 (Celgene), SelClD(TM) CC—10004 (Celgene),
VM554/UM565 (Vernalis), T—440 e), KW-4490 (Kyowa Hakko Kogyo), and
those disclosed in WO 92/19594, WO 93/19749, WO 93/19750, WO 93/19751, WO
98/18796, WO 99/16766, WO 01/13953, WO 03/104204, W0 03/104205, WO
03/39544, W0 04/000814, W0 04/000839, W0 04/005258, W0 450, W0
04/018451, W0 04/018457, W0 04/018465, W0 04/018431, W0 04/018449, W0
2O 04/018450, W0 04/018451, WO 04/018457, W0 04/018465, WO 04/019944, W0
04/019945, W0 04/045607 and W0 04/037805; adenosine A28 receptor antagonists
such as those described in W0 02/42298; and beta—2 ceptor agonists, such
as albuterol tamol), metaproterenol, terbutaline, salmeterol fenoterol,
procaterol, and especially, formoterol, carmoterol and pharmaceutically able
salts f, and compounds (in free or salt or solvate form) of formula (I) of
WO 4, which document is incorporated herein by nce, preferably
indacaterol and pharmaceutically acceptable salts thereof, as well as compounds (in
free or salt or solvate form) of formula (I) of WO 04116601, and also compounds of
EP 6, JP 05025045, WO 93/18007, WO 99/64035, USP 2002/0055651, WO
01/42193, W0 01/83462, WO 02/66422, W0 02/70490, W0 02/76933, WO
03/24439, W0 60, WO 64, WO 03/72539, WO 03/91204, WO
03/99764, WO 04/16578, WO 04/22547, WO 04/32921, WO 04/33412, WO
04/37768, WO 04/37773, W0 04/37807, WO 04/39762, WO 04/39766, WO
04/45618, W0 04/46083, WO 04/80964, W0 04/108765 and W0 04/108676.
Suitable bronchodilatory drugs include anticholinergic or antimuscarinic agents, in
particular, ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226
(Chiesi), and glycopyrrolate, but also those described in EP 424021, USP 3,714,357,
USP 5,171,744, WO 01/04118, WO 02/00652, WO 02/51841, WO 02/53564, WO
40, WO 03/33495, WO 03/53966, WO 03/87094, WO 04/018422 and WO
04/05285.
Suitable dual anti-inflammatory and bronchodilatory drugs include dual beta—2
adrenoceptor t/muscarinic antagonists such as those disclosed in USP
200410167167, WO 46 and WO 04/74812.
Suitable antihistamine drug nces include cetirizine hydrochloride,
acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine,
diphenhydramine and fexofenadine hloride, activastine, astemizole,
azelastine, ne, epinastine, mizolastine and tefenadine, as well as those
disclosed in JP 7299, WO 03/099807 and WO 04/026841.
Accordingly, the invention includes as a further aspect a combination of PDGFR
inhibitor with agents that inhibit ALK5 and/or ALK4 phosphorylation of Smad2 and
Smad3.
Accordingly, the invention includes as a further aspect a combination of PDGFR
inhibitor with second agents that are Rho—kinase inhibitors. Accordingly, the
invention includes as a r aspect a combination of PDGFR inhibitor with second
agents that are TPH’i antagonists.
Accordingly, the invention includes as a further aspect a combination of PDGFR
inhibitor with second agents that are [P receptor agonist.
Accordingly, the invention includes as a further aspect a combination of PDGFR
tor with second agents that are multi-kinase inhibitors, such as imatinib
mysilate( Gleevec®) or nilotinib. lmatinib functions as a c inhibitor of a number
of tyrosine kinase enzymes. it occupies the TK active site, leading to a decrease in
activity. TK enzymes in the body, include the insulin receptor. lmatinib is specific for
the TK domain in the Abelson proto—oncogene, c—kit and PDGF-R (platelet—derived
growth factor or).
Accordingly, an embodiment of this invention provides a pharmaceutical combination
comprising the compounds of a (I), (ll) or (ill) ,or pharmaceutical salts thereof,
and a second agent wherein the second agent is selected from phosphodiesterase V
(PDEV) tors, such as sildenafil or tadalafil; neutral ptidase inhibitors
such as neutral endopeptidase 1 inhibitors; anti—inflammatory drugs including
nists of chemokine ors; steroids including corticosteroids such as long—
acting corticosteroids; Bz—agonists including ultra—long-acting Bg-agonists;
bronchodilatory drugs including anticholinergic or antimuscarinic , such as
long—acting muscarinic antagonists; dual anti-inflammatory and bronchodilatory drugs
including dual beta-2 adrenoceptor agonist/muscarinic antagonists; antihistamine
drug substances; lP receptor agonists, such as as those disclosed in
W02012/007539; agents that induce pulmonary vascular vasodilation; agents that
are tryptophan hydroylase i (TPHi) tors; multi-kinase inhibitors such as c—Kit
inhibitors; tyrosine kinase inhibitors such as ib (Gleevec®) or nilotinib; MAPK
(e.g. p38) inhibitors; mTOR inhibitors (alone or in combination with P13K inhibitors);
LPA-i tors; endothelin antagonists; diuretics; aldosterone receptor blockers;
and endothelin receptor blockers.
Formulation and Administration
The nds of the invention may be administered by any appropriate route,
e.g.,
orally, e.g., in the form ofa tablet or capsule; parenterally, e.g., intravenously; by
inhalation, e.g., in the treatment of inflammatory or obstructive airways disease;
intranasally, e.g., in the treatment of allergic rhinitis; topically to the skin, e.g., in the
treatment of atopic dermatitis; topically to the eye, e.g., in the treatment of glaucoma;
or rectally, e.g., in the treatment of atory bowel disease.
In a further aspect, the invention also provides a pharmaceutical composition
comprising a compound of a (l), (ll), or (ill) in free form or in the form of a
pharmaceutically able salt, optionally together with a pharmaceutically
acceptable nt, diluent or carrier.
The composition may contain a co—therapeutic agent such as an anti-inflammatory,
broncho-dilatory, antihistamine or anti-tussive drug as hereinbefore described. Such
compositions may be prepared using conventional diluents or excipients and
techniques known in the galenic art. Thus oral dosage forms may include tablets and
capsules. Formulations for topical administration may take the form of creams,
nts, gels or transdermal delivery s, e.g., patches. Compositions for
inhalation may comprise aerosol or other atomisable formulations or dry powder
formulations.
2012/054501
When the composition comprises an aerosol formulation, it preferably contains, e.g.,
a hydro-fluoro—alkane (HFA) propellant, such as HFA134a or HFA227 or a mixture of
these, and may contain one or more co-solvents known in the art such as ethanol (up
to 20% by weight), and/or one or more surfactants such as oleic acid or sorbitan
trioleate, and/or one or more bulking agents, such as lactose. When the composition
ses a dry powder formulation, it preferably contains, e.g., the compound of
formula (I)—(Ill) having a particle diameter up to 10 microns, optionally together with a
diluent or carrier, such as lactose, of the desired particle size distribution and a
compound that helps to protect against product performance deterioration due to
moisture, e.g., magnesium stearate. When the composition comprises a nebulised
formulation, it preferably contains, e.g., the compound of formula (I), (II) or (III) either
dissolved, or suspended, in a vehicle containing water, a co-solvent, such as ethanol
or propylene glycol and a stabiliser, which may be a surfactant.
Thus, the present invention further es:
(a) a compound of a II) in inhalable form, e.g., in an aerosol or other
atomisable composition or in inhalable particulate, e.g., micronised, form;
(b) an inhalable medicament sing a compound of formula (I), (II) or (III) in
inhalable form;
(c) a pharmaceutical product comprising a compound of formula (I), (II) or (III)) in
inhalable form in association with an inhalation device; and
(d) an tion device containing a compound of formula (I), (II) or (III) in inhalable
form.
Dosages of nds of a (I), (II) or (III) employed in practising the present
invention will of course vary ing, e.g., on the particular condition to be treated,
the effect desired and the mode of administration. In general, suitable daily dosages
for stration by inhalation are of the order of 0005-10
mg, while for oral
3O administration suitable daily doses are of the order of 0.05-100 mg.
The present invention includes all pharmaceutically acceptable isotopicalIy-Iabelled
compounds of formula (I), (II) or (III) wherein one or more atoms are replaced by
atoms having the same atomic number, but an atomic mass or mass number
different from the atomic mass or mass number usually found in nature.
2012/054501
Examples of es suitable for inclusion in the compounds of the invention e
isotopes of hydrogen, such as 2H and 3H, , such as 110, 130 and 14C,
ne, such as 360i, fluorine, such as 18F, iodine, such as 123| and 125i, nitrogen,
such as 13M and 15N, oxygen, such as 150, 170 and 180, phosphorus, such as
32F, and sulphur, such as 358.
Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain
therapeutic advantages resulting from greater metabolic stability, for example,
increased in vivo ife or reduced dosage requirements, and hence may be
preferred in some circumstances.
lsotopically~labeled compounds of formula (I), (ll) or (lll) can generally be prepared
by conventional techniques known to those skilled in the art or by processes
analogous to those described in the accompanying Examples and Preparations using
an appropriate icalIy-labeled reagents in place of the non-labeled reagent
usly employed.
Compounds of formula (1), (H) or (III) may be prepared by the general reactions
shown in the examples herein.
Referring to the examples that follow, compounds of the preferred embodiments are
synthesized using the methods bed herein, or other methods, which are known
in the art.
It should be understood that the organic compounds according to the preferred
embodiments may exhibit the phenomenon of tautomerism. As the chemical
structures within this specification can only represent one of the possible tautomeric
forms, it should be understood that the preferred embodiments encompasses any
tautomeric form of the drawn structure.
It is understood that the invention is not limited to the embodiments set forth herein
for illustration, but embraces all such forms thereof as come within the scope of the
above disclosure.
The ion is illustrated by the following Examples.
Examples
General Conditions:
Mass spectra were run on LCMS systems using electrospray ionization. These were
either t 1100 HPLC/Micromass Platform Mass Spectrometer combinations or
Waters Acquity UPLC with SQD Mass Spectrometer. [M+H]+ refers to sotopic
molecular weights.
NMR spectra were run on open access Bruker AVANCE 400 NMR spectrometers
using ICON—NM R. a were measured at 298K and were referenced using the
t peak.
The following es are intended to illustrate the invention and are not to be
construed as being limitations thereon. Temperatures are given in degrees
centigrade. If not mentioned otherwise, all ations are performed under
reduced pressure, preferably between about 15 mm Hg and 100 mm Hg (= 20-133
mbar). The structure of final products, intermediates and starting materials is
confirmed by standard analytical methods, e.g., microanalysis and spectroscopic
characteristics, e.g., MS, IR, NMR. Abbreviations used are those conventional in the
art. if not defined, the terms have their generally accepted meanings.
Abbreviations:
aq. aqueous
br broad
d doublet
DCM dichloromethane
DMF methylformamide
DMAC dimethylacetamide
DMSO dimethylsulfoxide
EtOAc ethyl acetate
hr hour
HOBt hydroxybenzotriazole
HPLC high pressure liquid chromatography
LC-MS liquid chromatography and mass spectrometry
MeOH methanol
MS mass spectrometry
m multiplet
min minutes
ml milliliter(s)
m/z mass to charge ratio
2012/054501
NMR> nuclear magnetic resonance
ppm parts per million
PEAX PE-anion exchange (e.g. e® PE-AX columns from Biotage)
Rt retention time
RT room temperature
8 t
SCX—2 strong cation exchange (e.g. lsolute® SCX~2 columns from Biotage)
t triplet
TEA triethylamine
TBD 2,3,4,6,7,8—hexahydro-1H-pyrimido[1,2-a]pyrimidine
THF tetrahydrofuran
Referring to the examples that follow, compounds of the preferred embodiments
were synthesized using the methods described herein, or other methods. which are
known in the art.
The various starting materials, intermediates, and compounds of the red
ments may be isolated and purified, where appropriate, using tional
ques such as precipitation, filtration, crystallization, evaporation, distillation,
2O and chromatography. Unless ise stated, all starting materials are obtained
from commercial suppliers and used without further purification. Salts
may be
ed from compounds by known salt-forming procedures.
It should be understood that the organic compounds according to the preferred
embodiments may exhibit the phenomenon of tautomerism. As the chemical
structures within this specification can only represent one of the possible tautomeric
forms, it should be understood that the preferred embodiments encompasses any
tautomeric form of the drawn structure.
3O if not indicated otherwise, the analytical HPLC conditions are as follows:
Method 2minLC_v001
Column Waters BEH 018 100x21 mm, 1.7 pm
Column Temp. 50 °C
Eluents A: H20, B: acetonitrile, both containing 0.1% TFA
Flow Rate 0.7 ml/min
nt 0.25 min 5% B; 5% to 95% B in 1.00 min, 0.25 min 95%
Method 2minLC_v002
Column Waters BEH C18 50x2.1 mm, 1.7 pm
Column Temperature 50 °C
Eluents A: H20, B: MeOH, both containing 0.1% TFA
Flow Rate 0.8 ml/min
Gradient 0.20 min 5% B; 5% to 95% B in 1.30 min, 0.25 min 95%
B
Method 2minLC_30_v003
Column Waters BEH C18 50x2.1 mm, 1.7 pm
Column Temperature 50 °C
Eluents A: H20, B: acetonitrile, both containing 0.1% TFA
Flow Rate 0.8 ml/min
Gradient 0.25 min 30% B; 30% to 95% B in 1.00 min, 0.25 min
95% B
Method 10minLC_v003
Column Waters BEH C18 50x2.1 mm, 1.7 pm
Column Temperature 50 °C
Eluents A: H20, B: itrile, both containing 0.1% TFA
Flow Rate 0.8 ml/min
Gradient 0.20 min 5% B; 5% to 95% B in 7.80 min, 1.00 min 95%
Method Lopr_v002
Column Phenomenex Gemini C18 50X4.6 mm, 3.0 mm
Column Temperature 50 °C
Eluents A: H20, B: MeOH, both containing 0.1% TFA
Flow Rate 1.0 ml/min
Gradient 5% to 95% B in 2.0 min, 0.2 min 95% B
Method A
Column: Aoquity HSS T31.8um 2.1x 50mm at 50°C
WO 30802
Eluent A: water + 0.05 % formic acid + 3.75 mM ammonium
acetate
Eluent B: acetonitrile + 0.04 % formic acid
Gradient: 2% to 98 % B in 1.4 min — flow 1.2 ml/min
Method 10 min LC
Column Aglient, Poroshell 120 88- C18 2.7 um 3.0x 50mm
Column Temp. 30 °C
Eluents B: H20, C: acetonitrile, both containing 0.1%
1O Formic acid
Flow Rate min
Gradient 0.50 min 5% C; 5% to 95% C in 6.50 min, 95% to
% C in 3 min
Example compounds of the present invention include:
Preparation of Final Compounds
Example 1.1
N -(2-F|uoro(2-(4-methyl pi perazin-1 -yl)benzylcarbamoyl)phenyl)(1 -methy| -
1H-pyrazoly|)imidazo[1,2-a]pyridinecarboxamide
/ N
HN O
Step 1: 7-Bromo-N-(2—fluoro(2—(4-methylpiperazinyl)benzylcarbamoyl)
phenyl)imidazo[1,2—a]pyridinecarboxamide
Methyl 3-(7-bromoimidazoi1,2-a]pyridinecarboxamido)—4-fluorobenzoate
(Intermediate 08 g, 2.75 mmol), TBD (0.383 g, 2.75 mmol) and (2—(4-
methylpiperaziny|)phenyl)methanamine (0.565 g, 2.75 mmol) in toluene (35 ml)
were heated to 80 °C for 6 hrs. A further portion of TBD (0.06 g, 0.431 mmol) and (2-
(4-methylpiperazin—1-y|)phenyl)methanamine (0.100 g, 0.487 mmol) were added and
the mixture was heated at 80 °C overnight. TBD (0.06 g, 0.431 mmol) was added and
heating continued at 110 °C overnight. e was d in vacuo and the
ing solid was partitioned between s sodium bicarbonate solution and
EtOAc. The organic portion was washed with sodium bicarbonate solution (2 x 50 ml)
1O and concentrated in vacuo. The resulting oil was dissolved in MeOH and purified by
chromatography on silica eluting with 0 — 10% MeOH in DCM. The fractions were
combined and the solvent removed in vacuo. The resulting solid was recrystallised
from EtOAc (50 ml) to afford the title compound;
LC-MS: Rt 0.85 mins; MS m/z 567.4 {M+H}+; Method 2minLC_v003
1H NMR (400MHz, d6-DMSO) 5 10.3 (1H, s), 9.4 (1 H, d), 8.9 (1H, t), 8.6 (1H, s),8.2
(1H, d), 8.1 (1H, s), 7.8 (1H, m), 7.4 (1H, d), 7.35 (1H, d), 7.2 (2H, m), 7.1 (1H, d), 7.0
(1H, t), 4.6 (1H, d), 2.9 (4H, m), 2.4 (3H, t), 2.2 (3H, s).
_St_ep_2: N—(2—Fluoro(2-(4-methylpiperazin-1—yl)benzylcarbamoyl)phenyl)—7-(1-
methyl-1 H—pyrazol-S-yl)imidazo[1,2-a]pyridinecarboxamide
A mixture sing 7—bromo—N-(2-fluoro(2-(4-methylpiperazinyl)benzyl
carbamoyl)phenyl)imidazo[1,2-a]pyridine—3—carboxamide (step 1) (120 mg, 0.212
mmol), 1-methyl(4,4,5,5-tetramethy|—1,3,2-dioxaborolanyI)—1H-pyrazole (44.2
mg, 0.212 mmol), cesium carbonate (69.1 mg, 0.212 mmol) and PdCl2(dpp0.CHzclg
adduct (17.33 mg, 0.021 mmol) in DMF (5 ml) under N2 was heated at 85 °C for 2 hrs.
After cooling to RT, the reaction mixture was partitioned between with EtOAc and
water. A precipiate formed which was removed by filtration and discuarded. The
organic portion was separated and washed with , water, dried ) and
concentrated in vacuo. The crude product was purified by chromatography on silica
eluting with 020% MeOH/DCM and the product fractions were combined and
3O concentrated in vacuo. The product was dissolved in MeOH and passed through a 1g
2,4,6-trimercaptotriazine silica column under gravity. The column was washed with
MeOH and the ed eluents were concentrated in vacuo. The product was
triturated with THF (1% MeOH) foilowed by ether to afford the title compound;
LC-MS: Rt 0.80 mins; MS m/z 567 {M+H}+; Method 2minLC_v003
1H NMR (400MHz, MeOD) 6 9.6 (1H, s), 8.6 (1H, s), 8.4 (1H, m), 7.9 (1H, s), 7.8
(1H, m), 7.6 (1H, s), 7.45-7.3 (5H, m), 7.2 (1H, m), 6.7 (1H, s), 4.75 (2H, s), 4.1 (3H,
s), 3.4 (4H, s broad), 3.2 (4H, s broad), 2.95 (3H, s).
WO 30802
Example 1.2
7-(3-Fluoro(2-hydroxyethylcarbamoyl)phenyl)-N—(2-fluoro(2-(4-
methylpiperazinyl)benzyicarbamoyl)phenyl)imidazo[1,2-a]pyridine
carboxamide
/ /N
HN O
A mixture comprising 7-bromo—N-(2-fluoro(2-(4-methylpiperazin
yl)benzylcarbamoyl) phenyl)imidazo[1,2-aipyridinecarboxamide (Ex 1.1, step 1)
1O (120 mg, 0.212 mmol), 3-fluoro—4—(2—hydroxyethylcarbamoyl) phenylboronic acid
(48.2 mg, 0.212 mmol), cesium carbonate (69.1 mg, 0.212 mmol) and
PdC|2(dppf).CHZCl2 adduct (17.33 mg, 0.021 mmol) in DMF (3 ml) under N2 was
heated at 85 °C for 2 hrs. Further portions of 3—fluoro~4—(2-hyd roxyethylcarbamoyl)
boronic acid (48.2 mg, 0.212 mmol), cesium carbonate (69.1 mg, 0.212 mmol)
and PdCl2(dppf).CH2Cl2 adduct (17.33 mg, 0.021 mmol) were added and heating
continued at 100 °C overnight. The reaction mixture was diluted with EtOAc and
water and the biphasic mixture was filtered. The filtercake was washed with MeOH
and the filtrate was trated under vacuum. Purification of the crude residue by
chromatography on silica eluting with 0—20% NH3 MeOH/DCM afforded a beige solid.
The solid was triturated with THF/ether and dried in vacuo at 45 °C overnight to afford
the title nd;
LC-MS: Rt 0.81 mins; MS m/z 668/669 {M+H}+; Method _v003
av55463 1H NMR (400MHz, CD3OD) 6 9.6 (1H, s), 8.6 (1H, s), 8.4 (1H, d), 8.1 (1H,
s), 8.0 (1H, t), 7.8 (3H, m), 7.6 (1H, d). 7.5-7.2 (4H, m), 7.2 (1H, t), 4.7 (2H, s), 3.75
(2H, t), 3.6 (2H, t), 3.1 (4H, s broad), 3.0 (4H, s broad), 2.6 (3H, s).
Example 1.3(i) and 1.3(ii)
Step1: Example 1.3 (i): 7-Bromo—N-(2—methyl-5—(2-(4—methylpiperazin
yl)benzylcarbamoy|)phenyl)imidazo[1,2-a]pyridine—3—carboxamide
Methyl 3—(7-bromoimidazo[1,2-a]pyridinecarboxamido)methylbenzoate
(Intermediate 1B)(4OO mg, 1.030 mmol) and TBD (143 mg, 1.030mmol) in toluene
(10 ml) was treated with (2-(4-methylpiperazinyl)phenyl)methanamine (212 mg,
1.030 mmol) and heated at 100 °C under nitrogen overnight. Further TBD (106 mg.
0.82 mmol) was added the mixture was heated at 100 °C for a further 24hrs.The
t was removed in vacuo and the residue was partitioned between EtOAc (50
ml) and sodium onate solution (50 ml).The organic portion was separated and
washed with sodium bicarbonate (2 x 25 ml), dried (MgSO4), filtered and evaporated
to s to give a yellow solid. Purification by chromatography on silica eluting with
O — 20 % 2M NH3 in MeOH / DCM ed a colourless oil. The oil was dissolved in
minimum volume of EtOAc and titurated iso—hexane to afford the title nd as a
white solid;
LC—MS: Rt 0.85 mins; MS m/z 561.4 {M+H}+; Method 2minLC_vOO3
1H NMR (400MHz, DMSO-d6)510.1 (s, 1H), 9.4 (d, 1H), 8.9 (t, 1H), 8.5 (s, 1H), 8.1
(s, 1H), 7.9 (s, 1H), 7.7 (d, 1H), 7.4 (d, 1H), 7.3 (d, 1H), 7.2 (m, 2H), 7.1 (d, 1H), 7.0
(m, 1H), 4.6 (d, 2H), 3.1 (t, 4H), 2.4 (s, 3H), 2.3 (s, 3H)
Step 2 Example 1.3 (ii): 7-(1-MethyI-1H-pyrazol—S-yl)—N-(2—methyl—5—(2-(4-
methylpiperaziny|)benzylcarbamoyl) phenyl)imidazo[1,2-a]pyridinecarboxamide
Under nitrogen, a mixture comprising 7-bromo—N—(2—methyl—5—(2—(4—methylpiperazin-
1—yl)benzylcarbamoyl) phenyl)imidazo[1,2-a1pyridinecarboxamide (step 1) (77.8
mg, 0.125 mmol), 1~methyl—5-(4,4,5,5—tetramethyl-1,3,2-dioxaborolanyl)—1 H-
pyrazole (51.9 mg, 0.249 mmol) and cesium carbonate (40.6 mg, 0.125 mmol) in
DMF (1 ml) was treated with PdCl2(dppf).CH2Cl2 adduct (50.9
mg, 0.062 mmol) and
heated at 110 °C for 1 hr. The solvent was removed in vacuo and purification by
chromatography on silica eluting with 0 — 20% 2M NH3 in MeOH / DCM afforded a
black solid. The solid was dissolved in 7M NH3 in MeOH (12 ml) and passed through
a 1 g Pd scavenger dge. The solvent was removed in vacuo and the ing
solid was dried to yield the title compound;
LC-MS: Rt 0.98 mins; MS m/z 563.5 {M+H}+; Method 2minLC__v003
av55760 1H NMR z, MeOD) 6 9.5 (1H, d), 8.55 (1 H, s), 8.0 (1H, s), 7.8 (1H,
s), 7.7 (1H, dd), 7.55 (1 H, s), 7.4 (2H, m), 7.2 (3H, m), 7.1 (1H, t), 6.6 (1H, d), 4.7
(2H, t), 4.0 (3H, s), 3.1 (7H, b), 2.7 (4H, s), 2.4 (3H, 8)
Example 1.4
N -(2-Fluoro (2-(4-me1:hylpiperazin-1 -yl)benzylcarbamoyl)phenyl)—7-(pyridine
yl)imidazo[1,2-a]pyridinecarboxamide
W0 2013/030802 PCT/IBZOIZ/054501
\ / /N
\ N /
HN O
Under nitrogen, 7-bromo-N-(2-fluoro(2-(4—methylpiperazin—1-yl)benzylcarbamoyl)
phenyl)imidazo[1,2-a]pyridine-3—carboxamide (Ex 1.1, step 1) (120 mg, 0.212 mmol),
pyridineylboronic acid (33.8 mg, 0.212 mmol), triethylamine (0.030 ml, 0.212
mmol), cesium carbonate (69.1 mg, 0.212 mmol) and PdCl2(dppf).CHQC|2 adduct
(17.33 mg, 0.021 mmol) in DMF (3 mi) were heated at 85 °C overnight. A r
portion of cesium carbonate (24.34 mg, 0.075 mmol) and PdCl2(dppf).CH2Cl2 adduct
(6.10 mg, 7.47 pmol) were added along with 3-(1,3,2-dioxaborinanyl)pyridine (34.6
mg, 0.212 mmol) and heated continued at 85 °C for 26 hrs. A further n of
1O cesium carbonate (24.34 mg, 0.075 mmol) and PdCl2(dppf).CH2Cl2 adduct (6.10
7.47 pmol) and 3—(1,3,2—dioxaborinan-2—yl)pyridine (34.6
mg, 0.212 mmol) were
added. The reaction was heated at 100 °C for 2hrs. The reaction mixture was diluted
with EtOAc and water and the resulting product which iated out was collected
by filtration. Further product was contained in the organic phase, which was washed
with set. NaHCOs, brine, dried (MgSO4) and concentrated in vacuo. The crude
residue was combined with the precipitated product and purified by chromatography
on silica eluting with 0-20% CM. The ing solid was purified by
ative LC-MS eluting with 0.1% diethylamine 30-70% acetonitrile/water. The
product fractions were partitioned between EtOAc and NaHCOS. The organic portion
was separated, dried (MgSO4) and concentrated in vacuo to afford the title
compound;
LC-MS: Rt 1.79/1.81 mins; MS m/z 564/565 {M+H}+; Method 10minLC_v003
1H NMR (400MHz, CD30D) 5 9.7 (1H, d), 9.1 (1 H, d), 8.7 (1H, m), 8.6 (1H, s), 8.4
(1H, m), 8.3 (1H, m), 8.2 (1H, s), 8.1 (1H, s), 7.8 (1H, m), 7.7-7.5 (2H, m), 1
(5H, m), 4.3 (2H, s), 3.1 (4H, m), 2.8 (4H, s broad), 2.5 (3H, t).
Example 1.5
N-(2-Fluoro(2-(4-methylpiperazinyl)benzylcarbamoyl)phenyI)(1-methyl-
1H-pyrazolyl)imidazo[1,2-a]pyridinecarboxamide hydrochloride
83:11; N-(2-Fluoro-5—(2—(4-methylpiperazinyl)benzylcarbamoyl)phenyl)(1-
methyle1 H-pyrazolyl)imidazo[1,2~a]pyridinecarboxamide
A e comprising 7-bromo-N-(2—fluoro—5—(2-(4—methylpiperazin-1—
y|)benzy|carbamoyl) phenyl)imidazo[1,2—a]pyridinecarboxamide (Ex 1.1, step 1)
(100 mg, 0.177 mmol) and cesium carbonate (230 mg, 0.707 mmol) in DME (2.5 ml)
and water (1 ml) under nitrogen was treated with 1-methyl-4—(4,4,5,5-tetramethyl-
1,3,2—dioxaborolan-2—yl)-1H-pyrazole followed by PdCl2(dppf).CH2Ci2 adduct (7.22
mg, 8.84 pmol) and heated using microwave radiation at 100 °C for 1 hr. After
cooling to RT, the on mixture was partitioned between water (4 ml) and EtOAc
(10 ml)/ MeOH (1ml). The organic portion was separated, dried (M9804) and
concentrated in vacuo. Puriifcation by chromatography on silica g with 0—20%
MeOH in DCM ed by trituration of the resulting solid with EtOAc afforded the
title compound;
LC-MS: Rt 0.89 mins; MS m/z 567 {M+H}+; Method 2minLC_v003
mg; N-(2—Fluoro(2—(4—methylpiperazin-1~yl)benzylcarbamoyl)phenyl)—7~(1-
methyl—1H-pyrazol—4-yl)imidazo[1,2-a]pyridinecarboxamide hydrochloride
N-(2—Fluoro—5-(2-(4-methylpiperazin-1—yl)benzyicarbamoyl)phenyl)-7—(1—methyl—1H-
pyrazol-4—yl)imidazo[1,2-a]pyridine-S-carboxamide (step 1) (30 mg, 0.053 mmol) in
MeOH (2 ml) was d with HCl in ether (0.053 ml, 0.053 mmol) and the solution
was evaporated to dryness and dried in vacuo overnight to afford the title compound;
LC-MS: Rt 0.82 mins; MS m/z 56, [M+H]+; Method 2minLC_v003
2012/054501
The compounds of the following tabulated Examples (Table 1) were prepared by a
similar methods to that of Example 1.1—1.5 from the appropriate starting compounds,
the preparations of which are detailed in the ‘Preparation of intermediates’ section.
INMR
505.4 [M+H]+; Method
10m in LC_v003
1H NMR (400 MHz, DMSO)
10.35 (1H, s), 9.50 (1H,
d), 9.17 (1H, t), 8.68 (1H,
s), 8.19 (1H, d), 8.00 (1H,
s), 7.75 (1H, m), 7.58 (1H,
s), 7.42-7.50 (3H, m), 7.18
(1H. m), 4.48 (2H, d), 4.01 l
(3H, s). l
5N—(5-(3,4-difluoro benzyicarbamoyl)—2- l
fluorophenyl)—7—(1—methyl—1H—pyrazol—S—yl)
1.6 ' imidazo [1 ,2-a]pyridine—3—carboxamide l
Rt 0.93 mins; MS m/z
489/470/471 {M+H}+;
Method 2minLC_v003
1H NMR (400MHz, DMSO-
d6) 510.3 (1H, s), 10.0 (1H,
s), 9.1 (1H. t), 8.6 (1H. s),
8.2 (1H, m). 7.9 (1H, d), 7.8
(3H. m), 7.5 (1H, t), 7.35
(4H, m), 7.3 (1H, m), 5.7
(1H, s). 4.5 (2H, d), 3.9 (3H,
N—(5—(benzylcarbamoyl)—2-f|uorophenyl)—6—(1 —
methyl-1 zoI—3-yl)imidazo[1,2—a]pyrldine—3—
“|.7 Ecarboxamide
Rt =0.78 mins; MS mlz
578.5 [M+H]+; Method
2minLC_v003 ;
1H NMR (400 MHz, DMSO)
9.60 (1H, s), 8.93 (1H, s),
8.62 (1H, d), 8.49 (1H. s),
8.18 (1H, d), 7.98 (1H, s),
7.87 (1 H, d), 7.57 (3H. m),
7.42 (1H, d). 7.38 (1H, d),
7.30 (1H, dd), 7.22 (1H, d),
N-(4—fluoro—2-me’thyl(2‘("r‘meth3"l piperazin-l- 7.13 (2H, m), 4.73 (2H, d),
yl) benzylcarbamoyl)phenyl)-7*(Dyridin9'3' 3.05 (4H. m), 2.90-2.75
yl)imidazo[1,2—a]pyridine—3—carboxamide (4H, m). 2.48 (3H, s), 2.39
(3H, s).
F 0.92 mins; MS m/z
n |:\ 2 603.6 {M+H}+; Method
_vOO3 ,
/ 1H NMR(400MH2, MeOD)
\ 6 9.6 (1H, s), 8.6 (1H, d),
8.5 (1 H, s), 8.4 (1H, dd),
F 8.2 (1 H, dd), 8.0 (1H, s),
F 7.8 (1H, m), 7.5 (1H, d), 7.4
N—(5-(3,4-dif!uorobenzyloarbamoyl)—2- (1H, d), 4.3 (3H, rn), 7.0
fluorophenyl)—7—(6~(3—(dimethyl amino) propoxy) (1H, d), 4.6 (2H, s), 4.5 (2H,
pyridine—3—yl)imid azo[1,2~a]pyridine—3— d), 2.6 (2H, t), 2.3 (6H, s),
1.9 carboxamide
2.0 (2H, m)
Rt 1.91mins; MS m/z
518.40 [M+H]+; Method
10min LC_v003
1H NMR z, DMSO—
d6) 6 10.7 (1H, s), 10.0 (1/2H,3
m), 9.5 (1H, d), 9 (1H, t), 8.8
(1H, s), 8.2 (1H, m) 8.1 (1H,
s), 7.6 (1H, s), 7.5 (2H, d), 6.6
(1H, s) 4 (3H, s), 3.6 (2H, m),
3.4 (2H, m), 3.3 (2H, m), 3.1
N-(5—(2-(2,S-cis-dimethylpiperidin (1H, m), 1.9 (1H, m), 1.6 (2H,
yl)ethylcarbamoyl)—2—fluorophenyI)—7-(1methyl- m), 1.5 (2H, m), 1.4 (4H, d),
1H—pyrazoI—5—y|)imidazo[1,2—a]pyridine~3- 1.3(2H,d)
31.10 carboxamide
Rt 0.88 mins; MS m/z 592
; Method
2minLC_v003
1H NMR (400MHz, DMSO—
d6) 510.3 (broad 1H, s), 9.52
(1H, d), 9.0 (1H, t), 8.7 (1H,
s), 8.25 (1H, d), 8.1 (1H, s),
7.9 (2H, d), 7.6 (1H, d), 7.5-:
7.4 (3H, m), 7.25—72 (2H,
m), 7.15 (1H, d), 7.1 (1H, t),
4.6 (2H, d), 3.8 (2H, s), 2.9
(4H, s), 2.5 (4H, s), 2.25
U\ (3H, s), 2.1 (2H, s broad).
:7-(4-(aminomethyl) phenyl)—N—(2-fluoro-5—(2—(4-
methylpiperaziny|)benzylcarbamoyl)
1.11 phe:yl)imidazo[1,2—-a]pyridine—3—carboxamide
Rt= 0.83 mins; MS m/z
578.5, [M+H]+; Method
_v003
1H NMR (400 MHz, DMSO)
10.25 (1H, s), 9.35 (1H,
d), 8.60—8.43 (2H, m), 8.15
(2H, s), 7.97 (1H, s), 7.77
2 N—(5-(2-tert—butoxy ethylcarbamoyI)-2— (1H, m), 7.60-7.35 (3H, m),
fluorophenyI)(1-(2—morphoIInoethyI)—1 H— 4.28 (2H, m), 3.55 (4H, m),
pyrazoly1)imidazo[1,2-a]pyridine—3- 3.40 (2H, m), 2.50—2.80
:1.12 carboxamide (8H, m), 1.004 .21 (9H, m).
Rt = 0.96 mins; MS m/z
590.5, [M+H]+; Method
(FEES?!F H I "1‘ 2minLC_v003
1H NMR (400 MHz, DMSO)
\ \ [E 1
o 5 10.20 (1H, s), 9.38 (1H,
d), 8.81 (2H, m), 8.45 (2H,
s), 8.18 (2H, m), 7.98 (1H,
O s), 7.79 (1H, m), 7.48-7.37
(2H, m), 4.28 (2H, t), 4.07
(5,5-dimethyltetrahydrofuran—2-yl)methyl
EcarbamoyI)—2—fluorophenyIH—(l -(2- (1H, m), 3.57 (4H, m), 2.78
(2H, t), 2.52 (2H, m), 2.45
morpholinoethyl)—1H—pyrazol-4—yl)imidazo [1 ,2-
Ea]pyridine-3~carboxamide (4H, m), 2.02 (1H, m), 1.70
(3H, m), 1.21 (3H, s), 1.17
(3H, s).
Rt =1.03 mins; MS mlz
Fm /\ 594.4, [M+H]+; Method
N\/N 2minLC_v003
o \/ 1H NMR (400 MHz, DMSO)
10.30(1H, s), 9.50 (1H,
d), 8.99 (1H, t), 8.78 (1H,
s), 8.65 (1H. s), 8.30 (1H,
m d), 8.23 (1H, d), 8.17 (1H,
N\ s), 7.85 (1H, m), 7.83 (1H,
N—(2—fluoro—5—(2~(4—methylpiperazin-1 - d), 7.52—7.36 (3H, m), 7.27
Eyl)benzlearbamoyl)phenyl)—7-(6-methoxy (1H, m), 7.05 (2H, m), 4.58
pyridineyl)imidazo [1,2-a]pyridine—3- (2H, d), 3.32 (3H, s), 2.87
Ecarboxamide (4H, m), 2.52 (4H, m), 2.23
(3H, s).
Rt 0.89 mins; MS m/z
567/568/569 {M+H}+;
Method 2minLC__vOO3
1H NMR (400MHz, DMSO-
d6) 5 10.0 (1H, s). 9.9 (1H,
m), 9.1 (1H, s), 9.0 (1H, t),
8.9 (1H, s), 8.3 (2H, m), 7.8 1
(1H. m), 7.7 (1H, d), 7.55
/ (1H, s), 7.4 (1H, t), 7.3 (2H,
N-(2—fluoro—5-(2-(4-methylpiperazin m), 7.2 (2H, m), 6.6 (1H, s),
y1)benzylcarbamoyl)pheny1)—6—(1 ~methy1-1 H- 4.6 (2H, d), 4.0 (3H, s), 3.6—
pyrazoI-S—yl)pyrazolo[1 ,5—a]pyridine~3— 3.0 (8H, m), 2.9 (3H, d).
1.1 5 carboxamide
Rt 0.70 mins; MS m/z
515{M+H}+; Method
2minLC_v003
\ NE. \ [/7474 N1
I 1H NMR z, DMSO)
/ 0 \ ,4} 510.71 (1H, 8), 10.01 (1H,
t), 9.72 (1H, d), 9.33 (1H,
0’; \3H s), 9.05 (1H, m), 8.90 (1H,
1/ CL s), 8.85 (1H, d), 8.70 (1H,
M8111 m), 8.47 (1H, s), 8.23 (1H,
m), 7.89 (3H, m), 7.51 (1H,
m), 3.55 (2H, m), .33
1-(2-(4—fluoro—3-(7-(pyridine—S-ymmidazo [1’2— (2H. m), 1.83 (1H, m), 1.70
Ia]pyridine—3—carboxamido)benzamido)ethyl)—2,6~ (2H, m), 1.50 (2H, m), 1.40
:1.1 6 cis—dimethylpiperidinium Chloride End 1.30 (6H, 2 X d).
Rt 0.92 mins; MS m/z
577{M+H}+; Method
2mlnl.C_v003
1H NMR(4OOMHz, MeOD)
9.0 (1H, s), 837 (1H, s),
8.5 (1H, d), 8.4 (1H, d), 8.3
(1H, d), 8.1 (1H, dd), 7.85
(1H, d), 7.75 (1H, m), 7.35
(1H, t), 5.95 (1H, d), 4.4
(2H, 1), 3.6 (2H, m), 3.5
(2H, m), 2.6 (2H, t), 2.3
(6H, s), 2.0 (2H, m), 1.25
(9H, s)
2-tert-butoxyethylcarbamoyl)
Efluorophenyl)—6—(6—(3-(dimethylamino)
1'17; propoxy)pyridine—3—yl)pyrazolo[1,5—a]pyridine—3-
3 carboxamide
Rt 0.75 mins; MS m/z
550.5 {M+H}+; Method
2minLC_vOO3
1H NMR z, MeOD),
9.6 (1H, d), 9.0 (1H, d),
8.6 (1H, dd), 8.5 (1H, s),
8.3 (1 H, d), 8.05 (1H. s),
7.95 (1H, d), 7.7 (1H, dd).
7.5 (1 H. s), 7.55 (1H, dd),
7.4 (1 H. d), 7.35 (1H, d).
7.25 (2H, m), 7.1 (1H, t),
4.7 (2H, s), 3.0 (4H, b), 2.8
(4H, b), 2.5 (3H, s), 2.4 (3H,
N-(2—methyl(2—(4—methylpiperazin-1 —
yI)benzylcarbamoyl)pheny|)—7—(pyridine—3-
1.1 8 yl)imidazo[1 ,2—a]pyridine—3~carboxamide
PCT/IBZOIZ/054501
Rt 0.76 mlns; MS mlz 564.5%
{M+H}+; Method
2minLC_vOO3 ,
1H NMR (400MHz, MeOD)
6 9.80 (1H. d), 8.85 (1H, d),
8.59 (1H,
\ s), 8.40 (1H, d),
7.91 (1H. s), 7.59 (1H. d).
N \ SW
l O 7.39 (2H, m), 7.30 (2H, m),
7.16 (1H, t), 8.85 (1H. d).
4.76 (2H, s). 4.04 (3H, s),
3.10 (4H, m), 2.98 (4H, b),
2.88 (3H, s), 2.59 (3H, s)
/OCIH
1—methyl-4—(2-((6-methyl-5—(7-(1-methyl -1H-
pyrazoI-S-yl)imld azo[1,2—a]pyrldlnecarbox
nicotina mido)methyl)phenyl)piperazin
chloride
Example 1.10
N-(5-(2-(2,6-cis-Di methyl piperidin-1 -yl)ethylcarbamoyl)f|uorophenyl)(1 -
methyl-1H-pyrazol-S-yl)imidazo[1,2-a]pyridinecarboxamide
PdCl2(dppf).CHZCl2 adduct (39.5 mg, 0.048 mmol) was added to a mixture
comprising 1-methy|(4,4,5,5-tetramethyl-1,3,2—dioxaborolanyl)—1H-pyrazole
(commercially available) (212 mg, 1.017 mmol), 7-bromo-N-(5—(2—(2,6—cis—
dimethylpiperidinyl)ethylcarbamoyl)—2-fluorophenyl)imidazo[1,2-a]pyridine-3—
carboxamide (lntermediate 4C) (500 mg, 0.968 mmol), Cs2C03 (1262
mg, 3.87
mmol) in 1,2-dimethoxyethane (10 ml) and water (4.29 ml). The mixture was
degassed thoroughly refilling with nitrogen (x3). The mixture was heated using
microwave radiation at 100°C for 1 hour. The water was removed by pipette and the
organic portion was concentrated in vacuo. The residue was dissolved in MeOH and
dry loaded onto . The crude t was purified by chromatography on silica
eluting with 0—20% MeOH in DCM to afford the title compound. (See Table 1 for
characterising data).
The citrate salt of 2-(2,6-cis—dimethylpiperidin—1-yi)ethylcarbamoyl)—2-
1O fluoropheny|)(1-methyl-1 H-pyrazoi—5—yl)imidazo[1,2-a]pyridinecarboxamide was
prepared according to the ing procedure:
$9.1; 3-[(7~Bromo-imidazo[1,2-a]pyridlne—3-carbony|)-amino]-4—fluoro—benzoic acid
methyl ester
To the solution of compound 7-bromoimidazo[1,2-a]pyridinecarboxylic acid
(intermediate A step 3) (1.26 Kg, 5.23 mol) in DMAC (15 L) was added dropwise
SOClz (1.86 kg, 15.6 mol) at 10 °C in 30 min. To the resulting mixture warmed to
°C was added compound methyl 3-amino—4—fluorobenzoate (884
g, 5.23 mol) in
DMAC (3.0 L) over 30 min. After addition, the reaction temperature went
up to 30 °C.
HPLC showed the reaction went to completion within 5 min. To the reaction mixture
was added water (20 L) over 20 min. The mixture was filtered and dried under
vacuum to afford the title compound as a white solid;
1H NMR (400 MHZ, DMSO-de) 8 3.87 (S, 3 H) 7.57 (dd, J=7.28, 2.01 Hz, 1 H)
7.51 (dd, J=10.16, 8.66Hz, 1 H) 7.90 (td, J=4.33, 2.38 Hz, 1 H) 8.29 (m, 2H)
8.90 (s, 1 H)9.43 (d, J=7.53 Hz,1 H) 10.78 (s, 1 H)
Rt 6.90 mins; MS m/z 394.0 ; Method 10 min LC
flag ro-3—{[7-(2-methyl-2H-pyrazol—3-yl)-imidazo[1,2-a]pyridinecarbonyl]~
amino}-benzoic acid
3-[(7-Bromo~imidazo[1,2—a]pyridine—3—carbonyl)—amino]—4-fluoro-benzoic acid methyl
ester (step 1)(1200 g, 3.060 mol), 1-methyl(4,4,5,5-tetramethyI-1,3,2-
dioxaborolan-Z-yl)-1H-pyrazole (commercially available) (764 g, 3.67 mol),
PdC12(dppf)-CH2C3|2 (75.0 g, 91.8 mmol) in dioxane (10 L) and aqueous N82C03 (2 N,
4.6 L) were heated to reflux for 6 hr. The reaction e was cooled to 50 °C and
filtered. The filtrate was heated to reflux, to which was added AcOH (600
g, 10.0 mol)
was added dropwise. During the course of on solids came out of solution to give
pale pink slurry. After addition the mixture was slowly cooled to RT and filtered. To
PCT/132012/054501
the filter cake was added dioxane (20 L) followed by heating to reflux to obtain a
on. The solution was cooled to RTand filtered to provide the title compound as a
white solid;
1H NMR (400 MHz, DMSO-ds) 54.00 (s, 3 H) 6.67 (s, 1 H) 7.46 (t, J=9.41 Hz, 1 H)
7.40 (d, J=7.03 Hz,1 H) 7.54 (s, 1 H)7.85 (d, J=2.26 Hz, 1 H) 7.99 (s, 1 H) 8.28 (d,
J=6.27 Hz, 1 H) 8.67 (s, 1 H) 9.47 (d, J=7.03Hz, 1 H) 10.35 (s, 1 H).
Rt 5.40 mins; MS m/z 380.1 {M+H}+; Method 10 min LC
_S_tep__3_: ethyl—2H-pyrazol-3—yl)—imldazo[1,2-a]pyridine—3-carboxylic acid {5-{2—
1O (2,6-dimethyl—piperidinyl)-ethylcarbamoyl]—2—fluoro~phenyl}-amide
4—F|uoro—3—{[7-(2-methyl-2H—pyrazoiyl)—imidazo[1,2-a]pyridine—3-carbonyl]—amino}—
benzoic acid (step 2) (450 g, 1.19 mol), EDC°HCl (454.8 g, 2.372 mol) and HOBt
(181.6 g, 1.186mol) in DMF (3.2 L) at 25 °C were stirred for 1.5 hr. The reaction was
monitored by HPLC. To the reaction mixture was se added cis 2-(2,6—dimethyl-
piperidinyl)-ethylamine (222.5 g, 1.423 mol) over 10 min and stirring continued for
min. To the on mixture was se an aqueous solution of Na2C03 (5%, 6
L) over 120 min and the ing solid was collected by filtration and washed with
water (5 L). To the solid was added ethanol (5 L) foliowed by heating to 70 °C to
obtain a clear solution. Water (1. 5 L) was se added at 70 °C and stirred for 30
min. The clear solution was slowly cooled to 25 °C over 2hr. The solid was filtered.
washed with ethanol (500 mL) and dried under vacuum at 50°C overnight to afford
the title compound as a white solid ;
1H NMR (400 MHZ, DMSO-d6)51.03 — 1.19 (m, 3 H) 1.10 (d, J=6.02 HZ, 6 H) 1.55
(br. s., 1 H) 1.50(d, J=12.30 Hz, 2 H) 2.42 (br. s., 2 H) 2.71 (br. 5., 2 H) 3.27 (d,
J=5.77 Hz, 2 H) 4.00(s, 3 H) 6.60 (s, 1H) 7.41 (d, J=6.02 Hz, 2 H) 7.54 (s, 1 H)
7.77(s, 1 H) 8.00 (s, 1 H) 8.14 (d, 1 H) 8.54 (s, 1 H) 8.67(s, 1 H) 9.48 (d, 1 H) 10.35
(s, 1 H).
Rt 4.80 mins; MS m/z 518.2 {M+H}+; Method 10 min LC
8395; N-(5—((2-(2,6-cis-Dimethylpiperidiny|)ethyl)carbamoyl)—2—fluorophenyl)—7-
(1-methyl-1H-pyrazolyl)imidazo[1,2-a]pyridineS—carboxamide citric acid (1:1)
7-(2-Methyl-2H-pyrazol—B-yl)-imidazo[1,2-a]pyridinecarboxylic acid {5-[2-(2,6-
dimethyl-piperidin-1—yl)-ethylcarbamoyl]—2—fluoro—phenyl}-amide (step 3)(480 g) was
suspended in ethanol (2300 mL) in a 5000 mL four-necked flask equipped with
thermometer, reflux condenser and a nitrogen inlet. The mixture was heated to 55
°C and the suspension gradually became clear. A solution of citric acid (180 g) in
PCT/IBZOIZ/054501
acetone (2.4 L) was added over 1h and the internal temperature was controlled at
45—50°C. The clear solution was stirred at 50°C for 2h. A crystal seed (1 g) was added
to the reactor and the internal temperature was cooled to 20°C at a speed of 8°C/h.
The mixture was stirred at 20°C for 60 h. The resulting solid was filtered and the filter
cake was washed with e (1 L) and dried in vacuum (under 4 mbar at 55°C) for
24 h to afford the title compound;
1H NMR (400 MHz, DMSO—ds) 8 1.46 (m, 3 H) 1.29 (d, J=6.02 Hz, 6 H) 1.65 (3., 1 H)
1.73(d, 2 H) 2.59 (m, 4 H) 3.18 (m. 4 H) 3.53 (d, 2 H) 4.00(s, 3 H) 6.68 (s, 1H) 7.41
(d, 1 H)7.48 (d, 1 H) 7.54 (s, 1 H)7.80(s, 1 H) 8.00 (s, 1 H)8.20 (d, 1 H)8.68 (s,1
H) 8.90 (s, 1 H) 9.48 (d, 1 H) 10.38 (s, 1 H).
Example 1.20
7-(1-Methyl-1 H-pyrazolyl)-imidazo[1,2-a]pyridinecarboxylic acid {5-[2-(2,6-
cis-dimethyl-piperidinyl)-ethylcarbamoyl ]fluoro-phenyl}-amide
hydrochloride
o-N—(5-(2-(2,6-cis—dlmethylpiperidinyl)ethylcarbamoyl)—2-fluorophenyl)
imidazo[1,2—a]pyridine-B—carboxamide (intermediate 4C) (50 mg, 0.097 mmol), 1-
methyl-1H—pyrazol~4—ylboronic acid (24.38 mg, 0.194 mmol) and cesium carbonate
(126 mg, 0.387 mmol) was dissolved in DME (215 pl)/water (108 pl) to form a
solution. Nitrogen was bubbled though the reaction mixture for 2 minutes.
PdCl2(dppf).CH20l2 adduct (3.95 mg, 4.84 umol) was added and the mixture was
heated using microwave radiation at 100°C for 15 mins. The water was removed and
the organic portion was dry loaded onto .
. The crude product was purified by
chromatography on silica g with O-20°/o 2M NH3 in MeOH and the product
fractions were ed and concentrated in vacuo. The product was dissolved in
MeOH and passed through a 1g trimercaptotriazine silica. The solvent was
2012/054501
removed in vacuo and the residue was triturated with ether. The resulting precipitate
was filtered and dried in the oven to afford the title compound;
LC—MS: Rt 0.30 mins; MS m/z H}+; Method 2minLC_v003
1H NMR (400MHz, DMSO)610.4(1H, s), 10 (1H, d), 9.4 (1H, d), 8.9 (1H, t), 8.7
(1H, s), 8.55 (1 H, s), 8.2 (2H, d), 8 (1H, s), 7.85 (1H, m), 7.6 (1H, d), 7.5 (1H, t), 4.2
(2H, q), 3.55 (2H, m), 3.4 (4H, m), 3.3 (2H, m), 3.1 (1H, m) 1.9 (1H, d), 1.7 (2H, m),
1.5 (2H, m), 1.4 (4H, m), 1.3 (2H, d), 1.1 (1H t).
Example 1.21:
1O 6-(1-Methyl-1H-pyrazoly|)-N-(2-methy|(2-(4-methylpiperazin
yl)benzylcarbamoyl)pyridinyl)pyrazolo[1,5-a]pyridinecarboxamide
The title compound was prepared from intermediate 1D and (2—(4—methylpiperazin-1—
yl)phenyl)methanamine analogously to Example 1.1 step 1;
LC-MS: Rt 0.66 mins; MS m/z 564.7{M+H}+; Method 2minLopr
Example 2.1
N-(5-(2-tert-ButoxyethylcarbamoyI)fluorophenyl)(6-(3-
(dimethylamino)propoxy) pyridinyl)imidazo{1,2-a]pyridinecarboxamide
PCT/IBZOIZ/054501
\\\\N/
7-Bromo—N-(5-(2—tert—butoxyethylcarbamoyI)—2-fluorophenyl)imidazo[1,2—a]pyridine—3—
carboxamide (Intermediate 2A) (300 mg, 0.629 mmol), N,N-dimethyl—3—(5—(4,4,5,5—
tetramethyl-1,3,2-dioxaborolan—2—yl)pyridinyloxy)propan—1~amine (202 mg, 0.660
mmol) and cesium carbonate (819 mg, 2.51 mmol) were combined in 1,2-
dimethoxyethane (7 ml) and water (3 ml). The mixture was degassed thoroughly
refilling with en and treated with PdCI2(dppf).CH20l2 adduct (25.7 mg, 0.031
mmol). The mixture was once again degassed thoroughly refilling with nitrogen and
heated using microwave radiation at 100 0C for 1 hr. The aqueous was removed by
1O pipette and the organic portion was absorbed onto silica and purified by
chromatography eluting with 0-20% MeOH in DCM. The resulting solid was
tallised from EtOAc to afford the title nd;
LC-MS: Rt 2.55 mins; MS m/z 577.5, [M+H]+; Method C_v003
1H NMR (400 MHz, DMSO) 6 10.25 (1H, s), 9.46 (1H, d), 8.73 (1H, s), 8.65 (1H, s),
8.55 (1H, t), 8.24 (1H, d), 8.16 (2H, m), 7.80 (1H, m), 7.63 (1H, d), 7.45 (1H, t), 6.95
(1H, d), 4.36 (2H, t), 3.45 (2H, m), 3.35 (2H, m), 2.35 (2H, m), 2.15 (6H,s), 1.87 (2H,
m), 1.16 (9H, 3).
Example 2.2
N~(5-((5,5-Dimethyltetrahydrofuran-Z-yl)methylcarbamoyl)-2—fl uorophenyl)(6-
(4-methylpiperaziny|)pyridinyl)imidazo{1,2-a]pyridinecarboxamide
The title nd was prepared from commercially available 1-methyl(5—(4,4,5,5-
tetramethyl-1,3,2—dioxaborolan—2—yl) pyrldin—Z-yl)piperazine and lntermediate 4E
analogously to Example 2.1;
LC-MS: Rt 0.71 mins; MS m/Z 586/587 {M+H}+; Method 2mlnLC_v003
Example 2.3:
N-(5-(3,4-Difluorobenzylcarbamoyl)fluorophenyl)—7-(1-(3-(dimethyl
amino)propyl)-1H-pyrazolyl)imidazo[1,2-a]pyridinecarboxamide
F N
The title compound was prepared from commercially available N,N—dimethyl—3—(4—
(4,4,5,5—tetramethyI—1,3,2—dioxaborolan—2—yl)4 H—pyrazoIy|)propan—1—amine and
lntermediate 3A analogously to Example 2.1;
LC-MS: Rt 0.69 mins; MS m/z 576/577/578 {M+H}+; Method 2minLC_vOO3
Example 2.4
N -(5-((5,5-Dimethyltetrahyd rofu ranyl)methylcarbamoyl)fluorophenyl)(5-
ahydro-2H-pyranylamino)methyl)pyridinyl)imidazo[1,2-a]pyridine
amide
Step 1: N-(5—(((5,5—Dimethyltetrahydrofuran—2-yl)methyl)carbamoyl)—2-fluoropheny|)-
7-(5—formylpyridinyl)imidazo[l ,2—a]pyridine—3-carboxamide The title compound was
prepared from 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)nicotinaldehyde and
Intermediate 4E analogously to Example 2.1;
LC-MS: Rt 0.87 mins; MS m/z 7/518 {M+H}+; Method 2minLC_v003
flap—2: N-(5—((5,5-Dlmethyltetrahydrofuranyl)methy|carbamoyl)-2—fluorophenyl)—7-
(5-((tetrahydro-2H—pyran-4—ylamino)methyl)pyridin—3-yl)imidazo[1,2-a]pyridine—3—
carboxamide
A suspension of N-(5-(((5,5-dimethyltetrahydrofuran-2—yl)methyl)carbamoyl)—2—
fluorophenyl)(5-formylpyridin-S—yl)imidazo[1,2—a]pyridine—3—carboxamide (step
1)(98 mg, 0.19 mmol), tetrahydro—2H-pyranamine (38.4 mg, 0.380 mmol), acetic
1O acid (0.2 ml, 3.49 mmol) and 2—picoline borane (24.16 mg, 0.228 mmol) in MeOH (2
ml) was heated at 50°C for 3 hrs. The on mixture was concentrated under
vacuum and the residue was redissolved in 10% MeOH/EtOAc. The mixture was
washed with sat. NaHC03 and H20. The organic portion was dried MgSO4 and
concentrated in vacuo. The crude product was purified by chromatography on silica
eluting with 0-20% 2M NH3 in MeOH/DCM. The product ons were combined and
concentrated in vacuo. The residue was triturated with EtOAc/iso—hexane to afford
the title compound;
LC-MS: Rt 0.69 mins; MS m/z 601/602 {M+H}+; Method 2minLC_v003
The compounds of the following ted Examples (Table 2) were prepared by a
similar method to that of e 2.4 from the appropriate starting compounds, the
preparations of which are ed in the ‘Preparation of intermediates’ section.
Table 2
Stru‘ct—r m«HA 7" -
LC-MS/NMR
Name
LCMS: Rt 0.66 mins;
MS m/z 563/564
{M+H}+; Method
2minLC__v003
(S)-N-(5—(((5,5—Dimethyltetrahydrofuran—2—yl)methyl)
carbamoyl)—2-fluorophenyl)—7-(5—(((2-fluoroethyl)
amino)methyl)pyridin—3-yi)imidazo[1,2-a]pyridine
LCMS: Rt 0.68 mins;
MS m/z 589 ;
Method 2min LC_v003
(R)-N-(5-(((5,5—dimethyltetrahydrofuran-2—yl)methyl)
carbamoyl)—2—fluorophenyl)—7-(5-(((2-methoxyethyl)
E(methyl)amino)methyl)pyridinyl) imidazo[1,2~a]
2.6 pyridine—3-carboxamide _*E
(R)(5-((tert—butyiamino)methy|)pyridin—3—yi)—N—(5- LCMS: Rt 0.69 mins;
(((5,5~dimethylt etrahydrofuran-2— MS m/z 573 {M+H}+;
yi)methyi)carbamoyi)-2—fluorophenyl) imidazo[1,2— Method 2min LC_v003
32.7 :;a]pyridine~3-carboxamide
Example 3.1
N-(5-(3,4—Difluorobenzylcarbamoyl)~2-fluoropheny|)(6-(2-(pyrroiidin
yl)ethoxy) pyridinyl)imidazo[1,2-a]pyridinecarboxamide hydrochloride
N \ \N
O \/o
F
m1; 7-(6—Chioropyridin—3-yl)—N-(5-(3,4—difluorobenzyicarbamoyi)—2—
fluorophenyl)imidazo[1,2—a]pyridine—3-carboxamide
A e comprising 7-bromo-N-(5-(3,4—difluorobenzyicarbamoyi)—2—
phenyl)imidazo[1,2—a]pyridine—3-carboxamide (intermediate 3A)100 mg, 0.199
mmol), 6-chloropyridinyiboronic acid (31.3 mg, 0.199 mmoi) and cesium carbonate
(259 mg, 0.795 mmol) in DME (631 uL)/water (31.5 (L) was purged with nitrogen and
d with PdClg(dppf).CH2C|2 adduct (8.11 mg, 9.93 umol) The resulting mixture
was heated using microwave radiation at 100°C for 15 mins. The water was removed
PCT/IBZOIZ/054501
by pipette and the reaction mixture was d with MeOH. Purification of the mixture
by tography on silica eluting with 0—20% 2M NH3 in MeOH/DCM afforded the
title nd;
LC-MS: Rt 0.75 mins; MS m/z 536 {M+H}+; Method _30_v003
mN-(5-(3,4-Difluorobenzylcarbamoyl)—2-fluorophenyI)—7-(6—(2-(pyrrolidin~1-
yl)ethoxy) pyridin-3—yl)imidazo[1,2—a]pyridine-3~carboxamide hydrochloride
A solution of 2-(pyrrolidin—1-y|)ethanol (30.5 mg, 0.265 mmol) and sodium hydride
(6.36 mg, 0.265 mmol) in toluene (442 pl) was stirred at RT for 30 mins and treated
with 7-(6-chloropyridinyl)—N-(5-(3,4—difluorobenzylcarbamoyl)—2-
1O fluorophenyl)imidazo[1,2—ajpyridinecarboxamide (step 1). The reaction mixture
was heated at 60°C for 1 hour and the reaction was ed with wet MeOH.
cation of the mixture by chromatography on silica eluting with 0-20% (2M NH3 in
MeOH)/DCM afforded a yellow solid. The solid was dissolved in MeOH and treated
with 2M HCI in diethyl ether (1eq). The solvent was removed in vacuo and
purification of the crude product by chromatography on silica eluting with 2M NH3 in
MeOHlTBME afforded a solid. The solid was treated again with 2M HCI in diethyl
ether and concentrated in vacuo to afford the title nd;
LC—MS: Rt 0.52mins; MS m/z 615 [M+H]+; Method 2minLC_30_v003
1H NMR (400MHz, DMSO-d6) 610.5 (1H, s), 9.6 (1H, s), 8.8 (2H, d) 8.4 (1H, d), 8.2
(1H, d), 7.9 (1H, m), 7.7 (1H, d), 7.45 (1H, t), 7.4 (1H, m), 7.3 (1 H, s), 7.2 (1H, m),
7.15 (1H, s), 7.1 (1H, d), 7(1H, s), 4.7(2H, d), (4.5 (2H, d), 3.3 (4H, m), 3.1 (2H, m),
2.05 (2H, m), 1.95 (2H, m).
The compounds of the following tabulated Examples (Table 3) were prepared by a
similar method to that of Example 3.1 from the appropriate starting compounds, the
preparations of which are detailed in the ‘Preparation of Intermediates’ section.
Table 3
- LC-MSINMR
Name
LC-MS: Rt 0.87 mins;
MS m/z 589 [M+H]+;
Method 2minLC_v003
N—(5-((2-(tert—Butoxy)ethyl)carbamoyl)—2—
fluorophenyl)~7—(6—(2-(pyrrolidin—1—yl) )pyridin—
13.2 3—yl) imidazo[1,2—a] pyridinecarboxamide
LC—MS: Rt 0.71 mins;
MS m/z 601/602
{M+H}+; Method
2minLC_v003.
:N—(5—(((5,5-dimethyl tetrahydrofuran—Z—
yl)methyl)carbamoyl)—2—fluorophenyl)—7-(6-((1—methy|
piperidinyl)oxy) pyridin—S—yl)imidazo[1 ,2—
3.3 a]pyridine—3-carboxamide
Example 4.1
6-(1 -Methyl-1 zol-S-yI)-N-(2-methyl(2-(4-methy|piperazin
yl)benzylcarbamoyl) phenyl)pyrazolo[1,5-a]pyridinecarboxamide
hydrochloride
6-Bromo—N—(Z-methyl~5~(2—(4~methyipiperazin-t—yl)benzylcarbamoyl)phenyl)pyrazolo
[1 ,5—a]pyridine—3—carboxamide (169 mg, 0.301 mmol), -dimethyl-2,4-dioxa
borabicyclo[3.1.0]hexan-3—yl)-1~methyl—1H-pyrazole (75 mg, 0.391 mmol) and cesium
carbonate (392 mg, 1.204 mmol) in DME (3209 1.1L) and water (1284ul) were
combined to give a yellow solution. PdCl2(dppf).CH20l2 adduct (6.15 mg, 7.52 umol)
was added and the mixture was heated using microwave radiation at 100°C for 1hr
A further portion of PdCl2(dppf).CHQCl2 adduct (6.15 mg, 7.52 umol) was added and
heating continued using microwave radiation at 100°C for 1hr. 5-(1,5-Dimethyl-2,4-
dioxaborabicyclo[3.1.0]hexanyl)—1-methyl-1H-pyrazole (75 mg, 0.391 mmol),
PdCl2(dppf).CH20|2 adduct (6.15 mg, 7.52 pmol) and cesium carbonate (392 mg,
1.204 mmol) were added. The mixture was heated using micriowave radiation at
100°C for 2hrs.The product was purified by tography on silica eluting with 0—
% 2M NH3 in MeOH/DCM followed by a second column using 0—15% 2M NH3 in
MeOH/DCM. The resulting e was ved in CM, filtered through a
glass fibre filter paper and purified by preparative chromatography eluting with 20-
50% MeCN/water (0.1% TFA). The appropriate fractions were partitioned between
with NaHC03 and EtOAc and the c portion was dried (M9804) and
concentrated to afford a colourless oil. HCl (1 equiv.) in dioxane was added and
trituration with EtOAc/EtOH afforded the title compound as a solid;
LC-MS: Rt 2.66 mins; MS m/z 563/564/565 {M+H}+; Method C__v003
1H NMR (400MHz, CDgOD) 6 8.9 (1 H, s), 8.7 (1 H, s), 8.4 (1H, d), 7.95 (1H, s), 7.7
(1H, d), 7.65 (1h, d), 7.6 (1H, s), 7.4 (1H, d), 7.35 (1H, d), 7.3 (1H, m), 7.2 (1H, m),
7.1 (1 H, t), 6.6 (1 H, s), 4.7 (2H, s), 4.0 (3H, s), 3.0 (4H, m), 2.7 (4H, s broad), 2.45
(6H, d).
Example 5.1
N-(2-Bromo-S-(Z-(4-methylpiperazinyl)benzylcarbamoyl)phenyl)imidazo[1,2-
a]pyridinecarboxamide
WO 30802
@111; 3—Amino—4—bromo—N—(2~(4—methylpiperazin—1~yl)benzyl)benzamide
N1,N1—dimethyl—N2—((propylimino)methylene)ethane~1,2—diamine (0.70 ml, 3.99
mmol) was added to a stirred solution / sion of o—4—bromobenzoic acid
(719 mg, 3.33 mmol), (2—(4-methylpiperazinyl)phenyl)methanamine (820 mg, 3.99
mmol) and HOBt (140 mg, 1.0 mmol) in dry DCM (20 ml) under argon. After 24 hrs
the reaction mixture was diluted with DCM and washed several times with water.
The solvent was removed in vacuo and the resulting yellow oil was triturated with
DCM/ diethyl to give a yellow crystalline powder;
LCMS: Rt 0.85 min; MS m/z 403.2 [M+H]+; Method 2minLC_v003
1H NMR (400 MHz, CDCI3) 5 6.48 (1H, d), 6.42 (1H, br s), 7.30 (3H, m), 7.20 (1H,
d), 7.14 (1H, t), 6.92 (1H, d), 4.72 (2H, d), 4.23 (2H, br s), 3.02 (4H, br s(, 2.62 (4H,
br s), 2.35 (3H, s)
mN-(2—Bromo—S—(Z—(4-methylpiperazin—1-y|)benzylcarbamoyl)phenyl)imidazo
[1 ,2-a]pyridine—3-carboxamide
lmidazo[1,2-a]pyridine—3~carbonyl chloride hydrochloride (0.97 mg, 4.46 mmol) was
slowly added in portions to a stirred on of 3-amino—4-bromo-N-(2—(4—
methylpiperazin-1~yl)benzyl)benzamide (step 1)(900 mg, 2.23 mmol) in dry pyridine
(15 ml). The reaction was stirred at RT for 18 hrs and quenched with water. The
solvent removed in vacuo. The residue was treated with a small amount of MeOH to
dissolve insoluble material then partitioned between aq. NaHC03 and DCM. The
organic t was washed with brine, dried over M9804 and concentrated in vacuo.
The crude product mixture was crystallised from MeOH to give a white solid;
LCMS: Rt 0.78 min; MS m/z 549.2 [M+H]+; Method 2minLC_v003
1H NMR (400 MHz, MeOD) 5 9.52 (1H, s), 8.53 (1 H, s), 8.25 (1H, s), 7.85 (1H, d),
7.77 (1H, d), 7.68 (1H, d), 7.60 (1H, t), 7.35 (1H, d), 7.22 (3H, m), 7.10 (1H, t), 4.72
(2H, d), 3.0 (4H, br s), 2.67 (4H, br s), 2.37 (3H, s).
Example 5.2
N-(2-Bromo(2-(4-methylpiperazinyl)benzy|carbamoyl)phenyl)pyrazolo[1,5-
a]pyridinecarboxamide
/N
The title compound was prepared from obromo-N-(2—(4-methylpiperazin
yl)benzyl)benzamide (Ex 5.1, step 1) and pyrazolo[1,5-a]pyridine-3~carbonyl chloride
(commercially available) ously to Example 5.1;
LCMS: Rt 2.12 min; MS m/z 547.3, 549.3 [M+H]+; Method Lopr_v002.
1O 1H NMR (500MHz, dB-DMSO) 6 9.90 (1H, s), 9.05 (1H, t), 8.85 (1H
, d), 8.79 (1H,s),
8.22 (1H,d), 8.14 (1 H, d), 7.84 (1 H, d), 7.74 (1H, dd), 7.54 (1 H, m), 7.23 (2H, m),
7.13 (2H, m), 7.05 (1H, m), 4.57 (2H, d), 2.87 (4H, m), 2.50 (4H, m), 2.23 (3H, s).
Example 6.1
N —(5-(3,4-Difluorobenzylcarbamoyl)fl uorophenyl)(3-hydroxymethyl
butyl)imidazo[1,2-a]pyridinecarboxamide
WO 30802
HN O
mEthyl 3—(3-(5-(3,4-difluorobenzylcarbamoyl)fluorophenylcarbamoyl)
imidazo[1 yridin-7—yl)propanoate
7-Bromo-N-(5—(3,4-difluorobenzylcarbamoyl)fluorophenyl)imidazo[1,2-a]pyridine
carboxamide (intermediate 3A)(1g, 1.987 mmol), Pd2(dba)3 (0.091 g, 0.099 mmol)
and tritertbutylphosphonium tetrafluoroborate (0.058 g, 0.199 mmol) were combined
in THF(60 ml) under nitrogen and the mixture was degassed thoroughly refilling with
nitrogen (X3). (3-Ethoxy—3—oxopropyl)zinc(ll) bromide (19.87 ml, 9.93 mmol) was
added and the mixture was heated at 60 °C for 100 mins. After cooling to RT, the
1O mixture was absorbed onto silica and purification by chromatography eluting with 0—
6% MeOH in DCM afforded a yellow oil which was triturated with EtOAc to give the
title compound;
LCMS: Rt 0.99 min; MS m/z 525 [M+H]+; Method _v003
SEQ; N—(5-(3,4—Difluorobenzylcarbamoyl)flu0rophenyl)—7—(3—hydroxymethyl
butyl)imidazo[1,2-a]pyridinecarboxamide
Ethyl 3—(3-(5-(3,4-dif|uorobenzylcarbamoyl)~2—fluorophenylcarbamoyl)imidazo[1 ,2-
a]pyridinyl)propanoate (step 1)(50 mg, 0.095 mmol) was suspended in dry ether
and cooled to 0 °C. Methylmagnesium bromide (0.318 ml, 3.0M in ether, 0.953 mmol)
was added and the e was stirred and allowed to warm to RT over 16 hrs. The
mixture was partitioned between 10% aq. Citric acid and EtOAc. The organics
were
ted, dried (M9804), filtered and evaporated to dryness. The residue was
purified by chromatography on silica eluting with 0-10% MeOH in DCM to afford the
title product;
LCMS: Rt 0.97 min; MS m/z 511.4 [M+H]+; Method 2minLC_v003
1H NMR (400 MHz, MeOD) 5 9.45 (2H, d), 9.08 (1H, t), 8.45 (1H, s), 8.35 (1H, d),
7.75 (1H, m), 7.55 (1H, s), .38 (3H, m), 7.10 (1H, d), 4.58 (2H, s), 2.88 (2H, m),
1.85 (2H, m), 1.30 (6H, 3).
Example 7.1
N-(5-(3,4-Difluorobenzyicarbamoyl)fluorophenyl)(3-fluoro(2-(piperidin
1O ylcarbamoyl)phenyl)imidazo[1,2-a]pyridinecarboxamide hydrochloride
(P“#5 F
. %13
§t_ep_1_: Methyl 4-(3-(5-(3,4-ditiuorobenzylcarbamoyl)—2-fluorophenylcarbamoyl)
imidazo[1,2—a]pyridinyl)fluorobenzoate
7~Bromo-N~(5-(3,4—difluorobenzylcarbamoyl)—2—fluorophenyl)imidazo[1,2—a]pyridine
carboxamide (intermediate 3A)(500 mg, 0.993 mmol), methyl 2—fluoro—4—(4,4,5,5-
tetramethyI—1,3,2-dioxaborolan—2-yl)benzoate (306 mg, 1.093 mmol) and cesium
carbonate (1295 mg, 3.97 mmol) in water (2 ml) /DME (5 ml) were mixed to give a
suspension. The mixture was degassed with nitrogen and PdCl2(dppt).CH2Clz adduct
(40.6 mg, 0.050 mmol) was added. The reaction mixture was heated using
microwave radiation at 100°C for 1hr and partitioned between EtOAc and water. The
organic portion was separated, dried (M9804) and concentrated in vacuo. The crude
product was triturated with MeOH/diethyl ether to afford the title compound;
LCMS: Rt 1.09 min; MS m/z 567.[M+H]+; Method _v003
fig; N-(5-(3,4-Difluorobenzylcarbamoyl)-2—fluorophenyl)(3-fluoro—4-(2-
(piperidinyl)ethylcarbamoyl)pheny|)imidazo[1,2-a]pyridinecarb0xamide
Methyl 4-(3-(5-(3,4-difluorobenzylcarbamoyl)fiuorophenylcarbamoyl)imidazo[1,2-
a]pyridin-7—yl)fluorobenzoate (step 1)(50 mg, 0.087 mmol), ridin-t—yl-
ethylamine ( 0.260 mmol), and TBD (12.07 mg, 0.087 mmol) in THF (289 pl) were
heated to 70°C for 2 days. The mixture was diluted with water (4 ml) and extracted
with DCM using a phase separator. The c portion was concentrated in vacuo
and the residue was dissolved in DMSO. Puriication of the crude product was carried
out by preparative LC-MS. The resulting ons were loaded onto a tted
(MeOH) Isolute® SCX-Z cartridge and washed with MeOH. The product was eluted
with 7M ammonia in MeOH. The resulting residue was d with 2M HCI (in EtOH,
1 equiv) and the concentrated in vacuo to afford the title compound as a
hloride salt;
LS-MS: Rt 3.79 mins; MS m/z 673 [M+H]+; Method 10minLC_v003
1O 1H NMR (400MHz. DMSO—d6) 6 9.1(1H, s), 9(1H, bs). 8.6(1H. d). 8.4(1H, s), 8.2(2H,
m), 7.9-7.7 (3H, m), 7.6(1H, s), 7.4(2H. m), 7.2(1H, m), 4.5(2H, d), 3.4(2H, m),
3.2(2H, s), 2.4(4H, m), 1.5 (4H, m) 1.4(2H, m).
Example 7.2
N-(5-(3,4-Difluorobenzylcarbamoyl)fluorophenyl)(3-fluoro(2-(tetrahyd ro-
2H-pyranyl)ethylcarbamoyl)phenyl)imidazo[1,2-a]pyridinecarboxamide
hydrochloride
H I N\
The title compound was prepared analogously to Example 7.1 using the appropriate
amine in step 2. The hydrochloride salt was obtained by ng N—(5—(3,4—
difluorobenzylcarbamoyl)—2—fluorophenyl)—7—(3—fluoro~4—(2—(tetrahydro—2H-pyran-4—
yl)ethylcarbamoyl)phenyl)imidazo[1,2—a]pyridine~3—carboxamide with 2M HCI (in
diethyl ether) and removing the solvent in vacuo;
LC-MS: Rt 3.49 mins; MS m/z 674 [M+H]+; Method 10minLC_v003
1H NMR (400MHz. DMSO-dG) 6 9.1 (1H. s) 8.4(2H, m), H, m), 7.9(1H, d),
7.8(1H, d), 7.7(1H, t), 7.65(2H, d), 7.4(3H, m), 7.2(1H, m), 4.5 (2H, d), 3.8 (2H, M).
3.3 (3H, m) 3.15 (1H, s), 1.6 (3H, m), 1.5 (2H. m). 1.1(2H, m).
Example 7.3
(2~(2,2—Dimethylpyrroiidin—1—yi)ethyi)carbamoyl)—2~fluorophenyi)—7—(1—methyi—
1 H-pyrazol-4—y|)imidazo[1,2—a]pyridine—3—carboxamide
HN O
m4-FIuoro—3-(7-(1-methyI—1H-pyrazoIy|)imidazo[1,2—a]pyridine
carboxamido)benzoic acid
A mixture comprising methyl 3—(7-bromoimidazo[1,2-a]pyridine-3~carboxamido)—4—
benzoate (Intermediate 1A)(5.41 g, 13.79 mmol), 1-methyi—1H—pyrazol
yiboronic acid (1.911 g, 15.17 mmol), Pd(dppf)Cl2.DCM (1.127 g, 1.379 mmol) and
cesium carbonate (13.48 g, 41.4 mmol) in DME (100 mi) and water (10ml) was
heated at 100°C for 4 hrs. 3 equivalents of sodium carbonate were added and the
mixture was heated to 100°C for 6 hrs. A further 3 equivalents of sodium carbonate
were added and the reaction was heated at 100°C overnight.
The reaction e was cooled to 50°C and filtered through glass fiber filter
paper.
The filtrate was acidified to pHS and allowed to cool to room temperature. A brown
precipitate formed which was collected by vacuum filtration and dried at 45°C to
afford the title nd;
LC—MS: Rt 0.68 mins; MS m/z 380/381 {M+H}+; Method 2minLC_v003.
MN-(5-((2—(2,2—Dimethylpyrrolidin-1—yl)ethyl)carbamoyl)-2—fluorophenyi)—7-(1 1H-pyrazoi-4—yi)imidazo[1,2—a]pyridinecarboxamide
A solution of4-fiuoro—3-(7-(1-methyi—1H—pyrazolyl)imidazo[1,2-a]pyridine
carboxamido) benzoic acid (step 1)(6.31 g, 16.63 mmol), 2—(2,2—dimethyipyrroiidin
yl)ethanamine (2.84 g, 19.96 mmol) and triethyiamine (6.96 mi, 49.9 mmol) in DMF
PCT/1B2012/054501
(36.9 ml) and EtOAc (2 ml) was treated dropwise with ®T3P (propylphosphonic
anhydride) (50% w/w in EtOAc) (15.88 g, 24.95 mmol). The resulting mixture was
stirred at RT for 16 hrs and diluted with 10% MeOH/EtOAc (62.7 ml). The mixture
was washed with 0.5 M LiCl, H20 and sat. NaHC03. The aqueous layer was back-
ted with 10% MeOH EtOAc (62.7 ml) (3 X 100 ml). The combined organic
extracts was dried M9804, filtered and trated in vacuo. The resulting solid
was triturated with EtOAc and dried at 45°C to afford the title nd;
LC-MS: Rt 0.59 mins; MS m/z 504/505/506 {M+H}+; Method 2mlnLC_v003
Further purification was carried out by loading the product onto 2 pre-washed 109
1O lsolute SCX—2 columns and washing through with MeOH. The product was eluted
with 2N NH3 in MeOH to afford a brown solution which was triturated with EtOAc to
the title compound;
1H NMR (400MHz), CDgOD) 6 9.4 (1H, d), 8.45 (1H, s), 8.3 (1 H, m), 8.2 (1H, s), 8.0
(1H, s), 7.85 (1H, s), 7.8 (1H, m), 7.4 (1H, m), 7.3 (1H, t), 4.0 (3H, s), 3.5 (2H, m), 2.9
(2H, t), 2.7 (2H, t), 1.8 (2H, m), 1.7 (2H, m), 1.0 (6H, 8).
Example 7.4
N -(5-(2-(2,2-Dimethylpyrrolidinyl)ethylcarbamoyl)fluorophenyl)(3-fluoro-
4-((1R,2R)hydroxycyclohexylcarbamoyl)phenyl)imidazo[1,2-a]pyridine
amide
)1 \
F \
“MI,HYLVN
l/ b
CNN/«Km 0
SEE 7-Bromo—N-(5-(2—(2,2—dimethylpyrrolidinyl)ethylcarbamoyI)-2—
fluorophenyl)imidazo[1,2-a]pyridine-3—carboxamide
3—(7-Bromoimidazo[1,2-a]pyridine-3—carboxamido)—4—fluorobenzoic acid (prepared by
hydrolysis of methyl 3-(7—bromoimidazo[1,2—a]pyridine—3-carboxamido)—4-
fluorobenzoate (Intermediate 1A) using NaOH) (700 mg, 1.851 mmol), 2-(2,2—
dimethylpyrrolidin-‘l-yl)ethanamine (290 mg, 2.036 mmol) and triethylamine (0.774
ml, 5.55 mmol) were dissolved in EtOAc (7.284 ml) and DMF (1.28mi) to give a
yellow solution. ®T3P (propylphosphonic anhydride)(1.620 ml, 2.036 mmol) was
added and the mixture was stirred at room temperature for 90 mins. The reaction
1O mixture was diluted with EtOAc and washed with 0.5M LiCI in H20 and sat NaHCO3.
The organic portion was dried M9804, ed and concentrated in vacuo. The
residue was triturated with EtOAc/iso-hexane to afford the title compound as a white
solid;
LC—MS: Rt 0.67 mins; MS m/z 503/504/505 {M+H}+; Method 2minLC_v003
mMethyl 4-(3—(5—(2—(2,2—dimethylpyrrolidin—1~yl)ethylcarbamoyl)—2-
fluorophenylcarbamoyl)imidazo[1,2-a]pyridin-7—yl)—2-fiuorobenzoate
The title compound was prepared from 4-(methoxycarbonyl)phenylboronic acid and
7—bromo—N—(5—(2—(2,2-dimethylpyrrolidin—1—yl)ethylcarbamoyl)-Z-fluorophenyl)
imidazo[1,2—a]pyridine—3-carboxamide (step 1) analogously to Example 7.3 step 1;
LC—MS: Rt 0.75 mins; MS m/z 576/577 [M+H]+; Method 2minLC_v003
: 4-(3—(5~(2-(2,2—Dimethylpyrrolidinyl)ethylcarbamoyl)fluorophenyl
carbamoyl)imidazo[1,2—a]pyridinyl)fiuorobenzoic acid
A mixture comprising methyl 4—(3—(5—(2—(2,2—dimethylpyrrolidinyl)ethylcarbamoyl}
2—fluorophenylca rbamoyl) imidazo[1,2—a]pyridinyl)~2-fluorobenzoate (step 2)(409
mg, 0.711 mmol) and sodium hydroxide (142 mg, 3.55 mmol) in MeOH (5 ml) was
heated at 60°C overnight. The reaction mixture was concentrated under vacuum and
the resulting residue was ved in water and adjusted to pH 5 using 1M HCl. The
solid precipitate was collected by filtration and dried at 45°C. The aqueous portion
was concentrated in vacuo and the residue was ted in 5% MeOH inDCM. The
resulting suspension was filtered and the filtrate was ed with the solid
precipitate from the first filtration. The combined t were evaporated to dryness
and dried at 45°C in the vacuum oven.
LC-MS: Rt 0.68 mins; MS m/z 562/563 {M+H}+; Method _v003
mN-(5—(2-(2,2-Dimethylpyrrolidiny|)ethylcarbamoyl)f|uorophenyl)-7—(3-
fluoro((1 2—hydroxycyclohexylcarbamoyl)phenyl)imidazo[1,2-a]pyridine
carboxamide
The title compound was prepared from (1R,2R)-2—aminocyclohexanol and 4-(3-(5~(2—
(2,2—dimethylpyrrolidin—1—yl)ethylcarbamoyl)—2—fluorophenylcarbamoyl)imidazo[1,2-
a]pyridin—7—yl)—2—fluorobenzoic acid (step 3) analogously to Example 7.3 step 2;
LC—MS: Rt 0.70 mins; MS m/z 659/660 {M+H}+; Method 2minLC_v003
Example 7.5
N-(5-(2-(2,2-Dimethylpyrrolidinyl)ethylcarbamoyl)fluorophenyl)—7-(3-fluoro-
4-(1-hydroxymethylpropanylcarbamoyl)phenyl)imidazo[1,2-a]pyridine
amide
The title compound was prepared analogously to Example 7.4 from 4—(3—(5—(2—(2,2—
dimethylpyrrolidin—1—y|)ethylcarbamoyl)—2—fluorophenylcarbamoyl)imldazo[1 ,2~
a]pyridin—7—yl)-2~fluorobenzoic acid (step 3) and 2—amino—2—methylpropan—1—ol;
LC-MS: Rt 0.69 mins; MS m/z 633/634/635 ; Method 2minLC_v003.
Example 7.6
N-(5-(2-(2,2-Dimethylpyrrolidinyl)ethylcarbamoyl)methylpyridinyl)(3-
fluoro(1-hydroxy-Z-methylpropan-2~ylcarbamoyl)phenyl)pyrazolo[1,5-
a]pyridlnecarboxamide
V”WK T.
““WDH
Steps 1, 2 and 3: 4—(3—(5-(2-(2,2~Dimethylpyrrolidinyl)ethylcarbamoyl)—2—
methylpyridin-B—ylcarbamoyl)pyrazolo[1,5—a]pyridin-6—yI)—2-fluorobenzoic acid
The title compound was prepared from intermediate 1E analogously to Example 7.4
steps 1, 2 and 3;
LC-MS: Rt 0.72 mins; MS m/z 559 {M+H}+; Method 2minLoprv01.
flew—4: N—(5-(2—(2,2-Dimethylpyrrolidin-1—yl)ethylcarbamoyl)-2—methylpyridin-B-yl)-6—
(3-fluoro-4—(1—hydroxymethylpropan-Z—ylcarbamoyl)phenyl)pyrazolo[1,5—a]pyridine-
3-carboxamide
1O A solution of 2-aminomethylpropanol (12.64 mg, 0.142 mmol), 4—(3-(5-(2—(2,2-
dimethylpyrrolidiny|)ethylcarbamoyl)methylpyridinylcarbamoyl)pyrazolo[1,5—
a]pyridinyl)fluorobenzoic acid (72 mg, 0.129 mmol) and ylamine (0.054 ml,
0.387 mmol) in DCM (5 ml) was treated with HATU (53.9 mg, 0.142 mmol) and DMF
(1 ml). After stirring at RT for 3 hrs, the reaction e was diluted with DCM and
washed with sat NaHCOs and H20. The organic portion was separated, dried
MgSO4 and trated in vacuo. The product was purified by flash column
chromatography on silica eluting with 0-25% 2M NH3 in MeOH/DCM. The product
fractions were combined and concentrated to afford an orange oil which was
triturated with EtOAc/hexane to afford a pale brown sold.
LC-MS: Rt 0.74 mins; MS m/z 630/631/632 {M+H}+; Method prvO1
Example 8.1
N-(5-(3,4-Difluorobenzylcarbamoyl)fluorophenyl)(3-fluoro(3-morpholino
propylcarbamoyl)phenyl)imidazo[1,2-a]pyridinecarboxamide hydrochloride
H ImN\
N N
N \ HN\/\/
O NH
SELL: 4—(3-(5—(3,4-Difluorobenzylcarbamoyl)-2—f|uorophenylcarbamoyl)imidazo[1 ,2-
a]pyridin-7—yl)—2-f|uorobenzoic acid
A solution of methyl 4—(3—(5—(3,4—difluorobenzylcarbamoyl)—2—fluorophenylcarbamoyl)
imidazo ]pyridin—7-yl)fluorobenzoate (Example 7.1, step 1) (497
mg, 0.862
mmol) and 2M NaOH (4311 uL, 8.62 mmol) in MeOH (2874 pt.) was stirred at RT
overnight. The solvent was removed in vacuo and the residue was acidified with 2M
HCI to pH 2 and extracted with DCM. The organic extracts were dried over MgSO4,
filtered and concentrated in vacuo to afford the title compound;
1O LCMS: Rt 0.66 min; MS m/z 563 ; Method 2minLC_30_v003
mN—(5-(8,4-Difluorobenzylcarbamoyl)-2—fluoropheny|)—7—(3-f|u0ro~4—(3-
morpholino propylcarbamoyl)phenyl)imidazo[1,2—a1pyridinecarboxamide
hydrochloride
A mixture comprising 4-(3—(5—(3,4-difluorobenzylcarbamoyl)—2—fluorophenyl
‘15 carbamoyl)imidazo[ 1,2-a]pyridin-7—yl)—2—fluorobenzoic acid (100 mg, 0.178 mmol), 3-
morpholinopropanamine (51.3 mg, 0.356 mmol), HATU (74.4 mg, 0.196 mmol)
and s base (34.2 uL, 0.196 mmol) in THF (593 uL) was stirred at room
temperature overnight. The solvent was removed in vacuo and the residue was
partitioned between water and DCM. The organic portion was dried over M9804,
filitered and concentrated in vacuo. The residue was purified by chromatography on
silica eluting with 0-20% 2M NH3 in Methanol in TBME. The resulting solid was
treated with 2M HCl in diethyl ether and concentrated in vacuo to afford the title
LCMS: Rt 3.09mins; MS m/z 688 ; Method 10minLC_v003
1H NMR (400MHz, DMSO-d6)610.5(1H, s), 10.4(1 H, bs), 9.5(1H, d), 9.2(1H, t),
8.8(1 H, s), 8.6(1 H, bs), , s), 8.2(1H, d), 7.9(1H, d) 7.8(1H, m), 7.7(1H, d),
7.5(1H, m)m 7.4(1H, m) 7.2(1H, m) 4.5(2H, d), 4(2H, d), 3.75(2H, t), 3.45(4H, m),
3.1(4H, m) 2(2H, m).
Example 8.2
N-(5-(2-(2,6-cis-Dimethylpiperidinyl)ethy|carbamoyl)f|uorophenyI)(3-
fluoro(‘l -hydroxymethylpropanylcarbamoyl)phenyl)imidazo[1,2-
a]pyridinecarboxamide
M4—(3—(5-(2-(2,6—cis—Dimethylpiperidin-1 ~yl)ethylcarbamoyl)—2—fluorophenyl
1O oyl)imldazo[1,2—a]pyridin—7~yl)—2—fluorobenzoic acid
The title compound was prepared from 7-bromo—N—(5-(2—(2,6—cis~dimethylpiperidin —1—
yl)ethylcarbamoyl)—2-fluorophenyl)imidazo[1,2—a]pyridine-3—carboxamide
(Intermediate 4C) and 3-fluoro—4—(methoxycarbonyl)phenylboronic acid analogously
to Example 1.20;
LCMS: Rt 0.50 mins; MS m/z 294 [M+H]+; Method pr
MN-(5-(2-(2,6~cis—Dimethylpiperidin-t—yl)ethylcarbamoyl)—2-fluorophenyl)-7—(3—
fluoro~4—(1-hydroxy-Z-methylpropan—Z-ylcarbamoyl)phenyl)imidazo[1,2-a]pyridine—3-
carboxamide
The title nd was ed from 4-(3—(5-(2—(2,6-cis-dimethylpiperidin
yl)ethylcarbamoyl)—2—fluorophenyl carbamoyl)imidazo[1,2-a]pyridinyl)
fluorobenzoic acid (step 1) and 2-aminomethylpropanol analogously to Example
8.1, step 2;
LCMS: Rt 0.73 mins; MS m/z 647 [M+H]+; Method 2minLopr
Example 8.3
7-(3-Fluoro(2-fluoroethylcarbamoyl)phenyI)-N-(2-fluoro(2-(4-
methylpiperaziny|)benzylcarbamoyl)phenyl)imidazo[1,2-a]pyridine
carboxamide
F O
I HWF
NR \\ \
HM C!
K‘VN \
mMethyl 2-fiuoro—4-(3-(2-fluoro(2—(4-methylpiperaziny|)benzylcarbamoy|)
phenylcarbamoy|)imidazo[1,2—a]pyrldinyl)benzoate
The title compound is prepared from 7-Bromo-N~(2—fluoro—5-(2-(4-methylpiperazin
yl) benzylcarbamoyl)phenyl)imidazo[1,2—a]pyridinecarboxamide (Example 1.1 step
1O 1) and ro-4—(methoxycarbonyl)phenylboronic acid analogously to Example 1.1
step 2;
LC-MS: Rt 0.79 mins; MS m/z 639/640 {M+H}+; Method 2minLC_v003
Step 2 and 3: 7—(3—Fluoro—4-(2—fluoroethylcarbamoyl)phenyl)—N-(2—fluoro—5-(2~(4—
methylpiperazin—1-yl)benzylcarbamoyl)phenyl)imidazo[1,2—a]pyridine—3—carboxamide
The title compound was prepared from methyl 2—fluoro-4—(3—(2—fluoro—5—(2-(4-
methylpiperaziny|)benzylcarbamoyl)phenylcarbamoyl)imldazo[1,2—a]pyridin-7—
yl)benzoate (step) and oethanamine analogously Example 8.1 steps 1 and 2;
LC—MS: Rt 0.74 mins; MS m/z 670/671 {M+H}+; Method 2minLC_v003
e 8.4
N-(2-Fluoro(2-(4-methy|piperazinyl)benzylcarbamoyl)phenyl)(3-fluoro
(2-hydroxy ethylcarbamoyl)phenyl)imidazo[1,2-a]pyridinecarboxamide
The title compound was prepared from 7-bromo-N-(2-fluoro(2—(4-methylpiperazin-
1-yl)benzylcarbamoyl) phenyl)imidazo{1,2—a]pyridine-3—carboxamide (Example 1.1
step1 and 2—amlnoethanol analogously to Example 8.2 steps 1 and 2;
LC—MS: Rt 0.71 mins; MS m/z 668/669/670 ; Method 2minLC_v003.
Example 9.0
N -(5-(2-(2,2-dimethylpyrrolidinyl)ethylcarbamoyl)methy|pyridinyl)(1-
methyl-1 H-pyrazolyl)pyrazolo[1 ,5-a]pyridinecarboxamide
§tap_1: Methyl 5-(6-bromopyrazolo[1,5-a]pyridine-3—carboxamido)methylnicotinate
opyrazolo[1,5-a]pyridinecarboxylic acid (7.71 g, 32.0 mmol) in toluene (80
ml) was treated with thionyl chloride (18.67 ml, 258 mmol) and was heated to 110 °C
for 6 hr. The solvent was removed in vacuo and the residue was treated with pyridine
(80 ml), methyl 5-aminomethylnicotinate (4.25 g, 25.6 mmol) and oven dried
molecular sieves. The reaction mixture was stirred at RT overnight and then treated
with MeOH (250 ml). The resulting suspension was removed by filtration. The filtrate
was triturated with ol and the solid produced was ed to afford the title
compound;
LCMS: Rt 0.91 mins; MS m/z 391.4 [M+H]+; Method 2minLopr
SE92; 6—Methyl—5—(6—(1-methyI-1H—pyrazolyl)pyrazolo[1,5-a]pyridine
carboxamido)nicotinic acid
Methyl 5—(6-bromopyrazolo[1.5-a]pyridine—3—carboxamido)—6-methylnicotinate (step
1) (7 g, 17.99 mmol), 1~methyl(4,4,5,5—tetramethyI-1,3,2—dioxaborolan-Z-yl)-1 H-
pyrazole (4.49 g, 21.58 mmol) and cesium carbonate (23.44 g, 71.9 mmol) were
stirred in methoxyethane (60 ml) and water (25.00 ml). The mixture was
degassed thoroughly ing with nitrogen. PdCl2(dppf).CHZCl2 adduct (0.350 g,
0.429 mmol) was added and the mixture was degassed thoroughly refilling with
nitrogen, The mixture was stirred at 100 °C for 7 hrs and then cooled to 50°C and
filtered through glass-fiber paper. The filtrate was acidified to pH 5 by the addition of
2M HO! and filtered. The foam residue was dissolved in OH (1:1) and
azeotroped with toluene (x2). The resulting solid was dried in a vacuum oven to
afford the title compound;
WO 30802
LCMS: Rt 0.69 mins; MS m/z 377.5 [M+H]+; Method 2minLopr
§_t_ep_3: N—(5—(2—(2,2—Dimethylpyrrolidin—1—yl)ethylcarbamoyi)methylpyridin—3—y|)—6—
(1-methyl-1H-pyrazoIyl)pyrazolo[1 yridine—3-carboxamide
6-Methyl(6-(1—methyl-1H-pyrazoiyl)pyrazolo[1,5-a]pyridine
carboxamido)nicotinic acid (6.6 g, 1.1 equiv) and 2-(2,2-dimethylpyrrolidin—1-
yl)ethanamine (2.397 g, 11.14 mmol) were combined in DMF (100 ml) and treated
with DlPEA (8.34 mi, 47.7 mmol) followed by HATU (4.44 g, 11.67 mmol). After
strring at RT for 90 mins, the mixture was partitioned between water (1 L) and EtOAc
(750 ml).The resulting suspension was removed by filtration and the organic portion
1O was washed with aqueous sodium bicarbonate, 0.5M lithium chloride, brine, dried
M9804, filtered and evaporated to s. cation by chromatography on silica
eluting with 0-20% 2M NH3 in MeOH/TBME afforded residue which was recrystallised
from acetone to afford the title compound;
LCMS: Rt 0.61 mins; MS m/z 501 ; Method 2minLopr
1H NMR (400 MHz, DMSO) 5 9.75 (1H, s), 9.15 (1 H, s), 8.75 (2H, m), 8.58 (1H, t),
8.32 (1H, s), 8.25 (1 H, s), 8.21 (1H, d), 8.07 (1 H, s), 7.82 (1H, d), 3.89 (3H, s), 3.34
(4H, m), 2.76 (2H, t), 2.56 (3H, s), 1.69 (2H, m), 1.53 (2H, m) 0.92 (6H, s)
The compounds of the following tabulated Examples (Table 4) were prepared by a
similar methods to that of Example 9 from the appropriate starting compounds, the
preparations of which are detailed herein and in the ‘Preparation of intermediates’
[M+H]+/NMR
WO 30802
Rt 0.59 mins; MS m/z
520 [M+H]+; Method
2minLoprv01
(S)—N-(2-Fluoro—5-(2—(2—(methoxy )
pyrrolidin-l -yl)ethyl carbamoyl)phenyl)(1—
methyl-1 H-pyrazolyl)imldazo[1,2—a]pyridine—3-
carboxamide
Rt 2.40mins: MS m/z
516.5[M+H]+ Method
10minLoprv0‘l
N-(2-Fluoro((2-(3-propylpyrrolidin
yl)ethyl)carba moyl)phenyl )(1 methyl-1 H-
pyrazolyl)imidazo [1 ,2-a]pyrldine
9.2 carboxamide
’l’lO
PCT/132012/054501
Rt 0.57 mins; MS m/z
F N
R [\ 520/521 [M+Hr; Method
N \ / N/ 2minLoprvO1
(R)—N—(2~Fluoro—5—((2-(2—(methoxymethyl)
idin—1~y|)ethyl) carbamoyl)pheny1)—7—(1~
methyl—1 H—pyrazoI—4—yl)imidazo[1,2—a]pyridine~3—
9.3 carboxamide
Rt 2.36mins: MS m/z 516
F N
a I \ [M+H]+ Method
N \ \ N 10minLoprv01
o \ \ [‘3
o N;
I LA
N-(5—((2—(3,5-Dimethylpiperidin-1~
yl)ethyl)carbamoyl)fluorophenyl)—7—(1~methyl-
1 H-pyrazo!-4—yl)imidazo[1,2-a]pyridine—3-
9.4 carboxamide
LCMS: Rt 0.81 mins; MS
m/z 546.4 [M+H]+;
Method 2minLopr
N-(2—fluoro—5-((2—(2,2,6,6-tetra methylpiperidln-l-
y$1)ethy1)carba moy|)phenyI)—7-(1-methyl-‘l H-
; pyrazol—5—yl)imidazo{1,2—a]pyridine~3—
carboxamide hydrochloride salt
[Eon/18: Rt 0.75 mins; MS
m/z 492.3 [M+H]+;
Method 2minLC_v003
N—(5-((2-(tert-
butyl(methyl)amino)ethyl)carbamoyl)—2-
fluorophenyl)—7-(1-methyl-1H-pyrazol—S—
yl)imidazo[1,2—a]pyridine—3-carboxamide
$9.6 chloride salt
LCMS: Rt 0.59 mins; MS
m/z 501/502/503{M+H}*;
Method _v003
l N-(5-((2-(2,2-dimethylpyrrolidin-1 -
yl)ethyl)carbamoyl)methylpyrldin-3—y|)(‘l -
methyl-1 H-pyrazolyl)pyrazolo[1,5-a]pyridine-
3—carboxamide hydrochloride salt
LCMS: Rt 0.66 mins; MS
m/z 607/608 {M+H}*;
Method 2minLC_v003
fluoro )(3-fluoro—4—((2—hyd roxy
35myl)0arb amoy|)phenyl)imidazo[1,2—a]pyri dine-
3-carboxamide
LCMS: Rt 0.79 mins; MS
m/z 648.6 [M+H]+;
Method 2minLopr
Int BB and Int 8A
7-(3—fluoro—4—((1-hydroxy—2—methylpropan—Z—
yl)carbamoyl)phenyl)—N—(2—fluor0—5—((2~(3—
propylpyrrolidin
yl)ethyl)carbamoyl)phenyl)imidazo[1,2-
a]pyridine-3~carboxamide
LCMS: Rt 0.74 mins; MS
m/z 650.6 [M+H]+;
Method 2minLopr
oA‘K
\\/N\/\m O
N—(5-((2-<3,3-
dimethylmorpholino)ethyl)carba moyl)—2—
fluorophenyl)(3-fiuoro—4-((1-hyd roxy-Z-
methylpropan-Z-
; bamoyl)phenyl)imidazo[1,2-a]pyridine-3—
19.10 carboxamide
LCMS: Rt 0.75 mins; MS
m/z 648.7 ;
Method 2minLopr
(R)—7-(3-fluoro-4~((1-hydroxy—Z-methylpropan—Z—
yl)carbamoyl)ph enyl)-N-(2-fluoro-5—((2—(2—
(methoxymethyl)pyrrolidinyl)ethyl)
carbamoyl)phenyl)imidazo[1,2-a1pyridine
9.11 carboxamide
LCMS: Rt 0.74 mins; MS
m/z 616.6 [M+H]+;
Method 2minLopr
N-(5~((3,4-Difluorobenzyl)carbamoyl)—2—
fluorophenyI)(6-((2~
(dimethylamino)ethyl)Carbamoyl)pyridin—3—
LCMS: Rt 0.66 mins; M8
m/z 515.7 ;
Method 2minLopr
N-(5-((2—(2,2—Dimethylpiperidin—1-
yl)ethy|)oarba moyl)-2—methy|pyridin—S—yl)—6—(1 —
methyl-1H-pyrazoIyl)pyrazolo[1,5-a]pyridine—
9.13 3-carboxamide
LC—MS: Rt 0.62 mins; MS
m/Z 515.7 {M+H}+;
Method 2minLC_v003
N—(5—((2-(2,6—dimethyl
piperidin-1—yl)ethyl)
carbamoyl)—2~methylpyridinyl)—6-(1~methyl—
1 H-pyrazol-4—yl)pyrazolo[1 ,5-a]pyridine—3-
LC-MS: Rt 0.66 mins; MS
E \ m/z 518.5 M+H +;
F H \ [ 1
N N \ \r}!
\ Method 2minLoprv01
_ N\
L O
‘ NH
‘ N-(5—((2—((28,3R)~2,3-diethylazetidin-1~yl)ethyl)
carbamoyl)fluoropheny!)~7-(1~methyl—1 H-
pyrazol-4—y8)imidazo[1,2—a]pyridine~3—
9.1 5 amide
Example 10.1:
N-(5-(3,4-Difluorobenzylcarbamoyl)—2-fluorophenyi)(6-(((2-hydroxyethyl)
(methyl)amino)methyl)pyridinyl)imidazo[1,2-a]pyridine—3-carboxamide
PCT/IBZOlZ/054501
(3,4-Difluorobenzylcarbamoyl)fluorophenyl)(6-formylpyridin
yl)imidazo[1,2—a]pyridine—3-carboxamide
A e comprising 7—bromo—N—(5—(3,4—difluorobenzylcarbamoyl)—2~fluorophenyl)
imidazo[1,2—a]pyridine—3—carboxamide (Intermediate 3A)(2.7 g, 5.36 mmol), 5»
(4,4,5,5—tetramethyl-1,3,2-dioxaborolanyl)picolinaldehyde (1.375 g, 5.90 mmol)
and cesium carbonate (6.99 g, 21.46 mmol) in DME (30 ml) and water (3 ml) was
d with PdCl2(dppf).CHQCl2 adduct (0.219 g, 0.268 mmol). The mixture was
placed under nitrogen and heated at 100°C for 1hr. The resulting mixture was
concentrated in vacuo and the residue was dissolved in 10% trifluoroethanol/CHClg.
The organics were washed with water and NaHCOa and concentrated in vacuo.
Purification by chromatography on silica eluting with 0-30% 2M NH3 in CM
afforded the title product;
LC-MS: Rt 0.67 mins; MS m/z 530/531 {M+H}+; Method 2minLC_v003
grep—2: N-(5-(3,4-Difluorobenzylcarbamoyl)-2—fluorophenyl)—7-(6—(((2—hydroxy
ethyl)(methyl)amino)methyl)pyridin-S-yl)imidazo[1,2-alpyridinecarboxamide
A suspension of N-(5-(3,4-difluorobenzylcarbamoy|)fluorophenyl)(6-
formylpyridin—B-yl)imidazo[1,2-a]pyridinecarboxamide (step 1)(1OO mg, 0.189
mmol), 2-(methylamino)ethanol (70.9 mg, 0.944 mmol) and molceular sieves in EtOH
(2 ml) was heated at 70°C overnight. The mixture was cooled to 0°C and treated with
sodium borohydride (7.15 mg, 0.189 mmoi). The mixture was allowed to warm to RT
and was stirred overnight. The resulting suspension was removed by filtration and
the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc
and water. The organic portion was separated, washed with Na H003, dried (MgSO4)
and concentrated in vacuo. Purification of the residue by preparative chromatography
eluting with 25—50% 0.1% TFA acetonitrile/water ed fractions that were
combined and diluted with NaHCOa and 5% trifluoroethanol/DCM. The organics were
separated, dried and trated in vacuo to afford a white solid. The solid was
1O triturated with EtOH/Ether to afford the title nd as a white solid;
LC—MS: Rt 0.74 mins; MS m/z 589/590/591 {M+H}+; Method 2minLC__v003
Example 10.2
N-(5-((3,4-difluorobenzyl)carbamoyl)fluorophenyl)(6-((methyl
(phenethyl)amino)methyl)pyridinyl)imidazo[1,2-a]pyridine-B-carboxamide
N\ VD
The title compound was prepared analogously to Example 10.1 from the appropriate
amine in step 2;
LC-MS: Rt 0.83 mins; MS m/z 649/650 {M+H}+; Method 2minLC_v003.
The compounds of the following tabulated Examples (Table 5) were prepared by a
r methods to that of Example 10 from the appropriate ng compounds, the
preparations of which are detailed herein and in the ‘Preparation of lntermediates’
section.
Table 5
Structure
[M+H]*/NMR
m/z 649/650 {M+H}+;
Method 2minLC_v003.
((3,4-Dif|uoro benzyl)carbamoyl)—2—
Efluorophenyl)—7~(6—
((methyl(phenethy|)amino)methyl)pyridin-3—
yl)imidazo[1,2—a]pyridine—3—carboxamide
EN-(5-((3,4-Difluoro benzyl)carbamoyl)-2— LCMS: Rt 0.71 mins; MS
Efluorophenyl)-7—(5—((methylamino) m/z 544.5 [M+H]+; Method
methyl)pyridinyl)lmidazo[1 ,2—a]pyridine—3~
110.3 carbox amide
LCMS: Rt 0.80 mins; MS
m/z 612.6 ; Method
7—(5—((Cyclohexyl amino)methyl)pyridin—B-yl)—N—
E(5-((3,4-dlfluorobenzyl) carba moyl)—2-fluoro A
E 10.4 i phenyl) imidazo[1,2-a]pyrid inecarboxamide
WO 30802
LCMS: Rt 0.74 mins; MS
N—(5—((3,4—Difluoro benzyl)carbamoyl)—2—
m/z 602.6 [M+H]+; Method
fluorophenyl)—7—(5-(((2-methoxyethyi)
(menu/[)3min0)m8thy1)pyridinyl)imid azo[1,2—
.5 a]pyridine~3-carboxamide
Preparation of Intermediates
Intermediate 1A Methyl 3-(7-bromoimidazo[1,2-a]pyridinecarboxamido)
fluorobenzoate
N\ \ Br
O O
§t§p_1: Potassium (Z)—2—chloro—1 -ethoxy—3~oxoprop-1~enolate
A cooled (0°C) sion of ethyl 2-chloroacetate (17.47 ml, 163 mmol) and ethyl
formate (13.18 ml, 163 mmol) in ether (250 ml) was treated slowly (over 3 hrs) with
ium 2-methylpropan-2—olate (18.31 g, 163 mmol) keeping the temperature
below 5°C. The mixture was concentrated in vacuo and the resulting solid was
washed with ether and dried (47 °C in a vacuum oven) to afford the title compound;
1H NMR (400MHz, d6—DMSO) 6 8.95 (1H, s), 3.9 (2H, q), 1.1 (3H, t).
E92; Ethyl 7-bromoimidazoi1,2-a]pyridine—S—carboxylate
WO 30802
A solution of 4-bromopyridin—2-amine (10 g, 57.8 mmol) and potassium (Z)chloro-
1-ethoxy—3—oxoprop—1—en—1—olate (step 1)(23.4 g, 124 mmol) in ethanol (200 ml) was
cooled to 5°C. Sulfuric acid (7.70 ml, 144 mmol) was added dropwise and the
reaction heated to reflux at 90°C for 3 hrs. The mixture was cooled to RT and TEA
(20.03 ml, 144 mmol) was slowly added and heating continued at 90°C for 18 hrs.
After cooling to RT, the mixture was filtered and the solid was partitioned between
EtOAc and aqueous 2M HCl. The aqueous layer was d (NaOH, solid pellets)
and extracted using EtOAc. The combined organic extracts were dried (M9804) and
concentrated in vacuo to afford the title compound;
1O 1H NMR (400MHz, d6-DMSO) 5 9.1 (1H, d), 8.3 (1H, s), 8.2 (1H, s), 7.4 (1H, d), 4.4
(2H, q), 1.4 (3H, t)
$93: 7—Bromoimidazo[1,2—a]pyridine—3-carboxylic
Ethyl 7—bromoimidazo[1,2~a]pyridine-3—carboxylate (step 2)(30.81 g, 114 mmol) in
MeOH (172 ml) was treated with 2M NaOH (172 ml, 343 mmol) and the mixture was
heated to 60°C for 40 minutes.The volatile solvent was removed in vacuo and the
crude material was treated with 2M sodium bisulfate solution to adjust the pH to 6—7.
The resulting solid was collected by filtrationand added to water (400 ml). The
mixture was stirred and heated to 90°C for 1h. After cooling to RT, the suspension
was filtered and dried in a vacuum over at 40°C to afford the title product;
LC-MS: Rt 0.59 mins; MS m/z 243.1 {M+H}+; Method 2minLC_v003
flap—4: Methyl 3-(7—bromoimidazo[1,2—a]pyridine—3-carboxamido)—4-fluorobenzoate
A e comprising 7-bromoimidazo[1,2-a]pyridinecarboxylic acid (step 3)(1.8
approximately 7.47 mmol) and thionyl chloride (10 ml, 137 mmol) under N2 was
heated at reflux for 1.5 hrs. The reaction e was concentrated in vacuo and
azeotroped with toluene. Methyl 3—aminofluorobenzoate (1.263 g, 7.47 mmol) (pre-
dried at 45°C) was added followed by pyridine and the mixture was stirred at room
temperature under N2 overnight. The reaction mixture was d with EtOAc and
washed with H20. The resulting solid was collected by tion. The filtrate was dried
(M9804) and concentrated in vacuo and triturated with ether to afford cream solid.
The solids were combined and dried at 450C to afford the title compound;
LC—MS: Rt 0.97 mins; MS m/z 392 {M+H}+; Method 2minLC_v003
1H NMR (400MHz, DMSO-d6) 5 10.3 (1H, s), 9.4 (1 H, d), 8.6 (1H, s), 8.3 (1H, m),
8.2 (1H, s), 7.9 (1 H, m), 7.5 (1H, t), 7.4 (1H, d), 3.9 (3H, 8).
Intermediate 1B Methyl romoimidazo[1,2-a]pyridinecarboxamido)
methylbenzoate
([3 O
A mixture comprising 7-bromoimidazo[1,2—a]pyridine-3—carboxylic acid (intermediate
1A step 3) (750 mg, 3.11 mmol) and thionyi chloride (5 mi, 68.5 mmol) under N2 was
heated at reflux for 2hrs. The mixture was concentrated in vacuo and azeotroped
with e. Methyl 3-amino-4—methylbenzoate (514 mg, 3.11 mmol) (pre—dried at
45°C) was added foiiowed by ne (5 mi) and the mixture was d at room
temperature under N2 overnight. The reaction mixture was diluted with EtOAc and
washed with sat. NaHC03, brine, H20, dried (MgSO4) and concentrated in vacuo.
Purification by chromatography on sitica eiuting with 50-100% EtOAc in iso-hexane
1O afforded the title compound as an orange solid;
LC—MS: Rt 0.94 mins; MS m/z 390/391/392 {M+H}+; Method 2minLC_v003
1H NMR (400MHz, DMSO-d6) 6 10.0 (1H, s), 9.4 (1H, d), 8.6 (1H, s), 8.2 (1H, d), 8.0
(1H, d), 7.8 (1H, d), 7.5 (1 H, d), 7.3 (1H. d), 3.9 (3H, s), 2.4 (3H, s).
ediate 10
Methyl 5-(7-bromoimidazo[1,2-a1pyridinecarboxamido)methylnicotinate
N \N
l o
O 0\
Step 1: Methyl 2-chloromethyinitronicotinate
To a suspension of 6-methyl—5-nitro—2—oxo—1,2-dihydropyridine—B—carboxyiic acid
(commercially available)(12.5 g, 63.1 mmol) in chlorobenzene (210 ml) was added
DMF (2.442 mi, 31.5 mmol) followed by POCls (23.52 mi, 252 mmol). The mixture
was heated at 133 °C for 1 hr. After cooling to RT, the mixture was concentrated in
vacuo. The residue was cooled in an ice bath, treated with MeOH (200 ml, 4944
mmol) and stirred at RT for 16hrs. The mixture was concentrated in vacuo and the
residue was ioned between water (300 ml) and EtOAc (300 ml). The organics
were dried (M9804) and concentrated in vacuo to afford the title compound as a red
crystalline solid;
LC-MS: Rt 1.10 mins; MS m/z 230.9 {M+H}+; Method 2minLC_vOO3
§teg_2_: Methyl 5-aminomethylnicotinate
Methyl 2—chloro~6—methyl-5—nitronicotinate (step 1)(6.9 g. 29.9 mmol) was added to a
suspension of ammonium formate (18.87 g. 299 mmol) and 10% Pd(Carbon)(0.522
g, 0.491 mmol) in MeOH (330 ml) and the e was heated at reflux for 3 hrs.
After cooling to RT, the mixture was filtered through Celite® (filter material) and
washed through with MeOH. The t was removed in vacuo and the crude
’15 product was ated with EtOAc to give an orange solid. Purification by
chromatography on silica eluting with O—100% EtOAc in iso-hexane afforded the title
product.
$93; Methyl 5-(7—bromoimidazo[1,2—a]pyridine—3—carboxamido)—6—methylnicotinate
The title compound was prepared from 7-bromoimidazo[1,2—a]pyridinecarboxylic
2O acid (Intermediate 1A, step 3)and methyl 5—aminomethylnicotinate (step 2)
analogously to intermediate 1A;
1H NMR(4OOMHZ,d6-DMSO)610.21 (1H, s), 9.40 (1H, J=7.4, d), 8.83 (1H, s), 8.55
(1H, s), 8.39 (1H, s), 8.13 (1H, J=1.6, d), 7.35 (1H, J=2.0,7.4, dd), 3.89 (3H, s), 2.58
(3H, 3)
Intermediate 1D
Methyl yl(6-(1-methyI-1H-pyrazolyl)pyrazolo[1,5-a]pyridine
carboxamido)nicotinate
0 OMe
mEthyl 6-(1—methyl-1H—pyrazol—S-yl)pyrazolo[1,5-a]pyridine-3—carboxylate
A mixture comprising ethyl 6-bromopyrazolo[1,5-a]pyridinecarboxylate (1.5
g, 5.57
mmol), 1-methyl-5—(4,4,5,5-tetramethyl-1,3,2-dioxaborolan~2-yl)—1H-pyrazole (1.218
g, 5.85 mmol), cesium carbonate (7.26 g, 22.30 mmol) and PdCl2(dppf).CH2012
adduct (91 mg, 0.111 mmol) in DME (10 ml) and water (4.00 ml) was heated using
microwave ion at 70 °C for 1 hr. r dppf).CH20l2 adduct (91 mg,
0.111 mmol) was added and the mixture was heated at 80 °C for 1 hr. 1-Methyl
(4,4,5,5-tetramethyl—1,3,2-dioxaborolan-2—y|)-1H-pyrazole (1.218 g, 5.85 mmol) and
PdCl2(dppf).Cchl2 adduct (91 mg, 0.111 mmol) were added and heating continued
at 100 °C for 3 hrs. The e was diluted with 10% MeOH in EtOAc (200 ml) and
washed with sat. NaHCOB. The organic solvent was removed under vacuum and
azeotroped with toluene. The resulting solid was loaded onto silica and purified by
chromatography eluting with 0 ~ 100% EtOAc in iso~hexane to afford the title
compound;
LC—MS: Rt 0.92 mins; MS m/z 271.4 {M+H}+; Method 2minLopr
m6-(1-Methyl—1H—pyrazol—S-yl)pyrazolo[1,5-a]pyridine-3~carboxylic acid
The title compound was prepared from ethyl 6—(1—methyl-1H—pyrazol—S-
yl)pyrazolo[1,5—a]pyridine—3-carboxylate analogously to Intermediate 1A step 3;
LC—MS: Rt 0.72 mins; MS m/z 243.3 {M+H}+; Method 2minLopr
l 6—methyl—5-(6—(1-methyl—1H-pyrazol-5—yl)pyrazolo[1,5-a]pyridine~3—
carboxamido)nicotinate
6-(1-Methyl—1H-pyrazolyl)pyrazolo[1,5-a]pyridine-3—carboxylic acid (step 2) was
dissolved in pyridine (5 ml, 61.8 mmol) and 6-methylnicotinate (247
mg, 1.486 mmol)
was added. The reaction mixture was stirred under nitrogen overnight. The mixture
was diluted with EtOAc (200 ml) and washed with sat. aq. NaH003 (200 ml). The
2012/054501
s portion was back-extracted with EtOAc (100 ml) and the combined organic
extracts were, dried MgSO4, filtered and concentrated under vacuum to give yellow
solid. Purification of the solid by tography on silica eluting with 0 - 20% 2M
NH3 in MeOH / TBME afforded the title compound;
LC—MS: Rt 0.83 mins; MS m/z 391.3 {M+H}+; Method 2minLopr
Intermediate 1E
-(6-Bromopyrazolo[1,5-a]pyridinecarboxamido)methylnicotinic acid
NEH KM...
6%!VJ
.2 “EM.
N xxx- ”Cb
O O H
A solution of methyl 5-(7-bromoimidazo[1,2-a1pyridinecarboxamido)
methylnicotinate (Intermediate 1C)(1 g, 2.57 mmol) and sodium hydroxide (1.028 g,
.7 mmol) in MeOH (20 ml) was heated at 50°C ght. The mixture was
concentrated in vacuo and the residue was dissolved in water. The pH was adjusted
to pH4 by addition of 1N HCI and the resulting solid was collected by filtration and
dried at 45°C to afford the title compound;
LC-MS: Rt 0.82 mins; MS m/z 376/377 {M+H}+; Method 2minLoprv01
Intermediate 2A
7—Bromo-N-(5-(2-tert-butoxyethylcarbamoyl)fluorophenyl)imidazo[1,2-
aIpyridinecarboxamide
F N
E. l \
N \
0 \
o ”No
Step 1: 3-Amino—N-(Z—tert—butoxyethyl)—4-fluorobenzamide
WO 30802
A mixture comprising 2—tert~butoxyethanamine (1.2
g, 5.12 mmol, 50%w/w) and
methyl ofluorobenzoate (0.866 g, 5.12 mmol) in THF (10 ml) was treated
with TBD (0.713 g, 5.12 mmol) and heated at 90 °C for 16 hrs. After cooling to RT,
the solvent was removed in vacuo and the residue was partitioned between water
and EtOAc. The organic portion was separated and washed with 10%
aq citric acid (x
2), NaHC03(sat. aq), brine, dried (MgSO4) and concentrated in vacuo. Purification of
the crude product by chromatography on silica eluting with O-100% EtOAc in iso-
hexane afforded the title compound as a clear oil;
LC—MS: Rt 1.09 mins; MS m/z 255 [M+H]+; Method 2minLC_v003
1O §E_Q_2_: 7—Bromo—N-(5—(2-tert—butoxyethylcarbamoyl)fluoropheny|)imidazo[1 ,2-
dine—3—carboxamide
6-Bromoimidazo[1,2-a]pyridine—3-carboxylic acid (commercially available)(1024 mg,
4.25 mmol) was ded in toluene (30 ml) and thionyl chloride (1.550 ml, 21.23
mmol) was added. The mixture was heated at 110 °C for 3 hrs. The solvent was
removed in vacuo and the resulting residue was treated with a solution of 3-amino—N-
(2-tert-butoxyethyl)-4—fluorobenzamide (step 1) (900 mg, 3.54 mmol) in pyridine (10
ml). Molecular sieves were added the mixture was stirred at RT for 16 hrs. In a
separate flask, 6-bromoimidazo[1,2-a]pyridine-3—carboxylic acid 640 mg, 2.65 mmol)
in e (30 ml) was treated with l chloride (0.969 ml, 13.27 mmol) at 110 °C
for 3 e solvent was removed in vacuo and the solid e was added to the
reaction mixture in the original flask. Stirring continued for 3 days. The mixture was
poured into MeOH and the resulting suspension was removed by filtration.The filtrate
was azeotroped with toluene to give a solid, which was triturated with MeOH to afford
the product. The filtrate was concentrated in vacuo and the residue was dissolved in
DCM (2% MeOH) and washed with water. The organic portion was dried (M9804)
and concentrated in vacuo to afford a solid that was triturated with EtOAc to give the
title compound;
LC-MS: Rt 0.96 mins; MS m/z 477(479); 1) [M+H]+; Method 2minLC_v003
Intermediate ZC
7-Bromo-N-(4-f|uoromethyl(2-(4-methylpiperazinyl)benzylcarbamoyl)
phenyl) imidazo[1,2-a]pyridinecarboxamide
YES.
O NH [NJ
ml; 2-FIuoro-4—methyl—5-nitrobenzoic acid
2-FIuoro—4-methyibenzoic acid (1 g, 6.49 mmol) in H2804 (19 ml, 356 mmol) was
cooled to 0 °C in an ice salt water bath and treated dropwise with mixture of H2804
(0.763 ml, 14.31 mmol) and nitric acid (0.65 ml, 14.54 mmol) over 10 min. The
reaction mixture was stirred at 0 °C for 3 hrs and poured into ice/water (200 ml) and
stirred for a further hour. The resulting sion was ted by filtration, dried in
vacuo and collected in EtOH, azeotroping to dryness to afford the title compound.
mg5—Aminofluoromethylbenzoic acid
2-Fluoro-4—methyI—5-nitrobenzoic acid (900 mg, 4.52 mmol) in MeOH (70 ml) was
treated with ammonium formate 1(425 mg, 22.60 mmol) and Pd (Carbon) (144
1.356 mmol). The mixture was degassed ghly refilling with nitrogen and heated
to 60 °C for 2 hrs. The mixture was filtered through silica and washed with MeOH.
The filtrate was passed through SCX—Z resin (309 0.67 mmoi lg) eluting with MeOH
(250 ml) followed by 2M ammonia in MeOH (250 ml). The ammonia/MeOH washings
were evaporated to dryness and the resulting crude residue was purified by
recrystallisation from MeOH to afford the title compound;
LC~MSz Rt 0.53 mins; MS m/z 170 {Mi-HF; Method 10minLC_v003
nofluoro-4—methyl-N-(2-(4-methylpiperazinyl)benzyl)benzamide
A mixture sing (2—(4-methylpiperaziny|)phenyl)methanamine (413
mg, 2.010
mmol) and 5-aminofluoromethylbenzoic acid (step 2)(340 mg, 2.010 mmol) in
DMF (3 ml) was treated with DIPEA (0.351 ml, 2.010 mmol) followed by HATU (764
mg, 2.010 mmol) and stirred at 25 °C for 24 hrs. The mixture was partitioned
between water and EtOAc. The organic portion was washed with sat.
aq. NaHCOa,
0.5 M LiCI and brine (each back extracted with EtOAc). The combined c layers
were dried (M9804), ed and evaporated to dryness to give a pink oil. Purification
by chromatography on silica eluting with O- 20% MeOH in DCM afforded the title
compound;
LC—MS: Rt 0.73 mins; MS m/z 357 {M+H}+; Method 2minLC_v003
_S_tep_4: o—N-(4—fluoromethyl—5-(2-(4—methylpiperazinyl)benzylcarbamoyl)
phenyl)imidazo[1,2-a]pyridine—3—carboxamide
The title compound was prepared from 5-amino-2—fluoro—4~methyI-N—(2-(4-
methylpiperazin-1~yl)benzyl)benzamide (step 3) analogously to 7-bromo—N—(5—(2—tert—
butoxyethylcarbamoyl)—2-fluorophenyl)imidazo[1,2-a]pyridine-S-carboxamide
mediate 2a step 2);
1O LC-MS: Rt 0.91 mins; MS m/z 5794/5824 {M+H}+; Method 2minLC_v003
Intermediate 2D
6-Bromo-N-(5-(2-tert-butoxyethylcarbamoyl)fluorophenyl)pyrazolo[1,5-
a]pyridi necarboxamide
N\ Br
/ N
O NH
The title compound was prepared analogously to Intermediate 2A by replacing 6-
bromoimidazo[1,2-a]pyridine-S-carboxylic acid (step 2) with 6—bromopyrazolo[1,5—
a]pyridine—3—carboxylic acid (commercially available);
LC-MS: Rt 1.13 mins; MS m/z 477.1 {M+H}+; Method _v003.
Intermediate 3A
o-N~(5-(3,4-difluorobenzylcarbamoyl)fluorophenyl)imidazo[1,2-
a]pyridinecarboxamide
955.F H l N\
no-N-(3,4~difluorobenzyl)-4—fluorobenzamide
A mixture comprising methyl 3—aminofiuorobenzoate (2
g, 11.82 mmol), (3,4-
difiuorophenyl)methanamine (2.54 g, 17.74 mmol) and TBD (1.646 g, 11.82 mmol) in
THF (39.4 ml) was heated at 80°C overnight. After cooling to RT, the mixture was
ed by chromatography on silica eluting with 0—20% 2M NH3 in MeOH/DCM to
afford the title compound.
grip—2: 7-Bromo—N-(5-(3,4-difiuorobenzylcarbamoyl)fiuorophenyl)imidazo[1,2—
a]pyridine-3~carboxamide
1O A mixture comprising 7-bromoimidazo[1,2—a]pyridine—3-carboxylic acid (intermediate
1A step 3) (1.4 g, 5.81 mmol) and thionyl chloride (8.48 ml, 116 mmol) was heated at
100°C for 1.5 hrs. The mixture was concentrated in vacuo. 3-Amin0-N—(3,4-
difluorobenzyl)—4—fluorobenzamide (step 1) (1.4 g, 5.00 mmol) and pyridine (16.65 ml)
was added and the ing suspension was stirred at RT for 1 hour. EtOAc and
MeOH were added and the mixture was filtered. The white solid was dried to afford
the title compound;
LC—MS: Rt 0.74 mins; MS m/z 503 {M+H}+; Method 2minLC_30_v003
Intermediate 4A 6-Bromo-N-(2-methyl(2-(4-methylpiperazin
yl)benzylcarbamoyl)phenyl)pyrazolo [1 ,5-a]pyridinecarboxamide
m3-Amino4—“methyl—N-(22-(—4~methyipiperazin——1—yl)benzyl)benzamide
A on of methyl 3—amin04-methylbenzoatec(commercially available) (1.609
9.74 mmol), TBD (2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine) (0.678
4.87 mmol) and methylpiperazinyl)phenyl)methanamine (commercially
available) (2 g, 9.74 mmol) in toluene (30 ml) was heated at reflux overnight. The
reaction mixture was diluted with EtOAc and washed with sat.NaH003 and water.
The organic portion was separated, dried ) and concentrated in vacuo. The
product was purified by chromagraphy on silica eluting with a gradient of 0-20% 2M
NH3 in MeOH/DCM to afford the title compound;
LC-MS: Rt 0.64-0.8 mins; MS m/z 339{M+H}+; Method 2minLC_v003
1H NMR (400MHz, DMSO-d6) d 8.6 (1H, t), 7.25-6.95 (7H, m), 5.0 (2H, s), 4.5 (2H,
d), 2.9 (4H, m), (4H, m), 2.2 (3H, s), 2.1 (3H, s).
m6—Bromo-N-(2—methyl-5—(2—(4-methylpiperazin—1 -
yl)benzylcarbamoyl)phenyl)pyrazolo [1 yridine-3—carboxamide
A mixture comprising 6-bromopyrazolo[1,5-a]pyridinecarboxylic acid (commercially
available)(196 mg, 0.813 mmol) and thionyl chloride (2 mi, 27.4 mmol) was heated at
60°C for 1 hr and concentrated in vacuo. To this was added 3—amino—4-methyl-N—(2-
(4-methylpiperazinyl)benzyl)benzamide (step 1) (220 mg, 0.651 mmol) and
pyridine (5 ml). The reaction was stirred under nitrogen at room temperature for 2
hrs. The mixture was diluted with 10% MeOH in EtOAc and washed with water, sat
NaHCOs, brine and concentrated in vacuo. The crude product was purified by
chromatography on silica eluting with 0—20% 2M NHS in MeOH/DCM to afford the title
compound;
LC-MS: Rt 0.95 mins; MS m/z 561/563/564 {M+H}+; Method 2minLC_v003
Intermediate 4B
N enzylcarbamoyl)f|uorophenyl)iodoimidazo[1,2-a]pyridine
carboxamide
$9.1; 6—lodoimidazo[1,2—a]pyridine—B—carboxyIic acid
The title compound was prepared from 5—iodopyridin—2—amine analogously to 7—
bromoimidazo[1,2-a]pyridine~3-carboxylic acid (Intermediate 1A step 2 and step 3);
LC-MS: Rt 1.07 mins; MS m/z 317 [M+H]+; Method 2minLC_v003
m3-Amino-N-benzylfluorobenzamide
The title compound was prepared from methyl o-4—fiuorobenzoate,
1O benzylamine and 2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine analogously to
3-amin0—4-methyl-N—(Z-(4—methylpiperazin—1-yI)benzyI)benzamide (Intermediate 4A,
step 1);
1H NIVIR (400MHz, DMSO-dS) 6 8.9 (1H, t), 7.4-7.2 (6H, m), 7.0 (2H, d), 5.3 (2H, s),
4.5 (2H, d).
_S_jt_e_g_3_: N—(5—(Benzylcarbamoyl)fluorophenyi)—6—iodoimidazo[1,2—a]pyridine—3—
carboxamide
The title compound was prepared from 6—iodoimidazo[1,2-a]pyridine~3~carb0xyIic acid
(step 1) and 3-3mino-N-benzyI—4~fluorobenzamide (step 2) anangously 6—bromo-N-
(2—methyI-5—(2—(4—methylpiperazin—1—yI)benzylcarbamoy|)phenyI)pyrazolo [1 ,5-
a]pyridine—3—carboxamide (Intermediate 4A);
LC-MS: Rt 0.99 mins; MS m/z 515/516/517 ; Method 2minLC_v003
Intermediate 4C
7-Bromo-N-(5—(2-(2,6-cis-dimethylpiperidinyl)ethylcarbamoyl)
fluorophenyl)imidazo[1,2-a]pyridine-S-carboxamide
8439;]; 3—Amino—N-(2—(2,6-cis—dimethylpiperidinyi)ethyi)—4—fluorobenzamide
A mixture comprising 2-(2,6—cis-dimethylpiperidin—1-yl)ethanaminium chloride (4
.75 mmol) and methyl 3—amino—4-fluorobenzoate (3.51 g, 20.75 mmol) in THF (50
ml) was treated with TBD (2.89 g, 20.75 mmol) and stirred at 80°C for 16 hrs. A
further portion of methyl o-4~fluoro benzoate (1 g) and TBD (0.5 g) were
added and heating continued for 24 hrs. The resulting mixture was partitioned
between ethyl acetate and aqueous sodium bicarbonate. The mixture was extracted
once with ethyl acetate and once with chloroform. The ed organic layers were
1O dried (M9804), filtered and ated to dryness. Purification of the e by
chromatography on silica eluting with 0-20% MeOH in DCM afforded the title
compound;
LC-MS: Rt 0.71 mins; MS m/z 294 {M+H}+; Method 2minLC_v003.
Step 2: 7—Bromo-N-(5-(2-(2,6—cis-dimethylpiperidinyl)ethylcarbamoyl)—2-
fluorophenyl)imidazo[1,2—a]pyridine—3—carboxamide
7—Bromoimidazo[1,2-a]pyridine—3-carboxylic acid (intermediate 1A step 3) (1.150 g,
4.77 mmol) was suspended in toluene (10 ml) and treated with thionyl chloride (1.045
ml, 14.32 mmoi). The mixture was at 100°C for 2hrs. The solvent was removed in
vacuo and the solid was added to a stirred solution of 3-amino—N—(2-(2,6-cis—dimethyl
piperidinyl)ethyl)fluorobenzamide (1.4 g, 4.77 mmol) in dry pyridine (5 ml)
containing oven dried molecular sieves. The mixture was stirred at RT under
nitrogen here overnight. The t was removed in vacuo and purification of
the crude t by chromatography on silica eluting with 0-20% MeOH in DCM
afforded the title compound;
LC—MS: Rt 0.82 mins; MS m/z 516{M+H}+; Method 2minLC_v003
Intermediate 4D
6-Bromo-N-(2-fluoro(2-(4-methylpiperazinyl)benzylcarbamoyl)phenyi)
pyrazolo[1,5-a]pyridinecarboxamide
The title compound was prepared analogously to lnteremdiate 4A from the
appropriate ng compounds;
LC—MS: Rt 0.95 mins; MS m/z 565/568/569 {M+H}+; Method 2minLC__v003
Intermediate 4E
7-Bromo-N-(5-((5,5-dimethyltetrahydrofuranyl)methylcarbamoyl)
phenyl) imidazo[1,2-a]pyridinecarboxamide
rjlj/ TEEa—jfiafirr: tn“?
1O Sim; 5—(Azidomethyl)-2,2-dimethyltetrahydrofuran
momethyl)—2,2-dimethyltetrahydrofuran (36 g, 186 mmol) in DMF (300 ml) was
treated with solid sodium azide (12.73 g, 196 mmol) and heated at 90 °C for 4 hrs.
The mixture was allowed to cool to RT and partitioned between water(1.5 l) and ether
(2 x 500 ml). The ether layer was separated and washed with (0.5M ) LiCl (500 ml),
dried M9804, filtered and ated to afford the title compound;
Slap; (5,5-Dimethyltetrahydrofuran—2-yl)methanamine
-(Azidomethyl)-2,2-dimethyltetrahydrofuran (22 g, 142 mmol) in THF (500 ml) was
treated with Triphenylphosphine (39.0 g, 149 mmol) and t stirred for 5 mins. Water
(50.0 ml) was added and the reaction mixture was heated at 80 °C for4 hrs. The
mixture was passed through lsolute® SCX—2 resin (2009 0.67 mmol Kg) eluting with
MeOH(500 ml), DMSO (100 ml), 20% MeOH2DCM (500 ml), MeOH (500 ml) followed
7M ammonia in MeOH (500 ml). The ammonia layer was evaporated to dryness to
afford the title compound.
LC—MS: Rt 0.63 mins; MS m/z 243 [M+H]+; Method 2minLC_v002_low mass
Step 3—4: 7-Bromo-N-(5-((5,5-dimethyltetrahydrofuranyl)methylcarbamoyl)—2—
fluorophenyl)imidazo[1,2-a]pyridine-3—carboxamide
The title compound was ed from (5,5-dimethyltetrahydrofuran—Z-yl)methan
amine (step 2) and methyl 3—amino-4—fluorobenzoate analogously to lntermediate 4A
steps 1 and 2;
LC—MS: Rt 0.96 mins; MS m/z 491 [M+H]+; Method 2minLC_v003
intermediate 4F
7-Bromo-imidazo[1,2-a]pyridinecarboxylic acid {5-[((S)-5,5-dimethyl
-tetrahydro-furanylmethyl)wcarbamoyfl-Z-fluoro-phenyl}-amide
The title compound was ed analogously to Intermediate 4E by replacing (5,5-
dimethyltetrahydrofuran-2—yl)methanamine (step 3) with (S)—(5,5~dimethyltetra
hydrofuran-Z—yl)methanamine;
LCMS Rt 0.87 mins; MS m/z 491/492 [M+H]+; Method __v003
Intermediate 5A
4-Fluoro(imidazo[1,2-a]pyridinecarboxamido)benzoic acid
FH]N\
O OH
Step 1: |midazo[1,2-a]pyridinecarbonyl chloride
A suspension of imidazo[1,2-a]pyridine—3—carboxylic acid (5.270
g, 32.5 mmol) in
DCM (200 ml) was treated with oxalyl chloride (3.13 ml, 35.8 mmol) followed by the
addition of DMF (0.252 ml, 3.25 mmol). The reaction mixture was stirred at RT
overnight. The solvent was removed in vacuo to afford the title compound as a
hydrochloride salt;
1H NMR (400 MHz, DMSO-d6) 6 9.48 (1H, d), 8.77 (1H, s), 7.99 (2H, m), 7.56 (1 H,
§t_e_p_2: Methyl o-3—(imidazo[1,2—a]pyridine—3-carboxamido)benzoate
A solution of methyl 3—amino—4—fluorobenzoate (5 g, 29.6 mmol) in pyridine (200 ml)
1O was treated with imidazo[1,2—a]pyridine-3—carbonyl chloride.HCl (step 1)(6.43 g, 29.6
mmol) and the mixture was stirred at RT for 2 days. The e was poured into
water (30 ml) and a small exotherm was observed. After cooling to RT, the resulting
itate was filtered and dried in a vacuum oven to afford the title compound;
LC-MS: Rt 0.81 mins; MS m/z 314.2 {M+H}+; Method 2minLC_v003
1H NMR (400 MHz, DMSO-d6) 6 10.30 (1H, s), 9.44 (1H, d), 8.63 (1H s), 8.34 (1H,
dd), 7.83 (1H, m), 7.78 (1H, d), 7.54 (1H, m), 7.48 (1H, m), 7.20 (1H, t), 3.90 (3H, s).
gm4—Fluoro(imidazo[1,2-a]pyridine—3-carboxamido)benzoic acid
A suspension of methyl 4-fluoro—3-(imidazo[1,2-a]pyridinecarboxamido)benzoate
(step 1) (7.2 g, 22.98 mmol) in water (30 ml), THF (45.0 ml) and MeOH (15.00 ml)
2O was treated with lithium hydroxide monohydrate (4.82 g, 115 mmol). The reaction
mixture was stirred at RT ght and concentrated in vacuo to remove THF and
MeOH. The resulting mixture was acidified with 2M HCl to yield a solid that was
collected by filtration and washed with ether (3 x). The white solid was dried in the
vacuum oven at 50°C to afford the title compound as a hloride salt;
LC-MS: Rt 0.71 mins; MS m/z 300.2 {M+H}+; Method 2minLC_v003
1H NMR (400 MHz, 6) 5 13.21 (1H, br 8), 10.68 (1 H, s), 9.60 (1 H, s), 8.94
(1H, s), 8.29 (1 H, dd), 8.00 (1H, d), 7.86 (2H, m), 7.47 (2H, m).
Intermediate 6A
(S)(2-(Methoxymethyl)pyrrolidinyl)ethanamine
§_t_e_L1_: (S)—tert—Butyl 2-(2-(methoxymethyl)pyrrolidin—1-yl)ethylcarbamate
A suspension comprising (S)—2—(methoxymethyl)pyrrolidine (1
g, 8.68 mmol), tert-
butyl 2—bromoethylcarbamate (1.946 g, 8.68 mmol), triethylamine (1.210 ml, 8.68
mmol) and potassium carbonate (1.200 g, 8.68 mmol) in MeCN (10 ml) was heated
at 85°C ght. The resulting mixture was filtered and washed with MeCN.
Purification of the crude product by chromatography on silica eluting with 0—5%
MeOH in DCM afforded the title compound as a colourless oil;
1H NMR (400MHz), DMSO-d6) 6 3.3 (1H, s), 3.25 (3H, s), 3.15 (1H, m), 3.0 (2H, m),
2.9 (1H, m), 2.8 (1H, m), 2.55 (1H, m), 2.3 (1H, m), 2.15 (1H, q), 1.8 (1H, m), 1.65
(2H, m), 1.45 (1H, m), 1.4 (9H, s).
_: (S)—2-(2-(Methoxymethyl)pyrrolidlnyl)ethanamine
A solution of (S)-tert-buty| 2—(2-(methoxymethyl)pyrrolidin-1—yl)ethylcarbamate (step
1)(1.89 g, 7.32 mmol) and in MeOH (5 ml) and treated with 2M HCl in MeOH (10
equivalents) at room temperature over the weekend. The solvent was d in
vacuo to afford the title compound;
1H NMR (400MHz, CDCl3) 5 3.45 (1H, m), 3.25 (1 H, m), 3.1 (1H, m), 2.9 (1H, m),
2.8 (2H, m), 2.6 (1H, m), 2.5 (3H, s), 2.4 (1H, m), 2.2 (1H, m), 0.8 (1H, m), 1.7 (2H,
m), 1.6 (1H, m).
The intermediates of the following table (Table 6) were ed by a similar method
to that of intermediate 6A from the appropriate commercially available ng
compounds.
MeOD)5 3.5 (2H, t), 2.9
2-(3-propylpyrrolidin- (1H, t): 2-75 (3H, m),
1-yl)ethanamine 2-55 (1H, m), 2 (3H, m),
1.4 (4H, m), 1 (3H, t)
PC17IB2012/054501
1H NMR (400MHz,
CDCI3)53.4 (1H, m),
3.38 (3H, s), 3.5 (1H, m),5
(S)-2—(2—(methoxy
2.9 (1H, m), 2.8 (2H, m),
methyl) pyrrolidin-‘l-
2.6 (1H, m), 2.4 (1H, m),
yl)ethanamine
2.2 (1H, q), 1.9 (1H, m),
1.7 (2H, m), 1.6 (1H, m).
1H NMR (400MHz,
00013) 5 3.45 (1H, m),
3.25 (1H, m), 3.1 (1H,
(2-(methoxy m), 2.9 (1H, m), 2.8 (2H,
methyl) pyrrolidin m), 2.6 (1H, m), 2.5 (3H,
yl)ethanamine s), 2.4 (1H, m), 2.2 (1H,
m), 0.8 (1H, m), 1.7 (2H,
m), 1.6 (1H, m).
0 _.
H NMR z),
(2-(tert-butyl(methyl) DMSO) 5 8.15 (3H, br),
amino)ethanamine 3.60 (1H, m), 3.30 (2H,
trifluoro acetate m), 3.07 (1H, m), 2.76 Mun—“mg“
(3H, s), 1.34 (9H, s),
1H NMR (400MHz),
CDSOD) 5 3.75—3.42
(4H, m), 3.17 (2H, m),
2—(2,2-dimethyl piper 1.87 (4H, m), 1.70 (2H,
idin—1-yl) ethanamine m), 1.55-0.82 (6H, m),
Intermediate 7A
3-(5-Carboxyfluorophenylcarbamoyl)(1-methy|-1H-pyrazoI
yl)imidazo[1,2-a]pyridinium chloride
Lula JIM tax
( I/ '
0"" Kim
The title compound was prepared analogously to yl—5—(6—(1—methy|—1 H~
pyrazol~4—yl)pyrazolo[1,5-a]pyridine—3—carboxamido)nicotinic acid (Example 9.0 step
2) from methyl romoimidazo[1,2—a}pyridine3—carboxamido)—4-f|uorobenzoate
(Intermediate 1A) and 1-methyl(4,4,5,5—tetramethyl-[1,3,2]dloxaborolan-2—yl)—1 H-
pyrazole followed hydrolysis of the resulting methyl ester using sodium ide;
LC-MS: Rt 0.77 mins; MS m/z 380 [M+H]+; Method 2minLC_v003
Intermediate TB
6-MethyI(6-(1-methyl-1H-pyrazolyl)pyrazolo[1,5-a]pyridinecarboxamido)
nicotinic acid
The title compound was prepared analogously to 6-methyl—5-(6-(1-methyl-1H-
pyrazolyl)pyrazolo[1,5-a]pyridine—3—carboxamldo)nicotinic acid (Example 9.0 step
2) from Intermediate 10 and 1-methy|—5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2—
yl)—’l H—pyrazole followed ysis of the resulting methyl ester using sodium
hydroxide;
LC—MS: Rt 0.69 mins; MS m/z 377/378 [M+H]+; Method 2minLC_vOO3
Intermediate 8A
4-Fluoro(7-(3-fluoro(1-hydroxymethylpropan
ylcarbamoyl)phenyl)imidazo[1 ,2-a]pyridinecarboxamido)benzoic acid
“‘ J
t/ \\ F
{4“-N’Z
: H
N K/\mRa
HO who
Steps 1 and 2: 7-(3-Fluoro-4~(1-hydroxy—2-methylpropan-2—ylcarbamoyl)phenyl)—N—(2-
fluoro(1-hydroxymethylpropanylcarbamoyl)phenyl)imidazo[1,2-a]pyridine—3-
carboxamide
The title compound was analogously to Example 9.0 steps 2 and 3 from
(1) ediate 1A and 4—borono—2—fluorobenzoic acid analogously to Example 9
step 2;
(2) 4-(3-(5-Carboxy—2-fluorophenylcarbamoyl)imidazo[1,2-a]pyridin-7—yI)
fluorobenzoic acid (step 1) and omethylpropanol;
LC-MS: Rt 0.91 mins; MS m/z 580.4 [M+H]+; Method prvO1
SE12; 4—Fluoro—3-(7-(3-fluoro—4-(1-hydroxy-2—methy|propan—2-
yloarbamoyl)phenyl)imidazo[1,2—a]pyridine—3—carboxamido)benzoic acid
7-(3—FIuoro—4—(1—hydroxy—2-methylpropan—2—ylcarbamoyl)pheny|)-N—(2~fluoro~5—(1—
hydroxy-2—methylpropan-2—ylcarbamoyl)phenyl)lmldazo[1,2-a]pyridine—3-carboxamide
(step 1)(590 mg, 1.129 mmol) in 1.2-dimethoxyethane (10 ml) and water (10.00 ml)
was treated with sodium hydroxide (181 mg, 4.52 mmol) and warmed to 60°C for 1hr.
After cooling to RT, the pH of the mixture was adjusted to pH5 using 2M HCl (2.2 ml).
The solvent was removed in vacuo and the resulting crude product was triturated
with water to afford the title compound;
LCMS: Rt 0.92 mins; MS m/z 509.4 [M+H]+; Method 2minLopr
intermediate 9A
(S)-(5,5-Dimethyltetrahydrofuranyl)methanamine
. '1.
”fit/1 ”f
To a stirred solution of (S)—(5,5~dimethyltetrahydrofuran—2-yl)methanol (14
g, 108
mmol) and PPh3 (33.8 g, 129 mmol) in THF (140 ml) under N2 was added
phthalimide (17.40 g, 118 mmol) to give a suspension. The mixture was cooled to
8°C and DlAD (27.2 ml, 140 mmol) was added dropwise over 30 mins keeping
1O internal T <10 °C. The resulting white slurry was diluted with water (100 ml) and
ted with EtOAc (100 ml). The organics were washed with sat. NaH003 (100
ml), brine (100 ml) and dried (M9804) and concentrated under reduced pressure.
Purification by chromatography on silica g with 0—20% EtOAc/iso—hexane
ed the title compound as a white crystalline solid;
LC—MS: Rt 1.02 mins; MS m/z 260 [M+H]+; Method 2minLopr
Step; (S)—(5,5-Dimethyltetrahydrofuran—Z-yl)methanamine hydrochloride
A solution of (S)—2-((5,5-dimethyltetrahydrofuran-2—yl)methyl)isoindoline—1,3-dione
(step 1) (21.9 g, 84 mmol) in EtOH (440 ml) was stirred at 60 °C under N2 and
hydrazine e (4.51 ml, 93 mmol) was added. The mixture was stirred at 60 °C
overnight and then allowed to cool to RT. 2M HCl (60 ml) was added dropwise to
adjust pH to pH 1. The slurry was filtered g with EtOH (50 ml) and the filtrate
was concentrated in vacuo to a volume of approximately 50 ml.
The mixture was filtered and washed through with TBME (20 ml) and water (20 ml).
The te was washed with TBME (100 ml) and the organic phase was extracted
with 2M HCl (50 ml). The acidic aqueous layers were combined and basified to pH 10
with 2M NaOH (~70 ml). This mixture was extracted with TBME (3 x 200 ml) and the
combined organic layers were washed with brine (200 ml) and dried (M9804) and
filtered. 4M HCl in dioxane (21 ml, 84 mmol) was added slowly and the resulting
solution was then concentrated in vacuo to yield a yellow oil. The oil was triturated
with diethyl ether to afford the title compound as a pale yellow solid;
LC-MS: Rt 0.57 mins; MS m/z 164.1 [M+H]+; Method 2minLopr
Intermediate 9B
,5-Dimethyltetrahydrofuranyl)methanaminium chloride
“sf /””.1.\‘I /NH3+
..--‘-1’5..-
_S_tep_£ (R)—(5,5—Dimethyltetrahydrofuran-Z-yl)methyl 4-methylbenzenesulfonate
1O (R)-(5,5-dimethyltetrahydrofuran—2—yl)methanol [refer Bull chem Soc Japan Vol. 45,
No.3, pp. 916-921. 1972 J Yoshimura et.al p921) (6.7 g, 51.5 mmol) in pyridine (50
ml) was treated with Tosyl-Cl (9.81 g, 51.5 mmol) at room temperature and stirred for
72hrs.The solvent was removed by evaporation and azeotroping with toluene. The
mixture was then partitioned between ethyl acetate and 10%
aqueous citric acid. The
organics were washed with brine and the s was back extracted with ethyl
acetate. The combined c layers were dried M9804, filtered and evaporated to
dryness to give a dark oil of (R)—(5,5-dimethyltetrahydrofuranyl)methyl 4-
methylbenzenesulfonate;
1H NMR (400 MHz, CDClg) 8 7.85 (2H, d), 7.36 (2H, d), 4.17 (1 H, m), 3.98 (2H, d),
2.47 (3H, s), 2.07 (1 H, m), 1.85-1.70 (3H, m), 1.18 (6H, s).
flap—2: (R)—5—(Azidomethyl)-2,2-dimethyltetrahydrofuran
(R)—(5,5~Dimethyltetrahydrofuran~2—yl)methyl 4—methylbenzenesulfonate (step 1)
(12.8 g, 45.0 mmol) in DMF (50 ml) was d with sodium azide (3.80 g, 58.5
mmol) at RT overnight then warmed to 70°C for 3hrs. Sodium azide (3.80 g, 58.5
mmol) was added and the mixture was warmed to 100°C for 3hrs. allowed to cool to
RT. The e was diluted with water and ethyl acetate. The ethyl acetate layer
was washed with 0.5 M lithium de in water and the organic layers were dried
M9804, ed and evaporated to dryness to afford the title compound;
1H NMR (400 MHz,CDC13)5 4.17 (1H, m), 3.49 (1H, dd), 3.20 (1H, dd), 2.05 (1H,
m), 1.85~1.75 (3H, m), 1.30 (3H, s) 1.23 (3H, s)
m(R)—(5,5-Dimethyltetrahydrofuran-2—yl)methanaminium chloride
(R)(Azidomethyl)—2,2-dimethyltetrahydrofuran (step 2)(6.98 g, 45 mmol) in
tetrahydrofuran (175 ml) and Water (35.0 ml) was treated with triphenylphosphine
(12.98 g, 49.5 mmol) and stirred at RT for 20 mins then warmed to 80 °C for 4 hrs.
Solid Isolute® SCX resin was added and stirred at RT for 1hr. The SCX—2 resin was
washed with 7M ammonia in MeOH (1 L). The ammonia layer was ated to
dryness with a cool water bath and vacuum > 80 mbar. The oily residue was treated
with 2N HCI (aq) and the solid precipitate was removed by filtration. The
aqueous
portion was washed with ethyl e and DCM (containing 10% trifluoroethanol.)
The aqueous was basified by the addition of 2N NaOH (aq) and was extracted with
ethyl acetate (x3). The combined organic layers were dried M9804, d and
treated with excess HCl in dioxane before being evaporated to dryness to afford the
title compound;
1H NMR (400 MHz, MeOD) 5 4.17 (1 H, m), 3.09 (1H, dd), 2.87 (1 H, dd), 2.19 (1 H,
m), 1.95—1.70 (3H, m), 1.31 (3H, s) 1.27 (3H, 3).
Intermediate 9C
(S)Bromo-N-(5-((5,5-dimethyltetrahydrofuranyl)methylcarbamoyl)
fluorophenyl)imidazo[1,2-a]pyridinecarboxamide
l 'i
C' ”“0
4‘. WEN
The title compound was prepared from (R)~(5,5—dimethyltetrahydrofuran-Z-
yl)methanaminium chloride (intermediate QB) and 3-(7—Br0m0imidazo[1,2-a]pyridine-
3—carboxamido)—4—fluoro c acid (prepared by hydrolysis of methyl 3-(7-
bromoimidazo[1,2-a]pyridinecarboxamido)fluorobenzoate (Intermediate 1A)
using NaOH) ously to Example 7.4 step 1;
LC-MS: Rt 0.97 mins; MS m/z 489/4912 {M+H}+; Method 2minLopr
Intermediate 9!):
2-((2RS,3SR)-2,3-Diethylazetidinyl)ethanamine
H EH
-.‘vflx‘
Diffs)r l3
xi” \H
o t] .
[2furl?
Chlorosulfonyiisocyanate (5.17 ml, 59.4 mmol) in DCM (12 ml) was stirred at 25 °C
and treated dropwise with (E)—hexene (7.39 mi, 59.4 mmoi) in DCM (6 ml). The
mixture was stirred at RT for 72 hrs. The reaction mixture was heated over 6 hrs at
40°C, before being poured onto ice. The mixture was extracted with DCM (3 x 100
ml) and the ed organics were washed with water (x1),dried M9804 and
evaporated to dryness to afford the title compound;
1H NMR (400 MHz, CDCI3) 6 3.95 (1H, dt), 3.09 (1H, cit), 2.21 (1H, m), 1.85 (3H, m),
1.11 (3H, t), 1.05 (3H, t).
$5522.; (3RS,4RS)—3,4~Diethyiazetidin—2-one
(2RS,3RS)—2,3-Diethyi—4—oxoazetidine~1—sulfonyl chloride (step 1) (3.2 g, 14.18
mmoi) in e (7 ml) was treated with enol (2.92 mi, 28.4 mmoi) and cooled
to -30 °C. ne (1.376 ml, 17.01 mmoi) in acetone (2.55 ml) was added dropwise
over 30 mins, maintaining the temperature around —30 °C. After stirring for 30
minutes, water (10 ml) was added slowly and the mixture was filtered. The e
was extracted with diethyl ether (5 X 25 ml) and the combined organic layers
were
dried M9804, filtered and evaporated to dryness (colorless oil 2.39). Purification by
chromatography on silica eluting with iso-hexane followed by diethyl ether afforded
the title compound;
1H NMR (400 MHZ, CDCI3) d 3.36 (1H, dt), 2.71 (1H, cit), 1.81 (1 H, m), 1.72-1.55
(3H, m), 1.03 (3H, t), 0.95 (3H, t).
m:2-((2RS,3RS)—2,3-Diethyl—4-oxoazetidinyl)acetonitrile
(3RS,4RS)—3,4-diethylazetidin-Z-one (step 2)(100 mg, 0.786 mmol) in dry THF (5 ml)
was cooled to —78 °C and was treated with lithium bis(trimethylsilyl)amide (0.786 ml,
0.786 mmol) [1 M in THF]. The solution was allowed to warm to 0 °C then re—cooled
to 0°C before adding bromoacetonitrile (0.060 ml, 0.865 mmol). The e
allowed to warm to RT overnight. 10% Aqueous citric acid (30 ml) was added and the
e was extracted with ether (4 x 40 ml). The ed organic layers
were dried
M9804, filtered and evaporated to dryness. Purification by chromatography on silica
eluting with 0-100% Et20 in iso-hexane ed the title compound;
1H NMR (400 MHz, CDCIg) 8 4.21 (1H, d), 3.99 (1H, d), 3.32 (1H, dt), 2.71 (1H, dt),
1.81 (1H, m), 1.72-1.55 (3H, m), 1.03 (3H, t), 0.95 (3H, t).
§t§_p_4_: 2—((2RS,38R)—2,3-Diethylazetidinyl)ethanamine hydrochloride
AlCls (3.37 g, 25.3 mmol) in dry ether (140 ml) was added to a stirred suspension of
1M LAlH4 in ether (25.3 mi, 25.3 mmol) in ether (140 ml). The mixture
was heated at
reflux for 30 mins and after g to RT the mixture was transferred by cannula into
a solution of 2-((2RS,3RS)~2,3—diethyl—4—oxoazetidin~1—yl)acetonitrile (step 3) (1.4
8.42 mmol) in dry ether (50 ml). Stirring was continued at RT for 16 hrs. The reaction
mixture was cooled to 0°C and Rochelle salt (aq 50 ml) was added. The mixture
allowed to stir at RT for 24hr. The aqueous was separated and the ether layer
retained. The aqueous was stirred with 10% trifluoroethanol/DCM (250 ml) for 3hrs
then the layers were separated and the aqueous was further stirred with 10%
trifluoroethanol/DCM {250 ml} for a further 2hrs. The remaining
aqueous was
extracted with 10% trifluoroethanol/DCM (x3). The ed organic layers
were
treated with 1 M HCl in methanol and concentrated in vacuo to afford the title
compound;
1H NMR (400 MHz, MeOD) 8 4.55 (1H, dd), 4.33 (1 H, t), 4.12 (1H, dd), 3.87 (1H, m),
3.72-3.46 (3H, m), 2.56 (1H, m), .91 (2H, m), 1.71 (2H, m),1.05 (3H, t), 0.90
(3H, t).
From the foregoing it will be appreciated that, although specific embodiments of the
ion have been described herein for purposes of illustration, various
modifications may be made without deviating from the spirit and
scope of the
invention. Accordingly, the invention is not d except as by the appended claims.
Claims (24)
1. A compound represented by formula (1) 5 or a pharmaceutically acceptable salt f, wherein, A is R3 R1 is C1—C4 alkyl; 01-04 alkoxy optionally substituted by one or more halogen atoms; 10 CN; or halogen; R1:11 is H, halogen, C1—C4 alkyl or C1-C4 haloalkyl; X is N or OH; R2 is H; C1—C8 alkyl optionally substituted by one or more OH, ~NR9R11 or C1—C4 alkoxy; C1—Cg haloalkyl; C2-C3 alkynyl tuted by one or more halogen, OH, - 15 NRQR“ or 01-04 alkoxy; 03-010 cycloalkyl; -(C1-C4 alkyl)-Cg-Cg cycloalkyl; 01-08 alkoxy optionally substituted by one or more halogen, -NR9R“ or OH; OH; CN; halogen; -(C0-C4 alkyl)—NR9R“; -(Co—C4 alkyl)—COZR15; -(C0~C4 alkyl)-C(O)NR9R“; - (Co-C4 alkyl)-C6-C14 aryl; or -(Co-C4 alkyl)—3 to 14 membered heterocyolyl; n the cycloalkyl, -(Co-C4 alkyl)—CG-Ci4 aryi and ~(Co-C4 alkyl)—3 to 14 heterocyclyl are each 20 optionally substituted by one or more 2" substituents; R3 is H; C1-C8 alkyl optionally substituted by one or more OH, -N R9R11 or C1-C4 alkoxy; C1-C8 haloalkyl; C2—C3 alkynyl tuted by one or more halogen, OH, — NRQR", or C1-C4 alkoxy; 03-010 cycloalkyl; —(C1—C4 —Cs-Ca oycloalkyl; C1-C8 alkoxy ally substituted by one or more halogen, —NR9R11 or OH; OH; CN; halogen; -(Co-C4 alkyl)—NR9R”; ~(Co-C4 alkyl)—COzR15; -(Co-C4 alkyl)-C(O)NR9R”; - (Co-C4 alkyl)-C5—C14 aryl; or ~(C0—C4 alkyl)-3 to 14 ed heterocyclyl; wherein the cycloalkyl, -(Co-C4 alkyl)—Ce-C14 aryl and -(Co-C4 alkyl)—3 to 14 heterocyclyl are each optionally substituted by one or more Za substituents; each Z3 is independently OH; (Co—C4 alkyl)—Cs aryl; O-Cs aryl; C1—C4 alkyl optionally substituted by one or more OH, ON or -NR193R213; C1-C4 haloalkyl; C1-C4 alkoxy optionally substituted by one or more OH, —COZR193, —NR1QE‘R21a or C1—C4 alkoxy; — (O)R21a; —C(O)NR19aR21a; _NR18aC(O)NR1QaR21a; _NR193R21a; 4 alkyl)- C(O)OR188; ~(Co-C4 alkyl)-C(O)R1ga; oxo; CN; N02; halogen; —(Co-C4 alkyl)—4 to 6 10 membered heterocyclyl; or ~O-(4 to 6 membered heterocyclyl); wherein the (Co—C4 alkyl)—Cs aryl, O—Cs aryl, -(Co-C4 alkyl)—4 to 6 membered heterocyclyl and —O-(4 to 6 membered heterocyclyl) are each optionally substituted by OH, halogen, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy optionally substituted by one or more ns; R4 is H; 15 R5 is H, C1—C4 alkyl or 01-04 haloalkyl; R6 is selected from 01-08 alkyl optionally tuted by one or more C1-C4 alkoxy -NR‘9R2‘; 01-08 haloalkyl; -(Co-C4alkyl)-Cg-Cscycloalkyl; C1—Caalkoxy optionally substituted by one or more halogen atoms; -NR19R21; —(Co—C4 alkyl)—Cs-C14aryl; and — (Co—C4 alkyl)—3 to 14 membered heterocyclyl; wherein the ~(Co-C4alkyl)-Cs- 20 Cgcycloalkyl, -(Co-C4 alkyl)—C5-C14aryl and -(Co-C4 alkyl)-3 to 14 heterocyclyl are each optionally substituted by one or more Z substituents; each Z is independently ed from (Co—C4 alkyl)—Cs aryl; O—Cs aryl; C1—Ce alkyl optionally substituted by one or more C1-Ce alkoxy, CN or —NR19R21; C1—Cs haloalkyl; C1-Cs alkoxy optionally substituted by one or more 21 or C1-C4 alkoxy; — 25 NR19R21; (Co~C4 alkyl)—C(O)R19; CN; n and (co-c4 alkyl)~4 to 6 membered heterocyclyl; and wherein the aryl and cyclyl are each optionally substituted by one or more halogen, C1-C5 alkyl, (31-06 haloalkyl and 01-06 alkoxy optionally substituted by one or more halogens; R9 and R11 are each independently selected from H; C1—C5 alkyl optionally substituted 30 by one or more C1-C4 alkoxy or OH; 01—06 haloalkyl; —(Co-C1alkyl)—Cs-Ce cycloalkyl; (Co-C4 - 06-014aryl optionally substituted by one or more groups selected from 01—05 alkyl, Ci-Cs alkoxy and halogen; and (Co-C4 alkyl)- 3- to 14-membered heterocyclyl ally substituted by one or more groups selected from halogen, oxo, 01-05 alkyl and C(O)C1—Cs alkyl; or 35 R9 and R11 together with the nitrogen atom to which they are ed form a 5- to 1 O-membered heterocyclyl, which heterocyclyl es 0 to 3 r heteroatoms selected from N, O and S, the heterocyclyl being ally substituted by one or more substituents selected from OH; halogen; phenyl, 5- to 10-membered heterocyclyl; C1—C6 alkyl; 01—06 haloalkyl; C1—C5 alkoxy optionally substituted by one or more OH or C1—C4 alkoxy; and C(O)OC1-C5alkyl; wherein the phenyl and heterocyclyl substituent groups are themselves optionally tuted by 01-06 alkyl, 01—05 haloalkyl or 01-05 alkoxy; R15 is selected from H; c1-c8 alkyl; 01—08 haloalkyl; 03-c10 cycloalkyl; (-01—C4alkyl)- Cg-Cg cycloalkyl; -(Co—C4 alkyl)—CG~C14aryl and -(Co-C4 alkyl)—3 to 14 membered cyclyl group; wherein the C3-C1o lkyl, (-C1—C4alkyl)—C3-Cg cycloalkyl, —(Co— C4 alkyl)—Cs—C14aryl and —(Co-C4 alkyl)—3 to 14 membered heterocyclyl groups are 10 each optionally substituted by one or more Z substituents; R183 is independently H or (31-06 alkyl; R193 and R213 are each ndently H; C1-Cs alkyl optionally substituted by one more C1—C4 alkoxy,~ 3', or OH; C1—C5 haloalkyl; ~(Co-C1alkyl)—C3-Cecycloalkyl; - (Co—C4 alkyl)— C5-C14aryl optionally substituted by one or more groups selected from 15 01-05 alkyl, 01-05 alkoxy and halogen; or -(Co—C4 alkyl)- 3- to 14—membered heterocyclyl optionally substituted by one or more groups ed from halogen, oxo, C1-Cs alkyl and C(O)C1-Cs alkyl; or R193 and R21"1 together with the nitrogen atom to which they attached form a 5— to 10— membered heterocyclyl, which heterocyclyl includes 0 to 3 further heteroatoms 2O selected from N, O and S, the heterocyclyl being optionally substituted by one or more substituents ed from OH; n; phenyl; 5- to 10—membered heterocyclyl; 01—05 alkyl; 01—05 haloalkyl; 01-05 alkoxy optionally tuted by one or more OH or C1-C4 alkoxy; and C(O)OC1-C5alkyl; wherein the phenyl and heterocyclyl substituent groups are themselves optionally substituted by 01-05 alkyl, 25 C1-Cs haloalkyl or 01—05 alkoxy; R18 is independently H or (31-06 alkyl; R19 and R21 are each independently C1—C5 alkyl optionally substituted by one or more C1—C4 alkoxy; C1-Ce kyl; —(Co—C1alkyl)~Cg-Cscycloa|kyl;- (Co—C4 alkyl)-C5-C14aryl optionally substituted by one or more groups selected from C1-C5 alkyl, C1-Cs alkoxy 30 and halogen; or -(Co-C4 alkyl)— 3— to 14—membered cyclyl, optionally substituted by one or more groups selected from n, 01—05 alkyl and -C(O)C1-CB alkyl; or R19 and R21 together with the nitrogen atom to which they attached form a 5- to 10— membered heterocyclyl, which heterocyclyl includes 0 to 3 further heteroatoms selected from N, O and S, the heterocyclyl being optionally substituted by one or 35 more substituents selected from halogen; phenyl; 5- to 10—membered heterocyclyl; C1-C5 alkyl; C1—Ce haloalkyl; C1-C5 alkoxy optionally substituted by one or more C1-C4 alkoxy and C(O)OCq-Cealkyl; n the phenyl and heterocyclyl substituent groups are themselves optionally substituted by a substituent ed from C1-C6 alkyl, C1- CG haloalkyl and C1—C5 alkoxy; and R22 and R23 are each ndently H or 01—06 alkyl.
2. A compound ing to claim 1, wherein R5 is H; R6 is 01—05 alkyl ally substituted by C1—C4 alkoxy; C1-Ce haloalkyl; —(Co—C4aikyl)- Cg-Cgcycloalkyl; C1-Cs alkoxy; ~Ce-C1oaryl; or -(Co-C2 alkyl)—5 to 6 membered heterocyclyl; wherein the -(Co-C4alkyl)-Cg—Cgcycloalkyl, -Ce—C1oaryl and 2 - 10 5 to 6 heterocycylyl are each optionally substituted by one or more Z substituents; each Z is independently selected from -(Co-C4 alkyl)—Cs aryl; ~O-Ce aryl; C1-C4 alkyl optionally substituted by one or more CN or -NR’9R21; C1-C4 haloalkyl; C1-C4 alkoxy optionally substituted by one or more -NR19R21 or C1—C4 alkoxy; -NR19R21; -(Co~C4 alkyl)—C(O)R19; CN; halogen or -(Co—C4 alkyl)—4 to 6 membered heterocyclyl; wherein 15 the —(Co-C4 alkyl)—Ce aryl, —O-Cs aryi and or -(CO~C4 alkyl)—4 to 6 ed heterocyclyl are each optionally substituted by n, 01-05 alkyl; 01-05 haloalkyl or C1—C6 alkoxy optionally substituted by one or more halogens; R18 is independently H or 01—05 alkyl; R19 and R21 are each ndently C1-Ce alkyl ally substituted by one or more 20 C1-C4 alkoxy; C1-C5 haloalkyl; -(Co-C1alkyl)-Cg—Cscycloaikyl; (Co-C4 alkyl)-ary| optionally substituted by one or more groups selected from 01-06 alkyl, C1—Cs alkoxy and halogen; or (Co—C4 alkyl)— 5- to 6-membered heterocyclyl optionally substituted by one or more groups selected from halogen, C1435 alkyl and C(O)C1-Cs alkyl; R19 and R21 together with the nitrogen atom to which they attached form a 5— to 10— 25 membered heterocyclyl, which heterocyclyl includes 0 to 3 further heteroatoms selected from N, O and S, the heterocyclyl being optionally substituted by one or more substituents selected from n; ; 5- to 10-membered heterocyclyl; 01-06 alkyl; C1—C5 haloalkyl; C1—C5 alkoxy optionally substituted by one or more C1-C4 alkoxy; or C(O)OC1-Cealkyl; wherein the phenyl and heterocyclyl substituent groups 3O are themselves optionally substituted by (31—06 alkyl, 01—06 haloalkyl or C1-Ce alkoxy.
3. A compound ing to claim 1 or 2, wherein R5 is H; R6 is 01-05 alkyl optionally substituted by C1—C4 alkoxy; —(Co-Cza|kyl)-Cg—Cacycloalkyl; 35 C1-C4 alkoxy; -Ce-C1oaryl or '(Co-Cz alkyl)—5 to 6 membered heterocyclyl; wherein the -(Co—Czalkyi)—C3—Cscycloaikyl, '(Cg-Cz alkyl)—Ce—C1oaryl and ~(Co-CgalkyI)-5 to 6 membered heterocyclyl are each optionally substituted by one or more Z substituents; each Z is independently C1-C4 alkyl ally substituted by one or more NHZ; C1-C4 haloalkyl; C1-C4 alkoxy optionally substituted by one or more C1-C4 alkoxy or - NngRZ‘; CN; halogen or 4 —4 to 6 membered heterocyclyl; wherein the - (Co—C4 alkyl)—4 to 6 membered heterocyclyl is optionally substituted by halogen, 01-05 alkyl, C1—C6 haloalkyl or 01-05 alkoxy optionally substituted by one or more halogens; R19 and R21 are each independently H; 01-05 alkyl optionally substituted by one or more C1-C4 alkoxy; C1—Cs haloalkyl; ~(Co-C1alkyl)—Cg-Cacycl0alkyl; (Co-C4 alkyl)—aryl 1O optionally substituted by one or more groups selected from C1-C5 alkyl, C1—Cs alkoxy and n; or (Co-C4 alkyl)— 5— to 6-membered heterocyclyl optionally substituted by one or more groups selected from halogen, C1-Cs alkyl and C(O)C1—C5 alkyl.
4. A compound according to any one of claims 1 to 3, wherein 15 R5 is H; R6 is C1-C4 alkyl optionally substituted by one or more C1-C4 alkoxy; phenyl; C1-C4 haloalkyl; ydrofuran; pyrrolidine, yrrolidine or —CH2—piperidine; wherein phenyl, tetrahydrofuran, pyrrolidine, —CH2-pyrrolidine and iperidine are each optionally substituted by one or more Z substituents; 20 each Z is independently C1-C4 alkoxy, halogen, C1-C4 alkyl or C1-C4 haloalkyl.
5. A compound ing to any one of claims 1 to 4, wherein R2 is H; C1-Cg alkyl optionally substituted by one or more OH, -NR9R“or C1-C4 alkoxy; C1—Ce haloalkyl; 02—08 alkynyl substituted by one or more halogen, OH, - 25 NRQR“ or c1-c4 alkoxy; 03-010 cycloalkyi; -(c1-c4 alkyl)-C3-Cg cycloalkyl; 01-08 alkoxy optionally substituted by one or more halogen, -NR9R11 or OH; OH; CN; halogen; -(co-c4 alkyl)—N RQR”; -(c0-c4 —COZR15; -(cO-c4 alkyl)-C(O)NR9R”; - (C0-C4 alkyl)—C5—C14 aryl; or {Co—C4 atkyl)—3 to 14 membered cyclyl; wherein the cycloalkyl, -(Co-C4 alkyl)-Cs-C14 aryl and -(C0-C4 alkyl)~3 to 14 heterocyclyl are each 3O optionally substituted by one or more Za substituents; R3 is H; R9 and R11 are each independently H; 01-05 alkyl ally substituted by one or more C1—C4 alkoxy or OH; 01-05 haloalkyl; 1alkyl)—C3—Cacycloalkyl; (Co-C4 alkyl)- Ce-C14 aryl optionally substituted by one or more groups selected from 01-05 alkyl, 35 C1-C5 alkoxy and halogen; or (Co-C4 — 5- to 6-membered heterocyclyl optionally substituted by one or more groups selected from halogen, 0X0, C1—Ca alkyl and C(O)C1-Cs alkyl; WO 30802 2a is independently OH; (Co-C4 allow-Cs aryl; O-Cs aryl; C1-C4 alkyl optionally substituted by one or more OH, ON or —NR198R21a; C1—C4 haloalkyl; C1—C4 alkoxy optionally substituted by one or more OH, 93, —NR193‘R21a or C1—C4 alkoxy; - NR1saC(O)R2‘a; —C(O)NR193R213; -NR18“C(O)NR193R213; —NR193R213; (Co-C4 - C(O)OR18a; (co-c4 alkyl)—C(O)R193; oxo; CN; N02; halogen; or (co-c4 alkyl)—4 to 6 membered heterocyclyl; wherein the aryl and heterocyclyl are each optionally substituted by halogen, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy optionally substituted by one or more halogens; R18a is independently H or Cl-Cs alkyl; 1O R193 and R216‘ are each independently H; Ci-Ce alkyl optionally substituted by one or more C1-C4 alkoxy or OH; 01-06 haloalkyl; 1alkyl)—Cg-Cscycloalkyl; -(Co-C4 alkyl)- 06-014 optionally substituted by one or more groups selected from (21-05 alkyl, (31-05 alkoxy and halogen; or (C0—C4 — 5- to 6-membered heterocyclyl optionally substituted by one or more groups selected from halogen, oxo, C1-Ce alkyl and 15 C(O)C1-C.~, alkyl; or R19a and R218 er with the nitrogen atom to which they attached form a 5- to 10- membered heterocyclyl, which heterocyclyl es 0 to 3 further heteroatoms selected from N, O and S, the heterocyclyl being optionally tuted by one or more substituents selected from OH; halogen; phenyl; 5- to 10-membered 20 cyclyl; C1-Cs alkyl; C1-C6 haloalkyl; C1-Ce alkoxy optionally substituted by one or more OH or C1-C4 alkoxy; or C(O)OC1—Csalkyl; wherein the phenyl and heterocyclyl substituent groups are lves optionally substituted by 01—05 alkyl, C1-C5 haloalkyl or C1-Ce . 25
6. A compound according to any one of claims 1 to 5, wherein R2 is H; C1—C4 alkyl optionally substituted by one or more OH or ~NR9R“; C1—C4 haloalkyl; C1-C4 alkoxy optionally substituted by one or more halogen, -NR9R11 or OH; OH; CN; halogen; -(Co-C4 alkyl)-NR9R“; ~(Co—C4 alkyl}C(O)NR9R“; phenyl; or - (Co-C4 —5 to 6 membered heterocyclyl; wherein the phenyl and —(Co-C4 alkyl)—5 30 to 6 heterocyclyl are each ally substituted by one or more Za substituents; R3 is H; R9 and R“ are each independently H; 01-05 alkyl optionally substituted by one or more C1-C4 alkoxy or OH; 01-06 haloalkyl; —(CO-C1alkyl)—C3—Cecycloalkyl; (Co—C4 alkyl)- 05-014 optionally substituted by one or more groups selected from 01-06 alkyl, C1-C5 35 alkoxy and halogen; or (Co-C4 alkyl)- 5- to 6—membered heterocyclyl optionally substituted by one or more groups selected from halogen, oxo, 01-06 alkyl and C(O)C1—Cs alkyl; each Za is ndently OH; C1-C4 alkyl optionally substituted by one or more one or more OH or -NR19aR21a; C1—C4 haloalkyl; C1-C4 alkoxy optionally tuted by one or more OH, 01—04 alkoxy or -NR193R213; -C(O)NR193R213; CN; halogen or -(<:0-C4 alkyl)- 4 to 6 membered heterocyclyl; wherein the heterocyclyl is optionally substituted by n, C1—C4 alkyl, C1-C4 haloalkyl or C1—C4 alkoxy optionally substituted by one or more halogens; R1981 and R21a are each independently H; C1—C4 alkyl optionally substituted by one or more C1—C4 alkoxy or OH; C1—C4 haloalkyl; -(Co—C1alkyl)—Cg-Cecycloalkyl;— (Co—C4 alkyl)~ Ce-C14 optionally substituted by one or more groups selected from C1—C5 alkyl, 10 C1-C6 alkoxy and n; or ~(Co-C4 alkyl)— 5— to 6-membered heterocyclyl optionally substituted by one or more groups selected from halogen, oxo, C1-Cs alkyl and -Ce alkyl.
7. A compound according to any one of claims 1 to 6, wherein 15 R2 is H; C1-C4 alkyl optionally tuted by one or more OH or —NH2; C1-C4 alkoxy optionally substituted by -NR9R11; F; Br; -(C1—Cz alkyl)-NR9R“; —C(O)NR9R“; phenyl; or -(Co-C4 alkyl)—5 to 6 membered heterocyclyl; wherein the phenyl and -(Co-C4 alkyl)- 5 to 6 membered heterocyclyl are each optionally substituted by one or more 23 substituents; 20 R3 is H; Z3 is independently C1-C4 alkyl optionally substituted by one or more OH or — NR193R213; C1-C4 haloalkyl; C1-C4 alkoxy optionally tuted by one or more OH, C1-C4 alkoxy or -NR19R21; -C(O)N ; halogen; or (Co-C4 alkyl)—4 to 6 membered heterocyclyl; wherein the heterocyclyl is optionally substituted by halogen, C1-C4 alkyl 25 or C1—C4 haloalkyl; R9 and R“ are each independently H; C1-Cs alkyl ally substituted by one or more C1-C4 alkoxy or OH; (31-06 haloalkyl; 1alkyl)—C3-Cecycloalkyl; (Co-C4 alkyl)- aryl optionally substituted by one or more groups selected from Ci-Ce alkyl, C1-Ce alkoxy and halogen; or (CO-C4 - 5- to 6-membered heterocyclyl optionally 30 substituted by one or more groups selected from halogen, oxo, 01—06 alkyl and C(O)C1-05 alkyl; R1921 and R21:3 are each independently H; C1-C4 alkyl optionally substituted by one or more C1-C4 alkoxy or OH; C1-C4 haloalkyl; -(Co—C1alkyl)—Cs—C60ycloalkyl; (Co—C4 alkyl)— aryl optionally substituted by one or more groups selected from 01-05 alkyl, 01-05 35 alkoxy and n; or (Co-C4 alkyl)— 5- to 6-membered heterocyclyl optionally substituted by one or more groups selected from halogen, oxo, 01-05 alkyl and C(O)C1—Cs alkyl.
8. A nd according to any one of claims 1 to 7, wherein R1 is fluorine or methyl; R121 is H; 5 R2 is H, F, Br, /‘\\\ /‘ F O H N/fi \ \ \ K/O I I /\\ ‘ ,\\ / ;\ / O \ N O \ R6 is F I \ —--N N F \——/ , or 5
9. A compound according to Ciaim 1, which is selected from: N—(2—Fluor0(2-(4—methylpiperazinyl)benzylcarbamoy!)phenyl)—7—(1-methyl-1H- pyrazol-S—yl)imidazo[1,2-a]pyridine—3—carboxamide; 7—(3—FIuoro(2-hydroxyethylcarbamoy!)pheny!)-N-(2—fluoro(2-(4-methylpiperazin- 1-y|)benzylcarbamoyl)phenyl)imidazo[1,2—a]pyridinecarboxamide; 10 7—Bromo—N—(2-methyI(2-(4-methylpiperazin-1— yl)benzylcarbamoyl)phenyl)imidazo[1,2-a]pyridine—3—carboxamide; 7-(1-MethyI-1 H-pyrazol—S-yl)—N—(2-methyl-5—(2—(4—methylpiperazin~1 - yl)benzylcarba moyl) phenyl)imidazo[1,2—a1pyridinecarboxamide; N—(2-Fluoro—5-(2-(4—methylpiperazin—1-yl)benzylcarbamoyl)phenyi)—7—(pyridinc 15 dazo[1,2-a]pyridine—3-carboxamide; N—(2—Fluoro—5-(2—(4—methylpiperazin—1-y1)benzyicarbamoyl)phenyi)-7~(1-methyI-1 H— pyrazol-4—yl)imidazo[1,2—a]pyridine—3-carboxamide; N-(5—(3,4-difluorobenzyicarbamoyl)-2—fluorophenyl)—7—(1methyl-1H-pyrazol-5—yl) imidazo [1,2-a]pyridine -3~carboxamide; 20 N-(5-(benzylcarba moyl)—2-fluorophenyl)—6—(1—methyl-1H-pyrazol—S-yl)imid 2— a]pyridine-3—carboxamide; uoromethyl(2-(4-methy! piperazin—fiyl) benzylcarbamoyl)phenyl)—7— (pyridineyl)imidazo[1,2—a]pyr idine—3—carboxamide; N~(5-(3,4-difluorobenzylcarbamoyl)fluorophenyl)—7-(6—(3-(dimethyl amino) propoxy) 25 pyridine—3~yl)imid azo[1,2-a]pyridine—3—carboxamide; N-(5-(2—(2,6—cis~dimethylpiperidinyl)ethy!carbamoyl)fluorophenyl)—7—(1-methyl- 1 H-pyrazol-S-yl)imidazo[1,2-a]pyridine-3—carboxamide; WO 30802 7~(4-(aminomethyl) phenyl)-N-(2-fluoro(2—(4-methylpiperazin—1 - yI)benzylcarbamoyl) phenyl)imidazo[1,2-a]pyridine—3—carboxamide; N—(5-(2-tert—butoxyethylcarbamoy1)-2—fluorophenyl)—7-(1-(2-morpholinoethyI)-1 H— pyrazolyl)imidazo[1,2-a]pyridine—S-carboxamide; N—(5—((5,5-dimethy1tetrahyd rofu yl)methy1 ca rbamoyl)—2—fluorophenyl )(1 -(2— morpholinoethy1)-1H—pyrazol—4-yl)imidazo [1 ,2—a]pyridine~3-carboxamide; N—(Z—fluoro—5-(2—(4—methylpiperaziny|)benzylcarbamoyl)phenyl)(6~methoxy pyridine—3—yl)imidazo [1 yridine—S—carboxamide; N-(Z—fluoro—5-(2—(4—methylpiperazin—1-yl)benzy10arbamoyl)phenyl)—6—(1-methyl—1 H— 1O pyrazol-5—yl)pyrazol0[1,5-a]pyridine-3—carboxamide; 1~(2-(4-fluoro(7—(pyridine—S-yl)imidazo [1 ,2—ajpyridine carboxamido)benzamido)ethy1)—2,6-cis-dimethyl dine; N—(5-(2—tert-butoxyethylcarbamoyl)—2—fluorophenyl)(6—(3-(dimethylamino) y)pyridine—3-y|)pyrazolo[1,5-a]pyridine-3—carboxamide; 15 N—(2—methyl(2~(4-methylpiperazinyl)benzylcarbamoyl)phenyl)-7—(pyridine yl)imidazo[1,2-a]pyridine—3—carboxamide; 1—methyl(2-((6—methyI(7-(1-methyl -1H—pyrazol-S—y1)imidazo[1,2-a]pyridine carbox amido)nicotina mido)methy1)phenyl)piperazine; 7-(1-Methyl-1 H-pyrazol—4—yl)—imidazo[1,2—a]pyridinecarboxylic acid {5-[2—(2,6-cis— 20 dimethyI-piperidinyI)-ethylcarbam oyl ]fluoro-phenyl}-amide; N-(5-(2—tert-Butoxyethylcarbamoyl)—2-fl uorophenyl)—7—(6—(3—(dimethylamino)propoxy) pyridin-S—yl)imidazo[1,2—a]pyridine—3—carboxamide; N—(5-(3,4—Difluorobenzylcarbam0y1)—2-fluorophenyl)—7-(6-(2~(pyrrolidin—1 —yl)ethoxy) pyridinyl)imidazo[1,2-a]pyridine-S-carboxamide; 25 6-(1-Methyl—1 H-pyrazol—S—y1)—N—(2—methyl(2—(4-methylpiperazin-1 — yl)benzylcarbamoyl) phenyl)pyrazolo[1,5-a]pyridine-3—carboxamide; N-(2-Bromo—5-(2—(4-methy1piperazin-1~yl)benzylcarbamoyl)pheny|)imidazo[1 ,2— a]pyridine—3-carboxamide; N-(2—Bromo—5-(2—(4—methylpiperazin-1 —yl)benzyicarbamoyl)phenyl)pyrazolo[1,5- 3O a]pyridinecarboxamide; N-(5—(3,4-Difluorobenzylcarbamoy1)-2—fluoroph enyl )—7-(3-hyd roxymethyl imidazo[1,2-a]pyridinecarboxamide; N~(5-(3,4—Difluorobenzylcarba moy1)-2—fl uorophenyl)—7—(3-fluoro—4~(2—(piperidin—1~ yl)ethylcarbamoy|)phenyl)imidazo[1,2-a]pyridine—3—carboxamide; 35 N—(5-(3,4-Difluoro benzylcarbamoyl)—2—fluorophenyl)(3-fluoro(2-(tetrahyd ro-2H- pyran-4~yl)ethylcarbamoyl)phenyl)imidazo[1,2—a]pyridine—3-carboxamide; PCT/182012/054501 N-(5-(3,4-Difluorobenzylcarbamoyl)-2—fluorophenyl)(3-f|uoro—4-(3-morpholino propylcarbamoyl)phenyl)imidazo[1,2—a]pyridine—3—carboxamide; 6-(1-Methyl-1 H-pyrazoI-S-yl)—N-(2-methyl—5—(2-(4—methylpiperazin yl)benzylcarbamoyl)pyridinyl)pyrazolo[1,5-a]pyridine-S—carboxamide; N-(5-((5,5~Dimethyitetrahyd rofuran—Z-yl )methylcarbamoyl)—2—fluorophenyl)—7—(6~(4- methylpiperaziny|)pyridin-3—yl)imidazo[1,2—a]pyridine-3—carboxamide; N—(5—(3,4—DifluorobenzylcarbamoyI)—2—fl uoropheny!)—7-(1~(3-(dimethyl amino)pr0pyl)— 1 H-pyrazoI—4-yl)imidazo[1 ,2—a]pyridine—3-carboxamid e; N~(5-((5,5-Dimethyltetrahyd rofuran-Z-yl lcarbamoyI)—2-fluorophenyl)—7—(5- 1O ((tetrahydro—2H-pyranylamino)methyl)pyridin-B-yl)imidazo[1,2-a]pyridine—3- carboxamide ; (S)-N-(5-(((5,5-Dimethyltetrahydrofuran-Z—yl)methyl) carbamoyl)—2-flu0r0phenyI)—7—(5- (((Z—fiuoroethyl) amino)methyl)pyridin—3-yl)imidazo[1,2-a}pyridine—S—carboxamide ; (R)—N—(5—(((5,5-dimethyltetrahydrofuran-2—yl)methyl) carbamoyl)fluorophenyl)—7-(5- 15 (((2-methoxyethyl) (methyl)amino)methyl)pyridinyl) imidazo[1,2—a] pyridine carboxamide ; (R)—7—(5-((tert—butylamino)methyl )pyridin-3—yl)-N-(5—(((5, 5-dimethyltetrahydrofura n~2- yl l)carbamoyl)-2—fluorophenyl) imidazofl ,2—a1pyridinecarboxamide ; N-(5-(3,4-DifluorobenzylcarbamoyI)-2—fluorophenyl)(6-(2—(pyrrolidinyl)ethoxy) 20 pyridin-B-yl)imidazo[1,2-a]pyridine—3—carboxamide ; N—(5-((2~(tert—Butoxy) ethyl)oarbamoyl)—2—fluoro phenyl)—7—(6-(2—(pyrrolidin—1 -yl) ethoxy)pyridin—3-yl) imidazo[1,2—a] pyridine~3—carb0xamide ; N—(5~(((5,5-dimethyl tetra hyd rofuran-Z-y|)methyl)ca rba moyl)—2~fluorophenyl)—7~(6—((1 - methyl din—4—yl)oxy) pyridin-3—yl)imidazo[1,2—a]pyridine—S-carboxamide ; 25 6-(1—Methyl—1 H—pyrazoI-S—yI)—N-(2—m ethyl—5-(2—(4—methyl piperazin—1 — yl)benzylcarbam0yl) phenyl)pyrazolo{1,5-a]pyridine—3—carboxamide ; N~(2-Bromo—5-(2—(4~methylpiperazin—1-yl)benzylcarbamoyl)phenyl)imidazo[1 ,2— a]pyridinecarboxamide; N-(2-Bromo—5-(2—(4—m ethylpiperazin-1 -yl)benzylcarbam oyl)phenyl ol0[1 ,5- 30 dine—3-carboxamide; N-(5-(3,4-Difluorobenzylcarbamoyl)-2—fluor0phenyl )(3—hyd roxy—3-methyl butyl)imidazo[1,2-a]pyridinecarboxamide; 3,4—Difluorobenzylcarba moyl)—2—fluorophenyl)-7—(3-f|uoro—4-(2—(piperidin—1— yl)ethylcarbamoyl)phenyl)imidazo{1,2—a]pyridine—3~oarboxamide; 35 N-(5-(3,4—Difluor0benzylcarbamoyl)fl enyl)—7-(3-fluoro(2-(tetrahyd ro-2H— pyran—4-yl)ethylcarbamoyl)pheny|)imidazo[1,2-a]pyridine—3—carboxamide; N-(5-((2-(2,2-Dimethylpyrro|idin-1—yl)ethyl)carbamoy|)—2—f|uorophenyl)(1-methy|— 1 H—pyrazol~4—yl)imidazo[1,2—21]pyridine—3—carboxamide; 2-(2.2—Dimethylpyrroiidiny1)ethylcarbamoyl)fluorophenyl)—7-(3—fluoro—4— ((1 R,2R)—2—hydroxycyclohexylcarbamoyl)phenyl)imidazo[1 ,2—a]pyridine carboxamide; N-(5-(2—(2,2—Dimethylpyrrolidin—1—yl)ethylcarbamoy1)—2—fl uorophenyl)—7—(3—f|uoro—4-(1 - y—Z-methylpropanylcarbamoyl)phenyl)imidazo[1,2—a]pyridine—3— carboxamide; N-(5—(2-(2,2-Dimethylpyrrolidin—1-yl)ethylcarbamoyl)—2-methylpyridinyl)~6—(3—fluoro— 1O 4-(1—hydroxy—Z—methylpropan-Z-ylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine—3- carboxamide; N—(5-(3,4-Difluorobenzylcarbamoyl)—2—fluoropheny!)—7-(3-f|uoro—4-(3-morpholino propylcarbamoyl)phenyl)imidazo[1,2-a]pyridinecarboxamide; N-(5-(2-(2,6-cis-Dimethylpiperidin—1-yl)ethylcarbamoyl)fluorophenyl)—7-(3-fluor0 15 (1-hydroxy-2~methy|propan-Z—ylcarbamoyl)pheny|)imidazo[1,2-a]pyridine-3— carboxamide; 7—(3—FIuoro(2-fluoroethylca rbamoyl )phenyl)—N-(2-fluoro(2—(4-methylpiperazin yl)benzylcarbamoyl)phenyl)imidazo[1,2—a]pyridine-3—carboxamide; N-(2-FIuoro—5-(2—(4-methylpiperazin—1-yl)benzylcarbamoyl)phenyl)(3-fluoro—5-(2— 20 hydroxy ethylcarbamoyl)phenyl)imidazo[1,2-a]pyridinecarboxamide; N-(5—(2—(2,2—dimethy|pyrrolidin—1~yl)ethylcarbamoyl)~2—methylpyridin-3—yl)—6—(1 — methyl—1 H—pyrazoI—4—y1)pyrazolo[1,5-a]pyridine—3—carboxamide; (S)-N—(Z—Fluoro—5-(2-(2-(methoxy methyl) pyrrolidinyl)ethyl carbamoyl)phenyi)—7— (1-me’thyl—1H-pyrazol—4-yl)imidazo[1,2~a]pyridine—3~carboxamide; 25 N—(2-F1uor0-5—((2—(3-propylpyrrolidin-1 -y|)ethy1)carbamoyl)phenyl)—7~(1-methyl—1 H- I-4—yl)imidazo [1 ,2—a}pyridinecarboxamide; (R)—N-(2-Fluoro-S-((2~(2—(methoxymethyl) pyrrolidinyl)ethyl) carbamoyl)phenyI) (1-methyl-1H-pyrazol—4—y1)imidazo[1,2-a]pyridine—3-carboxamide; N-(5-((2-(3,5-Dimethylpiperidin-1~yl)ethyl)carbamoyl)—2—fluorophenyI)-7—(1-methy|—1 H— 30 pyrazolyl)imidazo[1,2-a]pyridine-S-carboxamide; uoro—5-((2-(2,2,6,6—tetra methylpiperidin—1-yl)ethy!)carbamoyl)phenyl)—7-(1 - methyl—1 H-pyrazolyl)imidazo[1,2—a]pyridine—3-carboxamide; N—(5—((2—(tert—butyl(methyl)amino)ethy| )carbamoyl)—2-fluorophenyl)—7-(1—methyl—1 H- pyrazol-5—yl)imidazo[1,2-a]pyridine—3-carboxamide; 35 (2-(2,2-dimethylpyrrolidin—1-y|)ethyl)carbamoyl)—2-methylpyridinyl)(1- methyl—1 H-pyrazoi~5-yl)pyrazolo[1 ,5-a]pyridine—S—carboxamide; N-(5-((2-(butyl (ethyl)amino)ethyl)carbamoyI)fluor0 phenyt)(3-fluoro-4—((2- hydroxy carbamoyl)phenyl)imidazo{1,2-a1pyridinecarboxamide; 7-(3-fluoro-4—((1-hydroxy-2—methylpropan—2-yl)carbamoyl)phenyl)-N¥(2-fluoro-5—((2- (3-propylpyrrolidiny|)ethyl)carbamoyl)phenyl)imidazo[1,2-a]pyridine carboxamide; (2—(3,3-dimethylmorpholino)ethyl)carbamoyt)-2—fluorophenyl)-7—(3-fluoro((1 - hydroxy-2—methylpropan-Z-yl)carbamoyt)phenyl)imidazo[1 ,2—a]pyridine-3— carboxamide; (R)(3-fluoro—4-((1—hydroxy—2—methytpr0panyt)carbamoyt)phenyl)-N—(2-tluoro-5— 1O ((2-(2—(methoxymethyl)pyrrolidiny|)ethyl) carbamoyl)phenyl)imidazo[1,2—a]pyridine- 3—carboxamide; N-(5-((3,4—Difluorobenzyt)carbamoyt)f|uorophenyl)—7-(6—((2— (dimethylamino)ethyl)carbamoyl)pyridin-B-yl)imidazo[1,2-a}pyridinecarboxamide; N-(5—((2-(2,2-Dimethylpiperidin-1 -y|)ethyl)carbamoyl)methylpyridinyl)(1 - 15 methyl-1 H-pyrazol-4—yl)pyrazolo[1 ,5-a]pyridinecarboxamide; N-(5-((2-(2,6-cis-Dimethylpiperidin~1 -y|)ethyl)carbamoyt)-2—methylpyridin—3-yl)—6—( 1 - methyl-1H-pyrazo|y|)pyrazo|o[1 ,5-a]pyridine-3—carboxamide; N-(5-((2-(v(28,3R)-2,3-diethylazetidinyt)ethyl) carbamoyl)-2—fluorophenyl)—7-(1 - methyl-1H-pyrazol-4—yl)imidazo[1,2-a]pyridinecarboxamide; 20 N-(5-(3,4-Difluorobenzylcarbamoyl)f!uorophenyl)—7-(6-(((2—hydroxyethyl) (methyl)amino)methy|)pyridin—B—yl)imidazo[1,2—a]pyridinecarboxamide ; N-(5—((3,4—difluorobenzyl)carbamoyl)fluorophenyl)—7-(6-((methyl (phenethyl)amino)methyl)pyridin-B-yl)imidazo[1,2-a]pyridinecarboxamide; N-(5—((3,4-Difluoro )carbamoyl)f|uorophenyt)—7-(6- 25 ((methyl(phenethyl)amino)methyl)pyridin-3—yl)imidazo[1,2—a]pyridinecarboxamide; N-(5—((3,4—Difluoro benzyl)carbamoyl)—2—fluorophenyl)—7-(5-((methylamino) methyl)pyridin—3-yl)imidazo[1,2-a]pyridine-S-carboxamide; 7-(5-((Cyclohexyl amino)methy|)pyridin-3—yl)-N—(5-((3,4—difluorcbenzyl) carba moyl)~2- fluoro phenyl) o[1,2-a]pyridine—3—carboxamtde; and 30 N-(5—((3,4-Difluoro benzyl)carbamoyl)-2—fluorophenyl)—7~(5-(((2—methoxyethyt) (methyl)amino)methyl)pyridinyl)imidazo[1,2—a]pyridinecarboxamide; or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1, which is 35 N—(5—((2—(2,2—Dimethylpyrrolidin-1—y|)ethyl)carbamoyl)-2—fluorophenyl)—7-(1-methyl- azoI-4—yt)imidazo[1,2—a]pyridine-3—carboxamide or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1, which is N-(5-(2-(2,6-cis-Dimethylpiperidinyl)ethylcarbamoyl)-2—fluorophenyl)(1-methyl— azolyl)imidazo[1,2-a]pyridinecarboxamide or a pharmaceutically acceptable salt thereof.
12. The compound of claim 1, which is N-(5-(2—(2,2—dimethylpyrrolidin-1—yl)ethy|carbamoyl)methylpyridinyl)—6—(1- methyl-1H-pyrazol—4—yl)pyrazolo[1,5~a]pyridine—3-carboxamide or a pharmaceutically 1O acceptable salt thereof.\
13. The compound of claim 1, which is 7-(1-Methyl-1H-pyrazolyl)—imidazo[1,2—a]pyridine-3—carboxylic acid {5—[2-(2,6-cis- dimethyl-piperidinyl)-ethylcarbamoyl uoro-phenyl}-amide or a 15 pharmaceutically acceptable salt thereof.
14. The compound of claim 1, which is N-(5-((2-(2,2-dimethylpyrrolidin—1-y|)ethyl)carbamoyl)—2-methy|pyridinyl)(1— methyl-1H-pyrazol-S-yl)pyrazolo[1,5-a]pyridine—3-carboxamide or a pharmaceutically 20 acceptable salt thereof.
15. The compound of claim 1, which is N—(5-(2-(2,6-cis—Dimethylpiperidin—1-yl)ethylcarbamoyl)—2—fluorophenyl)-7—(3—fluoro—4- (1—hydroxy—2—methylpropanylcarbamoyl)phenyl)imidazo[1,2—a]pyridine-3— 25 carboxamide or a pharmaceutically acceptable salt thereof.
16. A pharmaceutical composition, sing: a therapeutically effective amount of the compound ing to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, and 30 one or more pharmaceutically acceptable carriers.
17. A pharmaceutical combination, comprising: a therapeutically effective amount of the compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, and 35 a second active agent.
18. Use of a nd ing to any one of claims 1 to 15, or a pharmaceutically able salt thereof, in the manufacture of a medicament for the treatment of a disorder or disease mediated by the PDGF receptor.
19. Use of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of pulmonary arterial hypertension.
20. The compound according to claim 1, substantially as herein described with 1O reference to any one of the Examples thereof.
21. The compound according to any one of claims 1 to 15, substantially as herein described. 15
22. The pharmaceutical composition according to claim 16, substantially as herein described.
23. The ceutical combination according to claim 17, substantially as herein described.
24. The use according to claim 18 or 19, substantially as herein described.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161530049P | 2011-09-01 | 2011-09-01 | |
US61/530,049 | 2011-09-01 | ||
US201261680119P | 2012-08-06 | 2012-08-06 | |
US61/680,119 | 2012-08-06 | ||
PCT/IB2012/054501 WO2013030802A1 (en) | 2011-09-01 | 2012-08-31 | Bicyclic heterocycle derivatives for the treatment of pulmonary arterial hypertension |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ621436A NZ621436A (en) | 2015-10-30 |
NZ621436B2 true NZ621436B2 (en) | 2016-02-02 |
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