NZ624635B2 - Amide derivatives of n-urea substituted amino acids as formyl peptide receptor like-1 (fprl-1) receptor modulators - Google Patents
Amide derivatives of n-urea substituted amino acids as formyl peptide receptor like-1 (fprl-1) receptor modulators Download PDFInfo
- Publication number
- NZ624635B2 NZ624635B2 NZ624635A NZ62463512A NZ624635B2 NZ 624635 B2 NZ624635 B2 NZ 624635B2 NZ 624635 A NZ624635 A NZ 624635A NZ 62463512 A NZ62463512 A NZ 62463512A NZ 624635 B2 NZ624635 B2 NZ 624635B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- amino
- carbamoyl
- optionally substituted
- alkyl
- hydrogen
- Prior art date
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- 102000005962 receptors Human genes 0.000 title claims abstract description 17
- 108020003175 receptors Proteins 0.000 title claims abstract description 17
- 150000001408 amides Chemical class 0.000 title claims description 12
- 239000004202 carbamide Substances 0.000 title abstract description 8
- 150000001413 amino acids Chemical class 0.000 title description 9
- 102100021126 N-formyl peptide receptor 2 Human genes 0.000 title description 2
- 101710091942 N-formyl peptide receptor 2 Proteins 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 103
- 102100021145 fMet-Leu-Phe receptor Human genes 0.000 claims abstract description 13
- 101710108492 fMet-Leu-Phe receptor Proteins 0.000 claims abstract description 12
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 517
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 316
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 290
- 229910052739 hydrogen Inorganic materials 0.000 claims description 269
- 239000001257 hydrogen Substances 0.000 claims description 269
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 236
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 171
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 127
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 116
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 98
- 229910052736 halogen Inorganic materials 0.000 claims description 95
- 150000002367 halogens Chemical class 0.000 claims description 87
- -1 tert-butyl {[2-{[(4-bromophenyl)carbamoyl]amino}(1H-indol yl)propanoyl]amino}acetate Chemical compound 0.000 claims description 78
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 77
- 125000000623 heterocyclic group Chemical group 0.000 claims description 72
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 70
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 67
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 57
- 235000011054 acetic acid Nutrition 0.000 claims description 53
- 229960000583 acetic acid Drugs 0.000 claims description 53
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 43
- 239000002253 acid Substances 0.000 claims description 40
- 125000000217 alkyl group Chemical group 0.000 claims description 40
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 40
- NTLKAXQBFYZMAH-UHFFFAOYSA-N 2-methylpentanamide Chemical compound CCCC(C)C(N)=O NTLKAXQBFYZMAH-UHFFFAOYSA-N 0.000 claims description 37
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 35
- 125000003118 aryl group Chemical group 0.000 claims description 33
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 24
- 125000005843 halogen group Chemical group 0.000 claims description 22
- 201000010099 disease Diseases 0.000 claims description 21
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 21
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- 125000000753 cycloalkyl group Chemical group 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
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- 125000003277 amino group Chemical group 0.000 claims description 15
- IPWFJLQDVFKJDU-UHFFFAOYSA-N pentanamide Chemical compound CCCCC(N)=O IPWFJLQDVFKJDU-UHFFFAOYSA-N 0.000 claims description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 14
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 13
- 235000019260 propionic acid Nutrition 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 125000003282 alkyl amino group Chemical group 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 11
- 125000000468 ketone group Chemical group 0.000 claims description 11
- 208000002780 macular degeneration Diseases 0.000 claims description 11
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 11
- 125000002950 monocyclic group Chemical group 0.000 claims description 11
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N Valeric acid Natural products CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- VYIBCOSBNVFEIW-UHFFFAOYSA-N 3-phenylpropanamide Chemical compound NC(=O)CCC1=CC=CC=C1 VYIBCOSBNVFEIW-UHFFFAOYSA-N 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 125000003367 polycyclic group Chemical group 0.000 claims description 9
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- 125000003368 amide group Chemical group 0.000 claims description 7
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- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 6
- 239000012453 solvate Substances 0.000 claims description 6
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- 206010038910 Retinitis Diseases 0.000 claims description 5
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- 230000002500 effect on skin Effects 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 150000004677 hydrates Chemical class 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
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Abstract
Disclosed are N-urea amide derivative compounds of formula (II), wherein the substituents as defined in the specification. Also disclosed is the use a compound of formula (II) as a modulator of the N-formyl peptide receptor like-1 (FPRL-1) receptor for treating ocular inflammatory diseases. An example of a compound of formula (II) is: (2S,3S)-N-(2-amino-2-oxoethyl)-2-{[(4-bromophenyl) carbamoyl]amino}-3-methylpentanamide ample of a compound of formula (II) is: (2S,3S)-N-(2-amino-2-oxoethyl)-2-{[(4-bromophenyl) carbamoyl]amino}-3-methylpentanamide
Description
AMIDE DERIVATIVES OF N-UREA SUBSTITUTED AMINO ACIDS AS FORMYL E RECEPTOR LIKE-1 (FPRL-1) RECEPTOR MODULATORS By inventors: Richard L. Beard, Tien T. Duong, John E. Donello, Veena Viswanath and Michael E. Garst CROSS NCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application Serial No. 61/551,772 filed October 26, 2011, which is hereby incorporated by reference in its entirety.
FIELD OF THE ION The present invention relates to novel amide derivatives of N-urea substituted amino acids, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of the N-formyl peptide receptor like-1 (FPRL-1) receptor. The invention relates specifically to the use of these compounds and their pharmaceutical compositions to treat disorders associated with the N-formyl peptide receptor like-1 (FPRL-1) or modulation.
BACKGROUND OF THE ION The N-formyl peptide receptor like-1 (FPRL-1) receptor is a G protein-coupled receptor that is expressed on inflammatory cells such as monocytes and neutrophils, as well as T cells and has been shown to play a critical role in leukocyte trafficking during inflammation and human pathology. FPRL-1 is an exceptionally promiscuous receptor that responds to a large array of ous and nous ligands, including Serum amyloid A (SAA), chemokine variant sCKβ8-1, the neuroprotective peptide human, anti-inflammatory eicosanoid lipoxin A4 (LXA4) and glucocorticoidmodulated protein annexin A1. FPRL-1 transduces anti-inflammatory effects of LXA4 in many systems, but it also can mediate the flammatory signaling cascade of peptides such as SAA. The ability of the receptor to mediate two opposite effects is proposed to be a result of different receptor domains used by different agonists (Parmentier, Marc et al. Cytokine & Growth Factor Reviews 17 (2006) 9).
Activation of FPRL-1 by LXA4 or its analogs and by Annexin I n has been shown to result in anti-inflammatory ty by promoting active resolution of inflammation which involves inhibition of polymorphonuclear phil (PMN) and eosinophil migration and also stimulate monocyte migration enabling clearance of apoptotic cells from the site of inflammation in a nonphlogistic manner. In addition, FPRL-1 has been shown to inhibit natural killer (NK) cell cytotoxicity and promote activation of T cells which further contributes to down regulation of tissue damaging inflammatory signals. / LXA4 interaction has been shown to be cial in experimental models of ischemia reperfusion, angiogenesis, dermal inflammation, herapy-induced alopecia, ocular inflammation such as endotoxin-induced uveitis, corneal wound healing, re-epithelialization etc. FPRL-1 thus represents an important novel pro-resolutionary molecular target for the development of new therapeutic agents in diseases with excessive inflammatory responses.
JP 88 ses the preparation of phenylalanine derivatives of general formula: (CH2)6 Me N H Ph HN O O . as inhibitors of acyl-coenzyme A:cholesterol acyltransferase derivatives useful for the ent of arteriosclerosis-related various diseases such as angina pectoris, cardiac tion, temporary ischemic spasm, peripheral thrombosis or obstruction.
Journal of Combinatorial Chemistry (2007), 9(3), 5 teaches a thymidinyl dipeptide urea library with structural similarity to the nucleoside peptide class of antibiotics: WO 9965932 discloses tetrapeptides or s or peptidomimetics that selectively bind mammalian opioid receptors: Helvetica Chimica Acta (1998), 81(7), 263 teaches the synthesis and spectroscopic characterization of 4-chlorophenyl nate (1-chloro isocyanatobenzene) adducts with amino acids as potential dosimeters for the biomonitoring of isocyanate exposure: .
EP 457195 discloses the preparation of peptides having elin antagonist activity and pharmaceutical compositions comprising them: Yingyong Huaxue (1990), 7(1), 1-9 teaches the structure-activity relations of di- and tripeptide sweeteners and of L-phenyl analine derivatives: COOH H H N N (S) Ph O O OMe S O N (S) Me O O .
FR 2533210 discloses L-phenyl analine derivatives as synthetic sweeteners: WO2005047899 discloses compounds which selectively activate the FPRL-1 receptor represented by the following lds: ; and .
SUMMARY OF THE INVENTION A group of amide derivatives of N-urea tuted amino acids, which are potent and selective FPRL-1 modulators, has been discovered. As such, the compounds described herein are useful in treating a wide variety of disorders associated with modulation of FPRL-1 receptor. The term "modulator" as used herein, includes but is not limited to: receptor agonist, antagonist, inverse agonist, inverse antagonist, l agonist, and partial antagonist.
This invention describes compounds of Formula I, which have FPRL-1 or biological activity. The compounds in accordance with the present invention are thus of use in medicine, for example in the treatment of humans with diseases and conditions that are alleviated by FPRL-1 modulation.
In a first aspect, the invention provides a nd represented by a II, its omers, diastereoisomers, tautomers, hydrates, solvates or a pharmaceutically acceptable salt thereof, Formula II wherein: a is 1 and b is 0; a is 0 and b is 1; a is 1 and b is 1; R1 is optionally substituted C1-8 alkyl, optionally tuted C3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C6-10 aryl, optionally substituted C3-8 cycloalkenyl, -NR11R12 or -OR13; R2 is optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R3 is en, optionally substituted C1-8 alkyl, halogen, -COOR15, - OR13, -NR11R12, NO2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 lkenyl; R4 is hydrogen, optionally substituted C1-8 alkyl, n, - COOR15, - OR13, 12, NO2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 lkenyl; R5 is halogen, -CF3 or –S(O)nR14; n is 0, 1 or 2; R6 is hydrogen, optionally substituted C1-8 alkyl, halogen, - COOR15, - OR13, -NR11R12, NO2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl; R7 is hydrogen, optionally substituted C1-8 alkyl, halogen, - COOR15 , - OR13 , -NR 11 R12 , NO 2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 lkenyl; R8 is hydrogen, optionally tuted C1-8 alkyl or optionally substituted C6-10 aryl; R9 is hydrogen, optionally substituted C1-8 alkyl or optionally tuted C6-10 aryl; R10 is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R9a is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R10a is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R11 is hydrogen or optionally substituted C1-8 alkyl; R12 is hydrogen or optionally substituted C1-8 alkyl; R13 is hydrogen or optionally substituted C1-8 alkyl; R14 is hydrogen, CF3 or optionally tuted C1-8 alkyl; R15 is hydrogen or optionally substituted C1-8 alkyl; wherein a substituted alkyl is an alkyl in which one methylene (-CH2-) group of the alkyl group can be replaced by oxygen, sulfur, ide, yl, carboxyl, yl, sulfate, sulfonate, amide, sulfonamide, by a divalent C 3-8 cycloalkyl, by a divalent heterocycle, or by a divalent aryl group, and can be independently substituted by halogen atoms, hydroxyl groups, cycloalkyl groups, amino groups, heterocyclic groups, aryl groups, carboxylic acid groups, phosphonic acid groups, sulphonic acid groups, phosphoric acid groups, nitro groups, amide groups, sulfonamide groups, n a cycloalkyl is a monovalent or divalent group of 3 to 8 carbon atoms d from a saturated cyclic hydrocarbon, which can be monocyclic or clic, independently substituted by halogen atoms, sulfonyl C1-8 alkyl groups, sulfoxide C1-8 alkyl groups, sulfonamide groups, nitro groups, cyano groups, -OC1-8 alkyl , -SC 1-8 alkyl groups, -C1-8 alkyl groups, -C2-6 alkenyl groups, -C2-6 alkynyl groups, ketone groups, alkylamino groups, amino groups, aryl groups, C3-8 cycloalkyl groups or hydroxyl groups, and wherein a cycloalkenyl is a lent or divalent group of 3 to 8 carbon atoms d from a saturated cycloalkyl having at least one double bond, which can be monocyclic or clic, independently substituted by halogen atoms, sulfonyl groups, sulfoxide groups, nitro groups, cyano groups, -OC 1-6 alkyl groups, -SC1-6 alkyl groups, -C1-6 alkyl , -C2-6 alkenyl groups, - C2-6 alkynyl groups , ketone groups, alkylamino groups, amino groups, aryl groups, C3-8 cycloalkyl groups or hydroxyl groups, n an aryl is an organic moiety derived from an aromatic hydrocarbon consisting of a ring containing 6 to 10 carbon atoms, by removal of one hydrogen atom, can be monocyclic or polycyclic, and can be substituted by halogen atoms, sulfonyl C1-6 alkyl groups, sulfoxide C1-6 alkyl groups, sulfonamide groups, carboxcyclic acid groups, C1-6 alkyl carboxylates (ester) groups, amide groups, nitro groups, cyano groups, -OC1-6 alkyl groups, -SC1-6 alkyl groups, -C1-6 alkyl groups, - C2-6 alkenyl groups, - C2-6 alkynyl groups , ketone groups, des, alkylamino groups, amino groups, aryl , C3-8 lkyl groups or hydroxyl groups, n an heterocycle is 3 to 10 membered ring, which can be aromatic or nonaromatic , saturated or unsaturated, containing at least one heteroatom selected form oxygen, nitrogen, sulfur, or combinations of at least two thereof, upting the yclic ring structure, wherein the heterocyclic ring can be interrupted by a C=O; the S and N atoms can be oxidized, can be monocyclic or polycyclic; and wherein the heterocyclic ring moieties can be substituted by halogen atoms, sulfonyl groups, sulfoxide , nitro groups, cyano groups, -OC 1-6 alkyl groups, -SC1-6 alkyl groups, -C1-8 alkyl groups, -C2-6 alkenyl groups, - C2-6 alkynyl groups , ketone groups, alkylamino groups, amino groups, aryl groups, C3-8 cycloalkyl groups or hydroxyl groups, with the provisos: a) when a = 1 and b=0 then: R9 is not ally substituted benzyl; R10 is H or methyl; and R11 is not: , , , , , , , or ; and the compound of a II is not of structures: ; ; H H N N i-Bu COOH Cl O N i-Bu H ; or ; NH COOH i-Bu NH ; and b) when a=0 and b=1 then: R1 is OR13; and the nd of Formula II is not of structure: ; and c) when a=1 and b=1 then: R11 is not: In a second aspect, the invention es a use of a compound of the invention in the manufacture of a medicament.
In a third aspect, the invention provides a use of a compound of the invention in the manfufacture of a ment for treating a disease or disorder associated with the modulators of the N-formyl peptide receptor like-1 or in need thereof, wherein the disorder associated with modulation of the N-formyl peptide receptor like-1 receptor is selected from the group consisting of inflammatory bowel disease; ocular inflammatory diseases; systemic inflammatory diseases; pain; immunological ers; dermal wound healing; burns; rosacea; atopic dermatitis; acne; sis; seborrheic dermatitis; actinic keratosis; viral warts; photoaging; toid arthritis and related inflammatory disorders.
In a fourth aspect, the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier.
Also described is a compound represented by Formula I or the individual geometrical isomers, individual omers, individual diastereoisomers, individual tautomers, individual zwitterions or a pharmaceutically acceptable salt thereof: wherein: a is 0 or 1; b is 0, 1, 2, 3 or 4; R1 is optionally substituted C1-8 alkyl, optionally substituted C3-8 cycloalkyl, ally substituted cycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, ally substituted C3-8 cycloalkenyl, -NH2, -OH, -O(C1-8 alkyl), R2 is optionally substituted C1-8 alkyl, optionally substituted C6-10 aryl, R3 is H, optionally substituted C1-8 alkyl, halogen, -COOH, -OH, -NH2, NO2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, ally substituted C3-8 cycloalkenyl; R4 is H, optionally substituted C1-8 alkyl, halogen, -COOH, -OH, -NH2, -NO2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C3-8 cycloalkenyl; R5 is optionally substituted C1-8 alkyl, halogen, -COOH, -OH, -NH2, -NO2, optionally tuted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally tuted C3-8 cycloalkenyl; R6 is H, optionally substituted C1-8 alkyl, halogen, -COOH, -OH, -NH2, -NO2, optionally tuted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C3-8 cycloalkenyl; R7 is H, optionally substituted C1-8 alkyl, halogen, -COOH, -OH, -NH2, -NO2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally tuted C3-8 cycloalkenyl; and compounds: , , , and .
Also described is a compound represented by Formula II or the geometrical isomers, enantiomers, diastereoisomers, ers, zwitterions, hydrates, cryslat forms, solvates or a pharmaceutically acceptable salt thereof: Formula II wherein: a is 1 and b is 0; a is 0 and b is 1; a is 1 and b is 1; R1 is optionally substituted C1-8 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C3-8 cycloalkenyl, -NR11R12 or -OR13; R2 is optionally substituted C1-8 alkyl or ally substituted C6-10 aryl; R3 is hydrogen, optionally substituted C1-8 alkyl, halogen, -COOR15, - OR13, - NR11R12, NO2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl; R4 is hydrogen, optionally tuted C1-8 alkyl, n, - COOR15, - OR13, - NR11R12, NO2, optionally tuted cycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl; R5 is halogen, -CF3 or –S(O)nR14; n is 0, 1 or 2; R6 is hydrogen, optionally substituted C1-8 alkyl, halogen, - COOR15, - OR13, - NR11R12, NO2, optionally tuted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl; R7 is hydrogen, optionally substituted C1-8 alkyl, halogen, - COOR15, - OR13, - 2, NO2, optionally substituted heterocycle, optionally substituted C3-8 lkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl; R8 is hydrogen, ally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R9 is en, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R10 is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R9a is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R10a is en, optionally substituted C1-8 alkyl or optionally tuted C6-10 aryl; R11 is hydrogen or optionally substituted C1-8 alkyl; R12 is hydrogen or optionally substituted C1-8 alkyl; R13 is hydrogen or optionally substituted C1-8 alkyl; R14 is hydrogen, CF3 or optionally substituted C1-8 alkyl; R15 is hydrogen or optionally substituted C1-8 alkyl; with the provisos: a). when a = 1 and b=0 then: R9 is not optionally substituted benzyl; and R11 is not: , , , COOH , , Ph , , or ; and the nd of Formula II is not of structures: ; ; ; or ; N H2N NH COOH NH Me i-Bu HN Cl O HN O or ; and b). when a=0 and b=1 then: R1 is OR13; and the compound of Formula II is not of structure: ; and c). when a=1 and b=1 then: R11 is not: Also described is a compound represented by Formula II, wherein: a is 1 and b is 0 ; R1 is optionally substituted C1-8 alkyl, optionally substituted C3-8 cycloalkyl, ally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C3-8 lkenyl, -NR11R12 or -OR13; R2 is optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R3 is hydrogen, optionally tuted C1-8 alkyl, halogen, -COOR15 , - OR13 , - NR 11 R12 , NO 2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 lkenyl; R4 is hydrogen, optionally substituted C1-8 alkyl, halogen, - COOR15 , - OR13 , - NR 11 R12 , NO 2, optionally substituted cycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or ally substituted C3-8 cycloalkenyl; R5 is halogen, -CF3 or –S(O)nR14 ; n is 0, 1 or 2; R6 is hydrogen, ally substituted C1-8 alkyl, halogen, - COOR15 , - OR13 , - NR 11 R12 , NO 2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 lkenyl; R7 is hydrogen, optionally substituted C1-8 alkyl, halogen, - COOR15 , - OR13 , - NR 11 R12 , NO 2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 lkenyl; R8 is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R9 is hydrogen, optionally substituted C1-8 alkyl or ally substituted C6-10 aryl; R10 is hydrogen, ally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R11 is hydrogen or optionally substituted C1-8 alkyl; R12 is hydrogen or optionally substituted C1-8 alkyl; R13 is hydrogen or optionally substituted C1-8 alkyl; R14 is hydrogen, CF3 or optionally substituted C1-8 alkyl; R15 is hydrogen or optionally substituted C1-8 alkyl; with the provisos: R9 is not optionally substituted benzyl ; and R11 is not: , , , COOH , , Ph , , or ; and the nd of Formula II is not of structures: ; ; or ; N H2N NH COOH NH Me i-Bu HN Cl O HN O ; or Also described is a compound ented by Formula II, wherein: a is 1 and b is 0 ; R1 is optionally tuted C1-8 alkyl, optionally substituted C3-8 cycloalkyl, ally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C3-8 cycloalkenyl, -NR11 R12 or -OR13 ; R2 is ally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R3 is hydrogen, optionally substituted C1-8 alkyl, halogen, -COOR15 , - OR13 , - NR 11 R12 , NO 2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, ally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl; R4 is hydrogen, optionally substituted C1-8 alkyl, n, - COOR15 , - OR13 , - NR 11 R12 , NO 2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl; R5 is –S(O)nR14 ; n is 0, 1 or 2; R6 is hydrogen, optionally substituted C1-8 alkyl, n, - COOR15 , - OR13 , - NR 11 R12 , NO 2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or ally substituted C3-8 cycloalkenyl; R7 is hydrogen, optionally substituted C1-8 alkyl, halogen, - COOR15 , - OR13 , - NR 11 R12 , NO 2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 lkenyl; R8 is en, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R9 is hydrogen, ally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R10 is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R11 is hydrogen or optionally substituted C1-8 alkyl; R12 is hydrogen or optionally substituted C1-8 alkyl; R13 is hydrogen or optionally substituted C1-8 alkyl; R14 is en, CF3 or optionally substituted C1-8 alkyl; R15 is hydrogen or optionally substituted C1-8 alkyl; with the provisos: R9 is not optionally substituted benzyl; and R11 is not: , , , COOH , , Ph , , or ; and the nd of Formula II is not of structures: ; ; or ; N H2N NH COOH NH Me i-Bu HN Cl O HN O ; or Also described is a nd represented by Formula II, wherein: a is 1 and b is 0 ; R1 is optionally substituted C1-8 alkyl, optionally substituted C3-8 cycloalkyl, ally substituted cycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C3-8 cycloalkenyl, -NR11 R12 or -OR13 ; R2 is optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R3 is hydrogen, optionally substituted C1-8 alkyl, halogen, -COOR15 , - OR13 , - NR 11 R12 , NO 2, optionally substituted cycle, ally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally tuted C3-8 cycloalkenyl; R4 is hydrogen, optionally substituted C1-8 alkyl, halogen, - COOR15 , - OR13 , - NR 11 R12 , NO 2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl; R5 is -CF3 ; R6 is hydrogen, optionally substituted C1-8 alkyl, halogen, - COOR15 , - OR13 , - NR 11 R12 , NO 2, optionally substituted heterocycle, optionally tuted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl; R7 is hydrogen, ally substituted C1-8 alkyl, halogen, - COOR15 , - OR13 , - NR 11 R12 , NO 2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally tuted C3-8 cycloalkenyl; R8 is hydrogen, optionally substituted C1-8 alkyl or ally substituted C6-10 aryl; R9 is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R10 is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R11 is hydrogen or optionally substituted C1-8 alkyl; R12 is hydrogen or optionally substituted C1-8 alkyl; R13 is hydrogen or optionally substituted C1-8 alkyl; R15 is en or optionally substituted C1-8 alkyl; with the provisos: R9 is not optionally tuted benzyl; and R11 is not: , , , COOH , , Ph , , or ; and the compound of a II is not of structures: ; ; or ; N H2N NH COOH NH Me i-Bu HN Cl O HN O ; or Also bed is a compound represented by Formula II, wherein: a is 1 and b is 0; R1 is optionally substituted C1-8 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally tuted C3-8 cycloalkenyl, -NR11 R12 or -OR13 ; R2 is optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R3 is hydrogen, optionally substituted C1-8 alkyl, halogen, -COOR15 , - OR13 , - NR 11 R12 , NO 2, optionally substituted heterocycle, optionally tuted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 lkenyl; R4 is hydrogen, optionally substituted C1-8 alkyl, halogen, - COOR15 , - OR13 , - NR 11 R12 , NO 2, optionally tuted heterocycle, optionally substituted C3-8 cycloalkyl, optionally tuted C6-10 aryl or optionally tuted C3-8 cycloalkenyl; R5 is halogen; R6 is hydrogen, optionally substituted C1-8 alkyl, halogen, - COOR15 , - OR13 , - NR 11 R12 , NO 2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally tuted C3-8 cycloalkenyl; R7 is hydrogen, optionally tuted C1-8 alkyl, halogen, - COOR15 , - OR13 , - NR 11 R12 , NO 2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl; R8 is hydrogen, optionally tuted C1-8 alkyl or optionally substituted C6-10 aryl; R9 is en, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R10 is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R11 is hydrogen or optionally substituted C1-8 alkyl; R12 is hydrogen or optionally substituted C1-8 alkyl; R13 is hydrogen or ally substituted C1-8 alkyl; R15 is hydrogen or optionally substituted C1-8 alkyl; with the provisos: R9 is not optionally substituted benzyl ; and the compound of Formula II is not of structures: ; ; ; or ; N H2N NH COOH NH Me i-Bu HN Cl O HN O ; or ; and R11 is not: , , , COOH , , Ph , , or .
Also described is a compound represented by Formula II, wherein a is 1 and b is 0; R1 is optionally substituted C1-8 alkyl, -NR11R12 or -OR13; R2 is optionally tuted C1-8 alkyl; R3 is hydrogen, optionally substituted C1-8 alkyl, halogen, -COOR15, - OR13, - R4 is hydrogen, optionally substituted C1-8 alkyl, halogen, - COOR15, - OR13, - NR11R12; R5 is halogen, -CF3 or –S(O)nR14; n is 0, 1 or 2; R6 is hydrogen, optionally substituted C1-8 alkyl, halogen, - , - OR13, - NR11R12; R7 is hydrogen, optionally substituted C1-8 alkyl, halogen, - COOR15, - OR13, - NR11R12; R8 is hydrogen or optionally substituted C1-8 alkyl; R9 is hydrogen , optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R10 is hydrogen or optionally substituted C1-8; R11 is en or ally substituted C1-8 alkyl; R12 is hydrogen or optionally substituted C1-8 alkyl; R13 is hydrogen or optionally substituted C1-8 alkyl; R14 is hydrogen or optionally substituted C1-8 alkyl; R15 is hydrogen or optionally tuted C1-8 alkyl; with the provisos: R9 is not optionally substituted benzyl ; and the compound of Formula II is not of structures: ; ; ; or ; N H2N NH COOH NH Me i-Bu HN Cl O HN O ; or ; and R11 is not: , , , COOH , , Ph , , or .
Also described is a compound represented by Formula II, wherein a is 1 and b is 0; R1 is optionally substituted C1-8 alkyl, -NR11R12 or -OR13; R2 is optionally substituted C1-8 alkyl; R3 is hydrogen or halogen; R4 is en; R5 is halogen, -CF3 or –S(O)nR14; n is 0, 1 or 2; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen, optionally substituted C1-8 alkyl; R9 is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R10 is hydrogen, optionally substituted C1-8 alkyl; R11 is hydrogen or optionally substituted C1-8 alkyl; R12 is hydrogen or optionally substituted C1-8 alkyl; R13 is hydrogen or optionally substituted C1-8 alkyl; R14 is hydrogen or ally tuted C1-8 alkyl; with the provisos: R9 is not optionally substituted benzyl ; and the compound of Formula II is not of structures: ; ; ; or ; N H2N NH COOH NH Me i-Bu HN Cl O HN O ; or ; and R11 is not: , , , COOH , , Ph , , or .
Also described is a compound represented by Formula II, wherein a is 0 and b is 1; R1 is -OR13; R2 is ally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R3 is hydrogen, optionally substituted C1-8 alkyl, halogen, -COOR15, - OR13, - NR11R12, NO2, optionally substituted cycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl; R4 is hydrogen, optionally substituted C1-8 alkyl, n, - COOR15, - OR13, - NR11R12, NO2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl; R5 is n, -CF3 or –S(O)nR14; n is 0, 1 or 2; R6 is hydrogen, ally substituted C1-8 alkyl, halogen, - COOR15, - OR13, - NR11R12, NO2, optionally tuted heterocycle, optionally tuted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl; R7 is hydrogen, optionally substituted C1-8 alkyl, halogen, - COOR15, - OR13, - NR11R12, NO2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl; R8 is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R9 is hydrogen, ally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R10 is en, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R9a is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R10a is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R11 is hydrogen or optionally substituted C1-8 alkyl; R12 is hydrogen or optionally substituted C1-8 alkyl; R13 is hydrogen or optionally substituted C1-8 alkyl; R14 is hydrogen, CF3 or optionally substituted C1-8 alkyl; R15 is hydrogen or optionally substituted C1-8 alkyl; and the compound of a II is not of structure: Also described is a compound represented by a II, wherein a is 0 and b is 1; R1 is -OR13; R2 is ally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R3 is hydrogen, optionally substituted C1-8 alkyl, halogen, -COOR15, - OR13, - NR11R12, NO2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 lkenyl; R4 is hydrogen, optionally substituted C1-8 alkyl, halogen, - COOR15, - OR13, - NR11R12, NO2, optionally substituted cycle, optionally substituted C3-8 cycloalkyl, optionally tuted C6-10 aryl or optionally substituted C3-8 cycloalkenyl; R5 is halogen; R6 is hydrogen, optionally substituted C1-8 alkyl, halogen, - COOR15, - OR13, - NR11R12, NO2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally tuted C3-8 cycloalkenyl; R7 is hydrogen, optionally substituted C1-8 alkyl, halogen, - COOR15, - OR13, - NR11R12, NO2, ally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl; R8 is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R9 is hydrogen, optionally substituted C1-8 alkyl or optionally tuted C6-10 aryl; R10 is hydrogen, ally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R9a is en, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R10a is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R11 is hydrogen or optionally substituted C1-8 alkyl; R12 is hydrogen or optionally substituted C1-8 alkyl; R13 is hydrogen or optionally tuted C1-8 alkyl; R15 is hydrogen or optionally substituted C1-8 alkyl; and the nd of Formula II is not of structure: Also described is a nd represented by Formula II, wherein: a is 0 and b is 1; R1 is -OR13; R2 is optionally substituted C1-8 alkyl; R3 is hydrogen, optionally substituted C1-8 alkyl, halogen; R4 is hydrogen, optionally substituted C1-8 alkyl, halogen; R5 is halogen, -CF3 or –S(O)nR14; n is 0, 1 or 2; R6 is hydrogen, optionally substituted C1-8 alkyl, halogen; R7 is hydrogen, optionally substituted C1-8 alkyl, halogen; R8 is en; R9 is hydrogen; R10 is hydrogen, optionally substituted C1-8 alkyl; R9a is hydrogen, optionally substituted C1-8 alkyl; R10a is hydrogen, optionally substituted C1-8 alkyl; R13 is hydrogen or optionally tuted C1-8 alkyl; and R14 is hydrogen, CF3 or optionally tuted C1-8 alkyl; and the compound of Formula II is not of structure: .
Also described is a compound represented by Formula II, wherein: a is 0 and b is 1; R1 is -OR13; R2 is optionally tuted C1-8 alkyl; R3 is hydrogen or halogen; R4 is hydrogen; R5 is halogen; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; R9 is hydrogen; R10 is en or optionally substituted C1-8 alkyl; R9a is hydrogen or optionally substituted C1-8 alkyl; R10a is hydrogen or optionally substituted C1-8 alkyl; and R13 is en; and the compound of Formula II is not of structure: Also described is a compound represented by Formula II, wherein: a is 0 and b is 1; R1 is -OR13; R2 is optionally substituted C1-8 alkyl; R3 is hydrogen or halogen; R4 is hydrogen; R5 is n; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; R9 is hydrogen; R10 is hydrogen or optionally substituted C1-8 alkyl; R9a is optionally substituted C1-8 alkyl; R10a is optionally substituted C1-8 alkyl; and R13 is hydrogen.
Also described is a compound represented by a II, wherein a is 1 and b is 1; R1 is optionally substituted C1-8 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C3-8 cycloalkenyl, -NR11 R12 or -OR13 ; R2 is optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R3 is en, optionally substituted C1-8 alkyl, halogen, -COOR15 , - OR13 , - NR 11 R12 , NO 2, optionally substituted heterocycle, optionally tuted C3-8 lkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl; R4 is hydrogen, optionally substituted C1-8 alkyl, halogen, - COOR15 , - OR13 , - NR 11 R12 , NO 2, optionally substituted heterocycle, optionally tuted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl; R5 is halogen, -CF3 or R14 ; n is 0, 1 or 2; R6 is hydrogen, optionally substituted C1-8 alkyl, n, - COOR15 , - OR13 , - NR 11 R12 , NO 2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl; R7 is hydrogen, optionally substituted C1-8 alkyl, halogen, - COOR15 , - OR13 , - NR 11 R12 , NO 2, optionally substituted heterocycle, optionally substituted C3-8 lkyl, ally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl; R8 is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R9 is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R10 is hydrogen, optionally substituted C1-8 alkyl or ally substituted C6-10 aryl; R9a is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R10a is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R11 is hydrogen or ally substituted C1-8 alkyl; R12 is hydrogen or optionally substituted C1-8 alkyl; R13 is hydrogen or optionally tuted C1-8 alkyl; R14 is hydrogen or optionally tuted C1-8 alkyl; and R15 is hydrogen or optionally substituted C1-8 alkyl; and with the proviso: that R11 is not: Also described is a compound represented by Formula II, wherein a is 1 and b is 1; R1 is optionally substituted C1-8 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C3-8 cycloalkenyl, -NR11R12 or -OR13; R2 is optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R3 is en, optionally substituted C1-8 alkyl, halogen, -COOR15, - OR13, - NR11R12, NO2, optionally tuted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 lkenyl; R4 is hydrogen, optionally substituted C1-8 alkyl, halogen, - COOR15, - OR13, - NR11R12, NO2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or ally substituted C3-8 cycloalkenyl; R5 is halogen; R6 is hydrogen, optionally substituted C1-8 alkyl, halogen, - COOR15, - OR13, - NR11R12, NO2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl; R7 is hydrogen, optionally substituted C1-8 alkyl, halogen, - , - OR13, - NR11R12, NO2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally tuted C3-8 cycloalkenyl; R8 is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R9 is hydrogen, ally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R10 is hydrogen, optionally substituted C1-8 alkyl or ally tuted C6-10 aryl; R9a is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R10a is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R11 is hydrogen or optionally substituted C1-8 alkyl; R12 is hydrogen or optionally tuted C1-8 alkyl; R13 is en or optionally substituted C1-8 alkyl; R15 is en or optionally substituted C1-8 alkyl; and with the proviso: that R11 is not: Also described is a compound represented by Formula II, wherein a is 1 and b is 1; R1 is optionally tuted C1-8 alkyl, -NR11R12 or -OR13; R2 is optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R3 is hydrogen, optionally substituted C1-8 alkyl, halogen; R4 is hydrogen, optionally substituted C1-8 alkyl, halogen; R5 is halogen, -CF3 or –S(O)nR14; n is 0, 1 or 2; R6 is hydrogen, optionally substituted C1-8 alkyl, halogen; R7 is hydrogen, ally tuted C1-8 alkyl, halogen; R8 is hydrogen; R9 is hydrogen, optionally substituted C1-8 alkyl; R10 is hydrogen, optionally substituted C1-8 alkyl; R9a is hydrogen, optionally substituted C1-8 alkyl; R10a is hydrogen, optionally substituted C1-8 alkyl; R11 is hydrogen or optionally substituted C1-8 alkyl; R12 is hydrogen or optionally substituted C1-8 alkyl; R13 is hydrogen or ally substituted C1-8 alkyl; R14 is hydrogen or optionally substituted C1-8 alkyl; and R15 is hydrogen or optionally substituted C1-8 alkyl; with the o: that R11 is not: Also described is a compound represented by Formula II, wherein a is 1 and b is 1; R1 is -OR13; R2 is optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R3 is hydrogen; R4 is hydrogen; R5 is halogen; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; R9 is en; R10 is hydrogen; R9a is hydrogen; R10a is hydrogen; and R13 is hydrogen or optionally substituted C1-8 alkyl; and with the proviso: that R11 is not: The term "alkyl", as used herein, refers to saturated, monovalent or divalent hydrocarbon moieties having linear or branched moieties or combinations thereof and containing 1 to 8 carbon atoms. One methylene (-CH2-) group, of the alkyl group can be replaced by oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, by a divalent C 3-8 cycloalkyl, by a divalent heterocycle, or by a divalent aryl group. Alkyl groups can have one or more chiral centers. Alkyl groups can be ndently substituted by halogen atoms, hydroxyl groups, cycloalkyl groups, amino groups, heterocyclic groups, aryl , carboxylic acid groups, phosphonic acid groups, sulphonic acid groups, phosphoric acid groups, nitro groups, amide groups, sulfonamide .
The term "cycloalkyl", as used herein, refers to a lent or nt group of 3 to 8 carbon atoms derived from a saturated cyclic arbon. Cycloalkyl groups can be monocyclic or polycyclic. Cycloalkyl can be independently substituted by halogen atoms, sulfonyl C1-8 alkyl , sulfoxide C1-8 alkyl groups, sulfonamide groups, nitro groups, cyano groups, -OC1-8 alkyl groups, -SC1-8 alkyl groups, -C1-8 alkyl groups, -C2-6 alkenyl , - C2-6 alkynyl groups, ketone groups, alkylamino groups, amino groups, aryl groups, C3-8 cycloalkyl groups or hydroxyl groups..
The term "cycloalkenyl", as used herein, refers to a monovalent or divalent group of 3 to 8 carbon atoms derived from a saturated cycloalkyl having at least one double bond. Cycloalkenyl groups can be clic or clic. Cycloalkenyl groups can be independently substituted by halogen atoms, sulfonyl groups, sulfoxide groups, nitro groups, cyano , -OC1-6 alkyl groups, -SC1-6 alkyl groups, -C1-6 alkyl groups, -C2-6 alkenyl groups, - C2-6 alkynyl groups , ketone groups, alkylamino groups, amino groups, aryl groups, C3-8 cycloalkyl groups or hydroxyl groups.
The term "halogen", as used herein, refers to an atom of ne, bromine, fluorine, iodine.
The term "alkenyl", as used herein, refers to a monovalent or divalent arbon radical having 2 to 6 carbon atoms, derived from a saturated alkyl, having at least one double bond. One methylene (-CH2-) group, of the alkenyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, by a divalent C 3-8 cycloalkyl, by a divalent heterocycle, or by a divalent aryl group. C 2-6 alkenyl can be in the E or Z configuration. Alkenyl groups can be substituted by alkyl groups, as defined above or by n atoms.
The term "alkynyl", as used herein, refers to a monovalent or nt hydrocarbon radical having 2 to 6 carbon atoms, derived from a saturated alkyl, having at least one triple bond. One methylene (-CH2-) group, of the l can be ed by oxygen, sulfur, sulfoxide, nitrogen, carbonyl, yl, sulfonyl, e, sulfonate, amide, sulfonamide, by a divalent C 3-8 cycloalkyl, by a divalent heterocycle, or by a divalent aryl group. Alkynyl groups can be substituted by alkyl groups, as defined above, or by halogen atoms.
The term "heterocycle" as used herein, refers to a 3 to 10 membered ring, which can be aromatic or non-aromatic, saturated or unsaturated, containing at least one heteroatom selected form oxygen, nitrogen, sulfur, or combinations of at least two thereof, interrupting the carbocyclic ring structure. The heterocyclic ring can be interrupted by a C=O; the S and N heteroatoms can be ed. cycles can be monocyclic or polycyclic. Heterocyclic ring moieties can be substituted by halogen atoms, sulfonyl groups, ide groups, nitro groups, cyano groups, -OC 1-6 alkyl groups, -SC1-6 alkyl groups, -C1-8 alkyl groups, -C2-6 alkenyl groups, - C2-6 alkynyl groups , ketone groups, alkylamino groups, amino groups, aryl groups, C3-8 cycloalkyl groups or hydroxyl groups.
The term "aryl" as used herein, refers to an organic moiety derived from an aromatic hydrocarbon consisting of a ring containing 6 to 10 carbon atoms, by removal of one en atom. Aryl can be substituted by halogen atoms, sulfonyl C1-6 alkyl , sulfoxide C1-6 alkyl groups, sulfonamide groups, carboxcyclic acid groups, C1-6 alkyl carboxylates (ester) groups, amide groups, nitro groups, cyano groups, -OC1-6 alkyl , -SC1-6 alkyl groups, -C1-6 alkyl , -C2-6 alkenyl groups, - C2-6 alkynyl groups , ketone groups, aldehydes, alkylamino groups, amino groups, aryl groups, C3-8 cycloalkyl groups or hydroxyl groups. Aryls can be monocyclic or polycyclic.
The term "hydroxyl" as used herein, represents a group of formula "–OH".
The term "carbonyl" as used herein, ents a group of formula "-C(O)-".
The term "ketone" as used herein, represents an organic compound having a carbonyl group linked to a carbon atom such as -(CO)R x wherein Rx can be alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.
The term "amine" as used herein, represents a group of formula y ",wherein Rx and Ry can be the same or ndently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.
The term xyl" as used herein, represents a group of formula "-C(O)O-".
The term nyl" as used herein, ents a group of formula "-SO2-".
The term "sulfate" as used herein, represents a group of formula O)2-O- The term "sulfonate" as used herein, represents a group of the formula "-S(O)2- O-".
The term "carboxylic acid" as used herein, represents a group of formula "- C(O)OH".
The term "nitro" as used herein, represents a group of formula "–NO2".
The term "cyano" as used herein, represents a group of formula "-CN".
The term "amide" as used , represents a group of formula "-C(O)NRxRy," wherein Rx and Ry can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.
The term "sulfonamide" as used herein, represents a group of formula "- S(O) 2NR xRy" wherein Rx and Ry can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.
The term "sulfoxide" as used herein, represents a group of formula "-S(O)-".
The term "phosphonic acid" as used herein, ents a group of formula "- P(O)(OH) 2".
The term "phosphoric acid" as used herein, ents a group of formula "- OP(O)(OH) 2".
The term "sulphonic acid" as used , represents a group of formula "- S(O) 2OH".
The formula "H ", as used herein, represents a hydrogen atom.
The formula "O ", as used herein, represents an oxygen atom.
The formula "N ", as used herein, represents a nitrogen atom.
The formula "S ", as used herein, represents a sulfur atom.
The term "comprising" as used in this ication and claims means "consisting at least in part of". When interpreting statements in this specification, and claims which e the term "comprising", it is to be understood that other features that are additional to the features prefaced by this term in each statement or claim may also be present. Related terms such as "comprise" and "comprised" are to be interpreted in similar manner.
Also described are compounds: {[2-{[(4-bromophenyl)carbamoyl]amino}(1H-indolyl)propanoyl]amino}acetic acid; tert-butyl {[2-{[(4-bromophenyl)carbamoyl]amino}(1H-indol yl)propanoyl]amino}acetate; [(4-amino{[(4-bromophenyl)carbamoyl]amino}oxobutanoyl)amino]acetic acid; tert-butyl [(4-amino{[(4-bromophenyl)carbamoyl]amino} oxobutanoyl)amino]acetate; 2-{[(2R){[(4-bromophenyl)carbamoyl]amino}methylpentanoyl]amino} methylpropanoic acid; tert-butyl 2-{[(2R){[(4-bromophenyl)carbamoyl]amino}methylpentanoyl]amino}- 2-methylpropanoate; {[2-{[(4-bromophenyl)carbamoyl]amino}(1H-imidazolyl)propanoyl]amino}acetic acid; tert-butyl {[2-{[(4-bromophenyl)carbamoyl]amino}(1H-imidazol yl)propanoyl]amino}acetate; {[(2S){[(4-bromophenyl)carbamoyl]amino}(methylsulfonyl)butanoyl]amino}acetic acid; tert-butyl {[(4-bromophenyl)carbamoyl]amino} (methylsulfonyl)butanoyl]amino}acetate; {[(2S){[(4-bromophenyl)carbamoyl]amino}(methylsulfanyl)butanoyl]amino}acetic acid; utyl {[(2S){[(4-bromophenyl)carbamoyl]amino} (methylsulfanyl)butanoyl]amino}acetate; yl{[(2S)methyl({[4- (trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}propanoic acid; tert-butyl 2-methyl{[(2S)methyl({[4- (trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}propanoate; {[(2S)methyl({[4- (methylsulfonyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetic acid; tert-butyl {[(2S)methyl({[4- (methylsulfonyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetate; {[(2S)methyl({[4- (methylsulfinyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetic acid; tert-butyl {[(2S)methyl({[4- (methylsulfinyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetate; 2-{[(2S){[(4-bromophenyl)carbamoyl]amino}methylpentanoyl]amino} methylpropanoic acid; tert-butyl 2-{[(2S){[(4-bromophenyl)carbamoyl]amino}methylpentanoyl]amino}- 2-methylpropanoate; methyl[({4- luoromethyl)sulfanyl]phenyl}carbamoyl)amino]pentanoyl}amino)acetic acid; tert-butyl methyl[({4- [(trifluoromethyl)sulfanyl]phenyl}carbamoyl)amino]pentanoyl}amino)acetate; {[(2S)methyl({[4- lsulfanyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetic acid; tert-butyl {[(2S)methyl({[4- (methylsulfanyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetate; {[(2R){[(4-bromophenyl)carbamoyl]amino}methylpentanoyl]amino}acetic acid; tert-butyl {[(2R){[(4-bromophenyl)carbamoyl]amino} methylpentanoyl]amino}acetate;; {[(2R,3R){[(4-bromophenyl)carbamoyl]amino}methylpentanoyl]amino}acetic acid tert-butyl {[(2R,3R){[(4-bromophenyl)carbamoyl]amino} methylpentanoyl]amino}acetate; {[(2S)methyl({[4- (trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetic acid; tert-butyl {[(2S)methyl({[4- (trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetate; {[(2R){[(4-bromofluorophenyl)carbamoyl]amino} methylpentanoyl]amino}acetic acid; (2S){[(4-bromophenyl)carbamoyl]amino}-N-[2-(dimethylamino)oxoethyl] methylpentanamide; [(2-{[(4-bromophenyl)carbamoyl]amino}methylpropanoyl)amino]acetic acid; tert-butyl [(2-{[(4-bromophenyl)carbamoyl]amino}methylpropanoyl)amino]acetate; [(2-{[(4-bromophenyl)carbamoyl]amino}ethylbutanoyl)amino]acetic acid; utyl [(2-{[(4-bromophenyl)carbamoyl]amino}ethylbutanoyl)amino]acetate; [(2-{[(4-bromophenyl)carbamoyl]amino}-2,4-dimethylpentanoyl)amino]acetic acid; tert-butyl [(2-{[(4-bromophenyl)carbamoyl]amino}-2,4- dimethylpentanoyl)amino]acetate; (2S)-N-[(1S)aminooxophenylethyl]{[(4-bromophenyl)carbamoyl]amino} methylpentanamide; (2S)-{[(2S){[(4-bromophenyl)carbamoyl]amino} methylpentanoyl]amino}(phenyl)ethanoic acid; tert-butyl (2S)-{[(2S){[(4-bromophenyl)carbamoyl]amino} methylpentanoyl]amino}(phenyl)ethanoate; (2S)-N-[(2S)aminooxopentanyl]{[(4-bromophenyl)carbamoyl]amino} methylpentanamide; (2S){[(2S){[(4-bromophenyl)carbamoyl]amino} methylpentanoyl]amino}pentanoic acid; tert-butyl (2S){[(2S){[(4-bromophenyl)carbamoyl]amino} methylpentanoyl]amino}pentanoate; -{[(4-bromophenyl)carbamoyl]amino}-N-[(2R)hydroxypropanyl] methylpentanamide; -{[(4-bromophenyl)carbamoyl]amino}-N-(2,3-dihydroxypropyl) methylpentanamide; (2S){[(4-bromophenyl)carbamoyl]amino}-N-(1,3-dihydroxypropanyl) methylpentanamide; (2S){[(4-bromophenyl)carbamoyl]amino}-N-(2-hydroxymethylpropyl) methylpentanamide; (2S)-N-[(2S)aminomethyloxobutanyl]{[(4- bromophenyl)carbamoyl]amino}methylpentanamide; (2S){[(2S){[(4-bromophenyl)carbamoyl]amino}methylpentanoyl]amino} methylbutanoic acid; tert-butyl (2S){[(2S){[(4-bromophenyl)carbamoyl]amino} methylpentanoyl]amino}methylbutanoate; (2S)-N-[(2S)aminooxopropanyl]{[(4-bromophenyl)carbamoyl]amino} methylpentanamide; (2S){[(2S){[(4-bromophenyl)carbamoyl]amino} methylpentanoyl]amino}propanoic acid; tert-butyl (2S){[(2S){[(4-bromophenyl)carbamoyl]amino} methylpentanoyl]amino}propanoate; (2S)-N-[(2S)aminooxopropanyl]{[(4-bromo phenyl)carbamoyl]amino}methylpentanamide; (2S){[(2S){[(4-bromofluorophenyl)carbamoyl]amino} pentanoyl]amino}propanoic acid; tert-butyl (2S){[(2S){[(4-bromofluorophenyl)carbamoyl]amino} methylpentanoyl]amino}propanoate; (2S){[(4-bromofluorophenyl)carbamoyl]amino}-N-(2-hydroxyethyl) methylpentanamide; -{[(4-bromofluorophenyl)carbamoyl]amino}methyl-N-(2- oxopropyl)pentanamide; (2S)-N-(2-aminooxoethyl){[(4-bromofluorophenyl)carbamoyl]amino} methylpentanamide; {[(2S){[(4-bromofluorophenyl)carbamoyl]amino} methylpentanoyl]amino}acetic acid; tert-butyl {[(2S){[(4-bromofluorophenyl)carbamoyl]amino} methylpentanoyl]amino}acetate; (2S)-N-(2-aminooxoethyl){[(4-bromo fluorophenyl)carbamoyl]amino}pentanamide; (2S)-N-(2-aminooxoethyl){[(4-bromophenyl)carbamoyl]amino}pentanamide; (2S){[(4-bromophenyl)carbamoyl]amino}methyl-N-(2-oxopropyl)pentanamide; (2S)-N-(2-aminooxoethyl){[(4-bromophenyl)carbamoyl]amino} methylpentanamide; {[(2S){[(4-bromophenyl)carbamoyl]amino}methylpentanoyl]amino}acetic acid; (2S){[(4-bromophenyl)carbamoyl]amino}-N-(2-hydroxyethyl) methylpentanamide; tert-butyl {[(2S){[(4-bromophenyl)carbamoyl]amino} methylpentanoyl]amino}acetate; {[(2S){[(4-bromofluorophenyl)carbamoyl]amino}pentanoyl]amino}acetic acid; tert-butyl {[(2S){[(4-bromo fluorophenyl)carbamoyl]amino}pentanoyl]amino}acetate; -{[(4-bromofluorophenyl)carbamoyl]amino}-N-(2-oxopropyl)pentanamide; (2S){[(4-bromophenyl)carbamoyl]amino}-N-(2-oxopropyl)pentanamide; propanyl {[(2S){[(4-bromophenyl)carbamoyl]amino}pentanoyl]amino}acetate; ethyl {[(2S){[(4-bromophenyl)carbamoyl]amino}pentanoyl]amino}acetate; methyl {[(2S){[(4-bromophenyl)carbamoyl]amino}pentanoyl]amino}acetate; (2S){[(4-bromofluorophenyl)carbamoyl]amino}-N-(2-hydroxyethyl)pentanamide; (2S){[(4-bromophenyl)carbamoyl]amino}-N-(2-hydroxyethyl)pentanamide; (2S){[(4-bromofluorophenyl)carbamoyl]amino}-N-(2-hydroxyethyl) phenylpropanamide; {[(2S){[(4-bromophenyl)carbamoyl]amino}pentanoyl]amino}acetic acid; tert-butyl {[(2S){[(4-bromophenyl)carbamoyl]amino}pentanoyl]amino}acetate; (2S){[(4-bromofluorophenyl)carbamoyl]amino}-N-(2-oxopropyl) phenylpropanamide; (2S){[(4-bromophenyl)carbamoyl]amino}-N-(2-oxopropyl)phenylpropanamide; (2S,3S){[(4-bromofluorophenyl)carbamoyl]amino}-N-(2-hydroxyethyl) pentanamide; ){[(4-bromophenyl)carbamoyl]amino}-N-(2-hydroxyethyl) methylpentanamide; (2S,3S){[(4-bromofluorophenyl)carbamoyl]amino}methyl-N-(2- oxopropyl)pentanamide; (2S,3S){[(4-bromophenyl)carbamoyl]amino}methyl-N-(2- oxopropyl)pentanamide; (2S,3S)-N-(2-aminooxoethyl){[(4-bromofluorophenyl)carbamoyl]amino} methylpentanamide; (2S,3S)-N-(2-aminooxoe;thyl){[(4-bromophenyl)carbamoyl]amino} methylpentanamide {[(2S,3S){[(4-bromophenyl)carbamoyl]amino}methylpentanoyl]amino}acetic acid; utyl {[(2S,3S){[(4-bromophenyl)carbamoyl]amino} methylpentanoyl]amino}acetate; 3S){[(4-bromofluorophenyl)carbamoyl]amino} methylpentanoyl]amino}acetic acid; tert-butyl {[(2S,3S){[(4-bromofluorophenyl)carbamoyl]amino} methylpentanoyl]amino}acetate; (2S){[(4-bromophenyl)carbamoyl]amino}-N-(2-hydroxyethyl) phenylpropanamide; 3-{[(2S){[(4-bromophenyl)carbamoyl]amino}phenylpropanoyl]amino}propanoic acid; tert-butyl 3-{[(2S){[(4-bromophenyl)carbamoyl]amino} phenylpropanoyl]amino}propanoate; {[(2S){[(4-bromophenyl)carbamoyl]amino}phenylpropanoyl]amino}acetic acid; tert-butyl {[(2S){[(4-bromophenyl)carbamoyl]amino} phenylpropanoyl]amino}acetate.
Also described are compounds: {[2-{[(4-bromophenyl)carbamoyl]amino}(1H-imidazolyl)propanoyl]amino}acetic acid; tert-butyl {[2-{[(4-bromophenyl)carbamoyl]amino}(1H-imidazol yl)propanoyl]amino}acetate; {[(2S){[(4-bromophenyl)carbamoyl]amino}(methylsulfonyl)butanoyl]amino}acetic acid; tert-butyl {[(2S){[(4-bromophenyl)carbamoyl]amino} (methylsulfonyl)butanoyl]amino}acetate; {[(2S){[(4-bromophenyl)carbamoyl]amino}(methylsulfanyl)butanoyl]amino}acetic acid; tert-butyl {[(2S){[(4-bromophenyl)carbamoyl]amino} lsulfanyl)butanoyl]amino}acetate; 2-methyl{[(2S)methyl({[4- (trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}propanoic acid; tert-butyl 2-methyl{[(2S)methyl({[4- (trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}propanoate; {[(2S)methyl({[4- (methylsulfonyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetic acid; tert-butyl {[(2S)methyl({[4- (methylsulfonyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetate; {[(2S)methyl({[4- (methylsulfinyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetic acid; tert-butyl {[(2S)methyl({[4- (methylsulfinyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetate; 2-{[(2S){[(4-bromophenyl)carbamoyl]amino}methylpentanoyl]amino} propanoic acid; tert-butyl S){[(4-bromophenyl)carbamoyl]amino}methylpentanoyl]amino}- 2-methylpropanoate; ({(2S)methyl[({4- [(trifluoromethyl)sulfanyl]phenyl}carbamoyl)amino]pentanoyl}amino)acetic acid; utyl ({(2S)methyl[({4- [(trifluoromethyl)sulfanyl]phenyl}carbamoyl)amino]pentanoyl}amino)acetate; {[(2S)methyl({[4- (methylsulfanyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetic acid; utyl {[(2S)methyl({[4- (methylsulfanyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetate; {[(2R){[(4-bromophenyl)carbamoyl]amino}methylpentanoyl]amino}acetic acid; tert-butyl {[(2R){[(4-bromophenyl)carbamoyl]amino} methylpentanoyl]amino}acetate; {[(2R,3R){[(4-bromophenyl)carbamoyl]amino}methylpentanoyl]amino}acetic acid; tert-butyl {[(2R,3R){[(4-bromophenyl)carbamoyl]amino} methylpentanoyl]amino}acetate; {[(2S)methyl({[4- (trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetic acid; tert-butyl {[(2S)methyl({[4- (trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetate; (2S){[(4-bromophenyl)carbamoyl]amino}-N-[2-(dimethylamino)oxoethyl] methylpentanamide; [(2-{[(4-bromophenyl)carbamoyl]amino}methylpropanoyl)amino]acetic acid; tert-butyl [(2-{[(4-bromophenyl)carbamoyl]amino}methylpropanoyl)amino]acetate; [(2-{[(4-bromophenyl)carbamoyl]amino}ethylbutanoyl)amino]acetic acid; tert-butyl [(2-{[(4-bromophenyl)carbamoyl]amino}ethylbutanoyl)amino]acetate; [(2-{[(4-bromophenyl)carbamoyl]amino}-2,4-dimethylpentanoyl)amino]acetic acid; tert-butyl [(2-{[(4-bromophenyl)carbamoyl]amino}-2,4- dimethylpentanoyl)amino]acetate; (2S)-N-[(1S)aminooxophenylethyl]{[(4-bromophenyl)carbamoyl]amino} pentanamide; (2S)-{[(2S){[(4-bromophenyl)carbamoyl]amino} methylpentanoyl]amino}(phenyl)ethanoic acid; tert-butyl (2S)-{[(2S){[(4-bromophenyl)carbamoyl]amino} pentanoyl]amino}(phenyl)ethanoate; (2S)-N-[(2S)aminooxopentanyl]{[(4-bromophenyl)carbamoyl]amino} methylpentanamide; (2S){[(2S){[(4-bromophenyl)carbamoyl]amino} methylpentanoyl]amino}pentanoic acid; tert-butyl (2S){[(2S){[(4-bromophenyl)carbamoyl]amino} methylpentanoyl]amino}pentanoate; -{[(4-bromophenyl)carbamoyl]amino}-N-[(2R)hydroxypropanyl] methylpentanamide; (2S){[(4-bromophenyl)carbamoyl]amino}-N-(2,3-dihydroxypropyl) methylpentanamide; (2S){[(4-bromophenyl)carbamoyl]amino}-N-(1,3-dihydroxypropanyl) methylpentanamide; (2S){[(4-bromophenyl)carbamoyl]amino}-N-(2-hydroxymethylpropyl) methylpentanamide; (2S)-N-[(2S)aminomethyloxobutanyl]{[(4- bromophenyl)carbamoyl]amino}methylpentanamide; (2S){[(2S){[(4-bromophenyl)carbamoyl]amino}methylpentanoyl]amino} methylbutanoic acid; tert-butyl (2S){[(2S){[(4-bromophenyl)carbamoyl]amino} methylpentanoyl]amino}methylbutanoate; (2S)-N-[(2S)aminooxopropanyl]{[(4-bromophenyl)carbamoyl]amino} methylpentanamide; (2S){[(2S){[(4-bromophenyl)carbamoyl]amino} methylpentanoyl]amino}propanoic acid; tert-butyl (2S){[(2S){[(4-bromophenyl)carbamoyl]amino} methylpentanoyl]amino}propanoate; (2S)-N-[(2S)aminooxopropanyl]{[(4-bromo fluorophenyl)carbamoyl]amino}methylpentanamide; (2S){[(2S){[(4-bromofluorophenyl)carbamoyl]amino} methylpentanoyl]amino}propanoic acid; utyl (2S){[(2S){[(4-bromofluorophenyl)carbamoyl]amino} methylpentanoyl]amino}propanoate; (2S){[(4-bromofluorophenyl)carbamoyl]amino}-N-(2-hydroxyethyl) methylpentanamide; (2S){[(4-bromofluorophenyl)carbamoyl]amino}methyl-N-(2- oxopropyl)pentanamide; (2S)-N-(2-aminooxoethyl){[(4-bromofluorophenyl)carbamoyl]amino} methylpentanamide; {[(2S){[(4-bromofluorophenyl)carbamoyl]amino} methylpentanoyl]amino}acetic acid; tert-butyl {[(2S){[(4-bromofluorophenyl)carbamoyl]amino} methylpentanoyl]amino}acetate; utyl 2-{[(2R){[(4-bromophenyl)carbamoyl]amino}methylpentanoyl]amino}- ylpropanoate; 2-{[(2R){[(4-bromophenyl)carbamoyl]amino}methylpentanoyl]amino} methylpropanoic acid; tert-butyl [(4-amino{[(4-bromophenyl)carbamoyl]amino} oxobutanoyl)amino]acetate; [(4-amino{[(4-bromophenyl)carbamoyl]amino}oxobutanoyl)amino]acetic acid; tert-butyl (4-bromophenyl)carbamoyl]amino}(1H-indol yl)propanoyl]amino}acetate; {[2-{[(4-bromophenyl)carbamoyl]amino}(1H-indolyl)propanoyl]amino}acetic acid.
Some compounds of Formula I and of Formula II and some of their intermediates have at least one asymmetric center in their structure. This asymmetric center may be present in an R or S configuration, said R and S notation is used in correspondence with the rules described in Pure Appli. Chem. (1976), 45, 11-13.
The term aceutically acceptable salts" refers to salts or xes that retain the desired biological activity of the above identified compounds and exhibit minimal or no undesired toxicological effects. The "pharmaceutically acceptable salts" according to the ion e therapeutically active, non-toxic base or acid salt forms, which the compounds of Formula I and of Formula II are able to form.
The acid addition salt form of a compound of Formula I and of Formula II that occurs in its free form as a base can be obtained by treating the free base with an appropriate acid such as an inorganic acid, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; or an organic acid such as for example, acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, c acid, malonic acid, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric acid, methylsulfonic acid, ethanesulfonic acid, benzenesulfonic acid, formic and the like (Handbook of Pharmaceutical Salts, P. Heinrich Stahal & Camille G. Wermuth (Eds), Verlag Helvetica Chemica Acta- Zürich, 2002, 329-345).
The base addition salt form of a compound of a I and of Formula II that occurs in its acid form can be obtained by treating the acid with an appropriate base such as an inorganic base, for example, sodium ide, magnesium hydroxide, potassium hydroxide, Calcium hydroxide, a and the like; or an organic base such as for example, L-Arginine, ethanolamine, betaine, hine, morpholine and the like. (Handbook of Pharmaceutical Salts, P.Heinrich & Camille G.
Wermuth (Eds), Verlag Helvetica Chemica Acta- Zürich, 2002, 329-345).
Compounds of Formula I and of Formula II and their salts can be in the form of a solvate, which is included within the scope of the present invention. Such solvates include for example hydrates, alcoholates and the like.
With respect to the present disclosure reference to a compound or nds, is intended to encompass that compound in each of its possible isomeric forms and mixtures thereof unless the particular ic form is referred to specifically.
Compounds described herein may exist in different polymorphic forms.
Although not explicitly indicated in the above formula, such forms are intended to be included within the scope of the present disclosure.
The compounds described herein are indicated for use in treating or preventing conditions in which there is likely to be a component involving the N- formyl peptide receptor like-1 receptor.
Also described are ceutical compositions including at least one compound bed herein in a pharmaceutically acceptable carrier.
Also described are s for ng disorders associated with modulation of the N-formyl peptide receptor like-1 receptor.
Such methods can be performed, for example, by administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of at least one compound described herein.
Therapeutic utilities of the N-formyl peptide or like-1 receptor modulators are ocular inflammatory diseases including, but not d to, wet and dry age-related r degeneration , uveitis, dry eye, Keratitis, allergic eye disease and conditions affecting the posterior part of the eye, such as maculopathies and retinal degeneration including non-exudative age related macular degeneration, exudative age related macular degeneration, choroidal neovascularization, diabetic retinopathy (proliferative), retinopathy of prematurity (ROP), acute r neuroretinopathy, central serous chorioretinopathy, cystoid macular edema, and diabetic macular edema; infectious keratitis, uveitis, herpetic keratitis, corneal angiogenesis, lymphangiogenesis, uveitis, retinitis, and choroiditis such as acute ocal placoid pigment epitheliopathy, Behcet’s disease, birdshot retinochoroidopathy, infectious (syphilis, lyme, tuberculosis, toxoplasmosis), intermediate uveitis (pars planitis), ocal choroiditis, le evanescent white dot syndrome (mewds), ocular dosis, posterior scleritis, serpiginous choroiditis, subretinal fibrosis and uveitis syndrome, Vogt-Koyanagi-and Harada syndrome; vasuclar diseases/ exudative diseases such as retinal arterial ive disease, central retinal vein occlusion, cystoids macular edema, disseminated intravascular coagulopathy, branch retinal vein occlusion, hypertensive fundus changes, ocular ischemic syndrome, retinal arterial microaneurysms, Coat’s disease, parafoveal telangiectasis, hemi-retinal vein occlusion, ophlebitis, central retinal artery occlusion, branch retinal artery occlusion, carotid artery disease (CAD), frosted branch is, sickle cell retinopathy and other hemoglobinopathies, angioid streaks, al exudative vitreoretinopathy, and Eales disease; traumatic/ surgical conditions such as sympathetic ophthalmia, uveitic l e, retinal detachment, trauma, post al corneal wound healing, conditions caused by laser, conditions caused by photodynamic therapy, photocoagulation, hypoperfusion during surgery, radiation retinopathy, and bone marrow transplant retinopathy; proliferative disorders such as proliferative vitreal retinopathy and epiretinal membranes, and proliferative diabetic retinopathy; infectious disorders such as ocular histoplasmosis, ocular toxocariasis, presumed ocular histoplasmosis syndrome , endophthalmitis, asmosis, retinal es associated with HIV infection, choroidal disease associate with HIV infection, uveitic disease associate with HIV infection, viral retinitis, acute retinal necrosis, progressive outer retinal necrosis, fungal retinal diseases, ocular syphilis, ocular tuberculosis, diffuse eral subacute neuroretinitis, and s; genetic disorders such as retinitis pigmentosa, ic disorders with accosiated retinal dystrophies, congenital stationary night blindness, cone dystrophies, Stargardt’s disease and fundus flavimaculatus, Best’s disease, pattern dystrophy of the retinal pigmented epithelium, X-linked retinoschisis, Sorsby’s fundus dystrophy, benign concentric maculopathy, Bietti’s crystalline dystrophy, and pseudoxanthoma elasticum; retinal tears/ holes such as retinal detachment, macular hole, and giant retinal tear; tumors such as retinal disease associated with tumors, congenital hypertrophy of the retinal pigmented epithelium, posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined hamartoma of the retina and l pigmented epithelium, blastoma, vasoproliferative tumors of the ocular fundus, l ytoma, and intraocular lymphoid tumors; and miscellaneous other diseases ing the posterior part of the eye such as punctate inner choroidopathy, acute posterior multifocal placoid pigment epitheliopathy, myopic retinal degeneration, and acute retinal pigement epitheliitis, systemic inflammatory diseases such as stroke, coronary artery disease, obstructive airway diseases, HIV- mediated retroviral ions, cardiovascular disorders including coronary artery e, neuroinflammation, neurological disorders, pain and immunological disorders, asthma, ic disorders, inflammation, systemic lupus matosus, psoriasis, CNS disorders such as Alzheimer’s disease, arthritis, , inflammatory bowel disease, cachexia, angina pectoris, post-surgical corneal inflammation, ritis, MGD, dermal wound healing, burns, rosacea, atopic dermatitis, acne, psoriasis, heic dermatitis, actinic keratoses, viral warts, photoaging rheumatoid arthritis and related inflammatory ers, alopecia, glaucoma, branch vein occlusion, Best’s vitelliform macular degenartion, retinitis pigmentosa, erative vitreoretinopathy (PVR), and any other degenerative disease of either the photoreceptors or the RPE (Perretti, Mauro et al. Pharmacology & Therapeutics 127 (2010) 175-188.) These compounds are useful for the treatment of mammals, including , with a range of conditions and diseases that are alleviated by the N-formyl peptide receptor like-1 receptor modulation: including, but not limited to the treatment of wet and dry age-related macular degeneration (ARMD), diabetic retinopathy (proliferative), retinopathy of prematurity (ROP), ic macular edema, uveitis, retinal vein occlusion, cystoids macular edema, glaucoma, branch vein occlusion, Best’s vitelliform macular degenartion, tis pigmentosa, proliferative vitreoretinopathy (PVR), and any other rative disease of either the photoreceptors or the RPE.
Also described are methods for treating disorders associated with modulation of the FPRL-1 receptor. Such methods can be performed, for example, by administering to a subject in need thereof a therapeutically ive amount of at least one compound of the invention, or any combination thereof, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual isomers, enantiomers, and diastereomers thereof.
The present dislcosure concerns the use of a compound of Formula I and of Formula II or a pharmaceutically acceptable salt f, for the manufacture of a medicament for the treatment of ocular inflammatory diseases including, but not d to, wet and dry age-related macular degeneration (ARMD), uveitis, dry eye, tis, allergic eye disease and conditions affecting the posterior part of the eye, such as maculopathies and retinal degeneration including non-exudative age related macular degeneration, exudative age related macular degeneration, choroidal cularization, diabetic retinopathy (proliferative), pathy of prematurity (ROP), acute macular neuroretinopathy, central serous retinopathy, d macular edema, and diabetic macular edema; infectious keratitis, uveitis, herpetic keratitis, corneal angiogenesis, lymphangiogenesis, uveitis, retinitis, and choroiditis such as acute multifocal placoid pigment epitheliopathy, ’s disease, birdshot retinochoroidopathy, infectious (syphilis, lyme, tuberculosis, toxoplasmosis), intermediate uveitis (pars is), multifocal choroiditis, multiple evanescent white dot syndrome (mewds), ocular dosis, posterior scleritis, serpiginous choroiditis, subretinal fibrosis and uveitis syndrome, Vogt-Koyanagi-and Harada syndrome; vasuclar diseases/ exudative diseases such as retinal arterial occlusive disease, central retinal vein occlusion, cystoids macular edema, inated intravascular coagulopathy, branch retinal vein occlusion, hypertensive fundus changes, ocular ischemic syndrome, retinal al microaneurysms, Coat’s e, parafoveal telangiectasis, hemi-retinal vein occlusion, papillophlebitis, central retinal artery occlusion, branch retinal artery occlusion, carotid artery disease (CAD), frosted branch angiitis, sickle cell retinopathy and other hemoglobinopathies, angioid streaks, familial exudative vitreoretinopathy, and Eales disease; traumatic/ surgical conditions such as sympathetic ophthalmia, uveitic retinal disease, retinal detachment, trauma, post al l wound healing, conditions caused by laser, conditions caused by photodynamic therapy, photocoagulation, hypoperfusion during surgery, radiation retinopathy, and bone marrow transplant retinopathy; proliferative disorders such as proliferative vitreal retinopathy and epiretinal membranes, and proliferative diabetic retinopathy; infectious disorders such as ocular histoplasmosis, ocular riasis, presumed ocular histoplasmosis syndrome (POHS), thalmitis, toxoplasmosis, retinal diseases associated with HIV ion, choroidal disease associate with HIV infection, uveitic disease associate with HIV infection, viral retinitis, acute retinal necrosis, ssive outer retinal necrosis, fungal retinal diseases, ocular syphilis, ocular tuberculosis, diffuse unilateral subacute neuroretinitis, and myiasis; genetic disorders such as retinitis pigmentosa, systemic ers with accosiated retinal dystrophies, congenital stationary night blindness, cone dystrophies, Stargardt’s disease and fundus flavimaculatus, Best’s disease, n phy of the retinal pigmented epithelium, X-linked retinoschisis, Sorsby’s fundus dystrophy, benign tric maculopathy, ’s crystalline dystrophy, and pseudoxanthoma elasticum; retinal tears/ holes such as retinal detachment, macular hole, and giant retinal tear; tumors such as retinal disease ated with , congenital hypertrophy of the retinal pigmented epithelium, posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, dal metastasis, ed hamartoma of the retina and retinal pigmented epithelium, blastoma, vasoproliferative tumors of the ocular fundus, retinal astrocytoma, and intraocular lymphoid tumors; and miscellaneous other diseases affecting the posterior part of the eye such as punctate inner choroidopathy, acute posterior multifocal placoid pigment epitheliopathy, myopic retinal degeneration, and acute retinal pigement epitheliitis, systemic matory diseases such as stroke, coronary artery disease, obstructive airway diseases, HIV- mediated iral infections, cardiovascular disorders including coronary artery disease, neuroinflammation, neurological disorders, pain and immunological disorders, asthma, allergic disorders, inflammation, ic lupus matosus, sis, CNS disorders such as Alzheimer’s disease, arthritis, sepsis, inflammatory bowel e, cachexia, angina pectoris, post-surgical corneal inflammation, blepharitis, MGD, dermal wound healing, burns, rosacea, atopic dermatitis, acne, psoriasis, seborrheic dermatitis, actinic keratoses, viral warts, ging toid arthritis and related inflammatory disorders, alopecia, glaucoma, branch vein occlusion, Best’s vitelliform macular degenartion, retinitis pigmentosa, proliferative vitreoretinopathy (PVR), and any other degenerative disease of either the photoreceptors or the RPE.
The actual amount of the compound to be administered in any given case will be determined by a physician taking into account the relevant circumstances, such as the severity of the condition, the age and weight of the patient, the patient’s general physical condition, the cause of the condition, and the route of administration.
The patient will be administered the compound orally in any acceptable form, such as a tablet, liquid, capsule, powder and the like, or other routes may be desirable or necessary, particularly if the patient suffers from nausea. Such other routes may include, without exception, transdermal, parenteral, aneous, intranasal, via an implant stent, intrathecal, intravitreal, topical to the eye, back to the eye, intramuscular, intravenous, and intrarectal modes of delivery. Additionally, the formulations may be designed to delay release of the active compound over a given period of time, or to carefully control the amount of drug released at a given time during the course of therapy.
Also described are pharmaceutical compositions including at least one compound described herein in a pharmaceutically acceptable carrier thereof. The phrase "pharmaceutically acceptable" means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not rious to the recipient f.
Pharmaceutical compositions described herein can be used in the form of a solid, a solution, an emulsion, a dispersion, a patch, a micelle, a liposome, and the like, wherein the resulting ition contains one or more compounds described herein, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for enteral or parenteral applications. Compounds bed herein may be combined, for e, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The carriers which can be used include glucose, e, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, dal silica, potato starch, urea, medium chain length triglycerides, dextrans, and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form. In on auxiliary, izing, thickening and ng agents and perfumes may be used. Invention compounds are included in the pharmaceutical composition in an amount ient to produce the desired effect upon the process or disease condition.
Pharmaceutical compositions containing compounds described herein may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, ons, hard or soft es, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group ting of a sweetening agent such as sucrose, lactose, or saccharin, flavoring agents such as peppermint, oil of wintergreen or cherry, coloring agents and preserving agents in order to e pharmaceutically elegant and palatable preparations. s containing invention compounds in admixture with non-toxic pharmaceutically acceptable excipients may also be manufactured by known methods. The excipients used may be, for example, (1) inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents such as corn starch, potato starch or alginic acid; (3) binding agents such as gum tragacanth, corn starch, n or acacia, and (4) ating agents such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
In some cases, formulations for oral use may be in the form of hard gelatin capsules wherein the compounds described herein are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin es n the compounds described herein are mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
The pharmaceutical itions may be in the form of a sterile injectable suspension. This suspension may be formulated according to known methods using suitable sing or wetting agents and suspending agents. The sterile able preparation may also be a sterile able solution or suspension in a non-toxic erally-acceptable diluent or solvent, for example, as a solution in 1,3- butanediol. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides, fatty acids (including oleic acid), naturally ing vegetable oils like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyl oleate or the like. Buffers, preservatives, antioxidants, and the like can be incorporated as required.
The nds described herein may also be administered in the form of suppositories for rectal administration of the drug. These compositions may be ed by mixing the compounds described herein with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
Since individual subjects may t a wide variation in severity of symptoms and each drug has its unique therapeutic characteristics, the precise mode of administration and dosage employed for each subject is left to the tion of the tioner.
The compounds and pharmaceutical compositions described herein are useful as medicaments in mammals, including humans, for treatment of diseases and/or alleviations of conditions which are responsive to treatment by agonists or functional antagonists of the N-formyl peptide or like-1 (FPRL-1) receptor.
Also described are methods for treating a disorder associated with modulation of the N-formyl peptide receptor like-1 (FPRL-1) receptor. Such methods can be performed, for e, by administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of at least one compound described herein. As used herein, the term "therapeutically ive amount" means the amount of the pharmaceutical composition that will elicit the biological or medical response of a subject in need thereof that is being sought by the researcher, veterinarian, medical doctor or other ian. In some embodiments, the t in need thereof is a mammal. In some embodiments, the mammal is human.
Also described are processes for preparing the compounds of Formula I. The nds of formula I according to the disclosure can be prepared analogously to conventional methods as understood by the person skilled in the art of synthetic organic chemistry. Synthetic Scheme 1 set forth below, illustrates how the compounds ing to the disclosure can be made.
Scheme 1 O R3 O H H R3 Et3N, l + O C N R4 N N R4 O CH2Cl2, O R2 R2 O R7 R5 R7 R5 R6 R6 H H R3 HCO2H N N R4 R2 O R7 R5 EDCI, HOBt O R3 DMF H H R1 N N R4 O H R2 O O a R7 R5 NH2 R6 a b Scheme 2 O R3 O R8 Et3N, R8H R3 NH2.HCl + O C N R4 N N R4 O CH2Cl2, O R2 R7 R5 O R2 R7 R5 R8 R3 H H HCO2H N N R4 R2 R7 R5 EDCI, HOBt DMF R1 R9R10O R3 R8H H ( ) N N R4 a ( ) b N R1 R9R10 O H R2 O ( ) ( ) b NH2 R5 a R10a R7 O R9a R10a Compounds of Formula I were prepared as depicted in Scheme 1.
Compounds of Formula II were prepared as depicted in Scheme 2. In l, a tbutyl ester derivative of an amino acid is reacted with a substituted phenylisocyanate to e a phenylurea derivative. The t-butyl ester protecting group is then removed under acidic conditions to give the amino acid urea. The carboxylic acid group is then ted to an amide by ng the compound with activating reagents, such as 1-ethyl(3-dimethylaminopropyl) carbodiimide (EDCI) and Hydroxybenzotriazole (HOBt) in the presence of an amine, or by other methods known to those skilled in the art. At this stage, those skilled in the art will appreciate that many additional compounds that fall under the scope of the disclosure may be ed by performing various common chemical reactions. Details of certain specific chemical transformations are provided in the examples.
Those skilled in the art will be able to routinely modify and/or adapt the following scheme to synthesize any compounds of the invention covered by Formula I or Formula II.
DETAILED DESCRIPTION OF THE INVENTION It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention claimed. As used herein, the use of the singular includes the plural unless specifically stated otherwise.
It will be y nt to those skilled in the art that some of the compounds described herein may n one or more asymmetric centers, such that the compounds may exist in enantiomeric as well as in diastereomeric forms.
Unless it is specifically noted otherwise, the scope of the present disclosure includes all enantiomers, reomers and racemic mixtures. Some of the compounds described herein may form salts with pharmaceutically acceptable acids or bases, and such pharmaceutically acceptable salts of the compounds described herein are also within the scope of the disclosure.
The present disclosure describes all pharmaceutically acceptable isotopically enriched compounds. Any nd bed herein may contain one or more isotopic atoms enriched or different than the l ratio such as deuterium 2H (or D) in place of hydrogen 1H (or H) or use of 13 C enriched material in place of 12 C and the like. r substitutions can be employed for N, O and S. The use of isotopes may assist in analytical as well as therapeutic aspects of the disclosure. For example, use of deuterium may increase the in vivo half-life by altering the lism (rate) of the compounds bed herein. These nds can be prepared in accord with the preparations described by use of isotopically enriched The following examples are for illustrative purposes only and are not intended, nor should they be construed as limiting the invention in any manner. Those skilled in the art will appreciate that variations and modifications of the following examples can be made without exceeding the spirit or scope of the invention.
As will be evident to those skilled in the art, individual isomeric forms can be obtained by separation of mixtures thereof in conventional manner. For example, in the case of roisomeric isomers, chromatographic separation may be employed.
Compound names were generated with ACD version 12.5. In general, characterization of the compounds is performed according to the following methods, NMR spectra are recorded on 300 or 600 MHz Varian and acquired at room temperature. Chemical shifts are given in ppm referenced either to internal TMS or to the solvent signal.
All the reagents, solvents, catalysts for which the sis is not described are purchased from chemical vendors such as Sigma Aldrich, Fluka, Bio-Blocks, Combi-blocks, TCI, VWR, Lancaster, Oakwood, Trans World Chemical, Alfa, Fisher, Maybridge, Frontier, Matrix, Ukrorgsynth, Toronto, Ryan Scientific, SiliCycle, Anaspec, Syn Chem, Chem-Impex, MIC-scientific, Ltd; r some known intermediates, were prepared according to published procedures.
Usually the compounds described herein were purified by medium pressure liquid chromatography, unless noted otherwise.
The following iations are used in the examples: Et 3N triethylamine CH 2Cl 2 dichloromethane CDCl 3 deuterated chloroform MeOH methanol CD 3OD deuterated methanol Na 2SO 4 sodium sulfate DMF N,N dimethylformamide EDCI 1-ethyl(3-dimethylaminopropyl) carbodiimide HOBt Hydroxybenzotriazole THF tertahydrofuran ClCO 2Et hloroformate NH 3 ammonia The following synthetic schemes illustrate how compounds ing to the sure can be made. Those skilled in the art will be routinely able to modify and/or adapt the following schemes to synthesize any nd of the invention covered by Formula II.
Example 1 Intermediate 1 tert-Butyl (2S){[(4-Bromophenyl)carbamoyl]amino}phenylpropanoate To a solution of L-phenyl-alanine utyl ester hydrochloride (100 mg, 0.41 mmol) and 6 mL of methylene chloride at 25 oC was added 4-bromo-phenyl isocyanate (81 mg, 0.41 mmol) and triethylamine (62 mg, 0.62 mmol). The resulting mixture was stirred at 25 oC for 30 s. The mixture was concentrated and the e was purified by medium pressure liquid chromatography on silica gel using ethyl acetate : hexane (20:80) to yield Intermediate 1, as a white solid. 1H NMR (CDCl δ: 7.20 - 7.35 (m, 5H), 7.13 - 7.20 (m, 2H), 7.01 - 3, 300MHz) 7.10 (m, 2H), 6.79 (br. s., NH), 5.52 (br. s., NH), 4.70 (t, J = 6.2 Hz, 1H), 2.91 (ddd, J = 19.0 Hz , J = 6.0 Hz, 2H), 1.47 (m, 9H).
Intermediates 2, 3 and 4 were prepared from the corresponding amino acid in a similar manner to the procedure described in Example 1 for Intermediate 1, starting with the appropriate amino acid. The results are described below in Table 1.
Table 1 Interm. IUPAC name 1H NMR δ (ppm) No. Structure 2 tert-Butyl (2S,3S){[(4-bromo 1H NMR (CDCl δ: 7.29 3, ) phenyl)carbamoyl]amino} - 7.39 (m, 2H), 7.10 - 7.22 (m, methylpentanoate 2H), 6.83 (br. s., 1H), 4.44 (d, J = 4.4 Hz, 1H), 1.81 - 1.99 (m, 1H), 1.36 - 1.46 (m, 1H), 1.08 - 1.31 (m, 1H), 0.86 - 1.02 (m, 6H). 3 tert-Butyl (2S){[(4- 1H NMR (CDCl δ: 7.26 3, 300MHz) henyl) - 7.36 (m, 2H), 7.09 - 7.18 (m, carbamoyl]amino}-pentanoate 2H), 6.95 (br. s., NH), 4.40 - 4.50 (m, 1H), 1.73 - 1.89 (m, 1H), 1.52 - 1.72 (m, 1H), 1.25 - 1.46 (m, 2H), 0.95 (t, 2H). 4 tert-butyl (2S){[(4-bromo 1H NMR (CDCl 7.20 3, 300MHz) δ: phenyl) carbamoyl]amino} - 7.33 (m, 2H), 7.04 - 7.15 (m, methylpentanoate 2H), 4.44 (dd, J = 9.1, 5.3 Hz, 1H), 1.74 (dd, J = 12.9, 6.4 Hz, 1H), 1.54 - 1.68 (m, 1H), 1.50 (s, 9H), 1.40 - 1.47 (m, 1H), 0.97 (d, J = 3.5 Hz, 3H), 0.95 (d, 3H).
Example 2 Intermediate 5 (2S){[(4-Bromophenyl)carbamoyl]amino}phenylpropanoic Acid H H N N A solution of Intermediate 1 (60 mg, 0.15 mmol) and 0.5 mL of formic acid was stirred at 25 oC for 3 hours. The resulting mixture was quenched with water (1mL) then ted with ethyl acetate. The organic layer was washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was rinsed 4 times with methylene chloride : hexane (1:1) to yield Intermediate 5 as a white solid. 1H NMR (acetone-d 8.29 (s, NH), 7.40 - 7.50 (m, 2H), 7.32 - 6, 300MHz) δ: 7.40 (m, 2H), 7.18 - 7.31 (m, 5H), 5.98 (d, J = 7.9 Hz, NH), 4.67 (m, 1H), 3.02 (ddd, J = 19.0 Hz , J = 6.0 Hz, 2H).
Intermediates 6, 7 and 8 and nds 1 through 6 were prepared from the corresponding urea derivative in a similar manner to the ure described in Example 2 for Intermediate 5. The results are described below in Table 2.
Table 2 Interm. IUPAC name 1H NMR δ (ppm) No. Structure 6 (2S,3S){[(4-bromophenyl) 1H NMR (acetone-d 6, 300MHz) δ: carbamoyl]amino} 8.24 (br. s., 1H), 7.44 - 7.53 (m, 2H), methylpentanoic acid 7.32 - 7.42 (m, 2H), 6.08 (d, J = 8.8 Hz, 1H), 4.44 (dd, J = 8.6, 4.8 Hz, 1H), 1.86 - 2.00 (m, J = 9.1, 6.9, 4.6, 4.6 Hz, 1H), 1.43 - 1.61 (m, 1H), 1.15 - 1.33 (m, 1H), 0.88 - 1.04 (m, 6H). (2S){[(4-bromophenyl) 1H NMR (acetone-d 6, 300MHz) δ: carbamoyl]amino}-pentanoic 8.20 (s, NH), 7.43 - 7.52 (m, 2H), 7.33 acid - 7.41 (m, 2H), 6.08 (d, J = 9.1 Hz, NH), 4.38 - 4.50 (m, 1H), 1.77 - 1.92 (m, 1H), 1.61 - 1.76 (m, 1H), 1.36 - 1.53 (m, 2H), 0.89 - 1.00 (m, 3H). 8 (2S){[(4-bromophenyl) 1H NMR (acetone-d 6, 300MHz) δ: carbamoyl]amino} 8.17 (s, NH), 7.43 - 7.51 (m, 2H), 7.35 methylpentanoic acid - 7.41 (m, 2H), 6.04 (d, J = 9.1 Hz, NH), 4.42 - 4.53 (m, 1H), 1.73 - 1.88 (m, 1H), 1.53 - 1.73 (m, 2H), 0.97 (d, J = 2.1 Hz, 3H), 0.95 (d, 3H).
Comp. IUPAC name 1H NMR δ (ppm) No. ure 1 {[(2S){[(4- 1H NMR (acetone-d 6, 300MHz) δ: bromophenyl)carbamoyl]ami 8.26 (s, NH), 7.71 (br. s., NH), 7.32 - no} 7.46 (m, 4H), 7.13 - 7.31 (m, 5H), 6.03 propanoyl]amino}aceti (d, J = 8.5 Hz, NH), 4.71 (td, J = 7.7, c 5.4 Hz, 1H), 3.98 (d, J = 5.9 Hz, 2H), acid 3.14 - 3.26 (m, 1H), 3.01 (dd, 1H). 2 3-{[(2S){[(4- 1H NMR (acetone-d 6, 300MHz) δ: bromophenyl)carbamoyl]ami 8.27 (s, NH), 7.44 (s, NH), 7.33 - 7.43 no} (m, 4H), 7.15 - 7.30 (m, 5H), 6.03 (d, J phenylpropanoyl]amino}prop = 7.9 Hz, NH), 4.53 - 4.65 (m, 1H), anoic 3.34 - 3.51 (m, 2H), 2.93 - 3.15 (m, acid 2H), 2.47 (td, 2H). 3 3S){[(4-bromo 1H NMR ne-d 6, 300MHz) δ: fluorophenyl)carbamoyl]amin 8.28 (t, J = 8.9 Hz, 1H), 8.16 (br. s., o} NH), 7.67 (br. s., NH), 7.34 (dd, J = methylpentanoyl]amino}aceti 11.0, 2.2 Hz, 1H), 7.23 - 7.30 (m, 1H), c 6.57 (d, J = 9.4 Hz, NH), 4.37 (dd, J = acid 8.6, 5.7 Hz, 1H), 3.89 - 4.08 (m, 2H), 1.86 - 1.98 (m, 1H), 1.53 - 1.67 (m, 1H), 1.10 - 1.27 (m, 1H), 0.98 (d, J = 6.7 Hz, 3H), 0.85 - 0.94 (m, 3H). 4 {[(2S,3S){[(4- 1H NMR (acetone-d 6, 300MHz) δ: bromophenyl)carbamoyl]ami 8.27 (s, NH), 7.66 (br. s., NH), 7.42 - no} 7.51 (m, 2H), 7.32 - 7.41 (m, 2H), 6.08 methylpentanoyl]amino}aceti (d, J = 8.2 Hz, NH), 4.34 (dd, J = 8.6, c 5.7 Hz, 1H), 3.88 - 4.09 (m, 2H), 1.81 - acid 1.96 (m, 1H), 1.49 - 1.67 (m, 1H), 1.06 - 1.27 (m, 1H), 0.97 (d, J = 6.7 Hz, 3H), 0.86 - 0.93 (m, 3H). {[(2S){[(4- 1H NMR (acetone-d 6, 300MHz) δ: bromophenyl)carbamoyl]ami 8.25 (s, NH), 7.67 (br. s., NH), 7.41 - no}pentanoyl]amino}acetic 7.51 (m, 2H), 7.34 - 7.41 (m, 2H), 6.13 acid (d, J = 7.9 Hz, NH), 4.42 (td, J = 7.7, .4 Hz, 1H), 3.89 - 4.08 (m, 2H), 1.73 - 1.89 (m, 1H), 1.54 - 1.69 (m, 1H), 1.34 - 1.51 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H). 6 1H NMR (acetone-d 6, 300MHz) δ: {[(2S){[(4- 8.19 (s, NH), 7.70 (br. s., NH), 7.42 - bromophenyl)carbamoyl]ami 7.51 (m, 2H), 7.33 - 7.41 (m, 2H), 6.07 no} (d, J = 7.6 Hz, NH), 4.46 (ddd, J = 9.6, methylpentanoyl]amino}aceti 8.3, 5.0 Hz, 1H), 3.87 - 4.07 (m, 2H), c 1.72 - 1.86 (m, 1H), 1.61 - 1.72 (m, acid 1H), 1.46 - 1.59 (m, 1H), 0.95 (s, 3H), 0.93 (s, 3H).
Example 3 nd 7 tert-Butyl {[(2S){[(4-bromophenyl)carbamoyl]amino} phenylpropanoyl]amino}acetate To a solution of Intermediate 5 (80 mg, 0.22 mmol) and 2 mL of anhydrous DMF at 25 oC was added EDCI (64 mg, 0.33 mmol), HOBt (45 mg, 0.33 mmol), glycine tert-butyl ester (44 mg, 0.33 mmol) and N-methylmorpholine (44 mg, 0.44 mmol). The resulting mixture was stirred at 25 oC for 12 hours. The mixture was quenched with water (1 mL), and the product was extracted with ethyl acetate (20 mL). The layers were separated, and the organic layer was washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting product was ed by medium pressure liquid chromatography on silica gel using ethyl acetate : hexane (40:60) to yield Compound 7 as a white solid. 1H NMR (CDCl 7.18 - 7.35 (m, 7H), 7.03 (d, J = 8.5 Hz, 2H), 3, 300MHz) δ: 6.85 (br. s., 1H), 4.69 (t, J = 7.5 Hz, 1H), 3.74 - 3.96 (m, 2H), 2.98 - 3.19 (m, 2H), 1.42 (s, 9H).
Compounds 8 through 27 and ediate 9 were prepared from the corresponding urea derivative in a similar manner to the procedure described in Example 3 for Compound 7. The results are bed below in Table 3.
Table 3 Comp. IUPAC name 1H NMR δ (ppm) No. Structure 8 tert-butyl S){[(4- 1H NMR (CDCl 3, 300MHz) δ: bromophenyl)carbamoyl]amino}- 7.18 - 7.35 (m, 7H), 7.08 - 7.17 3-phenylpropanoyl] (m, 2H), 4.54 - 4.64 (m, 1H), 3.28 amino}propanoate - 3.52 (m, 2H), 2.94 - 3.17 (m, 2H), 2.18 - 2.40 (m, 2H), 1.41 (s, 9H). 9 (2S){[(4-bromophenyl) carbamoyl]amino}-N-(2- 1H NMR (CD 3OD, ) δ: hydroxyethyl) 7.30 - 7.37 (m, 2H), 7.17 - 7.30 propanamide (m, 7H), 4.50 (dd, J = 7.8, 6.3 Hz, O 1H), 3.44 - 3.59 (m, 2H), 3.23 - H H HO N N 3.30 (m, 2H), 3.05 - 3.15 (m, 1H), H 2.90 - 3.01 (m, 1H). 1H NMR (CDCl 3, 300MHz) δ: tert-butyl {[(2S,3S){[(4-bromo 7.92 - 7.99 (t, J = 8.9 Hz, 1H), fluorophenyl) carbamoyl]amino}- 7.40 (br. s., NH), 7.07 - 7.16 (m, 3-methylpentanoyl]amino}acetate 2H), 6.67 (s, NH), 6.54 (br. s., NH), 4.21 - 4.27 (m, 1H), 4.05 - 4.15 (m, 1H), 3.83 - 3.92 (m, 1H), 1.79 - 1.88 (m, 1H), 1.57 - 1.64 (m, 1H), 1.47 (s, 9H), 1.19 - 1.24 (m, 1H), 1.00 (d, J = 6.7 Hz, 3H), 0.92 (t, 3H) . 11 tert-butyl {[(2S,3S){[(4- 1H NMR (CD 3OD, 300MHz) δ: bromophenyl) carbamoyl]amino}- 8.55 (s, NH), 8.36 (br. s., NH), 3-methylpentanoyl]amino} acetate 7.33 - 7.40 (m, 2H), 7.26 - 7.33 (m, 2H), 6.28 (d, J = 8.5 Hz, NH), 4.20 (dd, J = 8.6, 6.3 Hz, 1H), 3.72 - 3.97 (m, 2H), 1.80 - 1.94 (m, 1H), 1.56 - 1.70 (m, 1H), 1.45 (s, 9H), 1.13 - 1.31 (m, 1H), 1.01 (d, J = 6.7 Hz, 3H), 0.92 - 0.98 (m, 3H). 12 (2S,3S){[(4-bromophenyl) 1H NMR (CD 3OD, 300MHz) δ: carbamoyl]amino}methyl-N-(2- 7.34 - 7.41 (m, 2H), 7.26 - 7.34 oxopropyl)pentanamide (m, 2H), 4.22 (d, J = 6.2 Hz, 1H), 4.05 (d, J = 8.2 Hz, 2H), 2.14 (s, 3H), 1.80 - 1.94 (m, 1H), 1.53 - 1.68 (m, 1H), 1.14 - 1.26 (m, 1H), 0.81 - 1.07 (m, 6H). 13 (2S,3S){[(4-bromo 1H NMR (CD 3OD, 300MHz) δ: fluorophenyl) carbamoyl]amino}- 7.99 (t, J = 8.8 Hz, 1H), 7.31 (dd, 3-methyl-N-(2- J = 10.7, 2.2 Hz, 1H), 7.16 - 7.27 oxopropyl)pentanamide (m, 1H), 4.22 (d, J = 5.9 Hz, 1H), 3.94 - 4.14 (m, 2H), 2.14 (s, 3H), 1.84 - 1.96 (m, 1H), 1.52 - 1.67 (m, 1H), 1.14 - 1.32 (m, 1H), 1.01 (d, J = 7.0 Hz, 3H), 0.92 - 0.98 (m, 3H). 14 1H NMR (CD 3OD, 300MHz) δ: (2S,3S){[(4-bromophenyl) 7.33 - 7.42 (m, 2H), 7.26 - 7.33 carbamoyl]amino}-N-(2- (m, 2H), 4.12 (d, J = 6.4 Hz, 1H), hydroxyethyl) 3.55 - 3.65 (m, 2H), 3.32 - 3.37 methylpentanamide (m, 1H), 1.76 - 1.91 (m, 1H), 1.48 - 1.63 (m, 1H), 1.09 - 1.31 (m, 2H), 0.90 - 0.99 (m, 6H). 1H NMR (CD 3OD, 300MHz) δ: (2S,3S){[(4-bromo 7.99 (t, J = 8.6 Hz, 1H), 7.31 (dd, fluorophenyl) carbamoyl]amino}- J = 10.8, 2.3 Hz, 1H), 7.18 - 7.27 ydroxyethyl) (m, 1H), 4.13 (d, J = 6.4 Hz, 1H), methylpentanamide 3.56 - 3.65 (m, 2H), 3.31 - 3.37 (m, 1H), 1.77 - 1.89 (m, 1H), 1.50 - 1.61 (m, 1H), 1.10 - 1.26 (m, 1H), 0.88 - 1.01 (m, 6H). 16 (2S){[(4-bromophenyl) 1H NMR (acetone-d 6, ) carbamoyl]amino}-N-(2- δ: 8.23 (s, NH), 7.59 (br. s., NH), oxopropyl)phenylpropanamide 7.32 - 7.47 (m, 4H), 7.15 - 7.29 (m, 5H), 6.01 (d, J = 8.2 Hz, NH), 4.70 (td, J = 7.7, 5.7 Hz, 1H), 4.05 (d, J = 5.3 Hz, 2H), 3.12 - 3.24 (m, 1H), 2.95 - 3.06 (m, 1H), 2.10 (s, 3H). 17 (2S){[(4-bromofluorophenyl) 1H NMR (acetone-d 6, 300MHz) carbamoyl]amino}-N-(2- δ: 8.22 (t, J = 8.9 Hz, 1H), 8.12 oxopropyl)phenylpropanamide (br. s., NH), 7.61 (br. s., NH), 7.32 (dd, J = 11.0, 2.2 Hz, 1H), 7.15 - 7.29 (m, 6H), 6.51 (d, J = 7.3 Hz, NH), 4.72 (td, J = 7.9, 5.6 Hz, 1H), 4.05 (dd, J = 5.6, 1.2 Hz, 2H), 3.14 - 3.24 (m, 1H), 2.95 - 3.05 (m, 1H), 2.10 (s, 3H). 18 tert-butyl {[(2S){[(4- 1H NMR (acetone-d 6, 300MHz) δ: bromophenyl) carbamoyl]amino}- 8.20 (s, NH), 7.60 (br. s., NH), pentanoyl]amino} acetate 7.42 - 7.51 (m, 2H), 7.32 - 7.41 (m, 2H), 6.07 (d, J = 7.6 Hz, NH), 4.41 (td, J = 7.9, 5.3 Hz, 1H), 3.75 - 3.99 (m, 2H), 1.73 - 1.89 (m, 1H), 1.53 - 1.70 (m, 1H), 1.43 (s, 9H), 1.37 - 1.48 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H). 19 (2S){[(4-bromofluorophenyl) 1H NMR (CD 3OD, 300MHz) δ: carbamoyl]amino}-N-(2- 7.91 (t, J = 8.6 Hz, 1H), 7.17 - hydroxyethyl) 7.34 (m, 7H), 4.50 (dd, J = 8.2, phenylpropanamide 6.2 Hz, 1H), 3.44 - 3.59 (m, 2H), 3.23 - 3.27 (m, 2H), 3.05 - 3.17 (m, 1H), 2.87 - 2.99 (m, 1H). (2S){[(4-bromophenyl) 1H NMR (CD 3OD, 300MHz) δ: carbamoyl]amino}-N-(2- 7.33 - 7.41 (m, 2H), 7.25 - 7.33 hydroxyethyl)pentanamide (m, 2H), 4.23 (dd, J = 8.2, 5.6 Hz, 1H), 3.56 - 3.63 (m, 2H), 1.69 - 1.84 (m, 1H), 1.54 - 1.68 (m, 1H), 1.29 - 1.51 (m, 2H), 0.91 - 1.02 (m, 3H). 21 (2S){[(4-bromofluorophenyl) 1H NMR (CD 3OD, 300MHz) δ: carbamoyl]amino}-N-(2- 7.97 (t, J = 8.6 Hz, 1H), 7.31 (dd, hydroxyethyl) amide J = 10.7, 2.2 Hz, 1H), 7.19 - 7.27 (m, 1H), 4.23 (dd, J = 8.1, 5.4 Hz, 1H), 3.56 - 3.66 (m, 2H), 1.68 - 1.83 (m, 1H), 1.54 - 1.68 (m, 1H), 1.34 - 1.51 (m, 2H), 0.91 - 1.03 (m, 3H). 22 methyl {[(2S){[(4-bromophenyl) 1H NMR (acetone-d 6, 300MHz) carbamoyl]amino}- δ: 8.19 (s, NH), 7.71 (br. s., NH), pentanoyl]amino}acetate 7.42 - 7.52 (m, 2H), 7.31 - 7.42 (m, 2H), 6.07 (d, J = 8.2 Hz, NH), 4.34 - 4.47 (m, 1H), 3.86 - 4.10 (m, 2H), 3.66 (s, 3H), 1.73 - 1.87 (m, 1H), 1.55 - 1.71 (m, 1H), 1.35 - 1.51 (m, 2H), 0.92 (t, 3H). 23 ethyl {[(4-bromophenyl) 1H NMR (acetone-d 6, ) carbamoyl]amino}- δ: 8.19 (s, NH), 7.69 (br. s., NH), pentanoyl]amino}acetate 7.42 - 7.50 (m, 2H), 7.32 - 7.40 (m, 2H), 6.07 (d, J = 8.2 Hz, NH), 4.42 (td, J = 7.9, 5.6 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 3.85 - 4.06 (m, 2H), 1.73 - 1.88 (m, 1H), 1.55 - 1.69 (m, 1H), 1.34 - 1.51 (m, 2H), 1.20 (t, J = 7.3, 3H), 0.92 (t, J = 7.3, 3H). 24 isopropyl {[(4- 1H NMR (acetone-d 6, 300MHz) bromophenyl) carbamoyl]amino}- δ: 8.20 (s, NH), 7.67 (br. s., NH), pentanoyl]amino} acetate 7.43 - 7.51 (m, 2H), 7.33 - 7.42 (m, 2H), 6.07 (d, J = 9.7 Hz, NH), 4.97 (dt, J = 12.5, 6.2 Hz, 1H), 4.41 (td, J = 7.8, 5.4 Hz, 1H), 3.82 - 4.04 (m, 2H), 1.73 - 1.89 (m, 1H), 1.55 - 1.70 (m, 1H), 1.34 - 1.50 (m, 2H), 1.22 (s, 3H), 1.20 (s, 3H), 0.92 (t, J = 7.3, 3H). 1H NMR (acetone-d 6, 300MHz) tert-butyl {[(2S){[(4- δ: 8.16 (s, NH), 7.62 (br. s., NH), bromophenyl) carbamoyl]amino}- 7.42 - 7.49 (m, 2H), 7.33 - 7.40 4-methylpentanoyl]amino} acetate (m, 2H), 6.03 (d, J = 8.8 Hz, NH), 4.40 - 4.51 (m, 1H), 3.76 - 3.95 (m, 2H), 1.72 - 1.84 (m, 1H), 1.60 - 1.73 (m, 1H), 1.45 - 1.58 (m, 1H), 0.95 (s, 3H), 0.93 (s, 3H). 26 (2S){[(4-bromophenyl) 1H NMR (CD 3 OD, 300MHz) δ: carbamoyl]amino}-N-(2- 7.34 - 7.41 (m, 2H), 7.26 - 7.33 hydroxyethyl) (m, 2H), 4.24 - 4.33 (m, 1H), 3.55 methylpentanamide - 3.64 (m, 2H), 3.32 - 3.35 (m, 2H), 1.64 - 1.79 (m, 1H), 1.48 - 1.62 (m, 2H), 0.98 (d, J = 4.1 Hz, 3H), 0.96 (d, J = 3.8 Hz, 3H). 27 -{[(4-bromophenyl) 1H NMR (acetone-d 6, 300MHz) carbamoyl]amino}methyl-N-(2- δ: 8.17 (s, NH), 7.61 (br. s., NH), oxopropyl)pentanamide 7.42 - 7.50 (m, 2H), 7.32 - 7.42 (m, 2H), 6.06 (d, J = 8.5 Hz, NH), 4.45 (ddd, J = 9.7, 8.1, 5.0 Hz, 1H), 4.04 (d, J = 5.6 Hz, 2H), 2.12 (s, 3H), 1.72 - 1.84 (m, 1H), 1.60 - 1.72 (m, 1H), 1.45 - 1.58 (m, 1H), 0.95 (s, 3H), 0.93 (s, 3H).
Interm. 1H NMR δ (ppm) No. IUPAC name Structure (2S){[(4-bromophenyl) 1H NMR (acetone-d6, 300MHz) 9 oyl]amino}-N- δ: 10.27 (br. s., OH), 8.18 (br. s., hydroxypentanamide NH), 8.03 (s, NH), 7.42 - 7.50 (m, 2H), 7.32 - 7.41 (m, 2H), 6.11 (d, J = 9.1 Hz, NH), 4.23 - 4.34 (m, 1H), 1.52 - 1.80 (m, 2H), 1.27 - 1.49 (m, 2H), 0.87 - 0.95 (t, J = 7.3 Hz, 3H).
Example 4 Compound 28 (2S,3S)-N-(2-aminooxoethyl){[(4-bromophenyl) carbamoyl]amino} methylpentanamide To a solution of Compound 11 (50 mg, 0.13 mmol) and 5 mL of ous tetrahydrofuran under argon at -78 oC was added triethylamine (24 mg, 0.17 mmol) and ethyl chloroformate (17 mg, 0.16 mmol). The mixture was stirred at -78 oC for 30 minutes, and then ammonia gas was bubbled into reaction flask for 1 minute. The ing mixture was stirred at 25 oC for 2 hours. The reaction was quenched with water (1 mL) , and the residue was extracted with ethyl acetate (20 mL). The layers were separated, and the organic layer was washed with water, brine, dried over Na2SO4, ed, and the filtrate was concentrated under reduced pressure. The resulting product was purified by medium pressure chromatography on silica gel using an eluent of methanol : dichloromethane (10:90) to yield to yield Compound 28 as a white solid. 1H NMR (CD 3OD, 300MHz) δ: 7.33 - 7.40 (m, 2H), 7.26 - 7.33 (m, 2H), 4.05 (d, J = 6.7 Hz, 1H), 3.85 (q, J = 17.0 Hz, 2H), 1.78 - 1.91 (m, 1H), 1.54 - 1.69 (m, 1H), 1.16 - 1.33 (m, 1H), 0.99 (d, J = 6.7 Hz, 3H), 0.92 - 0.98 (m, 3H) .
Compounds 29 through 85 as well as Intermediates 10 through 35 were prepared from the corresponding acid tive in a similar manner to the procedure described in Example 4 for Compound 28.
Table 4 Comp. IUPAC name 1H NMR δ (ppm) No. Structure 29 (2S,3S)-N-(2-aminooxoethyl)- 1H NMR (CD 3OD, 300MHz) δ: 8.00 2-{[(4-bromofluorophenyl) (t, J = 8.6 Hz, 1H), 7.32 (dd, J = carbamoyl]amino} 10.7, 2.2 Hz, 1H), 7.18 - 7.26 (m, methylpentanamide 1H), 4.05 (d, J = 6.4 Hz, 1H), 3.74 - 3.95 (m, 2H), 1.80 - 1.91 (m, 1H), 1.51 - 1.69 (m, 1H), 1.18 - 1.32 (m, 1H), 1.00 (d, J = 7.0 Hz, 3H), 0.92 - 0.98 (m, 3H). (2S)-N-(2-aminooxoethyl) 1H NMR (acetone-d 6, 300MHz) δ: {[(4-bromophenyl) 8.27 (s, NH), 7.70 (br. s., NH), 7.41 carbamoyl]amino}-pentanamide - 7.48 (m, 2H), 7.33 - 7.41 (m, 2H), 7.02 (s, NH), 6.30 (s, NH), 6.22 (d, J = 5.3 Hz, NH), 4.22 - 4.32 (m, 1H), 3.72 - 3.91 (m, 2H), 1.73 - 1.88 (m, 1H), 1.56 - 1.71 (m, 1H), 1.37 - 1.53 (m, 2H), 0.88 - 0.97 (m, 3H). 31 (2S)-N-(2-aminooxoethyl) 1H NMR ne-d 6, 300MHz) δ: romofluorophenyl] 8.23 (t, J = 8.8 Hz, 1H), 8.13 (br. s., carbamoyl} amino)pentanamide NH), 7.72 (s, NH), 7.35 (dd, J = .8, 2.3 Hz, 1H), 7.26 (dt, J = 8.9, 1.9 Hz, 1H), 7.00 (s, NH), 6.66 (d, J = 6.7 Hz, NH), 6.34 (s, NH), 4.29 (dd, J = 12.2, 8.1 Hz, 1H), 3.82 (dd, J = 5.9, 1.8 Hz, 2H), 1.75 - 1.90 (m, 1H), 1.58 - 1.73 (m, 1H), 1.37 - 1.53 (m, 2H), 0.89 - 0.98 (m, 3H). 32 (2S)-N-(2-aminooxoethyl) 1H NMR (acetone-d 6, 300MHz) δ: {[(4-bromophenyl) 8.20 (s, NH), 7.77 (br. s., NH), 7.40 carbamoyl]amino} - 7.47 (m, 2H), 7.32 - 7.39 (m, 2H), methylpentanamide 7.04 (br. s., NH), 6.38 (br. s., NH), 6.18 (d, J = 7.3 Hz, NH), 4.31 (ddd, J = 9.4, 7.0, 5.3 Hz, 1H), 3.71 - 3.93 (m, 2H), 1.69 - 1.85 (m, 1H), 1.49 - 1.69 (m, 2H), 0.96 (d, J = 3.2 Hz, 3H), 0.93 (d, J = 3.2 Hz, 3H). 33 tert-butyl {[(2S){[(4-bromo 1H NMR (CDCl 7.89 3, 300MHz) δ: phenyl) carbamoyl] (t, J = 8.8 Hz, 1H), 7.55 (br. s., NH), amino}methylpentanoyl] 7.07 (dd, J = 10.7, 2.2 Hz, 1H), 6.95 amino}acetate - 7.04 (m, 1H), 6.84 (br. s., NH), 4.43 (br. s., NH), 4.00 - 4.16 (m, 1H), 3.81 - 3.92 (m, 1H), 1.69 - 1.88 (m, 1H), 1.56 - 1.70 (m, 2H), 1.47 (s, 9H), 0.97 (d, J = 4.7 Hz, 3H), 0.95 (d, 3H). 34 {[(2S){[(4-bromo 1H NMR (acetone-d 6, 300MHz) δ: fluorophenyl) 8.27 (t, J = 8.8 Hz, 1H), 8.07 (br. s., carbamoyl]amino} NH), 7.71 (br. s., NH), 7.34 (dd, J = methylpentanoyl]amino}acetic 10.8, 2.1 Hz, 1H), 7.27 (dt, J = 8.8, acid 1.8 Hz, 1H), 6.54 (d, J = 8.8 Hz, NH), 4.42 - 4.53 (m, 1H), 3.93 - 4.01 (m, 2H), 1.72 - 1.86 (m, 1H), 1.63 - 1.74 (m, 1H), 1.46 - 1.60 (m, 1H), 0.96 (s, 3H), 0.93 (s, 3H). (2S){[(4-bromo 1H NMR (acetone-d 6, 300MHz) δ: fluorophenyl) 8.30 (t, J = 8.8 Hz, 1H), 8.06 (br. s., carbamoyl]amino}methyl-N- NH), 7.62 (br. s., NH), 7.31 - 7.38 (2-oxopropyl)pentanamide (m, 2H), 7.24 - 7.30 (m, 2H), 6.52 (d, J = 8.2 Hz, NH), 4.39 - 4.53 (m, 1H), 4.04 (d, J = 5.6 Hz, 2H), 2.10 - 2.15 (m, 3H), 1.70 - 1.86 (m, 1H), 1.61 - 1.71 (m, 1H), 1.47 - 1.62 (m, 1H), 0.96 (s, 3H), 0.93 (s, 3H). 36 (2S){[(4-bromo 1H NMR (CD 7.97 3OD, ) δ: fluorophenyl) (t, J = 8.8 Hz, 1H), 7.31 (dd, J = carbamoyl]amino}-N-(2- 10.8, 2.3 Hz, 1H), 7.18 - 7.27 (m, hydroxyethyl) 1H), 4.28 (dd, J = 9.2, 5.4 Hz, 1H), pentanamide 3.56 - 3.64 (m, 2H), 3.32 - 3.37 (m, 2H), 1.64 - 1.80 (m, 1H), 1.50 - 1.62 (m, 2H), 0.98 (d, J = 4.4 Hz, 3H), 0.96 (d, 3H). 37 (2S)-N-(2-aminooxoethyl) 1H NMR (acetone-d 6, 300MHz) δ: {[(4-bromofluorophenyl) 8.22 (t, J = 8.8 Hz, 1H), 8.09 (br. s., carbamoyl]amino} NH), 7.77 (br. s., NH), 7.34 (dd, J = methylpentanamide 11.0, 2.2 Hz, 1H), 7.25 (dt, J = 8.9, 1.7 Hz, 1H), 6.99 (br. s., NH), 6.62 (d, J = 7.0 Hz, NH), 6.37 (br. s., NH), 4.33 (ddd, J = 9.6, 7.0, 5.1 Hz, 1H), 3.72 - 3.92 (m, 2H), 1.68 - 1.86 (m, 1H), 1.49 - 1.70 (m, 2H), 0.96 (d, J = 3.5 Hz, 3H), 0.94 (d, 3H). 38 tert-butyl (2S){[(2S){[(4- 1H NMR (CDCl 7.90 3, 300MHz) δ: 2-fluorophenyl) (t, J = 8.8 Hz, 1H), 7.45 (br. s., NH), carbamoyl]amino} 7.02 - 7.15 (m, 2H), 6.92 (s, NH), methylpentanoyl]amino}propan 6.61 (br. s., NH), 4.37 - 4.54 (m, oate 2H), 1.79 (dt, J = 13.2, 6.9 Hz, 1H), 1.56 - 1.69 (m, 2H), 1.46 (s, 9H), 1.40 (d, J = 7.3 Hz, 3H), 0.97 (s, 3H), 0.95 (s, 3H). 39 (2S){[(2S){[(4-bromo 1H NMR (acetone-d 6, 300MHz) δ: fluorophenyl) 8.26 (t, J = 8.9 Hz, 1H), 8.08 (br. s., oyl]amino} NH), 7.67 (d, J = 7.0 Hz, NH), 7.33 methylpentanoyl]amino}propan (dd, J = 10.8, 2.3 Hz, 1H), 7.27 (dt, oic acid J = 8.8, 1.8 Hz, 1H), 6.52 (d, J = 9.1 Hz, NH), 4.40 - 4.54 (m, 2H), 1.72 - 1.87 (m, 1H), 1.59 - 1.72 (m, 1H), 1.45 - 1.57 (m, 1H), 1.39 (d, J = 7.3 Hz, 3H), 0.95 (s, 3H), 0.93 (s, 3H). 40 (2S)-N-[(1S)aminomethyl- 1H NMR (acetone-d 6, 300MHz) δ: 2-oxoethyl]{[(4-bromo 8.25 (t, J = 8.8 Hz, 1H), 8.09 (br. s., fluorophenyl) NH), 7.57 (d, J = 5.6 Hz, NH), 7.35 oyl]amino} (dd, J = 11.0, 2.2 Hz, 1H), 7.22 - methylpentanamide 7.31 (m, 1H), 6.92 (br. s., NH), 6.54 (d, J = 7.3 Hz, NH), 6.29 (br. s., NH), 4.30 - 4.44 (m, 2H), 1.73 - 1.90 (m, 1H), 1.47 - 1.72 (m, 2H), 1.30 (d, J = 7.0 Hz, 3H), 0.95 (d, J = 1.5 Hz, 3H), 0.93 (d, 3H). 41 tert-butyl (2S){[(2S)({[(4- 1H NMR (CDCl 7.62 3, 300MHz) δ: bromophenyl) (br. s., NH), 7.21 - 7.29 (m, 2H), carbamoyl}amino) 7.08 - 7.16 (m, 2H), 6.90 (br. s., methylpentanoyl]amino}propan NH), 4.39 - 4.50 (m, 1H), 4.35 (t, J = oate 7.0 Hz, 1H), 1.73 - 1.86 (m, 1H), 1.54 - 1.67 (m, 2H), 1.45 (s, 9H), 1.38 (d, 3H), 0.97 (d, J = 2.9 Hz, 3H), 0.95 (d, J = 2.9 Hz, 3H). 42 tert-butyl (2S){[(2S){[(4- 1H NMR (CDCl 7.45 3, 300MHz) δ: bromophenyl) (br. s., NH), 7.21 - 7.30 (m, 2H), carbamoyl]amino} 7.10 - 7.18 (m, 2H), 4.45 (t, J = 7.2 methylpentanoyl]amino} Hz, 1H), 4.32 (dd, J = 8.5, 5.0 Hz, methylbutanoate 1H), 2.07 - 2.20 (m, 1H), 1.77 (dt, J = 13.3, 6.8 Hz, 1H), 1.56 - 1.67 (m, 2H), 1.47 (s, 9H), 0.98 (d, J = 2.3 Hz, 3H), 0.96 (d, 3H), 0.93 (s, 3H), O O 0.91 (s, 3H).
N N O H H 43 (2S){[(2S){[(4- 1H NMR (acetone-d 6, 300MHz) δ: bromophenyl) 8.22 (s, NH), 7.66 (d, J = 6.4 Hz, carbamoyl]amino} NH), 7.43 - 7.50 (m, 2H), 7.34 - 7.41 pentanoyl]amino}propan (m, 2H), 6.05 (d, J = 7.9 Hz, NH), oic acid 4.39 - 4.52 (m, 2H), 2.81 (br. s., 4H), 1.71 - 1.86 (m, 1H), 1.57 - 1.71 (m, 1H), 1.43 - 1.57 (m, 1H), 1.39 (d, J = 7.3 Hz, 3H), 0.94 (s, 3H), 0.92 (s, 3H). 44 (2S){[(2S){[(4- 1H NMR (acetone-d 6, 300MHz) δ: bromophenyl) 7.45 (br. s., NH), 7.21 - 7.30 (m, carbamoyl]amino} 2H), 7.10 - 7.18 (m, 2H), 4.45 (t, J = methylpentanoyl]amino} 7.2 Hz, 1H), 4.32 (dd, J = 8.5, 5.0 methylbutanoic acid Hz, 1H), 2.07 - 2.20 (m, 1H), 1.77 (dt, J = 13.3, 6.8 Hz, 1H), 1.56 - O O 1.67 (m, 2H), 1.47 (s, 9H), 0.98 (d, J N = 2.3 Hz, 3H), 0.96 (d, 3H), 0.93 (s, N N OH H H 3H), 0.91 (s, 3H). 45 (2S)-N-[(1S)aminomethyl- 1H NMR (acetone-d 6, 300MHz) δ: 2-oxoethyl]{[(4-bromophenyl) 8.21 (s, NH), 7.56 (s, NH), 7.42 - carbamoyl]amino} 7.49 (m, 2H), 7.33 - 7.40 (m, 2H), methylpentanamide 6.06 - 6.12 (s, NH), 4.28 - 4.44 (m, 2H), 1.70 - 1.89 (m, 1H), 1.59 - 1.70 (m, 1H), 1.47 - 1.59 (m, 1H), 1.30 (d, J = 7.3 Hz, 3H), 0.95 (s, 3H), 0.92 (s, 3H). 46 (2S)-N-[(2S)(aminomethyl- 1H NMR (CD 7.34 3OD, 300MHz) δ: 1-oxobutanyl]{[(4- - 7.40 (m, 2H), 7.26 - 7.33 (m, 2H), bromophenyl) 4.34 (dd, J = 9.5, 5.4 Hz, 1H), 4.21 carbamoyl]amino} (d, J = 7.0 Hz, 1H), 2.02 - 2.16 (m, methylpentanamide 1H), 1.67 - 1.79 (m, 1H), 1.51 - 1.65 (m, 1H), 0.94 - 1.00 (m, 9H). 47 (2S){[(4-bromophenyl) 1H NMR (CD 7.93 3OD, 300MHz) δ: carbamoyl]amino}-N-(2- (s, NH), 7.33 - 7.40 (m, 2H), 7.26 - ymethylpropyl) 7.33 (m, 2H), 6.28 (br. s., NH), 4.25 methylpentanamide - 4.36 (m, 1H), 3.15 - 3.27 (m, 2H), 1.67 - 1.81 (m, 1H), 1.50 - 1.67 (m, 2H), 1.17 (s, 6H), 0.99 (d, J = 4.7 Hz, 3H), 0.97 (d, 3H). 48 (2S){[(4-bromophenyl) 1H NMR (CD 7.33 3OD, 300MHz) δ: carbamoyl]amino}-N-[2- - 7.41 (m, 2H), 7.26 - 7.33 (m, 2H), hydroxy 4.30 (dd, J = 9.4, 5.6 Hz, 1H), 3.86 - (hydroxymethyl)ethyl] 3.96 (m, 1H), 3.62 (t, J = 5.6 Hz, methylpentanamide 4H), 1.67 - 1.81 (m, 1H), 1.52 - 1.67 (m, 2H), 0.98 (d, J = 3.8 Hz, 3H), 0.96 (d, 3H). 47 (2S){[(4-bromophenyl) 1H NMR (CD 3OD, 300MHz) δ: 7.33 carbamoyl]amino}-N-(2,3- - 7.41 (m, 2H), 7.27 - 7.34 (m, 2H), dihydroxypropyl) 4.28 (dd, J = 8.9, 5.1 Hz, 1H), 3.64 - methylpentanamide 3.76 (m, 1H), 3.46 - 3.52 (m, 2H), 3.33 - 3.42 (m, 1H), 3.15 - 3.27 (m, 1H), 1.67 - 1.80 (m, 1H), 1.48 - 1.67 (m, 2H), 0.98 (d, J = 4.7 Hz, 3H), 0.96 (d, 3H). 48 (2S){[(4-bromophenyl) 1H NMR (CD 3OD, 300MHz) δ: 7.33 carbamoyl]amino}-N-[(1R) - 7.40 (m, 2H), 7.26 - 7.32 (m, 2H), hydroxymethylethyl] 4.26 (dd, J = 8.2, 6.7 Hz, 1H), 3.88 - pentanamide 3.99 (m, 1H), 3.49 (dd, J = 5.4, 1.3 Hz, 2H), 1.72 (dt, J = 13.3, 6.8 Hz, 1H), 1.50 - 1.60 (m, 2H), 1.14 (d, J = 6.7 Hz, 3H), 0.98 (d, J = 3.8 Hz, 3H), 0.96 (d, 3H). 49 tert-butyl (2S){[(2S){[4- 1H NMR (CD 3OD, 300MHz) δ: 7.33 bromophenyl)carbamoyl]amino - 7.39 (m, 2H), 7.27 - 7.32 (m, 2H), }methyl pentanoyl] 4.36 (dd, J = 9.5, 5.4 Hz, 1H), 4.26 propanoate (dd, J = 8.6, 5.4 Hz, 1H), 1.49 - 1.84 (m, 6H), 1.45 (s, 9H), 1.36 - 1.43 (m, 1H), 0.99 (d, J = 4.4 Hz, 3H), 0.97 (d, J = 4.1 Hz, 3H), 0.90 - 0.96 (m, 3H). 50 tert-butyl (2S)-{[(2S){[(4- 1H NMR (CD 7.32 3OD, 300MHz) δ: bromophenyl)carbamoyl]amino - 7.43 (m, 6H), 7.25 - 7.31 (m, 2H), } 4.41 (dd, J = 9.4, 5.3 Hz, 1H), 1.72 - methylpentanoyl]amino}(phenyl 1.81 (m, 1H), 1.49 - 1.70 (m, 2H), )ethanoate 1.40 (s, 9H), 1.17 - 1.19 (m, 0H), 0.99 (t, J = 6.7 Hz, 6H).
O O N N O H H 51 (2S){[(2S){[(4- 1H NMR (CD 7.33 3OD, 300MHz) δ: bromophenyl)carbamoyl]amino - 7.40 (m, 2H), 7.25 - 7.33 (m, 2H), } 4.32 - 4.44 (m, 2H), 1.35 - 1.90 (m, methylpentanoyl]amino}pentan 7H), 0.99 (d, J = 3.8 Hz, 3H), 0.97 oic acid (d, J = 3.8 Hz, 3H), 0.91 - 0.96 (m, 3H). 52 (2S)-{[(2S){[(4- 1H NMR (CD 7.40 3OD, ) δ: henyl)carbamoyl]amino - 7.47 (m, 2H), 7.23 - 7.39 (m, 7H), } 4.41 (dd, J = 9.4, 5.3 Hz, 1H), 1.70 - methylpentanoyl]amino}(phenyl 1.84 (m, 1H), 1.48 - 1.69 (m, 2H), )ethanoic acid 0.98 (t, 6H). 53 (2S)-N-[(2S)amino 1H NMR (CD 7.33 3OD, 300MHz) δ: oxopentanyl]{[(4- - 7.41 (m, 2H), 7.26 - 7.33 (m, 2H), bromophenyl)carbamoyl]amino 4.30 (ddd, J = 16.0, 9.4, 5.1 Hz, }methylpentanamide 1H), 1.50 - 1.86 (m, 5H), 1.33 - 1.48 (m, 2H), 0.95 - 1.01 (m, 6H), 0.89 - 0.96 (m, 3H). 54 (2S)-N-[(1S)aminooxo 1H NMR (CD 7.41 3OD, 300MHz) δ: phenylethyl]{[(4- - 7.48 (m, 2H), 7.24 - 7.42 (m, 7H), bromophenyl)carbamoyl]amino 4.36 (dd, J = 9.7, 5.0 Hz, 1H), 1.52 - }methylpentanamide 1.82 (m, 3H), 0.92 - 1.02 (m, 6H). 55 tert-butyl {[2-{[(4-bromophenyl) 1H NMR (CDCl 7.30 - 3, 300MHz) δ: carbamoyl]amino}-2,4- 7.39 (m, 2H), 7.15 - 7.23 (m, 2H), ylpentanoyl]amino}aceta 6.82 (br. s., 1H), 2.15 - 2.32 (m, te 1H), 1.68 - 1.79 (m, 2H), 1.63 (s, 3H), 1.48 (s, 9H), 0.93 (d, J = 6.4 Hz, 3H), 0.89 (d, J = 6.2 Hz, 3H). 56 (4-bromophenyl) 1H NMR (CD 3OD, 300MHz) δ: 7.31 carbamoyl]amino}-2,4- (d, J = 14.4 Hz, 2H), 3.92 (d, J = 1.2 dimethylpentanoyl] Hz, 2H), 2.03 - 2.15 (m, 1H), 1.70 - amino}acetic acid 1.86 (m, 2H), 1.58 (s, 3H), 0.95 (d, J Br = 6.4 Hz, 3H), 0.91 (d, J = 6.4 Hz, O O H 3H).
N N OH H H 57 tert-butyl {[2-{[(4-bromophenyl) 1H NMR (CD 3OD, 300MHz) δ: carbamoyl]amino} 7.247.39 (m, 2H), 7.24 (m, 2H), ethylbutanoyl] amino}acetate 6.50 (s, NH), 3.85 (s, 2H), 2.21 - 2.40 (m, 2H), 1.82 (dq, J = 14.2, 7.3 Hz, 2H), 1.45 (s, 9H), 0.85 (t, J = 7.3 Hz, 6H). 58 {[2-{[(4-bromophenyl) 1H NMR (CD 7.35 3OD, 600MHz) δ: carbamoyl]amino} (d, J = 8.8 Hz, 2H), 7.26 - 7.30 (m, ethylbutanoyl]amino}acetic 2H), 3.92 (s, 2H), 2.23 - 2.34 (m, acid 2H), 1.78 - 1.89 (m, 2H), 0.85 (t, J = 7.5 Hz, 6H). 59 utyl {[2-{[(4-bromophenyl) 1H NMR (CDCl 3, 300MHz) δ: 7.23 carbamoyl]amino} (m, 2H), 7.39 (m, 2H), 3.81 (s, 2H), methylpropanoyl]amino}acetate 1.52 (s, 6H), 1.45 (s, 9H). 60 {[2-{[(4-bromophenyl) 1H NMR (CDCl 3, 300MHz) δ: 7.23 - carbamoyl]amino} 7.40 (m, 4H), 3.81 (s, 2H), 1.51 (s, methylpropanoyl] amino}acetic 6H). acid 61 (2S){[(4-bromophenyl) 1H NMR (CD 7.34 3OD, 300MHz) δ: carbamoyl]amino}-N-[2- - 7.39 (m, 2H), 7.28 - 7.33 (m, 2H), (dimethylamino)oxoethyl] 4.36 (dd, J = 10.0, 4.7 Hz, 1H), 3.97 methylpentanamide - 4.13 (m, 2H), 3.03 (s, 3H), 2.94 (s, 3H), 1.51 - 1.83 (m, 3H), 0.94 - 1.03 (m, 6H). 62 utyl {[(2S)methyl({[4- 1H NMR (CD 7.49 3OD, 300MHz) δ: (trifluoromethyl)phenyl]carbam - 7.56 (m, 4H), 4.36 (dd, J = 9.7, 5.3 oyl}amino)pentanoyl]amino}ace Hz, 1H), 3.70 - 3.95 (m, 2H), 1.69 - tate 1.86 (m, 1H), 1.51 - 1.68 (m, 2H), 1.43 - 1.46 (m, 9H), 0.99 (dd, J = 6.4, 4.1 Hz, 6H). 63 {[(2S)methyl({[4- 1H NMR (CD 7.50 3OD, 300MHz) δ: (trifluoromethyl)phenyl]carbam - 7.56 (m, 4H), 6.37 (d, J = 7.6 Hz, oyl}amino)pentanoyl]amino}ace NH), 4.38 (dd, J = 9.7, 5.0 Hz, 1H), tic 3.79 - 4.04 (m, 2H), 1.69 - 1.87 (m, acid 1H), 1.50 - 1.70 (m, 2H), 0.99 (dd, J = 6.4, 3.8 Hz, 6H). 64 tert-butyl {[(2R,3R){[(4- 1H NMR (CD 7.33 3OD, 300MHz) δ: bromophenyl)carbamoyl]amino - 7.39 (m, 2H), 7.26 - 7.32 (m, 2H), } 6.29 (s, NH), 4.17 - 4.24 (m, 0H), methylpentanoyl]amino}acetate 3.73 - 3.95 (m, 2H), 1.87 (dtd, J = 9.8, 6.5, 3.2 Hz, 0H), 1.61 (ddt, J = 17.0, 7.4, 3.6 Hz, 0H), 1.43 - 1.47 (m, 9H), 1.11 - 1.27 (m, 0H), 0.90 - 1.03 (m, 6H). 65 {[(2R,3R){[(4- 1H NMR (CD 7.33 3OD, 300MHz) δ: bromophenyl)carbamoyl]amino - 7.39 (m, 2H), 7.27 - 7.32 (m, 2H), } 6.29 (s, NH), 4.19 - 4.26 (m, 1H), pentanoyl]amino}acetic 3.81 - 4.00 (m, 2H), 1.84 - 1.94 (m, acid 1H), 1.60 (ddd, J = 13.2, 7.6, 3.5 Hz, 1H), 1.13 - 1.30 (m, 2H), 1.13 - 1.30 (m, 2H), 0.96 (d, J = 17.6 Hz, 3H). 66 tert-butyl {[(2R){[(4- 1H NMR (CD 7.35 3OD, 600MHz) δ: bromophenyl)carbamoyl]amino - 7.38 (m, 2H), 7.28 - 7.31 (m, 2H), } 4.34 (dd, J = 10.0, 5.0 Hz, 1H), 3.75 methylpentanoyl]amino}acetate - 3.91 (m, 2H), 1.73 - 1.80 (m, 1H), 1.63 - 1.68 (m, 1H), 1.53 - 1.59 (m, 1H), 1.44 - 1.47 (m, 9H), 0.99 (d, J = 6.7 Hz, 3H), 0.97 (d, J = 6.7 Hz, 3H). 67 {[(2R){[(4- 1H NMR (CD 7.34 3OD, 600MHz) δ: bromophenyl)carbamoyl]amino - 7.39 (m, 2H), 7.26 - 7.32 (m, 2H), } 4.32 - 4.38 (m, 1H), 3.84 - 4.00 (m, methylpentanoyl]amino}acetic 2H), 1.72 - 1.81 (m, 1H), 1.63 - 1.70 acid (m, 1H), 1.52 - 1.60 (m, 1H), 0.99 (d, J = 6.7 Hz, 3H), 0.97 (d, J = 6.7 Hz, 3H). 68 tert-butyl {[(2S)methyl({[4- 1H NMR (CD 7.27 3OD, 300MHz) δ: lsulfanyl)phenyl]carbam - 7.34 (m, 2H), 7.17 - 7.24 (m, 2H), oyl}amino)pentanoyl]amino}ace 6.24 (d, J = 7.9 Hz, NH), 4.30 - 4.40 tate (m, 1H), 3.72 - 3.95 (m, 2H), 2.40 - 2.43 (m, 3H), 1.69 - 1.84 (m, 1H), 1.50 - 1.68 (m, 2H), 1.44 - 1.47 (m, 9H), 0.99 (dd, J = 6.4, 4.7 Hz, 6H). 69 2-methyl{[(2S)methyl 1H NMR (CD 8.27 3OD, 300MHz) δ: ({[4- (s, NH), 7.52 (d, J = 19.9 Hz, 4H), (trifluoromethyl)phenyl]carbam 6.29 (d, J = 8.5 Hz, NH), 4.27 - 4.43 ino)pentanoyl]amino}pro (m, 1H), 1.70 - 1.85 (m, 1H), 1.45 - panoic acid 1.67 (m, 8H), 0.98 (dd, J = 6.4, 2.9 F Hz, 6H).
F O O N N OH H H 70 {[(2S)methyl({[4- 1H NMR (CD 7.26 3OD, 300MHz) δ: (methylsulfanyl)phenyl]carbam - 7.34 (m, 2H), 7.17 - 7.24 (m, 2H), oyl}amino)pentanoyl]amino}ace 4.30 - 4.41 (m, 1H), 3.80 - 4.03 (m, tic 2H), 2.39 - 2.43 (m, 3H), 1.49 - 1.84 acid (m, 3H), 0.98 (dd, J = 6.4, 4.1 Hz, 6H). 71 tert-butyl ({(2S)methyl[({4- 1H NMR (CD 7.52 3OD, 300MHz) δ: [(trifluoromethyl)sulfanyl]pheny - 7.57 (m, 2H), 7.47 - 7.52 (m, 2H), l}carbamoyl)amino]pentanoyl}a 4.32 - 4.40 (m, 1H), 3.72 - 3.95 (m, mino)acetate 2H), 1.69 - 1.84 (m, 1H), 1.50 - 1.68 (m, 2H), 1.42 - 1.47 (m, 9H), 0.99 (dd, J = 6.3, 4.2 Hz, 6H). 72 methyl[({4- 1H NMR (CD 7.47 3OD, 300MHz) δ: [(trifluoromethyl)sulfanyl]pheny - 7.57 (m, 4H), 4.37 (dd, J = 9.5, 5.1 amoyl)amino]pentanoyl}a Hz, 1H), 3.83 - 4.02 (m, 2H), 1.70 - mino)acetic 1.83 (m, 1H), 1.51 - 1.68 (m, 2H), acid 0.99 (d, J = 3.8 Hz, 3H), 0.97 (d, J = 3.8 Hz, 3H). 73 tert-butyl 2-{[(2S){[(4- 1H NMR (CD 7.33 3OD, 300MHz) δ: bromophenyl)carbamoyl]amino - 7.38 (m, 2H), 7.26 - 7.32 (m, 2H), }methylpentanoyl]amino} 4.31 (dd, J = 9.1, 5.6 Hz, 1H), 1.67 - methylpropanoate 1.80 (m, 1H), 1.45 - 1.63 (m, 2H), 1.39 - 1.44 (m, 15H), 0.97 (dd, J = 6.6, 3.1 Hz, 6H). 74 2-{[(2S){[(4- 1H NMR (CD 8.46 3OD, 300MHz) δ: bromophenyl)carbamoyl]amino (s, NH), 8.26 (s, NH), 7.33 - 7.38 }methylpentanoyl]amino} (m, 2H), 7.25 - 7.31 (m, 2H), 4.32 methylpropanoic acid (dd, J = 9.2, 5.4 Hz, 1H), 1.68 - 1.80 (m, 1H), 1.51 - 1.65 (m, 2H), 1.49 (s, 3H), 1.48 (s, 3H), 0.98 (d, J = 3.5 Hz, 3H), 0.96 (d, J = 3.5 Hz, 3H). 75 tert-butyl {[(2S)methyl({[4- 1H NMR (CD 7.61 3OD, 300MHz) δ: (methylsulfinyl)phenyl]carbamo (s, 4H), 4.37 (dd, J = 9.8, 5.1 Hz, yl}amino)pentanoyl]amino}acet 1H), 3.72 - 3.96 (m, 2H), 2.77 (s, ate 3H), 1.69 - 1.85 (m, 1H), 1.51 - 1.69 (m, 2H), 1.45 (s, 9H), 0.94 - 1.05 (m, 6H). 76 tert-butyl {[(2S)methyl({[4- 1H NMR (CD 3OD, 300MHz) δ: 7.77 lsulfonyl)phenyl]carbam - 7.86 (m, 2H), 7.57 - 7.67 (m, 2H), oyl}amino)pentanoyl]amino}ace 4.37 (dd, J = 9.7, 5.0 Hz, 1H), 3.71 - tate 3.96 (m, 2H), 3.07 (s, 3H), 1.69 - 1.83 (m, 1H), 1.51 - 1.70 (m, 2H), 1.40 - 1.49 (m, 9H), 0.94 - 1.03 (m, 6H). 77 {[(2S)methyl({[4- 1H NMR (CD 7.57 3OD, 300MHz) δ: (methylsulfinyl)phenyl]carbamo - 7.66 (m, 4H), 4.38 (dd, J = 9.7, 5.0 yl}amino)pentanoyl]amino}aceti Hz, 1H), 3.81 - 4.03 (m, 2H), 2.77 c (s, 3H), 1.69 - 1.85 (m, 1H), 1.48 - acid 1.68 (m, 2H), 0.92 - 1.03 (m, 6H). 78 {[(2S)methyl({[4- 1H NMR (CD 7.76 3OD, 300MHz) δ: (methylsulfonyl)phenyl]carbam - 7.87 (m, 2H), 7.57 - 7.68 (m, 2H), oyl}amino)pentanoyl]amino}ace 6.43 (d, J = 8.5 Hz, NH), 4.32 - 4.45 tic (m, 1H), 3.81 - 4.04 (m, 2H), 3.07 acid (s, 3H), 1.71 - 1.83 (m, 1H), 1.49 - 1.70 (m, 2H), 0.98 (dd, J = 6.4, 3.5 Hz, 6H). 79 tert-butyl 2-methyl{[(2S) 1H NMR (CD 3OD, 300MHz) δ: 7.46 methyl({[4- - 7.58 (m, 2H), 4.33 (dd, J = 9.2, 5.7 (trifluoromethyl)phenyl]carbam Hz, 1H), 1.69 - 1.86 (m, 1H), 1.46 - oyl}amino)pentanoyl]amino}pro 1.66 (m, 2H), 1.36 - 1.46 (m, 15H), e 0.94 - 1.04 (m, 6H). 80 tert-butyl {[(2S){[(4- 1H NMR (CD 7.24 3OD, 300MHz) δ: bromophenyl)carbamoyl]amino - 7.41 (m, 4H), 4.44 (dd, J = 7.8, 5.4 } Hz, 1H), 3.70 - 3.99 (m, 2H), 2.54 - (methylsulfanyl)butanoyl]amino 2.68 (m, 2H), 2.12 - 2.18 (m, 1H), }acetate 2.11 (s, 3H), 1.85 - 2.02 (m, 1H), 1.41 - 1.50 (m, 9H). [α]D = -21.8 0, MeOH) 81 tert-butyl {[(2S){[(4- 1H NMR (CD 7.26 3OD, 300MHz) δ: bromophenyl)carbamoyl]amino - 7.43 (m, 4H), 4.43 - 4.57 (m, 1H), } 3.70 - 4.03 (m, 2H), 3.24 (s, 2H), (methylsulfonyl)butanoyl]amino 2.99 (s, 4H), 2.28 - 2.42 (m, 1H), }acetate 2.11 - 2.26 (m, 1H), 1.47 (s, 9H). 82 {[(2S){[(4- 1H NMR (CD 3OD, 300MHz) δ: 7.25 bromophenyl)carbamoyl]amino - 7.44 (m, 4H), 6.55 (d, J = 7.3 Hz, } NH), 4.53 (m, 1H), 3.79 - 4.10 (m, (methylsulfanyl)butanoyl]amino 2H), 3.26 (m., 2H), 2.98 (s, 3H), }acetic 2.26 - 2.42 (m, 1H), 2.20 (m, 1H). acid 83 {[(2S){[(4- 1H NMR (CD 7.26 3OD, 300MHz) δ: henyl)carbamoyl]amino - 7.42 (m, 4H), 6.55 (d, J = 7.3 Hz, } NH), 4.47 - 4.58 (m, 1H), 3.80 - 4.11 (methylsulfonyl)butanoyl]amino (m, 2H), 3.25 (m, 2H), 2.98 (s, 3H), c 2.28 - 2.43 (m, 1H), 2.11 - 2.27 (m, acid 1H). 84 tert-butyl {[2-{[(4- 1H NMR (CD 7.61 3OD, 300MHz) δ: bromophenyl)carbamoyl]amino (s, 1H), 7.21 - 7.41 (m, 4H), 6.94 (s, }(1H-imidazol 1H), 4.51 - 4.64 (m, 1H), 3.75 - 3.96 yl)propanoyl]amino}acetate (m, 2H), 3.07 - 3.22 (m, 1H), 2.93 - 3.06 (m, 1H), 1.49 (s, 9H). 85 {[2-{[(4- 1H NMR (DMSO-D 6, 300MHz) δ: bromophenyl)carbamoyl]amino 8.93 (NH, 1H), 8.42 (br. s., NH), }(1H-imidazol 7.67 (s, 1H), 7.34 (d, J = 4.1 Hz, yl)propanoyl]amino}acetic 4H), 6.88 (s, 1H), 6.28 (d, J = 7.3 acid Hz, NH), 4.44 (m., 1H), 3.55 - 3.90 (m, 2H), 2.93 (m., 2H). 86 tert-butyl 2-{[(2R){[(4- 1H NMR (CD 3OD, 300MHz) δ: 7.33 bromophenyl)carbamoyl]amino - 7.38 (m, 2H), 7.26 - 7.32 (m, 2H), }methylpentanoyl]amino} 4.31 (dd, J = 9.1, 5.6 Hz, 1H), 1.67 - methylpropanoate 1.80 (m, 1H), 1.45 - 1.63 (m, 2H), 1.39 - 1.44 (m, 15H), 0.97 (dd, J = 6.6, 3.1 Hz, 6H). 87 2-{[(2R){[(4-bromophenyl) 1H NMR (CD 3OD, 300MHz) δ: 8.46 carbamoyl]amino} (s, NH), 8.23 (s, 2NH), 7.33 - 7.39 methylpentanoyl] amino} (m, 2H), 7.26 - 7.31 (m, 2H), 6.19 methylpropanoic acid (d, J = 8.2 Hz, NH), 4.31 (m 1H), 1.73 (m, 1H), 1.51 - 1.65 (m, 2H), 1.49 (s, 3H), 1.48 (s, 3H), 0.98 (d, J = 3.8 Hz, 6H), 0.96 (d, J = 3.5 Hz, 6H). 88 tert-butyl {[4-amino{[(4- 1H NMR (CD 7.27 3OD, 300MHz) δ: bromophenyl) - 7.42 (m, 4H), 4.69 (t, J = 6.0 Hz, carbamoyl]amino} 1H), 3.75 - 3.94 (m, 2H), 2.70 - 2.78 oxobutanoyl]amino}acetate (m, 2H), 1.45 (s, 9H). 89 o{[(4-bromophenyl) 1H NMR (CD 3OD, 300MHz) δ: 7.26 carbamoyl]amino} - 7.44 (m, 4H), 4.62 (t, J = 5.3 Hz, oxobutanoic acid 1H), 2.70 - 2.94 (m, 2H). 90 tert-butyl (4-bromophenyl) 1H NMR (CD 3OD, 300MHz) δ: 7.56 carbamoyl]amino}(1H-indol- - 7.61 (m, 1H), 7.30 - 7.36 (m, 3H), 3-yl) propanoyl]amino}acetate 7.23 - 7.26 (m, 2H), 7.16 (s, NH), 7.08 (td, J = 7.6, 1.2 Hz, 1H), 6.95 - 7.02 (m, 1H), 6.13 (d, J = 7.3 Hz, NH), 4.60 - 4.68 (m, 1H), 3.80 (s, Br NH 2H), 3.32 - 3.38 (m, 1H), 3.11 - 3.23 O O H (m, 1H), 1.43 - 1.47 (m, 9H).
N N O H H 91 tert-butyl {[4-amino{[(4- 1H NMR (CD 7.27 3OD, 300MHz) δ: bromophenyl) - 7.42 (m, 4H), 4.69 (t, J = 6.0 Hz, carbamoyl]amino} 1H), 3.75 - 3.94 (m, 2H), 2.70 - 2.78 oxobutanoyl]amino}acetate (m, 2H), 1.45 (s, 9H).
Br NH O O N N OH H H Interm. IUPAC name 1H NMR δ (ppm) No. Structure (2S,3S){[(4-bromophenyl) 1H NMR (CD 3OD, 300MHz) δ: carbamoyl]amino} 7.33 - 7.41 (m, 2H), 7.26 - 7.33 (m, methylpentanamide 2H), 4.18 (d, J = 6.2 Hz, 1H), 1.74 - 1.91 (m, 1H), 1.50 - 1.66 (m, 1H), 1.11 - 1.33 (m, 1H), 0.99 (d, J = 7.0 Hz, 3H), 0.91 - 0.97 (m, 3H). 11 (2S,3S){[(4-bromo 1H NMR (CD 3OD, 300MHz) δ: 7.99 phenyl) (t, J = 8.8 Hz, 1H), 7.31 (dd, J = oyl]amino} 10.7, 2.2 Hz, 1H), 7.19 - 7.27 (m, methylpentanamide 1H), 4.18 (d, J = 6.2 Hz, 1H), 1.78 - 1.95 (m, 1H), 1.49 - 1.65 (m, 1H), 1.10 - 1.27 (m, 1H), 1.00 (d, J = 6.7 Hz, 3H), 0.91 - 0.98 (m, 3H). 12 (2S){[(4-bromo 1H NMR (acetone-d6, 300MHz) δ: fluorophenyl) 8.28 (t, J = 8.8 Hz, 1H), 8.12 (br. s., carbamoyl]amino}-pentanamide NH), 7.33 (dd, J = 11.0, 2.2 Hz, 1H), 7.26 (dt, J = 8.9, 1.9 Hz, 1H), 7.07 (br. s., NH), 6.55 (d, J = 7.0 Hz, NH), 6.40 (br. s., NH), 4.38 (td, J = 7.8, 5.3 Hz, 1H), 1.73 - 1.89 (m, 1H), 1.54 - 1.70 (m, 1H), 1.24 - 1.49 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H). 13 (2S){[(4-bromophenyl) 1H NMR (acetone-d6, 300MHz) δ: carbamoyl]amino} 8.17 (s, NH), 7.41 - 7.50 (m, 2H), methylpentanamide 7.33 - 7.40 (m, 2H), 6.03 (d, J = 8.2 Hz, NH), 4.39 (ddd, J = 9.4, 8.2, 5.0 Br Hz, 1H), 3.58 (q, J = 5.6 Hz, 2H), 3.26 - 3.37 (m, 2H), 1.66 - 1.81 (m, N N 1H), 1.44 - 1.67 (m, 2H), 0.94 (d, J H H = 1.5 Hz, 3H), 0.92 (d, J = 1.4 Hz , 3H). 14 (2S)-2({[(4-bromo 1H NMR (acetone-d6, 300MHz) δ: fluorophenyl) 8.27 (t, J = 8.9 Hz, 1H), 8.06 (br. s., carbamoyl]amino} NH), 7.34 (dd, J = 10.8, 2.3 Hz, 1H), methylpentanoic acid 7.25 - 7.31 (m, 1H), 6.53 (d, J = 7.0 Hz, NH), 4.43 - 4.55 (m, 1H), 1.73 - 1.87 (m, 1H), 1.53 - 1.71 (m, 2H), 0.98 (d, J = 1.5 Hz, 3H), 0.96 (d, J = 1.5 Hz, 3H). (2S){[(4-bromo 1H NMR (acetone-d6, ) δ: fluorophenyl) 8.28 (t, J = 8.9 Hz, 1H), 8.07 (br. s., carbamoyl]amino} NH), 7.33 (dd, J = 10.8, 2.3 Hz, 1H), methylpentanamide 7.23 - 7.30 (m, 1H), 7.10 (br. s., NH), 6.50 (d, J = 8.2 Hz, NH), 6.38 (br. s., NH), 4.42 (ddd, J = 9.6, 8.3, .0 Hz, 1H), 1.70 - 1.87 (m, 1H), 1.59 - 1.70 (m, 1H), 1.44 - 1.59 (m, 1H), 0.95 (d, J = 1.5 Hz, 3H), 0.93 (d, 3H). 16 tert-butyl (2S){[(4-bromo 1H NMR (CDCl 3, 300MHz) δ: 7.89 fluorophenyl) (t, J = 8.8 Hz, 1H), 7.14 (dd, J = carbamoyl]amino} 10.4, 2.2 Hz, 1H), 7.06 (d, J = 9.1 methylpentanoate Hz, 1H), 6.80 (d, J = 2.6 Hz, NH), .79 (br. s., NH), 4.45 (dd, J = 8.8, .0 Hz, 1H), 1.69 - 1.85 (m, 1H), 1.57 - 1.69 (m, 1H), 1.52 (s, 9H), 1.41 - 1.48 (m, 1H), 0.97 (d, J = 3.5 Hz, 3H), 0.95 (d, 3H). 17 -bromophenyl) 1H NMR (CD 3OD, 300MHz) δ: 7.31 carbamoyl]amino}-2,4- - 7.39 (m, 2H), 7.22 - 7.30 (m, 2H), dimethylpentanoic acid 1.80 - 1.92 (m, 2H), 1.71 - 1.82 (m, 1H), 1.56 - 1.67 (m, 2H), 1.44 (s, 3H), 0.98 (d, J = 1.2 Hz, 3H), 0.95 (d, J = 1.2 Hz, 3H). 18 tert-butyl {[2-{[(4-bromophenyl) 1H NMR (CD 3OD, 300MHz) δ: 9.29 carbamoyl]amino} (br. s., NH), 8.58 - 8.75 (m, 4H), methylpropanoate 7.33 (br. s., NH), 2.65 - 2.75 (m, 9H). 19 2-{[(4-bromophenyl) 1H NMR (CD3OD, 300MHz) δ: carbamoyl]amino} 7.32 - 7.37 (m, 2H), 7.24 - 7.29 (m, methylpropanoic acid 2H), 1.52 (s, 6H). -bromophenyl) 1H NMR (acetone-d6, 300MHz) δ: carbamoyl]amino} 8.76 (br. s., 1H), 7.44 - 7.52 (m, ethylbutanoic acid 2H), 7.31 - 7.40 (m, 2H), 6.30 (br. s., 1H), 2.29 - 2.48 (m, 2H), 1.75 - 1.92 (m, 2H), 0.76 - 0.86 (m, 6H) . 21 tert-butyl (2S)methyl({[4- 1H NMR (CD 3OD, 300MHz) δ: 7.50 (trifluoromethyl)phenyl]carbam (s, 4H), 4.27 (dd, J = 9.1, 5.6 Hz, oyl}amino)pentanoate 1H), 1.68 - 1.86 (m, 1H), 1.52 - 1.66 (m, 2H), 1.45 - 1.50 (s, 9H), 0.95 (t, J = 6.9 Hz, 6H). 22 (2S)methyl({[4- 1H NMR (CD 3OD, 300MHz) δ: 7.49 (trifluoromethyl)phenyl]carbam - 7.57 (m, 4H), 4.38 (dd, J = 9.4, 5.0 oyl}amino)pentanoic acid Hz, 1H), 1.69 - 1.87 (m, 1H), 1.51 - 1.69 (m, 2H), 0.92 - 1.01 (m, 6H). 23 tert-butyl (2S)({(4- 1H NMR (CD 3OD, 300MHz) δ: 7.30 chlorophenyl) - 7.39 (m, 2H), 7.17 - 7.28 (m, 1H), carbamoyl}amino)4- 4.25 (dd, J = 8.9, 5.7 Hz, 1H), 1.74 pentanoate (dd, J = 13.6, 7.5 Hz, 1H), 1.51 - 1.67 (m, 2H), 1.47 (s, 9H), 0.97 (t, J = 6.9 Hz, 6H). 24 -({(4-chlorophenyl) 1H NMR (CD 3OD, 300MHz) δ: 7.29 carbamoyl}amino)4- - 7.38 (m, 2H), 7.17 - 7.27 (m, 2H), methylpentanoic acid 4.36 (dd, J = 9.4, 5.0 Hz, 1H), 1.73 (dd, J = 18.3, 5.7 Hz, 1H), 1.51 - 1.68 (m, 2H), 0.98 (dd, J = 6.4, 3.5 Hz, 6H). tert-butyl (2S)({(4- 1H NMR (CD 3OD, 300MHz) δ: 7.50 iodophenyl) - 7.59 (m, 2H), 7.12 - 7.23 (m, 2H), carbamoyl}amino)4- 4.25 (m, 1H), 1.73 (m, 1H), 1.49 - methylpentanoate 1.63 (m, 2H), 1.47 (s, 9H), 0.91 - 1.03 (m, 6H). 26 (2S)({(4-iodophenyl) 1H NMR (CD 3OD, 300MHz) δ: 7.50 carbamoyl}amino)4- - 7.58 (m, 2H), 7.13 - 7.21 (m, 2H), methylpentanoic acid 4.35 (dd, J = 9.4, 5.0 Hz, 1H), 1.50 - 1.86 (m, 2H), 1.01 (m, 6H). 27 (2R,3R)({(4-bromophenyl) 1H NMR (CD 3OD, 300MHz) δ: 7.35 carbamoyl}amino)3- - 7.39 (m, 2H), 7.28 - 7.32 (m, 2H), methylpentanoic acid 4.32 (d, J = 4.7 Hz, 1H), 1.92 (dq, J = 6.8, 4.6 Hz, 1H), 1.46 - 1.60 (m, 1H), 1.16 - 1.33 (m, 1H), 0.93 - 1.02 (m, 6H). 28 tert-butyl -({(4- 1H NMR (CDCl 3, 300MHz) δ: 7.33 bromophenyl) (d, J = 8.5 Hz, 2H), 7.17 (s, 2H), carbamoyl}amino)4- 4.43 (dd, J = 9.1, 5.3 Hz, 1H), 1.68 - methylpentanoate 1.79 (m, 1H), 1.56 - 1.67 (m, 1H), 1.48 (s, 9H), 1.44 (s, 1H), 0.97 (d, J = 4.1 Hz, 3H), 0.95 (d, J = 4.4 Hz, 3H). 29 (2R)({(4-bromophenyl) 1H NMR (acetone-D6, 300MHz) δ: carbamoyl}amino)4- 8.17 (s, NH), 7.43 - 7.50 (m, 2H), methylpentanoic acid 7.33 - 7.41 (m, 2H), 6.04 (d, J = 7.9 Hz, NH), 4.42 - 4.52 (m, 1H), 1.71 - 1.87 (m, 1H), 1.52 - 1.69 (m, 2H), 0.97 (d, J = 2.1 Hz, 3H), 0.95 (d, J = 2.3 Hz, 3H). utyl (2S)methyl({[4- 1H NMR (CD3OD, ) δ: 7.27 (methylthio)phenyl] - 7.32 (m, 2H), 7.18 - 7.23 (m, 2H), carbamoyl}amino)pentanoate 4.22 - 4.29 (m, 1H), 2.42 (s, 3H), 1.70 - 1.79 (m, 1H), 1.51 - 1.61 (m, 2H), 1.47 (s, 9H), 0.97 (t, J = 6.7 Hz, 6H). 31 (2S)methyl({[4- 1H NMR (CD3OD, 300MHz) δ: 7.25 (methylthio)phenyl] - 7.31 (m, 2H), 7.14 - 7.20 (m, 2H), carbamoyl}amino)pentanoic 4.37 (dd, J = 9.2, 5.1 Hz, 1H), 2.39 acid (s, 3H), 1.68 - 1.83 (m, 1H), 1.51 - 1.67 (m, 2H), 0.96 (dd, J = 6.2, 2.3 Hz, 6H). 32 (2S)methyl{({4- 1H NMR (CD3OD, 300MHz) δ: 7.52 [(trifluoromethyl)thio]phenyl} - 7.58 (m, 2H), 7.47 - 7.52 (m, 2H), carbamoyl}amino)pentanoic 4.37 (dd, J = 9.4, 5.0 Hz, 1H), 1.70 - acid 1.82 (m, 1H), 1.53 - 1.69 (m, 2H), 0.99 (d, J = 3.2 Hz, 3H), 0.97 (d, J = 3.2 Hz, 3H). 33 tert-butyl (2S)methyl{({4- 1H NMR (CD3OD, 300MHz) δ: 7.53 [(trifluoromethyl)thio]phenyl} - 7.57 (m, 2H), 7.47 - 7.51 (m, 2H), carbamoyl}amino)pentanoate 4.26 (dd, J = 8.9, 5.7 Hz, 1H), 1.74 (td, J = 13.6, 6.7 Hz, 1H), 1.51 - 1.65 (m, 2H), 1.47 (s, 9H), 0.97 (t, J = 6.7 Hz, 6H). 34 (2S)({(4-bromophenyl) 1H NMR (CD 7.23 3OD, 300MHz) δ: oyl}amino)4- - 7.41 (m, 4H), 4.31 - 4.42 (m, 1H), (methylthio)butanoic acid 2.56 (d, J = 15.5 Hz, 2H), 2.12 - 2.23 (m, 1H), 2.08 (s, 3H), 1.98 (dt, J = 14.0, 7.2 Hz, 1H). 2-({(4-bromophenyl) 1H NMR (CD 8.76 3OD, 300MHz) δ: carbamoyl}amino)3-(1H- (s, 1H), 7.23 - 7.40 (m, 6H), 4.65 imidazolyl)propanoic acid (m, 1H), 3.03 - 3.27 (m, 2H).
Biological Data Biological activity of compounds according to Formula II is set forth in Table 5 below. CHO-Gα16 cells stably expressing FPRL1 were ed in (F12, 10% FBS, 1% PSA, 400 µg/ml geneticin and 50 µg/ml hygromycin) and HEK- Gqi5 cells stable expressing FPR1 were cultured in (DMEM high glucose, 10% FBS, 1% PSA, 400 µg/ml geneticin and 50 µg/ml hygromycin). In general, the day before the experiment, 18,000 cells/well were plated in a 384-well clear bottom poly-d-lysine coated plate. The following day the ing compound-induced calcium activity was assayed on the FLIPRTetra. The drug plates were prepared in 384-well lates using the EP3 and the MultiPROBE robotic liquid handling systems.
Compounds were tested at concentrations g from 0.61 to 10,000 nM. Results are expressed as EC50 (nM) and efficacy values.
Table 5 IUPAC Name FPRL-1 Compound Ga16-CHO EC50 (nM) (Rel. eff.) (4-bromophenyl)carbamoyl]amino}(1H-imidazol- 10.0 4-yl)propanoyl]amino}acetic acid (0.95) tert-butyl {[2-{[(4-bromophenyl)carbamoyl]amino}(1H- 263 imidazolyl)propanoyl]amino}acetate (0.95) {[(2S){[(4-bromophenyl)carbamoyl]amino} 247 (methylsulfonyl)butanoyl]amino}acetic acid (1.01) tert-butyl {[(2S){[(4-bromophenyl)carbamoyl]amino}- 1238 4-(methylsulfonyl)butanoyl]amino}acetate (0.97) {[(2S){[(4-bromophenyl)carbamoyl]amino} 7 (methylsulfanyl)butanoyl]amino}acetic acid (1.03) utyl {[(2S){[(4-bromophenyl)carbamoyl]amino}- 127 4-(methylsulfanyl)butanoyl]amino}acetate (0.98) yl{[(2S)methyl({[4- 2.3 (trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]ami (0.92) no}propanoic acid tert-butyl 2-methyl{[(2S)methyl({[4- 1016 (trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]ami (1.07) no}propanoate {[(2S)methyl({[4- (methylsulfonyl)phenyl]carbamoyl}amino)pentanoyl]ami 459 no}acetic acid (1.12) tert-butyl {[(2S)methyl({[4- 1083 (methylsulfonyl)phenyl]carbamoyl}amino)pentanoyl]ami (0.90) no}acetate {[(2S)methyl({[4- 358 (methylsulfinyl)phenyl]carbamoyl}amino)pentanoyl]amin (1.21) o}acetic acid tert-butyl {[(2S)methyl({[4- 668 (methylsulfinyl)phenyl]carbamoyl}amino)pentanoyl]amin (0.97) o}acetate 2-{[(2S)({[(4-bromophenyl)amino]carbamoyl}amino)- 1 4-methylpentanoyl] amino}methylpropanoic acid (0.96) tert-butyl 2-{[(2S){[(4- 133 henyl)carbamoyl]amino} (1.16) methylpentanoyl]amino}methylpropanoate ({(2S)methyl[({4- 560 [(trifluoromethyl)sulfanyl]phenyl}carbamoyl)amino]penta (1.07) mino)acetic acid tert-butyl methyl[({4- 3103 [(trifluoromethyl)sulfanyl]phenyl}carbamoyl)amino]penta (0.78) noyl}amino)acetate {[(2S)methyl({[4- 2.95 (methylsulfanyl)phenyl]carbamoyl}amino)pentanoyl]ami (1.05) no}acetic acid utyl {[(2S)methyl({[4- 116 (methylsulfanyl)phenyl]carbamoyl}amino)pentanoyl]ami (0.98) no}acetate {[(2R){[(4-bromophenyl)carbamoyl]amino} 1229 methylpentanoyl]amino}acetic acid (0.97) tert-butyl {[(2R){[(4-bromophenyl)carbamoyl]amino}- 3657 4-methylpentanoyl]amino}acetate (0.92) {[(2R,3R){[(4-bromophenyl)carbamoyl]amino} 19315 methylpentanoyl]amino}acetic acid (0.45) tert-butyl {[(2R,3R){[(4- 3974 bromophenyl)carbamoyl]amino} (0.44) methylpentanoyl]amino}acetate {[(2S)methyl({[4- 1.8 (trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]ami (0.99) no}acetic acid tert-butyl {[(2S)methyl({[4- (trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]ami 309 no}acetate (0.81) {[(2R){[(4-bromofluorophenyl)carbamoyl]amino} 1489 methylpentanoyl]amino}acetic acid (0.87) (2S){[(4-bromophenyl)carbamoyl]amino}-N-[2- 1.4 (dimethylamino)oxoethyl]methylpentanamide (0.90) [(2-{[(4-bromophenyl)carbamoyl]amino} 480 methylpropanoyl)amino]acetic acid (0.99) tert-butyl [(2-{[(4-bromophenyl)carbamoyl]amino} 114 methylpropanoyl)amino]acetate (1.02) [(2-{[(4-bromophenyl)carbamoyl]amino} 19 ethylbutanoyl)amino]acetic acid (1.04) tert-butyl [(2-{[(4-bromophenyl)carbamoyl]amino} 31 ethylbutanoyl)amino]acetate (1.03) [(2-{[(4-bromophenyl)carbamoyl]amino}-2,4- 22 dimethylpentanoyl)amino]acetic acid (0.98) tert-butyl [(2-{[(4-bromophenyl)carbamoyl]amino}-2,4- 58 dimethylpentanoyl)amino]acetate (0.98) (2S)-N-[(1S)aminooxophenylethyl]{[(4- 84 bromophenyl)carbamoyl]amino}methylpentanamide (0.99) (2S)-{[(2S){[(4-bromophenyl)carbamoyl]amino} 9.1 methylpentanoyl]amino}(phenyl)ethanoic acid (1.08) tert-butyl (2S)-{[(2S){[(4- 122 bromophenyl)carbamoyl]amino} (1.02) pentanoyl]amino}(phenyl)ethanoate (2S)-N-[(2S)aminooxopentanyl]{[(4- 6.4 henyl)carbamoyl]amino}methylpentanamide (1.03) (2S){[(2S){[(4-bromophenyl)carbamoyl]amino} 1.0 methylpentanoyl]amino}pentanoic acid (0.89) utyl (2S){[(2S){[(4- 13 bromophenyl)carbamoyl]amino} (1.06) methylpentanoyl]amino}pentanoate (2S){[(4-bromophenyl)carbamoyl]amino}-N-[(2R) 3.0 hydroxypropanyl]methylpentanamide (1.00) (2S){[(4-bromophenyl)carbamoyl]amino}-N-(2,3- 5.1 dihydroxypropyl)methylpentanamide (0.98) (2S){[(4-bromophenyl)carbamoyl]amino}-N-(1,3- 7.4 dihydroxypropanyl)methylpentanamide (0.96) (2S){[(4-bromophenyl)carbamoyl]amino}-N-(2- 2.1 hydroxymethylpropyl)methylpentanamide (1.01) (2S)-N-[(2S)aminomethyloxobutanyl]{[(4- 1.3 bromophenyl)carbamoyl]amino}methylpentanamide (1.03) (2S){[(2S){[(4-bromophenyl)carbamoyl]amino} 1.83 methylpentanoyl]amino}methylbutanoic acid (1.13) tert-butyl (2S){[(2S){[(4- 68 bromophenyl)carbamoyl]amino} (0.98) methylpentanoyl]amino}methylbutanoate (2S)-N-[(2S)aminooxopropanyl]{[(4- 24 bromophenyl)carbamoyl]amino}methylpentanamide (0.96) (2S){[(2S){[(4-bromophenyl)carbamoyl]amino} 11 methylpentanoyl]amino}propanoic acid (1.05) tert-butyl -{[(2S){[(4- bromophenyl)carbamoyl]amino} 147 methylpentanoyl]amino}propanoate (0.96) (2S)-N-[(2S)aminooxopropanyl]{[(4-bromo fluorophenyl)carbamoyl]amino}methylpentanamide 31 (1.05) -{[(2S){[(4-bromo 12 fluorophenyl)carbamoyl]amino} (0.95) methylpentanoyl]amino}propanoic acid tert-butyl (2S){[(2S){[(4-bromo 174 fluorophenyl)carbamoyl]amino} (1.00) methylpentanoyl]amino}propanoate (2S){[(4-bromofluorophenyl)carbamoyl]amino}-N- 77 (2-hydroxyethyl)methylpentanamide (1.05) (2S){[(4-bromofluorophenyl)carbamoyl]amino} 20 methyl-N-(2-oxopropyl)pentanamide (0.99) (2S)-N-(2-aminooxoethyl){[(4-bromo 4.5 phenyl)carbamoyl]amino}methylpentanamide (0.95) {[(4-bromofluorophenyl)carbamoyl]amino} 3.6 methylpentanoyl]amino}acetic acid (1.10) tert-butyl {[(2S){[(4-bromo 134 fluorophenyl)carbamoyl]amino} (1.19) methylpentanoyl]amino}acetate (2S)-N-(2-aminooxoethyl){[(4-bromo 5.2 fluorophenyl)carbamoyl]amino}pentanamide (0.98) (2S)-N-(2-aminooxoethyl){[(4- 2.5 bromophenyl)carbamoyl]amino}pentanamide (0.97) -{[(4-bromophenyl)carbamoyl]amino}methyl-N- 4.7 (2-oxopropyl)pentanamide (0.82) (2S)-N-(2-aminooxoethyl){[(4- 1.05 bromophenyl)carbamoyl]amino}methylpentanamide (1.08) {[(2S){[(4-bromophenyl)carbamoyl]amino} 0.88 methylpentanoyl]amino}acetic acid (0.91) (2S){[(4-bromophenyl)carbamoyl]amino}-N-(2- 11 hydroxyethyl)methylpentanamide (0.92) tert-butyl {[(2S){[(4-bromophenyl)carbamoyl]amino}- 140 4-methylpentanoyl]amino}acetate (0.85) {[(2S){[(4-bromo 4.8 fluorophenyl)carbamoyl]amino}pentanoyl]amino}acetic (0.92) acid tert-butyl {[(2S){[(4-bromo 83 fluorophenyl)carbamoyl]amino}pentanoyl]amino}acetate (0.95) (2S){[(4-bromofluorophenyl)carbamoyl]amino}-N- 92 (2-oxopropyl)pentanamide (0.92) (2S){[(4-bromophenyl)carbamoyl]amino}-N-(2- oxopropyl)pentanamide 35 (1.05) propanyl {[(2S){[(4- bromophenyl)carbamoyl]amino}pentanoyl]amino}acetat 14 e (1.04) ethyl {[(2S){[(4- 57 bromophenyl)carbamoyl]amino}pentanoyl]amino}acetat (1.18) methyl {[(2S){[(4- bromophenyl)carbamoyl]amino}pentanoyl]amino}acetat 17 e (0.88) (2S){[(4-bromofluorophenyl)carbamoyl]amino}-N- 105 (2-hydroxyethyl)pentanamide (0.87) (2S){[(4-bromophenyl)carbamoyl]amino}-N-(2- 38 hydroxyethyl)pentanamide (0.92) -{[(4-bromofluorophenyl)carbamoyl]amino}-N- 16 (2-hydroxyethyl)phenylpropanamide (0.98) {[(2S){[(4- 3.2 bromophenyl)carbamoyl]amino}pentanoyl]amino}acetic (0.91) acid utyl {[(2S){[(4- 31 bromophenyl)carbamoyl]amino}pentanoyl]amino}acetat (0.95) (2S){[(4-bromofluorophenyl)carbamoyl]amino}-N- (2-oxopropyl)phenylpropanamide 12 (0.94) (2S){[(4-bromophenyl)carbamoyl]amino}-N-(2- oxopropyl)phenylpropanamide 29 (0.96) (2S,3S){[(4-bromofluorophenyl)carbamoyl]amino}- 62 N-(2-hydroxyethyl)methylpentanamide (1.00) (2S,3S){[(4-bromophenyl)carbamoyl]amino}-N-(2- 24 hydroxyethyl)methylpentanamide (1.00) (2S,3S){[(4-bromofluorophenyl)carbamoyl]amino}- 3-methyl-N-(2-oxopropyl)pentanamide 36 (1.01) (2S,3S){[(4-bromophenyl)carbamoyl]amino} 10 methyl-N-(2-oxopropyl)pentanamide (0.97) (2S,3S)-N-(2-aminooxoethyl){[(4-bromo 10 fluorophenyl)carbamoyl]amino}methylpentanamide (1.00) (2S,3S)-N-(2-aminooxoethyl){[(4- 4.6 bromophenyl)carbamoyl]amino}methylpentanamide (0.81) {[(2S,3S){[(4-bromophenyl)carbamoyl]amino} 2.7 pentanoyl]amino}acetic acid (1.00) tert-butyl {[(2S,3S){[(4- 280 bromophenyl)carbamoyl]amino} (0.85) methylpentanoyl]amino}acetate {[(2S,3S){[(4-bromo 5.5 fluorophenyl)carbamoyl]amino} (0.95) methylpentanoyl]amino}acetic acid tert-butyl {[(2S,3S){[(4-bromo 757 phenyl)carbamoyl]amino} (0.86) methylpentanoyl]amino}acetate (2S){[(4-bromophenyl)carbamoyl]amino}-N-(2- 6 hydroxyethyl)phenylpropanamide (0.92) 3-{[(2S){[(4-bromophenyl)carbamoyl]amino} 18 phenylpropanoyl]amino}propanoic acid (0.98) utyl 3-{[(2S){[(4- 255 bromophenyl)carbamoyl]amino} (1.00) phenylpropanoyl]amino}propanoate {[(2S){[(4-bromophenyl)carbamoyl]amino} 7.7 phenylpropanoyl]amino}acetic acid (0.99) tert-butyl {[(2S){[(4-bromophenyl)carbamoyl]amino}- 118 3-phenylpropanoyl]amino}acetate (0.91) tert-butyl 2-{[(2R){[(4- 2725 bromophenyl)carbamoyl]amino} (0.74) pentanoyl]amino}methylpropanoate 2-{[(2R){[(4-bromophenyl)carbamoyl]amino} 490 methylpentanoyl]amino}methylpropanoic acid (0.74) {[2-{[(4-bromophenyl)carbamoyl]amino}(1H-indol 0.73 yl)propanoyl]amino}acetic acid (0.97) tert-butyl {[2-{[(4-bromophenyl)carbamoyl]amino}(1H- 305 indolyl)propanoyl]amino}acetate (1.03) 2938 [(4-amino{[(4- (0.81) bromophenyl)carbamoyl]amino} oxobutanoyl)amino]acetic acid tert-butyl [(4-amino{[(4- 2306 bromophenyl)carbamoyl]amino} (0.90) oxobutanoyl)amino]acetate In this specification where nce has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a t for discussing the features of the invention. Unless ically stated ise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art.
In the description in this specification reference may be made to subject matter that is not within the scope of the claims of the current application. That subject matter should be readily identifiable by a person skilled in the art and may assist in putting into practice the invention as defined in the claims of this application.
Claims (3)
1. A compound represented by Formula II, its enantiomers, diastereoisomers, tautomers, hydrates, solvates or a pharmaceutically acceptable salt thereof, Formula II a is 1 and b is 0; a is 0 and b is 1; 10 a is 1 and b is 1; R1 is optionally substituted C1-8 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C6-10 aryl, optionally substituted C3-8 cycloalkenyl, -NR11R12 or -OR13; R2 is optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; 15 R3 is hydrogen, optionally substituted C1-8 alkyl, halogen, -COOR15, - OR13, -NR11R12, NO2, optionally tuted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl; R4 is en, optionally tuted C1-8 alkyl, halogen, - COOR15, - OR13, -NR11R12, NO2, ally substituted heterocycle, optionally tuted C3-8 20 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl; R5 is halogen, -CF3 or –S(O)nR14; n is 0, 1 or 2; R6 is hydrogen, optionally substituted C1-8 alkyl, halogen, - COOR15, - OR13, -NR11R12, NO2, optionally substituted heterocycle, optionally substituted C3-8 25 lkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl; R7 is hydrogen, ally substituted C1-8 alkyl, halogen, - , - OR13, -NR11R12, NO2, optionally substituted heterocycle, optionally substituted C3-8 lkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl; R8 is hydrogen, optionally substituted C1-8 alkyl or optionally tuted C6-10 aryl; R9 is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R10 is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R9a is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; 5 R10a is en, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R11 is en or ally substituted C1-8 alkyl; R12 is hydrogen or optionally substituted C1-8 alkyl; R13 is en or optionally substituted C1-8 alkyl; R14 is hydrogen, CF3 or optionally tuted C1-8 alkyl; 10 R15 is hydrogen or optionally substituted C1-8 alkyl; wherein a substituted alkyl is an alkyl in which one methylene (-CH2-) group of the alkyl group can be replaced by oxygen, , sulfoxide, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, by a divalent C 3-8 cycloalkyl, by a divalent cycle, or by a divalent aryl group, 15 and can be ndently substituted by halogen atoms, hydroxyl groups, cycloalkyl groups, amino groups, heterocyclic groups, aryl groups, carboxylic acid groups, phosphonic acid groups, sulphonic acid groups, oric acid groups, nitro groups, amide groups, amide groups, wherein a cycloalkyl is a monovalent or divalent group of 3 to 8 carbon atoms 20 derived from a saturated cyclic hydrocarbon, which can be monocyclic or polycyclic, independently substituted by n atoms, sulfonyl C1-8 alkyl groups, sulfoxide C1-8 alkyl groups, sulfonamide groups, nitro groups, cyano groups, -OC1-8 alkyl groups, -SC 1-8 alkyl groups, -C1-8 alkyl groups, -C2-6 l groups, -C2-6 alkynyl groups, ketone groups, alkylamino groups, amino groups, aryl groups, C3-8 cycloalkyl groups 25 or hydroxyl groups, and wherein a cycloalkenyl is a monovalent or divalent group of 3 to 8 carbon atoms derived from a saturated cycloalkyl having at least one double bond, which can be monocyclic or polycyclic, independently substituted by halogen atoms, sulfonyl groups, sulfoxide groups, nitro groups, cyano groups, -OC 1-6 alkyl groups, -SC1-6 30 alkyl groups, -C1-6 alkyl groups, -C2-6 alkenyl groups, - C2-6 alkynyl groups , ketone groups, alkylamino groups, amino groups, aryl groups, C3-8 cycloalkyl groups or hydroxyl groups, wherein an aryl is an organic moiety d from an aromatic hydrocarbon consisting of a ring containing 6 to 10 carbon atoms, by l of one hydrogen atom, can be monocyclic or polycyclic, and can be substituted by n atoms, sulfonyl C1-6 alkyl groups, sulfoxide C1-6 alkyl groups, sulfonamide groups, carboxcyclic acid , C1-6 alkyl carboxylates (ester) , amide groups, nitro groups, cyano groups, -OC1-6 alkyl groups, -SC1-6 alkyl groups, -C1-6 alkyl groups, - 5 C2-6 alkenyl groups, - C2-6 alkynyl groups , ketone groups, des, alkylamino groups, amino groups, aryl groups, C3-8 cycloalkyl groups or yl groups, wherein an heterocycle is 3 to 10 membered ring, which can be aromatic or nonaromatic , saturated or unsaturated, containing at least one atom selected form oxygen, nitrogen, sulfur, or combinations of at least two thereof, interrupting the 10 carbocyclic ring structure, wherein the heterocyclic ring can be interrupted by a C=O; the S and N heteroatoms can be oxidized, can be monocyclic or polycyclic; and wherein the heterocyclic ring moieties can be substituted by halogen atoms, sulfonyl groups, sulfoxide groups, nitro groups, cyano groups, -OC1-6 alkyl groups, -SC1-6 alkyl groups, -C1-8 alkyl groups, -C2-6 alkenyl , - C2-6 alkynyl groups , ketone 15 groups, alkylamino groups, amino groups, aryl groups, C3-8 cycloalkyl groups or hydroxyl , with the provisos: a) when a = 1 and b=0 then: R9 is not optionally substituted benzyl; R10 is H or methyl; and 20 R11 is not: , , , , , , , or ; and the compound of a II is not of structures: ; ; H H N N i-Bu COOH Cl O N i-Bu H ; 5 ; or ; NH COOH i-Bu NH 5 or ; and b) when a=0 and b=1 then: R1 is OR13; and the nd of Formula II is not of structure: 5 ; and c) when a=1 and b=1 then: R11 is not: 10 2). A compound according to claim 1, wherein: a is 1 and b is 0. 3). A compound according to claim 1, wherein: a is 1 and b is 0; and 15 R5 is –S(O)nR14 or R5 is -CF3. 4) A nd according to claim 1, wherein: a is 1 and b is 0; and R5 is halogen. 5). A compound according to claim 1, wherein: a is 1 and b is 0; R1 is optionally substituted C1-8 alkyl, -NR11 R12 or -OR13 ; R2 is optionally substituted C1-8 alkyl; 10 R3 is hydrogen, optionally substituted C1-8 alkyl, halogen, -COOR15 , -OR13 or -NR 11 R12 ; R4 is hydrogen, optionally substituted C1-8 alkyl, halogen, -COOR15 , -OR13 or - NR 11 R12 ; R5 is halogen, -CF3 or –S(O)nR14 ; 15 n is 0, 1 or 2; R6 is hydrogen, optionally substituted C1-8 alkyl, halogen, 5 , -OR13 or -NR 11 R12 ; R7 is hydrogen, optionally substituted C1-8 alkyl, halogen, -COOR15 , -OR13 or -NR 11 R12 ; 20 R8 is hydrogen or optionally substituted C1-8 alkyl; R9 is hydrogen, ally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R10 is hydrogen or ally tuted C1-8; R11 is hydrogen or optionally substituted C1-8 alkyl; R12 is hydrogen or optionally substituted C1-8 alkyl; 25 R13 is hydrogen or optionally substituted C1-8 alkyl; R14 is hydrogen or optionally substituted C1-8 alkyl; and R15 is hydrogen or optionally tuted C1-8 alkyl. 6). A compound according to claim 1, wherein: 30 a is 1 and b is 0; R1 is optionally substituted C1-8 alkyl, -NR11 R12 or -OR13 ; R2 is optionally substituted C1-8 alkyl; R3 is hydrogen or halogen; R4 is hydrogen; R5 is halogen, -CF3 or –S(O)nR14 ; n is 0, 1 or 2; R6 is hydrogen; R7 is hydrogen; 5 R8 is hydrogen or optionally substituted C1-8 alkyl; R9 is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R10 is hydrogen or optionally substituted C1-8 alkyl; R11 is hydrogen or optionally substituted C1-8 alkyl; R12 is hydrogen or ally tuted C1-8 alkyl; 10 R13 is hydrogen or optionally substituted C1-8 alkyl; and R14 is hydrogen or optionally substituted C1-8 alkyl. 7). A compound according to claim 1, wherein: a is 1 and b is 0; 15 R1 is optionally substituted C1-8 alkyl, -NR11 R12 or -OR13 ; R2 is optionally substituted C1-8 alkyl; R3 is hydrogen or halogen; R4 is hydrogen; R5 is halogen; 20 R6 is hydrogen; R7 is hydrogen; R8 is hydrogen or optionally substituted C1-8 alkyl; R9 is hydrogen, ally tuted C1-8 alkyl or optionally substituted C6-10 aryl; R10 is hydrogen or optionally substituted C1-8 alkyl; 25 R11 is hydrogen or optionally substituted C1-8 alkyl; R12 is hydrogen or optionally tuted C1-8 alkyl; and R13 is hydrogen or optionally substituted C1-8 alkyl. 8). A nd according to claim 1, wherein: 30 a is 0 and b is 1. 9). A compound according to claim 1, wherein: a is 0 and b is 1; R1 is -OR13 ; R2 is ally substituted C1-8 alkyl; R3 is hydrogen, optionally substituted C1-8 alkyl or halogen; R4 is hydrogen, ally substituted C1-8 alkyl or halogen; R5 is halogen, -CF3 or –S(O)nR14 ; 5 n is 0, 1 or 2; R6 is hydrogen, optionally substituted C1-8 alkyl or halogen; R7 is hydrogen, optionally tuted C1-8 alkyl or halogen; R8 is hydrogen; R9 is hydrogen; 10 R10 is en or optionally substituted C1-8 alkyl; R9a is hydrogen or optionally substituted C1-8 alkyl; R10a is hydrogen or optionally substituted C1-8 alkyl; R13 is hydrogen or optionally substituted C1-8 alkyl; and R14 is hydrogen, CF3 or optionally substituted C1-8 alkyl. 10). A compound according to claim 1, wherein: a is 0 and b is 1; R1 is -OR13 ; R2 is optionally substituted C1-8 alkyl; 20 R3 is hydrogen or halogen; R4 is hydrogen; R5 is n; R6 is hydrogen; R7 is hydrogen; 25 R8 is hydrogen; R9 is hydrogen; R10 is hydrogen or optionally substituted C1-8 alkyl; R9a is hydrogen or optionally substituted C1-8 alkyl; R10a is hydrogen or optionally substituted C1-8 alkyl; and 30 R13 is hydrogen. 11). A compound ing to claim 1, wherein: a is 1 and b is 1. 12). A compound according to claim 1, wherein: a is 1 and b is 1; R1 is optionally substituted C1-8 alkyl, -NR11 R12 or -OR13 ; R2 is optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; 5 R3 is hydrogen, optionally substituted C1-8 alkyl or halogen; R4 is hydrogen, optionally tuted C1-8 alkyl or halogen; R5 is halogen, -CF3 or –S(O)nR14 ; n is 0, 1 or 2; R6 is hydrogen, optionally substituted C1-8 alkyl or halogen; 10 R7 is en, optionally tuted C1-8 alkyl or halogen; R8 is en; R9 is hydrogen or optionally substituted C1-8 alkyl; R10 is hydrogen or ally substituted C1-8 alkyl; R9a is hydrogen or optionally substituted C1-8 alkyl; 15 R10a is hydrogen or optionally substituted C1-8 alkyl; R11 is hydrogen or optionally substituted C1-8 alkyl; R12 is hydrogen or optionally substituted C1-8 alkyl; R13 is en or optionally substituted C1-8 alkyl; R14 is hydrogen or optionally substituted C1-8 alkyl; and 20 R15 is hydrogen or optionally substituted C1-8 alkyl. 13). A compound according to claim 1, wherein: a is 1 and b is 1; R1 is -OR13 ; 25 R2 is optionally substituted C1-8 alkyl or ally substituted C6-10 aryl; R3 is hydrogen; R4 is hydrogen; R5 is halogen; R6 is hydrogen; 30 R7 is hydrogen; R8 is hydrogen; R9 is hydrogen; R10 is hydrogen; R9a is hydrogen; R10a is hydrogen; and R13 is en or optionally substituted C1-8 alkyl. 14). A compound according to claim 1 selected from: {[2-{[(4-bromophenyl)carbamoyl]amino}(1H-indolyl)propanoyl]amino}acetic 5 acid; tert-butyl {[2-{[(4-bromophenyl)carbamoyl]amino}(1H-indol yl)propanoyl]amino}acetate; [(4-amino{[(4-bromophenyl)carbamoyl]amino}oxobutanoyl)amino]acetic acid; utyl [(4-amino{[(4-bromophenyl)carbamoyl]amino} 10 oxobutanoyl)amino]acetate;
2.-{[(2R){[(4-bromophenyl)carbamoyl]amino}methylpentanoyl]amino} methylpropanoic acid; tert-butyl 2-{[(2R){[(4-bromophenyl)carbamoyl]amino}methylpentanoyl]amino}- 2-methylpropanoate; 15 {[2-{[(4-bromophenyl)carbamoyl]amino}(1H-imidazolyl)propanoyl]amino}acetic acid; tert-butyl {[2-{[(4-bromophenyl)carbamoyl]amino}(1H-imidazol panoyl]amino}acetate; {[(2S){[(4-bromophenyl)carbamoyl]amino}(methylsulfonyl)butanoyl]amino}acetic 20 acid; tert-butyl {[(2S){[(4-bromophenyl)carbamoyl]amino} (methylsulfonyl)butanoyl]amino}acetate; {[(2S){[(4-bromophenyl)carbamoyl]amino}(methylsulfanyl)butanoyl]amino}acetic acid; 25 tert-butyl {[(2S){[(4-bromophenyl)carbamoyl]amino} (methylsulfanyl)butanoyl]amino}acetate; 2-methyl{[(2S)methyl({[4- (trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}propanoic acid; tert-butyl 2-methyl{[(2S)methyl({[4- 30 (trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}propanoate; {[(2S)methyl({[4- (methylsulfonyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetic acid; tert-butyl {[(2S)methyl({[4- (methylsulfonyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetate; {[(2S)methyl({[4- (methylsulfinyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetic acid; 5 tert-butyl {[(2S)methyl({[4- (methylsulfinyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetate; 2-{[(2S){[(4-bromophenyl)carbamoyl]amino}methylpentanoyl]amino} methylpropanoic acid; utyl 2-{[(2S){[(4-bromophenyl)carbamoyl]amino}methylpentanoyl]amino}- 10 2-methylpropanoate; ({(2S)methyl[({4- [(trifluoromethyl)sulfanyl]phenyl}carbamoyl)amino]pentanoyl}amino)acetic acid; tert-butyl ({(2S)methyl[({4- [(trifluoromethyl)sulfanyl]phenyl}carbamoyl)amino]pentanoyl}amino)acetate; 15 {[(2S)methyl({[4- (methylsulfanyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetic acid; tert-butyl {[(2S)methyl({[4- (methylsulfanyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetate; {[(2R){[(4-bromophenyl)carbamoyl]amino}methylpentanoyl]amino}acetic acid; 20 utyl {[(2R){[(4-bromophenyl)carbamoyl]amino} methylpentanoyl]amino}acetate; {[(2R,3R){[(4-bromophenyl)carbamoyl]amino}methylpentanoyl]amino}acetic acid utyl {[(2R,3R){[(4-bromophenyl)carbamoyl]amino} 25 methylpentanoyl]amino}acetate; {[(2S)methyl({[4- uoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetic acid; tert-butyl {[(2S)methyl({[4- (trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetate; 30 {[(2R){[(4-bromofluorophenyl)carbamoyl]amino} methylpentanoyl]amino}acetic acid; (2S){[(4-bromophenyl)carbamoyl]amino}-N-[2-(dimethylamino)oxoethyl] methylpentanamide; [(2-{[(4-bromophenyl)carbamoyl]amino}methylpropanoyl)amino]acetic acid; tert-butyl [(2-{[(4-bromophenyl)carbamoyl]amino}methylpropanoyl)amino]acetate; [(2-{[(4-bromophenyl)carbamoyl]amino}ethylbutanoyl)amino]acetic acid; tert-butyl (4-bromophenyl)carbamoyl]amino}ethylbutanoyl)amino]acetate; [(2-{[(4-bromophenyl)carbamoyl]amino}-2,4-dimethylpentanoyl)amino]acetic acid; 5 tert-butyl [(2-{[(4-bromophenyl)carbamoyl]amino}-2,4- dimethylpentanoyl)amino]acetate; (2S)-N-[(1S)aminooxophenylethyl]{[(4-bromophenyl)carbamoyl]amino} methylpentanamide; (2S)-{[(2S){[(4-bromophenyl)carbamoyl]amino} 10 methylpentanoyl]amino}(phenyl)ethanoic acid; tert-butyl (2S)-{[(2S){[(4-bromophenyl)carbamoyl]amino} methylpentanoyl]amino}(phenyl)ethanoate; (2S)-N-[(2S)aminooxopentanyl]{[(4-bromophenyl)carbamoyl]amino} methylpentanamide; 15 -{[(2S){[(4-bromophenyl)carbamoyl]amino} methylpentanoyl]amino}pentanoic acid; tert-butyl (2S){[(2S){[(4-bromophenyl)carbamoyl]amino} methylpentanoyl]amino}pentanoate; (2S){[(4-bromophenyl)carbamoyl]amino}-N-[(2R)hydroxypropanyl] 20 methylpentanamide; -{[(4-bromophenyl)carbamoyl]amino}-N-(2,3-dihydroxypropyl) methylpentanamide; (2S){[(4-bromophenyl)carbamoyl]amino}-N-(1,3-dihydroxypropanyl) methylpentanamide; 25 (2S){[(4-bromophenyl)carbamoyl]amino}-N-(2-hydroxymethylpropyl) pentanamide; (2S)-N-[(2S)aminomethyloxobutanyl]{[(4- bromophenyl)carbamoyl]amino}methylpentanamide; (2S){[(2S){[(4-bromophenyl)carbamoyl]amino}methylpentanoyl]amino} 30 methylbutanoic acid; tert-butyl (2S){[(2S){[(4-bromophenyl)carbamoyl]amino} methylpentanoyl]amino}methylbutanoate; (2S)-N-[(2S)aminooxopropanyl]{[(4-bromophenyl)carbamoyl]amino} methylpentanamide; (2S){[(2S){[(4-bromophenyl)carbamoyl]amino} methylpentanoyl]amino}propanoic acid; tert-butyl (2S){[(2S){[(4-bromophenyl)carbamoyl]amino} methylpentanoyl]amino}propanoate; 5 (2S)-N-[(2S)aminooxopropanyl]{[(4-bromo fluorophenyl)carbamoyl]amino}methylpentanamide; -{[(2S){[(4-bromofluorophenyl)carbamoyl]amino} methylpentanoyl]amino}propanoic acid; tert-butyl (2S){[(2S){[(4-bromofluorophenyl)carbamoyl]amino} 10 methylpentanoyl]amino}propanoate; (2S){[(4-bromofluorophenyl)carbamoyl]amino}-N-(2-hydroxyethyl) methylpentanamide; (2S){[(4-bromofluorophenyl)carbamoyl]amino}methyl-N-(2- oxopropyl)pentanamide; 15 (2S)-N-(2-aminooxoethyl){[(4-bromofluorophenyl)carbamoyl]amino} methylpentanamide; {[(2S){[(4-bromofluorophenyl)carbamoyl]amino} methylpentanoyl]amino}acetic acid; tert-butyl {[(2S){[(4-bromofluorophenyl)carbamoyl]amino} 20 methylpentanoyl]amino}acetate; (2S)-N-(2-aminooxoethyl){[(4-bromo fluorophenyl)carbamoyl]amino}pentanamide; (2S)-N-(2-aminooxoethyl){[(4-bromophenyl)carbamoyl]amino}pentanamide; (2S){[(4-bromophenyl)carbamoyl]amino}methyl-N-(2-oxopropyl)pentanamide; 25 -(2-aminooxoethyl){[(4-bromophenyl)carbamoyl]amino} pentanamide; {[(2S){[(4-bromophenyl)carbamoyl]amino}methylpentanoyl]amino}acetic acid; (2S){[(4-bromophenyl)carbamoyl]amino}-N-(2-hydroxyethyl) methylpentanamide; 30 tert-butyl {[(2S){[(4-bromophenyl)carbamoyl]amino} methylpentanoyl]amino}acetate; {[(2S){[(4-bromofluorophenyl)carbamoyl]amino}pentanoyl]amino}acetic acid; tert-butyl {[(2S){[(4-bromo fluorophenyl)carbamoyl]amino}pentanoyl]amino}acetate; (2S){[(4-bromofluorophenyl)carbamoyl]amino}-N-(2-oxopropyl)pentanamide; (2S){[(4-bromophenyl)carbamoyl]amino}-N-(2-oxopropyl)pentanamide; propanyl {[(2S){[(4-bromophenyl)carbamoyl]amino}pentanoyl]amino}acetate; ethyl {[(2S){[(4-bromophenyl)carbamoyl]amino}pentanoyl]amino}acetate; 5 methyl {[(2S){[(4-bromophenyl)carbamoyl]amino}pentanoyl]amino}acetate; (2S){[(4-bromofluorophenyl)carbamoyl]amino}-N-(2-hydroxyethyl)pentanamide; (2S){[(4-bromophenyl)carbamoyl]amino}-N-(2-hydroxyethyl)pentanamide; (2S){[(4-bromofluorophenyl)carbamoyl]amino}-N-(2-hydroxyethyl) propanamide; 10 {[(2S){[(4-bromophenyl)carbamoyl]amino}pentanoyl]amino}acetic acid; tert-butyl {[(2S){[(4-bromophenyl)carbamoyl]amino}pentanoyl]amino}acetate; (2S){[(4-bromofluorophenyl)carbamoyl]amino}-N-(2-oxopropyl) phenylpropanamide; (2S){[(4-bromophenyl)carbamoyl]amino}-N-(2-oxopropyl)phenylpropanamide; 15 (2S,3S){[(4-bromofluorophenyl)carbamoyl]amino}-N-(2-hydroxyethyl) methylpentanamide; ){[(4-bromophenyl)carbamoyl]amino}-N-(2-hydroxyethyl) methylpentanamide; (2S,3S){[(4-bromofluorophenyl)carbamoyl]amino}methyl-N-(2- 20 oxopropyl)pentanamide; (2S,3S){[(4-bromophenyl)carbamoyl]amino}methyl-N-(2- oxopropyl)pentanamide; (2S,3S)-N-(2-aminooxoethyl){[(4-bromofluorophenyl)carbamoyl]amino} methylpentanamide; 25 (2S,3S)-N-(2-aminooxoe;thyl){[(4-bromophenyl)carbamoyl]amino} methylpentanamide {[(2S,3S){[(4-bromophenyl)carbamoyl]amino}methylpentanoyl]amino}acetic acid; tert-butyl {[(2S,3S){[(4-bromophenyl)carbamoyl]amino} 30 methylpentanoyl]amino}acetate; {[(2S,3S){[(4-bromofluorophenyl)carbamoyl]amino} pentanoyl]amino}acetic acid; tert-butyl {[(2S,3S){[(4-bromofluorophenyl)carbamoyl]amino} methylpentanoyl]amino}acetate; (2S){[(4-bromophenyl)carbamoyl]amino}-N-(2-hydroxyethyl) phenylpropanamide;
3.-{[(2S){[(4-bromophenyl)carbamoyl]amino}phenylpropanoyl]amino}propanoic acid; 5 tert-butyl 3-{[(2S){[(4-bromophenyl)carbamoyl]amino} propanoyl]amino}propanoate; {[(2S){[(4-bromophenyl)carbamoyl]amino}phenylpropanoyl]amino}acetic acid; tert-butyl {[(2S){[(4-bromophenyl)carbamoyl]amino} 10 phenylpropanoyl]amino}acetate. 15). The compound according to claim 1: {[(2S){[(4- bromophenyl)carbamoyl]amino}methylpentanoyl]amino}acetic acid, which has the 15 following structure: 16). A use of a nd as claimed in any one of claims 1-15 in the manufacture of a medicament. 17). A use of a compound as claimed in any one of claims 1-15 in the manfufacture of a medicament for treating a disease or disorder associated with the modulators of the N-formyl peptide receptor like-1 or in need thereof, wherein the disorder associated with modulation of the N-formyl peptide receptor like-1 25 receptor is selected from the group ting of inflammatory bowel disease; ocular inflammatory diseases; ic inflammatory diseases; pain; immunological disorders; dermal wound healing; burns; rosacea; atopic dermatitis; acne; psoriasis; seborrheic dermatitis; actinic keratosis; viral warts; photoaging; rheumatoid arthritis and related inflammatory disorders. 18). A use as claimed in claim 17, wherein the ocular matory diseases is selected from s, dry eye, keratitis, allergic eye disease, ious keratitis, herpetic keratitis, corneal angiogenesis, lymphangiogenesis, retinitis, choroiditis, acute multifocal placoid pigment epitheliopathy, Behcet’s disease, post-surgical 5 corneal wound healing, wet and dry age-related macular degeneration (ARMD). 19). A pharmaceutical composition comprising a compound as claimed in any one of claims 1-15 and a pharmaceutically acceptable carrier. 10 20). A compound as claimed in claim 1, substantially as herein described with reference to any e thereof. 21). A use as claimed in claim 16 or 17, substantially as herein described with reference to any example thereof. 22). A composition as claimed in claim 18, substantially as herein described with reference to any example thereof.
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US201161551772P | 2011-10-26 | 2011-10-26 | |
US61/551,772 | 2011-10-26 | ||
PCT/US2012/061448 WO2013062947A1 (en) | 2011-10-26 | 2012-10-23 | Amide derivatives of n-urea substituted amino acids as formyl peptide receptor like-1 (fprl-1) receptor modulators |
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