SG175877A1 - Compounds and methods for inhibition of renin, and indications therefor - Google Patents
Compounds and methods for inhibition of renin, and indications therefor Download PDFInfo
- Publication number
- SG175877A1 SG175877A1 SG2011081015A SG2011081015A SG175877A1 SG 175877 A1 SG175877 A1 SG 175877A1 SG 2011081015 A SG2011081015 A SG 2011081015A SG 2011081015 A SG2011081015 A SG 2011081015A SG 175877 A1 SG175877 A1 SG 175877A1
- Authority
- SG
- Singapore
- Prior art keywords
- lower alkyl
- dimethyl
- quinolin
- ethyl
- fluoro
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 418
- 108090000783 Renin Proteins 0.000 title claims abstract description 44
- 102100028255 Renin Human genes 0.000 title claims abstract description 43
- 238000000034 method Methods 0.000 title claims abstract description 42
- 230000005764 inhibitory process Effects 0.000 title description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 40
- 201000010099 disease Diseases 0.000 claims abstract description 37
- -1 heterocyeloalkyl Chemical group 0.000 claims description 205
- 125000000217 alkyl group Chemical group 0.000 claims description 177
- 125000001153 fluoro group Chemical group F* 0.000 claims description 153
- 239000000203 mixture Substances 0.000 claims description 137
- 125000001424 substituent group Chemical group 0.000 claims description 86
- 125000003545 alkoxy group Chemical group 0.000 claims description 73
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 72
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 67
- 125000001072 heteroaryl group Chemical group 0.000 claims description 65
- 125000003118 aryl group Chemical group 0.000 claims description 56
- 229910052739 hydrogen Inorganic materials 0.000 claims description 55
- 239000001257 hydrogen Substances 0.000 claims description 54
- 125000004414 alkyl thio group Chemical group 0.000 claims description 50
- 150000003839 salts Chemical class 0.000 claims description 48
- 229940002612 prodrug Drugs 0.000 claims description 40
- 239000000651 prodrug Substances 0.000 claims description 40
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 29
- 150000002431 hydrogen Chemical class 0.000 claims description 29
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 27
- 229910052799 carbon Inorganic materials 0.000 claims description 27
- 229910052736 halogen Inorganic materials 0.000 claims description 27
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 25
- 150000002367 halogens Chemical class 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 125000006578 monocyclic heterocycloalkyl group Chemical group 0.000 claims description 15
- 230000001404 mediated effect Effects 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000006413 ring segment Chemical group 0.000 claims description 4
- 229910021386 carbon form Inorganic materials 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 abstract description 10
- 230000036454 renin-angiotensin system Effects 0.000 abstract description 6
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- 238000002360 preparation method Methods 0.000 description 162
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 128
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- 125000004429 atom Chemical group 0.000 description 16
- 239000003795 chemical substances by application Substances 0.000 description 16
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- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 1
- 229960002871 tenoxicam Drugs 0.000 description 1
- LZNWYQJJBLGYLT-UHFFFAOYSA-N tenoxicam Chemical compound OC=1C=2SC=CC=2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 LZNWYQJJBLGYLT-UHFFFAOYSA-N 0.000 description 1
- 229960001693 terazosin Drugs 0.000 description 1
- VCKUSRYTPJJLNI-UHFFFAOYSA-N terazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1CCCO1 VCKUSRYTPJJLNI-UHFFFAOYSA-N 0.000 description 1
- MBANUWYCRNYGGK-UHFFFAOYSA-N tert-butyl n-[1-[6-ethyl-4,4-dimethyl-1-[(2-methylpyridin-4-yl)methyl]-2,3-dihydroquinolin-7-yl]ethyl]carbamate Chemical compound C1=C(C(C)NC(=O)OC(C)(C)C)C(CC)=CC(C(CC2)(C)C)=C1N2CC1=CC=NC(C)=C1 MBANUWYCRNYGGK-UHFFFAOYSA-N 0.000 description 1
- 229950007324 tesicam Drugs 0.000 description 1
- 229950000997 tesimide Drugs 0.000 description 1
- TUGDLVFMIQZYPA-UHFFFAOYSA-N tetracopper;tetrazinc Chemical compound [Cu+2].[Cu+2].[Cu+2].[Cu+2].[Zn+2].[Zn+2].[Zn+2].[Zn+2] TUGDLVFMIQZYPA-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229950000584 tezosentan Drugs 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 229960002898 threonine Drugs 0.000 description 1
- 229960001312 tiaprofenic acid Drugs 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- 229950002345 tiopinac Drugs 0.000 description 1
- LERNTVKEWCAPOY-DZZGSBJMSA-N tiotropium Chemical compound O([C@H]1C[C@@H]2[N+]([C@H](C1)[C@@H]1[C@H]2O1)(C)C)C(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 LERNTVKEWCAPOY-DZZGSBJMSA-N 0.000 description 1
- 229940110309 tiotropium Drugs 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 229940110851 tolazine Drugs 0.000 description 1
- JIVZKJJQOZQXQB-UHFFFAOYSA-N tolazoline Chemical compound C=1C=CC=CC=1CC1=NCCN1 JIVZKJJQOZQXQB-UHFFFAOYSA-N 0.000 description 1
- 229960002905 tolfenamic acid Drugs 0.000 description 1
- YEZNLOUZAIOMLT-UHFFFAOYSA-N tolfenamic acid Chemical compound CC1=C(Cl)C=CC=C1NC1=CC=CC=C1C(O)=O YEZNLOUZAIOMLT-UHFFFAOYSA-N 0.000 description 1
- 229960001017 tolmetin Drugs 0.000 description 1
- UPSPUYADGBWSHF-UHFFFAOYSA-N tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 229960005461 torasemide Drugs 0.000 description 1
- 229960002051 trandolapril Drugs 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- PAJMKGZZBBTTOY-ZFORQUDYSA-N treprostinil Chemical compound C1=CC=C(OCC(O)=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 PAJMKGZZBBTTOY-ZFORQUDYSA-N 0.000 description 1
- 229960005032 treprostinil Drugs 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 229960002117 triamcinolone acetonide Drugs 0.000 description 1
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 1
- 229960001288 triamterene Drugs 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- VSVSLEMVVAYTQW-VSXGLTOVSA-N triclonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(Cl)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CCl)[C@@]2(C)C[C@@H]1Cl VSVSLEMVVAYTQW-VSXGLTOVSA-N 0.000 description 1
- 229950008073 triclonide Drugs 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- 229950000451 triflumidate Drugs 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- CHQOEHPMXSHGCL-UHFFFAOYSA-N trimethaphan Chemical compound C12C[S+]3CCCC3C2N(CC=2C=CC=CC=2)C(=O)N1CC1=CC=CC=C1 CHQOEHPMXSHGCL-UHFFFAOYSA-N 0.000 description 1
- 229940035742 trimethaphan Drugs 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 229960004799 tryptophan Drugs 0.000 description 1
- 229960004441 tyrosine Drugs 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 229960001130 urapidil Drugs 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 229960004699 valsartan Drugs 0.000 description 1
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 description 1
- 229960002381 vardenafil Drugs 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- GDJZZWYLFXAGFH-UHFFFAOYSA-M xylenesulfonate group Chemical group C1(C(C=CC=C1)C)(C)S(=O)(=O)[O-] GDJZZWYLFXAGFH-UHFFFAOYSA-M 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- 229950007802 zidometacin Drugs 0.000 description 1
- 229960002555 zidovudine Drugs 0.000 description 1
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- 229960003414 zomepirac Drugs 0.000 description 1
- ZXVNMYWKKDOREA-UHFFFAOYSA-N zomepirac Chemical compound C1=C(CC(O)=O)N(C)C(C(=O)C=2C=CC(Cl)=CC=2)=C1C ZXVNMYWKKDOREA-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
- C07D215/06—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
-
- 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
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
Compounds active as inhibitors of renin (e.g., compounds of Formula I) are described, as well as methods of using such compounds to treat diseases and conditions associated with the renin-angiotensin system. Formula (I)
Description
COMPOUNDS AND METHODS FOR INHIBITION OF RENIN, AND INDICATIONS
THEREFOR
[0001] Disclosed are novel compounds and uses thereof. In certain embodiments disclosed compounds are renin inhibitors.
[0002] In certain aspects and embodiments disclosed herein, compounds are provided, as well as various salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof and uses thereof. Also contemplated in accordance with the present invention are methods for the use of the compounds in treating renin-mediated diseases and conditions. Thus, the use of compounds for therapeutic methods involving inhibition of renin are provided. In certain embodiments, the compounds are used for therapeutic methods involving inhibition of renin activity, including treatment of a variety of indications, including, but not limited to, hypettension. In some embodiments, compounds are of Formula I, Formula Ia or Formula Ib, as described below.
[0003] In a first aspect, compounds having the structure according to the following Formula I are provided:
R!
Li NH,
RE
RY N X, R2
RN
[= TI R?3 =
R® 2 Y X3 R?
Formula I or a salt, a prodrug, a tautomer or a stereoisomer thereof, wherein:
X, and X, are independently -N= or -C(H)=; nis orl;
L, is a bond, -C(R'R)-, -C(O)-, -C(R°R)-C(R"'R')-, -C(R’R'")-C(O)-, -C(O)-C(R''R)-, -C(O)-N(R®)-, N(R"™)-C(0), -8(0),-NR")-, -N(R")-S(O)z, -N(R")-C(O)-N(R")-, or -N(R"™)-8(0)-NR")-;
Y is -O- or -C(R“R")-;
R' is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents R”,
and wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents R*®;
R? and R’ arc independently hydrogen, lower alkyl, -R'®, or -[C(R'7R'")],-L-[C(R""R™)},-R"¢, wherein lower alkyl is optionally substituted with one or more substituents R*’; or
R’ and R’ combine with the carbon to which they are bound to form a 3-7 membered cycloalkyl or a 5-7 membered monocyclic heterocycloalkyl, wherein the 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH,, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; ais 1,2, or3; bis0,1,2, or 3;
L, is a bond, -O-, -S-, -N(R")-, -C(0)-N(R")-, -N(R")-C(0), -C(S)-N(R")-, -N(R")-C(S)-, -S(0)-N(R")-, -8(0),-N(R")-, -NR)-8(0), -NR™)-S(0),, -N(R')-C(0)-NR")-,
NR'™-C(S)-NR)-, or -N(R')-8(0),-NR")~;
Ris -R* or -Ls-R*';
L; is -O-, -S-, or NR)-;
R* is -(CR¥R¥),-R*, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents
RY: pis1,2,3,4 Sor6;
R®, and R® are independently hydrogen, fluoro, lower alkyl, fluoro substituted lower alkyl, phenyl, or benzyl, wherein the phenyl ring of phenyl or benzyl is optionally substituted with one or more substituents R*;
R’ and R* are independently hydrogen, fluoro, lower alkyl, fluoro substituted lower alkyl, phenyl, or benzyl, wherein the phenyl ring of phenyl or benzyl is optionally substituted with one or more substituents R*'; or
R’ and R® together form oxo;
R% RY RY R'?, and each R* and R* arc independently hydrogen, fluoro, lower alkyl, or fluoro substituted lower alkyl; or
R% and R'’, or R' and R"?, or any two R* and R* on the same carbon, combine with the carbon to which they arc bound to form a 3-7 membered cycloalkyl or a 5-7 membered monocyclic heterocycloalkyl, wherein the 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, -OI1, -NI1,, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamine;
each R" is independently hydrogen or lower alkyl;
R'" and R" are independently hydrogen, fluoro, lower alkyl, or fluoro substituted lower alkyl;
R'® is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents R*;
RY R"™ RY and R¥ are independently hydrogen, fluoro, lower alkyl, or fluoro substituted lower alkyl; or any two R' and R"® on the same carbon, or any two R' and R* on the same carbon, combine with the carbon to which they are bound to form a 3-7 membered cycloalkyl or a 5-7 membered monocyclic hetcrocycloalkyl, wherein the 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH,, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; or any two R'" and R"® on the same carbon, or any two R' and R* on the sam carbon form oxo;
R** is selected from the group consisting of hydrogen, fluoro, -0-R*, -S-R* -N(R**)-R™, -C(0)-R™, -C(S)-R*™, -S(0)-R*, -S(0),-R*, -C(0)-0-R*, -C(O)-N(R*)-R¥, -C(S)-N(R¥)-R*, -S(0)-N(R*)-R*, -S(0),-N(R**)-R*, -N(R**)-C(0)-R*, -N(R*)-C(S)-R™,
N(R®)-S(0)-R*, -N(R**)-5(0),-R**, -N(R¥)-C(0)-N(R™)-R*, -N(R*¥)-C(S)-N(R**)-R¥, -N(R*)-S(0),-N(R*)-R*, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents R¥; each R* and RY, if present, is independently selected from the group consisting of fluoro, -O-R’, -S-R* and -N(R*)-R”’; each R*® R*, R*, R¥ and R*, if present, is independently selected from the group consisting of -CN, -NO,, -0-RY, -S-R*, -N(R*)-R*, -C(0)-R", -C(S)-R*!, -S(0)-R*, -S(0),-R", -C(0)-0-R*, -C(0)-N(R**)-R", -C(S)-N(R¥)-R¥, -S(0)-N(R*)-R™, -S(0),-NR*)-R¥, -N(R*)-C(0)-R", -N(R*)-C(S)-R*', -N(R*)-S(0)-R*', -N(R*)-S(0),-R",
N(R¥)-C(0)-N(R¥™)-R¥, -N(R**)-C(S)-N(R*™)-R*, -N(R*)-S(0),-N(R*)-R*, 0x0, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R* R* R*’ RY or R”, or as a substituent of lower alkyl are optionally substituted with one or more substituents sclected from the group consisting of -CN, -NO,, -O-R*, -S-R* -N(R*)-R*, -NR®)-C(0)-R¥, -N(R*)-$(0),-R*, -C(0)-R", -S(0)-R", -S(0),-R*, -C(0)-0-R*,
-C(0)-N(R™)-R®, -S(0),-N(R™)-R*, oxo, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; or any two R*, any two R*, any two R¥, any two RY, or any two rR’ b on adjacent ring atoms, combine to form a fused ring selected from the group consisting of 3-7 membered cycloalkyl and 5-7 membered heterocycloalkyl, wherein the 3-7 membered cycloalkyl or 5-7 membered heterocycloalkyl are optionally substituted with one or more halogen, -OH, -NH,, oxo, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; each R R¥ R* and RY is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R* R* R* or R* or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -CN, -NO,, -O-R", -S-R", N(R™)-R®, N(R*)-C(0)-R*,
NR¥)-8(0),-R*, -C(0)-R*, -S(0)-R*, -S(0),-R*, -C(0)-0-R*, -C(0)-N(R**)-R*, -S(0);-N(R*¥)-R™, oxo, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; each R* and R*' is independently selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono- alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R* or R*, or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -CN, -NO,, -0-R¥, -S-R*, -N(R*)-R", -N(R*)-C(0)-R¥, -N(R*)-S(0),-R*, -C(0)-R*, -S(0)-R*, -S(0),-R*, -C(0)-0-R¥, -C(O)-N(R*)-R*, -5(0),-N(R*)-R*, oxo, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; each R* is hydrogen or lower alkyl; cach R* and R” is independently hydrogen, lower alkyl, or fluoro substituted lower alkyl; each R* is lower alkyl or fluoro substituted lower alkyl; each R* and R* is independently selected from the group consisting of hydrogen, lower alkyl, heterocycloalkyl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-
alkylamino, di-alkylamino, and cycloalkylamino, and wherein heterocycloalkyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy and fluoro substituted lower alkoxy; and each R* is independently selected from the group consisting of lower alkyl, heterocycloalky! and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, and wherein heterocycloalkyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy and fluoro substituted lower alkoxy.
[0004] In some embodiments of compounds of Formula I, X; and X; are both -N=, nis 0 or 1, preferably 1, and Y is -O- or -C(R™R")-, preferably -C(RMRY)-; X, is -N= and X, is -C(H)=,n 1s 0 or 1, preferably 1, and Y is -O- or -C(R'*R")-, preferably -C(R"*R")-; X, is -C(H)= and X, is -N=, n is 0 or 1, preferably 1, and Y is -O- or -C(R"R")-, preferably -C(RMR")-; X; and X, are both -C(H)=, nis 0 or 1, preferably 1, and Y is -O- or -C(R"*R'®)-, preferably -C(R"*R")-.
[0005] In some embodiments of compounds of Formula I, further to any of the above embodiments of compounds of Formula I, L, is a bond, -C(R°R'%)-, -C(0)-, -C(R’R'%)-C(R"'R'?})-, -C(R°R')-C(0)-, or -C(0)-C(R"'R™), preferably -C(R’R'%)- or -C(R’R'")-C(R''R")-, and R' is phenyl or monocyclic heteroaryl, wherein phenyl! or monocyclic heteroaryl are optionally substituted with one or more substituents R”.
[0006] In some embodiments of compounds of Formula I, further to any of the above embodiments of compounds of Formula I, Y is -C(R'*R")- and R'* and R"* are independently lower alkyl or fluoro substituted lower alkyl.
[0007] In a second aspect, compounds of Formula I having a structure according to one of the following structures, Formulae Ia or Ib, are provided: 45 45
Ly” R NH, ] / ¢ NH,
R54 | ih \ i” 52 " R% © gis
R50 R49 or R49
Formula Ia Formula Ib or a salt, a prodrug, a tautomer or a stereoisomer thereof,
wherein:
Ly is a bond, -C(R¥R%)-, -C(0)-, -C(R*R*)-C(R'R®)-, -C(R¥R)-C(O)-, or -C(O)-C(R*R*);
R* is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents R™, and wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents R”';
R*" and RY are independently hydrogen, lower alkyl, or -[C(R*R**)]-R*', wherein lower alkyl is optionally substituted with one or more substituents R*; or
R* and RY combine with the carbon to which they are bound to form a 3-7 membered cycloalkyl or a 5-7 membered monocyclic heterocycloalkyl, wherein the 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH,, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; cis0,1,2,3,4, or 5;
R* is -R® or -Ls-R™;
Ly is -O-, -S-, or -N(R®)-; qis 1,2,3,4,50r6;
R* and R*® arc independently lower alkyl or fluoro substituted lower alkyl;
R’! and R* are independently hydrogen, fluoro, lower alkyl, or fluoro substituted lower alkyl;
R** and R* are independently hydrogen, fluoro, lower alkyl, or fluoro substituted lower alkyl; or
R* and R* together form oxo;
R**, R*®, R¥, R*®, and each R*’, R®, R* and R® are independently hydrogen, fluoro, lower alkyl, or fluoro substituted lower alkyl; or
R* and R*, or R¥ and R*®, any two R* and R® on the same carbon, or any two R* and R® on the same carbon, combine with the carbon to which they are bound to form a 3-7 membered cycloalkyl or a 5-7 membered monocyclic heterocycloalkyl, wherein the 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl are optionally substituted with onc or morc substituents selected from the group consisting of halogen, -OH, -NH,, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino;
R® is cycloalkyl, heterocycloalkyl, aryl or heterearyl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents R™;
R* is -(CR“R® Je RY, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents
R™ each R” is independently hydrogen or lower alkyl;
R" is independently selected from the group consisting of hydrogen, fluoro, -O-R%’, -S-R%, -NR)-R®, -C(0)-R®, -C(S)-R?, -S(0)-R¥, -S(0),-R”, -C(0)-N(R?)-R*, -S(0)-N(R”)-R*, -N(R®)-C(0)-R®, -N(R*)-S(0),-R¥, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or morc substituents R™; each Rand R™, if present, is independently selected from the group consisting of fluoro, -O-R”*, -S-R”7, and -N(R”*)-R’®; cach R”', R™ and R™, if present, is independently selected from the group consisting of -CN, -NO,, -O-R™, -S-R¥, -N(R™)-R”’, -C(0)-R¥, -S(0)-R¥, -S(0),-R*’, -C(0)-N(R"*)-R"’, -S(0),-N(R™*)-R”, -N(R")-C(0)-R¥, -N(R"")-S(0),-R"’, oxo, fluoro, chloro, lower alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, and cycloalkylamino, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R”', R” or
R™, or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -CN, -NO, -0-R¥ _S.R¥ N(R¥)-R¥,
NR®)-C(0)-R¥, -N(R¥)-8(0),-R¥, -C(0)-R¥, -S(0)-R¥, -S(0),-R¥, -C(0)-0-R*, -C(0)-N(R*)-R¥, -5(0),-N(R*)-R*, 0x0, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; or any two R”' any two R™®, or any two R™, on adjacent ring atoms, combine to form a fused ring selected from the group consisting of 3-7 membered cycloalkyl and 5-7 membered heterocycloalkyl, wherein the 3-7 membered cycloalkyl or 5-7 membered heterocycloalkyl are optionally substituted with one or more halogen, -OH, -NH, oxo, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; each RY R® R™ and R" is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, and cycloalkylamino, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as RY’, R®,
R™ or R”, or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -CN, -NO,, -O-R¥, -S-R®, -N(R*)-R¥,
NR®)-C(0)-R®, -N(R¥)-8(0),-R*, -C(0)-RY, -S(0)-R™, -S(0),-R¥, -C(0)-O-R¥, -C(0)-N(R™)-R¥, -S(0),-N(R*")-R™, 0x0, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
each R* and R" is independently selected from the group consisting of lower alkyl, cycloalkyl, heterocyeloalkyl, aryl, and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, and cycloalkvlamino, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R” or R™, or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -CN, -NO,, -O-R*, -S-R¥, -N(R*)-R¥, -N(R®)-C(0)-R¥, -N(R*)-S(0),-R¥, -C(0)-R¥, -S(0)-RY, -S(0),-R¥, -C(0)-0-R¥, -C(0)-N(R*")-R¥, -S(0),-N(R*)-R¥, oxo, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; each R” and R", if present, is independently hydrogen, lower alkyl, or fluoro substituted lower alkyl; cach R”” is lower alkyl or fluoro substituted lower alkyl; each R* and R* is independently selected from the group consisting of hydrogen, lower alkyl, heterocycloalkyl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, and cycloalkylamino, and wherein heterocycloalkyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy and fluoro substituted lower alkoxy; and each R¥ is independently selected from the group consisting of hydrogen, lower alkyl, heterocycloalkyl and heteroaryl, wherein lower alkyl is optionally substituted with one or morc substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, and cycloalkylamino, and wherein heterocycloalkyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy and fluoro substituted lower alkoxy.
[0008] In reference to compounds herein, unless clearly indicated to the contrary, specification of a compound or group of compounds includes salts of such compound(s) (including pharmaceutically acceptable salts), formulations of such compound(s) (including pharmaceutically acceptable formulations), conjugates thereof, derivatives thereof, forms thereof, prodrugs thereof, and all stereoisomers thereof. In reference to compositions, kits, methods of use, etc. of compounds of
Formula I described herein, it is understood (unless indicated otherwise) that a compound of Formula
I includes all sub-embodiments thereof (e.g. including Formula Ia, Formula Ib and all embodiments as described above).
[0009] In one embodiment of compounds of Formula I, the compound is selected from the group consisting of’ 1-[7-(1-Amino-cthyl)-6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinolin-1-yl]-2-methoxy-ethanone (P-0001), 1-[6-Ethyl-1-(2-methoxy-ethyl)-4,4-dimethyl-1,2,3 4-tetrahydro-quinolin-7-yl]-ethylamine (P-0002), 1-[6-Ethyl-1-(3-methoxy-propyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl]-cthylamine (P-0003), 1-[6-Ethyl-4,4-dimethyl-1-(3,3,3-trifluoro-propyl)-1,2,3,4-tetrahydro-quinolin-7-yl]-ethylamine (P-0004), 1-[6-Ethyl-4,4-dimethyl-1-(4,4,4-trifluoro-butyl})-1,2,3,4-tetrahydro-quinolin-7-yl]-ethylamine (P-0005),
N-{2-[7-(1-Amino-ethyl)-6-cthyl-4,4-dimethyl-3,4-dihydro-2H-quinolin-1-yl]-ethyl} -acetamide (P-0006), 1-[7-(1-Amino-ethyl)-6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinolin-1-yl]-ethanone (P-0007),
C-[6-Ethyl-1-(3-methoxy-propyl)-4,4-dimethyl-1,2,3 4-tetrahydro-quinolin-7-yl]-methylamine (P-0008), 1-[6-Ethyl-4,4-dimethyl-1-(2-pyrazol-1-yl-ethyl)-1,2,3 4-tetrahydro-quinolin-7-yl]-ethylamine (P-0009), 1-(6-Ethyl-4,4-dimethyl-1-pyridin-3-ylmethyl-1,2,3,4-tctrahydro-quinolin-7-yl)-ethylamine (P-0010), 7-(1-Amino-ethyl)-6-bromo-1-(3-methoxy-propyl}-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (P-0011), 7-(1-Amino-cthyl)-1-(3-mcthoxy-propyl)-4,4-dimethyl-3,4-dihydro-111-quinolin-2-one (P-0012), 7-(1-Amino-ethyl)-6-methoxy-1-(3-methoxy-propyl)-4,4-dimethyl-3,4-dihydro- 1H-quinolin-2-one (P-0013), 7-(1-Amino-ethyl)-6-¢thyl-1-(3-methoxy-propyl)-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (P-0014), 1-(6-Ethyl-4,4-dimethyl-1-pyridin-4-ylmethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethylamine (P-0015), 1-[6-Ethyl-1-(3-methoxy-propyl)-4,4-dimethyl-1,2,3 4-tetrahydro-quinolin-7-yl]-propylamine {(P-0016), 1-[6-Ethyl-4,4-dimethyl-1-(5-methyl-isoxazol-3-ylmethyl}-1,2,3,4-tetrahydro-quinolin-7-yl]- gthylamine (P-0017), [7-(1-Amino-ethyl)-6-cthyl-4,4-dimcthyl-3,4-dihydro-2H-quinolin-1 -y1]-pyridin-3-yl-methanone (P-0018), [7-(1-Amino-ethyl)-6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinolin- 1 -yl]-pyridin-4-yl-methanone (P-0020), 1-[1-(3-Methoxy-propyl)-4,4-dimethyl-6-phenyl-1,2,3,4-tetrahydro-quinolin-7-yl]-ethylamine (P0021),
[7-(1-Amino-ethyl)-6-cthyl-4,4-dimethyl-3,4-dihydro-2H-quinolin-1-yl]-isoxazol-5-yl-methanone (P-0022), 1-[1-(3-Bromo-isoxazol-5-ylmethyl)-G-ethyl-4 4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl]- ethylamine (P-0023), 1-[6-Ethyl-4,4-dimethyl-1-(3-methyl-isoxazol-5-ylmethyl}-1,2,3,4-tetrahydro-quinolin-7-yl]- ethylamine (P-0024), 1-(1-Benzyl-6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethylamine (P-0025), 1-[6-Ethyl-4,4-dimethyl-1-(3-trifluoromethyl-benzyl)-1,2,3 4-tetrahydro-quinolin-7-yl]-ethylamine (P-0026), 1-[1-(3,5-Difluoro-benzyl)-6-cthyl-4,4-dimethyl-1,2,3 ,4-tetrahydro-quinolin-7-yl]-ethylamine (P-0027), 1-[6-Ethyl-1-(3-fluoro-benzyl)-4,4-dimethyl-1,2,3 4-tetrahydro-quinolin-7-yl]-ethylamine (P-0028), 1-[6-Lthyl-1-(4-methoxy-benzyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl]-ethylamine (P-0029), 1-[1-(2,3-Difluoro-benzyl)-6-ethyl-4,4-dimethyl-1,2,3 4-tetrahydro-quinolin-7-yl]-ethylamine (P-0030), 1-[6-Ethyl-1-(3-methoxy-benzyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl]-ethylamine (P-0031), 1-[6-Fthyl-1-(4-fluoro-benzyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl]-cthylamine (P-0032), 4-[7-(1-Amino-ethyl)-6-cthyl-4,4-dimethyl-3,4-dihydro-2H-quinolin-1-ylmethyl]-pyridine-2- carbonitrile (P-0033), 1-[6-Ethyl-1-(2-fluoro-pyridin-4-ylmethyl)-4,4-dimethyl-1,2,3 4-tetrahydro-quinolin-7-yl]-ethylamine (P-0034), 1-(6-Ethyl-4,4-dimethyl-1-phenethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethylamine (P-0035), 1-[6-Ethyl-1-(6-fluoro-pyridin-3-ylmethyl)-4,4-dimethyl-1,2,3 4-tetrahydro-quinolin-7-yl]-ethylamine (P-0036), 1-[6-Ethyl-4,4-dimethyl-1-(2-methyl-pyridin-4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-7-yl]- ethylamine (P-0037), 1-[1-(2,2-Difluoro-benzo[1,3]dioxol-5-ylmethyl)-6-ethyl-4,4-dimethyl-1,2,3 4-tetrahydro-quinolin-7- yl]-ethylamine (P-0038), 1-(1-Benzyl-4,4-dimethyl-6-p-tolvl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethylamine (P-0039), 7-(1-Amino-ethyl)-1-(3-methoxy-propyl)-4,4-dimethyl-6-p-tolyl-3,4-dihydro-1H-quinolin-2-one
(P-0040), 1-[6-Ethyl-1-(2-methoxy-pyridin-4-ylmethyl)-4,4-dimethyl-1,2,3, 4-tetrahydro-quinolin-7-yl]-
ethylamine (P-0041), 1-[6-Ethyl-4,4-dimecthyl-1-(6-mecthyl-pyridin-3-ylmethyl)-1,2,3.4-tctrahydro-quinolin-7-yl]-
ethylamine (P-0042),
1-[1-(3-Methoxy-propyl)-4,4-dimethyl-6-p-tolyl-1,2,3,4-tetrahydro-quinolin-7-yl]-ethylamine (P-0043), 1-[1-Benzyl-6-(4-fluoro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl]-ethylamine (P-0044), 1-[1-Benzyl-6-(4-chloro-phenyl)-4,4-dimethyl-1,2,3 4-tetrahydro-quinolin-7-yl]-ethylamine (P-0046), 1-(1-Benzyl-6-¢thyl-4 4-dimethyl-1,2,3 4-tetrahydro-quinolin-7-yl)-propylamine (P-0047), (R)-1-(1-Benzyl-6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethylamine (P-0048), (S)-1-(1-Benzyl-6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethylamine (P-0049), 1-[1-Benzyl-6-(3-methoxy-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl]-ethylamine (P-0050), 1-(1-Benzo[1,3]dioxol-4-ylmethyl-6-¢thyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethylamine (P0051), 7-(1-Amino-ethyl)-1-benzyl-6-ethyl-4,4-dimethyl-3,4-dihydro- 1 H-quinolin-2-one (P-0052), 1-[1-(2,2-Difluoro-benzo[ 1,3 Jdioxol-4-ylmethyl)-6-ethyl-4,4-dimcthyl-1,2,3,4-tetrahydro-quinolin-7- yl]-ethylamine (P-0053), 1-[1-Benzyl-6-(4-methoxy-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl]-ethylamine (P-0054), 1-(1-Benzyl-4,4-dimethyl-6-thiophen-2-yl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethylamine (P-0055), (R)-1-[6-Ethyl-4,4-dimethyl-1-(2-methyl-pyridin-4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-7-yl]- ethylamine (P-0056), (8)-1-[6-Ethyl-4,4-dimethyl-1-(2-methyl-pyridin-4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-7-yl]- ethylamine (P-0057), 1-[6-LCthyl-4,4-dimethyl-1-(tetrahydro-pyran-4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-7-yl]-
cthylamine (P-0058), 1-[1-Benzyl-6-(3-ethyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl]-ethylamine (P-0059), 1-(1-Benzyl-6-benzyloxy-4,4-dimethyl-1,2,3 4-tetrahydro-quinolin-7-yl)-ethylamine (P-0060),
7-(1-Amino-ethyl)-6-ethyl-4,4-dimethyl-1-(2-methyl-pyridin-4-ylmcthyl)-3,4-dihydro-11-quinolin-2-
one (P-0061), 1-[4,4-Dimethyl-1-(2-methyl-pyridin-4-ylmethyl})-6-p-tolyl-1,2,3 4-tetrahydro-quinolin-7-y1]-
cthylamine (P-0062),
1-[1-Benzyl-6-(3-benzyloxy-4-methoxy-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl ethylamine (P-0063),
1-[1-Benzyl-4,4-dimethyl-6-(3-methyl-3H-imidazol-4-y1)-1,2,3,4-tetrahydro-quinolin-7-yl]-
ethylamine (P-0064),
5-[7-(1-Amino-ethyl)-1-benzyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-6-y1]-2-methoxy-phencl
(P-0065),
1-[1-Benzyl-6-(3-chloro-phenyl)-4,4-dimethyl-1,2.3,4-tetrahydro-quinolin-7-yl]-ethylamine (P-0066),
1-(6-Benzo[1,3]dioxol-5-yl-1-benzyl-4,4-dimethyl-1,2,3 4-tetrahydro-quinolin-7-yl)-ethylamine (P-0067), 1-[1-Benzyl-6-(4-ethyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl]-ethylamine (P-0068), 7-(1-Amino-ethyl)-6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (P-0069), 1-(6-Ethyl-4,4-dimcthyl-1-phenyl-1,2,3,4-tctrahydro-quinolin-7-yl)-cthylamine (P-0070), 6-(1-Amino-ethyl)-7-ethyl-4-(2-methoxy-ethyl)-4H-benzo[1,4]oxazin-3-one (P-0071), 3-[7-(1-Amino-ethyl)-1-benzyl-4,4-dimethyl-1,2,3 4-tetrahydro-quinolin-6-yl]-benzamide (P-0072), 4-[7-(1-Amino-ethyl)-1-benzyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl]-benzamide (P-0073), 1-[1-Benzyl-6-(3-fluoro-4-methyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl]-ethylamine (P-0074), 1-[1-Benzyl-6-(2,4-dimethyl-thiazol-5-yl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl]-ethylamine (P-0075), 1-(1-Benzyl-4,4,6-trimethyl-1,2,3 4-tetrahydro-quinolin-7-yl}-ethylamine (P-0076), 1-[1-Benzyl-6-(1H-indol-5-y1}-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl]-ethylamine (P-0077), 7-(1-Aminoc-ethyl)-1-benzyl-4,4-dimethyl-6-p-tolyl-3,4-dihydro-1H-quinolin-2-one (P-0078), 1-[6-Ethyl-1-(3-methoxy-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl]-ethylamine (P-0079), 1-[1-Benzyl-4,4-dimethyl-6-(5-methyl-thiophen-2-y1)-1,2,3,4-tetrahydro-quinolin-7-yl]-ethylamine (P-0080), and any salt, prodrug, tautomer, or stereoisomer thereof.
[0010] In a third aspect, methods arc provided for treating or prophylaxis of a renin-mediated disease or condition in an animal subject in need thereof, wherein the method involves administering to the subject an effective amount of any one or more compound(s) of Formula I. The terms “treat,” “therapy,” and like terms refer to the administration of material, e.g., one or more compound(s) of
Formula I in an amount effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or condition, i.e., indication, and/or to prolong the survival of the subject being treated. The term “renin-mediated disease or condition” refers to a disease or condition in which the biological function of renin affects the development, course, and/or symptoms of the discasc or condition, and/or in which inhibition of the renin activity alters the development, course, and/or symptoms of the disease or condition. A renin-mediated disease or condition includes a disease or condition for which inhibition of renin provides a therapeutic benefit, e.g. whercin treatment with renin inhbitors, including compounds described herein, provides a therapeutic benefit to the subject suffering from or at risk of the disease or condition. In one aspect, the method involves administering to the subject an effective amount of a compound of Formula I in combination with one or more other therapies for the disease or condition.
[0011] In a fourth aspect, compositions are provided that include a therapeutically effective amount of any one or more compound(s) of Formula I and at least one pharmaceutically acceptable carrier, excipient, and/or diluent, including combinations of any two or more compounds of Formula I. The composition can further include a plurality of different pharmacologically active compounds, which can include a plurality of compounds of Formula I. In certain embodiments, the composition can include any one or more compound(s) of Formula I along with onc or more compound(s) that are therapeutically effective for the same disease indication. In one embodiment, the composition includes any one or more compound(s) of Formula I along with one or more compound(s) that are therapeutically effective for the same disease indication, wherein the compounds have a synergistic effect on the disease indication.
[0012] In a fifth aspect, methods are provided for treating or prophylaxis of a renin-mediated discasc or condition in an animal subject in need thereof, wherein the method involves administering to the subject an effective amount of a composition including any one or more compound(s) of
Formula I.
[0013] In a sixth aspect, the invention provides a kit that includes any one or more compound(s) of
Formula I, or a composition thereof as described herein. In some embodiments, the composition is packaged, e.g., in a vial, bottle, flask, which may be further packaged, e.g., within a box, envelope, or bag; the composition is approved by the U.S. Food and Drug Administration or similar regulatory agency for administration to a mammal, e.g., a human; the composition is approved for administration to a mammal, ¢.g., a human, for a renin-mediated disease or condition; the invention kit includes written instructions for use and/or other indication that the composition is suitable or approved for administration to a mammal, e.g., a human, for a renin-mediated discasc or condition; and the composition is packaged in unit dose or single dose form, e.g., single dose pills, capsules, or the like.
[0014] In a seventh aspect, the invention provides methods for treating or prophylaxis of a renin- mediated disease or condition in an animal subject in need thereof, wherein the method involves administering to the subject an effective amount of any one or more compound(s) of Formula , or an effective amount of a composition including any one or more compound(s) of Formula I, wherein the discasc or condition is, for example, without limitation:
Cardiovascular and cardiovascular-related diseases, including, but not limited to, hypertension, essential hypertension, malignant hypertension, pulmonary hypertension, atherosclerosis, congestive heart failure, coronary artery disease, myocardial infarction, cardiac hypertrophy, cardiac fibrosis, ischemic or hemorrhagic stroke, stenosis of arteries, restenosis after angioplasty or other interventions, myocarditis, cardiomyopathy (e.g. diabetic cardiac myopathy, post-infarction cardiac myopathy), arrhythmia (e.g. supraventricular and ventricular arrhythmia, atrial fibrillation and atrial flutter), myocardial ischemia, cardiac insufficiency, unstable coronary syndrome, detrimental vascular remodeling, angina (stable or unstable), diastolic dysfunction, left ventricular dysfunction, and abnormal vascular growth;
Pulmonary-related diseases, including, but not limited to, chronic obstructive pulmonary disease, cor pulmonale, bronchiectasis, acute respiratory distress syndrome, acute lung injury, asthma, bronchiolitis obliterans, bronchiolitis obliterans with organizing pneumonia, cystic fibrosis, idiopathic pulmonary fibrosis, connective tissue or autoimmune disease-related pulmonary fibrosis (e.g. resulting from scleroderma, systemic lupus erythematosus, rheumatoid arthritis, or polymyositis), hypersensitivity pneumonitis, eosinophilic granuloma (Langerhan’s cell histiocytosis), chronic eosinophilic pneumonia, Wegener’s granulomatosis, idiopathic pulmonary hemosiderosis, lymphangioleiomyomatosis, silicosis, asbestosis, berylliosis, sarcoidosis, systemic sclerosis, atypical pneumonia, pneumocystis pneumonia, Hamman-Rich syndrome, histiocytosis X, collagen vascular disease, granulomatous vasculitis,
Goodpasture’s syndrome, Hermansky-Pudlak syndrome, pulmonary alveolar proteinosis, lung cancer, and tuberculosis;
Vasculitis and autoimmune disease and related tissue fibrosis, including, but not limited to, fibrosis caused by sclerodactyly, scleroderma, amyloidosis, systemic sclerosis, dermatomyositis, dupytren’s contracture, peyronie’s disease, polymyositis, amyloidosis, atrophoderma of Pasini and Pierini, Raynaud’s phenomenon, Still’s disease, eosinophilic fasciitis, Hutchinson-Gilford progeria syndrome, Lichen myxedematosus, mixed connective tissue disease, morphoea, porphyria cutanea tarda type |, scleredema adultorum, systemic sclerosis or lymphangitis carcinomatosis;
Nephropathies, including, but not limited to, diabetic nephropathy, IgA nephropathy, Fabry nephropathy, renal fibrosis, nephritis, lupus nephritis, glomcruloncphritis, glomerular sclerosis, renal vascular hypertension, hyperaldosteronism, chronic kidney disease, renal insufficiency, renal ischemia, renal failure, and renal colic;
Liver diseases, including, but not limited to, hepatocellular carcinoma, liver fibrosis, liver cirrhosis, and hepatitis;
Diabetes and complications resulting from diabetes, including, but not limited to, nephropathy, vasculopathy, neuropathy, and diabetic retinopathy; and
Other diseases, including metabolic syndrome, obesity, thyroiditis, gastritis, peptic ulcer, inflammatory bowel syndrome (e.g. ulcerative colitis, Crohn's disease), multiple sclerosis, rheumatoid arthritis, osteoarthritis, osteoporosis, endometriosis, preeclampsia, brain infarction, interstitial cystitis, pancreatitis, pancreatic cancer, erectile dysfunction, proteinuria, albuminuria, cognitive impairment, alzheimer’s disease, dementia, anxiety states, cognitive disorders, increased intraocular pressure, glaucoma, angiogenesis related disorders (e.g. macular degeneration), carcinoid tumor, graft versus host disease (transplant), Sjogren’s disease, uveitis, pemphigus, bullous pemphigoid, epidermolysis bullosa, aphthous ulcers,
stomatitis, Behcet's disease, and other diseases known to be related to the the Renin
Angiotensin System.
[0015] In an eighth aspect, the invention provides methods for treating or prophylaxis of a renin- mediated disease or condition in an animal subject in need thereof, wherein the method involves administering to the subject an effective amount of any one or more compound(s) of Formula I, or an effective amount of a composition including any one or more compound(s) of Formula I, in combination with one or morc other therapies for the disease or condition. In some embodiments, the one or more other therapies include, for example, without limitation: angiotensin converting enzyme (ACE) inhibitors, including, but not limited to, benazepril, cilazapril, captopril, delapril, enalapril, fosinopril, indolapril, lisinopril, meoxipril, perindopril, pivopril, quinapril, ramipril, rescinnamine, spirapril, trandolapril, and zofenopil; angiotensin II receptor antagonists, including, but not limited to, candesartan, eprosartan, irbesartan, losartan, olmesartan, saprisartan, tasosartan, telmisartan, and valsartan; endothelin receptor antagonists, including, but not limited to, ambrisentan, avosentan, bosentan, clazosentan, sitaxsentan, tezosentan), alpha- and beta-adrenergic antoginists, including, but not limited to, acebutolol, albutcrol, alfuzosin, alprenolol, atenolol, betaxolol, bisoprolol, butaxamine, carteolol, carvedilol, celiprolol, dilevalol, doxazosin, esmolol, labetalol, levobunolol, mepindolol, metipranolol, metoprolol, nadolol, nebivolol, oxprenolol, penbutolol, phentolamine, phenoxybenzamine, pindolol, prazosin, propranolol, salmeterol, sotalol, tamsulosin, terazosin, timolol, and tolazine; vasodilators, including, but not limited to, diazoxide, dipyridamole, fenoldopam, flosequinan, hydralazine, iloprost, isosorbide mononitrate, minoxidil, nitroprusside, and treprostinil; calcium channel blockers such as amlodipine, azelnidipine, bencyclane, cilnidipine, diltiazem, felodipine, fendiline, flunarizine, gallopamil, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, perhexilene, teludipine, and verapamil; potassium activators, including, but not limited to, nicorandil and pinacidil; diuretics, including, but not limited to, acetazolamide, amiloride, bendroflumethiazide, benzthiazide, bumetanide, canrenone, chlorothiazide, chlortalidone, eplerenone, ethacrynic acid, furosemide, hydrochlorothiazide, indacrinone, indapamide, mefruside, metolazone, spironolactone, torasemide, tricrynafen, and triamterene; sympatholytics, including, but not limited to, clonidine, dobutamine, guanabenz, guanethidine, guanfacine, indoramin, lofexidine, mecamylamine, methyldopa, moxonidine, reserpine, rilmenidine, trimethaphan, and urapidil; serotonin receptor antagonists, including, but not limited to,?(sec below);
thromboxane-synthetase inhibitors;
neutral endopeptidase inhibitors (NEP inhibitors);
renin inhibitors, including, but not limited to, aliskerin;
phosphodiesterase inhibitors, including, but not limited to, amrinone, pentoxifylline, sildenafil, tadalafil, and vardenafil;
anti-inflammatory agents, such as aceclofenac, acemetacin, alclofenac, algestone, alminoprofen, amcinafal, amcinafide, amfenac, amiprilose, ampyrone, anakinra, anirolac, apazone, azapropazone, balsalazide, bendazac, benoxaprofen, benzydamine, bromelains, bromfenac, broperamole, carprofen, cicloprofen, cintazone, cliprofen, clobetasol, clobetasone, clofezone, clopirac, cloticasone, cortodoxone, deflazacort, desonide, desoximetasonc, dexibuprofen, dexketoprofen, diclofenac, diflumidone, diflunisal, difluprednate, diftalone, drocinonide, droxicam, enlimomab, enolicam, epirizole, etodolac, etofenamate, felbinac, fenamole, fenbufen, fenclofenac, fenclorac, fendosal, fenpipalone, fentiazac, flazalone, fluazacort, flufenamic acid, flumizole, flunisolide acetate, flunixin, flunoxaprofen, fluocortin butyl, fluorometholone, fluquazone, flurbiprofen, fluretofen, furaprofen, furobufen, ibufenac, ibuprofen, ibuproxam, ilonidap, indomethacin, indoprofen, indoxole, intrazole, isoflupredone, isoxepac, isoxicam, kebuzone, ketorolac, ketoprofen, lofemizole, lornoxicam, loxoprofen, meclofenamic acid, mefenamic acid, meloxicam, meseclazone, metamizole, mofebutazone, morniflumate, nabumetone, naproxen, naproxol, nimazone, olsalazine sodium, orgotein, orpanoxin, oxametacin, oxaprozin, oxyphenbutazone, paranyline, pentosan, phenazone, phenylbutazone, pirfenidone, piroxicam, pirprofen, prednazate, prifelone, prodolic acid, proglumetacin, proquazone, proxazole, rimexolone, romazarit, salcolex, salsalate, salycilates, sanguinarium chloride, seclazone, sermetacin, sudoxicam, sulfinpyrazone, sulindac, suprofen, talmetacin, talniflumate, talosalate, tebufelone, tenidap, tenoxicam, tesicam, tesimide, tetrydamine, tiaprofenic acid, tiopinac, tolfenamic acid, tolmetin, triclonide, triflumidate, zidometacin, and zomepirac;
agents suitable for treating inflammatory bowel syndrome, including, but not limited to, corticosteroids, 6-mercaptopurine, mesalamine, and TNF anatogonists (including, but not limited to, adalimumab, etanercept, and infliximab);
agents suitable for treating diabetes and complications associated with diabetes, including, but not limited to, benzafibrate, ciprofibrate, clofibrate, fenofibrate, gemfibrozil, metformin, pioglitazone, repaglinide, and rosiglitazone;
agents suitable for treating cystic fibrosis, including, but not limited to, alendronate, dornase alfa, denufosol, fluticasone, inhaled sodium bicarbonate, miglustat, and perfenidone;
agents suitable for treating pulmonary fibrosis, including, but not limited to, azathioprine, budesonide, cyclophosphamide, dapsonc, dexamethasone, etanercept, imatinib, interferon gamma-1b, interferon alpha-2b, minocycline, prednisone, methylprednisolone, and thalidomide; agents suitable for treating COPD, including, but not limited to, advair and tlovent; agents suitable for treating liver fibrosis, including, but not limited to, adefovir dipivoxil, colchicine, conivaptan, cyclosporine, everolimus, gabapentin, methotrexate, satavaptan, tacrolimus, and zilcuton; agents suitable for treating hepatitis, including, but not limited to, 4-methylumbelliferone and cystadane; agents suitable for treating other nephropathies, including, but not limited to, rapamycin, rituximab, and daclizumab:; agents suitable for treating pancreatitis, including, but not limited to, pancrelipase; agents suitable for treating scleroderma, including, but not limited to, abatacept; agents suitable for treating macular degeneration, including, but not limited to, ranibizumab; agents suitable for treating infections that may be result in fibrosis, including, but not limited to, adefovir, azithromycin, aztreonam, ceftazidime, ciprofloxacin, clarithromycin, efavirenz, itraconazole, lamivudine, lopinavir, ritonavir, nelfinavir, tefibazumab, telbivudine, tenofovir, tobramycin, and zidovudine; other agents suitable for treatment of, for example, hypertension, cardiovascular diseases, or fibrotic diseases, including, but not limited to, amitriptyline, L-arginine, depclestat, hydroxychloroquine, ketanserin, Nitric oxide, nitroglycerin, octreotide, perhexiline, ranolazine, statins (including, bul not limited to, atorvastatin, cirivastatin, fluvastatin, lovastatin, pravastatin, and simvastatin), and tetrahydrobiopterin.
[0016] In a ninth aspect, the invention provides a method of treating or prophylaxis of a disease or condition in an animal subject in need thereof, by administering to the subject a therapeutically effective amount of any one or more compound(s) of Formula I, a prodrug of such compound, a pharmaceutically acceptable salt of such compound or prodrug, or a pharmaceutically acceptable formulation of such compound or prodrug. The compound can be alone or can be part of a composition. In some embodiments, the invention provides a method of treating or prophylaxis of a disease or condition in an animal subject in need thereof, by administering to the subject a therapeutically effective amount of any one or more compound(s) of Formula I, a prodrug of such compound, a pharmaceutically acceptable salt of such compound or prodrug, or a pharmaceutically acceptable formulation of such compound or prodrug in combination with one or more other suitable therapies for the disease or condition.
[0017] In a tenth aspect, a compound of Formula I will have an ICs; of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM as determined in a generally accepted renin activity assay. In some embodiments, the compound selectively inhibits renin relative to other enzymes, including, but not limited to, selectivity of the compound relative to other proteases, whether a protease discussed herein, or other proteases. In some embodiments, the selectivity is such that the compound is at least 2-fold, 5-fold, 10-fold, or 100- fold more active on renin than any other aspartyl protease, including, but not limited to, any of pepsin, cathepsin-D or BACE. Selective inhibition of renin relative to another protease is such that the ICs, for the renin may be at least about 2-fold, also 5-fold, also 10-fold, also 20-fold, also 50-fold, or at least about 100-fold less than the ICs, for any of the other proteases as determined in a generally accepted activity assay for said protease.
[0018] Additional aspects and embodiments will be apparent from the following Detailed
Description of the Invention and from the claims.
[0019] As used herein the following definitions apply unless clearly indicated otherwise:
[0020] All atoms designated within a Formula described herein, either within a structure provided, or within the definitions of variables related to the structure, is intended to include any isotope thereof, unless clearly indicated to the contrary. It is understood that for any given atom, the isotopes may be present essentially in ratios according to their natural occurrence, or one or more particular atoms may be enhanced with respect to one or more isotopes using synthetic methods known to one skilled in the art. Thus, hydrogen includes for example 'H, 2H, *H; carbon includes for example "ne, 2c, Ve, Me; oxygen includes for example 0, "0, "0; nitrogen includes for example PN, MN, PN; sulfur includes for example **S, »*S,**S, ¥*S, *%S, ¥’S, *¥S; fluoro includes for example ''F, "°F, °F; chloro includes for example *°Cl, **Cl, *’Cl, **Cl, **CJ; and the like.
[0021] “Halogen” refer to all halogens, that is, chloro (Cl), fluoro (F), bromo (Br), or iodo (I).
[0022] “Oxo” refers to =0, e.g. an oxo substituted carbon atom provides a carbonyl (C=0) group.
[0023] “Lower alkyl” alone or in combination means an alkane-derived radical containing from 1 to 6 carbon atoms (unless specifically defined) that includes a straight chain alkyl or branched alkyl.
The straight chain or branched lower alkyl group is chemically feasible and attached at any available point to provide a stable compound. In many embodiments, a lower alkyl is a straight or branched alkyl group containing from 1-6, 1-4, or 1-2, carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and the like. Lower alkyl that is “optionally substituted” denotes lower alkyl that is optionally independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents as indicated, for example, in the description of compounds of
Formula I. Furthermore, possible substitutions include subsets of these substitutions, such as are indicated herein. For example, fluoro substituted lower alkyl denotes a lower alkyl group substituted with one or more fluoro atoms, such as perfluoroalkyl, where preferably the lower alkyl is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. It is understood that any substitutions are chemically feasible and attached at any available atom to provide a stable compound.
[0024] "Cycloalkyl" refers to saturated or unsaturated, non-aromatic monocyclic, bicyclic or tricyclic carbon ring systems of 3-10, also 3-8, more preferably 3-6, ring members per ring, such as cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, and the like. Cycloalkyl that is “optionally substituted” denotes cycloalkyl that is optionally independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents as indicated, for example, in the description of compounds of Formula I. It is understood that any substitutions are chemically feasible and attached at any available atom to provide a stable compound.
[0025] “Heterocycloalkyl” refers to a saturated or unsaturated non-aromatic cycloalkyl group having from 5 to 10 atoms in which from 1 to 3 carbon atoms in the ring are replaced by heteroatoms of O, S or N, and are optionally fused with benzo or heteroaryl of 5-6 ring members. Heterocycloalkyl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen.
Heterocycloalkyl is also intended to include compounds in which a ring carbon may be oxo substituted, i.e. the ring carbon is a carbonyl group, [or example as found in lactones and lactams.
The point of attachment of the heterocycloalkyl ring is chemically feasible, at a carbon or nitrogen atom, such that a stable compound is provided. Examples of heterocycloalky! groups include, but are not limited to, morpholino, tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl, pyrrolidonyl, piperazinyl, dihydrobenzofuryl, and dihydroindolyl. Heterocycloalkyl that is “optionally substituted” denotes heterocycloalkyl that is optionally independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents as indicated, for example, in the description of compounds of Formula I. It is understood that any substitutions are chemically feasible and attached at any available atom to provide a stable compound.
[0026] “Aryl” alone or in combination refers to a monocyclic or bicyclic ring system containing aromatic hydrocarbons such as phenyl or naphthyl, which may be optionally fused with a cycloalkyl of preferably 5-7, more preferably 5-6, ring members. Aryl that is "optionally substituted” denotes aryl that is optionally independently substituted, unless indicated otherwise, with one or more, preferably 1,2,3,4 or 5, also 1, 2, or 3 substituents as indicated, for example, in the description of compounds of Formula I. It is understood that any substitutions are chemically feasible and attached at any available atom to provide a stable compound.
[0027] “Heteroaryl” alone or in combination refers to a monocyclic aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing one or more, preferably 1-4, more preferably 1-3, even more preferably 1-2, heteroatoms independently selected from the group consisting of O, S, and N. Heteroaryl is also intended to include oxidized S or N, such as sulfiny!, sulfonyl and N-oxide of a tertiary ring nitrogen. The point of attachment of the heteroaryl ring is chemically feasible, at a carbon or nitrogen atom, such that a stable compound is provided. Examples of heteroaryl groups include, but arc not limited to, pyridinyl, pyridazinyl, pyrazinyl, quinaoxalyl, indolizinyl, benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuryl, and indolyl. Hctcroaryl that is "optionally substituted” denotes heteroaryl that is optionally independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3,4 or 5, also 1, 2, or 3 substituents as indicated, {or example, in the description of compounds of Formula I. It is understood that substitutions are chemically feasible and attached at any available atom to provide a stable compound.
[0028] “Lower alkoxy” denotes the group -OR?, where R" is lower alkyl. Lower alkoxy that is "optionally substituted” denotes lower alkoxy in which R" is lower alkyl optionally independently substituted with onc or more substituents as indicated herein, for example, in the description of compounds of Formula 1. Preferably, substitution of lower alkoxy is with 1, 2, 3, 4, or 5 substituents, also 1, 2, or 3 substituents. For example “fluoro substituted lower alkoxy” denotes lower alkoxy in which the lower alkyl is substituted with one or more fluoro atoms, where preferably the lower alkoxy is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. It is understood that any substitutions on alkoxy are chemically feasible and attached at any available atom to provide a stable compound.
[0029] “Lower alkylthio” denotes the group -SR®, where R® is lower alkyl. Lower alkylthio that is "optionally substituted” denotes lower alkylthio in which R" is lower alkyl substituted with one or more substituents as indicated herein, for example, in the description of compounds of Formula I.
Preferably, substitution of lower alkylthio is with 1, 2, 3, 4, or 5 substituents, also 1, 2, or 3 substituents. For example “fluoro substituted lower alkylthio” denotes lower alkylthio in which the lower alkyl is substituted with one or more fluoro atoms, where preferably the lower alkylthio is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. It is understood that any substitutions on alkylthio are chemically feasible and attached at any available atom to provide a stable compound.
[0030] “Amino” denotes the group -NH,. “Mono-alkylamino” denotes the group -NHR® where R° is lower alkyl. “Di-alkylamino” denotes the group -NR°R?, where R® and R” are independently lower alkyl. “Cycloalkylamino” denotes the group -NR°R’, where R® and R” combine with the nitrogen to form a 5-7 membered heterocycloalkyl, where the heterocycloalkyl may contain an additional heteroatom within the ring, such as O, N, or S, and may also be further substituted with lower alkyl.
Examples of 5-7 membered heterocycloalkyl include, but are not limited to, piperidine, piperazine, 4-methylpiperazine, morpholine, and thiomorpholine. It is understood that when mono-alkylamino, di-alkylamino, or cycloalkylamino are substituents on other moieties, these substitutions are chemically feasible and attached at any available atom to provide a stable compound.
[0031] The terms “animal subject”, “subject” and the like refer to human and non-human vertebrates, ¢.g. mammals, such as non-human primates, sports and commercial animals, e.g., equines, bovines, porcines, ovines, rodents, and pets, e.g., canines and felines.
[0032] As used herein, the term “solid form’ refers to a solid preparation (i.e. a preparation that is neither gas nor liquid) of a pharmaceutically active compound that is suitable for administration to an intended animal subject for therapeutic purposes. The solid form includes any complex, such as a salt, co-crystal or an amorphous complex, as well as any polymorph of the compound. The solid form may be substantially crystalline, semi-crystalline or substantially amorphous. The solid form may be administered directly or used in the preparation of a suitable composition having improved pharmaceutical properties. For example, the solid form may be uscd in a formulation comprising at least one pharmaceutically acceptable carrier or excipient.
[0033] As used herein, the term “substantially crystalline’ material embraces material which has greater than about 90% crystallinity; and “crystallinc” material embraces material which has greater than about 98% crystallinity.
[0034] As used herein, the term “substantially amorphous” material embraces material which has no more than about 10% crystallinity; and “amorphous” material embraces material which has no more than about 2% crystallinity.
[0035] As used herein, the term “semi-crystalline” material embraces material which is greater than 10% crystallinity, but no greater than 90% crystallinity; preferably “semi-crystalline” material embraces material which is greater than 20% crystallinity, but no greater than 80% crystallinity. In one aspect of the present invention, a mixture of solid forms of a compound may be prepared, for example, a mixture of amorphous and crystalline solid forms, e.g. to provide a “semi-crystalline” solid form. Such a “semi-crystalline” solid form may be prepared by methods known in the art, for example by mixing an amorphous solid form with a crystalline solid form in the desired ratio. In some instances, a compound mixed with acid or base forms an amorphous complex; a semi-crystalline solid can be prepared employing an amount of compound component in excess of the stoichiometry of the compound and acid or base in the amorphous complex, thereby resulting in an amount of the amorphous complex that is based on the stoichiometry thereof, with excess compound in a crystalline form. The amount of excess compound used in the preparation of the complex can be adjusted to provide the desired ratio of amorphous complex to crystalline compound in the resulting mixture of solid forms. For example, where the amorphous complex of acid or base and compound has a 1:1 stoichiometry, preparing said complex with a 2:1 mole ratio of compound to acid or base will result in a solid form of 50% amorphous complex and 50% crystalline compound. Such a mixture of solid forms may be beneficial as a drug product, for example, by providing an amorphous component having improved biopharmaceutical properties along with the crystalline component. The amorphous component would be more readily bioavailable while the crystalline component would have a delayed bioavailablity. Such a mixture may provide both rapid and extended exposure to the active compound.
[0036] As used herein, the term “complex” refers to a combination of a pharmaceutically active compound and an additional molecular species that forms or produces a new chemical species in a solid form. In some instances, the complex may be a salt, i.e. where the additional molecular species provides an acid/base counter ion to an acid/base group of the compound resulting in an acid:base interaction that forms a typical salt. While such salt forms are typically substantially crystalline, they can also be partially crystalline, substantially amorphous, or amorphous forms. In some instances, the additional molecular species, in combination with the pharmaceutically active compound, forms a non-salt co-crystal, i.e. the compound and molecular species do not interact by way of a typical acid:base interaction, but still form a substantially crystalline structure. Co-crystals may also be formed from a salt of the compound and an additional molecular species. In some instances, the complex is a substantially amorphous complex, which may contain salt-like acid:base interactions that do not form typical salt crystals, but instead form a substantially amorphous solid, i.e. a solid whose
X-ray powder diffraction pattern exhibits no sharp peaks (e.g. exhibits an amorphous halo).
[0037] As used herein, the term “stoichiometry” refers to the molar ratio of two or more reactants that combine to form a complex, for example, the molar ratio of acid or base to compound that form an amorphous complex. For example, a 1:1 mixture of acid or base with compound (i.e. 1 mole acid or base per mole of compound) resulting in an amorphous solid form has a 1:1 stoichiometry.
[0038] As uscd herein, the term “composition” refers to a pharmaceutical preparation suitable for administration to an intended animal subject for therapeutic purposes that contains at least one pharmaceutically active compound, including any solid form thereof. The composition may include at least one pharmaceutically acceptable component to provide an improved formulation of the compound, such as a suitable carrier or excipient.
[0039] The term “pharmaceutically acceptable” indicates that the indicated material does not have properties that would cause a reasonably prudent medical practitioner to avoid administration of the material to a patient, taking into consideration the disease or conditions to be trcated and the respective route of administration. For example, it is commonly required that such a material be essentially sterile, e.g., for injectibles,
[0040] In the present context, the term “therapeutically effective” or "effective amount” indicates that the materials or amount of material is effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or medical condition, and/or to prolong the survival of the subject being treated.
[0041] In the present context, the terms “synergistically effective” or “synergistic effect” indicate that two or more compounds that are therapeutically effective, when used in combination, provide improved therapeutic effects greater than the additive effect that would be expected based on the cttect of cach compound used by itself.
[0042] The term “inhibit” is used to refer to a decrease the activity of a target biomolecule, e.g., an enzyme such as a protease, Generally an inhibitor will be a small molecule, i.e. a compound with a molecular weight of 1500 daltons or less, or preferably 1000 daltons or less, 800 daltons or less, or 600 daltons or less. As such, a compound that inhibits renin (a renin inhibitor) will decrease the activity of renin, for example, the compound will reduce the conversion by renin of angiotensinogen to angiotensin I.
Renin Angiotensin System
[0043] The renin-angiotensin system (RAS) is involved in the regulation of blood pressure and uid homeostasis. Renin is an endopeptidase of approximately 40 kDa that is produced and secreted by the juxtaglomerular cells of the kidney, and circulates through the blood. It is also produced locally in tissues, including, but not limited to brain, heart, vasculature, adipose tissue, adrenal glands, pancreas, placenta and kidney, as well as in mast cells, and thus is active in a variety of tissues. Renin specifically cleaves angiotensinogen, a naturally occurring plasma glycoprotein, to form angiotensin I.
Angiotensin-converting enzyme (ACE) acts in the lungs, kidneys, or other tissues to cleave angiotensin I, forming angiotensin II. Angiotensin II constricts blood vessels and acts to release aldosterone from the adrenal gland, resulting in a significant increase in blood pressure. Thus, any mechanism to block the activity of angiotensin II, for example, by inhibiting the formation of angiotensin I or by blocking the receptors of angiotensin II may be effective in (reating cardiovascular diseascs such as hypertension and congestive heart failure. While ACE inhibitors may be useful in such treatment, these inhibitors interfere with other functions of the enzyme as well,
including degradation of bradykinin, enkephalins, and substance P, which may result in undesired side effects. Additional concerns in using ACE inhibitors or angiotensin II receptors involve feedback whereby renin increases, resulting in increased angiotensin I, which can overwhelm the ACE inhibitor, or increase in angiotensin II, which can overwhelm the angiotensin II receptor antagonists.
Renin, by contrast, is very specific to cleaving angiotensinogen, and inhibitors of renin are expected to have few side effects. The renin inhibitor aliskerin was approved for use in treating hypertension in
March of 2007.
[0044] In addition to hypertension and other cardiovascular diseases, blocking of the renin- angiotensin system, for example with renin inhibitor, can provide therapeutic benefits in a variety of diseases. Segall et al. (Nephrol Dial Transplant, 2007, 22: 2435-2439) discusscs the usc of renin inhibitors in treating nephropathies, including chronic kidney disease, diabetic nephropathy and proteinuria, as well as treating cardiovascular diseases, including heart failure and myocardial infarction. Discussion of renin-angiotensin system inhibition in renal diseases is also found in
Remuzzi ct al. (Annals of Internal Medicine, 2002, 136(8): 604-615), MacKinnon et al. (American
Journal of Kidney Diseases, 2006, 48(1): 8-20), Russo et al. (American Journal of Kidney Diseases, 2001, 38(1): 18-25), and Kelly et al. (Diabetologia, 2007, 50: 2398-2404).
[0045] Renin inhibitors may also be used to treat fibrosis, for example fibrotic diseases in various tissues, including liver (e.g. cirrhosis, as caused, for example, by viral hepatitis, schistosomiasis or alcoholism), lung (e.g. interstitial lung diseases, such as idiopathic pulmonary disease, sarcoidosis, silicosis, drug reactions and infections, as well as collagen vascular diseases, such as rheumatoid arthritis and systemic sclerosis), kidney (e.g. diabetic nephropathy), heart and vascular (e.g. post myocardial infarction, hypertension, atherosclerosis and restenosis), eye (e.g. macular degeneration, retinal and vitreal retinopathy), skin (e.g. keloids, hypertrophic scars, and scleroderma), pancreas (e.g. pancreatitis), intestine (e.g. inflammatory bowel disease), and brain (e.g. Alzheimer’s disease and
AIDS). Fibrosis results from, for example, chronic inflammation, which is induced by a variety of stimuli, such as infection, autoimmune reaction, allergic reaction, chemical insults, radiation, or tissue injury. Discussion of the role of the renin-angiotensin system in fibrosis is found in T.A. Wynn (Journal of Pathology, 2008, 214: 199-210), Kisseleva et al. (Journal of Gastroenterology and
Hepatology, 2007, 22 (Suppl. 1): S73-S78), Zhang ct al. (Current Eye Research, 2007, 32(10): 883- 889), Nagai et al. (Investigative Ophthalmology & Visual Science, 2007, 48(5): 2321-2326;
Investigative Ophthalmology & Visual Science, 2005, 46(8): 2925-2931; and Investigative
Ophthalmology & Visual Science, 2005, 46(3): 1078-1084), Yoshiji et al. (Journal of
Gastroenterology and Hepatology, 2007, 22(Suppl. 1); S93-595), Yao et al. (Respiration, 2006, 73: 236-242), Kuba et al. (Current Opinion in Pharmacology, 2006, 6:271-276), and Kurihara et al. (Investigative Ophthalmology & Visual Science, 2006, 47(12): 5545-5552). Inhibition of renin produced by mast cells in various tissues may also be used to treat a variety of diseases, as discussed in Veerappan ct al. (PNAS, 2008, 105(4): 1315-1320) and Reid et al. (Immunological Reviews, 2007, 217: 123-140).
[0046] Renin inhibitors may be useful in treating cardiovascular and cardiovascular-related diseases, such as hypertension, essential hypertension, malignant hypertension, pulmonary hypertension, atherosclerosis, congestive heart failure, coronary artery disease, myocardial infarction, cardiac hypertrophy, cardiac fibrosis, ischemic or hemorrhagic stroke, stenosis of arteries, restenosis after angioplasty or other interventions, myocarditis, cardiomyopathy (e.g. diabetic cardiac myopathy, post- infarction cardiac myopathy), arrhythmia (e.g. supraventricular and ventricular arrhythmia, atrial fibrillation and atrial flutter), myocardial ischemia, cardiac insufficiency, unstable coronary syndrome, detrimental vascular remodeling, angina (stable or unstable), diastolic dysfunction, left ventricular dysfunction, and abnormal vascular growth; pulmonary-related diseases, such as chronic obstructive pulmonary disease, cor pulmonale, bronchiectasis, acute respiratory distress syndrome, acute lung injury, asthma, bronchiolitis obliterans, bronchiolitis obliterans with organizing pneumonia, cystic fibrosis, idiopathic pulmonary fibrosis, connective tissue or autoimmune disease-related pulmonary fibrosis (e.g. resulting from scleroderma, systemic lupus erythematosus, rheumatoid arthritis, or polymyositis), hypersensitivity pneumonitis, eosinophilic granuloma (Langerhan’s cell histiocytosis), chronic cosinophilic pneumonia, Wegener’s granulomatosis, idiopathic pulmonary hemosiderosis, lymphangioleiomyomatosis, silicosis, asbestosis, berylliosis, sarcoidosis, systemic sclerosis, atypical pneumonia, pneumocystis pneumonia, Hamman-Rich syndrome, histiocytosis X, collagen vascular disease, granulomatous vasculitis, Goodpasture’s syndrome, Hermansky-Pudlak syndrome, pulmonary alveolar proteinosis, lung cancer, and tuberculosis; vasculitis and autoimmune disease and related tissue fibrosis, such as fibrosis caused by sclerodactyly, scleroderma, amyloidosis, systemic sclerosis, dermatomyositis, dupytren’s contracture, peyronie’s disease, polymyositis, amyloidosis, atrophoderma of Pasini and Pierini, Raynaud’s phenomenon, Still’s disease, eosinophilic fasciitis,
Hutchinson-Gilford progeria syndrome, Lichen myxedematosus, mixed connective tissue disease, morphoea, porphyria cutanea tarda type 1, scleredema adultorum, systemic sclerosis or lymphangitis carcinomatosis; Nephropathies, such as diabetic nephropathy, IgA nephropathy, Fabry nephropathy, renal fibrosis, nephritis, lupus nephritis, glomerulonephritis, glomerular sclerosis, renal vascular hypertension, hyperaldosteronism, chronic kidney discase, renal insufficiency, renal ischemia, renal failure, and renal colic; liver diseases, such as hepatocellular carcinoma, liver fibrosis, liver cirrhosis, and hepatitis; diabetes and complications resulting from diabetes, such as nephropathy, vasculopathy, neuropathy, and diabetic retinopathy; and other diseases, including metabolic syndrome, obesity, thyroiditis, gastritis, peptic ulcer, inflammatory bowel syndrome (e.g. ulcerative colitis, Crohn's disease), multiple sclerosis, rheumatoid arthritis, osteoarthritis, osteoporosis, endometriosis, preeclampsia, brain infarction, interstitial cystitis, pancreatitis, pancreatic cancer, erectile dysfunction,
proteinuria, albuminuria, cognitive impairment, Alzheimer’s discase, dementia, anxiety states, cognitive disorders, increased intraocular pressure, glaucoma, angiogenesis related disorders (e.g. macular degeneration), carcinoid tumor, graft versus host disease (transplant), Sjogren’s disease, uveitis, pemphigus, bullous pemphigoid, epidermolysis bullosa, aphthous ulcers, stomatitis, Behcet's disease, and other diseases known to be related to the the Renin Angiotensin System.
Aspartyl Protease Activity Assays
[0047] A number of different assays for renin activity can be utilized for assaying for the ability of a compound to inhibit renin. Such assays can be formatted either in a fluorescence resonance energy transfer (FRET) format, or using an AlphaScreen (amplified luminescent proximity homogeneous assay) format by varying the donor and acceptor reagents accordingly. Similar assays may be utilized for assaying the activity against other aspartyl proteases, or other proteases, in order to assess the selectivity of the compound for inhibition of renin. One of ordinary skill in the art will know of assays that can be utilized or modified for a particular application, including, for example, the assays described in the Examples below. Further, animal models (e.g. rat, marmoset) known in the art may be used to test the activity of renin inhibitors in vivo.
Organic Synthetic Techniques
[0048] A wide array of organic synthetic techniques exist in the art to facilitate the preparation of potential inhibitors. Many of these organic synthetic methods are described in detail in standard reference sources utilized by those skilled in the art. One example of such a reference is March, 1994,
Advanced Organic Chemistry; Reactions, Mechanisms and Structure, New York, McGraw Hill.
Thus, the techniques useful to synthesize a potential renin inhibitor are readily available to those skilled in the art of organic chemical synthesis.
Alternative Compound Forms or Derivatives
[0049] Compounds contemplated herein are described with reference to both generic formulae and specific compounds. In addition, invention compounds may exist in a number of different forms or derivatives, all within the scope of the present invention. Alternative forms or derivatives, include, for example, (a) prodrugs, and active metabolites (b) tautomers, isomers (including stereoisomers and regioisomers), and racemic mixtures (c) pharmaceutically acceptable salts and (d) solid forms, including different crystal forms, polymorphic or amorphous solids, including hydrates and solvates thereof, and other forms.
(a) Prodrugs and Metabolites
[0050] In addition to the present formulae and compounds described herein, the invention also includes prodrugs (generally pharmaceutically acceptable prodrugs), active metabolic derivatives (active metabolites), and their pharmaccutically acceptable salts.
[0051] Prodrugs are compounds or pharmaceutically acceptable salts thereof which, when metabolized under physiological conditions or when converted by solvolysis, yield the desired active compound. Prodrugs include, without limitation, csters, amides, carbamates, carbonates, ureides, solvates, or hydrates of the active compound. Typically, the prodrug is inactive, or less active than the active compound, but may provide one or more advantageous handling, administration, and/or metabolic properties. For example, some prodrugs are esters of the active compound; during metabolysis, the ester group is cleaved to yield the active drug. Esters include, for example, esters of a carboxylic acid group, or S-acyl or O-acyl derivatives of thiol, alcohol, or phenol groups. In this context, a common example is an alkyl ester of a carboxylic acid. Some prodrugs arc activated enzymatically to yield the active compound, or a compound may undergo further chemical reaction to yield the active compound. Prodrugs may proceed from prodrug form to active form in a single step or may have one or more intermediate forms which may themselves have activity or may be inactive.
Prodrug of a compound of Formula I includes, for example, a carbamate derivative of the primary amine substitution at the 7 position, i.e. a prodrug includes where the amine at this position is in the form of NH-C(0)-OR, where R, for example, is alkyl, such that the compound is metabolized to give the free NH, at this position.
[0052] As described in The Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth, Academic
Press, San Diego, CA, 2001), prodrugs can be conceptually divided into two non-exclusive categories, bioprecursor prodrugs and carrier prodrugs. Generally, bioprccursor prodrugs are compounds that are inactive or have low activity compared to the corresponding active drug compound, that contain one or more protective groups and are converted to an active form by metabolism or solvolysis. Both the active drug form and any released metabolic products should have acceptably low toxicity. Typically, the formation of active drug compound involves a metabolic process or reaction that is one of the following types:
[0053] Oxidative reactions: Oxidative reactions are exemplified without limitation by reactions such as oxidation of alcohol, carbonyl, and acid functionalities, hydroxylation of aliphatic carbons, hydroxylation of alicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation of carbon- carbon double bonds, oxidation of nitrogen-containing functional groups, oxidation of silicon, phosphorus, arsenic, and sulfur, oxidative N-dealkylation, oxidative O- and S-dealkylation, oxidative deamination, as well as other oxidative reactions.
[0054] Reductive reactions: Reductive reactions are exemplified without limitation by reactions such as reduction of carbonyl functionalitites, reduction of alcohol functionalities and carbon-carbon double bonds, reduction of nitrogen-containing functional groups, and other reduction reactions.
[0055] Reactions without change in the oxidation state: Reactions without change in the state of oxidation arc cxcmplified without limitation to reactions such as hydrolysis of esters and ethers, hydrolytic cleavage of carbon-nitrogen single bonds, hydrolytic cleavage of non-aromatic heterocycles, hydration and dehydration at multiple bonds, new atomic linkages resulting from dehydration reactions, hydrolytic dehalogenation, removal of hydrogen halide molecule, and other such reactions.
[0056] Carrier prodrugs are drug compounds that contain a transport moiety, e.g., that improves uptake and/or localized delivery to a site(s) of action. Desirably for such a carrier prodrug, the linkage between the drug moiety and the transport moiety is a covalent bond, the prodrug is inactive or less active than the drug compound, the prodrug and any release transport moiety are acceptably non-toxic. For prodrugs where the transport moiety is intended to enhance uptake, typically the release of the transport moiety should be rapid. In other cases, it is desirable to utilize a moiety that provides slow release, e.g., certain polymers or other moieties, such as cyclodextrins. (See, e.g,
Cheng et al., U.S. Patent Publ. No. 20040077595, App. No. 10/656,838, incorporated herein by reference.) Such carrier prodrugs are often advantageous for orally administered drugs. In some instances, the transport moiety provides targeted delivery of the drug, for example the drug maybe conjugated to an antibody or antibody fragment. Carrier prodrugs can, for example, be used to improve onc or morc of the following properties: increased lipophilicity, increased duration of pharmacological effects, increased site-specificity, decreased toxicity and adverse reactions, and/or improvement in drug formulation (e.g., stability, water solubility, suppression of an undesirable organoleptic or physiochemical property). For example, lipophilicity can be increased by esterification of hydroxyl groups with lipophilic carboxylic acids, or of carboxylic acid groups with alcohols, e.g., aliphatic alcohols. Wermuth, supra.
[0057] Metabolites, e.g., active metabolites, overlap with prodrugs as described above, c.g, bioprecursor prodrugs. Thus, such metabolites are pharmacologically active compounds or compounds that further metabolize to pharmacologically active compounds that are derivatives resulting from metabolic processes in the body of a subject. Of these, active metabolites are such pharmacologically active derivative compounds. For prodrugs, the prodrug compound is generally inactive or of lower activity than the metabolic product. For active metabolites, the parent compound may be either an active compound or may be an inactive prodrug. For example, in some compounds, one or more alkoxy groups can be metabolized to hydroxyl groups while retaining pharmacologic activity and/or carboxyl groups can be esterified, e.g., glucuronidation. In some cases, there can be more than one metabolite, where an intermediate metabolite(s) is further metabolized to provide an active metabolite. For example, in some cases a derivative compound resulting from metabolic glucuronidation may be inactive or of low activity, and can be further metabolized to provide an active metabolite.
[0058] Metabolites of a compound may be identified using routine techniques known in the art, and their activities determined using tests such as those described herein. See, e.g., Bertolini et al., 1997,
J. Med. Chem., 40:2011-2016; Shan et al., 1997, J Pharm Sci 86(7):756-757; Bagshawe, 1995, Drug
Dev. Res., 34:220-230; Wermuth, supra. (b) Tautomers, Stereoisomers, and Regioisomers
[0059] It is understood that some compounds may exhibit tautomerism. In such cases, the formulae provided herein expressly depict only one of the possible tautomeric forms. It is therefore to be understood that the formulac provided herein are intended to represent any tautomeric form of the depicted compounds and are not to be limited merely to the specific tautomeric form depicted by the drawings of the formulae.
[0060] Likewise, some of the compounds according to the present invention may exist as stereoisomers, i.e. having the same atomic connectivity of covalently bonded atoms yet differing in the spatial orientation of the atoms. For example, compounds may be optical stereoisomers, which contain one or more chiral centers, and therefore, may exist in two or more stereoisomeric forms (e.g. cnantiomers or diastereomers). Thus, such compounds may be present as single stereoisomers (i.e., essentially free of other stereoisomers), racemates, and/or mixtures of enantiomers and/or diastereomers. As another example, stercoisomers include geometric isomers, such as cis- or trans- orientation of substituents on adjacent carbons of a double bond. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention. Unless specified to the contrary, all such steroisomeric forms arc included within the formulae provided herein.
[0061] In some embodiments, a chiral compound of the present invention is in a form that contains at least 80% of a single isomer (60% enantiomeric excess (“¢.c.”) or diastereomeric excess (“d.e.”)), or at least 85% (70% c.c. or d.e.), 90% (30% e.e. or d.e.}, 95% (90% e.e. or d.e.), 97.5% (95% e.e. or d.e.), or 99% (98% c.c. or d.e.). As generally understood by those skilled in the art, an optically pure compound having one chiral center is one that consists essentially of onc of the two possible enantiomers (i.c., is enantiomerically pure), and an optically pure compound having more than one chiral center is one that is both diastereomerically pure and enantiomerically pure. In some embodiments, the compound is present in optically pure form, such optically pure form being prepared and/or isolated by methods known in the art (e.g. by recrystallization techniques, chiral synthetic techniques (including synthesis from optically pure starting materials), and chromatographic separation using a chiral column. (c) Pharmaceutically acceptable salts
[0062] Unless specified to the contrary, specification of a compound herein includes pharmaceutically acceptable salts of such compound. Thus, compounds of Formula I can be in the form of pharmaceutically acceptable salts, or can be formulated as pharmaceutically acceptable salts.
Contemplated pharmaceutically acceptable salt forms include, without limitation, mono, bis, tris, tetrakis, and so on. Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. The preparation of such salts can facilitate the pharmacological use by altering the physical characteristics of a compound without preventing it from exerting its physiological effect. Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate administering higher concentrations of the drug. A compound of the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly can react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
[0063] Pharmaceutically acceptable salts include acid addition salts such as those containing chloride, bromide, iodide, hydrochloride, acetate, dichloroacetate, phenylacetate, acrylate, ascorbate, aspartate, benzoate, 2-phenoxybenzoate, 2-acetoxybenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, bicarbonate, butyne-1,4 dioate, hexyne-1,6-dioate, caproate, caprylate, chlorobenzoate, cinnamate, citrate, decanoate, formate, fumarate, glycolate, gluconate, glucarate, glucuronate, glucose-6-phosphate, glutamate, heptanoate, hexanoate, isethionate, isobutyrate, gamma-hydroxybutyrate, phenylbutyrate, lactate, malate, maleate, hydroxymaleate, methylmaleate, malonate, mandelate, nicotinate, nitrate, isonicotinate, octanoate, oleate, oxalate, pamoate, phosphate, monohydrogenphosphate, dihydrogenphosphate, orthophosphate, metaphosphate, pyrophosphate, 2-phosphoglycerate, 3-phosphoglycerate, phthalate, propionate, phenylpropionatc, propiolate, pyruvate, quinate, salicylate, 4-aminosalicylate, sebacate, stearate, suberate, succinate, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, sulfamate, sulfonate, benzenesulfonate (i.e. besylate), ethancsulfonate (i.e. esylate), ethane-1,2-disulfonate, 2-hydroxyethanesulfonate (i.c. isethionate), methanesulfonate (i.e. mesylate), naphthalene-1- sulfonate, naphthalene-2-sulfonate (i.e. napsylate), propanesulfonate, p-toluenesulfonate (i.e. tosylate), xylenesulfonates, cyclohexylsulfamate, tartrate, and trifluoroacetate. These pharmaceutically acceptable acid addition salts can be prepared using the appropriate corresponding acid.
[0064] When acidic functional groups, such as carboxylic acid or phenol are present, pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, ethanolamine, diethanolamine, triethanolamine, t-butylamine, dicyclohexylamine, ethylenediamine, N,N’-dibenzylethylenediamine, meglumine, hydroxyethylpyrrolidine, piperidine, morpholine, piperazine, procaine, aluminum, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium, zinc, ammonium, and mono-, di-, or tri- alkylamines (e.g. diethylamine), or salts derived from amino acids such as L-histidine, L-glycine,
L-lysine, and L-arginine. For example, see Remington's Pharmaceutical Sciences, 19" ed., Mack
Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995. These pharmaceutically acceptable base addition salts can be prepared using the appropriate corresponding base.
[0065] Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free-base form of a compound can be dissolved in a suitable solvent, such as an aqueous or aqueous- alcohol solution containing the appropriate acid and then isolated by evaporating the solution. In another example, a salt can be prepared by reacting the free base and acid in an organic solvent. If the particular compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an appropriate inorganic or organic base.
[0066] The pharmaceutically acceptable salt of the different compounds may be present as a complex. Examples of complexes include 8-chlorotheophylline complex (analogous to, e.g., dimenhydrinate: diphenhydramine 8-chlorotheophylline (1:1) complex; Dramamine) and various cyclodextrin inclusion complexes. (d) Other compound forms
[0067] In the case of agents that are solids, it is understood by those skilled in the art that the compounds and salts may exist in different crystal or polymorphic forms, or may be formulated as co- crystals, or may be in an amorphous form, or may be any combination thereof (e.g. partially crystalline, partially amorphous, or mixtures of polymorphs) all of which are intended to be within the scope of the present invention and specified formulae. Whereas salts are formed by acid/base addition, i.e. a free base or free acid of the compound of interest forms an acid/base reaction with a corresponding addition base or addition acid, respectively, resulting in an ionic charge interaction, co- crystals are a new chemical species that is formed between neutral compounds, resulting in the compound and an additional molecular species in the samc crystal structure.
[0068] In some instances, compounds of the invention are complexed with an acid or a base, including base addition salts such as ammonium, diethylamine, ethanolamine, ethylenediamine, diethanolamine, t-butylamine, piperazine, meglumine; acid addition salts, such as acetate,
acetylsalicylate, besylate, camsylate, citrate, formate, fumarate, glutarate, hydrochlorate, maleate, mesylate, nitrate, oxalate, phosphate, succinate, sulfate, tartrate, thiocyanate and tosylate; and amino acids such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine or valine. In combining the compound of the invention with the acid or base, an amorphous complex is preferably formed rather than a crystalline material such as a typical salt or co-crystal. In some instances, the amorphous form of the complex is facilitated by additional processing, such as by spray-drying, mechanochemical methods such as roller compaction, or microwave irradiation of the parent compound mixed with the acid or base. Such amorphous complexes provide several advantages. For example, lowering of the melting temperature relative to the free base facilitiates additional processing, such as hot melt extrusion, to further improve the biopharmaceutical properties of the compound. Also, the amorphous complex is readily friable, which provides improved compression for loading of the solid into capsule or tablet form.
[0069] Additionally, the formulac are intended to cover hydrated or solvated as well as unhydrated or unsolvated forms of the identified structures. For example, the indicated compounds include both hydrated and non-hydrated forms. Other examples of solvates include the structures in combination with a suitable solvent, such as isopropanol, cthanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.
Formulations and Administration
[0070] The methods and compounds will typically be used in therapy for human subjects.
However, they may also be used to treat similar or identical indications in other animal subjects.
Compounds of Formula I can be administered by different routes, including injection (i.c. parenteral, including intravenous, intraperitoneal, subcutaneous, and intramuscular), oral, transdermal, transmucosal, rectal, or inhalant. Such dosage forms should allow the compound to reach target cells.
Other factors are well known in the art, and include considerations such as toxicity and dosage forms that retard the compound or composition from exerting its effects. Techniques and formulations generally may be found in Remington: The Science and Practice of Pharmacy, 21% edition,
Lippincott, Williams and Wilkins, Philadelphia, PA, 2005 (hereby incorporated by reference herein).
[0071] In some embodiments, compositions will comprise pharmaceutically acceptable carriers or excipients, such as fillers, binders, disintegrants, glidants, lubricants, complexing agents, solubilizers, and surfactants, which may be chosen to facilitate administration of the compound by a particular route. Examples of carriers include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose, or sucrose, types of starch, cellulose derivatives, gelatin, lipids, liposomes, nanoparticles, and the like. Carriers also include physiologically compatible liquids as solvents or for suspensions, including, for example, sterile solutions of water for injection (WF1), saline solution, dextrose solution, Hank's solution, Ringer's solution, vegetable oils, mineral oils, animal oils, polyethylene glycols, liquid paraffin, and the like. Excipients may also include, for example, colloidal silicon dioxide, silica gel, talc, magnesium silicate, calcium silicate, sodium aluminosilicate, magnesium trisilicate, powdered cellulose, macrocrystalline cellulose, carboxymethyl cellulose, cross- linked sodium carboxymethylcellulose, sodium benzoate, calcium carbonate, magnesium carbonate, stearic acid, aluminum stearate, calcium stearate, magnesium stearate, zinc stearate, sodium steary! fumarate, syloid, stearowet C, magnesium oxide, starch, sodium starch glycolate, glyceryl monostearate, glyceryl dibehenate, glyceryl palmitostearate, hydrogenated vegetable oil, hydrogenated cotton seed oil, castor seed oil mineral oil, polyethylene glycol (e.g. PEG 4000-8000), polyoxyethylene glycol, poloxamers, povidone, crospovidone, croscarmellose sodium, alginic acid, casein, methacrylic acid divinylbenzene copolymer, sodium docusate, cyclodextrins (e.g. 2- hydroxypropyl-.delta.-cyclodextrin), polysorbates (e.g. polysorbate 80), cetrimide, TPGS (d-alpha- tocopheryl polyethylene glycol 1000 succinate), magnesium lauryl sulfate, sodium lauryl sulfate, polyethylene glycol ethers, di-fatty acid ester of polyethylene glycols, or a polyoxyalkylene sorbitan fatty acid ester (e.g., polyoxyethylene sorbitan ester Tween”), polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid ester, e.g. a sorbitan fatty acid ester from a fatty acid such as oleic, stearic or palmitic acid, mannitol, xylitol, sorbitol, maltose, lactose, lactose monohydrate or lactose spray dried, sucrose, fructose, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, dextrates, dextran, dextrin, dextrose, cellulose acetate, maltodextrin, simethicone, polydextrosem, chitosan, gelatin, HPMC (hydroxypropyl methyl celluloses), HPC (hydroxypropyl cellulose), hydroxycthyl cellulose, hypromellose, and the like.
[0072] In some embodiments, oral administration may be used. Pharmaceutical preparations for oral use can be formulated into conventional oral dosage forms such as capsules, tablets, and liquid preparations such as syrups, elixirs, and concentrated drops. Compounds of Formula I may be combined with solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain, for example, tablets, coated tablets, hard capsules, soft capsules, solutions (e.g. aqueous, alcoholic, or oily solutions) and the like.
Suitable excipients are, in particular, fillers such as sugars, including lactose, glucose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose (CMC), and/or polyvinylpyrrolidone (PVP: povidone); oily excipients, including vegetable and animal oils, such as sunflower oil, olive oil, or codliver oil. The oral dosage formulations may also contain disintegrating agents, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid, or a salt thereof such as sodium alginate; a lubricant, such as talc or magnesium stearate; a plasticizer, such as glycerol or sorbitol; a sweetening such as sucrose, fructose, lactose, or aspartame; a natural or artificial flavoring agent, such as peppermint, oil of wintergreen, or cherry flavoring; or dye-stuffs or pigments, which may be used for identification or characterization of different doses or combinations. Also provided are dragee cores with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain, for example, gum arabic, talc, poly-vinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures,
[0073] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin (“gelcaps”), as well as soft, scaled capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stcaratc and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
[0074] In some embodiments, injection (parenteral administration) may be used, e.g., intramuscular, intravenous, intraperitoneal, and/or subcutaneous. Compounds of Formula I for injection may be formulated in sterile liquid solutions, preferably in physiologically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution. Dispersions may also be prepared in non-aqueous solutions, such as glycerol, propylene glycol, cthanol, liquid polyethylene glycols, triacetin, and vegetable oils. Solutions may also contain a preservative, such as methylparaben, propylparaben, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In addition, the compounds may be formulated in solid form, including, for example, lyophilized forms, and redissolved or suspended prior to use.
[0075] In some embodiments, transmucosal, topical or transdermal administration may be used. In such formulations of compounds of Formula I, penetrants appropriate to the barrier to be permeated are used. Such penetrants arc generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives. In addition, detergents may be used to facilitate permeation. Transmucosal administration, for example, may be through nasal sprays or suppositories (rectal or vaginal). Compositions of compounds of Formula I for topical administration may be formulated as oils, creams, lotions, ointments, and the like by choice of appropriate carriers known in the art. Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohol (greater than C,;). In some embodiments, carriers are selected such that the active ingredient is soluble. Emulsifiers, stabilizers, humectants and antioxidants may also be included as well as agents imparting color or fragrance, if desired. Creams for topical application are preferably formulated from a mixture of mineral oil, self- emulsifying beeswax and water in which mixture the active ingredient, dissolved in a small amount of solvent (e.g., an oil), is admixed. Additionally, administration by transdermal means may comprise a transdermal patch or dressing such as a bandage impregnated with an active ingredient and optionally one or more carriers or diluents known in the art. T'o be administered in the form of a transdermal delivery system, the dosage administration will be continuous rather than intermittent throughout the dosage regimen.
[0076] In some embodiments, compounds are administered as inhalants. Compounds of Formula I may be formulated as dry powder or a suitable solution, suspension, or aerosol. Powders and solutions may be formulated with suitable additives known in the art. For example, powders may include a suitable powder base such as lactose or starch, and solutions may comprise propylene glycol, sterile water, ethanol, sodium chloride and other additives, such as acid, alkali and buffer salts.
Such solutions or suspensions may be administered by inhaling via spray, pump, atomizer, or nebulizer, and the like. The compounds of Formula I may also be used in combination with other inhaled therapies, for example corticosteroids such as fluticasone proprionate, beclomethasone dipropionate, triamcinolone acetonide, budesonide, and mometasone furoate; beta agonists such as albuterol, salmeterol, and formoterol; anticholinergic agents such as ipratroprium bromide or tiotropium; vasodilators such as treprostinal and iloprost; enzymes such as DNAase; therapeutic proteins; immunoglobulin antibodies; an oligonucleotide, such as single or double stranded DNA or
RNA, siRNA; antibiotics such as tobramycin; muscarinic receptor antagonists; leukotriene antagonists; cytokine antagonists; protcasc inhibitors; cromolyn sodium; nedocril sodium; and sodium cromoglycate.
[0077] The amounts of various compounds to be administered can be determined by standard procedures taking into account factors such as the compound activity (in vitre, e.g. the compound ICs, vs. target, or in vivo activity in animal efficacy models), pharmacokinetic results in animal models (e.g. biological half-life or bioavailability), the age, size, and weight of the subject, and the disorder associated with the subject. The importance of these and other factors are well known to those of ordinary skill in the art. Generally, a dose will be in the range of about 0.01 to 50 mg/kg, also about 0.1 to 20 mg/kg of the subject being treated. Multiple doses may be used.
[0078] The compounds of Formula I may also be used in combination with other therapies for treating the same disease. Such combination use includes administration of the compounds and one or more other therapeutics at different times, or co-administration of the compound and one or more other therapies. In some embodiments, dosage may be modified for one or more of the compounds of the invention or other therapeutics used in combination, e.g., reduction in the amount dosed relative to a compound or therapy used alone, by methods well known to those of ordinary skill in the art.
[0079] It is understood that use in combination includes use with other therapies, drugs, medical procedures etc., where the other therapy or procedure may be administered at different times (e.g.
within a short time, such as within hours (e.g. 1, 2, 3, 4-24 hours), or within a longer time (e.g. 1-2 days, 2-4 days, 4-7 days, 1-4 weeks)) than a compound of Formula I, or at the same time as a compound of Formula I. Use in combination also includes use with a therapy or medical procedure that is administered once or infrequently, such as surgery, along with a compound of Formula I administered within a short time or longer time before or after the other therapy or procedure. In some embodiments, the present invention provides for delivery of a compound of Formula I and one or more other drug therapeutics delivered by a different route of administration or by the same route of administration. The use in combination for any route of administration includes delivery of a compound of Formula I and one or more other drug therapeutics delivered by the same route of administration together in any formulation, including formulations where the two compounds are chemically linked in such a way that they maintain their therapeutic activity when administered. In one aspect, the other drug therapy may be co-administered with a compound of Formula I. Usc in combination by co-administration includes administration of co-formulations or formulations of chemically joined compounds, or administration of two or more compounds in separate formulations within a short time of each other (c.g. within an hour, 2 hours, 3 hours, up to 24 hours), administered by the same or different routes. Co-administration of separate formulations includes co- administration by delivery via one device, for example the same inhalant device, the same syringe, etc., or administration from separate devices within a short time of each other. Co-formulations of a compound of Formula I and one or more additional drug therapies delivered by the same route includes preparation of the materials together such that they can be administered by one device, including the separate compounds combined in one formulation, or compounds that are modified such that they are chemically joined, yet still maintain their biological activity. Such chemically joined compounds may have a linkage that is substantially maintained in vivo, or the linkage may break down in vivo, separating the two active components.
[0080] Examples related to the present invention are described below. In most cases, alternative techniques can be used. The examples are intended to be illustrative and are not limiting or restrictive to the scope of the invention. In some examples, the mass spectrometry result indicated for a compound may have more than one value due to the isotope distribution of an atom in the molecule, such as a compound having a bromo or chloro substituent.
[0081] Unless specifically indicated otherwise, the Formula enumeration and R group enumeration used in the following examples is not related to such enumeration in other sections of this application.
The reagents and solvents used in these examples can be readily substituted with appropriate alternatives as are known in the art and isolation of products is readily achieved by methods known in the art, including, but not limited to, extraction, crystallization, and chromatographic methods.
[0082] Ring numbering for the 1,2,3,4-tetrahydroquinoline and 3,4-dihydro-1H-quinolin-2-one comopunds in the following Examples is as follows: 1 i
H 8 H 8 : N 0 N 2 7 > 7 3 6 3 6 4 3 and 4 3 , respectively.
Example 1: Preparation of 1-(6-ethyl-4,4-dimethyl-1,2,3.4-tetrahydro-quinolin-7-yl)-ethanone 9.
[0083] 1-(6-Lthyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethanone 9 was prepared in six steps from 4-ethylaniline 1 as shown in Scheme 1.
Scheme 1
NH, H H
H
Oo Cl oC N N + Step 1 Step2 Oxp-N Step 3 my — -_ = 1 2 3 4 5
CF, Fy Faong© 0 H 0
N o=( Step 4 N Step 5 N Step 6 + 0 emer ee mm o=
CF, 8 9 6 7
Step I - Preparation of 3-methyl-but-2-enoic acid (4-ethyl-phenyl)-amide (3):
[0084] To a mixture of 4-ethylaniline (1, 100 mL, 0.809 mol) and 730 mL of 10% aqueous sodium hydroxide in 454 mL of dichloromethane, 3,3-dimethylacryloyl chloride (2, 115 g, 0.970 mol) in 454 mL of dichloromcthanc was slowly added. The reaction mixture was stirred at room temperature overnight, poured into 200 mL of water and extracted with 3 x 500 mL of dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting matcrial was crystallized using heptane to provide the desired compound as a light brown solid that was used without further purification in the next step (3, 175 g, >100%).
Step 2 — Preparation of 6-ethyl-4,4-dimethyl-3,4-difydro-1H-quinolin-2-one (4):
[0085] To a solution of 3-methyl-but-2-enoic acid (4-cthyl-phenyl)-amide (3, 164.4 g, 0.809 mol theoretical) in 1.6 L of 1,2-dichlorobenzene, aluminum trichloride (162 g, 1.21 mol) was added. The reaction mixture was stirred at 100 °C for 2 hours, allowed to cool to room temperature and poured into 7 L of ice water. To this, 1 L of 2M hydrochloric acid was added and the suspension was extracted with 2 x 4 L of heptanes. The organic layers were pooled, washed with saturated sodium bicarbonate solution, washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with a gradient of heptane and ethyl acetate. Appropriate fractions were combined and concentrated under vacuum, and the resulting material was triturated with heptane to provide the desired compound as a white solid (4, 136 g, 83% for steps 1 and 2).
Step 3 — Preparation of 6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydrogquinoline (5):
[0086] To a solution of 6-ethyl-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (4, 70 g, 0.344 mol) in 700 mL of toluene, 140 mL of borane-dimethyl sulfide complex (1.48 mol) was slowly added at 0 °C.
The reaction mixture was stirred at 0 °C for 15 minutes and then stirred at 100 °C for 2 hours. The reaction mixture was cooled to room temperature and poured slowly into 1 L of 10% aqueous sodium carbonate. After stirring at room temperature for 30 minutes, the organic layer was collected. The aqueous layer was extracted with 1 L of ethyl acetate and the pooled organic layers were dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with a gradient of 0-50% ethyl acetate in heptane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a clear oil (5, 50 g, 77%).
Step 4 — Preparatoin of 1-(6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinolin-1-yl)-2,2, 2-trifluoro- ethanone (7):
[0087] To a solution of 6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydroquinoline (5, 50 g, 0.264 mol) in 500 mL of dichloromethane, triethylamine (93 mL, 0.660 mol), 4-dimethylaminopyridine (3.2 g, 0.026 mol), and trifluoroacetic anhydride (6, 66 mL, 0.475 mol) were added. The reaction mixture was stirred at 40 °C for 2 hours, allowed to cool to room temperature and poured into saturated aqueous sodium bicarbonate. The organic layer was collected and the aqueous layer was back- extracted with cthyl acetate. The organic layers were combined and dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with a gradient of 0-50% ethyl acetate in heptane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a clear oil (7,70 g, 92%).
Step § — Preparation of 1-(7-acetyl-6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinolin-1-yl)-2,2,2- trifluoro-ethanone (8).
[0088] A mixture of |-(6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinolin-1-yl)-2,2,2-trifluoro- ethanone (7, 100 mg, 0.4 mmol), acetyl chloride (78 mg, 1.0 mmol) and aluminum trichloride (100 mg, 1.0 mmol) in 5 mL of nitromethane was warmed to reflux for 5 hours. The reaction mixture was cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting crude material was purified by silica gel chromatography to provide the desired compound as a colorless oil (8, 0.11 g, 90%). MS (ESD [M+H']" = 328.05.
Step 6 — Preparation of 1-(G-ethyl-4,4-dimethyl-1,2,3,4-1etrahydro-quinolin-7-yl)-ethanone (9):
[0089] To a solution of 10% potassium hydroxide in 5 mL of methanol, 1-(7-acetyl-6-ethyl-4,4- dimethyl-3,4-dihydro-2H-quinolin-1-y1)-2,2 2-trifluoro-ethanone (8, 107 mg, 0.327 mol) was added.
The reaction mixture was stirred at room temperature for 1.5 hours, then concentrated under reduced pressure and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting crude material was purified by silica gel chromatography to provide the desired compound as a colorless oil (9, 61 ng, 81%). MS (ESI) [M+H']" = 232.40,
Example 2: Alternative preparation of 1-(6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7- yD)-ethanone 9.
[0090] 1-(6-Ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethanone 9 was prepared in five steps from 1-(6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinolin-1-yl)-2,2 2 -trifluoro-ethanone 7 as shown in Scheme 2.
Scheme 2
F3C. 0 F3C. 0 N- 3 ¥ 3 hd H 0 J
N N Br N Br YY
CIC, Step 1 CL Step 2 GL + Oy-0 7 10 11 No 12 0 Y O40
Y 0 nog
Step 3 CC Step 4 CoC Step 5 yee
Nas | 12 ‘Ne
Step 1 - Preparation of 1-(7-bromo-6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinolin-1-y[)-2,2,2- trifluoroethanone (10):
[0091] 1-(6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinolin-1-y1)-2,2,2-trifluoro-ethanone (7, 65 g, 0.224 mol) was stirred in 2 I of nitromethane at room temperature. Bromine (135.2 ml, 0.296 mol) was added dropwise followed by the addition of aluminum trichloride (33 ¢, 0.244 mol). The reaction mixture was stirred overnight at room temperature under an inert atmosphere. The reaction mixture was concentrated under reduced pressure and was poured into aqueous sodium thiosulfate and extracted with ethyl acetate. The organic fraction was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound (10, 79 g, 95%).
MS (ESI) [M+H']" = 364.1, 366.0.
Step 2 - Preparation of 7-bromo-6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydroquinoline (11):
[0092] A solution of 1-(7-bromo-6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinolin-1-y1)-2,2,2- trifluoroethanone (10, 79 g, 0.217 mol) in 800 mL of 10% potassium hydroxide in methanol was stirred at room temperature overnight. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was collected and the aqueous layer was back- extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with a gradient of 0-20% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a light orange solid (11,70 g, 52%). MS (ESI) [M+H']" = 267.9, 270.0.
Step 3 - Preparation of 7-bromo-6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinoline- I-carboxylic acid tert-butyl ester (13).
[0093] To 7-bromo-6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydroquinoline (11, 26 g, 97 mmol) in 300 mL of tetrahydrofuran, 1 M sodium hexamcthyldisilazide in 107 mL tetrahydrofuran was added at room temperature and was allowed to stir for 30 minutes. Di-tert-butyldicarbonate (12, 32 g, 146 mmol) was added as a solution in tetrahydrofuran. The reaction mixture was stirred for 1 hour and then quenched with the addition of 300 mL of brinc. The mixture was extracted with ethyl acetate and the organic layer was separated and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with a gradient of 0-20% ethy! acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a clear oil (13, 25 g, 70%).
Step 4 - Preparation of 7-acetyl-6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (14).
[0094] A mixture of 7-bromo-6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid tert-butyl ester (13, 25 g, 68 mmol), tri-n-butyl tin-vinyl ether (31 mL, 238 mmol), palladium(II) acetate (0.47 g, 2.1 mmol), 1,3-bis(diphenylphosphino)propane (1.74 g, 4.2 mmol), and potassium carbonate (9.7 g, 70 mmol) in 125 mL of dimecthylformamide and 7.5 mL of water under nitrogen was heated to 80 °C overnight. The mixture was cooled to room temperature and quenched by adding 250 mL of 10% aqueous hydrochloric acid. This mixture was transferred to a separatory funnel containing saturated aqueous potassium carbonate and cxtracted with methyl ters-butyl cther. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting crude material was purified by silica gel column chromatography eluting with a gradient of (-20% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a light brown oil (14, 6 g, 27 %). MS (ESI) [M+H"]" = 354.3,
Step 3 - Preparation of 1-(6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl}-ethanone (9):
[0095] To a solution of 7-acetyl-6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl cster (14, 1.40 g, 0.00422 mol) in 35 mL of dichloromethane, 8.0 mL of 4 M hydrogen chloride in 1,4-dioxane was added. The reaction mixture was stirred at room temperature for 0.5 hours, then concentrated under vacuum. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel chromatography to provide the desired compound as a pale yellow solid (9, 0.88 g, 88%). MS (ESI) [M+H']" = 232.2.
Example 3: Preparation of [1-(6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethyl]- carbamic acid tert-butyl ester 17.
[0096] [1-(6-Ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethyl]-carbamic acid tert-butyl ester 17 was prepared in three steps from 1-(6-cthyl-4,4-dimethyl-1,2,3 4-tetrahydro-quinolin-7-yl)- ethanone 9 as shown in Scheme 3.
Scheme 3
Lk
N I Step 1 N 3 Step 2 : C ¥ Ae ep ep 9 15 16 12
Step 1 - Preparation of 1-(6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethanone oxime (15):
[0097] A solution of 1-(6-cthyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-cthanone (9, 3 g, 10.0 mmol), hydroxylamine (1 g, 40.0 mmol), and pyridine (1 mL, 10.0 mmol) in 50 mL of ethanol was stirred at 80 °C overnight. The reaction mixture was concentrated under vacuum and the resulting matcrial was partitioned between cthyl acctatc and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel chromatography to provide the desired compound as a yellow solid (15, 1.65 g, 50%). MS (ESI) [MI11']" = 247.15.
Step 2 - Preparation of 1-(6-ethyl-4,4-dimethyl-1,2, 3,4-tetrahydro-quinolin-7-yl)-ethylamine (16).
[0098] A mixture of 1-(6-cthyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethanone oxime (15, 0.8 g, 3.0 mmol) and Raney nickel (50%, aqueous slurry) in 40 mL of methanol and 8 mL of ammonium hydroxide was agitated under hydrogen (55 psi) in a Parr shaker for 3.5 hours. The mixture was filtered and the filtrate was concentrated under vacuum to provide the desired compound as a brownish oil (16, 0.8 g, 80%). MS (ESI) [M+H']" = 234.05.
Step 3 - Preparation of [1-(6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin- 7-yl)-ethyl]-carbamic acid tert-butyl ester (17):
[0099] To a solution of 1-(6-cthyl-4,4-dimethyl-1 2,3 4-tetrahydro-quinolin-7-yl)-ethylamine (16, 1.2 g, 2.8 mmol) in 100 mL of dichloromethane, N,N-diisopropylethylamine (1.5 mL, 8.6 mmol) and di-tert-butyldicarbonate (12, 0.4 g, 2.0 mmol) were added. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was partitioned between ethyl acetate and water. The organic layer was washed with sodium bicarbonate and brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The crude material was purified by silica gel chromatography to provide the desired compound as a light yellow solid (17, 645 mg, yield 90%). MS(ESI): [M+H']" =333.05.
Example 4: Preparation of 1-[6-ethyl-1 -(2-methoxy-ethyl)-4,4-dimethyl-1,2,3,4-tetrahydro- quinolin-7-yl]-ethylamine P-0002.
[0100] 1-[6-Ethyl-1-(2-methoxy-ethyl)-4,4-dimethyl-1,2.3 .4-tetrahydro-quinolin-7-yl]-cthylamine
P-0002 was prepared in three steps from 1-(6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)- ethanone 9 as shown in Scheme 4.
Scheme 4 ~0 —0 —~0
H 0 “6 — 0 r "ON — NH, a a
Z Br ° 18 * « P-0002
Step I - Preparation of 1-{6-ethyl-1-(2-methoxy-ethyl)-4,4-dimethyl-1 ,2, 3, 4-tetrahydro-guinolin-7-yl]- ethanone (19).
[0101] To a solution of 1-(6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethanone (9, 55 mg, 0.17 mmol) in 10 mL of acetonitrile, 1-bromo-2-methoxy-ethane (18, 0.043 mL, 0.45 mmol), potassium iodide (25 mg, 0.15 mmol) and potassium carbonate (84 mg, 0.60 mmol) were added. The reaction mixture was stirred at 100 °C for 20 hours. The mixture was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum.
The crude material was purified by silica gel chromatography to provide the desired compound as a yellow oil (19, 13 mg, 27%). MS (ESD) [M+H |" = 290.50.
Step 2 - Preparation of 1-[6-ethyl-1-(2-methoxy-ethyl)-4,4-dimethyl-1,2,3, 4-tetrahydro-quinolin-7-yl]- ethanone oxime (20):
[0102] A solution of 1-[6-cthyl-1-(2-mcthoxy-ethyl)-4,4-dimethyl-1 12,3, 4-tetrahydro-quinolin-7- yl]-ethanonc (19, 13 mg, 0.045 mmol), hydroxylamine hydrochloride (6.2 mg, 0.090 mmol), and pyridine (0.018 mL, 0.22 mmol) in 5 mL of ethanol was stirred at 80 °C for 2 hours. The reaction mixture was concentrated under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The crude material was used for the next step without further purification (20, 10 mg, 70%). MS (ESI) [M+H']" = 305.65.
Step 3 - Preparation of 1-[6-ethyl-1-(2-methoxy-cthyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl] - ethylamine (P-0002):
[0103] A mixture of 1-[6-ethyl-1-(2-methoxy-ethyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7- yl]-ethanone oxime (20, 10 mg, 0.03 mmol) and Raney nickel (50%, aqueous slurry) in 5 mL of methanol and 2 mL of ammonium hydroxide was agitated under hydrogen (55 psi) in a Parr shaker for 4 hours. The mixture was filtered and the filtrate was concentrated under vacuum. The resulting material was purified by silica gel chromatography eluting with dichloromethane and methanol to provide the desired compound as a pale yellow viscous oil (P-0002, 4 mg, 40%). MS (ESD) [M+H']" = 291.00. [p104] 1-[7-(1 -Amino-ethyl)-6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinolin-1-yl]-cthanone P-0007, ~yr° NH, (CC was prepared similarly to the protocol of Scheme 4, where 1-(6-ethyl-4,4-dimethyl-1 ,2.3,4-tetrahydro- quinolin-7-yl)-ethanone (9, 20 mg, 0.09 mmol) in 10 mI. of acetonitrile is mixed with methyl iodide (0.016 mL, 0.26 mmol) in step 1, where the 1-acctyl derivative was formed instead of the desired 1-methyl derivative and carried through the last two steps. MS (ESI) [M+H]" = 275.95.
[0105] Additional compounds may be prepared similarly to the protocol of Scheme 4, replacing 1- bromo-2-methoxy-ethane 18 with a suitably substituted alkyl halide in Step 1. The following compounds were made following this procedure: 1-[7-(1-Amino-ethyl)-6-ethyl-4,4-dimethyl-3 4-dihydro-2H-quinolin-1-yl]-2-methoxy-cthanone (P-0001), 1-[6-Fthyl-1-(3-methoxy-propyl)-4,4-dimethyl-1,2,3 4-tetrahydro-quinolin-7-yl]-ethylamine
(P-0003), 1-[6-Ethyl-4,4-dimethyl-1~(3,3,3-tritluoro-propyl)-1.2,3 .4-tetrahydro-quinolin-7-yl]-ethylamine (P-0004), 1-[6-Ethyl-4,4-dimethyl-1-(4,4,4-trifluoro-butyl)-1,2,3,4-tetrahydro-quinolin-7-yl] -cthylamine (P-0005),
N-{2-[7-(1 -Amino-ethyl)-6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinolin-1-yl]-ethyl} -acetamide (P-0006), and 1-[6-Ethyl-4,4-dimethyl-1-(2-pyrazol-1-yl-ethyl)-1 ,2,3 4-tetrahydro-quinolin-7-yl]-ethylamine (P-0009).
The following table shows compounds that were prepared similarly to the protocol of Scheme 4. where optimal reaction conditions may have varied, for cxample, in terms of solvents, time and temperature of the reaction, and in chromatography conditions for purification of the desired compounds, with the compound number in Column 1, the alkyl halide used in Step 1 in Column 2, the resulting compound in Column 3 and the experimental mass spectrometry result in Column 4.
Compound number Compound structure | MS (ESD [M-HT
So
P-0001 Aon CCC 304.50
P-0003 Bre ~~. Ow. (CC 305.60 oo CF, - REE
P-0004 gr CF3 (ICC 330.65 == i; - ee
P-0005 Bro CFs CCC 334.65 = 0 A NH,
P-0006 Cla A HN | 318.05
Cw poe
AN NH,
P-0009 & nT “ to 328.05 =N
Example 5: Preparation of 1-(6-ethyl-4,4-dimethyl-1-pyridin-3-ylmethyl-1,2,3,4-tetrahydro- quinolin-7-yl)-ethylamine P-0010 and related compounds.
[0106] 1-(6-Ethyl-4,4-dimethyl-1-pyridin-3-ylmethyl-1 ,2,3,4-tetrahydro-quinolin-7-yl)-ethylamine
P-0010 was prepared in two steps from [1-(6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-y1)- ethyl]-carbamic acid tert-butyl ester 17 as shown in Scheme 5. Compounds such as 1-[6-Ethyl-4,4- dimethyl-1-(3-trifluoromethyl-benzyl)-1,2,3 4-tetrahydro-quinolin-7-yl]-ethylamine P-0026 were prepared similarly according to Scheme Sa. Compounds such as 1-[6-Ethyl-4 4-dimethyl-1-(2- methyl-pyridin-4-ylmethyl)-1,2,3 4-tetrahydro-quinolin-7-yl]-cthylamine P-0037 were prepared similary, using an aldehyde instead of bromomethyl compound in step 1, according to Scheme 5b.
Scheme 5 _N _N _Boc LL _ Bac CL
H HN oN HN NH,
N he Step 1 N Step 2 N + —
Coc QUT = QC 17 21 22 P-0010
Step 1 - Preparation of [1-(6-ethyl-4, 4-dimethyl-1-pyridin-3-ylmethyl-1,2,3,4-tetrahydroquinolin-7- yl)-ethyl]-carbamic acid tert-butyl ester (22):
[0107] To a solution of [1-(6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethyl]- carbamic acid tert-butyl ester (17, 42.3 mg, 0.127 mmol) in 10 mL of acetonitrile, 3-bromomethyl-pyridine (21, 96 mg, 0.38 mmol), potassium iodide (21 mg, 0.13 mmol) and sodium bicarbonate (107 mg, 1.27 mmol) were added. The reaction mixture was stirred at 80 °C overnight, then cooled to room temperature and poured into water, extracted with ethyl acetate, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The crude material was purified by silica gel chromatography to provide the desired compound as a yellow solid (22, 20 mg, 40%). MS (ESI) [M+H']" = 424.20.
Step 2 - Preparation of 1-(6-ethyl-4,4-dimethyl-1-pyridin-3-ylmethyl-1,2,3, 4-tetrahydroquinolin-7-yl)- ethylamine (P-0010): 10108] To a solution of [1-(6-ethyl-4,4-dimethyl-1-pyridin-3-ylmethyl-1.2,3 4-tetrahydro-quinolin- 7-yl)-ethyl]-carbamic acid tert-butyl ester (22, 16 mg, 0.038 mmol) in 0.5 mL of dichloromethane, hydrochloric acid (3 mL, 100 mmol) was added. The mixture was stirred at room temperature for 1.5 hours and concentrated under vacuum to provide the desired compound as a yellow solid (P-0010, 15.1 mg, 88%). MS (ESI): [M+H']' = 325.05.
Scheme Sa
CFs CF, ’ Nat ou QQ a 2, NH,
Ny Step 1a N Step 2a N
GCC = OC =r OC 17 21a 22a P-0026
Step la - Preparation of {1-[6-ethyl-4,4-dimethyl-1-(3-trifluoromethyl-benzyl)-1,2, 3,4-tetrahydro- quinolin-7-yl]-ethyl}-carbamic acid tert-butyl ester (22a):
[0109] To a solution of [1-(6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethyl]- carbamic acid iert-butyl ester (17, 15 mg, 0.045 mmol) in 500 pL of N-methylpyrrolidone, 1-bromomethyl-3-trifluoromethyl-benzene (21a, 32.3 mg, 0.135 mmol), and N,N- diisopropylethylamine (32 pL, 0.18 mmol) were added. The reaction mixture was irradiated 5 minutes at 150 °C in microwave, then extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate, then brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The residue was used in the next step without further purification.
Step 2a - Preparation of 1-[6-ethyl-4,4-dimethyl-1-(3-trifluoromethyl-benzyl)-1,2, 3, 4-tetrahydro- quinolin-7-ylj-ethylamine (P-0026):
[0110] {1-[6-Ethyl-4,4-dimethyl-1-(3-triflucromethyl-benzyl)-1,2,3 4-tetrahydro-quinolin-7-yl]- ethyl} -carbamic acid tert-butyl ester (22a, Step 1a) was dissolved in 500 pL of dioxanc and 250 nL of 4M hydrochloric acid in dioxane. The mixture was stirred at room temperature for 30 minutes and concentrated under vacuum. The residue was dissolved in 1 mL of dimethyl sulfoxide and purified by
HPLC using a Hamilton PRP-3 column eluting with 10%-80% solvent B at a flow rate of 7 mlI/minute, where solvent A was 10 mM ammonium hydroxide in water and solvent B was 10 mM ammonium hydroxide in acetonitrile. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (P-0026). MS (ESI): [M-NH, "= 374.3.
Scheme 5b
Boc 0, Boc 0, } HN Ny = HN = NH, 17 21b 22b P-0037
Step 1b - Preparation of {1-[6-ethyl-4,4-dimethyl-1 ( 2-methvi-pyridin-4-vimethylj-1,2,3,4-tetrahydro-
guinolin-7-yl]-ethyl}-carbamic acid tert-butyl ester (22h):
[0111] [1-(6-Ethyl-4,4-dimethyl-1,2,3,4-tctrahydro-quinolin-7-yl)-ethyl]-carbamic acid rerz-butyl ester (17, 12 mg, 0.036 mmol) and 2-methyl-pyridine-4-carbaldehyde (21b, 13.2 mg, 0.12 mmol) were dissolved in 600 pL of 95:5 ethanol:acetic acid, and cyanoborohydride on silica (55 mg, 0.05 mmol) was added and the mixture irradiated for 15 minutes at 120 °C in the microwave. The vial was centrifuged to remove the silica, and the supernatant transferred to a new vial. The silica residue was washed with 500 uL of ethanol, centrifuged and the supernatants combined. The solvents were removed under vacuum and the residue used in the next step without further purification.
Step 2b - Preparation of 1-[6-ethyl-4,4-dimethyl-1-(2-methyl-pyridin-4-ylmethyl)-1,2,3, 4-tetrahydro- quinolin-7-yl]-ethylamine (P-0037):
[0112] {1-[6-Ethyl-4,4-dimethyl-1-(2-methyl-pyridin-4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-7- yl]-ethyl} -carbamic acid tert-butyl ester (22b, 16 mg, 0.038 mmol) was dissolved in 0.3 mL of dioxane and 0.3 mL of 4M hydrochloric acid in dioxane and stirred for 30 minutes. The solvents were removed under vacuum and the residue purified by HPLC as per step 2a of Scheme 5a. MS (EST) [M+H']"= 339.00.
[0113] 1-[6-Ethyl-4,4-dimethyl-1-(2-methyl-pyridin-4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-7-yl]- ethylamine P-0037 was further purified by chiral HPLC to provide (R)-1-|6-Ethyl-4,4-dimethyl-1-(2- methyl-pyridin-4-ylmethyl)-1,2,3,4-tctrahydro-quinolin-7-yl]-ethylamine P-0056 and (S)-1-[6-Ethyl- 4,4-dimethyl-1-(2-methyl-pyridin-4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-7-yl]-cthylamine P-0057,
NH, N NH,
P-0056 and P-0057 using a ChiralCel OD-H column, with isocratic 6% Buffer A (Isopropanol with 0.1% trifluoroacetic acid), and 94% Buffer B (hexane with 0.1% trifluoroacetic acid).
[0114] Additional compounds may be prepared similarly to the protocols of Scheme 5, 5a, and 5b, replacing the bromomethyl compound or aldehyde compound with an appropriate aryl/heteroaryl- alkyl halide or aryl/heteroaryl-aldehyde in Step 1/1a/1h. The following compounds were made following this procedure: 1-(6-Ethyl-4,4-dimethyl-1-pyridin-4-ylmethyl-1,2,3 4-tetrahydro-quinolin-7-yl)-ethylamine (P-0015), 1-[6-Ethyl-4,4-dimethyl-1-(5-methyl-isoxazol-3-ylmethyl)-1,2,3,4-tctrahydro-quinolin-7-yl]- ethylamine (P-0017), 1-[1-(3-Bromo-isoxazol-5-ylmethyl)-6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl]- ethylamine (P-0023),
1-[6-Ethyl-4,4-dimethyl-1-(3-methyl-isoxazol-5-ylmethyl)-1,2,3 ,4-tetrahydro-quinolin-7-yl]- ethylamine (P-0024), 1-(1-Benzyl-6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethylamine (P-0025), 1-[6-Ethyl-4,4-dimethyl-1-(3-trifluoromethyl-benzyl)-1 ,2,3,4-tetrahydro-quinolin-7-yl]-cthylamine (P-0026), 1-[1-(3,5-Difluoro-benzyl)-6-ethyl-4,4-dimethyl-1,2,3 A-tetrahydro-quinolin-7-yl]-ethylamine (P-0027), 1-[6-Ethyl-1-(3-fluoro-benzyl)-4,4-dimethyl-1,2,3,4-tctrahydro-quinolin-7-yl] -ethylamine (P-0028), 1-[6-Ethyl-1-(4-mcthoxy-benzyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7 -yl]-ethylamine (P-0029), 1-[1-(2,3-Difluoro-benzyl)-6-ethyl-4,4-dimethyl-1,2,3,4-tctrahydro-quinolin-7-yl]-cthylamine (P-0030), 1-[6-Ethyl-1-(3-methoxy-benzyl)-4,4-dimethyl-1,2,3 4-tetrahydro-quinolin-7 -yl]-ethylamine (P-0031), 1-[6-Ethyl-1-(4-fluoro-benzyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl] -ethylamine (P-0032), 4-[7-(1-Amino-ethyl)-6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinolin-1 -ylmethyl]-pyridine-2- carbonitrile (P-0033), 1-[6-Ethyl-1-(2-fluoro-pyridin-4-ylmethyl)-4,4-dimethyl-1 ,2,3,4-tetrahydro-quinolin-7-yl]-ethylamine (P-0034), 1-(6-Ethyl-4,4-dimethyl-1-phenethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-cthylamine (P-0033), 1-[6-Ethyl-1-(6-fluoro-pyridin-3-ylmethyl)-4,4-dimcthyl-1,2,3,4-tetrahydro-quinolin-7-yl] -ethylamine (P-00306), 1-[6-Ethyl-1-(2-methoxy-pyridin-4-ylmethyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl]- ethylamine (P-0041), 1-[6-Ethyl-4,4-dimethyl-1-(6-methyl-pyridin-3-ylmethyl)-1,2,3,4-tetrahydro-quinolin-7-yl]- ethylamine (P-0042), 1-(1-Benzo[1,3]dioxol-4-ylmethyl-6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethylamine (P-0051), and 1-[1-(2,2-Difluoro-benzo[ 1,3 ]dioxol-4-ylmethyl)-6-¢thyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7- yl]-ethylamine (P-0053).
The following table shows compounds that were prepared similarly to the protocol of Scheme 5/5a/5b, or suitable variations thereof, where optimal reaction conditions may have varied, for example, in terms of solvents used, time and temperature of the reaction, and in chromatography conditions for purification of the desired compounds, with the compound number in Column 1, the aryl-alkyl halide or aryl-aldehyde used in Step 1/1a/1b in Column 2, the resulting compound in
Column 3 and the experimental mass spectrometry result in Column 4.
Compound BE Aryl/heteroaryl- Compound structure MS (ESD) number alkyl halide or aldehyde M+H'T
I)
NTS = NH, }
P-0015 i (OC 325.25 7 Br
H
P-0017 LF i : 329.05
Br
Br, oT
Br )
A Nor NH 129.95
N 2 ’
P-0023 I N 394.95
Br tN
N NH, <
P-0024 Lg \ 329.05 cl a "
Br
F ® 342.3
F NH
P-0027 0 5 CCC [M-NH,T' r
F
Cet ; Br | C0 [M-NH,]" 0 sn eee
P0029 © | - 3 NH; 3363 ’ Br (C0 [MNHT™ x | Pe
P-0030 | = Br " F we | 342.3 } F CCC [M-NH,T
F
"0 y NH 336.3
P-0031 ~ pe Br (CC [M-NH,T' \ ~ :
P0032 NS | id 324.3
Poo Je soe MNILT
HL NH
N72 2 332.3
P-0033 J @! N i"
NGF BY Cc [M-NH;] ear
N7
NX FON NH,
P-0034 i | ar Ic 343.05
Cr N NH,
O
H
F No NH
P-0036 | TL N ’ 343.0
N._= Br
BE 0. ou SoS NH; 337.5
P-0041 “6 LJ ar eC IMNIL 7 = N > NH, 321.1 - N.# H co
P-0042 [OS N [M-NH,
Oo
P-0051 Lo “On ’ 368.0 “0 H er ee =
SY
0 | q I NH; i
P-0053 | 0 | FXO _N 404.0
FO H F
F
[0115] 1-(1-Benzyl-6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethylamine P-0025 was further purified by chiral HPLC to provide (R)-1-(1-Benzyl-6-ethyl-4 4-dimethyl-1,2,3 4-tetrahydro- quinoclin-7-yl)-ethylamine P-0048 and (S)-1-(1-Benzyl-6-ethyl-4,4-dimethyl-1.2.3,4-tctrahydro-
quinolin-7-yl)-ethylamine P-0049, ] NH; NH,
P-0048 4 P-0049 using a ChiralCel OD-H column, with isocratic 6% Buffer A (Isopropanol with 0.1% trifluoroacetic acid), and 94% Buffer B (hexane with 0.1% trifluoroacetic acid).
Example 6: Preparation of 7-(1-amino-cthyl)-1-benzyl-6-ethyl-4,4-dimethyl-3,4-dihydro-1H- quinolin-2-one P-0052.
[0116] 7-(1-Amino-ethyl)-1-benzyl-6-ethyl-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-onc P-0052 was prepared in four steps from 1-(6-cthyl-4,4-dimethyl-1,2,3 4-tetrahydro-quinolin-7-yl)-ethanone 9 as shown in Scheme 6.
Scheme 6
Co a, ON
Br 9 23 24 25
OH
GN N SN NH;
Step 3 ToC Step 4 "TCC 26 P-0052
Step I — Preparation of 1-(1-benzyl-6-ethyi-4,4-dimethyl-1,2,3,4-retrahydro-quinolin-7-yl)-ethanone (24).
[0117] A mixture of 1-(6-cthyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethanone (9, 500 mg, 2 mmol), benzyl bromide (23, 0.43 mL, 3.6 mmol) and N,N-diisopropylethylamine (0.92 mL, 5.3 mmol) were combined with 0.4 mL of N-methylpyrrolidone. The reaction was irradiated in a microwave at 100 °C for 40 minutes. The mixturc was diluted with ethyl acetate, and the organic layer was washed with brine, dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum. The crude material was purified by silica gel chromatography to provide the desired compound as a light yellow oil (24, 590 mg, 90%). MS (ESI) [M+H']" = 322.30.
Step 2 — Preparation of 7-acetyl-1-benzyl-6-ethyl-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (25):
[0118] To a solution of 1-(1-benzyl-6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethanone (24, 55.0 mg, 0.17 mmol) in 10 mL of dichloromethane, a premixed {ine powder of potassium permanganate (140 mg, 0.86 mmol) and copper(II) sulfate pentahydrate (210 mg, 0.86 mmol) was added. The reaction mixture was gently refluxed for 20 hours, then filtered through a Celite pad and the pad was washed with dichloromethane and ether. The organic portions were collected and combined, the solvent was removed under vacuum, and the residue was purified by silica gel chromatography to provide the desired compound as a light yellow oil (25, 8 mg, 14%). MS (ESI) [M+H"|" = 335.95.
Step 3 — Preparation of 1-benzyl-6-ethyl-7-(1-hydroxyimino-ethyl)-4,4-dimethyl-3,4-dihydro-1H- quinolin-2-one (26):
[0119] A solution of 7-acetyl-1-benzyl-6-ethyl-4,4-dimethyl-3,4-dihydro-1 H-quinolin-2-one (25, 10.0 mg, 0.028 mmol) , hydroxylamine hydrochloride (9.8 mg, 0.14 mmol), and pyridine (0.014 mL, 0.17 mmol) in 5 mL of ethanol was stirred at 80 °C for 4 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate, the organic layer washed with water, brine, and dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The residue was purified by silica gel chromatography to provide the desired compound as a light yellow solid (26, 10 mg, 70%). MS (ESI) [M+H']"= 350.95.
Step 4- Preparation of 7-(1-amino-ethyl)-1-benzyl-6-ethyl-4,4-dimethyl-3,4-dihydro-111-quinolin-2- one (P-0052):
[01201] A mixture of 1-benzyl-6-ethyl-7-(1-hydroxyimino-ethyl)-4,4-dimethyl-3,4-dihydro-1H- quinolin-2-one (26, 10 mg, 0.03 mmol) and Raney nickel (50%, aqueous slurry) in 10 mL of methanol and 3 mL of ammonium hydroxide was stirred under an hydrogen balloon for 5 hours. The catalyst was removed by filtration and the filtratc was concentrated under vacuum. The residue was purified by silica gel chromatography to provide the desired compound as a colorless viscous liquid (P-0052, 4.6 mg, 40%). MS (ESI) [M+H']"= 337.95.
Example 7: Preparation of 1-(1-benzyl-6-ethyl-4,4-dimethyl-1,2,3,4-tctrahydro-quinolin-7-yl)- propylamine P-0047.
[0121] 1-(1-Benzyl-6-ethyl-4 4-dimethyl-1,2,3 4-tetrahydro-quinolin-7-yl)-propylamine P-0047 was prepared in three steps from 1-(1-benzyl-6-cthyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-y1)- cthanone 24 as shown in Scheme 7.
Scheme 7 g
J 0 Q 0 Ig NOH Ig NH. 24 ' 2 2 P-0047
Step 1 - Preparation of 1-(1-benzyl-6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-propan-1- one (27):
[0122] 1-(1-Benzyl-6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethanone (24, 0.115 g, 0.358 mmol) was dissloved in 10 mL of tetrahydrofuran and chilled to -78 °C. Lithium hexamethyldisilazide in tetrahydrofuran (1.0 M, 0.36 mL) was added dropwise and the reaction mixture was stirred for 15 minutes at -78 °C. Methyl iodide (0.0223 mL, 0.358 mmol) was added in one portion and the reaction mixture was allowed to warm to room temperature. Ammonium chloride solution was added to quench the reaction and the mixture was washed with cthyl acetate. The organic layer was washed with brinc, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The crude material was purified by silica gel chromatography to provide the desired compound as a pale yellow waxy solid (27, 40 mg). MS (ESI) [M+H']' = 336.05.
Step 2 — Preparation of 1-(1-benzyl-G-ethyl-4,4-dimethyl-1,2,3, 4-tetrahydro-quinolin-7-yl)-propan-1- one oxime (28).
[0123] 1-(1-Benzyl-6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-propan-1-onc (27, 0.040 g, 0.12 mmol), and hydroxylamine hydrochloride (0.043 g, 0.62 mmol) were added to a solution of 0.5 mL of pyridine in 10 mL of ethanol. The reaction mixture was warmed to reflux for 4 hours and then concentrated under vacuum. The residue was partitioned between ethyl acetate and ammonium chloride solution. The organic layer was washed with water and brine, then dried over magnesium sulfate, filtered and filtrate concentrated under vacuum. The resulting material was purified by silica gel chromatography to provide the desired compound (28, 20 mg). MS (ESI) [M+H']" = 377.0.
Step 3 — Preparation of 1-(1-benzyl-6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)- propylamine (P-0047):
[0124] 1-(1-Benzyl-6-ethyl-4,4-dimethyl-1,2,3 4-tetrahydro-quinolin-7-yl)-propan-1-one oxime (28, 0.0055 g, 0.016 mmol) was dissolved in 10 mL of ethanol in a Parr vessel. Raney nickel (0.05 g, 0.8 mmol) was added, and the vessel was evacuated and charged with hydrogen (10 g, 5 mol, 55 PSI).
The reaction mixture was agitated for 20 minutes. The Raney nickel was removed via filtration and the filtrate concentrated under vacuum to provide the desired compound as a pale, yellow, waxy solid
(P-0047, 3.3 mg). MS (ESI) [M+H']" = 338.05.
[0125] 1-[6-Ethyl-1-(3-methoxy-propyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl]- propylamine P-0016 ~On NH;
CoC was prepared similarly to the protocol of Scheme 7, replacing 1-(1-benzyl-6-ethyl-4,4-dimethy!- 1,2,3,4-tetrahydro-quinolin-7-yl)-ethanone 24 with 1-[6-ethyl-1-(3-methoxy-propyl)-4,4-dimethyl- 1,2,3,4-tetrahydro-quinolin-7-yl]-ethanone (isolated after Step 1 of Scheme 4 in preparation of P-0003 per Example 4). MS (ESI) [M+H']" = 338.05.
Example 8: Preparation of trifluoro-methanesulfonic acid 7-acetyl-4,4-dimethyl-1-(2,2,2- trifluoro-acetyl)-1,2,3,4-tetrahydro-quinolin-6-yl ester 35.
[0126] Trifluoro-methanesulfonic acid 7-acetyl-4,4-dimethyl-1-(2,2,2-trifluoro-acetyl)-1,2,3,4~ tetrahydro-quinolin-6-yl ester 35 was prepared in six steps from 4-methoxybenzenamine 29 as shown in Scheme 8.
Scheme 8
H H
HN OC H O._N N
TL + _ Step 1 Q TL Step 2 Step 3 0 z = 0 0 0 29 | 30 3 | 32
FsC pO FsC- pO o FaC 0 0
Step 4 N Step 5 N Step 6 N 0 OH OTf 33 | 34 35
Step 1 - Preparation of 3-methyl-but-2-enoic acid (4-methoxy-phenyl)-amide (30):
[0127] To a chilled (0 °C) mixture of 4-methoxybenzenamine (29, 2.50 g, 20.3 mmol) and sodium hydroxide (2.0 g, 51.0 mmol) in 20 mL of water and 30 mL of dichloromethane, 3,3-dimethylacryloyl chloride (2, 2.7 mL, 24.0 mmol} was added over a period of ~5 minutes. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous layer was washed 3x with ethyl acetate and the pooled organic layer was washed with ammonium chloride solution and brine, then dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting brown oil was purified by silica gel column chromatography eluting with a gradient of 0-7% methanol in dichloromethane. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound as a tan waxy solid (30, 3.78g, 91%).
Step 2 - Preparation of 6-methoxy-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (31):
[0128] Aluminum trichloride (19.1 g, 143 mmol) was suspended in 300 mL of nitromethane and 3-methyl-but-2-enoic acid (4-mcthoxy-phenyl)-amide (30, 9.5 g, 46.0 mmol) was added dropwise over a period of ~5 minutes. The reaction mixture was stirred under an inert atmosphere overnight.
Ice was added piece-by-peice to quench the reaction and the mixture was partitioned between ethyl acetate and water. The organic layer was collected and the aqueous layer was washed 3x with ethyl acetate. The organic fractions were pooled and washed with water, sodium bicarbonate solution and brine, then concentrated under vacuum. The resulting material was crystalized from an cthyl acetate and hexane solution to provide the desired compound as long colorless needles (31, 7.8 g, 82%).
Step 3 - Preparation of 6-methoxy-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline (32):
[0129] To a solution of 6-methoxy-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (31, 2.0 g, 9.7 mmol) in 150 mL of toluene, borane-dimethy! sulfide complex (1.7 mL, 19.0 mmol) was slowly added at 0 °C. The reaction mixture was stirred at 0 °C for 15 minutes and then stirred at 100 °C for 2 hours. The reaction mixture was cooled to room temperature and poured into 150 mL of 10% sodium carbonate solution. The mixture was stirred at room temperature for 30 minutes. The organic layer was collected and the aqueous layer was extracted with 2 x 60 mL of ethyl acetate. The organic layers were combined and dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The crude material was purified by silica gel chromatography to provide the desired compound as a light brown liquid (32, 1.2g, 64%).
Step 4 - Preparation of 2,2,2-trifluoro-1-(6-methoxy-4,4-dimethyl-3,4-dihydro-2H-quinolin-1-yl)- ethanone (33).
[0130] To a solution of 6-methoxy-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline (32, 4.49 g, 23.5 mmol) in 25 mL of dichloromethane, triethylamine (65.0 mL, 47.0 mmol} and trifluoroacetic anhydride (6.6 mL, 47.0 mmol) were added. The reaction mixture was stirred overnight, then partitioned between dichloromethane and water. The organic layer was washed with brine and dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel chromatography eluting with 10% ethyl acetate in hexanes to provide the desired compound (33, 5.4g, 80%).
Step 5 - Preparation of 1-(7-acetyl-6-hydroxy-4,4-dimethyl-3,4-dihydro-2H-quinolin-1-yl)-2,2,2- trifluoro-ethanone (34).
[0131] To a suspension of aluminum trichloride (2.6 g, 19.0 mmol) in 8 mL of nitromethane,
chilled to at 0 °C, a solution of acetyl chloride (1.1 mL, 16.0 mmol) and 2,2,2-trifluoro-1-(6-methoxy- 4 4-dimethyl-3,4-dihydro-2H-quinolin-1-yl)-ethanone (33, 1.24 g, 4.32 mmol) in 10 mL of nitromethane was slowly added. Once addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was chilled to at 0 °C and water was added dropwise, resulting in heat and foaming, until all solids were dissolved.
The mixture was cxtracted with 100 mL dichloromethane. The organic layer was washed with water, ammonium chloride solution and brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum, The resulting golden colored oil was purified by silica gel column chromatography eluting with a gradient of 0-5% methanol in dichloromethane over 40 minutes.
Appropriate fractions were combined and the solvents removed to provide the desired compound (34, 656 mg, 48%). MS (ESI) [M+H"]"= 316.2.
Step 6 - Preparation of trifluoro-methanesulfonic acid 7-acetyl-4,4-dimethyl-1-(2,2, 2-trifluoro- acetyl)-1,2,3,4-tetrahydro-quinolin-6-yl ester (33):
[0132] To a chilled (-78 °C) solution of 1-(7-acetyl-6-hydroxy-4,4-dimethyl-3,4-dihydro-2H- quinolin-1-y1)-2,2,2-trifluoro-ethanone (34, 2.1 g, 6.7 mmol) in 10 mL of dichloromethane, pyridine (1.2 mL, 15.0 mmol) and trifluoromethane sulfonyl! anhydride (1.4 mL, 8.4 mmol) were added. The reaction mixture was stirred at -78 °C for 30 minutes and at room temperature for 2 hours. The reaction mixture was poured into 1M aqueous hydrochloric acid, then extracted with dichloromethane. The organic layer was collected and washed with 1M hydrochloric acid, sodium bicarbonate and brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel chromatography to provide the desired compound (35, 2.4 g, 84%). MS (ESD) [M+H'] = 448.2.
Example 9: Preparation of 1-[1-benzyl-6-(4-fluoro-phenyl)-4,4-dimethyl-1,2,3 4-tetrahydro- quinolin-7-yl]-ethylamine P-0044.
[0133] 1-[1-Benzyl-6-(4-fluoro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl]-ethylamine
P-0044 was prepared in five steps from trifluoro-methanesulfonic acid 7-acetyl-4,4-dimethyl-1-(2,2,2- trifluoro-acetyl)-1,2,3,4-tetrahydro-quinolin-6-yl ester 35 as shown in Scheme 9.
Scheme 9
F100 o B(OH), FCO o } o
Gk Om Tol + ph ee
OTF 0) Cl "35 F 36 37 F 38 F
Br ® o 2 or 2 NH,
QL, Na C 39 FE a0 F P0044 F
Step 1 - Preparation of 1-[7-acetyl-6-(4-fluoro-phenyl)-4,4-dimethyl-3,4-dihydro-2H-quinolin-1-yl]- 2,2, 2-trifluoro-ethanone (37):
[0134] Into a solution of trifluoromethanesulfonic acid 7-acetyl-4,4-dimethyl-1-(2,2,2-trifluoro- acetyl)-1,2,3,4-tetrahydro-quinolin-6-yl ester (35, 50.0 mg, 0.112 mmol) in 2.00 mL tetrahydrofuran and 0.12 mL of dimethy! sulfoxide in a microwave reaction vial, 4-fluorophenylboronic acid (36, 36.0 mg, 0.257 mmol), palladium acetate (25.1 mg, 0.112 mmol), tricyclohexylphosphine (37.6 mg, 0.134 mmol) and potassium fluoride (23 mg, 0.39 mmol) were added. The reaction mixture was warmed to 70 °C for 80 minutes via microware irradiation. The reaction mixture was diluted with ethyl acetate and the organic layer washed with brine, dried over magnesium sulfate, filtered, and purified by silica gel chromatography to provide the desired compound (37, 46 mg, 70%). MS (ESI) [M+H']" = 393.95.
Step 2 - Preparation of 1-[6-(4-fluovo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl]- ethanone (38):
[0135] Into a l-neck round-bottom flask was added 1-[7-acetyl-6-(4-fluoro-phenyl)-4,4-dimethyl- 3,4-dihydro-2H-quinolin-1-yl1]-2,2,2-trifluoro-ethanone (37, 87 mg, 0.16 mmol), potassium hydroxide (26 mg, 0.46 mmol), 15.0 mL of methanol and 2.0 mL of water. The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and brine. The organic layer was dried over magnesium sulfate, filtered and purified by silica gel chromatography to provide the desired compound as a pale yellow solid (38, 35 mg, 57%). MS (ESI) [M+H'] = 298.46
Step 3 - Preparation of 1-[1-benzyl-6-(4-fluoro-phenyl)-4,4-dimethyl-1,2, 3,4-tetrahydro-quinolin-7- yl]-ethanone (39):
[0136] A solution of 1-[6-(4-fluoro-phenyl)-4,4-dimethyl-1,2.3 4-tetrahydro-quinolin-7-yl]- cthanonc (38, 35 mg, 0.088 mmol), benzyl bromide (23, 0.026 mL, 0.22 mmol) and 0.038 mL of N,N- diisopropvlethylamine in 0.1 mL of N-methylpyrrolidone was warmed to 100 “C for 40 minutes via microwave irradiation. The reaction mixture was diluted with ethyl acetate and the organic phasc washed 2x with brine, dried over magnesium sulfate, filtered and purified by silica gel chromatography to provide the desired compound as a pale yellow oil (39, 45 mg, 99%). MS (ESI) [M+H']" = 388.0.
Step 4 - Preparation of 1-[1-benzyl-6-(4-fluoro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7- yl]-ethanone oxime (40):
[0137] A solution of 1-[1-benzyl-6-(4-fluoro-phenyl}-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7- yl]-ethanone (39, 45 mg, 0.087 mmol), hydroxylamine hydrochloride (50 mg, 0.7 mmol), and pyridine (0.1 mL, 1.0 mmol) in 15 mL of ethanol was stirred at 80 °C for 4 hours. The reaction mixture was concentrated under vacuum and the residue was partitioned between cthyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The residue was purified by silica gel chromatography to provide the desired compound as a pale yellow solid (40, 29 mg). MS (ESI) [M+H']" = 403.45
Step 5 - Preparation of 1-[1-benzyl-6-(4-fluoro-phenyl)-4,4-dimethyl-1,2, 3, 4-tetrahydro-quinolin-7- vi]-ethylamine (P-0044):
[0138] A mixture of 1-[1-benzyl-6-(4-fluoro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7- yl]-ethanone oxime (40, 29 mg, 0.070 mmol) and Raney nickel (50%, aqueous slurry) in 20 mL of methanol and 3 mL of ammonium hydroxide was agitated in a Parr shaker under hydrogen (55 psi) for 1.5 hours. The mixture was filtered and the filtrate purified by silica gel chromatography to provide the desired compound as a yellow oil (P-0044, 4.0 mg, 14%). MS (ESI) [M-H'] =387.00.
[0139] Additional compounds may be prepared similarly to the protocol of Scheme 9, replacing 4- fluorophenylboronic acid 36 with an appropriate boronic acid or boronic acid ester in Step 1.
Purification for the last step was alternatively done by HPLC, using Phenomenex C18 column with 20-100% solvent B gradient over 40 minutes, with flow rate of 20 mL/minute. Solvent A was water with 0.1% trifluoroacetic acid and solvent B was acetonitrile with 0.1% trifluoroacetic acid. For compounds P-0059, P-0063, P-0064, P-0065, P-0066, P-0067, P-0068, P-0072-P-0075, P-0077 and
P-0080 the first two steps of the reaction were performed in one step (per the following Step 1a for compound P-0059):
Fol p© 0 B(OH), H 0 oTf > # =~ 36a 38a
Step la - Preparation of 1-{6-(3-ethyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl]- ethanone (38a):
[0140] Into a solution of triflucromethanesuifonic acid 7-acetyl-4,4-dimethyl-1-(2,2,2-trifluoro-
acetyl)-1,2,3,4-tetrahydro-quinolin-6-yl ester (35, 80 mg, 0.18 mmol) and 3-ethylphenylboronic acid (36a, 54 mg, 0.36 mmol) in 800ul of acetonitrile, 400 ul of 1M aqueous potassium carbonate and [1,1"-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (~0.02 mmol) as catalysis were added and the reaction mixture was irradiated under microwave conditions for 10 minutes at 155 °C. The reaction mixture was diluted with water and extracted 2x with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated under vacuum. The residue was dissolved in 1 ml of dichloromethane and excess of hexane was added. A precipitate was removed by filtration and washed with hexane. The filtrate solution was concentrated under vacuum to provide the desired compound as yellow oil (38a, 67 mg), which was used in the next step without further purification.
The following compounds were made similarly to the protocol of Scheme 9: 1-(1-Benzyl-4,4-dimethyl-6-p-tolyl-1,2,3 ;4-tetrahydro-quinolin-7-yl)-ethylamine (P-0039), 1-[1-Benzyl-6-(4-chloro-phenyl)-4,4-dimethyl-1,2,3 .4-tetrahydro-quinolin-7-yl]-ethylamine (P-0046), 1-[1-Benzyl-6-(3-methoxy-phenyl)-4,4-dimethyl-1 ,2,3,4-tctrahydro-quinolin-7-yl]-ethylamine (P-0050), 1-[1-Benzyl-6-(4-mcthoxy-phenyl)-4,4-dimethyl-1 ,2,3,4-tetrahydro-quinolin-7-yl]-ethylamine (P-0054), 1-(1-Benzyl-4,4-dimethyl-6-thiophen-2-yl1-1,2,3 ,4-tetrahydro-quinolin-7-yl)-ethylamine (P-0055), 1-[1-Benzyl-6-(3-ethyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl]-ethylamine (P-0059), 1-[1-Benzyl-6-(3-benzyloxy-4-methoxy-phenyl)-4,4-dimethyl-1,2,3 ,4-tetrahydro-quinolin-7-yl]- ethylamine (P-0063), 1-[1-Benzyl-4,4-dimethyl-6-(3-methyl-3H-imidazol-4-yl)-1,2,3 4-tetrahydro-quinolin-7-yl]- ethylamine (P-0064), 5-[7-(1-Amino-ethyl)-1-benzy!-4,4-dimethyl-1 ,2,3,4-tetrahydro-quinolin-6-yl]-2-methoxy-phenol (P-0065), 1-[1-Benzyl-6-(3-chloro-phenyl)-4,4-dimethyl-1,2,3 ,4-tetrahydro-quinolin-7-yl]-ethylamine (P-0066), 1-(6-Benzo[1,3]dioxol-5-yl-1-benzyl-4,4-dimethyl-1,2,3,4-tctrahydro-quinolin -7-yl)-ethylamine (P-0067), 1-[1-Benzyl-6-(4-ethyl-phenyl)-4,4-dimethyl-1,2,3,4-t etrahydro-quinolin-7-yl]-ethylamine (P-0068), 3-[7-(1-Amino-ethyl)-1-benzyl-4,4-dimethyl-1,2,3 A-tetrahydro-quinolin-6-yl]-benzamide (P-0072), 4-[7-(1-Amino-ethyl)-1-benzyl-4,4-dimethyl-1,2,3 ,4-tetrahydro-quinolin-6-yl]-benzamide (P-0073), 1-[1-Benzyl-6-(3-fluoro-4-methyl-phenyl)-4,4-dimethyl-1 .2,3,4-tetrahydro-quinolin-7-yl]-ethylaminc (P-0074), 1-[1-Benzyl-6-(2,4-dimethyl-thiazol-5-y1)-4,4-dimethyl-1,2, 3,4-tctrahydro-quinolin-7-yl]-ethylamine (P-0075), 1-[1-Benzyl-6-(1H-indol-5-y1)-4,4-dimethyl-1 ,2,3,4-tetrahydro-quinolin-7-yl]-ethylamine (P-0077), and
1-[1-Benzyl-4,4-dimethyl-6-(5-methyl-thiophen-2-yl)-1,2,3,4-tetrahydro-quinolin-7-yl]-ethylamine (P-0080).
The following table shows compounds that were prepared similarly to the protocol of Scheme 9, where optimal reaction conditions may have varied, for example, in terms of solvents, time and temperature of the reaction, and in chromatography conditions for purification of the desired compounds, with the compound number in Column 1, the boronic acid or ester used in Step 1 or la in
Column 2, the resulting compound in Column 3 and the experimental mass spectrometry result in
Column 4,
Compound number Boronic acid/ester Compound structure | MS (ESD
TL \ 368.0 , LOH N .
P0039 2 [M-NH, ” J o a
N 399.9
P-0046 5-OH § NH, [M-NH,]'
OH CO)
Cl
Clon | Sa - . N 2
P-0050 ~0 B CH ) . 400.20 > <8 “CL a NH,
N 384.0
Pos oo" pT
OH 0)
ES
SN CC NH,
P-0055 sg OH N 376.95
OH s
WY
Xx QL NH i . OH N “2
P-0059 B | | [M-NH,
OH
# | ]
Toa. ~
NA | I 0 ¢ a I 490.3
P-0063* Po N co
Clo (CC oD [M-NH:] ; © : | “Ao
N
¢ o _ 3 NHy
P-0064 NE CCC, 375.8 oe _ ™ Or —~ z : \_7 ~~ a,
P-0065* - 19] N 400.3
BO ® oH [M-NH,] 0-5 CL
Q
~~:
LL 388.3
P-0066 TL JOH Nee, . ar 7 (ye [M-NH;]
OH
0 | NH 2
P-0067 CTO _OH N 398.3
B OD [M-NH,
SU — 0 0 aC
N
P-0068 0" 0 382 3
OH CO)
P-0072 HN 5 OF N ® “ 0 OH 0 0 0 eg Nt
P-0073 a " . LOH 2)
B
OH q NH, 0 12 Se
P-0074 | pg OH No 386.3 : | [M-NH,]
OH AF
— | CL
N ! | KJ NH — i 2 :
P-0075 s gO N A 389.5 0 . [M-NH;]
Na , N
OH © g NH;
B N
P-0077 HO OR )
N CL
N momen H nro oH ie NH,
P-0080 HO o oe 374.3
SR
0 * P-0063 and P-0065 isolated from the same reaction.
Example 10: Preparation of 1-(1-Benzyl-6-benzyloxy-4,4-dimethyl-1,2,3 d-tetrahydro-quinolin- 7-yD)-ethylamine P-0060.
[0141] 1-(1 -Benzyl-6-benzyloxy-4,4-dimethyl-1 ,2,3,4-tetrahydro-quinolin-7-yl)-cthylamine P-0060 was prepared in five steps from I-(7-acetyl-6-hydroxy-4,4-dimethyl-3,4-dihydro-2H-quinolin-1-yl)- 2,2,2-trifluoro-ethanone 34 as shown in Scheme 10.
Scheme 10
Oy CFs 0 Br Oy CFs 0 H 0 Step 3
N . A Step 1 step2 oN Br 34 23 #“ 42 23 i EN
OH
2 0 0 Nig Z NH,
N Stepa oN Steps N
UO a0 ae 43 a4 P-0060
Step | — Preparation of I-( 7-acetyl-6-benzyloxy-4,4-dimethyl-3,4-dihydro-2-quinolin-1-yl)-2,2, 2- trifluoro-ethanone (41):
[0142] To a solution of 1-(7-acetyl-6-hydroxy-4,4-dimethyl-3 4-dihydro-2H-quinolin- 1-y1)-2,2,2- trifluoro-ethanone (34, 500.0 mg, 1.58 mmol) in 30 mL of acctone, potassium carbonate (600 mg, 4.8 mmol), potassium iodide (260 mg, 1.6 mmol) and benzyl bromide (23, 0.21 mL, 1.7 mmol) were added. The reaction mixture was stirred at room temperature for 4 hours, then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered and the filtrate purified by silica gel chromatography to provide the desired compound (41, 422 mg, 65%).
Step 2 — Preparation of 1-(6-benzyloxy-4,4-dimethyl-1,2,3, 4-tetrahydro-quinolin-7-yl)-ethanone 142):
[0143] Into a 1-neck round-bottom flask, 1-(7-acetyl-6-benzyloxy-4,4-dimethyl-3,4-dihydro-2H- quinolin-1-y1)-2,2,2-trifluoro-ethanone (41, 550 mg, 1.35 mmol) and 1 N potassium hydroxide (1.5 mL, 1.5 mmol), were mixed in 25 mL of methanol. The reaction mixture was stirred at room temperature for 2 hours and concentrated under vacuum. The residue was partitioned between ethyl acetate and brine. The organic layer was dried over magnesium sulfate, filtered and the filtrate purified by silica gel chromatography to provide the desired compound as pale yellow solid (42, 400 mg, 95 %). MS (ESI) [M+H']" = 310.2.
Step 3 — Preparation of 1-(1-benzyl-6-benzyloxy-4,4-dimethyl-1,2, 3,4-tetrahydro-quinolin-7-yl)- ethanone (43).
[0144] A solution of 1-(6-benzyloxy-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethanone (42, 422 mg, 1.36 mmol), benzyl bromide (23, 0.49 mL, 4.1 mmol) and N,N-diisopropylethylamine (0.71 mL) in 20 mL of N-methylpyrrolidonc was warmed to 100 °C for 40 minutes via microwave irradiation. The reaction mixture was diluted with ethyl acetate and washed 2x with brine. The organic phase was dried with magnesium sulfate, filtered and the filtrate purified by silica gel chromatography to provide the desired compound as pale yellow oil (43, 266 mg, 41 %). MS (ESI) [M~H"]" = 400.2.
Step 4 — Preparation of 1-(1-benzyl-6-benzyloxy-4, 4-dimethyl-1,2, 3, 4-tetrahydro-quinolin-7-yl)- ethanone oxime (44):
[0145] A solution of 1-( 1-benzyl-6-benzyloxy-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)- ethanone (43, 100 mg, 0.25 mmol), hydroxylamine hydrochloride (35 mg, 0.50 mmol), and pyridine (0.04 mL, 0.5 mol) in 15 mL of ethanol was stirred at at 80 °C for 4 hours. The reaction mixture was concentrated under reduced pressure and the residuc was partitioned between ethyl acetate and water.
The organic layer was washed with brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The residue was purified by silica gel chromatography to provide the desired compound as a pale yellow solid (44, 60 mg, 57 %). MS (ESI) [M+H']" = 415.2.
Step 5 — Preparation of 1-(1-benzyl-6-benzyloxy-4,4-dimethyl-1,2,3, 4-tetrahydro-quinolin-7-yl}- ethylamine (P-0060):
[0146] A mixture of 1-(1-benzyl-6-benzyloxy-4,4-dimethyl-1 ,2,3,4-tetrahydro-quinolin-7-yl)- ethanone oxime (44, 30 mg, 0.072 mmol) and Raney nickel (50%, aqueous slurry) in 5 mL of methanol and 2 ml. of ammonium hydroxide was agitated in a Parr shaker under hydrogen (55 psi) for 1.5 hours. The mixture was filtered and the filtrate purified by silica gel chromatography to provide the desired compound as a yellow oil (P-0060, 7.2 mg, 25 %). MS (EST) [M+H"]" = 400.8.
Example 11: Preparation of 2-methyl-pyridine-4-carbaldehyde 21b.
[0147] 2-Methyl-pyridine-4-carbaldehyde 21b (used e.g. in Scheme 5b) was prepared in three steps from 2-methyl-isonicotinic acid 45 as shown in Scheme 11.
Scheme 11
OH
— OR F — 0 F F Step2 Step3 = MH ‘eS, sun NO S02 (DS \_ OH + CX 0 F \ vs OH WW 0
F FoF 45 46 47 21b
Step 1 — Preparation of 2-methyl-isonicotinic acid pentafluorophenyl ester (47):
[0148] To a suspension of 2-methyl-isonicotinic acid (45, 2.74 g, 20 mmol) and pentafluorophenol (46, 3.7 g, 20 mmol) in 100 mL of anhydrous tetrahydrofuran, N,N'-diisopropylcarbodiimide (3.1 mL, mmol) was added. The mixture was stirred at room temperature overnight, then filtered through a pad of Celite. The filtrate was collected and used in the next step without further purification.
Step 2 — Preparation of (2-methyl-pyridin-4-yl)-methanol (48):
[0149] To a solution of 2-methyl-isonicotinic acid pentafluorophenyl ester (47), lithium borohydride (12 mL, 2.0 M in tetrahydrofuran) was added slowly. The reaction mixture was stirred at Toom temperature overnight, then cooled with ice water bath and 40 mL of IN sodium hydroxide was slowly added. The mixture was then extracted with chloroform and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum.
The residue was purified by silica gel chromatography eluting with hexanes and ethyl acetate to provide the desired compound as a white solid (48, 2.38 g, 80%). MS (ESD [M+H']" = 123.85.
Step 3 ~ Preparation of 2-methylpyridine-4-carbaldehyde (215):
[0150] A solution of chromium (VI) oxide (2 g, 20 mmol), pyridine (4 mL, 50 mmol) and 20 mL of dichloromethane was stirred at room temperature for 30 minutes. To this mixture, cooled with an ice water bath, (2-methyl-pyridin-4-yl)-methanol (48, 0.5 g, 4.0 mmol) in 5 mL of dichloromethane was added. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled with an ice water bath and diluted with ethyl acetate, then filtered through a pad of Celite.
The filtrate was concentrated under vacuum and the residue was purified by silica gel chromatography eluting with hexanes and ethy! acetate to provide the desired compound as a colorless liquid (21b, 0.1 g, 20%).
Example 12: Preparation of 1-[4,4-dimethyl-1-(2-methyl-pyridin-4-ylmethyl)-6-p-tolyl-1,2 3.4- tetrahydro-quinolin-7-yl]-ethylamine P-0062.
[0151] 1-[4,4-Dimcthyl-] -(2-methyl-pyridin-4-ylmethyl)-6-p-tolyl-1,2,3,4-tetrahydro-quinolin-7- yl]-ethylamine P-0062 was prepared in four steps from trifluoromethanesulfonic acid 7-acetyl-4,4- dimethyl-1-(2,2,2-trifluoro-acetyl)-1 ,2,3,4-tetrahydro-quinolin-6-yl ester 35 as shown in Scheme 12.
Scheme 12
FeO 0 B(OH), H 0 Step 2 oTf 49 50 + A
N
21b
Oo 0 © N on © NH;
CO, 2 CIO 2 (0) suas 51 52 P-0062
Step | — Preparation of 1-(4,4-dimethyl-6-p-tolyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethanone (50).
[0152] Into a solution of trifluoromethanesulfonic acid 7-acetyl-4,4-dimethyl-1-(2,2,2-trifluoro- acetyl)-1,2,3,4-tetrahydro-quinolin-6-yl ester (35, 100 mg, 0.20 mmol) in 3 mL of tetrahydrofuran in a microwave reaction vial, 4-toluene boronic acid (49, 61 mg, 0.45 mmol) and tetrakis(triphenylphosphine)palladium (0) (~2 mg, catalyst) were added. The reaction mixture was warmed to 70 °C for 20 minutes via microware irradiation. The reaction mixture was diluted with ethyl acetate and the organic layer washed with brine, dried over magnesium sulfate, filtered, and the filtrate purified by silica gel chromatography to provide the desired compound (50, 28 mg, 42%). MS (ESI) [M+H']"= 294.3.
Step 2 — Preparation of 1-f4,4-dimethyl-1 ~(2-methyl-pyridin-4-ylmethyl)-6-p-tolyl-1,2,3,4-tetrahydro- quinolin-7-yl]-ethanone (51):
[0153] To a mixture of 2-methylpyridine-4-carbaldehyde (21b, 14 mg, 0.11 mmol) and 1-(4,4- dimethyl-6-p-tolyl-1,2,3,4-tetrahydro-quinolin-7-yl)-cthanone (50, 100 mg, 0.4 mmol) in S mL of acetonitrile, triethylsilane (0.2 mL, 1.2 mmol) and trifluoroacetic acid (0.4 mL, 5.0 mmol) were added. The reaction mixture was stirred at 100 °C for 2 hours. The reaction mixture was concentrated under vacuum and partitioned between aqueous potassium carbonate and ethyl acetate,
The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate purified by silica gel chromatography to provide the desired compound as a yellow solid (51, 18 mg, 47%). MS (ESI) [M+H'T" = 399.2.
Step 3 Preparation of 1-[4,4-dimethyl-1-(2-methyl-pyridin-4-ylmethyl)-6-p-tolyl-1,2, 3, 4-tetrahydro- quinolin-7-ylj-ethanone oxime (52).
[0154] A solution of 1-[4,4-dimethyl-1-(2-methyl-pyridin-4-ylmethyl)-6-p-tolyl-1,2,3,4-tetrahydro- quinolin-7-yl]-ethanonc (51, 22.7 mg, 0.057 mmol), hydroxylamine hydrochloride (7.9 mg, 0.11 mmol), and 0.03 mL of pyridine in 15 mL of ethanol was stirred at 80 °C for 4 hours. The reaction mixture was concentrated under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magenesium sulfate, filtered and the filtrate concentrated under vacuum. The residue was purificd by silica gel chromatography to provide the desired compound as a pale yellow solid (52, 10 mg, 43 %). MS (ESI) [M+H'] = 414.2.
Step 4 — Preparation of 1-[4,4-dimethyl-1-(2-methyl-pyridin-4-ylmethyl)-6-p-tolyl-1,2,3, 4-tetrahydro- quinolin-7-yl]-ethylamine (P-0062):
[0155] A mixture of 1-[4,4-dimethyl-1-(2-methyl-pyridin-4-ylmethyl)-6-p-tolyl-1,2,3,4-tetrahydro- quinolin-7-yl]-ethanone oxime (52, 10 mg, 0.024 mmol) and Raney nickel (50%, aqueous slurry) in 5 mL of methanol and 1 mL of ammonium hydroxide was agitated in a Parr shaker under hydrogen (55 psi) for 1.5 hours. Filtration and silica gel chromatography provided the desired compound as a yellow oil (P-0062, 0.9 mg, 9%). MS (ESI) [M+H']"= 400.3.
Example 13: Preparation of 1-[7-(1-amino-ethyl)-6-ethyl-4,4-dimethyl-3,4-dihydro-2H- quinolin-1-yl]-2-methoxy-ethanone P-0001
[0156] 1-[7-(1-Amino-ethyl)-6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinolin-1 -yl]-2-methoxy- ethanone P-0001 was prepared in three steps from 1-(6-ethyl-4,4-dimethyl-1,2,3 4-tetrahydro- quinolin-7-yl)-ethanone 9 as shown in Scheme 13.
Scheme 13 0 ~ 0 OH 0 f 0 c ony 0 om N oY NH, 53 ~ ? 54 55 P-0001
Step | — Preparation of 1-(7-acetyl-6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinolin-1 -yl)-2-methoxy- ethanone (54):
[0157] To a mixture of 1-(6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-cthanone 9,110 mg, 0.43 mmol), N,N-diisopropylethylamine (0.38 mL, 2.2 mmol), and 4-dimethylaminopyridine (5 mg, 0.04 mmol) in 20 mL of tetrahydrofuran, methoxyacetyl chloride (53, 0.12 mL, 1.3 mmol) in 2 mL of tetrahydrofuran was added dropwisc at 0 °C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with dichloromethanc. The organic layer was collected, washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum.
The residue was purified by silica gel chromatography eluting with ethyl acetate and hexanes to provide the desired compound as a light brown oil (54, 81 mg, 62%). MS (ESI) [M+H']" = 304.50.
Step 2 — Preparation of 1-(6-ethyl-7-(1 -hydroxyimino-ethyl)-4, d-dimethyl-3,4-dihydro-2H-quinolin-1- yl)-2-methoxy-ethanone (55):
[0158] A solution of 1-(7-acetyl-6-cthyl-4,4-dimethyl-3,4-dihydro-2H-quinolin-1-y1)-2-methoxy- ethanone (54, 75 mg, 0.25 mmol), hydroxylamine hydrochloride (30 mg, 0.5 mmol), and pyridine 01 mL, 1 mmol) in 10 mL of ethanol was stirred at 80 °C for 2 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The residue was purified by silica gel chromatography eluting with ethyl acetate and hexanes to provide the desired compound as a colorless oil (55, 40 mg, 50%). MS (ESI) [M+H'] = 319.45,
Step 3 Preparation of 1-[7-(1-amino-ethyl)-6-ethyl-4, 4-dimethyl-3,4-dikydro-2H-quinolin-1-yl)-2- methoxy-ethanone (P-0001):
[0159] A mixture of 1-(6-ethyl-7-( 1-hydroxyimino-ethyl)-4,4-dimcthyl-3,4-dihydro-2H-quinolin-1 - yl)-2-methoxy-cthanone (55, 40 mg, 0.1 mmol) and Raney nickel (50%, aqueous slurry) in 6 mL of methanol and 3 mL of ammonium hydroxide was shaken under hydrogen (55 psi) for 5 hours. The reaction mixture was filtered and the filtrate concentrated under vacuum. The residue was purified by silica gel chromatography eluting with methanol and dichloromethane to provide the desired compound as a colorless oil (P-0001, 22 mg, 60%). MS (ESI) [M+H']"= 305.95.
Example 14: Preparation of 7-( I-amino-cthyl)-1-(3-methoxy-propyl)-4,4-dimethyl-6-p-tolyl-3,4- dihydro-1H-quinolin-2-one P-0040 and 1-[1-(3-methoxy-propyl)-4,4-dimethyl-6-p-tolyl-1,2,3 4- tetrahydro-quinolin-7-yl]-ethylamine P-0043.
[0160] 7-(1-amino-ethyl)-1 -(3-methoxy-propyl)-4,4-dimethyl-6-p-tolyl-3,4-dihydro-1 H-quinolin-2- onc P-0040 and 1-[1+( 3-methoxy-propyl)-4,4-dimethyl-6-p-tolyl-1 ,2,3,4-tetrahydro-quinolin-7-yl}- cthylamine P-0043 werc prepared in eight steps from 3-ethylaniline 56 as shown in Scheme 14.
Scheme 14
N oN
H Os N
HN 9 sept ON Step 2 Step 3 Step 4 + Cl — - I Br 59 oO. Oo
J Step 6 J 0 q — 0 oN Step5 Og N , B(OH), Og N 0 : Step?
Br +Br "0 Br CO 49
O<
J NH,
ICC
.
OH Step 8a
J N ji P-0040
ON
2 = aN ow 64 Step 8b
P-0043
Step 1 - Preparation of 3-methyl-but-2-enoic acid (3-ethyl-phenyl)-amide (57);
[0161] To a mixture of 3-ethylaniline (56, 20.00 g, 0.16 mol) and sodium hydroxide (16 g, 0.41 mol) in 160 mL of water and 100 mL of dichloromethane, a solution of 3,3-dimcthylacryloyl chloride (2, 22 mL, 0.20 mol) in 50 mL of dichloromethane was slowly added at <5 °C. The reaction mixture was then stirred at room temperature for 16 hours, then poured into 400 mL of water and extracted with dichloromethane. The combined organic layers were collected, washed with brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by recrystallization from ethyl acetate and hexanes to provide the desired compound as a white solid (57, 31.1 g, 93%). MS (ESI) [M+H']"= 204.15.
Step 2 ~ Preparation of 7-ethvl-4,4-dimethyl-3,4-dihydro-1 H-quinolin-2-one (58):
[0162] To a suspension of aluminum trichloride (13.1 g, 98.4 mmol) in 50 mL of 1,2- dichlorobenzene, a solution of 3-methyl-but-2-enoic acid (3-ethyl-phenyl)-amide (57, 10 g, 49.19 mmol} in chlorobenzene was added dropwisc at 0-10 °C. After completion of addition, the mixture was stirred at 110 °C for 2 hours, then cooled down to room temperature and poured into crushed ice.
To this mixture was added 60 mL of 2 M hydrochloric acid solution, followed by extraction with dichloromethane. The organic layers were collected, washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum, The resulting material was purified by recrystallization from ethyl acetate to provide the desired compound as a white solid (58, 9.9 g, 89%).
Step 3 — Preparation of 6-bromo-7-cthyl-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (59):
[0163] To a solution of 7-ethyl-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (58, 3.0 g, 15.0 mmol) in 100 mL of nitromethane, bromine (0.84 mL, 16.0 mmol) was added dropwise, followed by aluminum trichloride (100 mg, 0.7 mmol). The reaction mixture was stirred at room temperature overnight, then poured into ice, extracted with dichloromethane, washed with sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum.
The resulting material was purified by silica gel chromatography, eluting with hexanes and dichloromethane and ethyl acetate to provide the desired compound as a white solid (39, 2.4 g, 58%).
MS (ESI) [M+H"]" = 283.90.
Step 4 — Preparation of 7-acetyl-6-bromo-4,4-dimethyl-3,4-dihydro-1 H-quinolin-2-one (60):
[0164] To a mixture of 6-bromo-7-ethyl-4,4-dimethyl-3,4-dihydro-1 H-quinolin-2-one (59, 1 g, 3 mmol) in 50 mL of dichloromethane, a premixed fine powder of potassium permanganate (4 g, 20.0 mmol) and copper(ID) sulfate pentahydrate (6 g, 20.0 mmol) were added. The reaction mixture was gently refluxed for 72 hours, and then filtered through a Celite pad. The Celite pad was washed with dichloromethane and ether. The organic portions were collected and combined and solvents removed under vacuum. The resulting material was purificd by silica gel chromatography, eluting with hexanes and dichloromethane and ethyl acetate to provide the desired compound as a white solid (60, 0.13 g, 20%). MS (ESI) [M+H']" = 295/297.87.
Step 5 — Preparation of 7-acetyl-6-bromo-1-(2-methoxy-ethyl)-4,4-dimethyl-3,4-dihydro- | H-quinolin- 2-one (62).
[0165] To a solution of 7-acetyl-6-bromo-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (60, 170 mg, 0.57 mmol) in 10 mL of acetonitrile, 1 -bromo-3-methoxy-propane (61, 120 mg, 0.75 mmol), potassium iodide (30 mg, 0.2 mmol) and potassium carbonate (240 mg, 1.7 mmol) were added. The reaction mixture was stirred at 80 °C for 20 hours, then cooled down and poured into water and extracted with ethyl acetate. The organic layers were dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel chromatography, eluting with hexanes/dichloromethane/ethyl acetate to provide the desired compound as a colorless oil (62, 0.11 g, 42%).
Step 6 — Preparation of 7-acetyl-1-(3-methoxy-propyl)-4,4-dimethyl-6-p-tolyl-3,4-dihydro- 1 H- guinolin-2-one (63):
[0166] To a mixture of p-tolyl boronic acid (49, 18 mg, 0.13 mmol), potassium phosphate (37 mg, 0.17 mmol), palladium acetate (4 mg, 0.02 mmol), and diphenyi(t-Bu), (10 mg, 0.03 mmol) in I mL of tetrahydrofuran in a sealed tube, 7-acetyl-6-bromo-1-(2-methoxy-cthyl)-4,4-dimethyl-3,4-dihydro- 1H-quinolin-2-one (62, 32 mg, 0.087 mmol) in 1 mL of tetrahydrofuran was added. The reaction mixture was stirred at 65 °C for 20 hours, then quenched with aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel chromatography, eluting with dichloromethane and methanol to provide the desired compound as a colorless oil (63, 15 mg, 44%). MS (ESI) [M+H']"= 380.05.
Step 7 — Preparation of 7-{1-[(E)-hydroxyimino]-ethyl}-1-(3-methoxy-propyl)-4, 4-dimethyl-6-p-tolyl- 3,4-dihydro-1H-quinolin-2-one (64).
[0167] A solution of 7-acetyl-1-(3-methoxy-propyl)-4,4-dimethyl-6-p-tolyl-3,4-dihydro-1H- quinolin-2-one (63, 19 mg, 0.04 mmol), hydroxylamine (3 mg, 0.09 mmol), and a drop of pyridine in 4 mL of ethanol was stirred at 80 °C for 2 hours. The reaction mixture was concentrated under vacuum and the residue was dissolved in ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was used in next step without further purification.
Step 8a ~ Preparation of 7-(1 -amino-ethyl)- 1-(3-methoxy-propyl)-4,4-dimethyl-6-p-tolyl-3,4-dihydro- 1H-quinolin-2-one (P-0040):
[0168] A mixture of 7-{1-[(E)-hydroxyimino]-ethyl} -1-(3-methoxy-propyl)-4,4-dimethyl-6-p-tolyl- 3,4-dihydro- 1 H-quinolin-2-one (64, 12 mg, 0.02 mmol) and Raney nickel (50%, aqueous slurry) in 5 mL of methanol and 1 mL of ammonium hydroxide was shaken under hydrogen (55 psi) for 4 hours.
The catalyst was removed by filtration and the filtrate was concentrated. The residue was purified by preparative reverse phase HPLC, mobile phase A, 5% of acetonitrile, 95% water, 0.1% acetic acid, and mobile phase B, 95% acetonitrile, 5% of water, 0.1% of acetic acid, to provide the desired compound as a white solid (P-0040, 6 mg, 70%). MS (ESI) [M-NH;]" = 364.00.
Step 8b — Preparation of 1-(1-butyl-4, 4-dimethyl-6-p-tolyl-1,2,3,4-tetrahydro-quinolin-7-yl)- ethylamine (P-0043):
[0169] To a solution of 7-{1-[(E)-hydroxyimino]-cthyl}-1-(3-methoxy-propyl)-4,4-dimethyl-6-p- tolyl-3,4-dihydro-1H-quinolin-2-one (64, 10 mg, 0.02 mmol) in 5 mL of toluene, borane-dimethyl sulfide complex (0.05 mL, 0.6 mmol) was added. The reaction mixture was stirred at 100 °C for 3 hours, then cooled down and poured into 20 mL of 10% aqucous sodium carbonate solution. The mixture was stirred at room temperature for 30 minutes. The organic layer was collected, and the aqueous layer was extracted with ethyl acetate. The combined organic laycrs were washed with brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was separated by preparative TLC, eluting with dichloromethane and methanol to provide the desired compound as a colorless oil (P-0043, 1.1 mg, 20%). MS (ESI) [M+H']" = 367.00.
Example 15: Preparation of 7-(1-amino-cthyl)-6-ethyl-1-(3-methoxy-propyl)-4,4-dimethyl-3,4- dihydro-1H-quinelin-2-one P-0014.
[0170] 7-(1-Amino-ethyl)-6-ethyl-1-(3-methoxy-propyl)-4,4-dimethyl-3,4-dihydro-1H-quinolin-2- one P-0014 was prepared in four steps from 1-(6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7- yl)-ethanone 9 as shown in Scheme 13.
Scheme 15
ON Oo
H 0 J 0 J 0 yee . S step CCC Step 2 “Coc ree Oo 22 9 Br ef 65 66
O- O.
J NO" J NH,
Step 3 Co Step 4 hose 67 P-0014
Step 1 — Preparation f -[6-ethyl-1-(3-methoxy-propyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7- vl]-ethanone (65):
[0171] To a solution of 1-(6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethanone (9, 190 mg, 0.82 mmol) in 10 mL of acctonitrile, 1-bromo-3-methoxy-propane (61, 184 mg, 1.2 mmol), potassium iodide (140 mg, 0.82 mmol) and potassium carbonate (450 mg, 3.3 mmol) were added.
The reaction mixture was stirred at 100 °C for 20 hours, then cooled down and poured into water and extracted with ethyl acetate. The organic layer was dricd over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel chromatography, eluting with hexanes and ethyl acetate to provide the desired compound as yellow oil (65, 84 mg, 34%).
Step 2 — Preparation of 7-acetvl-6-ethyl-1-(3-methoxy-propy 1)-4,4-dimethyl-3,4-dihydro- 1 H- quinolin-2-one (66):
[0172] To a solution of 1-[6-¢thyl-1-(3-methoxy-propyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin- 7-yl]-ethanone (65, 81 mg, 0.27 mmol) in 10 mL of dichloromethane, a premixed fine powder of potassium permanganate (210 mg, 1.3 mmol) and copper(1l) sulfate pentahydrate (330 mg, 1.3 mmol) was added. The reaction mixture was gently refluxed for 3 days. The reaction mixture was filtered through a Celite pad and the pad was washed with dichloromethane and ether. The organic portions were collected and combined, the solvent removed under vacuum, and the residue was purified by silica gel chromatography, eluting with dichloromethane and methanol to provide the desired compound as light yellow oil (66, 50 mg, 60%). MS (ESI) [M+H ] = 318.05.
Step 3 — Preparation of 6-ethyl-7-{1-[(E)-hydroxyimino[-ethyl}-1-(3-methoxy-propyl)-4,4-dimethyl- 3, 4-dihydro-1H-quinolin-2-one (67):
[0173] A solution of 7-acetyl-6-ethyl-1-(3-methoxy-propy 1)-4,4-dimethyl-3,4-dihydro-1H-quinolin- 2-one (66, 0.08 g, 0.1 mmol), hydroxylamine hydrochloride (0.04 g, 0.5 mmol), and pyridine (0.1 mL, 1 mol) in 5 mL of cthanol was stirred at 80 °C for 24 hours. The reaction mixture was concentrated under vacuum and the residue was dissolved in ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and the filtrated concentrated under vacuum. The resulting material was used in the next step without purification.
Step 4 ~ Preparation of 7-(1-amino-ethyl)-6-ethyl-1-(3-methoxy-propyl)-4,4-dimethyl-3,4-dihydro- 1H-guinolin-2-one (P-0014):
[0174] A mixture of 6-ethyl-7-{1-[(E)-hydroxyimino]-ethyl} -1-(3-methoxy-propyl)-4,4-dimethyl- 3,4-dihydro-1H-quinolin-2-one (67, 32 mg, 0.048 mmol) and Raney nickel (50%, aqueous slurry) in 5 mL of methanol and 2 mL of ammonium hydroxide was shaken under hydrogen (55 psi) for 4 hours.
The catalyst was filtered off and the filtratc was concentrated under vacuum. The resulting material was purified by preparative reverse phase HPLC, mobile phase A, 5% acetonitrile, 95% water, 0.1% acetic acid and mobile phase B, 95% acetonitrile, 5% water, 0.1% of acetic acid, to provide the desired compound as a colorless oil (P-0014, 4.3 mg, 28%). MS (ESI) [M+H']" = 319.2.
Example 16: Preparation of | 7-(1-amino-ethyl)-6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinolin- 1-yl]-pyridin-3-yl-methanone P-0018.
[0175] [7-(1-Amino-ethyl)-6-cthyl-4,4-dimethyl-3,4-dihydro-2H-quinolin-1-yl]-pyridin-3-yl- methanone P-0018 was prepared in two steps from nicotinic acid 68 and [1-(6-ethyl-4,4-dimethyl- 1,2,3,4-tetrahydro-quinolin-7-yl)-ethyl]-carbamic acid terr-butyl ester 17 as shown in Scheme 16.
Scheme 16
Boc = | ~ 7 yo ANT {yo Ho Uo NH, oo \ CIC Step 1 CC Step 2 CC ea OF 17 69
P-0018
Step | — Preparation of {1-[6-ethyl-4,4-dimethyl-1-(pyridine-3-carbonyl)-1,2, 3, 4-tetrahydro-quinolin- 7-yl]-ethyl}-carbamic acid tert-butyl ester (69):
[0176] A suspension of nicotinic acid (68, 100 mg, 0.8 mmol) in thionyl chloride (5 mL, 70.0 mmol) was stirred at 85 °C for 2 hours. The excess of thionyl chloride was removed under vacuum, and the residue was dissolved in 5 mL of dichloromethane, to which a mixture of [1-(6-ethyl-4,4- dimethyl-1,2,3 4-tetrahydro-quinolin-7-yl)-cthyl]-carbamic acid tert-butyl ester (17, 60 mg, 0.2 mmol) and N,N-diisopropylethylamine (0.10 mL, 0.6 mmol) in 2 mL of dichloromethane was added.
The reaction mixture was at room temperature for 3 hours, then poured into water and extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, filtercd and the filtrate concentrated under vacuum. The resulting material was purified by silica gel chromatography, eluting with dichloromethane and methanol to provide the desired compound as a light yellow solid (69, 64 mg, 80%). MS (ESI) [M+H']" = 438.70.
Step 2 — Preparation of [7-(1-amino-ethyl)-6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinolin-1-yl]- pyridin-3-yl-methanone (P-0018):
[0177] To a solution of {1-[6-ethyl-4,4-dimethyl-1-(pyridine-3-carbonyl)-1,2,3,4-tetrahydro- quinolin-7-yl]-ethyl}-carbamic acid tert-butyl ester (69) in 3 mL of dichloromethane, a solution of hydrochloric acid (0.2 mL, 4 M in dioxane) in 1 mL of dichloromethane was added. The reaction mixture was at room temperature for 2 hours, then poured into water and extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, filtered and the filtrate concentrated and dried under vacuum to provide the hydrochloric acid salt of the desired compound as a light yellow viscous oil (P-0018, 7 mg, 90%). MS (ESI) [M+H']"= 339.00.
[0178] [7-(1-Amino-cthyl)-6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinolin-1-yl]-pyridin-4-yl- methanone P-0020, and [7-(1-amino-ethyl)-6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinolin-1-yl]- isoxazol-5-yl-methanone P-0022,
UU) N
Lo NH, oho NH;
N N
CCC P-0020, and CoC P-0022,
were prepared similarly to the protocol of Scheme 16, where optimal reaction conditions may have varied, for example, any of time and temperature of the reaction or chromatography conditions for purification of the desired compounds, replacing nicotinic acid 68 with isonicotinic acid and isoxazole-5-carboxylic acid, respectively, in step I. MS (ESI) [M+H] = 338.95 (P-0020); 329.15 (P-0022).
Example 17: Preparation of 1-[1-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-6-ethyl-4,4- dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl]-ethylamine P-0038.
[0179] 1-[1+2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro- quinolin-7-yl]-ethylamine P-0038 was prepared in two steps from [1-(6-ethyl-4,4-dimethyl-1,2,3,4- tetrahydro-quinolin-7-yl)-ethyl]-carbamic acid tert-butyl ester 17 as shown in Scheme 17.
Scheme 17 0 Fol , an A SSON an Boe ol NH,
Oo 17 20H n P-0038
Step 1 — Preparation of {1-[1-(2,2-difluoro-benzof 1,3]dioxol-5-ylmethyl)-6-ethyl-4,4-dimethyl- 1,2, 3 4-tetrahydro-quinolin-7-yl]-ethyl}-carbamic acid tert-butyl ester (71):
[0180] To a mixture of 2,2-difluoro-benzo[1,3]dioxole-5-carbaldehyde (70, 48 mg, 0.26 mmol) and sodium cyanoborohydride (8.1 mg, 0.13 mmol) in 1 mL of tetrahydrofuran in a sealed tube, [1-(6- ethyl-4,4-dimethyl-1,2,3 4-tetrahydro-quinolin-7-yl)-ethyl]-carbamic acid tert-butyl ester (17, 29 mg, 0.086 mmol) in 1 mL of tetrahydrofuran was added. The reaction mixture was stirred at 65 °C for 20 hours, then quenched with aqueous saturated sodium bicarbonate and extracted with ethyl acetate.
The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel chromatography, eluting with hexanes and ethyl acctate to provide the desired compound as a colorless oil (71, 32 mg, 74%).
MS (ESI) [M+H']" = 503.10.
Step 2 Preparation of 1-[1-(2,2-difluoro-benzof 1, 3 ]dioxol-5-ylmethyl)-6-ethyl-4,4-dimethyl-1,2,3, 4- tetrahydro-quinofin-7-yl]-ethylamine (P-0038).
[0181] To {I-[1-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-6-ethyl-4,4-dimethyl-1,2,3,4- tetrahydro-quinolin-7-yl]-ethyl}-carbamic acid rers-butyl ester (71, 32 mg, 0.064 mmol) dissolved in 1 ml. of dichloromethane, hydrochloric acid (0.2 ml, 4.0 M in dioxane) was added and the mixture was stirred at room temperature for 4 hours. The mixture was concentrated under vacuum and the resulting material was purified by silica gel chromatography, eluting with dichleromethane and methanol to provide the desired compound as a pale yellow solid (P-0038, 20 mg, 74%). MS (ESD) [M+H']' = 404.45.
Example 18: Preparation of 1-[6-ethyl-4,4-dimethyl-1-(tetrahydro-pyran-4-ylmethyl)-1,2,3 4- tetrahydro-quinolin-7-yl]-ethylamine P-0058.
[0182] 1-[6-Ethyl-4,4-dimethyl-1-(tetrahydro-pyran-4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-7-yl]- ethylamine P-0058 was prepared in two steps from [1-(6-cthyl-4,4-dimethyl-1,2,3,4-tetrahydro- quinolin-7-yl)-cthyl]-carbamic acid tert-butyl ester 17 as shown in Scheme 18.
Scheme 18 0 an BC | 3 _Boc I$
H HN NH,
N N N
+ Step 1 Step 2 0 17 72 3 P-0058
Step 1 — Preparation of {1-[6-ethyl-4,4-dimethyl-1-(tetrahydro-pyran-4-ylmethyl)-1,2,3,4-tetrahydro- quinolin-7-yl]-ethyl}-carbamic acid tert-butyl ester (73):
[0183] A solution of [1-(6-cthyl-4,4-dimethyl-1,2,3 4-tetrahydro-quinolin-7-yl)-ethyl]-carbamic acid tert-butyl ester (17, 16 mg, 0.048 mmol), iodomethyl tetrahydropyran (72, 13 mg, 0.058 mmol), and diisopropylethylamine in 3 mL of acetonitrile was irradiated in a microwave at 180 °C for 30 minutes. The reaction mixture was concentrated under vacuum and the residue was dissolved in ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum, The resulting material was purified by silica gel chromatography, eluting with hexanes and ethyl acetate to provide the desired compound as a colorless oil (73, 14 mg, 68%). MS (ESI) [M+H']’ = 431.06.
Step 2 — Preparation of I-[6-ethyl-4,4-dimethyl-1-(tetrahydro-pyran-4-ylmethyl)-1,2, 3, 4-tetrahydro- quinolin-7-yl]-ethylamine (P-0058).
[0184] To a solution of {1-[6-ethyl-4,4-dimethyl-1-{tetrahydro-pyran-4-ylmethyl)-1,2,3,4- tetrahydro-quinolin-7-yl]-ethyl} -carbamic acid zerr-butyl ester (73, 85 mg, 0.2 mmol) in 5 mL of acetonitrile, hydrochloric acid (0.2 ml, 4.0 M in dioxane) was added and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under vacuum and the residue was dissolved in ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel chromatography, eluting with dichloromethane and methanol to provide the desired compound as a yellow viscous liquid (P-0058, 52 mg, 74%). MS (ESI) [M+H']" = 330.95.
Example 19: Preparation of 7-(1-amino-ethyl)-6-ethyl-4,4-dimethyl-1-(2-methyl-pyridin-4- ylmethyl)-3,4-dihydro-1H-quinolin-2-one P-0061,
[0185] 7-(1-Amino-ethyl)-6-ethyl-4 4-dimethyl-1-(2-methyl-pyridin-4-ylmethyl)-3,4-dihydro-1H- quinolin-2-one P-0061 was prepared in three steps from [1-(6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro- quinolin-7-yl)-ethyl]-carbamic acid tert-butyl! ester 17 as shown in Scheme 19.
Scheme 19
SN SN ~N _Boc Boc | _Boc o
H HN Cy on of Z NH,
N oe H N Os N RS 7 Re S 2 x Y 17 49 4 7s P-0061
Step I — Preparation of {1-6-ethyl-4,4-dimethyl-1-(2-methyl-pyridin-4-ylmethyl)-1,2,3,4-tetrahydro- quinolin-7-yl]-ethyl}-carbamic acid tert-butyl ester (74):
[0186] To a mixture of 2-methylpyridine-4-carbaldehyde (49, 100 mg, 0.8 mmol) and [1-(6-ethyl- 4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethyl]-carbamic acid rert-butyl ester (17, 100 mg, 0.3 mmol) in 3 mL ethanol:acetic acid (95:5), sodium cyanoborohydride (50 mg, 0.8 mmol) was added.
The reaction mixture was irradiated at 120 °C for 30 minutes, then concentrated under vacuum. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel chromatography, eluting with dichloromethane and methanol to provide the desired compound as a colorless oil (74, 40 mg, 30%). MS (ESI) [M+H™" = 439.00.
Step 2 — Preparation of {1-[6-ethyl-4,4-dimethyl-1-(2-methy l-pyridin-4-yimethyl)-2-oxo-1,2,3,4 - tetrahydro-quinolin-7-yl[-ethyl }-carbamic acid tert-butyl ester (75):
[0187] To a solution of {1-[6-ethyl-4,4-dimethyl-1-(2-methyl-pyridin-4-ylmethy!)-1,2,3,4- tetrahydro-quinolin-7-yl]-ethyl} carbamic acid tert-butyl ester (74, 20 mg, 0.044 mmol) in 10 mL of dichloromethane, a fine powder pre-mixturc of potassium permanganate (25 mg, 0.16 mmol) and copper(ll) sulfate pentahydrate (39 mg, 0.16 mmol) was added. The reaction mixture was gently refluxed for 2.5 hours, then filtered through a Celite pad and the Celite residue was washed with dichloromethane and ether. The organic portions were collected and combined, the solvents removed under vacuum, and the residue purified by silica gel chromatography, eluting with dichloromethane and methanol to provide the desired compound as a light yellow oil (75, 7 mg, 35%). MS (ESI) [M+H"]" = 452.15.
Step 3 — Preparation of 7-(1-amino-ethyl)-6-ethyl-4,4-dimethyl-1-(2-methyl-pyridin-4-ylmethyl)-3,4- dihydro-1H-quinolin-2-one (P-0061):
[0188] A solution of {1-[6-ethyl-4,4-dimethyl-1-(2-methy l-pyridin-4-ylmethyl)-2-oxo0-1,2,3,4 - tetrahydro-quinolin-7-ylJ-ethyl} -carbamic acid tert-butyl ester (75, 7 mg, 0.016 mmol) in 5 mL of dichloromethane, hydrogen chloride (0.1 mL, 3 mmol) was added. The mixture was stirred at room temperature for 1.5 hours, then concentrated under vacuum and the residue was purified by reverse phase HPLC, mobile phase A, 5% acetonitrile, 95% water, and mobile phase B, 95% acetonitrile, 5% water, to provide the desired compound as a light yellow solid (P-0061, 1.6 mg, 28%). MS (ESI) [M+H']" = 352.3.
Example 20: Preparation of 6-(1-amino-ethyl)-7-ethyl-4-(2-methoxy-ethyl)-4H- benzo[1,4]oxazin-3-one P-0071,
[0189] 6-(1-Amino-ethyl)-7-ethyl-4-(2-methoxy-ethyl)-4H-benzo[1,4]oxazin-3-one P-0071 was prepared in seven steps from N-(4-acetyl-2-hydroxyphenyl) acetamide 80 as shown in Scheme 20.
Scheme 20 0 0 H 0
Ty sy pe ser PC EOI se OS odo — AT ISON ai 0 0 76 77 8 79 “ 80 81 0. Ow Ou
OH
Step 5 J 0 J N J NH,
So OC TOOL Sm SC ~0™Br No 0 0 61 82 83 P-0071
Step 1 Preparation of N-(4-ethyl-2-hydroxy-phenyl)-acetamide (77):
[0190] A mixture of N-(4-acetyl-2-hydroxyphenyl) acetamide (76, 12.00 g; 62.0 mmol) and trifluoroacetic acid (46.8 mL, 0.62 mol) was cooled down to 0°C in an ice water bath. To this suspension, triethylsilane (22.4 mL, 0.14 mol) was added. The reaction mixture was stirred at room temperature for 64 hours, then poured into 750 mL of ice water. The precipitated solid was collected by filtration, washed with water and dissolved in 150 mL of ethyl acetate. Thc organic solution was washed with 30 mL of water and 50 mL of brine, then dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum to provide crude compound as a beige solid, which was used in the next step without further purification.
Step 2 — Preparation of 2-amino-5-ethyl-phenol (78):
[0191] To N-(4-ethyl-2-hydroxy-phenyl)-acetamide (77, 10 g, 34.0 mmol) in 70 mL of ethyl acetate, 12.5 mL of water was added. The mixture was stirred vigorously and hydrochloric acid (30 ml, 0.99 mol) was added and the mixture was heated at reflux for 17 hours. The reaction mixturc was cooled down to 0 °C in an ice water bath, and the pH of the solution was adjusted to 7 by addition of aqueous sodium bicarbonate. The organic phase was separated and the aqueous phase was washed with 2x 100 mL of ethyl acetate. The organic extracts were combined, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel chromatography, eluting with ethyl acetate to provide the desired compound as a dark beige solid.
Step 3 — Preparation of 7-ethyl-4H-benzof 1,4] oxazin-3-one (80).
[0192] To a solution of 2-amino-5-ethyl-phenol (78, 2.40 g, 17.5 mmol) in 145 mL of acetonitrile, 2-chloroacetyl chloride (79, 1.5 mL, 19.2 mmol) was added dropwise, followed by potassium carbonate (6.28 g, 45.5 mmol). The reaction mixture was heated at reflux for 2 hours, then cooled down to room temperature. The mixture was filtered and the solid washed with 50 mL of acetonitrile.
The filtrates were combined and concentrated under vacuum, The residue was dissolved in 120 mL of dichloromethane, washed with 150 mL of water, dried over magnesium sulfate, filtered and the filtrated concentrated under vacuum. The resulting material was purificd by flash silica gel column chromatography, eluting with hexane and ethyl acetate. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a beige solid (80, 1.2 g, 40%).
Step 4 — Preparation of G-acetyl-7-ethyl-4[-benzo[ 1,4] oxazin-3-one (81).
[0193] To aluminium chloride (229 mg; 1.7 mmol), cooled in an ice water bath, 52 pL of dimethylformamide was added dropwise. The mixture was stirred at 10 °C for | hour, then heated to 50 °C. To this mixture, 7-ethyl-4H-benzo[1,4]oxazin-3-one (80, 50 mg, 0.28 mmol) was added, followed by 28 pL of acctyl chloride. The mixture was stirred at 50-70 °C for 20 minutes, then cooled down to room temperature and the melt was taken up in 1 mL of toluene and quenched with 3 g of ice. The mixture was stirred for 30 minutes until all of the ice melted. The mixture was extracted 2 x 5 mL with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by flash silica gel column chromatography, eluting with dichloromethane and hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a pale yellow solid (81, 6 mg, 10%)
Step 5 — Preparation of 6-acetyl-7-ethyl-4-(3-methoxy-propyl}-4H-benzof I 4] oxazin-3-one (82):
[0194] To 6-acetyl-7-cthyl-4H-benzo[1,4)oxazin-3-one (81, 120 mg, 0.55 mmol) in 6 mL of acetonitrile, |-bromo-3-methoxy-propane (61, 210 mg, 1.37 mmol), potassium fluoride on alumina (412 mg, 2.84 mmol), and potassium iodide (5 mg, 0.03 mmol) were added. The mixture was stirred at 80 °C for 3 hours, then cooled down to room temperature. The inorganic material was filtered off and the filtrate was concentrated under vacuum. The residue was purified by flash silica gel column chromatography, eluting with ethyl acetate and hexanc. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a colorless oil (82, 120 mg, 78%).
Step 6 — Preparation of 7-ethyl-6-{1-[(E)-hydroxyimino]-ethyl}-4-(3-methoxy-propyl)-4H- benzo[l,4]oxazin-3-one (83).
[0195] To 6-acetyl-7-ethyl-4-(3-methoxy-propyl)-4H-benzo[ 1,4]oxazin-3-one (82, 122 mg, 0.42 mmol) in § mL of ethanol, hydroxylamine hydrochloride (58 mg, 0.84 mmol) and pyridine (73 mg, 0.92 mmol) were added. The mixture was stirred at 80°C for 2 hours, then cooled down to room temperature and concentrated. The residue was purified by flash silica gel column chromatography, eluting with ethyl acetate and hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a white solid (83, 30 mg, 23%).
Step 7 ~ Preparation of 6-(1-amino-ethyl)-7-ethyl-4-(2-methoxy-ethyl)-4H-benzo/ 1,4] oxazin-3-one (P-0071):
[0196] A mixture of 7-ethyl-6-{1-[(E)-hydroxyimino]-ethyl}-4-(3-methoxy-propyl)-4H- benzo[1,4]oxazin-3-one (83, 7 mg, 0.02 mmol) and Raney nickel (50%, aqueous slurry) in 5 mL of methanol and 2 mL of ammonium hydroxide was shaken under hydrogen (55 psi) for 4 hours. The catalyst was filtered off and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography, cluting with dichloromethane and methanol to provide the desired compound as a colorless oil (P-0071, 4 mg, 70%). MS (ESI) [M+H']" = 280.00.
Example 21: Preparation of 1-(6-ethyl-4,4-dimethyl-1-phenyl-1,2,3 4-tetrahydro-quinolin-7-yl)- ethylamine P-0070.
[0197] 1-(6-Ethyl-4,4-dimethyl-1-phenyl-1,2,3 4-tetrahydro-quinolin-7-yl)-ethylamine P-0070 was prepared in three steps from 1-(6-cthyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethanone 9 as shown in Scheme 21.
Scheme 21
SC, ©, ©
H 0 0 ! 1 NH,
N BOM): step 1 Nu Step 2 Step 3 + ni | I» — > / 9 84 85 86 P-0070
Step 1 — Preparation of 1-(6-ethyl-4,4-dimethyl-1-phenyl-1,2,3, 4-tetrahydro-quinolin-7-yl)-ethanone (85):
[0198] A mixture of 1-(6-ethyl-4,4-dimethyl-1,2,3 4-tetrahydro-quinolin-7-yl)-ethanone (9, 62 mg, 0.27 mmol), phenylboronic acid (84, 49 mg, 0.4 mmol), cupric acetate (80 mg, 0.4 mmol),
triethylamine (0.06 mL, 0.4 mmol), and molecular sieves (powder) in 10 mL of dichloromethane was stirred at 35 °C for 22 hours. The residue was dissolved in ethyl acetate, washed with water and brine, and dried over magnesium sulfate. The mixture was filtered, the filtrated concentrated under vacuum and the residue was purified by silica gel chromatography, eluting with hexanes and ethyl acetate to provide the desired compound as a pale yellow oil (85, 20 mg, 20%). MS (ESI) [M+H' = 308.52
Step 2 — Preparation of 1-(6-ethyl-4,4-dimethyl-1-phenyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethanone oxime (86):
[0199] A solution of 1-(6-ethyl-4,4-dimethyl-1-phenyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethanone (85, 51 mg, 0.13 mmol), hydroxylamine hydrochloride (30 mg, 0.4 mmol), and pyridine (0.1 mL, 1 mmol) in 10 mL of ethanol was stirred at 90 °C for 5 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water and brine, and dried over magnesium sulfate. The mixture was filtered, the filtrated concentrated and dried under vacuum, The resulting material was used in the next step without further purification.
Step 3 — Preparation of 1-(6-ethyl-4, 4-dimethyl-1-phenyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethylamine (P-0070):
[0200] A mixture of 1-(6-ethyl-4,4-dimethyl-1-phenyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethanone oxime (86, 40 mg, 0.1 mmol) and Raney nickel (50%, aqueous slurry) in 5 mL of methanol and 2 mL of ammonium hydroxide was stirred under an hydrogen balloon for 3 hours. The mixture was filtere and the filtrate was concentrated under vacuum. The resulting material was purified by silica gel chromatography, eluting with dichloromethane and methanol to provide the desired compound as a pale yellow oil (P-0070, 25 mg, 80%). MS (ESI) [M+H'T" = 309.90.
[0201] 1-[6-Ethyl-1-(3-methoxy-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl]-ethylamine
P-0079, l
LSI
CIC was prepared similarly to the protocol of Scheme 21, replacing phenylboronic acid 84 with 3- methoxy-phenylboronic acid in step 1, where optimal reaction conditions may have varied, for example, any of time and temperature of the reaction, or chromatography conditions for purification of the desired compound, MS (ESI) [M+H']"= 339.25.
Example 22: Preparation of C-[6-ethyl-1-(3-methoxy-propyl)-4,4-dimcthyl-1,2,3,4-tetrahydro- quinolin-7-yl]-methylamine P-0008.
[0202] C-[6-Ethyl-1-(3-methoxy-propyl)-4,4-dimethyl-1,2,3 4-tetrahydro-quinolin-7-yl]- methylamine P-0008 was prepared in three steps from 7-bromo-6-ethyl-4,4-dimethyl-1,2,3,4- tetrahydroquinoline 11 (see Scheme 2) as shown in Scheme 22.
Scheme 22
Bd | 5
RB i ~ or ON ~ 11 A oe LI 87 88 P-0008
Step 1 — Preparation of 7-bromo-6-ethyl-1-(3-methoxy-propyl)-4,4-dimethyl-1,2,3,4-tetrahydro- quinoline (87):
[0203] To 7-bromo-6-ethyl-4.4-dimethyl-1,2,3, 4-tetrahydro-quinoline (11, 500.00 mg, 1.86 mmol) in 5.00 mL of acetonitrile, potassium carbonate (260 mg, 1.9 mmol) and 1-bromo-3-methoxy-propane (61, 0.86 g, 5.6 mmol) were added and the reaction stirred for 2 days at 100 °C. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 1% ethyl acetate in hexane. Appropriate fractions were combined and solvents removed under vacuum to provide the desired compound (87, 513 mg) as a light orange oil. MS (EST) [M+H']" = 342.
Step 2 — Preparation of 6-ethyl-1-(3-methoxy-propyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-7- carbonitrile (88).
[0204] To 7-bromo-6-ethyl-1-(3-methoxy-propyl )-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline (87, 25.00 mg, 0.073 mmol) in 1.2 mL of N-methylpyrrolidone, zinc cyanide (9.5 mg, 0.081 mmol) and a catalytic amount of 4% tetrakis(triphenylphosphine)palladium(0) were added. The reaction was microwaved on 60 watts, 175 °C for 3 minutes. The organic layer was washed with brine, dried, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 5% ethyl acetate in hexane. Appropriate fractions were combined and solvents removed under vacuum to provide the desired compound (88, 16 mg). MS (ESI) [M+H']" = 287.
Step 3 — Preparation of C-[6-eihyl-1-(3-methoxy-propyl)-4.4-dimethyl-1,2, 3, 4-tetrahydro-quinolin-7- yi]-methylamine (P-0008):
[0205] 6-Ethyl-1-(3-methoxy-propyl)-4,4-di methyl-1,2,3,4-tetrahydro-quinoline-7-carbonitrile (88, 21.0 mg, 0.073 mmol) in 5.00 mL of methanol was degassed with nitrogen. Hydrochloric acid (0.0045 mL, 0.15 mmol) and a catalytic amount of palladium on carbon were added and the reaction was stirred in a hydrogenation apparatus at 50 psi for 3 hours. The reaction was filtered through celite and the filter rinsed with methanol. The filtrate was combined and concentrated under vacuum to solid, which was purificd by silica gel column chromatography eluting with 5% methanol in dichloromethane. Appropriate fractions were combined and solvents removed under vacuum to provide the desired compound (P-0008, 8 mg). MS (ESI) [M+H']" = 291.
Example 23; Preparation of 7-(1-amino-ethyl)-6-methoxy-1-(3-methoxy-propyl)-4,4-dimethyl- 3,4-dihydro-1H-quinolin-2-one P-0013.
[0206] 7-(1-Amino-ethyl)-6-methoxy-1-(3-methoxy-propyl)-4,4-dimethyl-3,4-dihydro-1H- quinolin-2-one P-0013 was prepared in five steps from 3-methyl-but-2-enoic acid (4-methoxy- phenyl)-amide 93 as shown in Scheme 23.
Scheme 23 0
N H 0 H Step 3
Oo N — oF NH Step! Step 2 + _ — _— 0” Br >"0 89 O 61 90 91
Oo. 4 0 0 1 o | n-CH L NH,
ON Step4 Oy N | Steps Og N 0” 0” 0” 92 23 P-0013
Step 1 — Preparation of 6-methoxy-4,4-dimethyl-3,4-dihydro-1 H-quinolin-2-one (90):
[0207] Aluminum trichloride (10.4 g, 77.9 mmol) was suspended in 100 mL of 1,2-dichloroethane and 3-methyl-but-2-enoic acid (4-methoxy-phenyl)-amide (89, 5.16 g, 25.1 mmol) was added dropwise over a period of ~5 minutes. The reaction mixture was stirred under an inert atmosphere for 4 hours and partitioned between ethyl acetate and water. The organic layer was collected and the aqucous layer was washed 3x with cthyl acetate. The organic fractions were pooled and washed with water, sodium bicarbonate solution and brine, then dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting yellow oil was purified by silica gel column chromatography, eluting with ethyl acetate and hexane. Appropriate fractions were collected and the solvents removed under vacuum to provide the desired compound as a light pink solid (90, 4.05 g). "H NMR was consistent with the compound structure.
Step 2 — Preparation of 7-acetvl-6-methoxy-4,4-dimethyl-3,4-dihydro-1 H-quinolin-2-one (91):
[0208] To a suspension of aluminum trichloride (2.9 g, 22.0 mmol) in 8 mL of nitromethane, chilled to 0 °C, a solution of acetyl chloride (0.48 ml, 6.8 mmol) and 6-methoxy-4,4-dimethyl-3,4- dihydro-1H-quinolin-2-one (90, 1.00 g, 4.87 mmol) in 10 mL of dichloromethane was added dropwise. Once addition was complete, the reaction was removed from the ice bath and stirred at room temperature for 4-5 hours. The reaction mixture was re-cooled to 0 °C and water was added dropwise, resulting in heat and foaming, until all solids were dissolved. The mixture was extracted with 100 mL of dichloromethane, and the organic layer was washed with water, ammonium chloride solution and brine, then dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting oil was purificd by silica gel column chromatography, eluting with gradient of 0-5% methanol in dichloromethane over 40 minutes. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound. "H NMR was consistent with the compound structure.
Step 3 — Preparation of 7-acetyl-6-methoxy-1-(3-methoxy-propyl)-4,4-dimethyl-3,4-dihydro-1 H- quinolin-2-one (92):
[0209] To a solution of 7-acetyl-6-methoxy-4,4-dimethyl-3,4-dihydro-1 H-quinolin-2-one (91, 261.00 mg, 1.055 mmol) in 3.0 mL of N,N-dimethylformamide, 1-bromo-3-methoxy-propane (61, 190 mg, 1.3 mmol) was added, followed by sodium hydride (33 mg, 1.4 mmol). The reaction mixture was heated in the microwave at 107 °C for 20 minutes. The reaction mixture was quenched with watcr and extracted 2x with dichloromethane. The combined organic layer was washed 2x with water, then with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum.
The resulting material was purified by silica gel column chromatography eluting with 5-40% ethyl acctate in hexane. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (92, 156 mg). 'H NMR was consistent with the compound structure.
Step 4 — Preparation of 7-{1-[(E)-hydroxyimino]-ethyl}-6-methoxy-1-(3-methoxy-propyl)-4,4- dimethyl-3,4-dihydro- 1 H-quinolin-2-one (93):
[0210] A solution of 7-acetyl-6-methoxy-1-(3-methoxy-propyl)-4,4-dimethyl-3,4-dihydro-1H- quinolin-2-one (92, 38 mg, 0.12 mmol), hydroxylamine hydrochloride (16.9 mg, 0.243 mmol), and pyridine (0.046 mL, 0.57 mmol) in 5 mL of ethanol was stirred at 80 °C for 2 hours. The reaction mixture was concentrated under vacuum and the residue was dissolved in ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum.
The resulting material was used for the next step without further purification (93, 45 mg). MS (ESI) [M+H'T" = 335.2.
Step 5 — Preparation of 7-(1-amino-ethyl)-6-methoxy-1-(3-methoxy-propyl)-4,4-dimethyl-3,4-dihydro-
IH-gquinolin-2-one (P-0013):
[0211] To a solution of 7-{1-[(E)-hydroxyimino]-ethyl}-6-methoxy-1-(3-methoxy-propyl)-4,4- dimethyl-3,4-dihydro-1H-quinolin-2-one (93, 63.00 mg, 0.188 mmol) in 5.0 mL of toluene, borane- dimethyl sulfide complex (0.026 mL, 0.30 mmol) was added slowly at 0 °C. The reaction mixture was stirred at 0 °C for 15 minutes and then stirred at 100 °C for 1.5 hours. The reaction mixture was cooled down and poured into 150 mL of 10% aqueous sodium carbonate solution. The mixture was stirred at room temperature for 30 minutes. The organic layer was removed and the aqucous layer extracted with 2 x 60 mL of cthyl acetate, The organic layers were combined and dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound (P-0013, 12 mg).
Example 24: Preparation of 1-[1-(3-methoxy-propyl)-4,4-dimethyl-6-phenyl-1,2,3,4-tetrahydro- quinolin-7-yl]-ethylamine P-0021.
[0212] 1-[1-(3-Methoxy-propyl)-4,4-dimethyl-6-phenyl-1,2,3,4-tetrahydro-quinolin-7-yl]- ethylamine P-0021 was prepared in four steps from trifluoro-methanesulfonic acid 7-acetyl-4,4- dimethyl-1-(2,2,2-trifluoro-acetyl)-1,2,3,4-tetrahydro-quinolin-6-y! ester 35 (see Scheme 8) as shown in Scheme 24.
Scheme 24
Fang © o B(OH), y o Re
Soh Ge Gy me
OTF + 35 84 94 O Br "07 61 95 O 6
Ue CL ,
Step 3 ~N Step 4 AN == 96 P-0021
Step 1 — Preparation of 1-(4,4-dimethyl-6-phenyi-1,2,3,4-tetrahydro-quinolin-7-yl)-ethanone (94):
[0213] Into a round bottom flask, triflucro-methanesulfonic acid 7-acetyl-4,4-dimethyl-1-(2,2,2- triflucro-acetyl)-1,2,3 4-tetrahydro-quinolin-6-y! ester (34 mg, 0.076 mmol), was combined with potassium carbonate (44 mg, 0.32 mmol), phenylboronic acid (84, 20 mg, 0.0002 mol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol), and 1.5 mL of water. The reaction was microwaved on 60 watts, 100°C for 10 minutes. Solvents were removed under vacuum and the residue extracted with cthyl acetate and saturated bicarbonate, then washed with brine. The solvents were removed from the organic layer and the residue purified by silica gel column chromatography eluting with hexanes:ethyl acetate 80:20. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (98, 19.5 mg). MS (ESI) [M+H"]" = 280.1.
Steps 2-4
[0214] 1-(4,4-Dimethyl-6-phenyl-1,2,3 4-letrahydro-quinolin-7-yl)-ethanone 94 was reacted similarly to steps 5-7 of Scheme 14 above to provide the desired compound 1-[1-(3-Methoxy-propyl)- 4,4-dimethyl-6-phenyl-1,2,3,4-tetrahydro-quinolin-7-yl]-ethylamine P-0021. MS (ESI) [M+H']" = 353.1.
Example 25: Preparation of 1-(1-benzyl-4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)- ethylamine P-0076.
[0215] 1-(1-Benzyl-4,4,6-trimethyl-1,2 3 4-tetrahydro-quinolin-7-yl)-ethylamine P-0076 was prepared in nine steps from 3-methyl-but-2-enoic acid p-tolylamide 101 as shown in Scheme 25.
Scheme 25
F,C._O
H H H TY
Ox N Step 1 OxN step2 oN Step 3 N —_— ee Tm
JO TIL CI a7 98 29 100
Step 6
F,C._O H a. LJ
Step 4 T Br Step 5 CCC pe CC Step 7
ES 102 Br 23 103 r _ 0 JOH J NH
N Step 8 N steps pn 2 pe N x x “ = ’ / 104 N 105 P-0076
Step | — Preparation of 4,4,6-Trimethyl-3,4-dihydro-1 H-quinolin-2-one (98).
[0216] Aluminum trichloride (11 g, 84.0 mmol) was suspended in 30 mL of nitromethane and 3- methyl-but-2-enoic acid p-tolylamide (97, 5.3 g, 28.0 mmol, prepared similarly to step 1 of Scheme 1, substituting 4-ethylaniline 1 with p-tolylamine) was added portionwise over a period of ~5 minutes.
The reaction mixture was stirred under an inert atmospherc at 80 °C for 12 hours, then partitioned between ethyl acetate and water. The organic layer was collected and the aqueous layer was washed additional 3x with ethyl acetate. The organic fractions were pooled and washed with water, aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum, The resulting yellow oil was purified by silica gel column chromatography eluting with ethyl acetate and hexane. The appropriate fractions were combined and solvents removed under vacuum to provide the desired compound as an off-white solid (98, 705 mg). 'H NMR was consistent with the compound structure. Additional material was prepared similarly for the next step.
Step 2 — Preparation of 4,4,6-Trimethyl-1,2,3,4-tetrahydro-quinoline (99):
[0217] To a solution of 4,4,6-trimethyl-3,4-dihydro-1H-quinolin-2-one (98, 3.86 g, 20.4 mmol) in 150 mL of toluene, borane-dimethyl sulfide complex (3.6 mL, 41.0 mmol) was added slowly at 0 °C.
The reaction mixture was stirred at 0 °C for 15 minutes and then stirred at 100 °C for 2 hours. The reaction mixture was cooled down and poured into 150 mL of aqueous 10% sodium carbonate solution. The mixture was stirred at room temperature for 30 minutes and the organic layer was collected. The aquous layer was extracted with 2 x 60 mL of ethyl acetate and the organic layers were combined and dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The residue was purified by silica gel chromatography to provide the desired compound as a light brown liquid (99, 2.3 g). '"H NMR was consistent with the compound structure.
Step 3 — Preparation of 2,2,2-Trifluoro-1-(4,4,6-trimethyl-3,4-dihydro-2H-quinolin-1-yl)-ethanone (100):
[0218] In areaction vessel, 4,4,6-trimethyl-1,2,3 4-tetrahydro-quinoline (99, 2.25 g, 12.8 mmol) was dissolved in 25.0 mL of dichloromethane and triethylamine (2.70 mL, 19.0 mmol) was added and the reaction stirred for a couple of minutes. Trifluoroacetic anhydride (2.20 mL, 15.0 mmol) in 5 mL of dichloromethane was then added and the reacion stirred for 3-4 hours. The reaction was diluted with additional dichloromethane, washed with water, then brine, and the organic solvents removed under vacuum. The resulting residue was purified by silica gel column chromatography cluting with 10% ethyl acetate in hexane. Appropriate fractions were combined and the solvents removed to provide the desired compound (100, 2.6 g).
Step 4 — Preparation of 1-(7-bromo-~4.4, 6-trimethyl-3,4-dihydro-2H-quinolin-1-yl)-2,2, 2-trifluoro- ethanone (101);
[0219] Into a reaction vessel, 2,2,2-trifluoro-1-(4,4,6-trimethyl- 3,4-dihydro-2H-quinolin-1-yl)- ethanone (100, 0.500 g, 1.84 mmol) and aluminum trichloride (0.24 g, 1.8 mmol) were combined in 10.0 mL of nitromethane. Bromine (0.125 ml, 2.43 mmol) was added dropwise at 0 °C and the reaction went overnight. The reaction was diluted with water, extracted with ether, and the organic laycr was washed with brine, then concentrated under vacuum. ‘The residue was purified by silica gel column chromatography, eluting with 0-5% ethyl acetate in hexane. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (101, 410.0 mg).
Step 5 — Preparation of 7-bromo-4,4,6-trimethyl-1,2,3,4-tetrahydro-quinoline (102):
[0220] 1-(7-bromo-4,4,6-trimethyl-3,4-dihydro-2H-quinolin-1-yl1}-2,2 2 -trifluoro-ethanone 101 was reacted similarly to step 6 of Scheme 1 to provide the desired compound.
Step 6 — Preparation of 1-benzyl-7-bromo-4,4,6-trimethyl-1,2,3,4-tetrahydro-quinoline (103).
[0221] A solution of 7-bromo-4,4,6-trimethyl-1,2,3 4-tetrahydro-quinoline (102, 249.1 mg, 0.98 mmol), benzyl bromide (23) and N,N-diisopropylethylamine (0.34 mL, 2.0 mmol) in 2 mL of N- methylpyrrolidone was heated at 80 °C overnight. The reaction mixture was partitioned between water and ethyl acetate and the organic layer was washed with brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The residue was purified by silica gel column chromataography, eluting with 0-25% ethyl acetate in hexanes. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (103, 177 mg).
Step 7 — Preparation of 1-(l-benzyl-4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethanone (104).
[0222] 1-Benzyl-7-bromo-4,4,6-trimethyl-1, 2,3 4-tetrahydro-quinoline (103, 177.0 mg, 0.514 mmol), was mixed with 1,3-bis(diphenylphosphino)propane (13 mg, 0.032 mmol), potassium carbonate (73.2 mg, 0.530 mmol), tributyl-(1-ethoxy-vinyl)-stannane (0.61 mL, 1.8 mmol), and palladium acetate (3.0 mg, 0.013 mmol) in 1.0 mL of water and 3.0 ml. of N,N-dimethylformamide under nitrogen and heated at 80 °C overnight. The reaction was cooled to room temperature and diluted with ethyl acetate, and the organic layer then washed with water, brine and concentrated under vacuum. The residue was purified by silica gel chromatography to provide the desired compound (104, 35 mg). '"H NMR was consistent with the compound structure.
Step 8 — Preparation of [-(1-benzyl-4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethanone oxime (105): 10223] 1-(1-Benzyl-4,4,6-trimethyl-1,2,3.4 -tctrahydro-quinolin-7-yl)-cthanone (104, 35.00 mg, 0.114 mmol), hydroxylamine hydrochloride (16 mg, 0.23 mmol), and pyridine (0.018 mL, 0.23 mmol) in 15 mL of ethanol was stirred at 80 "C for 3 hours. The reaction mixture was concentrated under vacuum and the residue dissolved in ethyl acetate, washed with water and brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum and the residue was purified by silica gel chromatography to provide the desired compound as a light vellow glue (105, 19 mg). 'H NMR was consistent with the compound structure.
Step 9 Preparation of 1-(I-benzyl-4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethylamine (P-0076).
[0224] 1-(1-Benzyl-4,4 6-trimethyl-1,2,3,4 -tetrahydro-quinolin-7-yl)-ethanone oxime (105, 19.0 mg, 0.059 mmol) was dissolved in 10 mL of ethanol in a parr vessel. Raney nickel (0.05 g, 0.8 mmol) was added and the vessel evacuated and charged with hydrogen (10 g, 5 mol, 55 PSI). The reaction mixture was shaken for 120 minutes. The raney nickel was removed via filtration and the filtrate concentrated under vacuum to provide the desired compound as a yellow, waxy solid (P-0076, 3.0 mg). 'H NMR was consistent with the compound structure. MS (ESI) [M+H']" = 308.2.
Example 26: Preparation of 7-(1-amino-ethyl)-1-benzyl-4,4-dimethyl-6-p-tolyl-3 4-dihydro-1H- quinolin-2-one P-0078,
[0225] 7-(1-Amino-ethyl)-1-benzyl-4,4-dimethyl-6-p-tolyl-3,4-dihydro-1H-quinolin-2-one P-0078 was prepared in four steps from 7-acetyl-6-bromo-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one 60 as shown in Scheme 26.
Scheme 26
OQ Step? Q oH Q stept of ep 0 +
Br 0 Br . Cl 60 Br 23 106 107 108
Ho B-oH
Q ou Q NH,
Os N w Ul
P-0078
Step 1 — Preparation of 7-acetyl-1-benzyl-6-bromo-4,4-dimethyl-3,4-dihydro-1 H-quinolin-2-one (106):
[0226] Into a quartz vial 7-acetyl-6-bromo-4,4-dimethyl-3,4-dihvdre-1H-quinelin-2-one (60, 25 mg, 0.083 mmol, see Scheme 14) was dissolved in 5S mL of acetonitrile (5S mL, 0.1 mol) and benzyl bromide (23, 0.015 mL, 0.12 mmol), potassium carbonate (40.0 mg, 0.29 mmol) and potassium iodide (4 mg, 0.02 mmol) were added. The reaction was stirred at 80 °C over the weekend, then poured into water and extracted 2x with ethyl acetate. All organic layers were combined, washed with brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with 10-35% ethyl acetate in hexane.
Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound as a light yellow solid (106, 33 mg, purity 98%, yield 98%).
Step 2 — Preparation of 7-acetyl-1-benzyl-4,4-dimethyl-6-p-tolyl-3,4-dihydro- 1 H-quinolin-2-one (108):
[0227] Into a quartz vial, 7-acetyl-1-benzyl-6-bromo-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (106, 28.0 mg, 0.0725 mmol) was mixed with 2.00 mL of tetrahydrofuran and 0.08 mL of dimethyl sulfoxide, then p-tolyl boronic acid (107, 15 mg, 0.11 mmol), palladium acetate (3 mg, 0.01 mmol), diphenyl(t-Bu), (9 mg, 0.03 mmol) and potassium phosphate (31 mg, 0.14 mmol) were added. The reaction was microwaved at 150 watts, 70 °C for 80 minutes. The reaction was diluted with ethyl acetate, extracted with sodium chloride solution, the organic layer dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The residue was purified by silica gel chromatography to provide the desired compound (108, 10 mg, purity 50%, yield 20%). MS (ESI) [M+H']" = 398.8.
Step 3 — Preparation of 1-benzyl-7-{1-[(E)-hydroxyimino]-ethyl}-4,4-dimethyl-6-p-tolyl-3,4-dihvdro- 1H-quinolin-2-one (109):
[0228] A solution of 7-acetyl-1-benzyl-4,4-dimethyl-6-p- tolyl-3,4-dihydro-1H-quinolin-2-one (108, 24 mg, 0.024 mmol), hydroxylamine hydrochloride (50 mg, 0.7 mmol), and pyridine (0.5 mL, 6.0 mmol) in 5 mL of ethanol was stirred at 80 °C overnight. The reaction mixture was concentrated under vacuum. The residue was dissolved in ethyl acelale, washed with water and brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound as a white solid (109, 24 mg, purity 40%), which was used in the next step without further purification. MS(ESI) [M+H']" = 413.89, 413.13.
Step 4 — Preparation of 7-(1-amino-ethyl)- 1-benzyl-4,4-dimethy!-6-p-tolyl-3,4-dihydro-1 H-quinolin-2- one (P-0078):
[0229] A mixture of 1-benzyl-7-{1-[(E)-hydroxyimino]-ethy!}-4,4-dimethyl-6-p-tolyl-3,4-dihydro- 1H-quinolin-2-one (109, 55 mg, 0.053 mmol) and Raney nickel (50%, aqueous slurry) in 15 mL methanol and 2.0 mL of ammonium hydroxide was stirred under an atmosphere of hydrogen for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by HPLC to provide the desired compound as a white solid (P-0078, 7.5 mg, purity >95%, yield 34%). MS(ESD) [M-NH, | = 383.05.
Example 27: Preparation of 7-(1-amino-ethyl)-6-cthyl-4,4-dimethyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid tert-butyl ester P-0069.
[0230] 7-(1-Amino-ethyl)-6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert- butyl ester P-0069 was prepared in two steps from 7-acetyl-6-ethyl-4,4-dimethyl-3,4-dihydro-2H- quinoline-1-carboxylic acid tert-butyl ester 14 as shown in Scheme 27.
Scheme 27 0.0 Y Oo Y
Y R 05 © no" Y He
N Step1 _N Step2 [ ~~
EE EE = 14 110 P-0069
Step 1 — Preparation of 6-ethyl-7-(1-hydroxyimino-ethyl)-4,4-dimethyl-3, 4-dihydro-2H-quinoline-1- carboxylic acid tert-butyl ester (110):
[0231] A solution of 7-acetyl-6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (14, 500.00 mg, 1.509 mmol, sec Scheme 2), hydroxylamine hydrochloride (300 mg, 4.0 mmol), and pyridine (0.6 mL, 8.0 mmol) in 35 mL of ethanol was stirred at 80 °C for 3 hours. The reaction mixture was concentrated under vacuum and the residue was dissolved in ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and the filtrate removed under vacuum. The resulting material was purified by silica gel chromatography to provide the desired compound as a white solid (110, 484 mg, purity >95%, yield 88%). MS (ESI) [M+H']" = 347.05.
Step 2 — Preparation of 7-(1-amino-ethyl)-6-ethyl-4,4-dimethyl-3,4-dihydro-2 H-quinoline-1- carboxylic acid tert-butyl ester (P-0069):
[0232] A mixture of 6-ethyl-7-(1-hydroxyimino-ethyl)-4,4-dimethyl-3,4-dihydro-2H-quinoline-1- carboxylic acid tert-butyl ester (110, 390.0 mg, 1.126 mmol) and Raney nickel (50%, aqueous slurry) in 50 mL of methanol and 15 mL of ammonium hydroxide was shaken under hydrogen (55 psi) for 4 hours. The reaction was filtered and the filtrate was concentrated under vacuum. The resulting material was purified by silica gel chromatography eluting with dichloromethane and methanol to provide the desired compound as a colorless oil (P-0069, 317 mg, yield 80.5%). MS (ESI) [M+H']" = 334.05.
Example 28: Synthesis of Compounds where L, is -S(0),- or -S(0),NH-.
[0233] Compounds of Formula I'V having a sulfone linker (or aminosulfone) at the 1-position can be prepared as exemplified from [1-(6-cthyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethyl]- carbamic acid tert-butyl ester 17. Compounds are prepared in two steps as shown in Scheme A.
Scheme A
R_O Boc RO ’ ane Ro “§=0 HN” 5=0 NH,
N + SC Step AS Step 2 N cro — | a — = i 17 In v
Step | — Preparation of Compounds of Formula III:
[0234] A mixture of sulfonyl chloride of Formula II (R is e.g. NHR' or R', where R' is as defined in paragraph [0003]), [1-(6-ethyl-4,4-dimethyl-1,2,3 4-tetrahydro-quinolin-7-yl)-ethyl]-carbamic acid tert-butyl ester (17), and an appropriate base, such as triethyl amine in an appropriate solvent, such as dichloromethane is stirred at 20-80 °C for 2-24 hours. The reaction is quenched with an aqueous work-up and purified by silica gel chromatography or crystallization to provide Compounds of
Formula IIL.
Step 2 — Preparation of Compounds of Formula IV:
[0235] A compound of Formula III is stirred in a suitable solvent, such as dioxane, tetrahydrofuran or dichloromethane with a suitable acid, such as hydrochloric acid, trifluoroacetic acid, or tosic acid at 0-80 °C for 0.25-24 hours. The reaction mixture is quenched with aqueous base and purified by silica gel chromatography or crystallization to provide a compound of Formula IV.
Example 29: Synthesis of Compounds where L, is -NH-, -NHS(O),- or -NHC(Q)-.
[0236] Compounds of Formula VIII having either -NHS(O),- or -NHC(O)- linker at the 1-position can be prepared, for cxample, in five steps from 1-(6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin- 7-yl)-ethanone 9 as shown in Scheme B.
Scheme B
H 0 Noo NH: 0 steps
N N N —_—
OC 2 COC m2 CC
R'Cl +
S 111 112 Y
RN
Rr! ~OH R'
NH 0 “NH N “NH NH,
N )
CoC Step 4 Cac Step 5 = > a vi vii Vill
Step | — Preparation of 1-(6-cthyl-4,4-dimethyl-1-nitraso-1,2,3,4-tetrahydro-quinolin-7-yl)-ethanone (111):
[0237] To a mixture of 1-(6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethanone (9) and a solution hydrochloric acid, cooled with an ice water bath, a solution of sodium nitrite is slowly added. The reaction mixture is then allowed to warm to room temperature and warmed for a few hours as needed. The reaction mixture is extracted with an appropriate solvent (such as cthyl acctate or toluene). The organic layer is collected, washed with water and dried over sodium sulfate. After removal of drying agent and solvent, the residue is dried under vacuum to provide the desired compound 111 that can be used without purification in the next step.
Step 2 — Preparation of 1-(1-amino-6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethanone (112):
[0238] To a solution of 1-(6-ethyl-4,4-dimethyl-1-nitroso-1,2,3,4-tetrahydro-quinolin-7-yl)- ethanone (111) in an appropriate solvent (such as tetrahydrofuran), a suspension of lithium aluminum hydride in an appropriate solvent (such as tetrahydrofuran) is added. The temperature can be maintained by use of an ice water bath. The reaction mixture is poured into water, extracted with an appropriate solvent (such as ethyl acetate or dichloromethane), and the organic layer is collected, washed with water and dried over sodium sulfate. After removal of drying agent and solvent, the residue is dried under vacuum to provide the desired compound 112 that can be used without purification in the next step.
Step 3 — Preparation of Compounds of Formula VI:
[0239] To a mixture of 1-(1-amino-6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-cthanone (112) and a base (such as triethylamine or potassium carbonate) in an appropriate solvent (such as dichloromethane or acetonitrile), organo-halide, acid halide, or sulfonyl halide of Formula V (R’ is e.g. R'-, R'-C(0)- or R'-S(0),-, where R' is as defined in paragraph [0003]) is slowly added. The reaction mixture is stirred at room temperature or heated in an oil bath for 2 to 24 hours. The reaction mixture is poured into water and extracted with an appropriate solvent (such as dichloromethane or ethyl acetate). The organic layer is collected, washed with saturated sodium bicarbonate solution and brine, and dried over magnesium sulfate. After removal of drying agent and solvent, the residue can be purified by silica gel chromatography to provide the desired compound of Formula VL
Step 4 — Preparation of Compounds of Formula VII:
[0240] A mixture of a compound of Formula VI, hydroxylamine hydrochloride, and pyridine in ethanol is stirred at 80-100 °C for 2-24 hours. The reaction mixture is concentrated and the residue dissolved in an appropriate solvent such ethyl acetate, washed with water and brine, and dried over magnesium sulfate. After removal of drying agent and solvent, the residue can be purified by silica gel chromatography to provide the desired compound of Formula VIL
Step 5 — Preparation of Compounds of Formula VIII:
[0241] A mixture of a compound of Formula VII, Raney nickel, and ammonium hydroxide in methanol! is stirred under an atmosphere of hydrogen gas for 0.5-20 hours. The catalyst is removed by filtration and the filtrate concentrated under reduced pressure. The residue can be purified by silica gel chromatography to provide the desired compound of Formula VIIL
[0242] Similar compounds with substituents other than ethyl at the 6 position, e.g. optionally substituted aryl, can be prepared similarly, for example, by replacing 1-(6-ethyl-4,4-dimethyl-1,2,3,4- tetrahydro-quinolin-7-yl)-ethanone 9 in step 1 with a suitable compound, including, but not limited to, 1-[6-(4-fluoro-phenyl)-4,4-dimethyl-1,2,3 4-tetrahydro-quinolin-7-yl]- ethanone 38 and similar compounds formed in the reaction Scheme 9 of Example 9; 1-(6-benzyloxy-4,4-dimethyl-1,2,3,4- tetrahydro-quinolin-7-yl)-ethanone 42 formed in the reaction Scheme 10 of Example 10; 1-(4,4- dimethyl-6-p-tolyl-1,2,3 4-tetrahydro-quinolin-7-yl)-ethanone 50 formed in the reaction Scheme 12 of
Example 12; 6-acctyl-7-ethyl-4H-benzo[1,4]oxazin-3-one 81 formed in the reaction Scheme 21 of
Example 21; 7-acetyl-6-methoxy-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one 91 formed in the reaction Scheme 23 of Example 23; and 1-(4,4-dimethyl-6-phenyl-1,2,3 4-tetrahydro-quinolin-7-yi)- cthanone 94 formed in the reaction Scheme 24 of Example 24.
Example 30: Synthesis of Compounds where L, is -NHC(O)NH-,
[0243] Compounds of Formula XII where L; is -NHC(O)NH- are prepared, for example, in three steps from 1-(1-amino-6-ethyl-4,4-dimcthyl-1,2,3,4-tctrahydro-quinolin-7-yl)-cthanone 112 as shown in Scheme C.
Scheme C
R'NH R'NH R'NH ki 0 - oA WH 0 on No oP NH NH,
IX
112 X xi xii
Step 1 ~ Preparation of Compounds of Formula X:
[0244] To a mixture of 1-(1-amino-6-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-cthanone (112) and a base (such as triethylamine, potassium carbonate) in an appropriate solvent (such as dichloromethane or acetonitrile) an isocyanate of Formula IX (R** is R' as defined in paragraph
[0003]) is slowly added. The reaction mixture is stirred at room temperature or heated in an oil bath for 2 to 24 hours. The reaction mixture is poured into water and extracted with an appropriate solvent (such as dichloromethane or ethyl acetate). The organic layer is collected, washed with saturated sodium bicarbonate solution and brine, and dried over magnesium sulfate. After removal of drying agent and solvent, the residue can be purified by chromatography to provide the desired compound of
Formula X.
Step 2 — Preparation of Compounds of Formula XI:
[0245] A solution of a compound of Formula X, hydroxylamine hydrochloride, and pyridine in ethanol is stirred at 80-100 °C for 2-24 hours. The reaction mixture is concentrated and the residue dissolved in an appropriate solvent such as ethyl acetate, washed with water and brine, and dried over magnesium sulfate. After removal of drying agent and solvent, the residue can be purified by silica gel chromatography to provide the desired compound of Formula XI.
Step 3 — Preparation of Compounds of Formula XII:
[0246] A mixture of a compound of Formula XI, Raney nickel, and ammonium hydroxide in methanol is stirred under a hydrogen balloon for 0.5-20 hours. The catalyst is removed by filtration and the filtrate is concentrated. The residue can be purified by chromatography to provide the desired compound of Formula XII.
[0247] Similar compounds with substituents other than ethyl at the 6 position, e.g. optionally substituted aryl, can be prepared similarly, for example, by replacing 1-(1-amino-6-ethyl-4,4- dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-ethanone 112 in step 1 with the product of step 1 of
Scheme B made by replacing 1-(6-ethyl-4,4-dimethyl-1,2,3 4-tetrahydro-quinolin-7-yl)-ethanone 9 with a suitable compound as described in Example 30.
Example 31: Synthesis of Compounds where -R” is alkyl.
[0248] Compounds of Formula XVI where R**" is alkyl (i.e. R* of Formula I, paragraph [0003] is alkyl) are prepared, for example, in five steps from 7-acctyl-4,4-dimcthyl-1-(2,2,2-trifluoro-acetyl)- 1,2,3,4-tetrahydro-quinolin-6-yl ester 35 as shown in Scheme IV.
Scheme IV
F,C. 0
YY oO H oO ! 0
N Step 1 N x Step 2 Sy oTf Pom 1 7 0Tf
IN \ R'-Ci ' 113 Xi is 0 Ry HON Ry NH,
N
Step 3a Step 4 steps [1 or R™" Rr" m——- Rr"
Step 3b ) / mS Xv XV Xvi
Step 1 — Preparation of trifluoro-methanesulfonic acid 7-acetyl-4,4-dimethyl-1,2,3,4-tetrahydro- quinolin-6-yl ester (113):
[0249] To a solution of 7-acctyl-4,4-dimethyl-1-(2,2,2-trifluoro-acetyl)-1,2,3,4-tctrahydro-quinolin- 6-yl ester (35, 110 mg, 0.25 mmol) in 3 mL of acetonitrile was added 1.5 mL of 2 M potassium carbonate in water. The reaction mixture was stirred at room temperature for 10 h and was concentrated under reduced pressure. The residue was partioned between ethyl acetate and water and the organic layer was dried over sodium sulfate. The solution was filtered and the filtrate concentrated under vacuum to provide the desired compound as a colorless oil (113, 57 mg, 65%).
Step 2 — Preparation of Compounds of Formula XIII
[0250] A mixture of trifluoro-methanesulfonic acid 7-acetyl-,4,4-dimethyl-1,2,3 4-tetrahydro- quinolin-6-yl ester (113), a halide such as R'-C1 (R' as defined in paragraph [0003]), a suitable base such as potassium carbonate, pyridine or diisopropylethylamine in a suitable solvent such as acetonitrile or tetrahydrofuran is stirred at a temperature below 80 °C for 1-36 hours. The reaction mixture is concentrated under reduced pressure and partitioned between an organic solvent such as ethyl acetate and an aqueous solution. The organic layer is dried over an anhydrous salt, filtered, concentrated and subjected to silica gel chromatography to provide the desired compound of Formula
XIII.
Step 3a — Preparation of Compounds of Formula XIV:
[0251] A mixturc of a compound of Formula XIII, a terminal alkync or olefin, a suitable ligated palladium catalyst (Cul and an amine solvent such as triethylamine for alkyne) in a suitable solvent such or tetrahydrofuran is stirred at a temperature below 80 °C for 1-36 hours. The reaction mixture is concentrated under reduced pressure and partitioned between an organic solvent such as ethyl acetate and an aqueous solution. The organic layer is dried over an anhydrous salt, filtered, concentrated and subjected to silica gel chromatography to provide the alkyne or olefin intermediate, which can be reduced to the corresponding saturated alkyl compound of Formula XIV by treatment with a transition metal catalyst such as palladium, nickel or platinum under a hydrogen atmosphere.
Step 3b — Preparation of Compounds of Formula XIV:
[0252] A mixture of a compound of Formula XIII, an alkyl tin compound for Stille cross-coupling, or an alkyl boronic acid, ester or alkyl! trifluorcborate salt for Suzuki cross-couplings, and a suitable ligated palladium catalyst in a suitable solvent such or tetrahydrofuran is stirred at a temperature below 80 °C for 1-36 hours. The reaction mixture is concentrated under reduced pressure and partitioned between an organic solvent such as cthyl acetate and an aqueous solution. The organic layer is dried over an anhydrous salt, filtered, concentrated and subjected to chromatography to provide the desired compound of Formula XIV. Note, vinyl tin and vinyl boronate reagents can also be employed to form olefin compounds. These olefin products can be reduced to the corresponding saturated alkyl compound of Formula XIV by treatment with a transition metal catalyst such as palladium, nickel or platinum under a hydrogen atmosphere.
Step 4— Preparation of Compounds of Formula XV:
[0253] A solution of a compound of Formula XIV, hydroxylamine hydrochloride, and pyridine in ethanol is stirred at 80-100 °C for 2-24 hours. The reaction mixture is concentrated and the residue dissolved in an appropriate solvent such as cthyl acetate, washed with water and brine, and dried over magnesium sulfate. After removal of drying agent and solvent, the residue can be purified by silica gel chromatography to provide the desired compound of Formula XV.
Step 5 —~ Preparation of Compounds of Formula XVI:
[0254] A mixture of a compound of Formula XV, Raney nickel, and ammonium hydroxide in methanol is stirred under a hydrogen balloon for 0.5-20 hours. The catalyst is removed by filtration and the filtrate is concentrated. The residue can be purified by chromatography to provide the desired compound of Formula XVI
Example 32: Enzyme Activity Assays
[0255] Assays for the activity of proteases, including, but not limited to, renin, pepsin, cathepsinD and BACE are known in the art. Examplary biochemical assays used to asscss the activity of compounds of the invention are described as follows.
[0256] Renin protease activity is assessed in a FRET (Fluorescent resonance energy transfer) screen.
The substrate peptide is linked to a Fluorescent probe (Hilyte Fluor 488) on one end and a quencher on the other end (QXL). In the absence of an inhibitor, protease such as renin will cleave the peptide and the fluorescence signal will increase. ICs, values are determined with respect to inhibition of renin activity, where inhibition of cleavage of the peptide substrate is measured as a function of compound concentration. Compounds to be tested were dissolved in DMSO to a concentration of 20 mM. These were diluted 30 pL into 120 pL of DMSO (4 mM) and 1 pL was added to an assay plate.
These were then serially diluted 1:3 (50 pL to 100 pL. DMSQ) for a total of 8 points. Plates were prepared such that each protease reaction is 20 pL in 1x protease buffer (25 mM Hepes, pH 7.4, 100 mM Nacl, 0.01%BSA, 0.01% Tween-20), 5% DMSO. Substrate was 2 uM Hilyte Fluor 488 -Arg- lle-His-Pro-Phe-His-Leu-Val-lle-His-Thr-Lys (QX1.-520)Arg-NH, (Anaspec, Inc.). Renin was at 4 ng per sample. The protease reaction was incubated for 210 minutes at 30 °C, and the signal per well was read on a Tecan Saffire reader. The fluorescence signal was measured and the signal vs. compound concentration was used to determine the ICs.
[0257] Porcine pepsin protease activity is assessed in a FRET screen similarly to that for renin.
Compounds to be tested were dissolved in DMSO to a concentration of 20 mM. These were diluted pL into 120 pL of DMSO (4 mM) and 1 pL was added to an assay plate. These were then serially diluted 1:3 (50 pL to 100 nL DMSO) for a total of 8 points. Plates were prepared such that each protease reaction is 20 nL in 1x protease buffer (50 mM Sodium Acetate, pH 3.5, 150 mM Nacl, 0.01%BSA, 0.01% Tween-20), 5% DMSO. Substrate was 4 uM Hilyte Fluor 488 -Glu-Dap-Lys-Pro-
Ile-Leu-Phe-Phe-Arg-Leu-Gly-Lys--Glu (QX1.-520)Glu-NH; (Anaspec, Inc.). Porcine pepsin was at 0.5 ng per sample. The protease reaction was incubated for 30 minutes at 30 °C and the signal per well was read on a Tecan Saffire reader. The fluorescence signal was measured and the signal vs. compound concentration was used to determine the ICs.
[0258] CathepsinD protease activity is assessed in a FRET screen similarly to that for renin.
Compounds to be tested were dissolved in DMSO to a concentration of 20 mM. These were diluted 30 pL into 120 nL of BMSO (4 mM) and 1 pl. was added to an assay plate. These were then serially diluted 1:3 (50 pL to 100 pL. DMSO) for a total of 8 points. Plates were prepared such that each protease reaction is 20 pL in 1x protease buffer (50 mM Sodium Acetate, pH 3.5, 150 mM Nacl, 0.01%BSA, 0.01% Tween-20), 5% DMSO. Substrate was 4 uM Hilyte Fluor 488 -Glu-Dap-Lys-Pro-
Ile-Leu-Phe-Phe-Arg-Leu-Gly-Lys--Glu (QX1.-520)Glu-NH, (Anaspec, Inc.). CathepsinD was at 0.15 ng per sample. The protease reaction was incubated for 60 minutes at 25 °C and the signal per well was read on a Tecan Saffire reader. The fluorescence signal was measured and the signal vs. compound concentration was used to determine the ICs.
[0259] BACE protease activity is assessed in a FRET screen similarly to that for renin. Compounds to be tested were dissolved in DMSO to a concentration of 20 mM. These were diluted 30 pL into 120 pL of DMSO (4 mM) and 1 pl. was added to an assay plate. These were then serially diluted 1:3 (50 nL to 100 pL. DMSO) for a total of 8 points. Plates were prepared such that each protease reaction is 20 pL in 1x protease buffer (50 mM Sodium Acetate, pH 4.5, 150 mM Nac], 0.01%BSA, 0.01% Tween-20), 5% DMSO. Substrate was 4 uM Hilyte Fluor 488 -Ser-Glu-Val-Asn-Leu-Asp-
Ala-Glu-Phe-Lys (QXL-520)Glu-NH; (Anaspec, Inc.). BACE was at 8 ng per sample. The protease reaction was incubated for 210 minutes at 30 °C and the signal per well was read on a Tecan Saffire reader. The {luorescence signal was measured and the signal vs. compound concentration was used to determine the ICs.
[0260] Compounds having ICs, of less than 10 uM in a renin biochemical assay as described above are listed in the following table: ] P-0002, P-0003, P-0005, P-0006, P-0009, P-0010, P-0014, P-0015, P-0016,
P-0017, P-0019, P-0021, P-0023, P-0025, P-0026, P-0027, P-0028, P-0029,
Renin <10 uM P-0030, P-0031, P-0032, P-0033, P-0034, P-0035, P-0036, P-0037, P-0039,
P-0040, P-0041, P-0042, P-0043, P-0044, P-0045, P-0046, P-0047, P-0048,
P-0049, P-0050, P-0051, P-0052, P-0053, P-0054, P-0055, P-0056, P-0057,
P-0059, P-0060, P-0061, P-0062, P-0063, P-0065, P-0066, P-0067, P-0068
[0261] Compounds were selective with respect to other proteases, as none of the compounds screened in a BACE or porcine pepsin assay as described above showed measureable inhibition up to 200 uM. Compounds having 1Csg between 10 uM and 100 uM in a cathepsinD biochemical assay as described above are listed in the following table:
P-0067, P-0068
[0262] All patents and other references cited in the specification are indicative of the level of skill of those skilled in the art to which the invention pertains, and are incorporated by reference in their entireties, including any tables and figures, to the same extent as if each reference had been incorporated by reference in its entirety individually.
[0263] One skilled in the art would readily appreciate that the present invention is well adapted to obtain the ends and advantages mentioned, as well as those inherent therein. The methods, variances, and compositions described herein as presently representative of preferred embodiments are exemplary and are not intended as limitations on the scope of the invention. Changes therein and other uses will occur to those skilled in the art, which are encompassed within the spirit of the invention, are defined by the scope of the claims.
[0264] The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. Thus, for example, in each instance herein any of the terms “comprising”, “consisting cssentially of” and “consisting of” may be replaced with either of the other two terms. Thus, for an embodiment of the invention using one of the terms, the invention also includes another embodiment wherein one of these terms is replaced with another of these terms. In cach embodiment, the terms have their established meaning. Thus, for example, one embodiment may encompass a method “comprising” a series of steps, another embodiment would encompass a method “consisting essentially of” the same steps, and a third embodiment would encompass a method “consisting of” the same steps. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.
[0265] In addition, where features or aspects of the invention are described in terms of Markush groups or other grouping of alternatives, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group or other group.
[0266] Also, unless indicated to the contrary, where various numerical values are provided for embodiments, additional embodiments arc described by taking any 2 different values as the endpoints of a range. Such ranges are also within the scope of the described invention.
[0267] Thus, additional embodiments are within the scope of the invention and within the following claims.
Claims (9)
1. A compound having the chemical structure of Formula I, 1 i " NH, RY N X5 R? FCC RS Y Z R* n Formula I or a salt, a prodrug, a tautomer or a stereoisomer thereof, wherein: X, and X,; are independently -N= or -C(H)=; nisQorl; L, is a bond, -C(R’R'’)-, -C(0)-, -C(R’R'")-C(R''R")-, -C(R’R'")-C(O)-, -C(0)-C(R'R"?)-, -C(0)-N(R")-, -N(R")-C(0), -S(0)2-N(R")-, -N(R")-8(0)s, -N(R")-C(0)-NR")-, or -N(R™)-8(0)-N(R")-: Y is -0- or -C(R"'R"%)-; R'is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with onc or more substituents R*, and wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents R*; R? and R? are independently hydrogen, lower alkyl, -R'®, or -[C(R'7R'®)],-L,-[C(R""R**)],-R"®, wherein lower alkyl is optionally substituted with one or more substituents R*’; or R’ and R' combine with the carbon to which they are bound to form a 3-7 membered cycloalkyl or a 5-7 membered monocyclic heterocycloalkyl, wherein the 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH,, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; ais 1, 2, or 3; bis0, 1,2, or 3; L, is a bond, -O-, -S-, -N(R")-, -C(0)-NR")-, -NR")-C(0), -C(S)-N(R")-, -NR')-C(S)-, -S(0)-N(R")-, -5(0)-N(R")-, -N(R”)-S(0), -N(R")-S(0);, -NR")-C(O)-N(R")-, NR™)-C(S)-N(R)-, or -N(R"*)-S(0),-N(R")-;
R'® is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents R*%;
R*is -R* or -L;-R*;
Ls is -O-, -S-, or -N(R')-;
R* is (CR¥R™),-R™, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents R*;
pis1,2,3,4,5or6;
R’, and R® are independently hydrogen, fluoro, lower alkyl, fluoro substituted lower alkyl, phenyl, or benzyl, wherein the phenyl ring of phenyl or benzyl is optionally substituted with one or more substituents R*":
R” and R® are independently hydrogen, fluoro, lower alkyl, fluoro substituted lower alkyl, phenyl, or benzyl, wherein the phenyl ring of phenyl or benzyl is optionally substituted with one or more substituents R*'; or
R" and R® together form oxo;
R’,R', R'", R"%, and each R* and R® arc independently hydrogen, fluoro, lower alkyl, or fluoro substituted lower alkyl; or
R’and RY, or R" and R" or any two R* and R* on the same carbon, combine with the carbon to which they are bound to form a 3-7 membered cycloalkyl or a 5-7 membered monocyclic heterocycloalkyl, wherein the 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH,, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino;
cach R" is independently hydrogen or lower alkyl;
R" and R" are independently hydrogen, fluoro, lower alkyl, or fluoro substituted lower alkyl;
RY R"™ R" and R” are independently hydrogen, fluoro, lower alkyl, or fluoro substituted lower alkyl; or any two R' and R" on the same carbon, or any two R'® and R?® on the same carbon, combine with the carbon to which they are bound to form a 3-7 membered cycloalkyl or a 5-7 membered monocyclic heterocycloalkyl, wherein the 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NIi,, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; or any two R'7 and R'® on the same carbon, or any two R" and R* on the sam carbon form 0X0;
R* is selected from the group consisting of hydrogen, fluoro, -0-R%, -S-R*, -N(R**)-R*, -C(0)-R*, -C(8)-R™, -S(0)-R*, -S(0),-R*, -C(0)-0-R*?, -C(0)-N(R*)-R¥, -C(S)-N(R™)-R™, -S(0)-N(R**)-R*, -S(0),-N(R**)-R*, -N(R**)-C(0)-R*, -N(R*¥)-C(S)-R*, N(R?)-S(0)-R¥, -N(R*)-S(0),-R*, -N(R*)-C(0)-N(R")-R*, -N(R**)-C(S)-N(R*)-R™, N(R¥)-S(0),-N(R*™)-R™, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents R*”;
each R* and R, if present, is independently selected from the group consisting of fluoro, -O-R*, -S-R™, and -N(R*)-R";
cach R*®, R®, R”, R¥ and RY, if present, is independently selected from the group consisting of -CN, -NO;, -0-R*” -S-R*!, -N(R*)-R*, -C(0)-R*, -C(S)-R", -S(Q)-R*, -8(0),-R*, -C(0)-0-R*, -C(0)-N(R¥)-R®, -C(S)-N(R*)-R*, -S(0)-N(R**)-R*, -S(0),-N(R**)-R*, N(R*¥)-C(0)-RY, -NR™-C(S)-RY, -N(R™)-S(0)-R*, -N(R*¥)-S(0),-R", NR?)-C(0)-NR¥)-R¥, -N(R¥)-C(S)-N(R**)-R*, -N(R*?)-S(0),-N(R*)-R*, 0x0, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R*®, R*®, R*’, R* or R*', or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -CN, -NO,, -0-R%, .8.R*™, N(R*)-RY, -N(R¥)-C(0)-R¥, -N(R*)-8(0),-R*, -C(0)-R*, -S(0)-R*, -S(0),-R*, -C(0)-0-R¥, -C(0)-N(R*)-R*, -S(0),-N(R*)-R*¥, oxo, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; or any two R*, any two R*, any two R”, any two R”, or any two R*', on adjacent ring atoms, combine to form a fused ring selected from the group consisting of 3-7 membered cycloalkyl and 5-7 membered heterocycloalkyl, wherein the 3-7 membered cycloalkyl or 5-7 membered heterocycloalkyl are optionally substituted with one or more halogen, -OH, -NH., oxo, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino;
each R* R*, R* and R* is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocyeloalkyl, aryl, and heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R¥ RY R¥ or RY, or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -CN, -NO,, -O-R*, -S-R* -N(R*)-R*, -N(R¥)-C(0)-R*, N(R*)-8(0),-R*, -C(0)-R*, -8(0)-R*, -S(0),-R*, -C(0)-0-R*, -C(0)-N(R*)-R¥, -$(0),-N(R*)-R*, 0x0, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; each R* and R* is independently selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono- alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R* or RY or as a substituent of lower alkyl arc optionally substituted with one or more substituents selected from the group consisting of -CN, -NO,, -O-R*, -S-R* -N(R*)-R®, -N(R*)-C(0)-R*, -N(R**)-S(0),-R*, -C(0)-R*, -S(0)-R*, -S(0),-R¥, -C(0)-0-R¥, -C(O)-N(R*™)-R¥, -$(0),-N(R*)-R*¥, 0x0, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; each R* is hydrogen or lower alkyl; each R* and R" is independently hydrogen, lower alkyl, or fluoro substituted lower alkyl, each R*® is lower alkyl or fluoro substituted lower alkyl: each R* and R* is independently selected from the group consisting of hydrogen, lower alkyl, heterocycloalkyl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono- alkylamino, di-alkylamino, and cycloalkylamino, and wherein heterocycloalkyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy and fluoro substituted lower alkoxy; and each R* is independently selected [rom the group consisting of lower alkyl, heterocycloalkyl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, and wherein heterocycloalkyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy and fluoro substituted lower alkoxy.
2. A compound of claim 1, wherein X; is -C(H)= and X; is -N=, and Y is -O- or -C(R"*R")-, preferably -C(R*R™)-.
3. A compound of claim 2, wherein nis 1 and Y is -C(R"*R")-.
4. A compound of claim 2, wherein nis 1 and Y is -O-.
5. A compound of any of claims 1-4, wherein L; is a bond, -C(R°R'Y)-, -C(Q)-, -C(R'R')-C(R''R")-, -C(R'R")-C(O)-, or -C(0)-C(R''R"%) and R' is phenyl or monocyclic heteroaryl, wherein phenyl or monocyclic heteroaryl are optionally substituted with one or more substituents R*®,
6. A compound of any of claims 1-3 and 5, wherein Y is -C(R'*R"*)- and R'* and R" are independently lower alkyl or fluoro substituted lower alkyl.
7. A composition comprising a pharmaceutically acceptable carrier; and a compound according to any of claims 1-6.
8. A method for treating a subject suffering from or at risk of a renin-mediated disease or condition, comprising administering to the subject an effective amount of a compound of any of claims 1-6 or a composition of claim 7.
9. A kit comprising a compound according to any of claims 1-6 or a composition of claim 7.
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008063888A2 (en) | 2006-11-22 | 2008-05-29 | Plexxikon, Inc. | Compounds modulating c-fms and/or c-kit activity and uses therefor |
US20100190777A1 (en) | 2007-07-17 | 2010-07-29 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
WO2009143018A2 (en) | 2008-05-19 | 2009-11-26 | Plexxikon, Inc. | Compounds and methods for kinase modulation, and indications therefor |
EP2296653B1 (en) | 2008-06-03 | 2016-01-27 | Intermune, Inc. | Compounds and methods for treating inflammatory and fibrotic disorders |
ES2627911T3 (en) | 2009-11-18 | 2017-08-01 | Plexxikon, Inc. | N- [2-Fluoro-3- (4-amino-7H-pyrrolo [2,3-d] pyrimidin-5-carbonyl) -phenyl] -4-benzenesulfonamide derivatives as modulators of the Raf protein kinase for the treatment of Cancer |
CN102753549A (en) | 2009-12-23 | 2012-10-24 | 普莱希科公司 | Compounds and methods for kinase modulation, and indications therefor |
US8598156B2 (en) | 2010-03-25 | 2013-12-03 | Glaxosmithkline Llc | Chemical compounds |
TWI619713B (en) | 2010-04-21 | 2018-04-01 | 普雷辛肯公司 | Compounds and methods for kinase modulation, and indications therefor |
MA34948B1 (en) | 2011-02-07 | 2014-03-01 | Plexxikon Inc | COMPOUNDS AND METHODS FOR MODULATING KINASE, AND INDICATIONS THEREOF |
GB201106817D0 (en) | 2011-04-21 | 2011-06-01 | Astex Therapeutics Ltd | New compound |
RU2631487C2 (en) | 2011-05-17 | 2017-09-22 | Плексксикон Инк. | Kinases modulation and indications for its use |
CN102993094B (en) * | 2011-09-08 | 2014-07-23 | 中国石油大学(北京) | Synthesizing method of tetrahydroquinoline derivative |
US9358235B2 (en) | 2012-03-19 | 2016-06-07 | Plexxikon Inc. | Kinase modulation, and indications therefor |
TW201414734A (en) | 2012-07-10 | 2014-04-16 | Takeda Pharmaceutical | Azaindole derivatives |
JP6318156B2 (en) | 2012-09-06 | 2018-04-25 | プレキシコン インコーポレーテッドPlexxikon Inc. | Compounds and methods for modulating kinases and indicators thereof |
AR092742A1 (en) | 2012-10-02 | 2015-04-29 | Intermune Inc | ANTIFIBROTIC PYRIDINONES |
GB201218850D0 (en) | 2012-10-19 | 2012-12-05 | Astex Therapeutics Ltd | Bicyclic heterocycle compounds and their uses in therapy |
US9980973B2 (en) | 2012-10-19 | 2018-05-29 | Astex Therapeutics Limited | Bicyclic heterocycle compounds and their uses in therapy |
GB201218862D0 (en) | 2012-10-19 | 2012-12-05 | Astex Therapeutics Ltd | Bicyclic heterocycle compounds and their uses in therapy |
GB201218864D0 (en) | 2012-10-19 | 2012-12-05 | Astex Therapeutics Ltd | Bicyclic heterocycle compounds and their uses in therapy |
PL2935248T3 (en) | 2012-12-21 | 2018-07-31 | Plexxikon Inc | Compounds and methods for kinase modulation, and indications therefor |
US20140303121A1 (en) | 2013-03-15 | 2014-10-09 | Plexxikon Inc. | Heterocyclic compounds and uses thereof |
CA2903293C (en) | 2013-03-15 | 2020-10-13 | Plexxikon Inc. | Heterocyclic compounds and uses thereof |
US9181272B2 (en) | 2013-04-30 | 2015-11-10 | Boehringer Ingelheim International Gmbh | Aldosterone synthase inhibitors |
CA2912568A1 (en) | 2013-05-30 | 2014-12-04 | Plexxikon Inc. | Compounds for kinase modulation, and indications therefor |
AU2014338549B2 (en) | 2013-10-25 | 2017-05-25 | Novartis Ag | Ring-fused bicyclic pyridyl derivatives as FGFR4 inhibitors |
MY186311A (en) | 2013-12-20 | 2021-07-08 | Astex Therapeutics Ltd | Bicyclic heterocycle compounds and their uses in therapy |
WO2015106012A1 (en) | 2014-01-09 | 2015-07-16 | Takeda Pharmaceutical Company Limited | Azaindole derivatives |
WO2015134536A1 (en) | 2014-03-04 | 2015-09-11 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
CA2943363A1 (en) | 2014-04-02 | 2015-10-08 | Intermune, Inc. | Anti-fibrotic pyridinones |
JP6832846B2 (en) | 2014-09-15 | 2021-02-24 | プレキシコン インコーポレーテッドPlexxikon Inc. | Heterocyclic compounds and their uses |
US20180185341A1 (en) | 2014-10-03 | 2018-07-05 | Novartis Ag | Use of ring-fused bicyclic pyridyl derivatives as fgfr4 inhibitors |
US9802917B2 (en) | 2015-03-25 | 2017-10-31 | Novartis Ag | Particles of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide |
WO2016164641A1 (en) | 2015-04-08 | 2016-10-13 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
US10829484B2 (en) | 2015-07-28 | 2020-11-10 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
TWI732785B (en) | 2015-09-21 | 2021-07-11 | 美商普雷辛肯公司 | Heterocyclic compounds and uses thereof |
SG11201804711RA (en) | 2015-12-07 | 2018-07-30 | Plexxikon Inc | Compounds and methods for kinase modulation, and indications therefor |
WO2017161045A1 (en) | 2016-03-16 | 2017-09-21 | Plexxikon Inc. | Compounds and methods for kinase modulation and indications therefore |
TW201815766A (en) | 2016-09-22 | 2018-05-01 | 美商普雷辛肯公司 | Compounds and methods for IDO and TDO modulation, and indications therefor |
AU2017395023B2 (en) | 2016-12-23 | 2022-04-07 | Plexxikon Inc. | Compounds and methods for CDK8 modulation and indications therefor |
US10577366B2 (en) | 2017-03-20 | 2020-03-03 | Plexxikon Inc. | Crystalline forms of a compound that inhibits bromodomain |
WO2018226846A1 (en) | 2017-06-07 | 2018-12-13 | Plexxikon Inc. | Compounds and methods for kinase modulation |
TWI805599B (en) | 2017-07-25 | 2023-06-21 | 美商第一三共公司 | Formulations of a compound modulating kinases |
CN111194318B (en) | 2017-10-13 | 2023-06-09 | Opna生物公司 | Solid forms of compounds for modulating kinases |
JP7175309B2 (en) | 2017-10-27 | 2022-11-18 | プレキシコン インコーポレーテッド | Formulations of compounds that modulate kinases |
CN112119072A (en) | 2018-03-20 | 2020-12-22 | 普莱希科公司 | Compounds and methods for IDO and TDO modulation, and indications thereof |
CN108752272B (en) * | 2018-06-19 | 2021-02-19 | 西安交通大学 | 8-aminoquinoline amide derivative, preparation method, application and fluorescence analysis method thereof |
WO2020223267A1 (en) | 2019-05-01 | 2020-11-05 | Boehringer Ingelheim International Gmbh | (r)-(2-methyloxiran-2-yl)methyl 4-bromobenzenesulfonate |
CN111053761B (en) * | 2020-01-16 | 2022-05-03 | 杭州旦承医药科技有限公司 | Bisphosphonic acid medicine for inhalation, preparation method thereof and application thereof in chronic obstructive pulmonary disease |
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