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Title:
HYDROXY FORMAMIDE DERIVATIVES AND THEIR USE
Document Type and Number:
WIPO Patent Application WO/2017/006295
Kind Code:
A1
Abstract:
Disclosed are compounds having the formula: (I) wherein R1, R2 and R3 are as defined herein, and methods of making and using the same, including use as inhibitors of BMP1, TLL1 and/or TLL2 and in treatment of diseases associated with BMP1, TLL1 and/or TLL2 activity.

Inventors:
DOWDELL SARAH E (US)
EIDAM HILARY SCHENCK (US)
ELBAN MARK (US)
FOX RYAN MICHAEL (US)
HILFIKER MARK A (US)
HOANG TRAM H (US)
KALLANDER LARA S (US)
LAWHORN BRIAN GRIFFIN (US)
MANNS SHARADA (US)
PHILP JOANNE (US)
WASHBURN DAVID G (US)
YE GUOSEN (US)
Application Number:
PCT/IB2016/054119
Publication Date:
January 12, 2017
Filing Date:
July 08, 2016
Export Citation:
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Assignee:
GLAXOSMITHKLINE INTELLECTUAL PROPERTY (NO 2) LTD (GB)
International Classes:
C07D213/81; A61K31/16; A61K31/44; A61P43/00; C07C239/16; C07D263/32
Domestic Patent References:
WO2004052919A22004-06-24
WO2015104684A12015-07-16
WO2008011193A22008-01-24
WO2013163479A12013-10-31
WO2009061879A12009-05-14
Foreign References:
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Claims:
What is claimed is:

1. A compound of formula (I):

(I)

or a salt thereof,

wherein: one or two of W1 , W2, W3 and W4 are N and the remainder are CRa, or each of W1 , W2, W3 and W4 are CRa,

wherein each Ra is H, or one Ra is selected from F, CF3, and C02H, and the remainder are H;

R1 is selected from H, (C C4) straight chain alkyl, and (C C4) straight chain alkyl substituted with one hydroxy group;

R2 is selected from H, (C Cn)alkyl, (CrC3)alkyl(C3-C6)cycloalkyl, (C C3)alkyl-phenyl, (C C3)alkyl-naphthyl, and (Ci-C3)alkyl-heterocyclyl, wherein heterocyclyl is a monocyclic ring having 5-6 ring atoms wherein 1-2 of the ring atoms are selected from nitrogen, oxygen and sulfur, and wherein said (d-Cn)alkyl, (Ci-C3)alkyl(C3-C6)cycloalkyl, (C C3)alkyl-phenyl, (C C3)alkyl-naphthyl, and (C C3)alkyl-heterocyclyl are optionally substituted with 1-2 groups independently selected from (C C4)alkyl, (C C4)alkoxy, halo, and cyano;

R3 is selected from phenyl and heteroaryl, wherein said phenyl and heteroaryl are optionally substituted with 1-3 groups independently selected from:

(CrC6)alkyl, optionally substituted with 1-3 groups independently selected from: fluoro (e.g., -CF3); -C02H; -P(0)RfR9; NRaR wherein Ra is selected from H and (C C4)alkyl and R is selected from (C C4)alkyl substituted with 1-3 -C02H or -P(0)RfR9; and - C(0)NRaR wherein Ra and R are independently selected from H and (C C4)alkyl, wherein the (C C4)alkyl is optionally substituted with 1-3 groups independently selected from hydroxy, -C02H, -C(0)0(C C4)alkyl and -P(0)RfR9;

cyclopropyl, optionally substituted with 1 -C02H;

-C(0)NRaR wherein Ra and R are independently selected from H and (C C4)alkyl, wherein the (C C4)alkyl is optionally substituted with 1-3 groups independently selected from hydroxy, -C02H, -C(0)0(C C4)alkyl, -P(0)RfR9, NRcRd and N+ RcRdRe;

(C C6)alkoxy, optionally substituted with 1-3 substituents independently selected from halo, hydroxy, -C02H, (C3-C6)cycloalkyl, -C(0)NH2 and pyrrolidinyl;

(C3-C6)cycloalkoxy, optionally substituted with 1-3 substituents independently selected from halo, hydroxy, and -C02H;

-NRaR wherein Ra and R are independently selected from H and (C C4)alkyl, wherein the (C C4)alkyl is optionally substituted with 1-3 groups independently selected from oxo and -C02H;

-SRa wherein Ra is selected from H and (C C4)alkyl;

-C02H; -C(NOH)NH2; cyano; -C(0)0(C C4)alkyl; -C(0)C02H; -P(0)RfR9; - OP(0)RfR9; halo; hydroxy; nitro; -NHS02(C C2)alkyl; -S03H; -S02(C C2)alkyl; -S02NRcRd; - S02NHC(0)(C C2)alkyl; -B(OH)2; and oxo;

wherein in each occurrence: Rc, Rd and Re are independently selected from H and (C C2)alkyl; and

Rf and R9 are independently selected from hydroxy, (C C2)alkyl and (C C2)alkoxy; and n is 0 or 1.

2. The compound or salt thereof according to claim 1 , wherein one or two of W1 , W2, W3 and W4 are N and the remainder are CRa.

3. The compound or salt thereof according to claim 1 , wherein W1 is N and the remainder are CRa.

4. The compound or salt thereof according to claim 1 , wherein W1 and one of W2 and W3 are N, and W4 is CRa.

5. The compound or salt thereof according to claim 1 , wherein each of W1 , W2, W3 and W4 are CRa.

6. The compound or salt thereof according to any one of the preceding claims, wherein each Ra is H.

7. The compound or salt thereof according to any one of the preceding claims, wherein R1 is H or (C1-C4) straight chain alkyl.

8. The compound or salt thereof according to claim 7, wherein R1 is H or ethyl.

9. The compound or salt thereof according to claim 7, wherein R1 is ethyl.

10. The compound or salt thereof according to any one of the preceding claims, wherein R2 is (Ci-Cn)alkyl (e.g. C3-C7 alkyl, e.g. C4-C6 alkyl).

11. The compound or salt thereof according to claim 10, wherein R2 is pentyl.

12. The compound or salt thereof according to any one of claims 1-9, wherein R2 is (Ci- C3)alkyl(C3-C6)cycloalkyl (e.g. cyclopropylmethyl).

13. The compound or salt thereof according to any one of claims 1-9, wherein R2 is (Ci- C3)alkyl-phenyl (e.g. phenylethyl).

14. The compound or salt thereof according to any one of the preceding claims, wherein R3 is phenyl optionally substituted as defined in claim 1.

15. The compound or salt thereof according to claim 14, wherein R3 is phenyl substituted with 1-3 groups independently selected from: -OCH3, -OC2H5, -OC3H7, -OCH(CH3)2, - OCF3, -OCHF2, -OCH2CF3, -OCH2CHF2, -OC2H4 - pyrrolidinyl, -OCH2C02H, - OCH2C(0)NH2, -CO2H, -CH3, cyclopropanyl-1-carboxylic acid, -CH2C02H, - C(CH3)2C02H, -CH(CH3)C02H, -CF2C02H, -CH2C(0)NHCH(C02H)(CH2C02H), - CH2P(0)(OH)2,-CH2N(CH3)(CH2C02H), -CH2NHCH2P(0)(OH)2, -C(NH2)(NOH), cyano, nitro, hydroxy, -S02NH2, -S02N(CH3)2, -S02NH(CH3), -SO2CH3, -S02NHC(0)C2H5, - S03H, -SCH3, -SC2H5, -C(0)OCH3, -C(0)OC(CH3)3, -C(0)NHCH3, -C(0)NH(C2H4NH2), -C(0)NHC2H4N+(CH3)3, -C(0)NHCH(C02H)(CH2C02H), - C(0)NHCH(C02H)(C2H4C02H), -C(0)NHCH2C02H, -C(0)N(CH2C02H)2, - C(0)NHCH2P(0)(OH)2, -C(0)NHC(CH20H)3, fluoro, -NH2, -N(CH3)2, - P(0)(CH3)(OC2H5), -P(0)(OCH3)2, -P(0)(CH3)(OH), -P(0)(OH)(OCH3), and - P(0)(OH)2.

16. The compound or salt thereof according to claim 14, wherein R3 is phenyl substituted with 1-3 groups selected from:

methyl, ethyl, isopropyl, -CF3, -CH2C02H, -CH(CH3)2(C02H), - CH2CONHCH(C02H)(CH2C02H), 1-C02Hcyclopropyl, -CONH2, - CONHCH(C02H)(CH2C02H), -OCH3, -OC2H5, -OCH(CH3)2, -OCF3, -OCH2CF3, - OCH2C02H, -N(CH3)2, -SH, -C02H, -CN, -C02C2H5, -P(0)(OH)2, -F, -OH, - NHS02CH3, -S03H, -S02CH3, -S02NH2, and -B(OH)2.

17. The compound or salt thereof according to claim 14, wherein R3 is phenyl substituted with 1-3 groups independently selected from: -OC2H5, -OCH2CO2H, - CONHCH(C02H)(CH2C02H), -P(0)(OH)2, -CO2H, -CH2CO2H, - CH2CONHCH(C02H)(CH2C02H), -OH, and -SOsH.

18. The compound or salt thereof according to claim 14, wherein R3 is phenyl substituted with 1-3 groups independently selected from: -OC2H5, -OCH2CO2H, - CONHCH(C02H)(CH2C02H), and -P(0)(OH)2.

19. The compound or salt thereof according to any one of claims 14-18, wherein the R3

substituted phenyl is 3,4- or 3,5- disubstituted phenyl (e.g. 3-ethoxy and 4- or 5- - P(0)(OH)2 or -CO2H; 3- ethoxy and 4- or 5- -OCH2CO2H or - C(0)NHCH(C02H)(CH2C02H); 3- -OCH2CO2H and 4- or 5- - C(0)NHCH(C02H)(CH2C02H)).

20. The compound or salt thereof according to any one of claims 1-13, wherein R3 is

heteroaryl, optionally substituted as defined in claim 1.

21. The compound or salt thereof according to claim 20, wherein R3 is monocyclic heteroaryl comprising 5-6 ring atoms comprising 1-4 heteroatoms selected from nitrogen, oxygen and sulfur (e.g. pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, tetrazolyl, or oxazolyl), optionally substituted as defined in claim 1.

22. The compound or salt thereof according to claim 20 or 21 , wherein R3 is heteroaryl

substituted with 1-3 groups independently selected from: -OCH3, -OC2H5, -OC3H7, - OCH(CH3)2, -OCF3, -OCHF2, -OCH2CF3, -OCH2CHF2, -OC2H4 - pyrrolidinyl, - OCH2CO2H, -OCH2C(0)NH2, -CO2H, -CH3, cyclopropanyl-1-carboxylic acid, -CH2CO2H, -C(CH3)2C02H, -CH(CH3)C02H, -CF2CO2H, -CH2C(0)NHCH(C02H)(CH2C02H), - CH2P(0)(OH)2,-CH2N(CH3)(CH2C02H), -CH2NHCH2P(0)(OH)2, -C(NH2)(NOH), cyano, nitro, hydroxy, -SO2NH2, -S02N(CH3)2, -S02NH(CH3), -SO2CH3, -S02NHC(0)C2H5, - SOsH, -SCH3, -SC2H5, -C(0)OCH3, -C(0)OC(CH3)3, -C(0)NHCH3, -C(0)NH(C2H4NH2), -C(0)NHC2H4N+(CH3)3, -C(0)NHCH(C02H)(CH2C02H), - C(0)NHCH(C02H)(C2H4C02H), -C(0)NHCH2C02H, -C(0)N(CH2C02H)2, - C(0)NHCH2P(0)(OH)2, -C(0)NHC(CH20H)3, fluoro, -NH2, -N(CHs)2, - P(0)(CH3)(OC2H5), -P(0)(OCH3)2, -P(0)(CH3)(OH), -P(0)(OH)(OCH3), and -P(0)(OH)2.

23. The compound or salt thereof according to claim 20 or 21 , wherein R3 is heteroaryl substituted with 1-3 groups selected from:

methyl, ethyl, isopropyl, -CF3, -CH2C02H, -CH(CH3)2(C02H), - CH2CONHCH(C02H)(CH2C02H), -1-C02Hcyclopropyl, -CONH2, - CONHCH(C02H)(CH2C02H), -OCH3, -OC2H5, -OCH(CH3)2, -OCF3, -OCH2CF3, - OCH2C02H, -N(CH3)2, -SH, -C02H, -CN, -C02C2H5, -P(0)(OH)2, -F, -OH, - NHS02CH3, -S03H, -S02CH3, -S02NH2, and -B(OH)2.

24. The compound or salt thereof according to claim 20 or 21 , wherein R3 is heteroaryl substituted with 1-3 groups independently selected from: -OC2H5, -OCH2CO2H, - CONHCH(C02H)(CH2C02H), -P(0)(OH)2, -CO2H, -CH2CO2H, - CH2CONHCH(C02H)(CH2C02H), -OH, and -SOsH.

25. The compound or salt thereof according to claim 20 or 21 , wherein R3 is heteroaryl, substituted with 1-3 groups independently selected from: -OC2H5, -OCH2CO2H, - CONHCH(C02H)(CH2C02H), and -P(0)(OH)2.

26. The compound or salt thereof according to any one of the preceding claims, wherein n is 0.

27. The compound or salt thereof according to any one of the preceding claims, wherein n is 1.

28. A compound selected from the group consisting of: (S)-2-(5-ethoxy-3'-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamiclo)methyl)carbamoyl)-[1 , T-biphi

ylcarboxamido)succinic acid

(S)-2-(2-(carboxymethoxy)-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2-yl)benzamido)succinic acid; and

(3-ethoxy-5-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl) carbamoyl)pyridin-2-yl)phenyl)phosphonic acid;

or a salt thereof. 29. A compound selected from the group consisting

3-ethoxy-5-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2-yl)benzoic acid

2-ethoxy-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2-yl)benzoic acid

2-(2-ethoxy-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2-yl)phenyl)acetic acid

2-(4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2-yl)phenyl)acetic acid (2-ethoxy-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2-yl)phenyl)pho acid

(R)-3-ethoxy-5-(6-(((2-((N- hydroxyformamido)methyl)heptanamido)methyl)carbamoyl)pyridin-2-yl)benzoic acid

2-ethoxy-4-(6-((((2R,3R)-3-(N-hydroxyformamido)-2- phenethylpentanamido)methyl)carbamoyl)pyridin-2-yl)benzoic acid

3-ethoxy-3'-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)- [1 , 1 '-biphenyl]-4-carboxylic acid

2-(3-ethoxy-3'-((((R)-2-((R)- 1 -(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 , 1 '-biphenyl]-4-yl)acetic acid

5-ethoxy-3'-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)- [1 , 1 '-biphenyl]-3-carboxylic acid

(S)-2-(3-ethoxy-5-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2-yl)benzamido)succinic acid

(S)-2-(2-ethoxy-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2-yl)benzamido)succinic acid (S)-2-(2-(2-ethoxy-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamiclo)methyl)carbamoyl)pyricliri-2- yl)phenyl)acetamido)succinic acid

2-ethoxy-4-(4-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyrimidin-2-yl)benzoic acid

2-ethoxy-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyrazin-2-yl)benzoic acid

(S)-2-(3-ethoxy-3'-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 ,1 '-biphenyl]-4- ylcarboxamido)succinic acid

3-hydroxy-3'-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)- [1 , 1 '-biphenyl]-4-carboxylic acid

(S)-2-(3-(carboxymethoxy)-3'-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 ,1 '-biphenyl]-4- ylcarboxamido)succinic acid

(5-ethoxy-3'-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)- [1 , 1 '-biphenyl]-3-yl)phosphonic acid

(3-ethoxy-3'-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)- [1 , 1 '-biphenyl]-4-yl)phosphonic acid (2-ethoxy-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyrazin-2-yl)phenyl)phosph acid

(2-ethoxy-4-(4-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyrirriidiri-2- yl)phenyl)phosphonic acid; and

5-ethoxy-3'-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)- [1 , 1 '-biphenyl]-3-sulfonic acid;

or a salt thereof.

30. A compound selected from the group consisting of:

(R)-N-((2-((N-hydroxyformamido)methyl)-4-phenylbutanamido)methyl)-6- phenylpicolinamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-6-phenylpicolinamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-6-(3- methoxyphenyl)picolinamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-6'-methoxy-[2,2'-bipyridine]- 6-carboxamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-2-phenylpyrimidine-4- carboxamide (R)-6-(4-fluorophenyl)-N-((2-((N- hydroxyformamido)methyl)heptanamido)methyl)picolinarriicle

(R)-6-(4-fluoro-3-methoxyphenyl)-N-((2-((N- hydroxyformamido)methyl)heptanamido)methyl)picolinamide

(R)-6-(2,4-difluorophenyl)-N-((2-((N- hydroxyformamido)methyl)heptanamido)methyl)picolinamide

(R)-6-(2-fluoro-3-methoxyphenyl)-N-((2-((N- hydroxyformamido)methyl)heptanamido)methyl)picolinamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-[2,3'-bipyridine]-6- carboxamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-6-(4- (trifluoromethyl)phenyl)picolinamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-6-(4- (trifluoromethoxy)phenyl)picolinamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-6-phenylpyrazine-2- carboxamide (R)-5-fluoro-N-((2-((N-hydroxyformamido)methyl)heptanarriiclo)methyl)-6- phenylpicolinamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-6-phenyl-4- (trifluoromethyl)picolinamide

2-(4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2-yl)phenyl)-2- methylpropanoic acid

1-(4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2- yl)phenyl)cyclopropanecarboxylic acid

3-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2- yl)-2-methyl benzoic acid

5-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2- yl)-2-methoxybenzoic acid

2-fluoro-5-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2-yl)benzoic acid

6-(3-((2-aminoethyl)carbamoyl)-5-ethoxyphenyl)-N-(((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)picolinamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-[1 , T-biph

carboxamide (R)-2-fluoro-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3'-methoxy-[1 , 1 '- biphenyl]-3-carboxamide

(R)-2,2'-difluoro-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3'-methoxy- [1 , 1 '-biphenyl]-3-carboxamide

(R)-2,2'-difluoro-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-5'-methoxy- [1 , 1 '-biphenyl]-3-carboxamide

(R)-3-(4,5-dimethyloxazol-2-yl)-N-((2-((N- hydroxyformamido)methyl)heptanamido)methyl)benzamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3-(4-methyl-1 H-pyrazol-1- yl)benzamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3-(2-methyloxazol-5- yl)benzamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3-(2-methoxypyrimidin-4- yl)benzamide

(R)-(3'-(((2-((N-hydroxyformamido)methyl)-4-phenylbutanamido)methyl)carbamoyl)-[1 , T- biphenyl]-3-yl)boronic acid

(R)-N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propanamido)methyl)-2'-methoxy- [1 , 1 '-biphenyl]-3-carboxamide (R)-N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propanamido)methyl)-3'-methoxy- [1 , 1 '-biphenyl]-3-carboxamide

(R)-N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propanamido)methyl)-4'- (trifluoromethyl)-[1 ,1 '-biphenyl]-3-carboxamide

(R)-3'-cyano-N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propanamido)methyl)-[1 ,1 '- biphenyl]-3-carboxamide

(R)-N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propanamido)methyl)-[1 , 1 -biphenyl]- 3-carboxamide

(R)-N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propanamido)methyl)-3- phenoxybenzamide

4-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2- yl)-3-methyl benzoic acid

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3-(5-methyloxazol-2- yl)benzamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3-(1 H-tetrazol-5- yl)benzamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3'-methoxy-[1 , T-biph carboxamide (R)-N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propanamido)methyl)-3'-ethoxy-[1 ,1 '- biphenyl]-3-carboxamide

(R)-N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propanamido)methyl)-3'-hydroxy- [1 , 1 '-biphenyl]-3-carboxamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3'-isopropyl-[1 , T-biphenyl]- 3-carboxamide

(R)-N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propanamido)methyl)-3'-ethyl-[1 , T- biphenyl]-3-carboxamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-2',5'-dimethoxy-[1 , 1 '- biphenyl]-3-carboxamide

(R)-N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propanamido)methyl)-3'- (trifluoromethoxy)-[1 , 1 '-biphenyl]-3-carboxamide

(R)-N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propanamido)methyl)-3'- (trifluoromethyl)-[1 ,1 '-biphenyl]-3-carboxamide

(R)-N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propanamido)methyl)-3',5'- dimethoxy-[1 , 1 '-biphenyl]-3-carboxamide

(R)-3-(3,6-dimethoxypyridazin-4-yl)-N-((2-((N- hydroxyformamido)methyl)heptanamido)methyl)benzamide (R)-3-(3,6-dimethoxypyridazin-4-yl)-N-((2-((N-hydroxyformamido)methyl)-4- phenylbutanamido)methyl)benzamide

(R)-3'-fluoro-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-[1 , 1 '-biphenyl]-3- carboxamide

(R)-3'-hydroxy-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-[1 , 1 '-biphenyl]-3- carboxamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3'-isopropoxy-[1 , T-biphenyl]- 3-carboxamide

(R)-4'-fluoro-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-[1 , 1 '-biphenyl]-3- carboxamide

(R)-N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propanamido)methyl)-3-(5- methoxypyridin-3-yl)benzamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3-(5-methoxypyridin-3- yl)benzamide

(R)-3-(1-ethyl-1 H-pyrazol-4-yl)-N-((2-((N- hydroxyformamido)methyl)heptanamido)methyl)benzamide

(R)-3'-(((2-((N-hydroxyformamido)methyl)heptanamido)methyl)carbamoyl)-[1 , 1 '-biphenyl]-3- carboxylic acid (R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3'-sulfamoyl-[1 , 1 -biphenyl]- 3-carboxamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3'-(2,2,2-trifluoroethoxy)- [1 , 1 '-biphenyl]-3-carboxamide

(R)-2'-fluoro-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3'-methoxy-[1 , 1 '- biphenyl]-3-carboxamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3'-(methylsulfonamido)-[1 , T- biphenyl]-3-carboxamide

(R)-4'-(dimethylamino)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-[1 , 1 '- biphenyl]-3-carboxamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3'-(methylsulfonyl)-[1 ,1 '- biphenyl]-3-carboxamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-4'-methoxy-[1 , T-biph carboxamide

(R)-2'-fluoro-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-[1 , 1 '-biphenyl]-3- carboxamide

(R)-4'-fluoro-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3'-methoxy-[1 , 1 '- biphenyl]-3-carboxamide (R)-N3-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-[1 , 1 '-biphenyl]-3,3'- dicarboxamide

(R)-3'-(dimethylamino)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-[1 , 1 '- biphenyl]-3-carboxamide ethyl 3-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin

sulfamoylbenzoate

N-(((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl)-3'-mercapto-[1 , T- biphenyl]-3-carboxamide

2-ethoxy-4-(3-fluoro-6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2-yl)benzoic acid

3-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2- yl)-5-sulfamoylbenzoic acid

5-ethoxy-2-hydroxy-3'-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 , 1 '-biphenyl]-3-carboxylic acid

5-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 , T- biphenyl]-3-carboxylic acid

5-ethoxy-5'-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)- [1 , 1 '-biphenyl]-3,3'-dicarboxylic acid; and (R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3-((6-methoxypyridin-3- yl)oxy)benzamide;

or a salt thereof.

31. A compound selected from the group consisting of:

((2-ethoxy-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2- yl)benzamido)methyl)phosphonic acid;

2,2'-((3-ethoxy-5-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2- yl)benzoyl)azanediyl)diacetic acid;

2,2'-((2-ethoxy-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2- yl)benzoyl)azanediyl)diacetic acid;

3- (carboxymethoxy)-5-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2-yl)benzoic acid;

4- (6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2- yl)phthalic acid;

(R)-2-(4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2-yl)benzamido)succinic acid;

(S)-2-(4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2-yl)benzamido)succinic acid;

(S)-2-(4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2- yl)benzamido)pentanedioic acid;

(S)-2-(2-ethoxy-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2- yl)benzamido)pentanedioic acid;

(3-hydroxy-5-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)m

acid;

((2-hydroxy-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2- yl)benzamido)methyl)phosphonic acid;

((4-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-

2-yl)benzamido)methyl)phosphonic acid;

(S)-2-(2-chloro-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2-yl)benzamido)succi acid;

((4-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-

2-yl)-2-methylbenzamido)methyl)phosphonic acid;

(S)-2-(4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2-yl)-2- methylbenzamido)succinic acid; and

(S)-2-(2-fluoro-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2-yl)benzamido)succinic acid; or a salt thereof.

32. The compound or salt thereof according to any one of the preceding claims, wherein the salt is a pharmaceutically acceptable salt of said compound.

33. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof according to claim 32, and one or more pharmaceutically acceptable excipients.

34. A pharmaceutical composition comprising a compound selected from:

(S)-2-(5-ethoxy-3'-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 , T-biphenyl]-3- ylcarboxamido)succinic acid;

(S)-2-(2-(carboxymethoxy)-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2- yl)benzamido)succinic acid; and

(3-ethoxy-5-(6-((((R)-2-((R)-1-(N-hydroxyformarnido)propyl)heptanamido)methyl) carbamoyl)pyridin-2-yl)phenyl)phosphonic acid;

or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable excipients.

35. A method of treating a disease associated with BMP1 , TLL1 and/or TLL2 activity in a human in need thereof comprising administering to said human a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof according to claim 32.

36. A method of treating a disease associated with BMP1 , TLL1 and/or TLL2 activity in a human in need thereof comprising administering to said human a therapeutically effective amount of a compound selected from:

(S)-2-(5-ethoxy-3'-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 , T-biphenyl]-3- ylcarboxamido)succinic acid;

(S)-2-(2-(carboxymethoxy)-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2- yl)benzamido)succinic acid; and

(3-ethoxy-5-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl) carbamoyl)pyridin-2-yl)phenyl)phosphonic acid;

or a pharmaceutically acceptable salt thereof.

37. A compound or pharmaceutically acceptable salt thereof according to claim 32 for use in the treatment of a disease associated with BMP1 , TLL1 and/or TLL2 activity.

38. A compound or pharmaceutically acceptable salt thereof according to claim 32, for use in therapy.

39. The compound or pharmaceutically acceptable salt thereof for use according to claim 37 or 38 which is a compound selected from:

(S)-2-(5-ethoxy-3'-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 , T-biphenyl]-3- ylcarboxamido)succinic acid;

(S)-2-(2-(carboxymethoxy)-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2- yl)benzamido)succinic acid; and

(3-ethoxy-5-(6-((((R)-2-((R)-1-(N-hydroxyformarnido)propyl)heptanamido)methyl) carbamoyl)pyridin-2-yl)phenyl)phosphonic acid;

or a pharmaceutically acceptable salt thereof.

40. Use of the compound, or pharmaceutically acceptable salt thereof, according to claim 32 in the manufacture of a medicament for the treatment of a disease associated with BMP1 , TLL1 and/or TLL2 activity.

41. Use of a compound selected from:

(S)-2-(5-ethoxy-3'-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 , T-biphenyl]-3- ylcarboxamido)succinic acid;

(S)-2-(2-(carboxymethoxy)-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2- yl)benzamido)succinic acid; and

(3-ethoxy-5-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl) carbamoyl)pyridin-2-yl)phenyl)phosphonic acid;

or a pharmaceutically acceptable salt thereof,

in the manufacture of a medicament for the treatment of a disease associated with BMP1 , TLL1 and/or TLL2 activity.

42. The method, compound or use according to any one of claims 35-41 , wherein the

disease associated with BMP1 , TLL1 and/or TLL2 activity is selected from diseases associated with pathological fibrotic conditions of the heart, lung, kidney, liver, eye, skin, skeletal muscle, vasculature, or nervous system.

43. The method, compound or use according to claim 42, wherein the disease is selected from: myocardial infarction, heart failure, cardiac arrhythmia, hypertrophic

cardiomyopathy, chronic obstructive pulmonary disease ("COPD", idiopathic pulmonary fibrosis ("IPF"), diabetic nephropathy, post-acute kidney injury, chronic kidney disease

("CKD"), delayed graft function post-transplantation, liver cirrhosis, non-alcoholic steatohepatitis ("NASH"), glaucoma, corneal scarring, muscular dystrophy, keloids, wound healing, adhesions, hypertrophic scarring, scarring, e.g., associated with burns, surgery or other trauma, stroke, collagen vascular diseases, systemic lupus erythematosus, rheumatoid arthritis, scleroderma, spinal cord injury, and multiple sclerosis.

44. The method, compound or use according to any one of claims 35-41 , wherein the

disease associated with BMP1 , TLL1 and/or TLL2 activity is selected from muscular diseases characterized by reduced muscle function and/or mass.

45. The method, compound or use according to claim 44, wherein the muscular disease is selected from: muscular dystrophy, sarcopenia, and cachexia associated with, e.g., heart failure, CKD, COPD, cancer, or old age.

46. A composition comprising a) the compound of formula (I) or a pharmaceutically

acceptable salt thereof according to claim 32; and b) a combination partner.

47. A composition comprising a) a compound selected from:

(S)-2-(5-ethoxy-3'-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 , T-biphenyl]-3- ylcarboxamido)succinic acid;

(S)-2-(2-(carboxymethoxy)-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2- yl)benzamido)succinic acid; and

(3-ethoxy-5-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl) carbamoyl)pyridin-2-yl)phenyl)phosphonic acid;

or a pharmaceutically acceptable salt thereof; and b) a combination partner.

48. A method for treating a disease associated with BMP1 , TLL1 and/or TLL2 activity in a human in need thereof comprising administering to said human a therapeutically effective amount of a) the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 32; and b) a combination partner.

49. A method for treating a disease associated with BMP1 , TLL1 and/or TLL2 activity in a human in need thereof comprising administering to said human a therapeutically effective amount of a) a compound selected from:

(S)-2-(5-ethoxy-3'-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 , T-biphenyl]-3- ylcarboxamido)succinic acid; (S)-2-(2-(carboxymethoxy)-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2- yl)benzamido)succinic acid; and

(3-ethoxy-5-(6-((((R)-2-((R)-1-(N-hydroxyformarnido)propyl)heptanamido)methyl) carbamoyl)pyridin-2-yl)phenyl)phosphonic acid;

or a pharmaceutically acceptable salt thereof; and b) a combination partner.

50. A combination of a) the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 32; and b) a combination partner.

51. A combination of a) a compound selected from:

(S)-2-(5-ethoxy-3'-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 , T-biphenyl]-3- ylcarboxamido)succinic acid;

(S)-2-(2-(carboxymethoxy)-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2- yl)benzamido)succinic acid; and

(3-ethoxy-5-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl) carbamoyl)pyridin-2-yl)phenyl)phosphonic acid;

or a pharmaceutically acceptable salt thereof; and b) a combination partner.

Description:
HYDROXY FOR MAM IDE DERIVATIVES AND THEIR USE

FIELD OF THE INVENTION

The present invention relates to compounds that inhibit BMP1 (also known as BMP-

1 , bone morphogenic protein 1 , bone morphogenetic protein 1 , procollagen C-proteinase, and procollagen C-endopeptidase), Tolloid-like 1 (TLL1) and/or Tolloid-like 2 (TLL2) metalloproteases, inclusive of isoforms, in particular multiple isoforms encoded by RNA splice variants, and methods of making and using the same. Specifically, the present invention relates to reverse hydroxamate compounds as BMP1 , TLL1 and/or TLL2 inhibitors.

BACKGROUND OF THE INVENTION

Fibrous collagens are integral parts of the extracellular matrix that support tissue integrity and maintain the cellular microenvironment for normal physiological functions.

Collagens l-lll, the major isoforms of the fibrous collagen protein family, are synthesized as procollagen precursors containing N-terminal and C-terminal propeptides. The procollagens are post-translationally modified by proline hydroxylation, and secreted into the peri-vascular space for further processing. N-terminal propeptides of the collagens are subsequently cleaved by proteinases of the ADAMTS (A Distintegrin And Metalloproteinase with

ThromboSpondin repeats) family, while the C-terminal propeptides are processed by the Tolloid family of metalloproteases, which include BMP1 , TLL1 and TLL2 (Hopkins, D.R. et al., Matrix Biology, 2007, 26, 508-523). The cleavage of both N-terminal and C-terminal propeptides allows further maturation of the collagen, leading to cross-linking at lysine residues and formation of insoluble fibrillar structures (Shoulders, M.D. et al., Annual Review of Biochemistry, 2009, 78, 929-958).

Whereas the BMP1 , TLL1 and TLL2 proteins are encoded by separate genes, this family also includes isoforms of BMP1 , including multiple isofoms of BMP1 that result from alternative splicing of the same gene product (see e.g.,Takahara, K., et al., The Journal of Biological Chemistry, 1994, 269. 32572-32578; and Cvetjeticanin, B. et al., Medical

Hypotheses, 2014, 83, 656-658). The originally discovered form of BMP1 is designated

BMP-1-1 or BMP1-1. Other BMP1 isoforms encoded by splice variant RNA transcripts have been described at the transcriptional level and designated with sequential suffixes, e.g., as BMP-1-2, BMP-1-3, BMP-1-4, BMP-1-5, BMP-1-6, and BMP-1-7 (see, e.g., Wozney et al., Science (1988), 242: 1528-1534; Kessler et al., Science, (1996) 271 : 360-362; Li et al., Proc. Natl. Acad. Sci. USA (1996), 93: 5127-5130; Janitz et al., J. Mol. Med. (1998), 76: 141-146; Takahara et al., J. Biol. Chem. (1994), 269: 32572-32578; and Ge and Greenspan, Birth Defect Res. (2006), 78: 47-68).

A number of BMP1 isoforms have also been confirmed at the protein level as circulating in the blood of patients with various diseases and in healthy humans (see, e.g., International Patent publication Nos. WO2008/01 1193 A2 and WO2013/163479 A1 , and Grgurevic et al., J. Am. Soc. Nephrol. (201 1), 21 :681-692). In addition, the role of BMP1 in processing procollagen leading to fibrosis and scar tissue formation in a variety of diseases as well as the discovery of blood profiles comprising individual BMP1 isoforms in patients with various diseases has made BMP1 an attractive target for developing new therapies (see, e.g. WO2008/01 1193 A2; WO2013/163479 A1 ; Grgurevic et al., J. Am. Soc. Nephrol. (201 1), 21 :681-692, Cvetjeticanin, B. et al., Medical Hypotheses, 2014, 83, 656-658; and Turtle et al., Expert Opin. Ther. Patents (2004), 14(8): 1 185-1 197).

For TLL1 , up to six theoretical RNA splice variants (www.ensembl.orq; gene identifier ENSG00000038295) may exist and at least two expressed proteins (wvvw.uniorot.org.

protein identifier 043897) have been reported. Three RNA splice variants have been reported for the gene that encodes TLL2 (www. ensem bl . org; gene identifier

ENSG00000095587), one of which is thought to encode functional protein ( vvyy unlprotorg, protein identifier Q9Y6L7).

Excessive production of extracellular matrix (ECM) proteins, including collagen, can lead to fibrotic pathologies in various organs or tissues that may be associated with increased tissue rigidity, parenchymal replacement, aberrant electrical conductance, sclerotic wound healing (e.g. infarction and burns), and/or abnormal cell-cell interactions. For example, increased fibrosis and collagen production are consistently observed in patients with acute and chronic cardiac diseases, e.g., heart failure, arrhythmias, hypertrophic cardiomyopathy, and myocardial infarction (Lopez, B. et al., Circulation, 2010, 121 , 1645- 1654; Ho, C.Y., et al., New England Journal of Medicine, 2010, 363, 552-563; Kostin, S. et al., Cardiovascular Research, 2002, 54, 361-379; See, F., et al., Current Pharmaceutical Design, 2005, 1 1 , 477-487; Cvetjeticanin, B. et al. Medical Hypotheses, 2014, 83, 656-658), chronic obstructive pulmonary disease ("COPD") (Salazar, L.M., et al., Lung, 201 1 , 189, 101-109), liver cirrhosis and nonalcoholic steatohepatitis ("NASH") (Bataller, R., et al., Journal of Clinical Investigation, 2005, 115, 209-218), idiopathic pulmonary fibrosis

(Chakraborty, S, et al., Expert Opin Investig Drugs, 2014, 23, 893-910), collagen vascular diseases, e.g. systemic lupus erythematosus, rheumatoid arhthritis and scleroderma (Eckes, B., et al., J Mol Med, 2014, 92, 913-924), muscular dystrophies (e.g., Serrano, A.C., et al., Experimental Cell Research, 2010, 316, 3050-3058; Klingler, W., et al., Acta Myoligica, XXXI, 2012, 184-195), chronic kidney disease (Liu, Y., Nature Reviews Nephrology, 201 1 , 7, 684-696), acute kidney injury (Molitoris, B., The Journal of clinical Investigation, 2014, 124, 2355-2363; Venkatachalam, M.A. et al., Am J Physiol Renal Physiol 298: F1078-F1094, 2010), diabetic nephropathy (Sun, Y.M., et a., Biochemical and Biophysical Research Communications, 2013, 433, 359-361), keloids, wound healing, adhesions, hypertrophic and other scarring associated with, e.g. burns, surgery and other trauma (Meier K., et al., Expert Opinion on Emerging Drugs, 2006, 11 , 39-47; Malecaze, F., et al., Investigative

Opthalmology and Visual Science, 2014, 55, 6712-6721 ; van der Weer, W. et al., Burns,

2009, 35, 15-29), stroke, multiple sclerosis and spinal cord injury (Fernandez-Klett, F. and Piller, J. Brain Pathology, 2014, 24, 404-13; Rimar, D. et al., Arthritis & Rheumatology, Vol. 66, No. 3, March 2014, 726-730). Therefore, reducing excessive collagen production and maturation by targeting the BMP1 , TLL1 and/or TLL2 pathway(s) can be an effective therapeutic strategy for treating fibrotic pathologies such as these diseases. This is supported by recent published studies using pharmacological agents that inhibit BMP1 , TLL1 and/or TLL2 activity in cardiac and kidney disease models in small animals (Grgurevic, L, et al., Journal of the AmericanSociety of Nephrology, 2011 , 21 , 681-692; He, W., et al., Proceedings of the National Academy of Sciences, 2010, 107, 21 110-211 15; Cvetjeticanin, B. et al., Medical Hypotheses, 2014, 83, 656-658; International Patent publication Nos.

WO2008/011 193 A2 and WO2013/163479 A1).

The Tolloid family of metal loproteases (BMP1 , TLL1 and TLL2) has additional substrates beyond collagens that may also contribute to its role in promoting ECM protein production. For example, the pro-form of lysyl oxidase 1 (LOX1) has been shown to be a substrate of BMP1 , and cleavage by BMP1 enhances the LOX enzyme activity and thereby induces collagen cross-linking (Uzel, M.I., et al., Journal of Biological Chemistry, 2001 , 276, 22537-22543). Thus, BMP1 also has a role in the development of pathological tissue stiffness via this mechanism, for example in glaucoma (Tovar-Vidales, T., et al., Investigative Ophthalmology & Visual Science, 2013, 54, 4741-4748) and in diastolic dysfunction in the heart (Lopez, B., et al., American Journal of Physiology - Heart and Circulatory Physiology,

2010, 299, H1-H9). BMP1 also cleaves additional collagens, e.g. procollagens V and XII which influence fibril size and shape, as well as non-fibrillar procollagen VII (Hopkins, D.R. et al., Matrix Biology, 2007, 26, 508-523). Latent TGF-beta binding protein (LTBP) has also been shown to be cleaved by BMP1 , allowing enhanced TGF-beta action to induce further collagen production (Ge, G., et al., Journal of Cell Biology, 2006, 175, 11 1-120). Regulation of TGF-beta by BMP1 may also play roles in other pathologies, such as control of cancer cell metastasis and invasion (Wu, X., et al. Oncogene, 2014, 33, 1506-1514). Similarly, BMP1 , TLL1 and/or TLL2 also activate a broader range of other TGF-beta like molecules, such as BMPs 2 and 4, by proteolytically processing interacting proteins (Hopkins, D.R. et al., Matrix Biology, 2007, 26, 508-523). The combined actions of BMP1 and its various substrates suggest that BMP1 , TLL1 and TLL2 are key regulators of tissue ECM production/maturation and that the members of the tolloid family of metalloproteases are particularly effective targets for anti-fibrosis therapeutic intervention.

BMP1 , TLL1 and TLL2 may also affect other biological pathways via additional substrate processing. In particular, they may affect muscle biology via promoting activation of myostatin. Myostatin is a hormone that negatively regulates muscle growth (Lee, S. J., 2004, Annual Review of Cell & Developmental Biology, 20, 61-86). BMP1 has been demonstrated to cleave an inhibitory pro-peptide of myostatin and thus enhance myostatin activity (Wolfman N.M., et al., Proceedings of the National Academy of Sciences, 2003, 100, 15842-15846). Knockout of TLL2 in mice demonstrated enhanced muscle mass, thereby providing support for the connection between tolloid metalloprotease and myostatin (Lee, S.J., PLoS one, 2008, 3, e1628). An inhibitor of BMP1 , TLL1 and/or TLL2 could therefore be beneficial in diseases where muscle function or muscle mass is diminished, including muscular dystrophy, sarcopenia, and cachexia associated with, e.g., heart failure, CKD, COPD, cancer or old age.

Taken together, the biology of BMP1 , TLL1 and TLL2 lends strong support for their key roles in collagen processing, assembly and cross-linking, leading to the formation of a fibrillar collagen network that maintains tissue integrity and proper cellular microenvironment. This family of proteins may also play important roles in the etiology of fibrotic conditions, for example in the heart, lung, skeletal muscle, kidney, liver, skin, vasculature, nervous system, and eye, and inhibitors of these metalloproteases may provide broad benefits as anti-fibrotic agents for the treatment of diseases associated with fibrosis, such as myocardial infarction, heart failure, cardiac arrhythmias, hypertrophic cardiomyopathy, chronic kidney disease (CKD), post-acute kidney injury, diabetic nephropathy, delayed graft function post- transplantation, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), liver cirrhosis, non-alcoholic steatohepatitis (NASH), muscular dystrophies (e.g., Duchenne, Becker, limb-girdle, congenital, facioscapulohumeral, myotonic,

oculopharyngeal, distal, and Emery-Dreifuss), glaucoma, corneal scarring, keloids, wound healing, adhesions, hypertrophic scarring, other scarring, e.g. associated with burns, surgery or other trauma, stroke, collagen vascular diseases such as systemic lupus erythematosus, rheumatoid arthritis and scleroderma, spinal cord injury and multiple sclerosis. Furthermore, BMP1 , TLL1 and TLL2 inhibitors may have additional therapeutic applications in muscular disease based on their impact on myostatin biology, in particular muscular dystrophies (e.g., Duchenne, Becker, limb-girdle, congenital, facioscapulohumeral, myotonic, oculopharyngeal, distal, and Emery-Dreifuss), sarcopenia, and cachexia associated with, e.g., heart failure, CKD, COPD, cancer or old age. SUMMARY OF THE INVENTION

In one aspect, the present invention relates to compounds of Formula (I):

and salts thereof,

wherein: one or two of W1 , W2, W3 and W4 are N and the remainder are CR a , or each of W1 , W2, W3 and W4 are CR a ,

wherein each R a is H, or one R a is selected from F, CF 3 , and C0 2 H, and the remainder are H;

R1 is selected from H, (C C 4 ) straight chain alkyl, and (C C 4 ) straight chain alkyl substituted with one hydroxy group;

R2 is selected from H, (C Cn)alkyl, (CrC 3 )alkyl(C3-C 6 )cycloalkyl, (C C 3 )alkyl-phenyl, (C C 3 )alkyl-naphthyl, and (CrC 3 )alkyl-heterocyclyl, wherein heterocyclyl is a monocyclic ring having 5-6 ring atoms wherein 1-2 of the ring atoms are selected from nitrogen, oxygen and sulfur, and wherein said (d-Cn)alkyl, (CrC 3 )alkyl(C 3 -C 6 )cycloalkyl, (CrC 3 )alkyl-phenyl, (C C 3 )alkyl-naphthyl, and (CrC 3 )alkyl-heterocyclyl are optionally substituted with 1-2 groups independently selected from (C C 4 )alkyl, (C C 4 )alkoxy, halo, and cyano;

R3 is selected from phenyl and heteroaryl, wherein said phenyl and heteroaryl are optionally substituted with 1-3 groups independently selected from:

(CrC 6 )alkyl, optionally substituted with 1-3 groups independently selected from: fluoro (e.g., -CF 3 ); -C0 2 H; -P(0)R f R 9 ; NR a R wherein R a is selected from H and (C C 4 )alkyl and R is selected from (C C 4 )alkyl substituted with 1-3 -C0 2 H or -P(0)R f R 9 ; and - C(0)NR a R wherein R a and R are independently selected from H and (C C 4 )alkyl, wherein the (C C 4 )alkyl is optionally substituted with 1-3 groups independently selected from hydroxy, -C0 2 H, -C(0)0(C C 4 )alkyl and -P(0)R f R 9 ; cyclopropyl, optionally substituted with 1 -C0 2 H;

-C(0)NR a R wherein R a and R are independently selected from H and (C C 4 )alkyl, wherein the (C C 4 )alkyl is optionally substituted with 1-3 groups independently selected from hydroxy, -C0 2 H, -C(0)0(C C 4 )alkyl, -P(0)R f R 9 , NR c R d and N + R c R d R e ;

(C C 6 )alkoxy, optionally substituted with 1-3 substituents independently selected from halo, hydroxy, -C0 2 H, (C 3 -C 6 )cycloalkyl, -C(0)NH 2 and pyrrolidinyl;

(C 3 -C 6 )cycloalkoxy, optionally substituted with 1-3 substituents independently selected from halo, hydroxy, and -C0 2 H;

-NR a R wherein R a and R are independently selected from H and (C C 4 )alkyl, wherein the (C C 4 )alkyl is optionally substituted with 1-3 groups independently selected from oxo and -C0 2 H;

-SR a wherein R a is selected from H and (C C 4 )alkyl;

-C0 2 H; -C(NOH)NH 2; cyano; -C(0)0(C C 4 )alkyl; -C(0)C0 2 H; -P(0)R f R 9 ; - OP(0)R f R 9 ; halo; hydroxy; nitro; -NHS0 2 (C C 2 )alkyl; -S0 3 H; -S0 2 (C C 2 )alkyl; -S0 2 NR c R d ; - S0 2 NHC(0)(C C 2 )alkyl; -B(OH) 2 ; and oxo;

wherein in each occurrence: R c , R d and R e are independently selected from H and (C C 2 )alkyl; and

R f and R 9 are independently selected from hydroxy, (C C 2 )alkyl and (C C 2 )alkoxy; and n is 0 or 1.

The compounds according to Formula (I), or salts, particularly pharmaceutically acceptable salts, thereof, are inhibitors of BMP1 , TLL1 and/or TLL2.

Accordingly, the present invention is also directed to a method of inhibiting BMP1 , TLL1 and/or TLL2 which method comprises contacting a biological material comprising the protein(s) with a compound according to Formula (I), or a salt, particularly a

pharmaceutically acceptable salt, thereof.

The invention is further directed to a method of treating a disease associated with BMP1 , TLL1 and/or TLL2 activity in a subject (e.g., a human or other mammal, particularly a human) in need thereof, including for example treatment of a disease where inhibition of BMP1 , TLL1 and/or TLL2 is of therapeutic benefit, which comprises administering to the subject a therapeutically effective amount of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof. This invention also provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy, e.g. as an active therapeutic substance in the treatment of a disease associated with BMP1 , TLL1 and/or TLL2 activity. The invention also provides for the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a disease associated with BMP1 , TLL1 and/or TLL2 activity. The present invention is further directed to a pharmaceutical composition comprising a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. Particularly, this invention is directed to a pharmaceutical composition for the treatment of a disease associated with BMP1 , TLL1 and/or TLL2 activity, where the composition comprises a compound according to

Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

In some embodiments, the disease associated with BMP1 , TLL1 and/or TLL2 activity is selected from those associated with pathological fibrotic conditions in body organs or tissues, e.g., such conditions of the: heart (e.g., myocardial infarction ("Ml"), heart failure (e.g., heart failure with reduced ejection fraction, heart failure with preserved ejection fraction), cardiac arrhythmias (e.g., atrial fibrillation), hypertrophic cardiomyopathy), lung (e.g. chronic obstructive pulmonary disease ("COPD"), idiopathic pulmonary fibrosis ("IPF")), kidney (e.g. diabetic nephropathy, post-acute kidney injury, chronic kidney disease ("CKD"), delayed graft function post- transplantation), liver (e.g. liver cirrhosis, non-alcoholic steatohepatitis ("NASH")), eye (e.g. glaucoma, corneal scarring), skeletal muscle (e.g.

muscular dystrophies, including Duchenne, Becker, limb-girdle, congenital,

facioscapulohumeral, myotonic, oculopharyngeal, distal, and Emery-Dreifuss), skin (e.g. keloids, wound healing, adhesions, hypertrophic scarring and other scarring, e.g., associated with burns, surgery or other trauma), the vasculature (e.g. stroke, and collagen vascular diseases such as systemic lupus erythematosus, rheumatoid arthritis and scleroderma), and the nervous system (e.g. spinal cord injury, multiple sclerosis). In some embodiments, the disease associated with BMP1 , TLL1 and/or TLL2 activity is selected from muscular diseases characterized by reduced muscle function and/or mass, e.g., muscular dystrophy (e.g., Duchenne, Becker, limb-girdle, congenital, facioscapulohumeral, myotonic, oculopharyngeal, distal, and Emery-Dreifuss), sarcopenia, and cachexia associated with, e.g., heart failure, CKD, COPD, cancer, or old age.

Other aspects of the present invention will be understood in light of this disclosure. DETAILED DESCRIPTION OF THE INVENTION

The alternative definitions for the various groups and substituent groups of Formula (I) provided throughout the specification are intended to particularly describe each compound species disclosed herein, individually, as well as groups of one or more compound species. The scope of this invention includes any combination of these group and substituent group definitions. The compounds of the invention are only those which are contemplated to be "chemically stable" as will be appreciated by those skilled in the art.

As used herein, the term "alkyi" represents a saturated hydrocarbon moiety which, unless otherwise stated, may be straight or branched. The terms "C C 2 alkyi", "C C 3 alkyi", "C1-C4 alkyi", "CrC 6 alkyi" , and "d-Cn alkyi" refer to an alkyi group or moiety containing 1- 2, 1-3, 1-4, 1-6, or 1-1 1 carbon atoms respectively. Exemplary alkyls include, but are not limited to methyl (Me), ethyl (Et), n-propyl, isopropyl (iPr), n-butyl, s-butyl, isobutyl, t-butyl, pentyl (also known as n-pentyl), and 2-ethylbutyl, as well as hexyl, heptyl, octyl, nonyl, decyl and undecyl, including the branched isomers of these groups.

As used herein, the term "cycloalkyl" refers to a non-aromatic, saturated, cyclic hydrocarbon ring moiety. The term "(C3-C 6 )cycloalkyl" refers to a non-aromatic cyclic hydrocarbon ring moiety having three to six ring carbon atoms. Exemplary

"(C 3 -C 6 )cycloalkyl" groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

"Alkoxy" refers to an alkyi radical attached through an oxygen linking atom. The terms "(C C 4 )alkoxy" and "(C C 6 )alkoxy" refer to a straight- or branched-chain hydrocarbon radical containing 1-4 or 1-6 carbon atoms respectively, attached through an oxygen linking atom. "(CrC 4 )alkoxy" and "(CrC 6 )alkoxy" may be alternatively designated as -0(C C 4 alkyi) and -0(C C 6 alkyi) respectively. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, isobutoxy, t-butoxy, pentoxy, and hexoxy, including the branched isomers of these groups.

"Cycloalkoxy" refers to a cycloalkyl radical attached through an oxygen linking atom. The term "(C3-C 6 )cycloalkoxy" refers to a cycloalkyl radical having 3 to 6 ring carbon atoms, attached through an oxygen linking atom. "(C3-C 6 )cycloalkoxy" may be alternatively designated as -0(C 3 -C 6 )cycloalkyl. Exemplary cycloalkoxy groups include cyclopropyloxy, cyclobutyloxy, cyclpentyloxy, and cyclohexyloxy.

A heterocyclic (alternatively referred to as heterocyclyl) group or moiety is a mono- or bi-cyclic group or moiety having as ring members atoms of at least two different elements (carbon and one or more of nitrogen, oxygen and/or sulfur). The ring(s) may be saturated or partially unsaturated (non-aromatic) or fully unsaturated (aromatic). Heterocyclic

encompasses heterocycloalkyl and heteroaryl. For example, heterocyclyl may be a cyclic group or moiety having 5-10 ring atoms (i.e. "5-10 membered") wherein 1-4 of the ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, e.g., a monocyclic ring having 5-6 ring atoms wherein 1-2 of the ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, or a bicyclic ring having 9-10 ring atoms wherein 1-4 of the ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur.

"Heterocycloalkyl" represents a group or moiety which is a non-aromatic, monocyclic radical, which is saturated or partially unsaturated, having 5-6 ring atoms wherein 1-2 of the ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur. Illustrative examples of heterocycloalkyl groups include, but are not limited to, piperidyl (or piperidinyl), piperazinyl, morpholinyl, tetrahydrofuryl (or tetrahydrofuranyl), tetrahydropyranyl,

tetrahydrothienyl, and thiomorpholinyl, including the various position isomers of the foregoing moieties.

"Heteroaryl" refers to a mono- or bi-cyclic group or moiety wherein at least one ring is aromatic, having 5- 10 ring atoms wherein 1-4 of the ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur. In bicyclic heteroaryl, at least one ring is aromatic and the other ring may be aromatic, or saturated or unsaturated non-aromatic, and at least one ring is heterocyclic and the other ring may be heterocyclic or carbocyclic. Thus, this term encompasses but is not limited to bicyclic heterocyclic compounds containing at least one aromatic carbocyclic or heterocylic ring moiety, e.g., a phenyl ring moiety fused to a heterocycloalkyl ring moiety. Illustrative examples of heteroaryls include, but are not limited to, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl (or furanyl), isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridyl (or pyridinyl), pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, indazolyl, benzothienyl, benzofuranyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, 2,3- dihydrobenzoisothiazolyl, and 1 ,1-dioxido-2,3-dihydrobenzoisothiazolyl (e.g., 1 , 1-dioxido- 2,3-dihydrobenzo[d]isothiazolyl), including the various position isomers of the foregoing moieties.

When a particular heterocyclic, heteroalkyl or heteroaryl group is referenced (e.g., pyridyl), it is intended to encompass any one of the various position isomers (e.g., 2-pyridyl, 3-pyridyl, etc).

In some embodiments, compounds of the invention comprise a 5-membered or

6-membered monocyclic heteroaryl group comprising at least one nitrogen ring atom, e.g., such groups as particularly disclosed herein. Selected 5-membered heteroaryl groups contain one nitrogen, and optionally contain one oxygen ring atom or 1 , 2 or 3 additional nitrogen ring atoms. Selected 6-membered heteroaryl groups contain 1 , 2, or 3 nitrogen ring heteroatoms. In other embodiments, compounds of the invention comprise a 9-membered or 10-membered bicyclic heteroaryl group, e.g. such groups as particularly disclosed herein. Selected 9-10 membered heteroaryl groups contain one nitrogen, oxygen or sulfur ring heteroatom, and optionally contain 1 , 2, or 3 additional nitrogen ring atoms.

It is to be understood that the terms heterocyclic, heteroaryl, and heterocycloalkyl are intended to encompass stable heterocyclic groups where a ring nitrogen heteroatom is optionally oxidized (e.g., heterocyclic groups containing an N-oxide, e.g., pyridine-N-oxide), or where a ring sulfur heteroatom is optionally oxidized (e.g., heterocyclic groups containing sulfones or sulfoxide moieties, e.g., tetrahydrothienyl-1 -oxide [a tetrahydrothienyl sulfoxide], tetrahydrothienyl- 1 , 1 -dioxide [a tetrahydrothienyl sulfone], or 1 ,1-dioxido-2,3- dihydrobenzoisothiazolyl [e.g., 1 , 1-dioxido-2,3-dihydrobenzo[d]isothiazolyl]).

When the term "alkyl" is used in combination with other groups, e.g., "(C C 3 )alkyl- (C 3 -C 6 )cycloalkyl", "(Ci-C 3 )alkyl-phenyl" and "(CrC 3 )alkyl-heterocyclyl", the alkyl moiety is intended to encompass a divalent straight or branched-chain hydrocarbon radical and the cycloalkyl, phenyl, and heterocyclyl moieties are as defined herein. For example, in "(C C 3 )alkyl-phenyl " the (C C 3 )alkyl moiety thereof is a divalent straight or branched-chain carbon radical linked to the aryl group phenyl, and is represented by the bonding

arrangement present in a benzyl group (-CH 2 -phenyl). Particular examples of such groups include (cyclopentyl)methyl, 2-phenylethyl, 3-phenylpropyl, and 2-naphthylethyl.

"Oxo" represents a double-bonded oxygen moiety; for example, if attached directly to a carbon atom forms a carbonyl moiety (C = O). The terms "halogen" and "halo" represent chloro, fluoro, bromo or iodo substituents. "Hydroxy" or "hydroxyl" is intended to mean the radical -OH. "Cyano" means the radical -CN. "Nitro" means the radical -N0 2 . "COO" and "C0 2 " may be used interchangeably (e.g., COOH and C0 2 H; COOEt and C0 2 Et are interchangeable respectively). P0 3 H 2 and P(0)(OH) 2 may be used interchangeably.

Where a numerical range is indicated, e.g., a carbon number range or a heteroatom number range, the range is intended to encompass particular embodiments corresponding to the particular integers within the range, and well as any range of integers within the most broadly stated range.

As used herein, the terms "compound(s) of the invention" or "compound(s) of this invention" mean a compound of Formula (I), as defined above (including more particular embodiments), in any form, i.e., any salt or non-salt form (e.g., as a free acid or base form, or as a salt, particularly a pharmaceutically acceptable salt thereof) and any physical form thereof (e.g., including non-solid forms (e.g., liquid or semi-solid forms), and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms, solvate forms, including hydrate forms (e.g., mono-, di- and hemi- hydrates)), and mixtures of various forms. Accordingly, included within the present invention are compounds of Formulas (I), as defined herein (including more particular embodiments), in any salt or non-salt form and any physical form thereof, and mixtures of various forms. While such are included within the present invention, it will be understood that the compounds of Formulas (I), as defined herein, in any salt or non-salt form, and in any physical form thereof, may have varying levels of activity, different bioavailabilities and different handling properties for formulation purposes.

As used herein, the term "optionally substituted" indicates that a group, ring or moiety (such as an alkyl, cycloalkyl, alkoxy, cycloalkoxy, heterocycloalkyl, phenyl, heteroaryl, carbocyclic or heterocyclic group, ring or moiety) may be unsubstituted, or the group, ring or moiety may be substituted with one or more substituent(s) as defined. In the case where more than one group, ring or moiety may be substituted with a number of alternative substituent(s), the selected substituent(s) for each group, ring or moiety may be the same or different, i.e. the substituent(s) are selected independently for each group, ring or moiety. In the case where more than one substituent is selected from a number of possible

substituents, those substituents may be the same or different, i.e. the substituents are selected independently.

As used herein, the terms "a", "an" and "the" are intended to include one or more of the indicated moiety, unless otherwise indicated.

As used herein, "BMP1 , TLL1 and/or TLL2" encompasses one or more of BMP1 ,

TLL1 and TLL2, including isoforms thereof (including particularly isoforms encoded by RNA splice variants). Thus, for example, as used herein BMP1 may include one or more of the isoforms BMP-1-1 , BMP-1-2, BMP-1-3, BMP-1-4, BMP-1-5, BMP-1-6, and BMP-1-7.

All references/publications are hereby incorporated by reference into this disclosure in their entirety.

In one aspect, the present invention is directed to a compound of Formula (I):

or a salt thereof,

wherein: one or two of W1 , W2, W3 and W4 are N and the remainder are CR a , or each of W1 , W2, W3 and W4 are CR a ,

wherein each R a is H, or one R a is selected from F, CF 3 , and C0 2 H, and the remainder are H;

R1 is selected from H, (C C 4 ) straight chain alkyl, and (C C 4 ) straight chain alkyl substituted with one hydroxy group;

R2 is selected from H, (C Cn)alkyl, (CrC 3 )alkyl(C3-C 6 )cycloalkyl, (C C 3 )alkyl-phenyl, (C C 3 )alkyl-naphthyl, and (CrC 3 )alkyl-heterocyclyl, wherein heterocyclyl is a monocyclic ring having 5-6 ring atoms wherein 1-2 of the ring atoms are selected from nitrogen, oxygen and sulfur, and wherein said (d-Cn)alkyl, (CrC 3 )alkyl(C 3 -C 6 )cycloalkyl, (CrC 3 )alkyl-phenyl, (C C 3 )alkyl-naphthyl, and (CrC 3 )alkyl-heterocyclyl are optionally substituted with 1-2 groups independently selected from (C C 4 )alkyl, (C C 4 )alkoxy, halo, and cyano; R3 is selected from phenyl and heteroaryl, wherein said phenyl and heteroaryl are optionally substituted with 1-3 groups independently selected from:

(C C 6 )alkyl, optionally substituted with 1-3 groups independently selected from: fluoro (e.g., -CF 3 ); -C0 2 H; -P(0)R f R 9 ; NR a R wherein R a is selected from H and (C C 4 )alkyl and R is selected from (C C 4 )alkyl substituted with 1-3 -C0 2 H or -P(0)R f R 9 ; and - C(0)NR a R wherein R a and R are independently selected from H and (C C 4 )alkyl, wherein the (C C 4 )alkyl is optionally substituted with 1-3 groups independently selected from hydroxy, -C0 2 H, -C(0)0(C C 4 )alkyl and -P(0)R f R 9 ;

cyclopropyl, optionally substituted with 1 -C0 2 H;

-C(0)NR a R wherein R a and R are independently selected from H and (C C 4 )alkyl, wherein the (C C 4 )alkyl is optionally substituted with 1-3 groups independently selected from hydroxy, -C0 2 H, -C(0)0(C C 4 )alkyl, -P(0)R f R 9 , NR c R d and N + R c R d R e ;

(C C 6 )alkoxy, optionally substituted with 1-3 substituents independently selected from halo, hydroxy, -C0 2 H, (C 3 -C 6 )cycloalkyl, -C(0)NH 2 and pyrrolidinyl;

(C 3 -C 6 )cycloalkoxy, optionally substituted with 1-3 substituents independently selected from halo, hydroxy, and -C0 2 H;

-NR a R wherein R a and R are independently selected from H and (C C 4 )alkyl, wherein the (C C 4 )alkyl is optionally substituted with 1-3 groups independently selected from oxo and -C0 2 H;

-SR a wherein R a is selected from H and (C C 4 )alkyl; -CO 2 H; -C(NOH)NH 2; cyano; -C(0)0(C C 4 )alkyl; -C(0)C0 2 H; -P(0)R f R 9 ; - OP(0)R f R 9 ; halo; hydroxy; nitro; -NHS0 2 (CrC 2 )alkyl; -SO 3 H; -S0 2 (C C 2 )alkyl; -S0 2 NR c R d ; - S0 2 NHC(0)(C C 2 )alkyl; -B(OH) 2 ; and oxo;

wherein in each occurrence: R c , R d and R e are independently selected from H and (C C 2 )alkyl; and

R f and R 9 are independently selected from hydroxy, (C C 2 )alkyl and (C C 2 )alkoxy; and n is 0 or 1. In some embodiments of the compounds of Formula (I), one or two of W1 , W2, W3 and W4 are N and the remainder are CR a .

In some embodiments of the compounds of Formula (I), W1 is N and the remainder are CR a .

In some embodiments of the compounds of Formula (I), W1 and one of W2 and W3 are N,and W4 is CR a .

In some embodiments of the compounds of Formula (I), each of W1 , W2, W3 and W4 are CR a .

In some embodiments of the compounds of Formula (I), each R a is H. In some embodiments of the compounds of Formula (I), R1 is H or (C C 4 ) straight chain alkyi, in more particular embodiments H, methyl or ethyl, in even more particular embodiments, H or ethyl and yet more particularly ethyl. In some embodiments, R1 is (C C 4 ) straight chain alkyi substituted with one hydroxy group; in particular embodiments -CH 2 OH.

In some embodiments of the compounds of Formula (I), R2 is H.

In some embodiments, R2 is selected from optionally substituted: (d-Cn)alkyl (e.g. C 3 -C 7 alkyi, e.g. C 4 -C 6 alkyi), in more particular embodiments n-pentyl (i.e. pentyl), or 2-ethylbutyl, and even more particularly pentyl.

In some embodiments, R2 is selected from optionally substituted: (CrC 3 )alkyl(C 3 - C 6 )cycloalkyl, in more partucular embodiments cyclopropylmethyl or cyclopentyl methyl.

In some embodiments, R2 is selected from optionally substituted: (CrC 3 )alkyl-phenyl, in particular embodiments benzyl, 2-phenylethyl (i.e. phenylethyl), or 3-phenylpropyl (i.e.

phenylpropyl).

In some embodiments, R2 is selected from (CrC 3 )alkyl-naphthyl; iin particular embodiments 2-naphthylethyl. In some embodiments, said R2 groups are substituted as defined in accordance with Formula (I). In some embodiments, said R2 groups are unsubstituted.

In some embodiments of the compounds of the invention (e.g. compounds of Formula (I)), R1 and R2 have (R) stereochemistry.

In some embodiments of the compounds of the invention (e.g. compounds of Formula (I)), R3 is phenyl, pyridyl, pyridazinyl, pyrimidinyl, oxazolyl, tetrazolyl, pyrazolyl, indazolyl, or 1 , 1-dioxido-2,3-dihydrobenzo[d]isothiazolyl (in more particular embodiments, phenyl, pyridyl, indazolyl, or 1 , 1-dioxido-2,3-dihydrobenzo[d]isothiazolyl), including the various position isomers thereof, where such groups are optionally substituted as defined above in accordance with Formula (I), including more particular embodiments of Formula (I). In more particular embodiments, R3 is phenyl optionally substituted in accordance with the definition of Formula (I), including more particular embodiments of Formula (I). In more particular embodiments of compounds of the invention (e.g. compounds of Formula (I)), R3 is 3,4- or 3,5- disubstituted phenyl wherein the substituent groups are selected in

accordance with the definition of Formula (I), including more particular embodiments of Formula (I) (said positions relative to the point of attachment of the phenyl ring to the remainder of the compound of Formula (I)).

In some embodiments, R3 is phenyl substituted with ethoxy in the 3-position and - P(0)(OH) 2 or -C0 2 H in the 4- or 5- position (especially -P(0)(OH) 2 , particularly in the 5- position) .

In some embodiments, R3 is phenyl substituted with ethoxy in the 3-position and - OCH 2 C0 2 H, or -C(0)NHCH(C0 2 H)(CH 2 C0 2 H) in the 4- or 5- position (especially - C(0)NHCH(C0 2 H)(CH 2 C0 2 H), particularly in the 4-position).

In some embodiments, R3 is phenyl substituted with -OCH 2 C0 2 H in the 3-position and -C(0)NHCH(C0 2 H)(CH 2 C0 2 H) in the 4 or 5 position (particularly in the 4-position).

In some embodiments of the compounds of the invention (e.g. a compound of Formula (I)), R3 is phenyl substituted with 1-3 groups independently selected from: -OCH 3 , - OC 2 H 5 , -OC 3 H 7 , -OCH(CH 3 ) 2 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -OCH 2 CHF 2 , -OC 2 H 4 - pyrrolidinyl, -OCH 2 C0 2 H, -OCH 2 C(0)NH 2 , -C0 2 H, -CH 3 , cyclopropanyl-1-carboxylic acid, - CH 2 C0 2 H, -C(CH 3 ) 2 C0 2 H, -CH(CH 3 )C0 2 H, -CF 2 C0 2 H, -CH 2 C(0)NHCH(C0 2 H)(CH 2 C0 2 H), - CH 2 P(0)(OH) 2 ,-CH 2 N(CH 3 )(CH 2 C0 2 H), -CH 2 NHCH 2 P(0)(OH) 2 , -C(NH 2 )(NOH), cyano, nitro, hydroxy, -S0 2 NH 2 , -S0 2 N(CH 3 ) 2 , -S0 2 NH(CH 3 ), -S0 2 CH 3 , -S0 2 NHC(0)C 2 H 5 , -S0 3 H, -SCH 3 , -SC 2 H 5 , -C(0)OCH 3 , -C(0)OC(CH 3 ) 3 , -C(0)NHCH 3 , -C(0)NH(C 2 H 4 NH 2 ), - C(0)NHC 2 H 4 N + (CH 3 ) 3 , -C(0)NHCH(C0 2 H)(CH 2 C0 2 H), -C(0)NHCH(C0 2 H)(C 2 H 4 C0 2 H), -

C(0)NHCH 2 C0 2 H, -C(0)N(CH 2 C0 2 H) 2 , -C(0)NHCH 2 P(0)(OH) 2 , -C(0)NHC(CH 2 OH) 3 , fluoro, -NH 2 , -N(CH 3 ) 2 , -P(0)(CH 3 )(OC 2 H 5 ), -P(0)(OCH 3 ) 2 , -P(0)(CH 3 )(OH), -P(0)(OH)(OCH 3 ), and -P(0)(OH) 2 . In some embodiments R3 is phenyl substituted with 1-3 groups independently selected from: -OC 2 H 5 , OCH 2 C0 2 H, CONHCH(C0 2 H)(CH 2 C0 2 H), P(0)(OH) 2 , C0 2 H, CH 2 C0 2 H, CH 2 CONHCH(C0 2 H)(CH 2 C0 2 H), OH, and S0 3 H, in more particular embodiments independently selected from: : -OC 2 H 5 , OCH 2 C0 2 H, -CONHCH(C0 2 H)(CH 2 C0 2 H), and P(0)(OH) 2 .

In some embodiments, R3 is phenyl substituted with 1-3 groups independently selected from: methyl, ethyl, isopropyl, CF 3 , CH 2 C0 2 H, CH(CH 3 ) 2 (C0 2 H),

CH 2 CONHCH(C0 2 H)(CH 2 C0 2 H), 1-C0 2 Hcyclopropyl, CONH 2 , CONHCH(C0 2 H)(CH 2 C0 2 H), OCH 3 , OC 2 H 5 , OCH(CH 3 ) 2 , OCF 3 , OCH 2 CF 3 , OCH 2 C0 2 H, N(CH 3 ) 2 , SH, C0 2 H,CN,

C0 2 C 2 H 5 , P(0)(OH) 2 , F, OH, NHS0 2 CH 3 , S0 3 H, S0 2 CH 3 , S0 2 NH 2 , and B(OH) 2 .

In some embodiments of the compounds of Formula (I), R3 is optionally substituted heteroaryl as defined above for Formula (I). In some embodiments, R3 is an optionally substituted monocyclic heteroaryl ring comprising 5-6 ring atoms comprising 1-4

heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments of the compounds of Formula (I), R3 is optionally substituted: pyridyl, pyridazinyl, pyrimidinyl, oxazolyl, tetrazolyl, pyrazolyl, indazolyl, or 1 ,1-dioxido-2,3-dihydrobenzo[d]isothiazolyl. In some embodiments, R3 is optionally substituted: pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, tetrazolyl, or oxazolyl.

In the aforementioned embodiments of heteroaryl R3, such R3 groups may be optionally substituted as defined in accordance with Formula (I).

In some of the aforementioned embodiments of the compounds of Formula (I) where R3 is heteroaryl, the heteroaryl ring is substituted with 1-3 groups independently selected from: - OCH 3 , -OC 2 H 5 , -OC 3 H 7 , -OCH(CH 3 ) 2 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -OCH 2 CHF 2 , -OC 2 H 4 - pyrrolidinyl, -OCH 2 C0 2 H, -OCH 2 C(0)NH 2 , -C0 2 H, -CH 3 , cyclopropanyl-1-carboxylic acid, - CH 2 C0 2 H, -C(CH 3 ) 2 C0 2 H, -CH(CH 3 )C0 2 H, -CF 2 C0 2 H, -CH 2 C(0)NHCH(C0 2 H)(CH 2 C0 2 H), - CH 2 P(0)(OH) 2 ,-CH 2 N(CH 3 )(CH 2 C0 2 H), -CH 2 NHCH 2 P(0)(OH) 2 , -C(NH 2 )(NOH), cyano, nitro, hydroxy, -S0 2 NH 2 , -S0 2 N(CH 3 ) 2 , -S0 2 NH(CH 3 ), -S0 2 CH 3 , -S0 2 NHC(0)C 2 H 5 , -S0 3 H, -SCH 3 , -SC 2 H 5 , -C(0)OCH 3 , -C(0)OC(CH 3 ) 3 , -C(0)NHCH 3 , -C(0)NH(C 2 H 4 NH 2 ), - C(0)NHC 2 H 4 N + (CH 3 ) 3 , -C(0)NHCH(C0 2 H)(CH 2 C0 2 H), -C(0)NHCH(C0 2 H)(C 2 H 4 C0 2 H), -

C(0)NHCH 2 C0 2 H, -C(0)N(CH 2 C0 2 H) 2 , -C(0)NHCH 2 P(0)(OH) 2 , -C(0)NHC(CH 2 OH) 3 , fluoro, -NH 2 , -N(CH 3 ) 2 , -P(0)(CH 3 )(OC 2 H 5 ), -P(0)(OCH 3 ) 2 , -P(0)(CH 3 )(OH), -P(0)(OH)(OCH 3 ), and -P(0)(OH) 2 .

In some embodiments, the heteroaryl R3 group is substituted with 1-3 groups independently selected from: -OC 2 H 5 , OCH 2 C0 2 H, CONHCH(C0 2 H)(CH 2 C0 2 H), P(0)(OH) 2 , C0 2 H, CH 2 C0 2 H, CH 2 CONHCH(C0 2 H)(CH 2 C0 2 H), OH, and S0 3 H, in more particular embodiments selected from: -OC 2 H 5 , OCH 2 C0 2 H, CONHCH(C0 2 H)(CH 2 C0 2 H), and

P(0)(OH) 2 .ln some embodiments, R3 is heteroaryl substituted with 1-3 groups independently selected from: methyl, ethyl, isopropyl, CF 3 , CH 2 C0 2 H, CH(CH 3 ) 2 (C0 2 H),

CH 2 CONHCH(C0 2 H)(CH 2 C0 2 H), 1-C0 2 Hcyclopropyl, CONH 2 , CONHCH(C0 2 H)(CH 2 C0 2 H), OCHs, OC 2 H 5 , OCH(CH 3 ) 2 , OCF3, OCH 2 CF 3 , OCH 2 C0 2 H, N(CH 3 ) 2 , SH, C0 2 C 2 H 5 , CN, C0 2 C 2 H 5 , P(0)(OH) 2 , F, OH, NHS0 2 CH 3 , S0 3 H, S0 2 CH 3 ,S0 2 NH 2 , and B(OH) 2 .

In some embodiments of the compounds of Formula (I), n is 0. In other

embodiments of the compounds of Formula (I), n is 1.

In some embodiments of a compound of Formula (I), R1 is (C C 4 ) straight chain alkyl; R2 is (C Cn) alkyl; R3 is phenyl substituted as defined in accordance with Formula (I); and n is 0. In more particular such embodiments, R3 phenyl is substituted with 1-2 groups or 1-3 groups independently selected from -OC 2 H 5 , OCH 2 C0 2 H, - CONHCH(C0 2 H)(CH 2 C0 2 H), and P(0)(OH)2. In even more particular embodiments, R3 phenyl is 3,4- or 3,5-disubstituted with 2 groups independently selected from -OC 2 H 5 , OCH 2 C0 2 H, -CONHCH(C0 2 H)(CH 2 C0 2 H), and P(0)(OH) 2.

Accordingly, a compound of the invention includes a compound of Formula (I), or a salt thereof, particularly a pharmaceutically acceptable salt thereof. Representative compounds of this invention include the specific compounds described herein, e.g., the compounds of the Examples, as well as any alternative stereoisomers, free acid/base forms, salt forms, and alternative salt forms thereof (particularly pharmaceutically acceptable salt or alternative salt forms thereof), as applicable.

Accordingly, in some embodiments the compound of the invention is a compound selected from the group consisting of:

2-(5-ethoxy-3'-(((2-(1-(N-hydroxyformamido)propyl)heptana mido)methyl)carbamoyl)- [1 , 1 '-biphenyl]-3-ylcarboxamido)succinic acid

2-(2-(carboxymethoxy)-4-(6-(((2-(1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2- yl)benzamido)succinic acid; (3-ethoxy-5-(6-(((2-(1-(N-hydroxyformamido)propyl)heptanamid o)methyl)

carbamoyl)pyridin-2-yl)phenyl)phosphonic acid;

3-ethoxy-5-(6-(((2-(1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzoic acid

2-ethoxy-4-(6-(((2-(1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzoic acid

2-(2-ethoxy-4-(6-(((2-(1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)phenyl)acetic acid

2-(4-(6-(((2-(1-(N-hydroxyformamido)propyl)heptanamido)me thyl)carbamoyl)pyridin-2- yl)phenyl)acetic acid

(2-ethoxy-4-(6-(((2-(1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2- yl)phenyl)phosphonic acid

3-ethoxy-5-(6-(((2-((N- hydroxyformamido)methyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzoic acid

2-ethoxy-4-(6-(((3-(N-hydroxyformamido)-2- phenethylpentanamido)methyl)carbamoyl)pyridin-2-yl)benzoic acid 3-ethoxy-3'-(((2-(1-(N-hydroxyformamido)propyl)heptanamido)m ethyl)carbamoyl)-[1 , 1 '- biphenyl]-4-carboxylic acid

2-(3-ethoxy-3'-(((2-(1-(N-hydroxyformamido)propyl)heptana mido)methyl)carbamoyl)- [1 , 1 '-biphenyl]-4-yl)acetic acid

5-ethoxy-3'-(((2-(1-(N-hydroxyformamido)propyl)heptanamid o)methyl)carbamoyl)-[1 , 1 '- biphenyl]-3-carboxylic acid

2-(3-ethoxy-5-(6-(((2-(1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2- yl)benzamido)succinic acid

2-(2-ethoxy-4-(6-(((2-(1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2- yl)benzamido)succinic acid

2-(2-(2-ethoxy-4-(6-(((2-(1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2- yl)phenyl)acetamido)succinic acid

2-ethoxy-4-(4-(((2-(1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyrimid in-2-yl)benzoic acid

2-ethoxy-4-(6-(((2-(1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyrazin -2-yl)benzoic acid 2-(3-ethoxy-3'-(((2-(1-(N-hydroxyformamido)propyl)heptanamid o)methyl)carbamoyl)- [1 , 1 '-biphenyl]-4-ylcarboxamido)succinic acid

3-hydroxy-3'-(((2-(1-(N-hydroxyformamido)propyl)heptanami do)methyl)carbamoyl)-[1 , 1 '- biphenyl]-4-carboxylic acid

2-(3-(carboxymethoxy)-3'-(((2-(1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 , 1 '-biph

ylcarboxamido)succinic acid

(5-ethoxy-3'-(((2-(1-(N-hydroxyformamido)propyl)heptanami do)methyl)carbamoyl)-[1 , 1 '- biphenyl]-3-yl)phosphonic acid

(3-ethoxy-3'-(((2-(1-(N-hydroxyformamido)propyl)heptanami do)methyl)carbamoyl)-[1 , 1 '- biphenyl]-4-yl)phosphonic acid

(2-ethoxy-4-(6-(((2-(1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyrazin -2- yl)phenyl)phosphonic acid

(2-ethoxy-4-(4-(((2-(1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyrirTi idiri-2- yl)phenyl)phosphonic acid;

5-ethoxy-3'-(((2-(1-(N-hydroxyformamido)propyl)heptanamid o)methyl)carbamoyl)-[1 , 1 '- biphenyl]-3-sulfonic acid; N-((2-((N-hydroxyformamido)methyl)-4-phenylbutanamido)methyl )-6-phenylpicolinami

N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-6-p henylpicolinarriide

N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-6-( 3- methoxyphenyl)picolinamide

N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-6'- methoxy-[2,2'-bipyridine]-6- carboxamide

N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-2-p henylpyrimidine-4- carboxamide

6-(4-fluorophenyl)-N-((2-((N- hydroxyformamido)methyl)heptanamido)methyl)picolinamide

6-(4-fluoro-3-methoxyphenyl)-N-((2-((N- hydroxyformamido)methyl)heptanamido)methyl)picolinamide

6-(2,4-difluorophenyl)-N-((2-((N- hydroxyformamido)methyl)heptanamido)methyl)picolinamide

6-(2-fluoro-3-methoxyphenyl)-N-((2-((N- hydroxyformamido)methyl)heptanamido)methyl)picolinamide N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-[2,3'- bipyridine]-6- carboxamide

N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-6-( 4- (trifluoromethyl)phenyl)picolinamide

N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-6-( 4- (trifluoromethoxy)phenyl)picolinamide

N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-6-p henylpyrazine-2- carboxamide

5-fluoro-N-((2-((N-hydroxyformamido)methyl)heptanamido)me thyl)-6-phenylpicolinamide

N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-6-p henyl-4- (trifluoromethyl)picolinamide

2-(4-(6-(((2-(1-(N-hydroxyformamido)propyl)heptanamido)me thyl)carbamoyl)pyridin-2- yl)phenyl)-2-methylpropanoic acid

1-(4-(6-(((2-(1-(N-hydroxyformamido)propyl)heptanamido)me thyl)carbamoyl)pyridin-2- yl)phenyl)cyclopropanecarboxylic acid 3-(6-(((2-(1-(N-hydroxyformamido)propyl)heptanamido)methyl)c arbamoyl)pyridin-2-yl)-2- methyl benzoic acid

5-(6-(((2-(1-(N-hydroxyformamido)propyl)heptanamido)methy l)carbamoyl)pyridin-2-yl)-2- methoxybenzoic acid

2-fluoro-5-(6-(((2-(1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzoic acid

6-(3-((2-aminoethyl)carbamoyl)-5-ethoxyphenyl)-N-((2-(1-( N- hydroxyformamido)propyl)heptanamido)methyl)picolinamide

N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-[1 , 1 '-biphenyl]-3-carboxamide

2-fluoro-N-((2-((N-hydroxyformamido)methyl)heptanamido)me thyl)-3'-methoxy-[1 , T- biphenyl]-3-carboxamide

2,2'-difluoro-N-((2-((N-hydroxyformamido)methyl)heptanami do)methyl)-3'-methoxy-[1 , T- biphenyl]-3-carboxamide

2,2'-difluoro-N-((2-((N-hydroxyformamido)methyl)heptanami do)methyl)-5'-methoxy-[1 , T- biphenyl]-3-carboxamide

3-(4,5-dimethyloxazol-2-yl)-N-((2-((N- hydroxyformamido)methyl)heptanamido)methyl)benzamide N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3-(4-m ethyl-1 H-pyrazol-1- yl)benzamide

N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3-( 2-methyloxazol-5- yl)benzamide

N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3-( 2-methoxypyrimidin-4- yl)benzamide

(3'-(((2-((N-hydroxyformamido)methyl)-4-phenylbutanamido) methyl)carbamoyl)-[1 , T- biphenyl]-3-yl)boronic acid

N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propanami do)methyl)-2'-methoxy- [1 , 1 '-biphenyl]-3-carboxamide

N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propanami do)methyl)-3'-methoxy- [1 , 1 '-biphenyl]-3-carboxamide

N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propanami do)methyl)-4'- (trifluoromethyl)-[1 , 1 '-biphenyl]-3-carboxamide

3'-cyano-N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl) propanamido)methyl)-[1 , T- biphenyl]-3-carboxamide

N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propanami do)methyl)-[1 , 1 -biphenyl]- 3-carboxamide N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propanamiclo )methyl)-3- phenoxybenzamide

4-(6-(((2-(1-(N-hydroxyformamido)propyl)heptanamido)methy l)carbamoyl)pyridin-2-yl)-3- methyl benzoic acid

N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3-( 5-methyloxazol-2- yl)benzamide

N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3-( 1 H-tetrazol-5-yl)benzamide

N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3'- methoxy-[1 , 1 '-biph carboxamide

N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propanami do)methyl)-3'-ethoxy-[1 , 1 '- biphenyl]-3-carboxamide

N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propanami do)methyl)-3'-hydroxy-[1 ,1 '- biphenyl]-3-carboxamide

N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3'- isopropyl-[1 , T-biph carboxamide

N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propanami do)methyl)-3'-ethyl-[1 , T- biphenyl]-3-carboxamide N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-2',5'- dimethoxy-[1 , T- biphenyl]-3-carboxamide

N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propanami do)methyl)-3'- (trifluoromethoxy)-[1 , 1 '-biphenyl]-3-carboxamide

N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propanami do)methyl)-3'- (trifluoromethyl)-[1 , 1 '-biphenyl]-3-carboxamide

N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propanami do)methyl)-3',5'-dimethoxy- [1 , 1 '-biphenyl]-3-carboxamide

3-(3,6-dimethoxypyridazin-4-yl)-N-((2-((N- hydroxyformamido)methyl)heptanamido)methyl)benzamide

3-(3,6-dimethoxypyridazin-4-yl)-N-((2-((N-hydroxyformamid o)

phenylbutanamido)methyl)benzamide

3'-fluoro-N-((2-((N-hydroxyformamido)methyl)heptanamido)m ethyl)-[1 , T-biphenyl]-3- carboxamide

3'-hydroxy-N-((2-((N-hydroxyformamido)methyl)heptanamido) methyl)-[1 , T-biphenyl]-3- carboxamide

N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3'- isopropoxy-[1 , 1 '-biphenyl]- 3-carboxamide 4'-fluoro-N-((2-((N-hydroxyformamido)methyl)heptanamido)meth yl)-[1 , T-biphenyl]-3- carboxamide

N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propanami do)methyl)-3-(5- methoxypyridin-3-yl)benzamide

N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3-( 5-methoxypyridin-3- yl)benzamide

3-(1-ethyl-1 H-pyrazol-4-yl)-N-((2-((N- hydroxyformamido)methyl)heptanamido)methyl)benzamide

3'-(((2-((N-hydroxyformamido)methyl)heptanamido)methyl)ca rbamoyl)-[1 ,1 '-biphenyl]-3- carboxylic acid

N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3'- sulfamoyl-[1 , T-biphenyl]-3- carboxamide

N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3'- (2,2,2-trifluoroethoxy)-[1 , 1 '- biphenyl]-3-carboxamide

2'-fluoro-N-((2-((N-hydroxyformamido)methyl)heptanamido)m ethyl)-3'-methoxy-[1 ,1 '- biphenyl]-3-carboxamide

N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3'- (methylsulfonarriido)-[1 , 1 '- biphenyl]-3-carboxamide 4'-(dimethylamino)-N-((2-((N-hydroxyformamido)methyl)heptana mido)methyl)-[1 , 1 '- biphenyl]-3-carboxamide

N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3'- (methylsulfonyl)-[1 , 1 '- biphenyl]-3-carboxamide

N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-4'- methoxy-[1 , 1 '-biph carboxamide

2'-fluoro-N-((2-((N-hydroxyformamido)methyl)heptanamido)m ethyl)-[1 , T-biphenyl]-3- carboxamide

4'-fluoro-N-((2-((N-hydroxyformamido)methyl)heptanamido)m ethyl)-3'-methoxy-[1 ,1 '- biphenyl]-3-carboxamide

N3-((2-((N-hydroxyformarnido)methyl)heptanamido)methyl)-[ 1 , 1 '-biphenyl]-3,3'- dicarboxamide

3'-(dimethylamino)-N-((2-((N-hydroxyformamido)methyl)hept anamido)methyl)- , 1 '- biphenyl]-3-carboxamide

ethyl 3-(6-(((2-(1-(N-hydroxyformamido)propyl)heptanarnido)methyl) carbamoyl)pyridin-2- yl)-5-sulfamoylbenzoate

N-((2-(1-(N-hydroxyformarnido)propyl)heptanamido)methyl)- 3'-mercapto-[1 , T-biphenyl]- 3-carboxamide 2-ethoxy-4-(3-fluoro-6-(((2-(1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzoic acid

3-(6-(((2-(1-(N-hydroxyformamido)propyl)heptanamido)methy l)carbamoyl)pyridin-2-yl)-5- sulfamoylbenzoic acid

5-ethoxy-2-hydroxy-3'-(((2-(1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 , 1 '-biphenyl]-3-carboxylic acid

5-(((2-(1-(N-hydroxyformamido)propyl)heptanamido)methyl)c arbamoyl)-[1 , T-biphi carboxylic acid

5-ethoxy-5'-(((2-(1-(N-hydroxyformamido)propyl)heptanamid o)methyl)carbamoyl)-[1 , 1 '- biphenyl]-3,3'-dicarboxylic acid;

N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3-( (6-methoxypyridin-3- yl)oxy)benzamide;

((2-ethoxy-4-(6-(((2-(1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2- yl)benzamido)methyl)phosphonic acid;

2,2'-((3-ethoxy-5-(6-(((2-(1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2- yl)benzoyl)azanediyl)diacetic acid;

2,2'-((2-ethoxy-4-(6-(((2-(1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2- yl)benzoyl)azanediyl)diacetic acid;

3-(carboxymethoxy)-5-(6-(((2-(1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzoic acid; 4-(6-(((2-(1-(N-hydroxyformamido)propyl)heptanamido)methyl)c arbamoyl)pyridin-2- yl)phthalic acid;

2-(4-(6-(((2-(1-(N-hydroxyformamido)propyl)heptanamido)methy l)carbamoyl)pyridin-2- yl)benzamido)succinic acid;

2-(4-(6-(((2-(1-(N-hydroxyformamido)propyl)heptanamido)methy l)carbamoyl)pyridin-2- yl)benzamido)succinic acid;

2-(4-(6-(((2-(1-(N-hydroxyformamido)propyl)heptanamido)methy l)carbamoyl)pyridin-2- yl)benzamido)pentanedioic acid;

2-(2-ethoxy-4-(6-(((2-(1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2- yl)benzamido)pentanedioic acid;

(3-hydroxy-5-(6-(((2-(1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2- yl)phenyl)phosphonic acid;

((2-hydroxy-4-(6-(((2-(1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2- yl)benzamido)methyl)phosphonic acid;

((4-(6-(((2-(1-(N-hydroxyformamido)propyl)heptanamido)methyl )carbamoyl)pyridin-2- yl)benzamido)methyl)phosphonic acid;

2-(2-chloro-4-(6-(((2-(1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2- yl)benzamido)succinic acid;

((4-(6-(((2-(1-(N-hydroxyformamido)propyl)heptanamido)methyl )carbamoyl)pyridin-2-yl)- 2-methylbenzamido)methyl)phosphonic acid;

2-(4-(6-(((2-(1-(N-hydroxyformamido)propyl)heptanamido)methy l)carbamoyl)pyridin-2- yl)-2-methylbenzamido)succinic acid; and

2-(2-fluoro-4-(6-(((2-(1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2- yl)benzamido)succinic acid; salt thereof (in more particular embodiments, a pharmaceutically acceptable salt thereof).

In some embodiments the compound of the invention is a compound selected from the group consisting of:

(S)-2-(5-ethoxy-3'-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 , T-biphenyl]-3- ylcarboxamido)succinic acid

(S)-2-(2-(carboxymethoxy)-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzamido)succinic acid; and

(3-ethoxy-5-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl )heptanamido)methyl) carbamoyl)pyridin-2-yl)phenyl)phosphonic acid;

or a salt thereof (in more particular embodiments, a pharmaceutically acceptable salt thereof). In some embodiments the compound of the invention is a compound selected from the group consisting of:

3-ethoxy-5-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzoic acid

2-ethoxy-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzoic acid

2-(2-ethoxy-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)phenyl)acetic acid 2-(4-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanami do)methyl)carbamoyl)pyridin- 2-yl)phenyl)acetic acid

(2-ethoxy-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)phenyl)phosphonic acid

(R)-3-ethoxy-5-(6-(((2-((N- hydroxyformamido)methyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzoic acid

2-ethoxy-4-(6-((((2R,3R)-3-(N-hydroxyformamido)-2- phenethylpentanamido)methyl)carbamoyl)pyridin-2-yl)benzoic acid

3-ethoxy-3'-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)he ptanamido)methyl)carbamoyl)- [1 , 1 '-biphenyl]-4-carboxylic acid

2-(3-ethoxy-3'-((((R)-2-((R)-1-(N-hydroxyformamido)propyl )heptanamido)methyl)carbamoyl)- [1 , 1 '-biphenyl]-4-yl)acetic acid

5-ethoxy-3'-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)he ptanamido)methyl)carbamoyl)- [1 , 1 '-biphenyl]-3-carboxylic acid

(S)-2-(3-ethoxy-5-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzamido)succinic acid

(S)-2-(2-ethoxy-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzamido)succinic acid (S)-2-(2-(2-ethoxy-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamiclo)methyl)carbamoyl)pyricl iri-2- yl)phenyl)acetamido)succinic acid

2-ethoxy-4-(4-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyrimid in-2-yl)benzoic acid

2-ethoxy-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyrazin -2-yl)benzoic acid

(S)-2-(3-ethoxy-3'-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 ,1 '-biphenyl]-4- ylcarboxamido)succinic acid

3-hydroxy-3'-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)h eptanamido)methyl)carbamoyl)- [1 , 1 '-biphenyl]-4-carboxylic acid

(S)-2-(3-(carboxymethoxy)-3'-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 ,1 '-biphenyl]-4- ylcarboxamido)succinic acid

(5-ethoxy-3'-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)h eptanamido)methyl)carbamoyl)- [1 , 1 '-biphenyl]-3-yl)phosphonic acid

(3-ethoxy-3'-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)h eptanamido)methyl)carbamoyl)- [1 , 1 '-biphenyl]-4-yl)phosphonic acid (2-ethoxy-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyrazin -2-yl)phenyl)phosph acid

(2-ethoxy-4-(4-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyrimid in-2-yl)phenyl)phosphoni acid; and

5-ethoxy-3'-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)he ptanamido)methyl)carbamoyl)- [1 , 1 '-biphenyl]-3-sulfonic acid;

or a salt thereof (in more particular embodiments a pharmaceutically acceptable salt thereof). In some embodiments the compound of the invention is a compound selected from the group consisting of:

(R)-N-((2-((N-hydroxyformamido)methyl)-4-phenylbutanamido )methyl)-6-phenylpicolinamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl) -6-phenylpicolinamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl) -6-(3- methoxyphenyl)picolinamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl) -6'-methoxy-[2,2'-bipyridine]-6- carboxamide (R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-2- phenylpyrimidine-4^ carboxamide

(R)-6-(4-fluorophenyl)-N-((2-((N- hydroxyformamido)methyl)heptanamido)methyl)picolinamide

(R)-6-(4-fluoro-3-methoxyphenyl)-N-((2-((N- hydroxyformamido)methyl)heptanamido)methyl)picolinamide

(R)-6-(2,4-difluorophenyl)-N-((2-((N- hydroxyformamido)methyl)heptanamido)methyl)picolinamide

(R)-6-(2-fluoro-3-methoxyphenyl)-N-((2-((N- hydroxyformamido)methyl)heptanamido)methyl)picolinamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl) -[2,3'-bipyridine]-6- carboxamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl) -6-(4- (trifluoromethyl)phenyl)picolinamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl) -6-(4- (trifluoromethoxy)phenyl)picolinamide (R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-6- phenylpyrazine-2- carboxamide

(R)-5-fluoro-N-((2-((N-hydroxyformamido)methyl)heptanamid o)methyl)-6-phenylpicolinamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl) -6-phenyl-4- (trifluoromethyl)picolinamide

2-(4-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptan amido)methyl)carbamoyl)pyridin- 2-yl)phenyl)-2-methylpropanoic acid

1- (4-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido )methyl)carbamoyl)pyridin-

2- yl)phenyl)cyclopropanecarboxylic acid

3-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanami do)methyl)carbamoyl)pyridin-2- yl)-2-methyl benzoic acid

5-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanami do)methyl)carbamoyl)pyridin-2- yl)-2-methoxybenzoic acid

2-fluoro-5-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzoic acid 6-(3-((2-aminoethyl)carbamoyl)-5-ethoxyphenyl)-N-(((R)-2-((R )-1-(N- hydroxyformarTiido)propyl)heptanarTiido)methyl)picolinarnide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl) -[1 , T-biphenyl]-3-carboxamide

(R)-2-fluoro-N-((2-((N-hydroxyformamido)methyl)heptanamid o)methyl)-3'-methoxy-[1 , 1 '- biphenyl]-3-carboxamide

(R)-2,2'-difluoro-N-((2-((N-hydroxyformamido)methyl)hepta namido)methyl)-3'-methoxy-[1 , T- biphenyl]-3-carboxamide

(R)-2,2'-difluoro-N-((2-((N-hydroxyformamido)methyl)hepta namido)methyl)-5'-methoxy-[1 , T- biphenyl]-3-carboxamide

(R)-3-(4,5-dimethyloxazol-2-yl)-N-((2-((N- hydroxyformamido)methyl)heptanamido)methyl)benzamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl) -3-(4-methyl-1 H-pyrazol-1- yl)benzamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl) -3-(2-methyloxazol-5- yl)benzamide (R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3- (2-methoxypyrimidi yl)benzamide

(R)-(3'-(((2-((N-hydroxyformamido)methyl)-4-phenylbutanam ido)methyl)carbamoyl)-[1 , T- biphenyl]-3-yl)boronic acid

(R)-N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propa namido)methyl)-2'-methoxy- [1 , 1 '-biphenyl]-3-carboxamide

(R)-N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propa namido)methyl)-3'-methoxy- [1 , 1 '-biphenyl]-3-carboxamide

(R)-N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propa namido)methyl)-4'- (trifluoromethyl)-[1 ,1 '-biphenyl]-3-carboxamide

(R)-3'-cyano-N-((3-cyclopentyl-2-((N-hydroxyformamido)met hyl)propanamido)methyl)-[1 ,1 '- biphenyl]-3-carboxamide

(R)-N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propa namido)methyl)-[1 , 1 -biphenyl]- 3-carboxamide

(R)-N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propa namido)methyl)-3- phenoxybenzamide 4-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido) methyl)carbamoyl)pyridin-2- yl)-3-methyl benzoic acid

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl) -3-(5-methyloxazol-2- yl)benzamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl) -3-(1 H-tetrazol-5- yl)benzamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl) -3'-methoxy-[1 , T-biph carboxamide

(R)-N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propa namido)methyl)-3'-ethoxy-[1 ,1 '- biphenyl]-3-carboxamide

(R)-N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propa namido)methyl)-3'-hydroxy- [1 , 1 '-biphenyl]-3-carboxamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl) -3'-isopropyl-[1 , T-biph carboxamide

(R)-N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propa namido)methyl)-3'-ethyl-[1 , T- biphenyl]-3-carboxamide (R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-2' ,5'-dimethoxy-[1 , 1 '- biphenyl]-3-carboxamide

(R)-N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propa namido)methyl)-3'- (trifluoromethoxy)-[1 , 1 '-biphenyl]-3-carboxamide

(R)-N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propa namido)methyl)-3'- (trifluoromethyl)-[1 ,1 '-biphenyl]-3-carboxamide

(R)-N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propa namido)methyl)-3',5'- dimethoxy-[1 , 1 '-biphenyl]-3-carboxamide

(R)-3-(3,6-dimethoxypyridazin-4-yl)-N-((2-((N- hydroxyformamido)methyl)heptanamido)methyl)benzamide

(R)-3-(3,6-dimethoxypyridazin-4-yl)-N-((2-((N-hydroxyform amido)methyl)-4- phenylbutanamido)methyl)benzamide

(R)-3'-fluoro-N-((2-((N-hydroxyformamido)methyl)heptanami do)methyl)-[1 , 1 '-biphenyl]-3- carboxamide

(R)-3'-hydroxy-N-((2-((N-hydroxyformamido)methyl)heptanam ido)methyl)-[1 , 1 '-biphenyl]-3- carboxamide (R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl)-3' -isopropoxy-[1 , 1'-biphenyl]- 3-carboxamide

(R)-4'-fluoro-N-((2-((N-hydroxyformamido)methyl)heptanami do)methyl)-[1 , 1 '-biphenyl]-3- carboxamide

(R)-N-((3-cyclopentyl-2-((N-hydroxyformamido)methyl)propa namido)methyl)-3-(5- methoxypyridin-3-yl)benzamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl) -3-(5-methoxypyridin-3- yl)benzamide

(R)-3-(1-ethyl-1 H-pyrazol-4-yl)-N-((2-((N- hydroxyformamido)methyl)heptanamido)methyl)benzamide

(R)-3'-(((2-((N-hydroxyformamido)methyl)heptanamido)methy l)carbamoyl)-[1 , 1 '-biphenyl]-3- carboxylic acid

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl) -3'-sulfamoyl-[1 ,1 '-biphenyl]-3- carboxamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl) -3'-(2,2,2-trifluoroethoxy)-[1 , 1'- biphenyl]-3-carboxamide (R)-2'-fluoro-N-((2-((N-hydroxyformamido)methyl)heptanamido) methyl)-3'-methoxy-[1 , 1 '- biphenyl]-3-carboxamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl) -3'-(methylsulfonamido)-[1 , T- biphenyl]-3-carboxamide

(R)-4'-(dimethylamino)-N-((2-((N-hydroxyformamido)methyl) heptanamido)methyl)-[1 , 1 '- biphenyl]-3-carboxamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl) -3'-(methylsulfonyl)-[1 ,1 '- biphenyl]-3-carboxamide

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl) -4'-methoxy-[1 , T-biph carboxamide

(R)-2'-fluoro-N-((2-((N-hydroxyformamido)methyl)heptanami do)methyl)-[1 , 1 '-biphenyl]-3- carboxamide

(R)-4'-fluoro-N-((2-((N-hydroxyformamido)methyl)heptanami do)methyl)-3'-methoxy-[1 , 1 '- biphenyl]-3-carboxamide

(R)-N3-((2-((N-hydroxyformamido)methyl)heptanamido)methyl )-[1 , 1 '-biphenyl]-3,3'- dicarboxamide (R)-3'-(dimethylamino)-N-((2-((N-hydroxyformamido)methyl)hep tanamido)methyl)-[1 , 1 '- biphenyl]-3-carboxamide

ethyl 3-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)-5-sulfamoylbenzoate

N-(((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)m ethyl)-3'-mercapto-[1 , T- biphenyl]-3-carboxamide

2-ethoxy-4-(3-fluoro-6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzoic acid

3-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanami do)methyl)carbamoyl)pyridin-2- yl)-5-sulfamoylbenzoic acid

5-ethoxy-2-hydroxy-3'-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 , 1 '-biphenyl]-3-carboxylic acid

5-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido) methyl)carbamoyl)-[1 , T- biphenyl]-3-carboxylic acid

5-ethoxy-5'-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)he ptanamido)methyl)carbamoyl)- [1 , 1 '-biphenyl]-3,3'-dicarboxylic acid; and

(R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)methyl) -3-((6-methoxypyridin-3- yl)oxy)benzamide; or a salt thereof (in more particular embodiments a pharmaceutically acceptable salt thereof).

In some embodiments the compound of the invention is a compound selected from the group consisting of:

((2-ethoxy-4-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propy l)heptanamido)methyl)carbamoyl)pyrid yl)benzamido)methyl)phosphonic acid;

2,2'-((3-ethoxy-5-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzoyl)azanediyl)di acid;

2,2'-((2-ethoxy-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzoyl)azanediyl)di acid;

3- (carboxymethoxy)-5-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzoic acid;

4- (6-((((R)-2-((R)-1-(N-hydroxyformam

acid;

(R)-2-(4-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)he ptanamido)methyl)carbamoyl)pyridin-2- yl)benzamido)succinic acid;

(S)-2-(4-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)he ptanamido)methyl)carbamoyl)pyridin-2- yl)benzamido)succinic acid;

(S)-2-(4-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)he ptanamido)methyl)carbamoyl)pyridin-2- yl)benzamido)pentanedioic acid;

(S)-2-(2-ethoxy-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzamido) acid; (3-hydroxy-5-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)h eptanamido)methyl)carbamoyl)p yl)phenyl)phosphonic acid;

((2-hydroxy-4-(6-((((R)-2-((R)-1-(N-hydroxyformamido)prop yl)heptanamido)methyl)carbamoyl)pyridi 2-yl)benzamido)methyl)phosphonic acid;

((4-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptana mido)methyl)carbamoyl)pyridin-2- yl)benzamido)methyl)phosphonic acid;

(S)-2-(2-chloro-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzamido)succ acid;

((4-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptana mido)methyl)carbamoyl)pyridin-2-yl)-2- methylbenzamido)methyl)phosphonic acid;

(S)-2-(4-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)he ptanamido)methyl)carbamoyl)pyridin-2-yl)-2- methylbenzamido)succinic acid; and

(S)-2-(2-fluoro-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzamid acid; or a salt thereof (in more particular embodiments a pharmaceutically acceptable salt thereof).

In some embodiments, the invention is directed to a method of inhibiting BMP1 , TLL1 and/or TLL2 comprising contacting a biological material comprising the protein(s) with a compound of the invention. In some embodiments the contact is made in-vitro, and the biological material is, e.g., cell culture or cellular tissue. In other embodiments, the contact is made in-vivo.

In other embodiments, the invention is directed to a method of treating a disease associated with BMP1 , TLL1 and/or TLL2 activity in a subject (e.g., a human or other mammal) in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention (particularly a compound of Formula (I) or a pharmaceutically acceptable salt thereof). The invention is still further directed to the use of a compound of the invention or a pharmaceutical composition comprising a compound of the invention (particularly a compound of Formula (I) or a pharmaceutically acceptable salt thereof) to treat a disease associated with BMP1 , TLL1 and/or TLL2 activity. The invention is further directed to a compound of the invention ((particularly a compound of Formula (I) or a pharmaceutically acceptable salt thereof) for use in therapy, particularly as an active therapeutic substance in the treatment of a disease associated with BMP1 , TLL1 and/or TLL2 activity. The invention is further directed to the use of a compound of the invention (particularly a compound of Formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for use in treating a disease associated with BMP1 , TLL1 and/or TLL2 activity.

In some embodiments, the disease associated with BMP1 , TLL1 and/or TLL2 activity is selected from those associated with pathological fibrotic conditions in body organs or tissues, e.g., such conditions of the heart, lung, kidney, liver, eye, skeletal muscle, skin, the vasculature, and the nervous system, e.g., myocardial infarction ("Ml"), heart failure (e.g., heart failure with reduced ejection fraction, heart failure with preserved ejection fraction), cardiac arrhythmias (e.g., atrial fibrillation), hypertrophic cardiomyopathy, chronic obstructive pulmonary disease ("COPD"), idiopathic pulmonary fibrosis ("IPF"), diabetic nephropathy, post-acute kidney injury, chronic kidney disease ("CKD"), delayed graft function posttransplantation, liver cirrhosis, non-alcoholic steatohepatitis ("NASH"), glaucoma, corneal scarring, muscular dystrophies (including Duchenne, Becker, limb-girdle, congenital, facioscapulohumeral, myotonic, oculopharyngeal, distal, and Emery- Dreifuss), keloids, wound healing, adhesions, hypertrophic scarring and other scarring, e.g., associated with burns, surgery or other trauma, stroke, collagen vascular diseases (such as systemic lupus erythematosus, rheumatoid arthritis and scleroderma), spinal cord injury, and multiple sclerosis.

In some embodiments, the disease associated with BMP1 , TLL1 and/or TLL2 activity is selected from muscular diseases characterized by reduced muscle function and/or mass, e.g., muscular dystrophy (e.g., Duchenne, Becker, limb-girdle, congenital,

facioscapulohumeral, myotonic, oculopharyngeal, distal, and Emery-Dreifuss), sarcopenia, and cachexia associated with, e.g., heart failure, CKD, COPD, cancer, or old age.

The compounds according to Formula (I) may contain one or more asymmetric center(s) (also referred to as a chiral center(s)) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof. Chiral centers, such as a chiral carbon, sulfur or phosphorus, may also be present in the compounds of this invention. Where the stereochemistry of a chiral center present in a compound of this invention (e.g., compound name or in any chemical structure illustrated herein) is not specified, the compound, compound name, or structure is intended to encompass all individual stereoisomers and all mixtures thereof. Thus, compounds according to Formula (I) containing one or more chiral center(s) may be present as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.

Individual stereoisomers of a compound according to Formula (I) which contain one or more asymmetric center(s) may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out (1) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent. The skilled artisan will appreciate that where the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired form. Alternatively, specific stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.

It is to be understood that a solid form of a compound of the invention may exist in crystalline forms, non-crystalline forms or a mixture thereof. Such crystalline forms may also exhibit polymorphism (i.e. the capacity to occur in different crystalline forms). These different crystalline forms are typically known as "polymorphs." Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. One of ordinary skill in the art will appreciate that different polymorphs may be produced, for example, by changing or adjusting the conditions used in crystallizing/recrystallizing the compound.

Because of their potential use in medicine, the salts of the compounds of Formula (I) are preferably pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts include those described by Berge, S.M. et al., Journal of Pharmaceutical Sciences, 1977, 66, 1-19.

When a compound of the invention is a base (contains a basic moiety), a desired salt form may be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, and the like, or with a pyranosidyl acid, such as glucuronic acid or galacturonic acid, or with an alpha-hydroxy acid, such as citric acid or tartaric acid, or with an amino acid, such as aspartic acid or glutamic acid, or with an aromatic acid, such as benzoic acid or cinnamic acid, or with a sulfonic acid, such as p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or the like.

Suitable acid addition salts include acetate, p-aminobenzoate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bismethylenesalicylate, bisulfate, bitartrate, borate, calcium edetate, camsylate, carbonate, clavulanate, citrate, cyclohexylsulfamate, edetate, edisylate, estolate, esylate, ethanedisulfonate, ethanesulfonate, formate, fumarate, gluceptate, gluconate, glutamate, glycollate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, dihydrochloride, hydrofumarate, hydrogen phosphate, hydroiodide, hydromaleate, hydrosuccinate, hydroxynaphthoate, isethionate, itaconate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate,

methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, /V-methylglucamine, oxalate, oxaloacetate, pamoate (embonate), palmate, palmitate, pantothenate,

phosphate/diphosphate, pyruvate, polygalacturonate, propionate, saccharate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, triethiodide, trifluoroacetate and valerate.

Other exemplary acid addition salts include pyrosulfate, sulfite, bisulfite, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, suberate, sebacate, butyne-1 ,4-dioate, hexyne-1 ,6-dioate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, phenylacetate,

phenylpropionate, phenyl butrate, lactate, γ-hydroxybutyrate, mandelate, and sulfonates, such as xylenesulfonate, propanesulfonate, naphthalene-1-sulfonate and

naphthalene-2-sulfonate.

If an inventive basic compound is isolated as a salt, the corresponding free base form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic base, suitably an inorganic or organic base having a higher pK a than the free base form of the compound.

When a compound of the invention is an acid (contains an acidic moiety), a desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, tertiary or quaternary), an alkali metal or alkaline earth metal hydroxide, alkoxide (e.g. (d.

4)alkoxide), alkyl ester (e.g., (Ci -4 )alkyl ester, e.g. acetate), or the like. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine, lysine, and arginine, ammonia, primary, secondary, tertiary, and quaternary amines, cyclic amines, and amino sugars, e.g., 2-amino-2-deoxysugars, such as /V-methyl-D-glucamine, diethylamine, isopropylamine, trimethylamine, ethylene diamine, dicyclohexylamine, ethanolamine, choline, piperidine, morpholine, piperazine, Tris (also known as THAM, or

tris(hydroxymethyl)aminomethane), 2-amino-2-hydroxymethyl-propane-1 ,3-diol, and 2- amino-2-(hydroxymethyl)-1 ,3-propanediol), meglumine (also known as 1-Deoxy-1- (methylamino)-D-glucitol), galactosamine, glucosamine, and N-acetylglucosamine, as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium (e.g., hydroxides, (Ci_ 4 )alkoxides, and (Ci -4 )alkyl esters of such alkali and alkaline earth metals).

Treatment of a compound of Formula (I) containing a free acid with an inorganic or organic base, or containing a free base with an acid, to form a salt of the compound of Formula (I) may be done by methods known in the art. For example, the free acid may be admixed with a suitable solvent (e.g. in which the free acid is soluble) and treated with the base, with stirring, and optionally with heating and/or temperature cycling. Analogously, for a compound of Formula (I) containing a free base, the free base may be admixed with a suitable solvent (e.g. in which the free base is soluble) and treated with the acid, with stirring, and optionally with heating and/or temperature cycling. Certain of the compounds of the invention may form salts with one or more equivalents of an acid (if the compound contains a basic moiety) or a base (if the compound contains an acidic moiety). The present invention includes within its scope all possible stoichiometric and non-stoichiometric salt forms.

Compounds of the invention having both a basic and acidic moiety may be in the form of zwitterions, acid-addition salts of the basic moiety or base salts of the acidic moiety.

This invention also provides for the conversion of one pharmaceutically acceptable salt of a compound of this invention into another pharmaceutically acceptable salt of a compound of this invention.

In some embodiments, the compound of the invention is a salt, e.g., a

pharmaceutically acceptable salt, of: (S)-2-(5-ethoxy-3'-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 , T-biphenyl]-3- ylcarboxamido)succinic acid; (S)-2-(2-(carboxymethoxy)-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzamido)succinic acid; or (3-ethoxy-5-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)he ptanamido)methyl) carbamoyl)pyridin-2-yl)phenyl)phosphonic acid, including all possible stoichiometric and non- stoichiometric forms of such salts. The compounds of Formula (I) and salts (including pharmaceutically acceptable salts) thereof may be in the form of a solvate. For solvates of the compounds of Formula (I), including solvates of salts of the compounds of Formula (I), that are in crystalline form, the skilled artisan will appreciate that pharmaceutically acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve nonaqueous solvents such as ethanol, isopropanol, dimethylsulfoxide, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates." Solvates include stoichiometric solvates as well as compositions containing variable amounts of the incorporated solvent(s), e.g. a hydrate includes stoichiometic hydrates and compositions containing variable amounts of water. The invention includes all such solvates, particularly hydrates. It is to be understood that the term "a salt, particularly a pharmaceutically acceptable salt, thereof, or solvate thereof" and the like in reference to a compound of Formula (I) encompasses a salt of a compound of Formula (I), a pharmaceutically acceptable salt of a compound of Formula (I), a solvate of a compound of Formula (I), a solvate of a salt of a compound of Formula (I), and a solvate of a pharmaceutically acceptable salt of a compound of Formula (I) (for example, where water is the incorporated solvent, said solvates are hydrates).

Because the compounds of the invention, particularly compounds of Formula (I), and pharmaceutically acceptable salts thereof, or a solvate (e.g., hydrate) thereof, are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions.

General Methods of Preparation

The compounds of Formula (I) may be obtained by using synthetic procedures illustrated in the Schemes below or by drawing on the knowledge of a skilled organic chemist. The syntheses provided in these Schemes are applicable for producing

compounds of the invention having a variety of different R1 , R2 and R3 groups employing appropriate precursors. Those skilled in the art will appreciate that in the preparation of compounds of the invention (e.g., compounds of Formula (I), salts thereof, and/or solvates thereof) it may be necessary and/or desirable to protect one or more sensitive groups in the molecule or the appropriate intermediate to prevent undesirable side reactions. Suitable protecting groups for use according to the present invention are well know to those skilled in the art and may be used in a conventional manner. See for example, "Protective groups in organic synthesis" by T.W. Green and P.G.M Wuts (Wiley & Sons, 1991) or "Protecting Groups" by P.J.Kocienski (Georg Thieme Verlag, 1994). Subsequent deprotection, where needed, affords compounds of the nature generally disclosed. While the Schemes are shown with compounds of Formula (I), they are illustrative of processes that may be used to make the compounds of the invention.

Compound names were generated using the software naming program Chem Draw Ultra v12.0 available from Perkin Elmer, 940 Wnter Street, Waltham, Massachusetts, 02451 , USA. (http://www.perkinelmer.com/).

(I)

In a general process, compounds of Formula (I) may be prepared according to reaction Schemes 1-4: Scheme 1

(ID (I)

1. React (II) and (III) in the presence of an amide coupling reagent (e.g. EDC/HOBT, HATU or HBTU), base and suitable solvent either at room temperature or at elevated temperature (Scheme 1). 2. Debenzylation may be achieved via hydrogenation using a catalyst such as Pd/C and a hydrogen source (e.g. hydrogen gas or ammonium formate). 3. If required, re- formylation may be achieved utilizing a pre-mixed solution of CDI/formic acid in a solvent such as DCM at room temperature to form (I). Alternatively re-formylation may be achieved via reaction with 5-methyl-2-thioxo-1 ,3,4-thiadiazole-3(2H)-carbaldehyde (Yazawa, H., et al., Tetrahedron Letters, 1985, 26(31), 3703-6) in a solvent such as DCM at room temperature. Reformylation may be needed following all debenzylation steps discussed below but for brevity it will be left out of the future schemes. As appreciated by those skilled in the art, the order of the synthetic steps may be varied or omitted if unnecessary. cheme 2

(IV) (I)

1. React (IV) and (V) in the presence of an amide coupling reagent, base and solvent at room temperature or an elevated temperature (Scheme 2). 2. Debenzylation may be achieved as described in Scheme 1 to yield (I).

Scheme 3

(I)

(VI)

1. React (VI) and (V) in the presence of an amide coupling reagent, base and solvent at room temperature or an elevated temperature to form (I) (Scheme 3).

Scheme 4

( II) (la)

In a general process, compounds of Formula (I) wherein n=0 and R3 is directly attached to the internal ring (la) may be prepared according to Scheme 4. 1. React (VII) (where X = Br or CI) with the appropriate boronic acid or boronate ester (R3-"B") derivative (VIII) in the presence of a catalyst (e.g. Pd(PPh 3 ) 4 or Pd(dppf)CI 2 ), inorganic base (e.g. potassium carbonate or aqueous sodium carbonate) and suitable solvent (e.g. 1 ,4-dioxane or

DME/water) at elevated temperature under microwave irradiation or standard heating. . In some situations, the R3-"B" (VIII) is formed in situ from the corresponding bromide (R3-Br) in the coupling reaction (e.g., Suzuki). 2. Debenzylation may be achieved as described in Scheme 1.

Scheme 5

1. React amine (VI) with 3-(6-methyl-4,8-dioxo-1 ,3,6,2-dioxazaborocan-2-yl)benzoic acid (IX) with coupling reagent and base in solvent (Scheme 7). 2. React appropriate bromide, R3-Br (XXXV), in the presence of a catalyst (e.g. Pd(dppf)CI 2 ) and inorganic base (e.g. aqueous sodium carbonate) in solvent at elevated temperature to form (lb).

Scheme 6

(Xd)

In a general process, compounds of Formula (I) wherein R3 contains a carboxylic acid (e.g., Formula (Ic or lh)) or phosphonic acid (e.g., Formula (Id or li)) may be prepared according to Schemes 1-5 and/or as outlined in Scheme 6 from their corresponding ester functionalities (Xc), (Xd), (Xh), and (Xg) The transformations in Scheme 6 are illustrated with a phenyl ring R3 however Scheme 6 applies analogously to preparation of corresponding molecules of Formula (1c-d) with all embodiments of R3 disclosed herein. 1. Debenzylation may be achieved as described in Scheme 1. 2. For compounds of Formula (Xc) and Formula (Xh), ester hydrolysis may be achieved by reaction with lithium hydroxide in a solvent and ester deprotection could be achieved via reaction with acid in a solvent and for compounds of Formula (Xd) and Formula (Xg), hydrolysis may be alternatively achieved by reaction with TMS-Br in a suitable solvent. Additionally, the order of these steps can be changed, wherein 1. ester hydrolysis and then 2. debenzylation can lead to (Ic) or (Id) when starting with the appropriate starting material. Additionally, a global debenzylation can be utilized if appropriate esters (e.g., benzyl esters) are being utilized. As appreciated by those skilled in the art the order of the synthetic steps may be varied or omitted if unecessary.

In a general process, compounds of Formula (I) wherein R3 contains an amine (e.g., Formula (le)) may be prepared according to Schemes 1-5 and/or as outlined in Scheme 7 from their corresponding protected amine (Xe). 1. Deprotection of the Fmoc amine by treatment of (Xe) with an amine base such as pyrrolidine in an appropriate solvent. 2.

Debenzylation may be achieved as described in Scheme 1 to yield (le). The transformations in Scheme 7 are illustrated with a phenyl ring R3 however Scheme 7 applies analogously to preparation of corresponding molecules of Formula (le) with all embodiments of R3 disclosed herein.

Scheme 8

In a general process, compounds of Formula (I) wherein the internal ring contains a carboxylic acid (e.g., Formula (If)) may be prepared according to Schemes 1-5 and/or as outlined in Scheme 8. 1. React amine (VI) with (XI), coupling reagent and base in solvent (Scheme 8). 2. React appropriate boronic acid or boronate, R3-"B" (VIII), in the presence of a catalyst (e.g. Pd(dppf)CI 2 ) and inorganic base in solvent. 3. Hydrolytic cleavage of the ester to form (If). It should be noted that Steps 2 and 3 can be reversed to form (If). Scheme 9

In a general process, compounds of Formula (I) wherein the distal ring contains a thiol (e.g., Formula (Ig)) may be prepared according to Schemes 1-5 and/or as outlined in Scheme 9. 1. React amine (VI) with (XII) with coupling reagent and base in solvent (Scheme 9). 2.

Deprotect thiol protecting group in the presence of Et 3 SiH, TFA and in a solvent such as DCM to yield (Ig). The transformations in Scheme 9 are illustrated with a phenyl ring R3 however Scheme 6 applies analogously to preparation of corresponding molecules of Formula (1g) with all embodiments of R3 disclosed herein.

In a general process, compounds of Formula (II), wherein R1 is H, may be prepared according to the following Schemes 10 or 1 1. In a general process, compounds of Formula (II) may be alternatively prepared according to the following Schemes 12 or 13.

Scheme 10

(XIII) (XV)

(XVI) ( χνι ') (ID

1. React formaldehyde O-benzyl oxime (XIV) with a pre-mixed solution of Nal and TMS-CI or TMS-OTf and then treat with a base and a compound (XIII) in a solvent (Scheme 10). 2. In instances where R' is not H but selected from Ci_ 2 alkyl, ester hydrolysis can be achieved by reaction with lithium hydroxide and solvent. 3. Lactam formation may be achieved by reaction with phosphoryl trichloride in the presence of a base such as 2,6-dimethylpyridine and solvent at an elevated temperature. 4. Chiral separation may be conducted at this stage using techniques known to those skilled in the art. 5. Lactam ring opening may be done by reaction with lithium hydroxide in a solvent. 6. Formylation may be achieved as described in Scheme 1. As appreciated by those skilled in the art synthetic steps may be omitted if unnecessary.

Scheme 11

N-OBn OH

(XVIII) (XX)

ΒΠ °-

(XXII) (XVI) (XVII)

1. React the appropriate enantiomer of (XVIII) with a base such as butyllithium followed by the acyl chloride (XIX) and solvent such as THF at -78 °C to 0 °C (Scheme 1 1). 2. React TiCI 4 in the presence of a base and solvent followed by reaction with

((chloromethoxy)methyl)benzene. 3. React with hydrogen peroxide and lithium hydroxide in solvent at 0 °C and then 4. debenzylation may be achieved via hydrogenation. 5. React with O-benzylhydroxylamine hydrochloride in the presence of a coupling and solvent. 6. Lactam formation may be achieved by reaction with DIAD and triphenylphosphine in solvent. 7. Lactam ring opening may be achieved by reaction with lithium hydroxide in solvent. 8. Formylation may be achieved utilizing a mixture of CDI/formic acid in a solvent to yield (II).

Scheme 12

4. Lactam formation

(XVIII)

(XXIV)

(XVI) (XVII) (ID

1. React the appropriate enantiomer of (XVIII) with a base such as butyllithium followed by the appropriate acyl chloride (XIX) in a suitable solvent such as THF (Scheme 12). 2. React with TiCI 4 in the presence of a base such as DIPEA with an additive such as NMP in a solvent followed by reaction with the appropriate aldehyde (XXIII). 3. React with O- benzylhydroxylamine hydrochloride in a solvent such as THF in the presence of

trimethylaluminium. 4. React with methanesulfonyl chloride using a suitable base such as pyridine. 5. React with tetrabutylammonium hydroxide in a solvent. 6. Formylation may be achieved utilizing a mixture of CDI/formic acid in a solvent such as DCM at room

temperature to form (II).

Scheme 13 5. Formylation

1. React the appropriate enantiomer of (XVIII) with a base such as butyllithium followed by the acyl chloride (XIX) in a solvent such as THF (Scheme 13). 2. React with a base such as NaHMDS in a solvent such as THF at -78 °C followed by the appropriate acyl chloride (XXV). 3. React with O-benzylhydroxylamine hydrochloride in the presence of sodium acetate in a solvent such as methanol. 4. React with sodium cyanoborohydride in a solvent mixture such as dichloroethane and acetic acid. 5. Formylation may be achieved utilizing a mixture of CDI/formic acid in a solvent such as DCM at room temperature. 6. React with hydrogen peroxide and lithium hydroxide in a suitable solvent such as a mixture of methanol and water at 0 °C to form (II).

In a general process, compounds of Formula (III) may be prepared according to the following Schemes 14-16. Scheme 14

X Y WI TA ) H H 2 N^NHFmoc (XXX) ¾ ^ " ^W^ ^ ^

½3 4

(III)

XXIX 3. Fmoc deprotection

In a general process, compounds of Formula (III) wherein n=0 and R3 is directly attached to the internal ring may be prepared according to Scheme 14. 1. React (XXIX) (where X = Br or CI) in the presence of a coupling reagent, base and solvent and amine (XXX) (Scheme 1 1). 2. React with the appropriate boronic acid or boronate ester (R3-"B") derivative (VIII) in the presence of a catalyst (e.g. Pd(dppf)CI 2 ) and inorganic base in a solvent at an elevated temperature or under microwave irradiation. 3. Fmoc deprotection may be achieved by reaction with a secondary amine such as piperidine, or pyrollidine in a solvent such as DCM to form compounds of the structure (III). As appreciated by those skilled in the art the order of the synthetic steps may be varied.

Scheme 15

(XXXI)

3. Fmoc deprotection

1. In instances where R' is not H but selected from Ci_ 2 alkyl, ester hydrolysis may be achieved by reaction of a compound of Formula (XXXI) with lithium hydroxide in a solvent such as a mixture of methanol and water to form acid (R' = H) (Scheme 15). 2. Amide formation may be achieved by reaction with oxalyl chloride in a solvent such as DMF followed by reaction with (XXX) in the presence of a base such as DIPEA in a solvent such as DCM. Alternatively, amide formation may be achieved by reaction with (XXXI) in the presence of a coupling reagent such as HATU, base, solvent and (XXX). 3. Fmoc deprotection may be achieved by reaction with a secondary amine such as pyrollidine or morpholine in a suitable solvent such as DCM.

Scheme 16

(XXXII) (III)

In a general process, compounds of Formula (III) may be prepared according to reaction Scheme 16. 1. React compound (XXXII) with (XXXIII) in the presence of a base and solvent. 2. Rearrangement with PIFA in a solvent to form (III).

In a general process, compounds of Formula (IV) may be prepared according to Scheme 17.

Scheme 17 2. Fmoc deprotection

(II) (IV)

1. React compound of Formula (II) with (XXX) in the presence of a coupling reagent and base such as DIPEA in a solvent (Scheme 17). 2. Fmoc deprotection may be achieved by reaction with a secondary amine such as morpholine in a solvent such as acetonitrile.

In a general process, compounds of Formula (VI) may be prepared according to Scheme 18 or 19. Scheme 18

(VI)

In a general process, compounds of Formula (VI) may be prepared according to reaction Scheme 18. 1. React compound (II) with (XXXIV) in the presence of a coupling reagent, base and solvent. 2. Deprotection of the amine protection group (PG = Cbz or Fmoc) and debenzylation may be achieved under similar conditions described in Scheme 1 to yield the amine (VI) For cases when PG = Cbz, the deprotection and debenzylation can be done in one step. Scheme 19

(II) (VI)

1. React compound of Formula (II) with (XXXIII) in the presence of a coupling reagent, base and solvent. 2. Rearrangement with PI FA in a solvent and then 3. debenzylation may be achieved under similar conditions described in Scheme 1 to yield the amine (VI).

With regard to the above Schemes: Compounds of Formula (V), (VIII), (IX), (XI), (XII), (XIII), (XIV), (XVIII), (XIX), (XXV), XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV) may be sourced commercially or may be prepared by methods known in the literature or by processes known to those skilled in the art.

Further details for the preparation of compounds of the invention are found in the Intermediates and Examples section hereinafter.

Use of Compounds of the Invention

The compounds of this invention are inhibitors of BMP1 , TLL1 and/or TLL2 activity, and may be particularly useful for treatment of diseases associated with BMP1 , TLL1 and/or TLL2 activity, including for example treatment of diseases where inhibition of BMP1 , TLL1 and/or TLL2 is of therapeutic benefit. For example, compounds of the invention may be particularly useful for treatment of diseases where inhibition of tissue ECM (extracellular matrix) production and/or maturation would be beneficial, or where inhibition of myostatin activity would be beneficial.

In some embodiments, the disease associated with BMP1 , TLL1 and/or TLL2 activity is selected from diseases associated with pathological fibrotic conditions in body organs or tissues, e.g., such conditions of the:

heart (e.g., myocardial infarction ("Ml"), heart failure (e.g., heart failure with reduced ejection fraction, heart failure with preserved ejection fraction), cardiac arrhythmias (e.g., atrial fibrillation), hypertrophic cardiomyopathy),

lung (e.g. chronic obstructive pulmonary disease ("COPD"), idiopathic pulmonary fibrosis ("IPF")),

kidney (e.g. diabetic nephropathy, post-acute kidney injury, chronic kidney disease ("CKD"), delayed graft function post-transplantation),

liver (e.g. liver cirrhosis, non-alcoholic steatohepatitis ("NASH")),

eye (e.g. glaucoma, corneal scarring),

skeletal muscle (e.g. muscular dystrophies, including Duchenne, Becker, limb-girdle, congenital, facioscapulohumeral, myotonic, oculopharyngeal, distal, and Emery-Dreifuss), skin (e.g. keloids, wound healing, adhesions, hypertrophic scarring and other scarring, e.g., associated with burns, surgery or other trauma),

the vasculature (e.g. stroke, and collagen vascular diseases such as systemic lupus erythematosus, rheumatoid arthritis and scleroderma), and

the nervous system (e.g. spinal cord injury, multiple sclerosis).

In some embodiments, the disease associated with BMP1 , TLL1 and/or TLL2 activity is selected from muscular diseases characterized by reduced muscle function and/or mass, e.g., muscular dystrophy (e.g., Duchenne, Becker, limb-girdle, congenital,

facioscapulohumeral, myotonic, oculopharyngeal, distal, and Emery-Dreifuss), sarcopenia, and cachexia associated with, e.g., heart failure, CKD, COPD, cancer, or old age.

Accordingly, this invention provides a method of treating a disease associated with BMP1 , TLL1 and/or TLL2 activity in a subject in need thereof (e.g. a human or other mammal, particularly a human), for example the diseases recited herein, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a salt thereof, particularly a pharmaceutically acceptable salt thereof.

In some embodiments, a compound of the invention is administered post-MI (i.e. to a subject who has suffered an Ml), e.g. to treat fibrosis associated with myocardial infarction.

In some embodiments, a compound of the invention is administered post-MI, e.g. to prevent fibrosis associated with myocardial infarction.

In some embodiments, the method of treating comprises administering a specific compound described herein, e.g., a compound of the Examples, or any alternative stereoisomer, free acid/base form, salt form, or alternative salt form (particularly

pharmaceutically acceptable salts or alternative pharmaceutically acceptable salt forms) thereof, as applicable.

In some embodiments, the method of treating comprises administering (S)-2-(5-ethoxy-3'- ((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methy l)carbamoyl)-[1 , T-biphenyl]- 3-ylcarboxamido)succinic acid; (S)-2-(2-(carboxymethoxy)-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzamido)succinic acid; or (3-ethoxy-5-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)he ptanamido)methyl) carbamoyl)pyridin-2-yl)phenyl)phosphonic acid. In some embodiments, the method of treating comprises administering a pharmaceutically acceptable salt of (S)-2-(5-ethoxy-3'- ((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methy l)carbamoyl)-[1 , T-biphenyl]- 3-ylcarboxamido)succinic acid; (S)-2-(2-(carboxymethoxy)-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzamido)succinic acid; or (3-ethoxy-5-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)he ptanamido)methyl) carbamoyl)pyridin-2-yl)phenyl)phosphonic acid.

This invention also provides a compound of Formula (I), or a salt thereof, particularly a pharmaceutically acceptable salt thereof, for use in therapy. This invention specifically provides for the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as an active therapeutic substance in the treatment of a disease associated with BMP1 , TLL1 and/or TLL2 activity, for example the diseases recited herein.

In some embodiments, the compound for use in therapy, e.g. for use in the treatment of a disease associated with BMP1 , TLL1 and/or TLL2 activity, is a specific compound described herein, e.g., a compound of the Examples, or any alternative stereoisomer, free acid/base form, salt form, or alternative salt form (particularly pharmaceutically acceptable salts or alternative pharmaceutically acceptable salt forms) thereof, as applicable.

In some embodiments, the compound for use in therapy is (S)-2-(5-ethoxy-3'-((((R)-2- ((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl)carbamo yl)-[1 ,1 '-biphenyl]-3- ylcarboxamido)succinic acid; (S)-2-(2-(carboxymethoxy)-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzamido)succinic acid; or (3-ethoxy-5-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)he ptanamido)methyl) carbamoyl)pyridin-2-yl)phenyl)phosphonic acid. In some embodiments, the compound for use in therapy is a pharmaceutically acceptable salt of (S)-2-(5-ethoxy-3'-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 , T-biphenyl]-3- ylcarboxamido)succinic acid; (S)-2-(2-(carboxymethoxy)-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzamido)succinic acid; or (3-ethoxy-5-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)he ptanamido)methyl) carbamoyl)pyridin-2-yl)phenyl)phosphonic acid.

The invention also provides for the use of a compound of Formula (I), or a salt thereof, particularly a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a disease associated with BMP1 , TLL1 and/or TLL2 activity, for example the diseases recited herein.

In some embodiments, the invention provides for the use of a specific compound described herein, e.g., a compound of the Examples, or any alternative stereoisomer, free acid/base form, salt form, or alternative salt form (particularly pharmaceutically acceptable salts or alternative pharmaceutically acceptable salt forms) thereof, as applicable, in the manufacture of a medicament for use in the treatment of a disease associated with BMP1 , TLL1 and/or TLL2 activity.

In some embodiments, the invention provides for the use of (S)-2-(5-ethoxy-3'-((((R)- 2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl)carba moyl)-[1 , T-biphenyl]-3- ylcarboxamido)succinic acid; (S)-2-(2-(carboxymethoxy)-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzamido)succinic acid; or (3-ethoxy-5-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)he ptanamido)methyl) carbamoyl)pyridin-2-yl)phenyl)phosphonic acid, in the manufacture of a medicament for use in the treatment of a disease associated with BMP1 , TLL1 and/or TLL2 activity. In some embodiments, the invention provides for the use of a pharmaceutically acceptable salt of (S)- 2-(5-ethoxy-3'-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)he ptanamido)methyl)carbamoyl)- [1 , T-biphenyl]-3-ylcarboxamido)succinic acid; (S)-2-(2-(carboxymethoxy)-4-(6-((((R)-2-((R)- 1-(N-hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)py ridin-2- yl)benzamido)succinic acid; or (3-ethoxy-5-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl) carbamoyl)pyridin-2-yl)phenyl)phosphonic acid, in the manufacture of a medicament for use in the treatment of a disease associated with BMP1 , TLL1 and/or TLL2 activity.

Treatment of a disease associated with BMP1 , TLL1 and/or TLL2 activity may be achieved using a compound of this invention as a monotherapy, or in dual or multiple combination therapy. For example, the compounds of this invention may be administered in combination with one or more therapeutically active agents selected from the group consisting of: anticoagulants, angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta('^")-blockers, aldosterone antagonists, diuretics,

vasodilators, cholesterol-lowering drugs (e.g., statins, fibrates, niacin, resins), statins, platelet antagonists, anti-arrhythmics, calcium channel blockers, erythropoiesis-stimulating agents (ESAs), iron, beta agonists, inhaled or oral steroids, anticholinergics, theophylline, PDE4 inhibitors, antibiotics, other antifibrotic agents, PDE5 inhibitors, immune modulators, neprilysin inhibitors, and digitalis preparations, e.g., any such agents as are known in the art, and combinations thereof. Particular therapeutic agents in these classes include those in the United States Pharmacopeia (USP). It will be understood that a particular active agent may fall within one or more of the foregoing classes. Such agents may be administered in therapeutically effective amounts, e.g., as is known in the art, or lesser or greater amounts than known in the art provided that the amount administered is therapeutically effective.

For example, treatment of cardiac diseases may include administration of one or more agents selected from the group: anticoagulants, ACE inhibitors, ARBs, β-blockers, aldosterone antagonists, diuretics, vasodilators (e.g. nitrates), cholesterol lowering drugs (e.g., statins, fibrates, niacin, resins), platelet antagonists, anti-arrhythmics, calcium channel blockers, neprilysin inhibitors, digitalis preparations, and combinations thereof. In particular embodiments, treatment of atrial fibrillation, heart failure, or hypertrophic cardiomyopathy may comprise administration of one or more such agents.

As another example, treatment of CKD may include administration of one or more agents selected from ESAs, iron, ACE inhibitors, ARBs, β-blockers, diuretics, calcium channel blockers, statins, and combinations thereof.

In other exemplary embodiments, treatment of COPD may include administration of one or more agents selected from the group: beta agonists, inhaled or oral steroids, anticholinergics, theophylline, PDE4 inhibitors, antibiotics, and combinations thereof.

For example, idiopathic pulmonary fibrosis may include administration of one or more agents selected from the group: antifibrotics, PDE5 inhibitors, immune modulators, and combinations thereof.

Particular examples of other therapeutically active agents which may be used in combination with one or more compounds of the invention, for example to treat cardiac diseases, include:

anticoagulants such as: dalteparin (FRAGMIN), danaparoid (ORGARAN), enoxaparin (LOVENOX), heparin, tinzaparin (INNOHEP), warfarin (COUMADIN), alteplase, aspirin, ardeparin, fondaparinux, lepirudin, desirudin, bivalirudin, urokinase, rivaroxaban, apixaban, dabigatran, argatroban;

ACE inhibitors such as benazepril (LOTENSIN), captopril (CAPOTEN), enalapril (VASOTEC), fosinopril (MONOPRIL), lisinopril (PRINIVIL, ZESTRIL), moexipril (UNIVASC), perindopril (ACEON), quinapril (ACCUPRIL), Ramipril (ALTACE), trandolapril (MAVIK), imidapril; ARBs such as candesartan (ATACAND), eprosartan (TEVETEN), irbesartan (AVAPRO), losartan (COZAAR), telmisartan (MICARDIS), valsartan (DIOVAN), olmesartan, azilsartan;

beta-blockers such as acebutolol (SECTRAL), atenolol (TENORMIN), betaxolol (KERLONE), bisoprolol/hydrochlorothiazide (ZIAC), bisoprolol (ZEBETA), carteolol

(CARTROL), metoprolol (LOPRESSOR, TOPROL XL), nadolol (CORGARD), propranolol (INDERAL), sotalol (BETAPACE), timolol (BLOCADREN);

aldosterone antagonists such as spironolactone, eplerenone, Canrenone

(canrenoate potassium), Prorenone (prorenoate potassium), Mexrenone (mexrenoate potassium);

diuretics such as amiloride (MIDAMOR), bumetanide (BUMEX), chlorothiazide (DIURIL), chlorthalidone (HYGROTON), furosemide (LASIX), hydro-chlorothiazide

(ESIDRIX, HYDRODIURIL), indapamide (LOZOL), spironolactone (ALDACTONE), metolazone, torsemide, triamterene;

vasodilators such as nitroglycerin, isosorbide dinitrate (ISORDIL), isosorbide mononitrate, nesiritide (NATRECOR), hydralazine (APRESOLINE)

cholesterol-lowering drugs, e.g., statins, such as atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, including combination products, such as ADVICOR (lovastatin/niacin extended-release), SIMCOR (simvastatin/niacin extended- release), and VYTORIN (simvastatin/ezetimibe); nicotinic acid (niacin), fibrates such as gemfibrozil (LOPID), fenofibrate (TRICOR, FIBRICOR), clofibrate;

platelet antagonists such as aspirin, ticlopidine, clopidogrel (PLAVIX), dipyridamole; anti-arrhythmics such as quinidine, procainamide, disopyramide, lidocaine, phenytoin, mexiletine, tocainide, encainide, flecainide, propafenone, moricizine, carvedilol, propranolol, esmolol, timolol, metoprolol, atenolol, bisoprolol, amiodarone, sotalol, ibutilide, dofetilide, dronedarone, verapamil, diltiazem, adenosine, digoxin, magnesium sulfate;

calcium channel blockers, such as amlodipine (NORVASC, LOTREL), bepridil (VASCOR), diltiazem (CARDIZEM, TIAZAC), felodipine (PLENDIL), nifedipine (ADALAT, PROCARDIA), nimodipine (NIMOTOP), nisoldipine (SULAR), verapamil (CALAN, ISOPTIN, VERELAN), isradipine, nicardipine;

neprilysin inhibitors such as sacubitril, including, e.g., a combination of sacubitril and valsartan, such as LCZ696;

digitalis preparations such as digoxin, digitoxin.

Combination therapy includes administration of the therapeutically active agents ' separate dosage forms or together in a single dosage form. Combination therapy may involve simultaneous administration or separate administration of the therapeutically active agents, which may be substantially simultaneous or substantially separate administration. Typically, combination therapy will involve administration of each agent such that therapeutically effective amounts of each agent are present in the subject's body in at least an overlapping period.

In some embodiments, combination therapy comprises administering a specific compound described herein, e.g., a compound of the Examples, or any alternative stereoisomer, free acid/base form, salt form, or alternative salt form (particularly

pharmaceutically acceptable salts or alternative pharmaceutically acceptable salt forms) thereof, as applicable, and one or more additional therapeutically active agents.

In some embodiments, combination therapy comprises administering (S)-2-(5- ethoxy-3'-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptana mido)methyl)carbamoyl)-[1 , T- biphenyl]-3-ylcarboxamido)succinic acid; (S)-2-(2-(carboxymethoxy)-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzamido)succinic acid; or (3-ethoxy-5-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)he ptanamido)methyl) carbamoyl)pyridin-2-yl)phenyl)phosphonic acid, and one or more additional therapeutically active agents. In some embodiments, combination therapy comprises administering a pharmaceutically acceptable salt of (S)-2-(5-ethoxy-3'-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 , T-biphenyl]-3- ylcarboxamido)succinic acid; (S)-2-(2-(carboxymethoxy)-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzamido)succinic acid; or (3-ethoxy-5-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)he ptanamido)methyl) carbamoyl)pyridin-2-yl)phenyl)phosphonic acid, and one or more additional therapeutically active agents.

Accordingly, the present invention provides a composition comprising a) a compound of formula (I) or a pharmaceutically acceptable salt thereof and b) a combination partner. As used herein, suitable combination partners include one or more other therapeutically active agents such as those described above by classification or more particularly.

The present invention further provides a method for treating a disease associated with BMP1 , TLL1 and/or TLL2 activity in a subject (e.g. a human or other mammal, particularly a human) in need thereof comprising administering to said subject a

therapeutically effective amount of a) a compound of formula (I) or a pharmaceutically acceptable salt thereof and b) a combination partner. The individual components of the combination may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route. The invention further provides a combination of a) a compound of formula (I) or a pharmaceutically acceptable salt thereof and b) a combination partner.

In the compositions, methods and combinations of the invention comprising a combination partner, suitable combination partners include other therapeutically active agents such as described above by classification or more particularly.

In some embodiments of the compositions, methods and combinations of the inventions comprising a combination partner, the compound of formula (I) or a

pharmaceutically acceptable salt thereof is a specific compound described herein, e.g., a compound of the Examples, or any alternative stereoisomer, free acid/base form, pharmaceutically acceptable salt form or alternative pharmaceutically acceptable salt form thereof, as applicable; in various more particular embodiments the compound of formula (I) or a pharmaceutically acceptable salt thereof is (S)-2-(5-ethoxy-3'-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 , T-biphenyl]-3- ylcarboxamido)succinic acid; (S)-2-(2-(carboxymethoxy)-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzamido)succinic acid; (3-ethoxy-5-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)he ptanamido)methyl) carbamoyl)pyridin-2-yl)phenyl)phosphonic acid; or a pharmaceutically acceptable salt thereof.

A "therapeutically effective amount" is intended to mean that amount of a compound that, when administered to a subject in need of such treatment, is sufficient to effect treatment, as defined herein. Thus, for example, a therapeutically effective amount of a compound of the invention, e.g. a compound of Formula (I) or a pharmaceutically acceptable salt thereof, is a quantity of such agent that, when administered to a subject (e.g., human) in need thereof, is sufficient to modulate or inhibit the activity of BMP1 , TLL1 and/or TLL2 such that a disease condition which is mediated or inhibited by that activity is reduced, alleviated or prevented. The amount of a given compound that will correspond to such an amount will vary depending upon factors such as the particular compound (e.g., the potency (plC 50 ) and the biological half-life of the particular compound), disease condition and its severity, and the identity (e.g., age, size and weight) of the subject in need of treatment, but can nevertheless be routinely determined by one skilled in the art. Likewise, the duration of treatment and the time period of administration (time period between dosages and the timing of the dosages, e.g., before/with/after meals) of the compound will vary according to the identity of the subject in need of treatment (e.g., weight), the particular compound and its properties (e.g., pharmaceutical characteristics), disease and its severity and the specific composition and method being used, but can nevertheless be determined by one of skill in the art. In some embodiments, 0.1 mg to 1000 mg (e.g., 0.1 - 500 mg, or 0.1 - 100 mg) of a compound of the invention, particularly a compound of Formula (I) or a pharmaceutically acceptable salt thereof, is administered at a frequency of twice a day, once a day, once a week, or frequencies therebetween. In some embodiments, a compound of the invention, particularly a compound of Formula (I) or a pharmaceutically acceptable salt thereof, is administered sub-cutaneously in an amount of less than 100 mg per dose (e.g., 0.1 - <100 mg per dose).

"Treat", "treating" or "treatment" is intended to mean at least the mitigation of a disease in a subject. The methods of treatment for mitigation of a disease include the use of the compounds in this invention in any conventionally acceptable manner, for example for prevention, retardation, prophylaxis, therapy, improvement or cure of a disease. Thus, treatment may involve at least the mitigation of one or more symptoms of a disease.

Specific diseases that may be particularly susceptible to treatment using a compound of this invention include those described herein.

The compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation. Oral administration includes enteral (digestive tract) and buccal or sublingual administration. Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion into tissue or blood. Parenteral administration includes intravenous, intramuscular, subcutaneous, intradermal, and transdermal implant injection or infusion. Inhalation refers to administration into the subject's lungs whether inhaled through the mouth or through the nasal passages. Topical administration includes application to the skin.

For use in therapy, the compounds of the invention will be normally, but not necessarily, formulated into a pharmaceutical composition prior to administration to a subject. Accordingly, the invention also is directed to pharmaceutical compositions comprising a compound of the invention, particularly a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

The pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein an effective amount of a compound of the invention can be extracted and then given to the subject such as with powders, syrups, and solutions for injection.

Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form. For oral application, for example, one or more tablets or capsules may be administered. A dose of the pharmaceutical composition contains at least a therapeutically effective amount of a compound of this invention (i.e., a compound of Formula (I), or a salt, particularly a pharmaceutically acceptable salt, thereof). When prepared in unit dosage form, the pharmaceutical compositions may contain from 0.1 mg to 1000 mg (e.g., 0.1 - 500 mg, or 0.1 - 100 mg) of a compound of this invention.

The pharmaceutical composition may include one or more compounds of the invention and/or one or more pharmaceutically acceptable excipients. The pharmaceutical compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. In addition, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds, e.g., the therapeutically active agents described above by classification or more particularly.

In some embodiments, the pharmaceutical composition comprises a) 0.01-100 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof and b) 0.001-900 mg of one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises a) 0.01-100 mg/mL of a compound of formula (I) or a pharmaceutically acceptable salt thereof and b) 0.001-900 mg/mL of one or more

pharmaceutically acceptable excipients.

In some embodiments, the pharmaceutical composition comprises a specific compound described herein, e.g., a compound of the Examples, or any alternative stereoisomer, free acid/base form, pharmaceutically acceptable salt form, or alternative pharmaceutically acceptable salt form thereof, as applicable.

In some embodiments, the pharmaceutical composition comprises (S)-2-(5-ethoxy-3'- ((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methy l)carbamoyl)-[1 , T-biphenyl]- 3-ylcarboxamido)succinic acid; (S)-2-(2-(carboxymethoxy)-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzamido)succinic acid; or (3-ethoxy-5-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)he ptanamido)methyl) carbamoyl)pyridin-2-yl)phenyl)phosphonic acid, and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of (S)-2-(5-ethoxy-3'-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 , T-biphenyl]-3- ylcarboxamido)succinic acid; (S)-2-(2-(carboxymethoxy)-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzamido)succinic acid; or (3-ethoxy-5-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)he ptanamido)methyl) carbamoyl)pyridin-2-yl)phenyl)phosphonic acid, and one or more pharmaceutically acceptable excipients.

As used herein, "pharmaceutically acceptable excipient" means a material, composition or vehicle other than a pharmaceutical active ingredient(s) intended for treating a disease (e.g., a compound of the invention). Pharmaceutically acceptable excipients are involved in providing a property or function useful to a pharmaceutical composition, for example an excipient may be involved in modifying physical, sensory, stability, or pharmaco-kinetic properties of the composition, for example in giving form or consistency to the composition, in bulking up the active ingredient (e.g. for convenient and accurate dispensation), in enhancing therapy (e.g. facilitating drug absorption or solubility, or other pharmacokinetic properties), in the manufacturing process (e.g. as a handling or processing aid), in stabilizing the composition, or in enhancing subject compliance (e.g., enhancing palatability or appearance of the composition). Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention (or any other active ingredient, if present) when administered to a subject and interactions which would result in pharmaceutical compositions that are sufficiently high purity to render it

pharmaceutically acceptable.

The compounds of the invention and the pharmaceutically acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the subject by the desired route of administration. Conventional dosage forms include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, lozenges, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, lyophiles, microparticles, nanocarriers, implants, preformed implants and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as aerosols and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, gels, dermal patches, and transdermal patches or sprays.

Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically acceptable excipients may be chosen for their ability to: facilitate the production of uniform dosage forms, to facilitate the production of stable dosage forms, to facilitate the carrying or transporting the compound or compounds of the invention once administered to the subject from one organ, or portion of the body, to another organ, or portion of the body, and/or to enhance subject compliance.

Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, carriers, and buffering agents. The skilled artisan will appreciate that certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.

Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically acceptable excipients and may be useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press), including current and past editions.

The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

In one aspect, the invention is directed to a solid oral dosage form such as a tablet or capsule comprising an effective amount of a compound of the invention and a diluent or filler, and optionally a binder, disintegrant, and/or lubricant. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. Suitable binders include starch (e.g. corn starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline cellulose). Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.

In another aspect, the invention is directed to a parenteral formulation, e.g., in-situ gels, microspheres, nanospheres, nanosuspensions, or lyophilized products to control the release of a compound following subcutaneous and/or intramuscular administration, comprising a compound of the invention, a surfactant and/or a polymeric carrier and/or a solubilising excipient and/or an excipient to control osmolality. Suitable surfactants include polysorbates, polyvinyl alcohol, polyvinyl pyrrolidone and combinations thereof. Suitable polymeric carriers include polyethylene glycol, polymethacrylate, ethylene vinyl acetate copolymer, polyglactin, polyoxyethylene fatty acid esters, poly(lactic-co-glycolic acid), poly(epsilon-caprolactone), poly(p-dioxanone), poly(anhydride esters) and combinations thereof. Suitable solubilising excipients include n-methyl pyrollidone, polyethoxylated castor oil (e.g., CREMOPHOR such as CREMOPHOR EL), polysorbates, Solutol® (Macrogol 15 Hydroxystearate Ph. Eur; Polyoxyl 15 Hydroxystearate USP), ethanol and combinations thereof. Suitable excipients to control osmolality (and in the case of lyophiles, to bulk the lyophilized material) include mannitol, sucrose, glycine, and polyvinyl pyrrolidone.

In-situ gels can be prepared by solubilising a compound of the invention in solvent phase and water-insoluble polymeric carrier(s). The solution is then sterilized, e.g., by gamma irradiation.

Nanosuspensions or micron-sized suspensions can be prepared by combining a compound of the invention, a surfactant, a polymeric carrier and an excipient to control osmolality in aqueous phase, then bead milling or microfluidising the combination in aqueous phase to deliver particles of the compound sized less than 5 μηι, e.g., less than 1 μηι, or e.g., between 100nm to less than 5 μηι or to less than 1 μηι. The nanosuspension is sterilized, e.g., by utilizing terminal heat sterilization or gamma irradiation techniques.

Microspheres and nanospheres can be prepared by various methods known in the art including water/oil/water emulsion methods, solvent/oil/water emulsion methods, oil/water emulsion methods, organic phase separation or melt extrusion/cryomilling techniques which involve inclusion of the compound of the invention and polymer(s) to control drug delivery. The particles are delivered to less than 100μηι for microspheres and between 100nm to less than 1 μηι for nanospheres. The microspheres and nanospheres can go through further processing, including lyophilization, and require sterilization, e.g., through gamma irradiation.

A lyophilized product may suitably include a compound of the invention in a concentration of from 0.01 - 100 mg/mL, a surfactant, a polymeric carrier, and a solubilizing excipient. General conditions to provide a lyophilized product involve forming a solution or suspension of the product ingredients, reducing the solution or suspension below the glass transition, providing differential pressure to pull off aqueous and/or solvent phase, and slowly increasing temperature to form a lyophilized cake. EXAMPLES

The following examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present invention. While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention.

It will be understood by the skilled artisan that purification methods (using acidic or basic modifiers) or compound workup procedures (using acidic or basic conditions) may result in formation of a salt of a title compound (for example, hydrobromic acid, formic acid, hydrochloric acid, trifluoroacetic acid, or ammonia salts of a title compound). The present invention is intended to encompass such salts. In the Examples the parent compound is depicted structurally.

In the following experimental descriptions, the following abbreviations may be used:

DIPEA, DIEA,

N,N-diisopropylethylamine

Hunig's base

DMAP 4-dimethylaminopyridine

DMF N,N-dimethylformamide

DME dimethoxyethane

DMSO dimethylsulfoxide

1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide

EDC

hydrochloride

Et ethyl

Et 3 N triethylamine

Et 2 0 diethyl ether

EtOAc ethyl acetate

EtOH ethanol

Fmoc or fmoc fluorenylmethyloxycarbonyl

g, G, gm, GM gram

h or hr hour(s)

H 2 hydrogen

H 2 0 2 hydrogen peroxide

H 2 0 water

H2SO4 sulfuric acid

(0-(7-azabenzotriazol- 1 -yl)- N , N , N ', N '-tetramethyl uronium

HATU

hexafluorophosphate)

2-(1 H-benzo[d][1 ,2,3]triazol-1-yl)-1 ,1 ,3,3-

HBTU

tetramethylisouronium hexafluorophosphate(V)

HCI hydrochloric acid

HC0 2 H formic acid

HOBt or HOBT 1 -hydroxybenzotriazole

HPLC high performance liquid chromatography

l 2 Iodine

JLR jacketed lab reactor

K2CO3 potassium carbonate KHS04 potassium hydrogen sulfate

KOAc potassium acetate

L or l liter

LAH lithium aluminum hydride

LCMS liquid chromatography-mass spectroscopy

LDA lithium diisopropyl amide

LiOH lithium hydroxide

LHMDS lithium bis(trimethylsilyl)amide

Me methyl

MeOH methanol

mg, MG milligram

MgBr 2 magnesium bromide

MgS0 4 magnesium sulfate

min or mins minute(s)

ml or ml_ or ML milliliter

mmol millimole

Mn0 2 manganese dioxide

Mol, mol mole

MS mass spectrum

MTBE methyl tert-butyl ether

μνν microwave

N 2 nitrogen

Na(CN)BH 3 sodium cyanoborohydride

NaCI sodium chloride

Na 2 C0 3 sodium carbonate

NaHC0 3 sodium bicarbonate

NaHMDS sodium bis(trimethylsilyl)amide

NaHS0 3 sodium bisulfite

NaH sodium hydride Nal sodium iodide

NaOH sodium hydroxide

Na 2 S0 3 sodium sulfite

Na 2 S0 4 sodium sulfate

NH 4 CI ammonium chloride

HC0 2 « NH 4 ammonium formate

NH 4 OH ammonium hydroxide

NMO 4-methylmorpholine N-oxide

NMP N-methyl-2-pyrrolidone

Pd/C palladium on carbon

PdCI 2 (dbpf) 1 , 1 '-bis(di-tert-butylphosphino)ferrocene dichloropalladium

Pd(dppf)CI 2 / [1 ,1 '-bis(diphenylphosphino)ferrocene]

PdCI 2 (dppf) dichloropalladium(ll)

PdCI 2 (dppf)- [1 ,1 '-bis(diphenylphosphino)ferrocene]

CH 2 CI 2 adduct dichloropalladium(ll), complex with dichloromethane

Pd(Ph 3 ) 4 ,

tetrakis(triphenylphosphine)palladium(0) tetrakis

Pd(OAc) 2 palladium acetate

Pd(OH) 2 palladium hydroxide

[Bis(trifluoroacetoxy)iodo]benzene

PI FA

Ph phenyl

PL HCO3 MP macroporus polystyrene supported carbonate

POCI3 phosphoryl chloride

psi pounds per square inch

PTFE polytetrafluoroethylene

rt or RT room temperature

sat. saturated

SFC supercritical fluid chromatography

Si silica

Si SPE silica gel cartridges Si0 2 silica gel

SPE solid phase extraction

T3P® propylphosphonic anhydride

tBu or t-Bu tert-butyl group

TBAF tetrabutylammonium fluoride

TBAI tetrabutylammonium iodide

TBDMSCI tert-butyldimethylsilyl chloride

TBME tert-butyl methyl ether

TBTU 2-(1 H-benzotriazole-1-yl)-1 , 1 ,3,3-tetramethyluronium tetrafluoroborate

TEA triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

TiCI 4 titanium tetrachloride

TMS-Br or

trimethylsilyl bromide

TMSBr

TMS-CI or

trimethylsilyl chloride

TMSCI

TMS-OTf

trimethylsilyl triflate

or TMSOtf

tR retention time

UPLC ultra performance liquid chromatography

INTERMEDIATE 1

(R)-2-((N-(benzyloxy)formamido)methyl)heptanoic acid

Step 1 : formaldehyde O-benzyl oxime

A suspension of O-benzylhydroxylamine hydrochloride (308 g, 1930 mmol) in t- butylmethyl ether (1800 ml) was added to a solution of sodium hydroxide (93 g, 2316 mmol) in water (570 ml) via an addition funnel. The funnel was rinsed with water (15 ml) and the reaction stirred for 10 minutes. Formaldehyde (37 % wt in water, 150 ml, 2015 mmol) was then added via an addition funnel slowly over ~ 20 minutes. The funnel was rinsed with water (15 ml) and the reaction mixture was stirred at 25 °C for 3 hours. The layers were then separated and the organic phase washed with 0.2 N HCI (480 ml), 5 % NaHC0 3 solution (300 ml), and 10 % brine solution (480 ml). The organic layer was then separated and concentrated to give the title compound as a colorless oil (247 g, 90 % yield). MS (m/z) 136.1 (M+H + ).

Step 2: 2-(((benzyloxy)amino)methyl)heptanoic acid

Acetonitrile (1250 ml) and sodium iodide (931 g, 6213 mmol) were charged to a 6 I reactor vessel under nitrogen at room temperature. The mixture was stirred vigorously for 10 minutes and chlorotrimethylsilane (790 ml, 6224 mmol) was then added. After stirring at room temperature for 15 minutes, the reaction was cooled to 15 °C. Triethylamine (870 ml, 6242 mmol) was added. Heptanoic acid (264 ml, 1864 mmol) was then added slowly, maintaining the temperature below 35 °C. The addition funnel was rinsed with acetonitrile (50 ml). The mixture was stirred at room temperature for 15 minutes and formaldehyde O- benzyl oxime (247 g, 1827 mmol) was added. The addition funnel was rinsed with acetonitrile (120 ml). The reaction was stirred at room temperature for 17 hours. The reaction mixture was then cooled to 12 °C and quenched with a freshly prepared solution of sodium thiosulfate (491 g, 3107 mmol) in water (2250 ml) maintaining the temperature below 30 °C. The reaction was stirred for 20 minutes and the pH of the reaction was then adjusted with 6N HCI (330 ml, 1980 mmol) to pH ~4. After stirring for 10 minutes ethyl acetate (500 ml) was added. The mixture was stirred for 5 minutes and then the layers were separated. The aqueous layer was back extracted with ethyl acetate (1750 ml). The combined organic layers were washed with water (2 x 1250 ml) and 5 % brine (1250 ml) and then separated and concentrated to give 620 g of the crude product as a yellow oil. The crude residue was preabsorbed on silica and purified by flash chromatography (ISCO Torrent, 1.5 kg RediSep column, 1-5 % DCM/MeOH (6 runs)) to give three batches of the title compound: as a colorless oil (176 g, 35 % yield), as a white solid (206 g, 41 % yield) and as a colorless oil (8 g, 2 % yield). MS (m/z) 266.1 (M+H + ).

Step 3: 1-(benzyloxy)-3-pentylazetidin-2-one

A 6 I reactor was charged with toluene (1750 ml) and 2,6-dimethylpyridine (232 ml,

1990 mmol) under a stream of nitrogen. Phosphoryl trichloride (99 ml, 1061 mmol) was added and the mixture was heated to 50 °C. A solution of 2-

(((benzyloxy)amino)methyl)heptanoic acid (176 g, 663 mmol) in toluene (1050 ml) was added over 40 minutes while maintaining the temperature below 55 °C. The addition funnel was rinsed with toluene (100 ml). The reaction mixture was then stirred at 50 °C for 1 hour. The reaction mixture was then cooled to 20 °C and then drained. The reactor was rinsed with toluene (400 ml) and combined with the reaction mixture. The reactor was then charged with water (1600 ml) and Na 2 C0 3 (239 g, 2255 mmol). The reaction mixture was slowly added to the Na 2 C0 3 solution while maintaining the temperature below 35 °C. The addition vessel was rinsed with toluene (400 ml). The biphasic mixture was stirred at 35 °C for 30 minutes. The layers were left to separate, and the aqueous layer was drained. The organic phase was held at 3 °C overnight and warmed up to 35 °C the next morning before proceeding with the workup. The organic phase was washed sequentially with a mixed solution of concentrated HCI (123 ml) and 10 % brine (1400 ml) to prevent emulsion formation, 10 % brine solution (900 ml), 5 % NaHC0 3 solution (900 ml) stirring for 10 minutes and then 10 % brine solution (900 ml). The organic phase was separated and concentrated to give the crude product as a yellow oil. The crude residue was preabsorbed on silica and purified by flash chromatography (ISCO Torrent 1.5 kg RediSep column, DCM/MeOH 0-5 %) to afford the title compound as a yellow oil (87 g, 52 % yield). MS (m/z) 248.1 (M+H + ).

Step 4: (R)-1-(benzyloxy)-3-pentylazetidin-2-one

1-(benzyloxy)-3-pentylazetidin-2-one (220 g, 889 mmol) was subjected to chiral separation utilizing a SFC-70 Thar prep system. (Chiralpak AS-H column at room temperature, 15 % isopropanol, 50 g/min, 5 minute run time at a concentration of 250 mg/ml). Concentration of the appropriate fractions yielded two batches of the title compound (13.5 g, 53.5 mmol, 6.0 % yield, >96 % ee) and (87 g, 345 mmol, 38.8 % yield, 96 % ee). MS (m/z) 248.1 (M+H + ).

Step 5: (R)-2-(((benzyloxy)amino)methyl)heptanoic acid

To a suspension of (R)-1-(benzyloxy)-3-pentylazetidin-2-one (10.0 g, 40.4 mmol) in

THF (108 ml) and water (53.9 ml) was added a freshly prepared solution of lithium hydroxide (4.84 g, 202 mmol) in water (53.9 ml) in a dropwise fashion. The reaction was then stirred at room temperature for 18 hours. The reaction was then cooled to -5 °C and 1 M HCI was added dropwise until pH 5 was obtained. The reaction was extracted twice with ethyl acetate and the combined organic layers were then washed with brine, dried and concentrated to give the title compound as a thick clear oil which was used without further purification or characterization.

Step 6: (R)-2-((N-(benzyloxy)formamido)methyl)heptanoic acid

Formic acid (4.65 ml, 121 mmol) was added dropwise to a solution of CDI (19.7 g,

121 mmol) in DCM (79 ml) and stirred at room temperature for 45 minutes. A solution of (R)- 2-(((benzyloxy)amino)methyl)heptanoic acid (10.7 g, 40.4 mmol) in DCM (79 ml) was then added and the reaction stirred at room temperature for 2 hours. The reaction was partitioned with 1 M HCI and the organic layer was collected via hydrophobic frit and concentrated to give a thick yellow oil which was dissolved in the minimum amount of DCM and passed through a Si plug (250 g Silica, DCM, 50:50 DCM:ether and ether in 250 ml fractions).

Concentration of the cleanest fractions yielded the title compound as a clear oil (3.65 g, 97 % ee). Concentration of additional fractions yielded 8 g of an orange oil which was purified by flash chromatography (ISCO Companion, 120 g, 15-100 % ethyl acetate/hexanes) to give additional batches of the title compound as an orange oil (2.38 g, 97 % ee and 1.38 g, 97 % ee). MS (m/z) 294.1 (M+H + ).

INTERMEDIATE 2

(R)-2-((N-(benzyloxy)formamido)methyl)-4-phenylbutanoic acid

Step 1 : 4-phenylbutanoyl chloride

Oxalyl chloride (6 ml, 68.5 mmol) was added to a solution of 4-phenylbutanoic acid (7 g, 42.6 mmol) in DCM (207 ml) and a few drops of DMF at 0 °C. The reaction was allowed to warm to room temperature overnight then concentrated to give the title compound as a yellow oil which was used without further purification or characterization.

Step 2: (S)-4-benzyl-3-(4-phenylbutanoyl)oxazolidin-2-one

n-Butyllithium (2.7 M in heptanes, 16.7 ml, 45.2 mmol) was added dropwise to a solution of (S)-4-benzyloxazolidin-2-one (7.28 g, 41.1 mmol) in THF (91 ml) at -78 °C under N 2 . After stirring for 30 minutes at -78 °C, 4-phenylbutanoyl chloride (7.5 g, 41.1 mmol) was added and the reaction was stirred at -78 °C for 1.5 hours and then at 0 °C for 2 hours. NH 4 CI (150 ml) was then added and the mixture extracted with EtOAc (2 x). The combined organic layers were dried over Na 2 S0 4 , filtered and concentrated to give the title compound as white crystals (13.2 g, 99 % yield). MS (m/z) 324.2 (M+H + ).

Step 3: (S)-4-benzyl-3-((R)-2-((benzyloxy)methyl)-4-phenylbutanoyl)o xazolidin-2-one DIPEA (8.28 ml, 47.4 mmol) was added dropwise to a solution of (S)-4-benzyl-3-(4- phenylbutanoyl)oxazolidin-2-one (13.9 g, 43.1 mmol) and TiCI 4 (4.99 ml, 45.3 mmol) in DCM (122 ml) at 0 °C. After stirring at 0 °C for 1.5 hours ((chloromethoxy) methyl) benzene (1 1.99 ml, 86 mmol) was added and the reaction was stirred at 0 °C for 3 hours. The reaction was then quenched with water (150 ml) and extracted with DCM (2 x). The combined organic layers were separated, dried over MgS0 4 and concentrated. The residue was purified via flash chromatography (ISCO, 320 g column, hexanes: 5 minutes; 0-10 % EtOAc/hexanes: 15 minutes; 10-30 %: EtOAc/DCM: 5 minutes) to give the title compound as a clear oil (14.7 g, 77 % yield). MS (m/z) 444.2 (M+H + ). Step 4: (R)-2-((benzyloxy)methyl)-4-phenylbutanoic acid

A mixture of (S)-4-benzyl-3-((R)-2-((benzyloxy)methyl)-4-phenylbutanoyl)o xazolidin- 2-one (14.7 g, 33.0 mmol) in THF (78 ml) and water (25.9 ml) was treated with hydrogen peroxide (30 % in water, 27.0 ml, 264 mmol) followed by lithium hydroxide (1.58 g, 66.1 mmol) at 0 °C. The reaction was allowed to warm to room temperature overnight. The THF was removed under reduced pressure and the residue was extracted with DCM. The DCM layer was washed with water (2 x). The combined aqueous layers were then acidified to pH 3 via addition of 6 N HCI and then extracted with EtOAc (4 x). The combined ethyl acetate extracts were dried over Na 2 S0 4 , filtered and concentrated to give the title compound as a clear oil (9.5 g). MS (m/z) 267.1 (M-17 + ). Step 5: (R)-2-(hydroxymethyl)-4-phenylbutanoic acid

A solution of (R)-2-((benzyloxy)methyl)-4-phenylbutanoic acid (9.5 g, 33.4 mmol) in ethanol (130 ml) was added to Pd/C (2.94 g, 2.76 mmol) under N 2 and the reaction was subjected to hydrogenation in a Parr shaker at ~ 35 psi at room temperature overnight. The reaction was then filtered through a pad of Celite® and the filtrate concentrated to give the title compound as a clear oil (6.65 g). MS (m/z) 177.1 (M-17 + ).

Step 6: (R)-N-(benzyloxy)-2-(hydroxymethyl)-4-phenylbutanamide

EDC (6.56 g, 34.2 mmol) was added to a solution of (R)-2-(hydroxymethyl)-4- phenylbutanoic acid (6.65 g, 34.2 mmol), O-benzylhydroxylamine hydrochloride (5.46 g, 34.2 mmol), and DMAP (8.37 g, 68.5 mmol) in DCM (143 ml) at 0 °C and the reaction was allowed to warm to room temperature overnight. 1 N HCI (55 ml) was then added and the reaction was extracted with DCM (2 x). The combined organic extracts were dried over Na 2 S0 4 , filtered and concentrated to give the title compound as a white solid (9.52 g, 93 % yield). MS (m/z) 300.1 (M+H + ).

Step 7: (R)-1-(benzyloxy)-3-phenethylazetidin-2-one

DIAD (7.42 ml, 38.2 mmol) was added to a solution of (R)-N-(benzyloxy)-2- (hydroxymethyl)-4-phenylbutanamide (9.52 g, 31.8 mmol) and triphenylphosphine (10.0 g, 38.2 mmol) in THF (200 ml) at 0 °C and the reaction was allowed to warm to room temperature over 3.5 hours. Water (100 ml) was then added and the reaction was extracted with DCM (2 x). The combined organic layers were dried over MgS0 4 and concentrated. The residue was triturated with Et 2 0 (3 x) and the solid removed by filtration. The filtrate was concentrated and purified via flash chromatography (ISCO, 220 g column, 0-20 %

EtOAc/hexanes: 15 minutes, 20 % EtOAc/hexanes: 10 minutes) to give the title compound as a clear oil (5.06 g, 57 % yield). MS (m/z) 282.1 (M+H + ).

Step 8: (R)-2-(((benzyloxy)amino)methyl)-4-phenylbutanoic acid (R)-1-(benzyloxy)-3-phenethylazetidin-2-one (5.06 g, 18.0 mmol) in THF (54 ml), methanol (18 ml) and water (18 ml) was treated with lithium hydroxide (4.30 g, 180 mmol) at room temperature for 1.5 days. The volatiles were removed under reduced pressure and the residue was acidified to ~ pH 5-6 via addition of 6 N HCI. The mixture was extracted with EtOAc (2 x) and the combined organic layers were dried over Na 2 S0 4 , filtered and concentrated to give the title compound as a clear oil (5.7 g). MS (m/z) 300.1 (M+H + ). Step 9: (R)-2-((N-(benzyloxy)formamido)methyl)-4-phenylbutanoic acid

Formic acid (1.5 ml, 39.1 mmol) was added dropwise to a solution of CDI (6.3 g, 38.9 mmol) in DCM (320 ml) and the reaction was stirred for 40 minutes before a solution of (R)- 2-(((benzyloxy)amino)methyl)-4-phenylbutanoic acid (5 g, 16.7 mmol) in DCM (40 ml) was added dropwise. The reaction was stirred at room temperature for 2 hours and then washed quickly with 1 N HCI. The organic layer was separated, washed with water, dried over Na 2 S0 4 , filtered and concentrated to give the title compound as a sticky yellow oil (5.8 g). MS (m/z) 328.1 (M+H + ).

INTERMEDIATE 3

(R)-2-((R)-1-(N-(benzyl )propyl)heptanoic acid

Step 1 : (R)-4-benzyl-3-heptanoyloxazolidin-2-one

(R)-4-benzyloxazolidin-2-one (9.95 g, 56.2 mmol) was dissolved in dry THF (100 ml) and the mixture cooled in a dry-ice acetone bath. BuLi (2.7 M in hexanes, 20.8 ml, 56.2 mmol) was added over 5 minutes under nitrogen resulting in a color change to dark yellow. The color was titrated out by addition of HCI in dioxane, then re-treated with enough BuLi to turn the mixture slightly yellow. Heptanoyl chloride (8.87 ml, 57.3 mmol) was then added. The mixture was stirred for ~ 30 minutes and then additional heptanoyl chloride (3 ml) was added. The reaction was then quenched by slow addition of water (10 ml). Solid formation was noted, additional water was added to obtain a solution. EtOAc (300 ml) was added and the layers separated. The organic layer was washed with saturate aqueous sodium carbonate then dried over sodium sulfate, filtered and concentrated. The residue was dissolved in heptane, and then concentrated to a thick oil. The residue was dissolved in heptane (100 ml) and the mixture cooled in an acetone/dry ice bath with stirring. The resultant precipitate was collected by filtration and dried under vacuum overnight to give the title compound as a white solid (15.1g, 93 % yield) which was used without further purification or characterization. Step 2: (R)-4-benzyl-3-((R)-2-((S)-1-hydroxypropyl)heptanoyl)oxazoli din-2-one

To a solution of (R)-4-benzyl-3-heptanoyloxazolidin-2-one (15 g, 51.8 mmol) in DCM (300 ml) under N 2 in a ice-acetone bath was added TiCI 4 (6.00 ml, 54.4 mmol). DIPEA (9.96 ml, 57.0 mmol) was then slowly added followed by NMP (9.98 ml, 104 mmol) and the mixture stirred for 15 minutes. Propionaldehyde (7 ml, 95 mmol) was then added and the reaction stirred for 1.5 hours. The reaction was then quenched by addition of a solution of AcOH in DCM (15 ml of a 50:50 mix by volume). Aqueous Rochelles salt was added followed by aq. HCI (50 % v/v) to dissolve any solids. The layers were then separated and the aqueous phase extracted with additional DCM. The combined organic extracts were treated with aq. NaHS0 3 for 30 minutes then the layers allowed to settle in a separation funnel overnight. The organic layer was then separated and filtered through a plug of silica (~3 cm), the filtrates were combined, concentrated and dried under vacuum to give the title compound (19 g, 87 % yield) which was used without further purification.

Step 3: (R)-N-(benzyloxy)-2-((S)-1-hydroxypropyl)heptanamide

THF was boiled out of a 2 I JLR and the reactor purged with N 2 while cooling to room temperature. O-benzylhydroxylamine hydrochloride (16.0 g, 100 mmol) was added and the vessel purged with N 2 . THF (800 ml) was then added and the mixture cooled to 0 °C.

Trimethylaluminum (50 ml, 2 M in toluene, 100 mmol) was then added slowly. The white slurry was stirred for 15 minutes to obtain a clear solution. A solution of (R)-4-benzyl-3-((R)- 2-((S)-1-hydroxypropyl)heptanoyl)oxazolidin-2-one (18 g, 51.8 mmol) in THF (200 ml) was then added over 5 minutes via cannula and the mixture stirred for 1.5 hours at 0 °C. The reaction mixture was warmed to 5 °C. Separately, O-benzylhydroxylamine hydrochloride (5 g, 31 mmol) was dissolved in THF (100 ml) and treated with trimethylaluminum (17 ml, 2 M in toluene, 34 mmol) at 0 °C. The mixture was stirred until a solution was obtained and then added to primary reaction via cannula. The reaction was then quenched by the addition of sat. aq. KHS0 4 . A HCI solution (500 ml water, 500 ml cone. HCI) was added and the layers separated. The organic layer was reduced in volume and re-combined with the aqueous phase, the volatiles were removed via rotovap and a white precipitate formed. The solids were collected by filtration and washed with 10 % HCI then water. The filter cake was then washed with toluene (2 x 100 ml) and air dried to give the title compound (10.7 g, 70.1 % yield). MS (m/z) 294.3 (M+H + ).

Step 4: (3R,4R)-1-(benzyloxy)-4-ethyl-3-pentylazetidin-2-one

(R)-N-(benzyloxy)-2-((S)-1-hydroxypropyl)heptanamide (4.61 g, 15.7 mmol) was dissolved in pyridine (14 ml) and cooled in an ice bath. Methanesulfonyl chloride (2.45 ml,

31.4 mmol) was then added dropwise maintaining the internal temperature below 10 °C. The reaction was then stirred for 2 hours. The reaction was diluted by the addition of TBME (23 ml) and 1 M HCI (46 ml) was added while cooling was applied. After stirring briefly the layers were separated. The organic layer was washed with 1 M HCI (23 ml), sat. aq. NaHC0 3 (9 ml) and brine (9 ml) and then concentrated to minimum volume then dissolved in acetone (46 ml). K 2 C0 3 (6.51 g, 47.1 mmol) was added and the reaction heated at 50 °C for 1 hour. The reaction was then cooled to room temperature and filtered. The flask and filter cake were rinsed with acetone (2 x 23 ml). The filtrate was concentrated give the title compound (4.26 g) which was used without further purification.

Step 5: (R)-2-((R)-1-((benzyloxy)amino)propyl)heptanoic acid

(3R,4R)-1-(benzyloxy)-4-ethyl-3-pentylazetidin-2-one (356 g, 1.27 mol) was dissolved in 2-methyltetrahydrofuran (3560 ml). Tetrabutylammonium hydroxide (40 % aqueous solution, 1245 ml, 1.90 mol) was added. The reaction was heated to 50 °C for 2 hours and then cooled to room temperature. The reaction was diluted with water (1780 ml) and acidified with 6 M HCI (338 ml) to pH 3-4. The phases were separated and the organic phase was concentrated down to 5 volumes (1780 ml) which was used without further purification.

Step 6: (R)-2-((R)-1-(N-(benzyloxy)formamido)propyl)heptanoic acid

Carbonyldiimidazole (822 g, 5.07 mol) was suspended in 2-methyltetrahydrofuran (5340 ml) and cooled to 0 °C. Formic acid (88 %, 276 ml, 6.33 mol) was added dropwise via addition funnel. The reaction was stirred at 5 °C for 10 minutes and then warmed to room temperature for an additional 30 minutes. The reaction was cooled back to 5 °C and (R)-2- ((R)-1-((benzyloxy)amino)propyl)heptanoic acid acid in 2-methyltetrahydrofuran (1780 ml solution from previous step) was added. The reaction was warmed to room temperature and stirred for 40 minutes. In a separate vessel, carbonyldiimidazole (279 g, 1.72 mol) was suspended in 2-methyltetrahydrofuran (1500 ml) and cooled to 0 °C. Formic acid, (88 %, 93.8 ml, 2.16 mol) was added dropwise via addition funnel and stirred at 5 °C for 10 minutes and then warmed to room temperature for an additional 30 minutes. This mixture was then added dropwise via addition funnel to the original reaction at 5 °C. The reaction was warmed to room temperature and stirred for 60 minutes. The reaction was then cooled to 10 °C and quenched by addition of NaOH (4 M, 2122 ml) to pH 9. The phases were separated and the organic phase was washed with a 1 : 1 mixture (v/v) of 6 M HCI and brine (4561 ml). The phases were separated and the organic phase was concentrated to 3.5 volumes (1246 ml) to give the title compound as a 30 % by weight solution in 2-methyltetrahydrofuran (1.15 kg, equates to 346 g of crude title product).

Steps 5 and 6 were repeated with (3R,4R)-1-(benzyloxy)-4-ethyl-3-pentylazetidin-2- one (365 g) scale to provide a second batch (R)-2-((R)-1-(N-

(benzyloxy)formamido)propyl)heptanoic acid as a 36 % by weight solution in 2- methyltetrahydrofuran (1.09 kg, equates to 363 g of crude title product). This process (steps 5 and 6) was repeated again on 20 g scale to provide (R)-2-((R)-1-(N- (benzyloxy)formamido)propyl)heptanoic acid as a 30 % by weight solution in 2- methyltetrahydrofuran (66 g, equates to 19.8 g of crude title product).

The 30 % by weight solution of crude title compound in 2-methyltetrahydrofuran (1.15 kg, 346 g crude) was concentrated, azeotroped three times with hexanes and then diluted with hexanes (2500 ml). The solution was seeded with crystals obtained from a previous SFC purification. Nitrogen was then passed over the solution with stirring overnight. The resulting crystalline material was broken up, diluted with hexanes and stirred at room temperature for 30 minutes then filtered to give the title compound as a light yellow crystalline solid (275 g).

The 36 % (1.09 kg, 363 g crude) and 30 % (66.04 g, 19.8 g crude) by weight solutions of crude title compound were concentrated, azeotroped three times with methanol and combined with the filtrate from the initial 30 % by weight batch. The residue was diluted with methanol to a concentration of 200 mg/ml and purified by SFC (Thar SFC-70, DEAP column, 5 μΜ, 30 x 250 mm, i.d., eluting with 35 % isocratic methanol co-solvent, 60 g/min, 7 minute run) to give the title compound as a yellow oil. The oil was diluted with hexanes (2500 ml) and the solution seeded with crystals obtained from previous isolates. Nitrogen was passed over the solution with stirring overnight. The resulting crystalline material was broken up, diluted with hexanes, and stirred at room temperature for 30 minutes then filtered to give the title compound as a light yellow crystalline solid (360 g). MS (m/z) 322.0 (M+H + ).

INTERMEDIATE 4

(2R,3R)-3-(N-(benzyloxy)formamido)-2-phenethylpentanoic acid

Intermediate 4 was prepared from 4-phenylbutanoyl chloride by methods analogous to that described for Intermediate 3. MS (m/z)

Step Name

(M+H + )

1 (R)-4-benzyl-3-(4-phenylbutanoyl)oxazolidin-2-one 324.1

(R)-4-benzyl-3-((2R,3S)-3-hydroxy-2-

2 382.1 phenethylpentanoyl)oxazolidin-2-one

3 (2R,3S)-N-(benzyloxy)-3-hydroxy-2-phenethylpentanamide 328.1

4 (3R,4R)-1-(benzyloxy)-4-ethyl-3-phenethylazetidin-2-one 310.1

5 (2R,3R)-3-((benzyloxy)amino)-2-phenethylpentanoic acid 328.1

6 (2R,3R)-3-(N-(benzyloxy)formamido)-2-phenethylpentanoic acid 356.1

INTERMEDIATE 5

(R)-3-(N-(benzyloxy)formamido)-2-(cyclopentylmethyl)propanoi c acid

Intermediate 5 may be prepared according to procedures detailed for Intermediate A in WO2009061879, page 55.

INTERMEDIATE 6

fluoren-9-yl)methyl (aminomethyl)carbamate, trifluoroacetic acid salt

Step 1 : (9H-fluoren-9-yl)methyl (2-amino-2-oxoethyl)carbamate

A mixture of 2-aminoacetamide hydrochloride (231 g, 2.09 mol) in DCM (4 I) at 0 °C was treated with DIPEA (1.1 I, 6.27 mol) and then portionwise with (9H-fluoren-9-yl)methyl carbonochloridate (541 g, 2.09 mol). This mixture was stirred for 1 hour and was warmed to room temperature and then treated with water (2 I). The white precipitate was collected by filtration, then washed thoroughly with water, DCM, water and Et 2 0 and then air dried to give the title compound (618 g, 80 % yield) as a white solid. MS (m/z) 297.0 (M+H + ).

Step 2: (9H-fluoren-9-yl)methyl (aminomethyl)carbamate, trifluoroacetic acid salt

To a solution of [bis(trifluoroacetoxy)iodo]benzene (109 g, 253 mmol), water (800 ml), and THF (800 ml) was added (9H-fluoren-9-yl)methyl (2-amino-2-oxoethyl)carbamate (50 g, 169 mmol) and the mixture was stirred with an overhead stirrer for 60 minutes. Diethyl ether (1 I) and hexane (250 ml) were added and the layers were separated. The aqueous phase was washed with diethyl ether (600 ml). The combined organic extracts were concentrated to a total volume of 350 ml and hexanes (600 ml) was then added with stirring. The mixture was stirred for an additional 1.5 hours then the precipitate was collected via filtration to yield the title compound as an off white solid (32.8 g, 51 % yield). MS (m/z) 269.1 (M+H + ).

INTERMEDIATE 7

(R)-N-(aminomethyl)-2-((N-(benzyloxy)formamido)methyl)heptan amide

Step 1 : (R)-(9H-fluoren-9-yl)methyl -((N-(benzyloxy)formamido)methyl)heptanamido) methyl)carbamate

(R)-2-((N-(benzyloxy)formamido)methyl)heptanoic acid (1.13 g, 3.84 mmol) was dissolved in DMF (10.8 ml) and treated with HATU (1.46 g, 3.84 mmol). 9H-fluoren-9- yl)methyl (aminomethyl)carbamate hydrochloride (1.17 g, 3.84 mmol) was added followed by DIPEA (2.01 ml, 1 1.5 mmol). The reaction was allowed to stir at room temperature for 18 hours. The reaction was then diluted with EtOAc (100 ml) and water (50 ml). The layers were separated, and the aqueous phase was washed with EtOAc (50 ml). The combined organic extracts were washed with brine (1 x 20 ml), dried over MgS0 4 , filtered, and concentrated. The residue was purified by flash chromatography (120 g silica gel column, 30 % EtOAc/hexanes, 10 minutes; 30-50 % EtOAc/hexanes, 3 minutes; 50 % EtOAc/hexanes, 15 minutes) to yield the title compound as a white solid (1.4 g, 67.1 % yield). MS (m/z) 544.3 (M+H + ). Step 2: (R)-N-(aminomethyl)-2-((N-(benzyloxy)formamido)methyl)heptan amide

(R)-(9H-fluoren-9-yl)methyl((2-((N- (benzyloxy)formamido)methyl)heptanamido)methyl)carbamate (1.4 g, 2.6 mmol) was suspended in acetonitrile (12 ml) and treated at room temperature with morpholine (6 ml, 68.9 mmol). The reaction was allowed to stir at room temperature for 2 hours. A white solid formed which was collected by filtration and washed with ether. The combined filtrates were concentrated and the residue was purified by flash chromatography (40 g column, 100 % DCM, 5 minutes; 0-10 % MeOH/DCM, 12 minutes; 10 % MeOH/DCM, 5 minutes) to yield the title compound as a clear, colorless oil (0.66 g, 80 % yield) which was used without further purification.

INTERMEDIATE S

(R)-N-(aminomethyl)-2- -hydroxyformamido)methyl)heptanamide

To a solution of (R)-N-(aminomethyl)-2-((N- (benzyloxy)formamido)methyl)heptanamide (55 mg, 0.17 mmol) in EtOH (10 ml) was added Pd/C (10 % wt, Degussa wet, 30 mg). The reaction mixture was hydrogenated at room temperature for 30 minutes. The catalyst was removed by filtration, washing with EtOH. The solvent was evaporated under reduced pressure to give the title compound as a grey solid (40 mg, 80 % purity) which was used without further purification.

INTERMEDIATE 9

inomethyl)-3-(N-(benzyloxy)formamido)-2-(cyclopentylmethyl)p ropanamide

Step 1 : (R)-N-(2-amino-2-oxoethyl)-3-(N-(benzyloxy)formamido)-2- (cyclopentylmethyl)propanamide

A solution of (R)-3-(N-(benzyloxy)formamido)-2-(cyclopentylmethyl)propanoi c acid (2.23 g, 7.30 mmol), 2-aminoacetamide, hydrochloride (0.97 g, 8.76 mmol), HOBt (0.22 g, 1.46 mmol), EDC (4.20 g, 21.9 mmol) and DIPEA (6.38 ml, 36.5 mmol) in DMF (10 ml) and THF (10 ml) was stirred at room temperature for 18 hours. The reaction was diluted with

EtOAc and NH 4 CI, and extracted into EtOAc (3 x). The combined organics were washed with brine (2 x), dried over Na 4 S0 4 , filtered and concentrated. The residue was purified by flash chromatography (ISCO, 120 g column, 65 mm/min elution, 0-10 % MeOH/DCM over 45 min). The desired fractions were combined and concentrated to give the title compound (2.27 g, 6.28 mmol, 86 % yield). MS (m/z) 362.2 (M+H + ).

Step 2: (R)-N-(aminomethyl)-3-(N-(benzyloxy)formamido)-2-(cyclopenty lmethyl)propanamide

[Bis(trifluoroacetoxy)iodo]benzene (4.05 g, 9.42 mmol) was dissolved in acetonitrile (15.7 ml). To this solution was added water (15.7 ml) followed by (R)-N-(2-amino-2- oxoethyl)-3-(N-(benzyloxy)formamido)-2-(cyclopentylmethyl)pr opanamide (2.27 g, 6.28 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction was diluted with DCM and saturated NaHC0 3 , and extracted three times into DCM. The combined organics were washed twice with brine, dried over Na 2 S0 4 , filtered and concentrated. The residue was dissolved in MeOH, passed through a 20 g SCX column, washed with MeOH then 1 M Et 3 N in MeOH. The basic eluent was concentrated to give the title compound (1.45 g, 4.35 mmol, 69 % yield). INTERMEDIATE 10

inomethyl)-2-( -1-(N-hydroxyformamido)propyl)heptanarnide

Step 1 : (S)-4-benzyl-3-heptanoyloxazolidin-2-one

A solution of (S)-4-benzyloxazolidin-2-one (10.0 g, 56.4 mmol) in dry THF (166 ml) was cooled down to -78 °C before being treated with BuLi (2.5 M in hexane) (22.6 ml, 56.4 mmol) slowly under nitrogen. The resulting mixture was stirred at -78 °C for 1 hour before heptanoyl chloride (8.39 g, 56.4 mmol) was added in slowly. After being quenched with water (3 ml), the reaction was partitioned between brine (30 ml) and EtOAc (150 ml). The layers were separated and the organic layer was washed with brine (20 ml), dried over Na 2 S0 4 , and concentrated to a yellow oil. This oil was purified by flash chromatography (ISCO, 220 g column, 100 ml/min, 0-20 % EtOAc/Hexanes over 5 column volumes, then hold at 20 % EtOAc until all product eluted). Concentration of pure fractions gave the title compound as a clear oil (13.8 g, 47.7 mmol, 85 % yield). MS (m/z) 290.2 (M+H + ).

Step 2: (R)-1-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-pentylpentane-1 ,3-dione

A solution of (S)-4-benzyl-3-heptanoyloxazolidin-2-one (13.0 g, 44.9 mmol) in dry THF (200 ml) was cooled down to -78 °C before being treated with sodium

bis(trimethylsilyl)amide (51.7 ml, 51.7 mmol) slowly under nitrogen. The resulting mixture was stirred at -78 °C for 1 hour before propionyl chloride (5.40 g, 58.4 mmol) was added in slowly and the reaction mixture stirred for 3 hours. A solution of citric acid (~4 g in 20 ml water) was added quickly to quench the reaction. The solvent was removed under reduced pressure and the residue partitioned between EtOAc and water, washed with brine, dried over Na 2 S0 4 and filtered. Concentration of the filtrate provided the title compound as a yellow oil (16.5 g, 43.0 mmol, 96 % yield). MS (m/z) 346.2 (M+H + ).

Step 3: (S)-4-benzyl-3-((R)-2-((E)-1-((benzyloxy)imino)propyl)heptan oyl)oxazolidin-2-one

To a solution of (R)-1-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-pentylpentane-1 ,3-dione (16.5 g, 47.8 mmol) in ethanol (113 ml) and water (12.5 ml) was added sodium acetate (4.70 g, 57.3 mmol) and O-benzylhydroxylamine, hydrochloride (9.15 g, 57.3 mmol). The resulting suspension was stirred at room temperature all the weekend and filtered the next day. The solids were washed with 1 : 1 water: EtOH. The solids were a single isomer. The filtrate was concentrated, diluted with EtOAc and NaHC0 3 . The solids were joined to the filtrate, the EtOAc was separated, concentrated and purified by flash chromatography (ISCO, 330 g column, 0-20 % EtOAc/hexanes over 30 minutes). Two peaks were isolated: a single isomer (5.58 g, 12.4 mmol) and a mixture of two isomers (E/Z). The mixture of two isomers was collected to give the title compound (8.51 g, 18.9 mmol) that was used in the next step. MS (m/z) 451.3 (M+H + ).

Step 4: (4S)-4-benzyl-3-((2R)-2-(1-((benzyloxy)amino)propyl)heptanoy l)oxazolidin-2-one (S)-4-benzyl-3-((R)-2-((E)-1-((benzyloxy)imino)propyl)heptan oyl)oxazolidin-2-one (8.51 g, 18.9 mmol) was disolved in acetic acid (62.9 ml) and cooled to 0°C before sodium cyanoborohydride (1.20 g, 18.9 mmol) was added in one portion. After 5 minutes, additional sodium cyanoborohydride (1.19 g, 18.9 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 21 hours. The next day, the acetic acid was removed on the rotovap and the residue azeotroped with toluene. The resulting oil was disolved in EtOAc, washed with water, 1 M Na 2 C0 3 and brine. The organic layer was dried over Na 2 S0 4 , filtered and concentrated to give a pale yellow oil. The oil was purified by flash chromatography (ISCO, 330 g column, 10 - 25 % EtOAc/hexanes over 30 minutes) to obtain title compound (7.51 g, 14.9 mmol, 79 % yield). MS (m/z) 453.3 (M+H + ). Step 5: N-((4R)-4-((S)-4-benzyl-2-oxooxazolidine-3-carbonyl)nonan-3- yl)-N- (benzyloxy)formamide

To a solution of di-(1 H-imidazol-1-yl)methanone (10.8 g, 66.4 mmol) in DCM (94 ml) was added formic acid (3.18 ml, 83 mmol). The mixture was stirred for 1 hour before (4S)-4- benzyl-3-((2R)-2-(1-((benzyloxy)amino)propyl)heptanoyl)oxazo lidin-2-one (7.51 g, 16.6 mmol) in DCM (94 ml) was added. The resulting mixture was stirred 20 hours at room temperature. The reaction was diluted with DCM and NH 4 CI, and extracted three times into DCM. The combined organic layers were washed twice with brine, dried over Na 2 S0 4 , filtered and concentrated to give a pale yellow oil. The oil was purified by flash

chromatography (ISCO, 330 g column, 0 - 20 % EtOAc/hexanes over 30 minutes). Two peaks were isolated: a single isomer (1.89 g, 3.93 mmol, 23.7 % yield) and a mixture of two isomers. The mixture of two isomers was collected to give the title compound (4.37 g, 9.09 mmol, 54.8 % yield) that was used in the next step. MS (m/z) 481.3 (M+H + ).

Step 6: (R)-2-((R)-1-(N-(benzyloxy)formamido)propyl)heptanoic acid

N-((4R)-4-((S)-4-benzyl-2-oxooxazolidine-3-carbonyl)nonan-3- yl)-N-

(benzyloxy)formamide (4.37 g, 9.09 mmol) was dissolved in THF (74.8 ml) and water (15.0 ml) and the solution was cooled in an ice-water bath. Hydrogen peroxide (1.14 ml, 37.3 mmol) was added followed immediately by lithium hydroxide (0.26 g, 10.9 mmol). The reaction was allowed to warm to room temperature and stirred for 5.5 hours at room temperature then sat overnight in the refrigerator. The reaction was diluted with DCM and water. The aqueous layer was diluted with ethyl acetate and hydrochloric acid (1 N, 10 ml) and extracted three times with ethyl acetate. The organic layer was washed twice with brine, dried over Na 2 S0 4 , filtered and concentrated to leave an oil which was purified by flash chromatography (silica gel, 0 % to 4 % methanol in DCM as eluant) to isolate two isomers. The two isomers that were separated were the R,S isomer (1.05 g, 2.95 mmol, 32.4 % yield) and the title compound, R,R isomer (0.54 g, 1.52 mmol, 16.7 % yield). MS (m/z) 322.2 (M+H + ).

Step 7: (9H-fluoren-9-yl)methyl (((R)-2-((R)-1-(N- (benzyloxy)formamido)propyl)heptanamido)methyl)carbamate

(R)-2-((R)-1-(N-(benzyloxy)formamido)propyl)heptanoic acid (406 mg, 1.26 mmol) was dissolved in DMF (3.6 ml) and treated with (9H-fluoren-9- yl)methyl(aminomethyl)carbamate, trifluoroacetic acid salt (483 mg, 1.26 mmol). HATU (480 mg, 1.26 mmol) was added followed by Hunig's base (0.66 ml, 3.79 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction was diluted with water and EtOAc. The layers were separated, and the organics were dried over Na 2 S0 4 , filtered, and concentrated and purified by flash chromatography (ISCO, 120 g column, 0-10 % MeOH/DCM over 30 minutes) to give the title compound as a yellow oil (530 mg, 0.93 mmol, 73.4 % yield). MS (m/z) 572.3 (M+H + ). Step 8: (R)-N-(aminomethyl)-2-((R)-1-(N-(benzyloxy)formamido)propyl) heptanamide

(9H-fluoren-9-yl)methyl(((R)-2-((R)-1-(N- (benzyloxy)formamido)propyl)heptanamido)methyl)carbamate (6.67 g, 11.7 mmol) was dissolved in acetonitrile (22.6 ml) and pyrrolidine (24.1 ml, 292 mmol) was added. The mixture was stirred at room temperature until all the fmoc was removed. The solution was concentrated and purified by flash chromatography (ISCO, 0-10 % MeOH/DCM over 30 minutes) to give the title compound (2.2 g, 6.30 mmol, 54 % yield). MS (m/z) 350.3 (M+H + ).

Step 9: (R)-N-(aminomethyl)-2-((R)-1-(N-hydroxyformamido)propyl)hept anamide

(R)-N-(aminomethyl)-2-((R)-1-(N-(benzyloxy)formamido)propyl) heptanamide (2.2 g, 6.30 mmol) was disolved in ethanol (126 ml) and flushed with nitrogen. Pd/C (0.67 g, 0.630 mmol) was then added followed by a H 2 balloon. The mixture stirred at room temperature for 2 hours before being filtered over Celite®, washed with EtOAc and then concentrated. The resulting solids were suspended in EtOAc and filtered to give the title compound as a tan solid (1.2 g, 4.63 mmol, 81 % yield). MS (m/z) 259.35 (M+H + ). Alternate synthesis of Intermediate 10: (R)-N-(aminomethyl)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamide

Step 1 : benzyl (aminomethyl)carbamate, trifluoroacetic acid salt To a 4 neck, 2 I round bottom flask under nitrogen, benzyl (2-amino-2- oxoethyl)carbamate (300 g, 1442 mmol) and DCM (8400 ml) were charged, followed by water (26 ml). To the reaction mixture, PI FA (682 g, 1586 mmol) was added and the mixture was maintained at 23 °C for 1 hour. Seeding material of product (2 wt %) was added and the reaction mixture was maintained for an additional 1 hour. The mixture was cooled to 18-20 °C for 1 hour and then the suspension was filtered and washed with 20 % DCM:n-heptane (3000 ml) and then air dried to give the title compound (389 g, 91 % yield) as a white solid.

Step 2: benzyl (((R)-2-((R)-1-(N-

(benzyloxy)formamido)propyl)heptanamido)methyl)carbamate

To a 4 neck round bottom flask (R)-2-((R)-1-(N-

(benzyloxy)formamido)propyl)heptanoic acid (190 g, 592 mmol) and acetonitrile (1900 ml) were charged, followed by triethylamine (175 ml, 1256 mmol). The reaction mixture was cooled to 0-5 °C and HATU (247 g, 650 mmol) was added. The reaction mixture was warmed to 23 °C and maintained for 1 hour to form the HATU-acid adduct. In a separate round bottom flask, combined benzyl (aminomethyl)carbamate, trifluoroacetic acid salt (365 g, 1184 mmol) and acetonitrile (3800 ml) and cooled to 10-15 °C. Triethylamine (963 ml, 6909 mmol) was added slowly to the reaction mixture. The prepared HATU-acid adduct mixture was then added to the benzyl (aminomethyl)carbamate solution. The combined mixture was warmed to 23 °C and maintained for 1 hour. The reaction mixture was concentrated under reduced pressure. MTBE (3420 ml) and water (2375 ml) were added to the residue and stirred for 15 minutes. The layers were separated and the organic layer was passed through 60-120 silica gel. The filtrate was concentrated under reduced pressure and the residue was diluted with MTBE (950 ml) and cooled to 0-5 °C. The slurry was maintained for 1 hour and filtered to obtain title compound (170 g, 65 % yield) as a white solid.

Step 3: (R)-N-(aminomethyl)-2-((R)-1-(N-hydroxyformamido)propyl)hept anamide To a 5 I pressure reaction vessel, benzyl (((R)-2-((R)-1-(N- (benzyloxy)formamido)propyl)heptanarnido)rnethyl)carbarnate (180 g, 372 mmol) and ethanol (3600 ml) were charged. Palladium on carbon, 10 wt % (18.0 g, 16.9 mmol) was added and the reaction vessel was purged with nitrogen and degassed. The reaction mixture was pressurized with 5.0 kg/cm 2 hydrogen gas at 20-25 °C for 4 hours. The mixture was then filtered through celite and the celite plug was washed with ethanol (900 ml). The filtrate was concentrated under reduced pressure at 40-45 °C. The crude product was slurried with n-heptane (900 ml), filtered, and dried at 35-40 °C for 6 hours to obtain the title compound (89 g, 90 % yield) as a white solid.

INTERMEDIATE 1 1

6-phenyl-4 colinic acid

Step 1 : 2-methyl-6-phenyl-4-(trifluoromethyl)pyridine

2-chloro-6-methyl-4-(trifluoromethyl)pyridine (1.12 g, 5.73 mmol), phenylboronic acid

(1.75 g, 14.3 mmol) and potassium acetate (2.81 g, 28.6 mmol) were combined in a vial. The contents were suspended in DMF (17.4 ml) and the mixture degassed with nitrogen gas. Tetrakis (0.66 g, 0.57 mmol) was then added and the reaction subjected to microwave irradiation at 140 °C for 10 minutes and then at 160 °C for 20 minutes. The reaction mixture was poured into water and EtOAc was added. The mixture was filtered and the layers separated. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed with water (6 x), brine and then dried over Na 2 S0 4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (40 g silica gel column, 100 % hexanes: 10 minutes, 0-20 % EtOAc/hexanes, 20 minutes) to give the title compound as a colorless liquid (1.07 g, 79 % yield). MS (m/z) 238.1 (M+H + ).

Step 2: 6-phenyl-4-(trifluoromethyl)picolinic acid

To a solution of 2-methyl-6-phenyl-4-(trifluoromethyl)pyridine (1.07 g, 4.50 mmol) in pyridine (5 ml) was added a solution of tetrabutylammonium permanganate (5.00 g, 13.5 mmol) in pyridine (4.5 ml). The reaction was stirred for 75 hours at 80 °C. The reaction was then poured into a mixture of water and ice and then NaHS0 3 solution (40 % in water) was added until the reaction turned light yellow. The mixture was then acidified by addition of 2 N HCI and extracted with EtOAc. The combined organic layers were then washed with 1 N HCI and brine, dried over Na 2 S0 4 , filtered and concentrated. The residue was re-submitted to the reaction under the same conditions and heated at 80 °C for 4 hours. Additional

tetrabutylammonium permanganate (1.67 g, 4.50 mmol) was added and the reaction was stirred overnight. The reaction was then poured into a mixture of water and ice and then NaHS0 3 solution (40 % in water) was added until the reaction turned light yellow. The mixture was then acidified by addition of 2 N HCI and extracted with EtOAc. The combined organic layers were then washed with 1 N HCI and brine, dried over Na 2 S0 4 , filtered and concentrated. The residue was purified by flash chromatography (40 g silica gel column, 100 % DCM: 10 minutes, 15 minutes, 0-10 % MeOH/DCM: 10 minutes, 10 % MeOH/DCM) to give the title compound (0.88 g, 73 % yield). MS (m/z) 268.0 (M+H + ).

INTERMEDIATE 12

6-phenylpyrazin -2-carboxylic acid di-hydrochloride

A mixture of methyl 6-chloropyrazine-2-carboxylate (0.57 g, 3.30 mmol),

phenylboronic acid (0.48 g, 3.96 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (0.14 g, 0.17 mmol) and sodium carbonate (1 M, 9.91 ml, 9.91 mmol) in 1 ,4-dioxane (6.61 ml) was subjected to microwave irradiation at 100 °C for 6 minutes. The reaction was then filtered through a pad of Celite® and then extracted with EtOAc. The aqueous phase was acidified to ~ pH 2-3 via addition of 1 N HCI. The resultant precipitate was collected. The aqueous phase was then concentrated and the resultant solid was suspended in methanol (10 ml). The suspension was stirred for 5 minutes and the solid then collected by filtration. The solid isolates were combined to give the title compound as a tan solid (0.99 g). MS (m/z) 201.1 (M+H + ). Intermediate 13 was prepared from the indicated bromide and boronic acid by methods analogous to those described for Intermediate 12.

INTERMEDIATE 14

6'-methoxy-[ '-bipyridine]-6-carboxylic acid

A mixture of methyl 6'-methoxy-[2,2'-bipyridine]-6-carboxylate (0.12 g, 0.48 mmol) and lithium hydroxide (0.05 g, 1.92 mmol) in methanol (3 ml) and water (1.8 ml) was stirred at room temperature for 3 hours. The solvent was then removed and the residue was acidified to ~ pH 2 by addition of 1 N HCI and extracted with EtOAc (3 x). The combined organic extracts were dried over Na 2 S0 4 , filtered and concentrated to give the title compound as an off white solid. (0.11 g, 96 % yield). MS (m/z) 231.1 (M+H + ).

INTERMEDIATE 15

6-(3-ethoxy-4-(e oropicolinic acid

To a solution of ethyl 2-ethoxy-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzoate (439 mg, 1.37 mmol) and 6-bromo-5-fluoropicolinic acid (302 mg, 1.37 mmol) in 1 ,4-dioxane (6.9 ml) was added a solution of sodium carbonate (436 mg, 4.1 1 mmol) in water (2 ml). The reaction was purged with nitrogen and PdCl 2 (dppf)-CH 2 Cl 2 adduct (1 12 mg, 0.14 mmol) was added and the reaction then heated at 80 °C for 18 hours. The reaction was then cooled to room temperature and concentrated. The residue was partitioned between water and EtOAc and the aqueous phase acidified. The layers were separated, and the aqueous phase was extracted with further EtOAc (3 x 20 ml). The combined organic extracts were dried over MgS0 4 , filtered, and concentrated to give the title compound as an orange solid (129 mg, 28 % yield). MS (m/z) 334.0 (M+H + ).

Intermediates 16-17 were prepared from dimethyl (2-ethoxy-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)phosphonate and the indicated chloride by methods analogous to those described for Intermediate 15. MS (m/z)

# Name Structure Chloride

(M+H + )

6-(4-(dimethoxyphosphoryl)- 6- 3-ethoxyphenyl)pyrazine-2- chloropyrazine-

16 352.9

carboxylic acid 2-carboxylic acid

2- (4-(dimethoxyphosphoryl)- 2-

3- ethoxyphenyl)pyrimidine- chloropyrimidin

17 352.9

4-carboxylic acid e-4-carboxylic acid

Intermediates 18-19 were prepared from ethyl 2-ethoxy-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzoate and the indicated chloride by methods analogous to those described for Intermediate 15.

INTERMEDIATE 20

6-bromo-5-fluoropicolinic acid

Potassium permanganate (2.50 g, 15.8 mmol) was added portionwise to a

suspension of 2-bromo-3-fluoro-6-methylpyridine (1 g, 5.26 mmol) in water (22 ml) at 90 °C. The reaction was stirred for 3 hours and then filtered through Celite® while hot, washing with hot water. The filtrate was acidified to pH 1 via addition of 6 N HCI. The resultant precipitate was collected by filtration to give the title compound (0.15 g, 13 % yield). MS (m/z) 219.9 (M+H + ).

INTERMEDIATE 21

3-(4,5-di nzoic acid

Step 1 : methyl 3-((3-oxobutan-2-yl)carbamoyl)benzoate

A mixture of 3-aminobutan-2-one (1.32 g, 10.7 mmol), 3-(methoxycarbonyl)benzoic acid (1.92 g, 10.7 mmol), EDC (2.46 g, 12.8 mmol) and HOBt (0.33 g, 2.14 mmol) in DCM (40 ml) was treated with DIPEA (5.60 ml, 32.0 mmol) and the reaction stirred at room temperature for 30 minutes. The reaction was then washed with water and the organic layer collected via hydrophobic frit, washed with 1 M HCI, collected via hydrophobic frit and then concentrated. The residue was purified by flash chromatography (ISCO CombiFlash, 40 g silica column, 20-100 % EtOAc/hexanes) to give the title compound as a pale yellow oil (1.17 g, 44 % yield). MS (m/z) 250.1 (M+H + ).

Step 2: methyl 3-(4,5-dimethyloxazol-2-yl)benzoate

A solution of methyl 3-((3-oxobutan-2-yl)carbamoyl)benzoate (827 mg, 3.32 mmol), sulfuric acid (1.00 ml, 18.8 mmol) and acetic anhydride (1.00 ml, 10.6 mmol) was heated at 90 °C for 2.5 hours. Water was then added to the reaction and the resultant precipitate collected by filtration to give the title compound as a beige solid (414 mg, 54 % yield). MS (m/z) 232.1 (M+H + ). The aqueous filtrate was extracted with ethyl acetate. The ethyl acetate layer was washed with brine and concentrated to give an additional batch of the title compound as an orange solid (270 mg, 80 % purity, 28 % yield). MS (m/z) 232.1 (M+H + ).

Step 3: 3-(4,5-dimethyloxazol-2-yl)benzoic acid

Sodium hydroxide (6.47 ml, 12.9 mmol) was added to a solution of methyl 3-(4,5- dimethyloxazol-2-yl)benzoate (748 mg, 3.23 mmol) in methanol (5 ml) and tetrahydrofuran (5 ml) and the reaction stirred at room temperature for 30 minutes. The volatiles were removed under reduced pressure and the residue adjusted to pH 5 via addition of 2 M HCI and extracted with ethyl acetate. The layers were separated and the aqueous layer extracted twice with ethyl acetate. The combined ethyl acetate fractions were then concentrated to give the title compound as a pale yellow solid (819 mg) which was used without further purification. MS (m/z) 218.1 (M+H + ).

INTERMEDIATE 22

3-(2-methyloxazol-5-yl)benzoic acid

Step 1 : methyl 3-(2-methyloxazol-5-yl)benzoate

A mixture of methyl 3-formylbenzoate (200 mg, 1.22 mmol) and N-methylidyne-1- tosylethanaminium (256 mg, 1.22 mmol) in methanol (5 ml) was treated with potassium carbonate (337 mg, 2.44 mmol) and the reaction stirred at room temperature for 1 hour. Additional N-methylidyne-1-tosylethanaminium (51.2 mg, 0.24 mmol) was added to the reaction which was stirred for a further 2.5 hours. The reaction was then concentrated and ethyl acetate and water added to the residue. The layers were separated and the organic layer washed with brine and concentrated. The residue was purified by flash

chromatography (ISCO CombiFlash, 12 g silica column, 10-70 % EtOAc/hexanes to give the title compound as a white solid (160 mg, 61 % yield). MS (m/z) 218.1 (M+H + ).

Step 2: 3-(2-methyloxazol-5-yl)benzoic acid

Sodium hydroxide (2 M, 1.47 ml, 2.95 mmol) was added to a solution of methyl 3-(2- methyloxazol-5-yl)benzoate (160 mg, 0.74 mmol) in methanol (2 ml) and tetrahydrofuran (2 ml) and the reaction stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure and the residue acidified to pH 5 via addition of 1 M HCI and extracted with ethyl acetate (2 x). The combined organic extracts were washed with brine and then concentrated to give the title compound as a white solid (180 mg, 100 % yield). MS (m/z) 204.1 (M+H + ).

INTERMEDIATE 23

2,2'-difluoro-3'- -carboxylic acid

(2-fluoro-3-methoxyphenyl)boronic acid (3.98 g, 23.4 mmol), monobasic potassium phosphate (2.49 g, 18.3 mmol), tribasic potassium phosphate (3.89 g, 18.3 mmol) and 3- bromo-2-fluorobenzoic acid (4.00 g, 18.3 mmol) were added to a degassed mixture of DME (70 ml), water (52 ml) and EtOH (20 ml). The mixture was degassed and then PdCI 2 (dbpf) (436 mg, 0.9 mmol) was added and the reaction was stirred at 60 °C for 5 hours. The reaction was reduced in volume and then diluted by the addition of 1 M NaOH solution (150 ml) and washed with diethyl ether (150 ml). The layers were separated and the aqueous layer was cooled to 0 °C and acidified by addition of HCI (37 %). The aqueous phase was filtered and the collected solid was dissolved in EtOAc (400 ml), washed with brine (100 ml), dried over Na 2 S0 4 then filtered through a silica gel plug, washing with EtOAc. The organic phase was concentrated to give a solid which was triturated with a mixture of

cyclohexane/EtOH at 70 °C for 1 hour. The mixture was then allowed to cool and was filtered. The collected solid was air dried to give the title compound as an off white solid (4.27 g, 88 % yield). MS (m/z) 264.8 (M+H + ).

Intermediates 24-25 were prepared from the indicated bromide and boronic acid by methods analogous to those described for Intermediate 23.

INTERMEDIATE 26

3-((6-methoxypyridin-3-yl)oxy)benzoyl chloride

Step 1 : methyl 3-((6-methoxypyridin-3-yl)oxy)benzoate

A mixture of 5-bromo-2-methoxypyridine (6.5 g, 34.6 mmol), methyl 3- hydroxy benzoate (7.89 g, 51.9 mmol), 2-(dimethylamino)acetic acid hydrochloride (1.45 g, 10.4 mmol), copper(l) iodide (1.98 g, 10.4 mmol) and Cs 2 C0 3 (22.5 g, 69.1 mmol) in 1 ,4- dioxane (100 ml) under N 2 was stirred at 90 °C for 2 days. The reaction was then diluted with DCM and water. The layers were separated and the aqueous phase extracted with DCM (3 x). The combined organic extracts were washed with brine (2 x), dried over Na 2 S0 4 , filtered and concentrated. The residue was purified via flash chromatography (ISCO, 120 g silica column, 65 ml/min, 0-40 % EtOAc/DCM over 45 minutes) to give the title compound (2.85 g, 32 % yield). MS (m/z) 260.1 (M+H + ). Step 2: 3-((6-methoxypyridin-3-yl)oxy)benzoic acid

A mixture of methyl 3-((6-methoxypyridin-3-yl)oxy)benzoate (2.85 g, 1 1.0 mmol) and lithium hydroxide (1.38 g, 33.0 mmol) in ethanol (30 ml) and water (10 ml) was stirred for 3 hours. The volatiles were removed under reduced pressure and the residual mixture adjusted to pH 5 by addition of 2 M HCI and extracted with EtOAc (3 x). The combined organic extracts were washed with brine (2 x), dried over Na 2 S0 4 , filtered and concentrated to give the title compound (2.7 g, 100 % yield). MS (m/z) 246.1 (M+H + ).

Step 3: 3-((6-methoxypyridin-3-yl)oxy)benzoyl chloride

To a mixture of 3-((6-methoxypyridin-3-yl)oxy)benzoic acid (2.7 g, 11.0 mmol) in DCM (50 ml) was added DMF (5 drops) followed by slow addition of oxalyl chloride (1.93 ml, 22.0 mmol). The reaction was stirred for 1 hour and then concentrated. The residue was dissolved in DCM and hexanes then concentrated to give the title compound which was used without further purification or characterization.

INTERMEDIATE 27

3'-((9H-xanthe -9-yl)thio)-[1 , T-biphenyl]-3-carboxylic acid

Step 1 : (3-bromophenyl)(2,4,6-trimethoxybenzyl)sulfane

A solution of 3-bromobenzenethiol (0.87 g, 4.59 mmol) and TFA (6 ml) in dry DCM (30 ml) at 0 °C, was treated with a solution of (2,4,6-trimethoxyphenyl)methanol (1 g, 5.05 mmol) in DCM (15 ml) and the reaction stirred for 15 minutes before being allowed to warm to room temperature and stirred for 30 minutes. The reaction was diluted with DCM and washed with Na 2 C0 3 . The organics were separated, washed with brine, dried over Na 2 S0 4 , filtered and concentrated. The residue was purified by flash chromatography (Biotage SP1 , SNAP silica column, 0-10 % EtOAc/cyclohexane) to give the title compound as a colorless oil (1.4 g, 83 % yield). MS (m/z) 370.8 (M+H + ). Step 2: methyl 3'-((2,4,6-trimethoxybenzyl)thio)-[1 , 1'-biphenyl]-3-carboxylate

To a mixture of (3-bromophenyl)(2,4,6-trimethoxybenzyl)sulfane (1.4 g, 3.87 mmol), (3-(methoxycarbonyl)phenyl)boronic acid (0.91 g, 5.04 mmol), monobasic potassium phosphate (0.53 g, 3.87 mmol), tribasic potassium phosphate (0.83 g, 3.87 mmol),

PdCI 2 (dbpf) (0.09 g, 0.19 mmol) and 1 , 1 '-bis(di-tert-butylphosphino)ferrocene (0.09 g, 0.19 mmol) under nitrogen was added DME (17 ml), water (13 ml) and EtOH (4.5 ml) and the reaction degassed with N 2 for 10 minutes. The reaction was stirred at room temperature overnight and then heated at 60 °C for 5 hours. The reaction was then diluted with DCM and filtered through Celite®. The filtrate was washed with water and brine and the organic layer then separated, dried over Na 2 S0 4 , filtered and concentrated. The residue was purified by flash chromatography (Biotage SP1 , SNAP silica column, 0-10 % EtOAc/cyclohexanes) to give the title compound (1.2 g, 75 % yield). MS (m/z) 424.9 (M+H + ).

Step 3: 3'-((2,4,6-trimethoxybenzyl)thio)-[1 , 1 '-biphenyl]-3-carboxylic acid

A solution of methyl 3'-((2,4,6-trimethoxybenzyl)thio)-[1 , T-biphenyl]-3-carboxylate in (1.2 g, 2.83 mmol) in THF (10 ml) and water (5 ml) was treated with LiOH monohydrate (0.40 g, 9.53 mmol) and stirred at room temperature for 3 hours. Additional LiOH monohydrate (0.30 g, 7.15 mmol) was added and the reaction stirred overnight. The reaction was then diluted with DCM and acidified to pH 2 via addition of 1 M HCI. The aqueous was extracted with DCM (3 x). The combined organic extracts were washed with brine, dried over Na 2 S0 4 , filtered and concentrated. The residue was purified by flash chromatography (Biotage SP1 , SNAP silica column, 20-50 % EtOAc/cyclohexanes) to give the title compound (0.84 g, 72 % yield). MS (m/z) 411.0 (M+H + ).

Step 4: 3'-mercapto-[1 , T-biphenyl]-3-carboxylic acid

A solution of 3'-((2,4,6-trimethoxybenzyl)thio)-[1 ,1 '-biphenyl]-3-carboxylic acid (0.40 g, 0.97 mmol) in DCM (14 ml) under nitrogen was treated with TFA (1.4 ml) and Et 3 SiH (0.4 ml) at room temperature for 45 minutes. The reaction was concentrated and the residue taken up in 2 N NaOH solution and extracted with Et 2 0. The aqueous phase was adjusted to pH 2 via addition of 1 N HCI and extracted with Et 2 0. The organic layer was separated, dried over Na 2 S0 4 , filtered and concentrated to give the title compound (0.22 g, 96.9 % yield). MS (m/z) 230.9 (M+H + ). Step 5: 3'-((9H-xanthen-9-yl)thio)-[1 ,1 '-biphenyl]-3-carboxylic acid

A solution of 3'-mercapto-[1 , 1 '-biphenyl]-3-carboxylic acid (238 mg, 1.03 mmol) and TFA (0.03 ml) in 1 ,2-dimethoxyethane (1.6 ml) was stirred at room temperature under N 2 for 10 minutes. 9,9a-dihydro-4aH-xanthen-9-ol (226 mg, 1.10 mmol) was then added and the reaction was stirred at room temperature for 30 minutes. Et 2 0 was then added and the suspension was stirred in an ice bath for 20 minutes. The reaction was filtered and the white solid was washed with Et 2 0, collected and then dried under vacuum at 45 °C to give the title compound as a white solid (251 mg, 60 % yield). MS (m/z) 409.0 (M-H " ).

INTERMEDIATE 28

N-(aminomethyl)-6-bromopicolinamide hydrochloride

Step 1 : N-(2-amino-2-oxoethyl)-6-bromopicolinamide

To a suspension of 6-bromopicolinic acid (5.0 g, 24.8 mmol), 2-aminoacetamide hydrochloride (3.28 g, 29.7 mmol) and DIPEA (13 ml, 74.4 mmol) in THF (100 ml) at room temperature was added BOP (12 g, 27.1 mmol). The reaction was stirred at 40 °C for 16 hours then cooled to room temperature and diluted by the addition of water (25 ml) and EtOAc (100 ml). The layers were separated and the organic phase was washed with saturated sodium bicarbonate solution (3 x 25 ml). The aqueous phases were combined and were extracted with EtOAc (3 x 50 ml). The combined organic extracts were then washed with brine (25 ml), dried over magnesium sulfate, filtered and concentrated. The residue was preabsorbed on to silica and purified by flash chromatography (ISCO Combiflash, 330 g Silicycle column, 1 to 5 % MeOH/DCM) to give the title compound as a white solid (6.1 g, 91 % yield). MS (m/z) 260.0 (M+2 + ).

Step 2: N-(aminomethyl)-6-bromopicolinamide hydrochloride

To a solution of [bis(trifluoroacetoxy)iodo]benzene (1.83 g, 4.26 mmol) in acetonitrile (6 ml) and water (6 ml) at room temperature was added N-(2-amino-2-oxoethyl)-6- bromopicolinamide (1.0 g, 3.87 mmol). The reaction was stirred at room temperature for 24 hours. The reaction was then diluted with water (75 ml) and acidified by addition of concentrated HCI (8 ml). The resulting mixture was extracted with ether (75 ml). The aqueous phase was evaporated in vacuo to give the title compound as a white solid (0.96 g, 93 % yield). MS (m/z) 232.0 (M+2 + ). INTERMEDIATE 29

N-(ami namide

Step 1 : N-(2-amino-2-oxoethyl)-6-phenylpicolinamide

A solution of 6-phenylpicolinic acid (1.0 g, 5.02 mmol), 2-aminoacetamide

hydrochloride (0.67 g, 6.02 mmol), HOBt (0.15 g, 1.00 mmol), EDC (2.89 g, 15.06 mmol) and DIPEA (4.38 ml, 25.1 mmol) in THF (20.7 ml) was stirred at 50 °C for 18 hours. The reaction was then cooled and reduced in volume. Water was added and the resultant solid collected by filtration and air dried to give the title compound as a white solid (0.59 g, 46 % yield). MS (m/z) 256.1 (M+H + ).

Step 2: N-(aminomethyl)-6-phenylpicolinamide

To a solution of [bis(trifluoroacetoxy)iodo]benzene (1.48 g, 3.45 mmol) in acetonitrile (5.8 ml) was added water (5.8 ml) followed by N-(2-amino-2-oxoethyl)-6-phenylpicolinamide (0.59 g, 2.30 mmol) and the reaction stirred at room temperature overnight. 1 N HCI was then added and the reaction was washed with Et 2 0 (2 x). The layers were separated and the aqueous phase was concentrated to give the title compound as a white solid (0.39 g, 56 % yield). MS (m/z) 211.1 (M-16 + ). The Et 2 0 phase was concentrated and the residue purified via flash chromatography (ISCO, 0-5 % MeOH/DCM) to give the title compound (0.13 g, 21 % yield). MS (m/z) 21 1.1 (M-16 + ).

Intermediate 30 was prepared from 6-(3-methoxyphenyl)picolinic acid by methods analogous to those described for Intermediate 29.

INTERMEDIATE 31

N-(aminomethyl)- -phenyl-4-(trifluoromethyl)picolinarnide

Step 1 : (9H-fluoren-9-yl)methyl ((6-phenyl-4-(trifluoromethyl)picolinamido)methyl)carbamate To a solution of 6-phenyl-4-(trifluoromethyl)picolinic acid (0.88 g, 3.29 mmol) in DMF

(1.53 ml) was added (9H-fluoren-9-yl)methyl (aminomethyl)carbamate (0.88 g, 3.29 mmol), HATU (1.25 g, 3.29 mmol) and DIPEA (1.15 ml, 6.58 mmol) and the reaction was stirred for 2 hours. The reaction was then quenched with water (10 ml) and diluted with EtOAc (30 ml). The layers were separated, and the organic layer was washed with water, dried over Na 2 S0 4 , filtered and concentrated. The residue was purified by flash chromatography (40 g silica gel column, 0-100 % EtOAc/hexanes, 25 minute gradient) to give the title compound (0.62 g, 36 % yield). MS (m/z) 541.1 (M+23 + ).

Step 2: N-(aminomethyl)-6-phenyl-4-(trifluoromethyl)picolinamide

Piperidine (3.33 ml, 33.6 mmol) was added to a suspension of (9H-fluoren-9- yl)methyl ((6-phenyl-4-(trifluoromethyl)picolinamido)methyl)carbamate (870 mg, 1.68 mmol) in acetonitrile (5.07 ml). The reaction mixture was stirred for 3 hours and then combined with a reaction conducted on 250 mg scale under the same conditions and concentrated. The residue was purified by flash chromatography (40 g silica gel column, 100 % DCM: 10 minutes, 0-10 % MeOH: 15 minutes, 10-15 % MeOH: 10 minutes) to give the title compound (227 mg, 46 % yield). MS (m/z) 279.0 (M-16 + ).

Intermediate 32 was prepared from 6-phenylpyrazine-2-carboxylic acid hydrochloride by methods analogous to those described for Intermediate 31.

INTERMEDIATE 33

N-(aminom icolinamide Step 1 : (9H-fluoren-9-yl)methyl ((6-bromo-5-fluoropicolinamido)methyl)carbamate

A solution of (9H-fluoren-9-yl)methyl (aminomethyl)carbamate trifluoroacetic acid salt (0.49 g, 1.28 mmol), (9H-fluoren-9-yl)methyl (aminomethyl)carbamate hydrochloride (0.6 g, 1.97 mmol), 6-bromo-5-fluoropicolinic acid (0.74 g, 3.38 mmol), HATU (1.54 g, 4.05 mmol) and DIPEA (1.77 ml, 10.1 mmol) in DMF (15.1 ml) was stirred at room temperature for 2 hours. Water was then added and the reaction placed in a refrigerator overnight. The reaction was then allowed to warm to room temperature and the solid was collected by filtration, washed with water and air dried to give the title compound as a grey solid (1.23 g, 77 % yield). MS (m/z) 472.1 (M+2 + ). Step 2: (9H-fluoren-9-yl)methyl ((5-fluoro-6-phenylpicolinamido)methyl)carbamate

A mixture of (9H-fluoren-9-yl)methyl ((6-bromo-5- fluoropicolinamido)methyl)carbamate (0.4 g, 0.85 mmol), phenylboronic acid (0.12 g, 1.02 mmol), sodium carbonate (1 M, 2.55 ml, 2.55 mmol) and PdCl 2 (dppf)-CH 2 Cl 2 adduct (0.04 g, 0.04 mmol) in 1 ,4-dioxane (4 ml) was subjected to microwave irradiation at 100 °C for 6 minutes. The reaction was extracted with DCM (2 x). The organic layers were passed through a phase separator and concentrated. The residue was purified via flash

chromatography (ISCO, 40 g column, 0-20 % EtOAc/DCM: 15 minutes, 20 % EtOAc/DCM: 10 minutes) to give the title compound as an off white solid. (0.27 g, 67 % yield). MS (m/z) 468.2 (M+H + ).

Step 3: N-(aminomethyl)-5-fluoro-6-phenylpicolinamide

A suspension of (9H-fluoren-9-yl)methyl((5-fluoro-6-phenylpicolinamido)methy l) carbamate (0.27 g, 0.57 mmol) in acetonitrile (2 ml) was treated with pyrrolidine (1 ml, 12.1 mmol) and stirred for 1 hour at room temperature. The reaction was concentrated and the residue purified via flash chromatography (ISCO, 40 g silica gel column, 0-5 % MeOH/DCM: 10 minutes, 5 % MeOH/DCM: 10 minutes, 5-10 % MeOH/DCM: 5 minutes, 10 %

MeOH/DCM: 5 minutes) to give the title compound as a white solid (0.13 g, 93 % yield). MS (m/z) 229.1 (M-16 + ). INTERMEDIATE 34

4-(6-((aminomethyl)ca benzoic acid

N-(aminomethyl)-6-bromopicolinamide (200 mg, 0.87 mmol), 2-ethoxy-4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoic acid (279 mg, 0.96 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (71 mg, 0.09 mmol) and sodium carbonate (1 M, 2.61 ml, 2.61 mmol) were combined in a microwave vial and 1 ,4-dioxane (1.09 ml) added. The vial was sealed and heated at 50 °C for 2 hours. The reaction was diluted by the addition of water and extracted with DCM and ethyl acetate. The aqueous phase was then reduced to ~ 1/3 volume and purified by OASIS column (6 g, washed with water, eluted with methanol). The methanol fractions were concentrated and the residue dissolved in DCM and purified by Si SPE (0-10 %

methanol/DCM) to give impure product. The water fractions were concentrated and the residue suspended in methanol and filtered. The collected solids were combined with isolated impure product and dissolved in methanol and purified by SCX (2 x 5 g columns, washed with methanol, eluted with 10 % of 2 M ammonia/methanol solution in DCM). The ammonia/methanol fractions were concentrated to give the title compound as a yellow solid (171 mg, 62 % yield). MS (m/z) 299.0 (M-16 + ).

INTERMEDIATE 35

N-(aminom l)benzamide

Step 1 : (9H-fluoren-9-yl)methyl ((3-(1 H-pyrazol-1-yl)benzamido)methyl)carbamate

A mixture of 3-(1 H-pyrazol-1-yl)benzoic acid (351 mg, 1.86 mmol), (9H-fluoren-9- yl)methyl (aminomethyl)carbamate trifluoroacetic acid salt (750 mg, 1.86 mmol), EDC (429 mg, 2.24 mmol) and HOBt (57.1 mg, 0.37 mmol) in DCM (6 ml) was treated with DIPEA (0.98 ml, 5.59 mmol) and stirred at room temperature for 17 hours. The reaction was then filtered and the solid collected to give the title compound as an off white solid (262 mg, 32 % yield). MS (m/z) 439.2 (M+H + ). Step 2: N-(aminomethyl)-3-(1 H-pyrazol-1 -yl)benzamide

Piperidine (1 .18 ml, 12.0 mmol) was added to a suspension of (9H-fluoren-9- yl)methyl ((3-(1 H-pyrazol-1-yl)benzamido)methyl)carbamate (262 mg, 0.6 mmol) in acetonitrile (3 ml) and the reaction was stirred at room temperature for 17 hours. The reaction was then filtered and the filtrate concentrated. The residue was purified by flash chromatography (5 g silica SPE column, DCM, diethyl ether, ethyl acetate, acetone and methanol) to give the title compound as an orange oil (1 16 mg, 76 % yield) which was used in the next step without further purification. MS (m/z) 200.1 (M-16 + ).

Intermediates 36-39 were prepared from (9H-fluoren-9-yl)methyl

(aminomethyl)carbamate trifluoroacetic acid salt and the indicated acid by methods analogous to those described for Intermediate 35.

(9H-fluoren-9- yl)methyl ((3-

N-(aminomethyl)-3- (4-methyl-1 H- 3-(4-methyl-1 H- (4-methyl-1 H- 214.1

pyrazol-1- 453.1 pyrazol-1-

38 pyrazol-1- (M- yl)benzamido) (M+H + ) yl)benzoic acid yl)benzamide 16 + )

methyl)carba

mate

(9H-fluoren-9- yl)methyl ((3-

(2-

N-(aminomethyl)-3-

3-(2-methyloxazol- (2-methyloxazol-5- 454.1

39 - L 1 215.1 methyloxazol- (M- 5- 5-yl)benzoic acid yl)benzamide (M+H + )

16 + ) yl)benzamido)

methyl)carba

mate

Intermediate 40 was prepared from (9H-fluoren-9-yl)methyl (aminomethyl)carbamate, trifluoroacetic acid salt and the indicated acid by methods analogous to those described for Intermediate 35 using pyrollidine in Step 2 instead of piperidine.

INTERMEDIATE 41

N-(aminomethyl)-2,2'-difluoro '-methoxy-[1 , 1 '-biphenyl]-3-carboxamide hydrochloride

Step 1 : N-(2-amino-2-oxoethyl)-2,2'-difluoro-3'-methoxy-[1 , 1 '-biphenyl]-3-carboxamide

TBTU (5.72 g, 17.8 mmol) was added to a mixture of 2,2'-difluoro-3'-methoxy-[1 ,1 '- biphenyl]-3-carboxylic acid (4.27 g, 16.2 mmol), 2-aminoacetamide hydrochloride (1.88 g, 17.0 mmol) and DIPEA (8.47 ml, 48.6 mmol) in DCM (60 ml) and the reaction was stirred at room temperature over the weekend. The reaction was then filtered and the solid was washed with DCM (2 x 5 ml). The solid was then collected by filtration and air dried to give the title compound as a white solid (5 g, 96 % yield). MS (m/z) 320.8 (M+H + ).

Step 2: N-(aminomethyl)-2,2'-difluoro-3'-methoxy-[1 , 1 '-biphenyl]-3-carboxamide

hydrochloride

To a solution of PI FA (8.05 g, 18.7 mmol) in acetonitrile/water (1 : 1 , 60 ml) at room temperature was added N-(2-amino-2-oxoethyl)-2,2'-difluoro-3'-methoxy-[1 ,1 '-biphenyl]-3- carboxamide (5 g, 15.6 mmol) and the reaction was stirred overnight. Additional PI FA (2 g, 6.24 mmol) was added and the reaction was stirred overnight. The volatiles were removed under reduced pressure and 1 M HCI (100 ml) and isopropyl ether (50 ml) were then added. The layers were separated and the aqueous phase was washed with diethyl ether (100 ml) then evaporated to give the title compound as a beige solid (2.76 g, 54 % yield). MS (m/z) 292.8 (M+H + ).

Intermediates 42-43 were prepared from 2-aminoacetamide hydrochloride and the indicated acid by methods analogous to those described for Intermediate 41.

N-(aminomethyl)-2,2'- 2,2'-difluoro-5'- difluoro-5'-methoxy- methoxy-[1 , 1 '-

43 [1 , 1'-biphenyl]-3- 292.8 biphenyl]-3- carboxamide carboxylic acid

INTERMEDIATE 44

N-(aminomethyl)-3-((6-methoxypyridin-3-yl)oxy)benzamide

Step 1 : N-(2-amino-2-oxoethyl)-3-((6-methoxypyridin-3-yl)oxy)benzami de

To a mixture of 3-((6-methoxypyridin-3-yl)oxy) benzoyl chloride (2.90 g, 1 1.0 mmol) and 2-aminoacetamide hydrochloride (1.68 ml, 22.0 mmol) in DCM (50 ml) was slowly added triethylamine (6.14 ml, 44.0 mmol). The reaction was stirred for 1 hour then concentrated. The residue was diluted with water, filtered and the solid collected to give the title compound (3.0 g, 90% yield) which was used without further purification. MS (m/z) 302.1 (M+H + ).

Step 2: N-(aminomethyl)-3-((6-methoxypyridin-3-yl)oxy)benzamide

A mixture of [bis(trifluoroacetoxy)iodo]benzene (6.42 g, 14.9 mmol) in acetonitrile (30 ml) and water (30 ml) was treated with N-(2-amino-2-oxoethyl)-3-((6-methoxypyridin-3- yl)oxy)benzamide (3.0 g, 9.96 mmol) and the reaction was stirred overnight. The reaction was then diluted by the addition of water (100 ml) and extracted with Et 2 0 (2 x). The layers were separated and the aqueous phase was concentrated. The residue was dissolved in aqueous Na 2 C0 3 (0.4 M) and extracted with DCM (6 x). The layers were separated and the combined organic extracts were dried over sodium sulfate, filtered and concentrated to give the title compound (1.45 g, 53 % yield). MS (m/z) 257.1 (M-16 + ).

INTERMEDIATE 45

N-(aminomethyl)- -biphenyl]-3-carboxamide hydrochloride

Step l : N-(2-amino-2-oxoethyl)-[1 , T-biphenyl]-3-carboxamide

- I l l - EDC (1.04 g, 5.43 mmol) was added to a suspension of [1 , 1 '-biphenyl]-3-carboxylic acid (0.90 g, 4.52 mmol), 2-aminoacetamide hydrochloride (0.5 g, 4.52 mmol), HOBt (0.83 g, 5.43 mmol) and N-methylmorpholine (1.49 ml, 13.6 mmol) in DCM (5 ml) and the reaction was stirred overnight. The reaction was then absorbed onto silica gel and purified by flash chromatography (ISCO, 80 g silica column, 0-10 % MeOH/DCM: 20 minutes, 10 %

MeOH/DCM: 10 minutes) to give the title compound (1.09 g, 95 % yield). MS (m/z) 254.9 (M+H + ).

Step 2: N-(aminomethyl)-[1 , T-biphenyl]-3-carboxamide hydrochloride

A solution of PIFA (3.65 g, 8.49 mmol) in acetonitrile (10.6 ml) and water (10.6 ml) was added to a 100 ml flask containing N-(2-amino-2-oxoethyl)-[1 , 1 '-biphenyl]-3- carboxamide (1.08 g, 4.25 mmol) and the sides of the flask rinsed with acetonitrile (5 ml). The reaction was stirred at room temperature overnight then partitioned between Et 2 0 and 1 N HCI. The layers were separated and the aqueous layer was extracted with Et 2 0, then concentrated and dried under vacuum to give the title compound as a tan solid (0.31 g, 28 % yield) which was used without further purification. MS (m/z) 227.0 (M+H + ).

INTERMEDIATE 46

N-(aminomethyl)-3-bromobenzamide hydrochloride

Step 1 : N-(2-amino-2-oxoethyl)-3-bromobenzamide

A solution of 2-aminoacetamide hydrochloride (2.75 g, 24.9 mmol) in DCM (100 ml) was treated with triethylamine (10.4 ml, 74.6 mmol) and stirred for 15 minutes. The reaction was then cooled in a water bath and 3-bromobenzoic acid (5.0 g, 24.9 mmol) was then added followed by dropwise addition of T3P® (50 % wt in EtOAc, 22.2 ml, 37.3 mmol). The reaction was stirred at room temperature overnight. Water (100 ml) was then added and the mixture stirred for -15 minutes. The mixture was filtered and the solid washed with DCM (50 ml) and water (50 ml). The solid was collected and dried under vacuum for four days to give the title compound (6.18 g, 97 % yield). MS (m/z) 256.9 (M + ).

Step 2: N-(aminomethyl)-3-bromobenzamide hydrochloride

A solution of [bis(trifluoroacetoxy)iodo]benzene (10.3 g, 24.0 mmol) in acetonitrile (50 ml) and water (50 ml) was stirred until a clear solution formed. N-(2-amino-2-oxoethyl)-3- bromobenzamide (6.18 g, 24.0 mmol) was then added and the reaction stirred for 6 hours at room temperature. The reaction was then diluted with 1 N HCI (200 ml) and washed with ether (2 x 100 ml). The aqueous layer was reduced in volume, filtered and the solid triturated with ether to give the title compound as a white solid (2.3 g, 36 % yield). MS (m/z) 230.9 (M+H + ). The filtrate was concentrated and the residue triturated with ether and the solid collected by filtration to give an additional batch of the title compound as a white solid (0.52 g, 8 % yield). MS (m/z) 229.0 (M + ).

INTERMEDIATE 47

(R)-N-((2-((N-(benzyloxy)formamido)methyl)heptanamido)methyl )-6-bromopicolinamide

To a suspension of N-(aminomethyl)-6-bromopicolinamide dihydrochloride salt (0.96 g, 3.17 mmol) and 2,6-lutidine (1.5 ml, 12.9 mmol) in DMF (12 ml) was added a solution of (R)-2-((N-(benzyloxy)formamido)methyl)heptanoic acid (0.93 g, 3.17 mmol) in DMF (3 ml) followed by HATU (1.21 g, 3.17 mmol). The reaction mixture was stirred at room

temperature for 2 hours. Water (15 ml) was then added and the mixture partitioned with EtOAc (50 ml) and brine (15 ml). The layers were separated and the aqueous phase extracted with additional EtOAc (2 x 50 ml). The combined organic extracts were washed with brine (15 ml), dried over magnesium sulfate, filtered and concentrated. The residue was preabsorbed on to silica and purified by flash chromatography (ISCO Combiflash, 120 g Silicycle column, 5-75 % EtOAc (+ 1 % MeOH)/hexanes) to give two batches of the title compound as colorless oils (0.84 g, 42 % yield and 1.03 g, 61 % yield). MS (m/z) 505.1 (M + ).

INTERMEDIATE 48

N-(((R)-2-((R)-1-(N-(benzyloxy)formamido)propyl)heptanami do)methyl)-6-bromopicolinamide

(R)-2-((R)-1-(N-(benzyloxy)formamido)propyl)heptanoic acid (3.2 g, 9.46 mmol) was dissolved in DMF (32.9 ml) and treated with N-(aminomethyl)-6-bromopicolinamide (2.29 g, 9.46 mmol), HBTU (4.30 g, 1 1.4 mmol) and DIPEA (4.96 ml, 28.4 mmol). The reaction was stirred at room temperature for 1.5 hours then partitioned between water and EtOAc. The organic layer was separated, washed with water, dried over Na 2 S0 4 , filtered and

concentrated. The residue was purified by flash chromatography (ISCO, 120 g column, 0-50 % EtOAc/DCM over 15 minutes) to give the title compound as a white foam (3 g, 59.5 % yield). MS (m/z) 533.2 (M + ).

INTERMEDIATE 49

(R)-N-((2-((N-(benzyloxy)formamido)methyl)-4-phenylbutanamid o)methyl)-3- bromobenzamide

A mixture of N-(aminomethyl)-3-bromobenzamide hydrochloride (0.42 g, 1.58 mmol), (R)-2-((N-(benzyloxy)formamido)methyl)-4-phenylbutanoic acid (0.57 g, 1.58 mmol), EDC (0.61 g, 3.16 mmol), HOBt (0.29 g, 1.89 mmol), and N-methylmorpholine (0.52 ml, 4.73 mmol) in DCM (12 ml) was stirred at room temperature overnight. 1 N HCI (20 ml) and DCM (10 ml) were then added and the mixture stirred for 10 minutes. The layers were then separated and the organic layer concentrated to give the title compound (0.86 mg, 91 % yield) which was used without further purification. MS (m/z) 540.1 (M+2 + ).

Intermediate 50 was prepared from N-(aminomethyl)-3-bromobenzamide

hydrochloride and the indicated acid by methods analogous to those described for

Intermediate 49.

INTERMEDIATE 51

(R)-N-((2-((N-(benzyloxy)formamido)methyl)heptanamido)methyl )-3- bromobenzamide

A mixture of N-(aminomethyl)-3-bromobenzamide hydrochloride (1.90 g, 7.16 mmol) and (R)-2-((N-(benzyloxy)formamido)methyl)heptanoic acid (2.31 g, 7.87 mmol) in DCM (40 ml) was treated with triethylamine (2 ml, 14.3 mmol). The reaction was then cooled in a water bath and T3P® (50 % wt in EtOAc, 6.39 ml, 10.7 mmol) was added dropwise and the reaction then stirred at room temperature for 2 hours. The reaction was then diluted by the addition of water (100 ml) and DCM (50 ml). The layers were separated and the organic layer was concentrated. The residue was triturated with ether and filtered. The collected solid was washed with DCM and ether then dried under vacuum for 3 days to give the title compound as an off white solid (1.22 g, 30 % yield). MS (m/z) 506.1 (M+2 + ). INTERMEDIATE 52

N-(((R)-2-((R)-1-(N-(benzyloxy)formamido)propyl)heptanamido) methyl)-3-bromobenzamide

To a mixture of N-(aminomethyl)-3-bromobenzamide hydrochloride (438 mg, 1.65 mmol) and (R)-2-((R)-1-(N-(benzyloxy)formamido)propyl)heptanoic acid (530 mg, 1.65 mmol) in DCM (10 ml) and DIPEA (0.86 ml, 4.95 mmol) was added HATU (752 mg, 2 mmol) and the reaction stirred at room temperature for 3.5 hours. The reaction was diluted by the addition of DCM (10 ml) and washed with water (2 x 20 ml). The organic layer was collected via a hydrophobic frit and concentrated. The residue was purified by flash chromatography (ISCO Combiflash Rf, 40 g silica column, 20-100 % EtOAc/hexanes) to give the title compound as a white solid (476 mg, 54 % yield). MS (m/z) 534.1 (M+2 + ). INTERMEDIATE 53

3-brom -5-ethoxybenzoic acid

Step 1 : ethyl 3-bromo-5-ethoxybenzoate

A mixture of 3-bromo-5-hydroxybenzoic acid (10 g, 46.1 mmol) and potassium carbonate (31.8 g, 230 mmol) in acetonitrile (453 ml) was treated with iodoethane (8.19 ml, 101 mmol) and the reaction heated at reflux overnight. The reaction was then cooled to room temperature and filtered. The filtrate was concentrated and the residue partitioned between DCM and water. The organic layer was collected via hydrophobic frit and concentrated to give the title compound as a yellow oil (12.2 g, 97 % yield). MS (m/z) 275.0 (M+2 + ).

Step 2: 3-bromo-5-ethoxybenzoic acid

To a solution of ethyl 3-bromo-5-ethoxybenzoate (5 g, 18.3 mmol) in methanol (18.3 ml) was added sodium hydroxide (2 M, 9.15 ml, 18.3 mmol) and the reaction stirred for 3 hours. The organics were removed in vacuo and the remaining solution extracted with ethyl acetate. The layers were separated and the aqueous phase adjusted to pH 4 by the addition of 2 M HCI and then extracted twice with ethyl acetate. The combined organic extracts were washed with brine then dried and concentrated to give the title compound as a white solid (3.44 g, 97 % yield). MS (m/z) 247.0 (M+2 + ).

INTERMEDIATE 54

ethyl -bromo-2-ethoxybenzoate

Iodoethane (17.2 ml, 213 mmol) was added dropwise to a mixture of 4-bromo-2- hydroxybenzoic acid (22 g, 101 mmol) and potassium carbonate (70.1 g, 507 mmol) in acetonitrile (659 ml) and the reaction mixture heated to 80 °C. After 3.5 hours DMF (300 ml) was added. The temperature was lowered to 50 °C and the reaction stirred overnight. The reaction mixture was then cooled to room temperature and combined with another reaction conducted on a 5 g scale using the same conditions and filtered. The volatiles were removed in vacuo and ethyl acetate (500 ml) added. The mixture was washed twice with water and the organic layer then separated and concentrated to give the title compound (34 g, 100 % yield) which was used without further purification. MS (m/z) 273.0 (M+H + ).

INTERMEDIATE 55

methyl 4 enzoate

lodoethane (6.12 ml, 76 mmol) was added dropwise to a mixture of methyl 4-bromo- 2-hydroxybenzoate (5.0 g, 21.6 mmol) and potassium carbonate (8.97 g, 64.9 mmol) in DMF (80 ml) and the reaction mixture stirred at room temperature overnight. The mixture was then filtered, diluted with EtOAc and washed twice with water. The organic layer was separated and then concentrated to give the title compound (5.61 g, 100 % yield). MS (m/z) 261.0 (M+2 + ).

INTERMEDIATE 56

4-brom -2-ethoxybenzoic acid

To a mixture of methyl 4-bromo-2-ethoxybenzoate (5.6 g, 21.6 mmol) in ethanol (25 ml) and THF (25 ml) was added NaOH (2 M, 10.3 ml, 20.5 mmol) and the reaction stirred for 2 hours. Similarly, to a mixture of ethyl 4-bromo-2-ethoxybenzoate (33.9 g, 124 mmol) in ethanol (146 ml) and THF (146 ml) was added NaOH (2 M, 62.1 ml, 124 mmol) and the reaction stirred at room temperature for 2 hours. The two reactions were then combined for workup, the volatiles were removed in vacuo and the residual aqueous extracted with DCM. The aqueous layer was then adjusted to ~pH 4 via addition of 6 N HCI. The mixture was then stirred and the light yellow solid collected by filtration, washed with water and air dried to give the title compound (33 g, 92 % yield) which was used without further purification. MS (m/z) 513.0 (2M+23 + ). INTERMEDIATE 57

1-bromo-3-eth nzene

To a 250 ml flask was added acetonitrile (158 ml), 3-bromo-5-iodophenol (12.1 g, 40.5 mmol), potassium carbonate (28.0 g, 202 mmol), and iodoethane (3.60 ml, 44.5 mmol). The reaction was heated at 80 °C overnight and then cooled to room temperature. The reaction was filtered and the solids washed with acetonitrile. The filtrate was concentrated and the residue was stirred with hexanes, then filtered and the solid washed with hexanes. The hexanes were concentrated to give the title compound as a yellow oil (13.2 g, 100 % yield). MS (m/z) 328.9 (M+2 + ).

INTERMEDIATE 58

4-bromo-2 obenzene

To a solution of 4-bromo-2-ethoxyaniline (8.78 g, 40.6 mmol) in acetonitrile (105 ml) at 0 °C was added dropwise a solution of l 2 (20.6 g, 81 mmol) and tert-butyl nitrite (5.79 ml, 48.8 mmol) in acetonitrile (400 ml) over 30 minutes and the reaction stirred for 1.5 hours. The mixture was then quenched with aqueous Na 2 S0 3 while maintaining the temperature below 10 °C and then extracted with hexanes (3 x 500 ml). The combined hexanes extracts were dried over MgS0 4 , filtered and concentrated. The residue was purified by flash chromatography (ISCO, 330 g column, 0-5 % EtOAc/hexanes over 30 minutes) to give the title compound as a clear oil (6 g, 45 % yield). MS (m/z) 327.2 (M+H + ). INTERMEDIATE 59

dimethyl (3-bromo- -ethoxyphenyl)phosphonate

To a 250 ml flask was added 1-bromo-3-ethoxy-5-iodobenzene (13.2 g, 40.5 mmol), Pd(OAc) 2 (0.91 g, 4.05 mmol) and trimethyl phosphate (10.8 ml, 92 mmol). The reaction was heated to 105 °C for 1 hour. Additional Pd(OAc) 2 (0.91 g, 4.05 mmol) was added. After an additional 1.5 hours, Pd(OAc) 2 (0.91 g, 4.05 mmol) was added along with trimethyl phosphite (4.79 ml, 40.5 mmol) and the reaction temperature increased to -110 °C. Trimethyl phosphite (5.98 ml, 50.6 mmol) was added and the reaction observed to go to completion in 1 hour. The reaction was cooled to room temperature, diluted with Et 2 0 and then filtered. The filtrate was concentrated, and the residue stirred with hexanes. The hexanes were decanted and the process repeated twice with additional hexanes. The combined hexanes decants were washed with water, dried over Na 2 S0 4 , filtered and concentrated to give the title compound as an orange oil (7.56 g, 60 % yield). MS (m/z) 309.0 (M + ).

Alternate synthesis of Intermediate 59: dimethyl (3-bromo-5-ethoxyphenyl)phosphonate

To 1-bromo-3-ethoxy-5-iodobenzene (53.7 g, 164 mmol) in 1 ,4-dioxane (469 ml) was added trimethyl phosphite (48.5 ml, 41 1 mmol) followed by Pd(OAc) 2 (4.61 g, 20.5 mmol). The reaction was refluxed at 105 °C overnight. LCMS indicated incomplete consumption of starting material. Additional trimethyl phosphite (9.70 ml, 82 mmol) and Pd(OAc) 2 (0.37 g, 1.64 mmol) was added, and the reaction was refluxed for another 2 hours and then cooled, and partitioned between DCM and water. DCM layer was separated, washed with brine, passed through a hydrophobic frit and concentrated to obtain crude material as a dark red- colored oil. The crude oil was loaded onto a silica cartridge and purified by flash

chromatography (ISCO Torrent, 750 g column, 100 % DCM for 20 minutes, 0-5 %

MeOH/DCM for 20 minutes, and then 5 % MeOH/DCM for the next 40 minutes. Desired fractions were combined and concentrated to give the title compound as a dark red colored liquid (51 g, 165 mmol, 100% yield). MS (m/z) (309.0/311.0) (bromine isotope). Intermediate 60 was prepared from the indicated iodide by methods analogous to those described for the alternate synthesis of Intermediate 59.

INTERMEDIATE 61

4-bromo-1-(c hoxybenzene

Step 1 : (4-bromo-2-ethoxyphenyl)methanol

To a 250 ml flask was added 4-bromo-2-ethoxybenzoic acid (10.3 g, 41.8 mmol) and THF (50 ml). The solution was cooled to 0 °C in an ice-bath and then BH 3 THF (1 M, 46.0 ml, 46.0 mmol) was added dropwise over -15 minutes while keeping the temperature below 20 °C. The reaction mixture was then stirred for 5 hours at room temperature and then carefully added to a saturated aq. K 2 C0 3 solution (50 ml). The suspension was diluted with water (100 ml) and the THF layer separated and concentrated. The aqueous layer was extracted with EtOAc (3 x). The residue from the concentrated THF layer was combined with the organic extracts and the combined solution was washed with brine and then dried over Na 2 S0 4 , filtered and concentrated to give the title compound as a yellow solid (9.68 g). MS (m/z) 213.0 (M-17 + ).

Step 2: 4-bromo-1-(chloromethyl)-2-ethoxybenzene

To a 100 ml flask was added (4-bromo-2-ethoxyphenyl)methanol (9.68 g, 41.9 mmol) and thionyl chloride (13.8 ml, 189 mmol). The solution was heated to reflux for 15 minutes and then cooled to room temperature. The reaction was then concentrated and the residue dissolved in EtOAc and washed with saturated aq. NaHC0 3 . The layers were separated. The aqueous layer was extracted with additional EtOAc and the combined organic extracts were dried over Na 2 S0 4 , filtered and concentrated to give the title compound as a yellow solid (9.8 g). MS (m/z) 212.2 (fragment corresponding to loss of chlorine). INTERMEDIATE 62

2-(4-brom -2-ethoxyphenyl)acetic acid

Step 1 : 2-(4-bromo-2-ethoxyphenyl)acetonitrile

To a 100 ml flask was added 4-bromo-1-(chloromethyl)-2-ethoxybenzene (6.01 ml,

39.3 mmol), DMF (33.3 ml) and sodium cyanide (2.18 g, 43.2 mmol). The solution was stirred at room temperature overnight under nitrogen. The reaction was then diluted by the addition of NH 4 CI, EtOAc and water. The layers were separated and the aqueous extracted with additional EtOAc. The combined organic layers were washed with brine (2 x), dried over Na 2 S0 4 , filtered and concentrated to give the title compound as a dark oil (9.4 g) which was used without further purification.

Step 2: 2-(4-bromo-2-ethoxyphenyl)acetic acid

To a 250 ml flask was added 2-(4-bromo-2-ethoxyphenyl)acetonitrile (5.79 ml, 39.3 mmol) followed by a solution of NaOH (11.5 g, 288 mmol) dissolved in water (140 ml). The reaction was heated to reflux for 5 hours, then cooled to room temperature and stirred for 7 hours. The reaction was extracted with DCM and while stirring rapidly the aqueous phase was acidified via addition of 6 N HCI. The resulting suspension was stirred at room temperature for 15 minutes and then filtered. The solids were dried under reduced pressure to give the title compound as a light yellow solid (8.9 g). MS (m/z) 278.0 (M+18 + ).

INTERMEDIATE 63

3-brom -5-ethoxybenzoic acid

Step 1 : ethyl 3-bromo-5-ethoxybenzoate

A mixture of 3-bromo-5-hydroxybenzoic acid (10 g, 46.1 mmol) and potassium carbonate (31.8 g, 230 mmol) in acetonitrile (453 ml) was treated with iodoethane (8.19 ml, 101 mmol) and the reaction heated at reflux overnight. The reaction was then cooled to room temperature and filtered. The filtrate was concentrated and the residue partitioned between DCM and water. The organic layer was collected via hydrophobic frit and concentrated to give the title compound as a yellow oil (12.2 g, 97 % yield). MS (m/z) 275.0 (M+2).

Step 2: 3-bromo-5-ethoxybenzoic acid

To a solution of ethyl 3-bromo-5-ethoxybenzoate (5.0 g, 18.3 mmol) in methanol

(18.3 ml) was added sodium hydroxide (2 M, 9.15 ml, 18.3 mmol) and the reaction stirred for 3 hours. The volatiles were removed in vacuo and the remaining solution extracted with ethyl acetate. The layers were separated and the aqueous phase adjusted to pH 4 by the addition of 2 M HCI. The aqueous was then extracted twice with ethyl acetate. The combined organic extracts were washed with brine and then dried and concentrated to give the title compound as a white solid (3.44 g, 97 % yield). MS (m/z) 247.0 (M+2).

INTERMEDIATE 64

ethyl 3-bromo-5-ethoxy-2-hydroxybenzoate

Step 1 : ethyl 5-ethoxy-2-hydroxybenzoate

A mixture of 5-ethoxy-2-hydroxybenzoic acid (3.2 g, 17.6 mmol) in EtOH (35 ml), toluene (1 1 ml) and cone. H 2 S0 4 (0.88 ml) was heated at reflux for 12 hours. The reaction was then concentrated. The solid was dissolved in EtOAC (100 ml), washed with sat.

NaHC0 3 dried over MgS0 4 and concentrated to give the title compound as a white solid (2.75 g).

Step 2: ethyl 3-bromo-5-ethoxy-2-hydroxybenzoate

Ethyl 5-ethoxy-2-hydroxybenzoate (500 mg, 2.4 mmol) was dissolved in glacial acetic acid (2.5 ml) and treated with sodium acetate (213 mg, 2.6 ml) and the mixture cooled in an ice bath. The mixture was then removed from the ice bath and a solution of bromine (125 μΙ, 2.45 mmol) in acetic acid (1 ml) was added dropwise. The reaction was stirred at room temperature for 1 hour and then concentrated. Water (20 ml) and sat. aq. NaHC0 3 solution (50 ml) were then added and the mixture extracted with ethyl acetate (50 ml). The reaction was repeated under the same conditions on a 2 g scale and the combined ethyl acetate extracts were dried over MgS0 4 and concentrated. The residue was crystallized from hexanes to give the title compound as a pink solid (2 g).

INTERMEDIATE 65

(S)-dimethyl 2-(4-bromo- -(2-methoxy-2oxoethoxy)benzamido)succinate

Step 1 : (S)-dimethyl 2-(4-bromo-2-hydroxybenzamido)succinate

To a solution containing (S)-dimethyl 2-aminosuccinate hydrochloride (5.46 g, 27.6 mmol) and 4-bromo-2-hydroxybenzoic acid (5 g, 23.0 mmol) in DMF (50 ml) was added DIPEA (12.1 ml, 69.1 mmol) followed by 1 H-benzo[d][1 ,2,3]triazol-1-ol (3.74 g, 27.6 mmol) and EDC (5.30 g, 27.6 mmol). The reaction was stirred for 18 hours and monitored by LCMS to show desired product. The reaction mixture was diluted with NH 4 CI aq. soln., extracted with diethyl ether (3 x 50 ml), dried over MgS0 4 , filtered and concentrated onto silica.

Purification by flash chromatography (Isco, 80 g column, 0-50 % EtOAc/hexanes) afforded the title compound as a yellow glass (3.1 g, 37.2 % yield). MS (m/z) 362.0 (M+H + ).

Step 2: (S)-dimethyl 2-(4-bromo-2-(2-methoxy-2oxoethoxy)benzamido)succinate

To a solution containing (S)-dimethyl 2-(4-bromo-2-hydroxybenzamido)succinate (3.09 g, 8.58 mmol) in acetone (40 ml) was added methyl 2-bromoacetate (0.89 ml, 9.44 mmol) and potassium carbonate (2.37 g, 17.2 mmol). The reaction was stirred for 3 hours and monitored via LCMS to show desired product. The reaction was diluted with water and extracted with EtOAc (3 x 50 ml). The combined organic layers were dried over MgS0 4 , filtered and concentrated onto silica. Purification by flash chromatography (Isco, 40g column, 0-70% ethyl EtOAc/hexanes) afforded the title compound as a colorless glass (3.5 g, 95 % yield). MS (m/z) 434.1 (M+H + ).

INTERMEDIATE 200

dimethyl 2,2'-((4-bro -2-ethoxybenzoyl)azanediyl)diacetate

4-bromo-2-ethoxybenzoic acid (0.5 g, 2.040 mmol), dimethyl 2, 2'- azanediyldiacetate (0.33 g, 2.040 mmol), EDC (0.39 g, 2.040 mmol), 1-hydroxy-7-

15 azabenzotriazole (0.31 g, 2.04 mmol) and N-methylmorpholine (0.22 ml, 2.04 mmol) were dissolved in DMF. The reaction mixture was stirred at room temperature for 18 hours.

The reaction was then poured into water and diluted with ethyl acetate (50 ml). The layers were separated and the aqueous layer was washed twice with DCM (50 ml each). The layers were separated, and the organic layers were combined, washed with brine, 20 dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (ISCO, 0-50 % ethyl acetate/hexanes) to give the title compound (0.64 g, 81 % yield). MS (m/z) 390.3 (M+H + ). INTERMEDIATE 201

(R)-dimethyl 2-(4-bromobenzamido)succinate

HATU (10.55 g, 27.8 mmol) was added to a stirring mixture of 4-bromobenzoic acid (4.65 g, 23.13 mmol) and (R)-dimethyl 2-aminosuccinate hydrochloride (5.49 g, 27.8 mmol) in DMF (46.3 ml) at RT. TEA (9.67 ml, 69.4 mmol) was then added, and the mixture was stirred for 18 h. EtOAc and brine were added. The organics were washed with brine (2x more), and then the combined washes were back extracted with EtOAc (1x). The combined organics were dried over MgS0 4 , filtered, and concentrated. Purification using ISCO

RF (0-60 % EtOAc/Hex) afforded (R)-dimethyl 2-(4-bromobenzamido)succinate (7.656 g, 22.02 mmol, 95 % yield). MS (m/z) 344 (M+H + ). INTERMEDIATE 202

(S)-dimethyl 2-(4-bromobenzamido)succinate

To a 100-mL round bottom flask was added 4-bromobenzoic acid (706 mg, 3.51 mmol), (S)- dimethyl 2-aminosuccinate hydrochloride (694 mg, 3.51 mmol), 2,4,6-tripropyl-1 ,3,5,2,4,6- trioxatriphosphinane 2,4,6-trioxide (3.14 mL, 5.27 mmol) and triethylamine (1.468 mL, 10.54 mmol) in DCM (8 mL). The resulting mixture was stirred at 23 °C for 2 h, after which the mixture was partitioned between EtOAc and water. The organic phase was separated and washed with 1 N HCI, sat. sodium bicarbonate, and brine. It was then dried over MgS0 4 , filtered, and concentrated by rotovap. The crude (S)-dimethyl 2-(4- bromobenzamido)succinate (1.07 g, 3.1 1 mmol, 89 % yield) was carried directly forward to the next reaction as the crude mixture. MS (m/z) 344 (M+H + ).

INTERMEDIATE 203

(S)-dimeth -(4-bromobenzamido)pentanedioate

To a solution containing (S)-dimethyl 2-aminopentanedioate, hydrochloride (4.63 g, 21.89 mmol) and 4-bromobenzoic acid (4 g, 19.90 mmol) in DMF (75 mL) was added HATU (7.45 g, 19.59 mmol) followed by DIPEA (8.55 mL, 49.0 mmol). The reaction was stirred for 18 h. Reaction mixture was diluted with aq. NH 4 CI, extracted with ethyl ether, dried over MgS0 4 , filtered and concentrated onto Si0 2 . Purification by flash chromatography on ISCO on Si0 2 (80 g) with 0-50 % ethyl acetate in hexanes as eluant afforded the desired product as a colorless solid. MS (m/z) 357.9 (M+H + ). INTERMEDIATE 204

(S)-dimethyl 2-( -bromo-2-ethoxybenzamido)pentanedioate

To a solution containing (S)-dimethyl 2-aminopentanedioate, hydrochloride (3.80 g, 17.95 mmol) and 4-bromo-2-ethoxybenzoic acid (4 g, 16.32 mmol) in DMF (75 ml_) was added HATU (7.45 g, 19.59 mmol) followed by DIPEA (8.55 ml_, 49.0 mmol). The reaction was stirred for 18 h. Reaction mixture was diluted with aq. NH 4 CI, extracted with ethyl ether, dried over MgS0 4 , filtered and concentrated onto Si0 2 . Purification by flash

chromatography on ISCO on Si0 2 (80 g) with 0-50 % ethyl acetate in hexanes as eluant afforded the desired product as a colorless solid. MS (m/z) 402 (M+H + ).

INTERMEDIATE 205

(S)-di-tert- butyl 2-(4-bromo-2-chlorobenzamido)succinate

HATU (1.615 g, 4.25 mmol) was added to a RT solution containing 4-bromo-2-chlorobenzoic acid (1 g, 4.25 mmol) and hunig's base (1.56 ml, 8.92 mmol) in DCM (21.23 ml). The reaction was stirred at RT for 5 minutes and then treated with (S)-di-tert-butyl 2- aminosuccinate, hydrochloride (1.197 g, 4.25 mmol). The reaction was allowed to stir overnight at RT. The reaction was quenched with water and allowed to stir for 1 h. Then 10 ml 1 N HCI was added and the layers were separated. The organic layer was washed with water (1 x 10 ml), dried over MgS0 4 , filtered, and concentrated. The crude product was purified on a Combiflash Rf using a 120 g silica gel gold cartridge eluting at 80 ml/min with a gradient running from 0 % EtOAc/hexanes to 20 % EtOAc/hexanes over 15 min and then 20 % EtOAc/hexanes for 15 min. The desired fractions were concentrated under reduced pressure to provide the title compound (1.528 g, 3.30 mmol, 78 % yield) as a clear, colorless oil. MS (m/z) 351.9 (M-2tBu+H+). INTERMEDIATE 206

dibenzyl (3-(ben nyl)phosphonate

To a degassed mixture of 1-(benzyloxy)-3-bromo-5-iodobenzene (1.00 g, 2.57 mmol), DIEA (0.449 ml, 2.57 mmol), and dibenzyl phosphonate (0.454 ml, 2.056 mmol) was added tetrakis (0.149 g, 0.129 mmol). The resulting mixture was stirred at 80 °C for 3 h. The mixture was concentrated. Purification using ISCO Rf (0-100 % EtOAc/Hex) afforded dibenzyl (3-(benzyloxy)-5-bromophenyl)phosphonate (318 mg, 0.608 mmol, 23.64 % yield) as a clear, thick oil. MS (m/z) 523.2 (M+H + ).

INTERMEDIATE 207

1-(benzylox -3-bromo-5-iodobenzene

Benzyl bromide (4.78 ml, 40.1 mmol) was added to a slurry of 3-bromo-5-iodophenol (10.00 g, 33.5 mmol) and potassium carbonate (13.87 g, 100 mmol) in acetonitrile (33.5 ml). The resulting mixture was stirred for 18 h. Water and excess EtOAc was added. The organics were washed with water (2x) and brine (1x). The combined washes were back- extracted using EtOAc (2x). The combined organics were dried over MgS0 4 , filtered, and concentrated to afford 1-(benzyloxy)-3-bromo-5-iodobenzene (14.06 g, 33.3 mmol, 99 % yield) as an orange oil. MS (m/z) 388.9 (M+H + ).

INTERMEDIATE 208

(S)-dimethyl 2-(4-bromo-2-methylbenzamido)succinate To a solution containing (S)-dimethyl 2-aminosuccinate hydrochloride (5.51 g, 27.9 mmol) and 4-bromo-2-methylbenzoic acid (5 g, 23.25 mmol) in DMF (100 mL) was added HATU (10.61 g, 27.9 mmol) followed by DIPEA (12.18 mL, 69.8 mmol). The reaction was stirred for 18 h. Reaction mixture was diluted with aq. NH 4 CI, extracted with ethyl ether, dried over MgS0 4 , filtered and concentrated onto Si0 2 . Purification by flash chromatography on

ISCO on Si0 2 (80 g) with 0-50 % ethyl acetate in hexanes as eluant afforded the title product as a colorless solid. MS (m/z) 360 (M+H + ).

INTERMEDIATE 209

(S)-dib ccinate

HATU (868 mg, 2.28 mmol) was added to a RT solution containing 4-bromo-2-fluorobenzoic acid (500 mg, 2.28 mmol) and hunig's base (1.20 mL, 6.85 mmol) in DCM (11.42 mL). After stirring for 5 minutes (S)-dibenzyl 2-aminosuccinate, 4-Methylbenzenesulphonic acid salt (1 110 mg, 2.28 mmol) was added to the reaction. The reaction was stirred at RT for 24 h. The reaction was diluted with DCM and 20 mL 1 N HCI. The layers were separated and the aqueous was washed with DCM (1x20 mL). The combined organics were dried over MgS04, filtered, and concentrated onto silica gel for purification. The crude product was purified on a Combiflash Rf using a 80 g silica gel cartridge eluting at 60 mL/min with a gradient running from 0 % EtOAc/hexanes to 20 %EtOAc/hexanes over 15 min and then 20% EtOAc/hexanes for 10 min. The desired fractions were concentrated under reduced pressure to provide the title compound (S)-dibenzyl 2-(4-bromo-2-fluorobenzamido)succinate (1.1 1 g, 2.15 mmol, 94 % yield) as a clear, colorless oil which slowly crystallized to a colorless solid. MS (m/z) 514.1 (M+H + ). INTERMEDIATE 66

dimethyl (3-ethoxy-5-(4,4,5,5-te orolan-2-yl)phenyl)phosphonate

PdCl 2 (dppf)-CH 2 Cl 2 adduct (1.00 g, 1.22 mmol) was added to a mixture of dimethyl (3-bromo-5-ethoxyphenyl)phosphonate (7.56 g, 24.46 mmol), bis(pinacolato)diboron (9.32 g, 36.7 mmol), and potassium acetate (9.60 g, 98 mmol) in 1 ,4-dioxane (48.9 ml) and the reaction heated at 105 °C for 3 hours. The reaction was then cooled to room temperature and diluted by the addition of Et 2 0 and water. The mixture was stirred for 5 minutes and then the layers were separated. The aqueous layer was extracted with additional Et 2 0. The combined Et 2 0 extracts were filtered and concentrated to give a dark residue. Hexanes were added to the residue and the solution stirred for 5 minutes. The hexanes were decanted off and the process repeated twice more. The combined hexanes decants were dried over Na 2 S0 4 , filtered and concentrated to give an orange oil which was purified by flash chromatography (ISCO, 330 g column, 0-100 % EtOAc/DCM over 20 minutes and then 0-20 % MeOH/DCM over 20 minutes) to give the title compound as an orange oil (6.5 g, 60 % yield) that crystallized on standing. MS (m/z) 275.1 (consistent with mass of boronic acid).

Intermediates 67-74 and 300-307 were prepared from the indicated bromide by methods analogous to those described for Intermediate 66.

MS

# Name Structure Bromide

(m/z)

ethyl 2-ethoxy-4- (4,4,5,5-tetramethyl- ethyl 4-bromo-2-

67 1 ,3,2-dioxaborolan-2- ethoxybenzoate yl)benzoate

2-ethoxy-4-(4, 4,5,5-

21 1.1

tetramethyl-1 ,3,2- (mass of 4-bromo-2-

68 dioxaborolan-2- boronic ethoxybenzoic acid yl)benzoic acid

acid)

(R)-dimethyl 2-(4- o V° o (R)-dimethyl 2-(4- (4,4,5,5-tetramethyl-

392.2 bromobenzamido)su 1 ,3,2-dioxaborolan-2- ccinate yl)benzamido)succinate

(S)-dimethyl 2-(4-

(S)-dimethyl 2-(4- (4,4,5,5-tetramethyl-

392.3 bromobenzamido)su 1 ,3,2-dioxaborolan-2- ccinate yl)benzamido)succinate

(S)-dimethyl 2-(4- (4,4,5,5-tetramethyl- (S)-dimethyl 2-(4- 1 ,3,2-dioxaborolan-2- 406.4 bromobenzamido)pe yl)benzamido)pentanedi ntanedioate oate

(S)-dimethyl 2-(2- ethoxy-4-(4,4,5,5- (S)-dimethyl 2-(4- tetramethyl-1 ,3,2- bromo-2-

450.1

dioxaborolan-2- ethoxybenzamido)p yl)benzamido)pentanedi entanedioate oate

(S)-di-tert-butyl 2-(2-

398.1 (S)-di-tert-butyl 2-(4- chloro-4-(4,4,5,5- ( - bromo-2- tetramethyl-1 ,3,2- 2tBu+H chlorobenzamido)su dioxaborolan-2- +) ccinate yl)benzamido)succinate dibenzyl (3-(benzyloxy)- dibenzyl (3- 5-(4,4,5,5-tetramethyl- (benzyloxy)-5-

571.3

1 ,3,2-dioxaborolan-2- bromophenyl)phosp yl)phenyl)phosphonate honate

(S)-dimethyl 2-(2-

(S)-dimethyl 2-(4- methyl-4-(4,4,5,5- bromo-2- tetramethyl-1 ,3,2- °V° 0 1

406.4

methylbenzamido)su dioxaborolan-2- ccinate yl)benzamido)succinate

INTERMEDIATE 75

3-ethoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoic acid

A mixture of 3-bromo-5-ethoxybenzoic acid (3.44 g, 14.0 mmol),

bis(pinacolato)diboron (5.35 g, 21.1 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (1.15 g, 1.40 mmol) and potassium acetate (6.89 g, 70.2 mmol) in 1 ,4-dioxane (35.1 ml) was heated at reflux for 18 hours. The reaction was then cooled and concentrated. The residue was partitioned between EtOAc and 2 M NaOH. The layers were separated and the aqueous phase then acidified to pH 4 by the addition of HCI and extracted twice with ethyl acetate. The combined organic extracts were then washed with brine, dried and concentrated. The residue was dissolved in DCM and purified by flash chromatography (ISCO Combiflash, 120 g silica column, 20-100 % EtOAc/hexanes) to give the title compound as a white solid (1.69 g, 80 % purity, 41 % yield) which was used without further purification. MS (m/z) 293.1 (M+H + ).

INTERMEDIATE 76

(S)-dimethyl 2-(2-ethoxy-4-(4,4 lan-2-yl)benzamido)succinate

To a mixture of 2-ethoxy-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoic acid (500 mg, 1.71 mmol) and (S)-dimethyl 2-aminosuccinate hydrochloride (406 mg, 2.05 mmol) in DCM (5.95 ml) was added DIPEA (0.90 ml, 5.13 mmol) and HATU (781 mg, 2.05 mmol). The reaction mixture was stirred at room temperature for 2 hours then washed with water and the layers separated. The DCM layer was concentrated and the residue was purified via flash chromatography (ISCO Combiflash Rf, 80 g column, 20-100 % EtOAc/hexanes) to yield the title compound as a light yellow solid (638 mg, 86 % yield). MS (m/z) 436.2 (M+H + ).

Intermediates 77-78 were prepared from (S)-dimethyl 2-aminosuccinate

hydrochloride and the indicated acid by methods analogous to those described for

Intermediate 76.

INTERMEDIATE 79

(9H-fluoren-9-yl)methyl (2-(3-ethoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-

To a mixture of 3-ethoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoic acid

(3.8 g, 13.0 mmol) and (9H-fluoren-9-yl)methyl (2-aminoethyl)carbamate hydrochloride

(4.15 g, 13.0 mmol) in DCM (45 ml) was added HATU (5.94 g, 15.6 mmol) and DIPEA (6.82 ml, 39.0 mmol) and the reaction was stirred at room temperature for 2 hours. The reaction was then reduced in volume, ether was added and the resultant suspension was filtered. The solid was washed with ether. The ether filtrates were reduced in volume and filtered. The combined isolated solids were stirred in a mixture of 5: 1 ether:DCM for 20 minutes then collected by filtration, washed with DCM and ether and dried under vacuum overnight. The solid was then pre-absorbed on to silica and purified by flash chromatography (Si plug, 100 % hexanes (200 ml), 25 % EtOAc/hexanes (200 ml), 100 % DCM (200 ml), 50 %

EtOAc/hexanes (500 ml), 75 % EtOAc/hexanes (500 ml), 100 % EtOAc (500 ml) and 100 % MeOH (200 ml)) to give a white solid which was dried under vacuum overnight to give the title compound as a white solid (2.8 g, 39 % yield). MS (m/z) 557.2 (M+H + ). The original filtrate was washed with water, the layers were separated and the organic phase passed through a phase separator and concentrated. The residue was purified via flash

chromatography (ISCO Combiflash Rf, 120 g column, 25-100 % EtOAc /hexanes) to give a solid that was dried under vacuum overnight to give an additional batch of the title compound as a white solid (3.0 g, 41 % yield). MS (m/z) 557.2 (M+H + ).

INTERMEDIATE 81

methyl 2-hydroxy-4-(4,4, aborolan-2-yl)benzoate

In a microwave vial, methyl 4-bromo-2-hydroxybenzoate (250 mg, 1.08 mmol), bis(pinacolato)diboron (330 mg, 1.30 mmol), potassium acetate (425 mg, 4.33 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (44.2 mg, 0.05 mmol) and 1 ,4-dioxane (6 ml) were combined. The reaction vial was then irradiated at 140 °C for 20 minutes in microwave reactor.The reaction mixture was then cooled to room temperature, diluted with EtOAc and brine (10 ml) and filtered through a 0.45 uM PTFE frit. The layers were then separated and the organic layer was passed through a hydrophobic frit, concentrated and purified via Si0 2

chromatogaphy (ISCO Combiflash Rf and eluted with 0 to 10% methanol in DCM over 20 minutes, 25 g column) to yield the desired compound. MS (m/z) 279.1.

INTERMEDIATE 400

Dimethyl 2, 2'-((3-ethoxy-5-(4, 4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)

benzoyl)azanediyl) diacetate

To a 100 ml round bottom flask was added 3-ethoxy-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzoic acid (607 mg, 2.078 mmol) and dimethyl 2,2'-azanediyldiacetate hydrochloride (41 1 mg, 2.078 mmol). The solids were dissolved in DCM (10 ml), then DIPEA (1.089 ml, 6.23 mmol) and HATU (948 mg, 2.493 mmol) were added successively. The mixture was stirred for 20 h, at which point the reaction was quenched with saturated aqueous NaHC0 3 solution. The organic phase was dilute with EtOAc and separated, then washed with saturated aqueous NH 4 CI and brine. It was then dried over MgS0 4 , filtered, and concentrated by rotovap. Purification was performed by ISCO (80 g column, 0 % to 100 % EtOAc in hexanes) to afford dimethyl 2,2'-((3-ethoxy-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzoyl)azanediyl)diacetate (256 mg, 0.588 mmol, 28.3 % yield). MS (m/z) 436.3 (M+H + ).

INTERMEDIATE 401

Dimethyl 2, 2'-((3-ethoxy-5-(4, 4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)

b

To a 100 ml round bottom flask was added dimethyl 2,2'-((4-bromo-2- ethoxybenzoyl)azanediyl)diacetate (773 mg, 1.99 mmol), bis(pinacolato)diboron (758 mg, 2.99 mmol), and potassium acetate (586 mg, 5.97 mmol) in 1 ,4-dioxane (10 ml). The mixture was degassed with N 2 for 5 min, at which point PdCl 2 (dppf)-CH 2 Cl 2 adduct (81 mg, 0.100 mmol) was added. The resulting mixture was stirred at 100 °C for 3 h. LCMS showed the desired mass and the crude solution was cooled to RT and carried onto the next reaction. MS (m/z) 436.3 (M+H + ). INTERMEDIATE 402

methyl 3-(2-methoxy-2-oxoethoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoate

To a 20 ml vial was added methyl 3-hydroxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzoate (866 mg, 3.1 1 mmol) and potassium carbonate (861 mg, 6.23 mmol) in acetonitrile (10 ml), followed by methyl bromoacetate (0.344 ml, 3.74 mmol). The vial was heated to 80 °C and stirred for 1 h. Another 0.240 ml methyl bromoacetate and 450 mg potassium carbonate were added. Stirred at 80 °C for an additional 18 h. Partitioned between EtOAc and water, organic phase separated and washed with water and brine. It was then dried over MgS0 4 , filtered, and concentrated by rotovap. Purification was performed by ISCO (120 g column, 0 % to 100 % EtOAc in hexanes) to afford methyl 3-(2- methoxy-2-oxoethoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoate(150 mg, 0.428 mmol, 13.76 % yield) as a white solid. MS (m/z) 351.2 (M+H + ).

INTERMEDIATE 82

(R)-N-((2-((N-(benzyloxy)formamido)methyl)heptanamido)methyl )-6'-methoxy-[2,2'-

(R)-N-(aminomethyl)-2-((N-(benzyloxy)formamido)methyl)heptan amide (0.1 g, 0.31 mmol) in DCM (1 ml) was added to a solution of 6'-methoxy-[2,2'-bipyridine]-6-carboxylic acid (0.07 g, 0.31 mmol), HATU (0.13 g, 0.34 mmol), and DIPEA (0.16 ml, 0.93 mmol) in DMF (1 ml) and the reaction was stirred at room temperature overnight. The reaction was then extracted with EtOAc (2 x). The combined organic extracts were washed with water, dried over Na 2 S0 4 , filtered and concentrated. The residue was treated with a pre-mixed solution of CDI (0.04 g, 0.23 mmol) and formic acid (0.01 ml, 0.31 mmol) in DCM (2 ml) and the reaction stirred at room temperature overnight. The reaction was then washed with 1 N HCI and water. The organic layer was separated, dried over Na 2 S0 4 , filtered and concentrated. The residue was purified by flash chromatography (ISCO, 24 g column, 0-40 % EtOAc/DCM: 30 minutes, 40 % EtOAc/DCM: 10 minutes) to give the title compound as a thick oil (0.07 g, 42 % yield). MS (m/z) 534.3 (M+H + ).

Intermediate 83 was prepared from (R)-N-(aminomethyl)-2-((N- (benzyloxy)formamido)methyl)heptanamide and the indicated acid by methods analogous to those described for Intermediate 82 with slight modifications to the base, solvent and coupling reagent.

INTERMEDIATE 84

(R)-N-((3-(N-(benzyloxy)formamido)-2-(cyclopentylmethyl)prop anamido)methyl)-3- phenoxybenzamide

A solution of EDC (423 mg, 2.20 mmol), (R)-N-(aminomethyl)-3-(N- (benzyloxy)formamido)-2-(cyclopentylmethyl)propanamide (245 mg, 0.74 mmol), HOBt (22.5 mg, 0.15 mmol), 3-phenoxybenzoic acid (189 mg, 0.88 mmol) and DIPEA (0.64 ml, 3.67 mmol) in DMF (5 ml) and THF (5 ml) was stirred at room temperature for 18 hours. The reaction was then diluted by the addition of NH 4 CI and EtOAc. The mixture was extracted with EtOAc (3 x) and the combined organic layers were washed with brine (2 x), dried over Na 2 S0 4 , filtered and concentrated. The residue was purified by flash chromatography (ISCO, 120 g silica column, 65 ml/min, 0-60 % EtOAc/DCM over 45 minutes) to give the title product (380 mg, 98 % yield). MS (m/z) 530.3 (M+H + ).

Intermediate 86 was prepared from (R)-N-(aminomethyl)-2-((N- (benzyloxy)formamido)methyl)heptanamide and the indicated acid by methods analogous to those described for Intermediate 84.

INTERMEDIATE 87

ethyl 2-ethoxy-4-(3-fluoro-6-((((R)-2-((R)-1-(N-hydroxyformamido)p ropyl)heptanamido)

6-(3-ethoxy-4-(ethoxycarbonyl)phenyl)-5-fluoropicolinic acid (129 mg, 0.39 mmol) and (R)-N-(aminomethyl)-2-((R)-1-(N-hydroxyformamido)propyl)hept anamide (100 mg, 0.39 mmol) were dissolved in dry DMF (1.8 ml) and treated with DIPEA (0.14 ml, 0.77 mmol) followed by HATU (161 mg, 0.42 mmol). The reaction was stirred at room temperature for 18 hours and then poured into water and the mixture extracted with EtOAc (3 x 50 ml). The combined organic extracts were dried over MgS0 4 , filtered, and concentrated. The residue was purified by reverse phase HPLC (Waters, Starise, 30 x 150 mm, 30-70 % CH 3 CN/water (+ 0.1 % TFA)) to give the title compound (61 mg, 27 % yield). MS (m/z) 575.2 (M+H + ). INTERMEDIATE 88

((R)-N-((2-((N-(benzyloxy)formamido)methyl)-4-phenylbutanami do)methyl)-6-

A solution of (R)-2-((N-(benzyloxy)formamido)methyl)-4-phenylbutanoic acid (0.13 g, 0.4 mmol), N-(aminomethyl)-6-phenylpicolinamide hydrochloride (0.12 g, 0.44 mmol), EDC (0.19 g, 0.99 mmol), HOBt (0.01 g, 0.08 mmol), and DIPEA (0.21 ml, 1.19 mmol) in THF (3 ml) was stirred at 50 °C overnight. The reaction was then concentrated and the residue purified by flash chromatography (ISCO, 0-70 % EtOAc/DCM: 15 minutes; 70 %

EtOAc/DCM: 10 minutes) to give the title compound as a thick clear oil (0.14 g, 62 % yield). MS (m/z) 537.3 (M+H + ).

Intermediates 89-91 and 93-97 were prepared from (R)-2-((N- (benzyloxy)formamido)methyl) heptanoic acid and the indicated amine by methods analogous to those described for Intermediate 88 with slight modifications to the base, solvent and coupling reagent.

(R)-N-((2-((N- (benzyloxy)formami

do)methyl)heptana N-(aminomethyl)-3-

91 mido)methyl)-3-(5- 417.2 (5-methyloxazol-2- methyloxazol-2- yl)benzamide

yl)benzamide

(R)-N-((2-((N- (benzyloxy)formami

N-(aminomethyl)-3- do)methyl)heptana

((6-methoxypyridin-

93 mido)methyl)-3-((6- 549.3

3-yl)oxy)benzamide methoxypyridin-3- yl)oxy)benzamide

(R)-N-((2-((N- (benzyloxy)formami N-(aminomethyl)- do)methyl)heptana [1 ,1 '-biphenyl]-3-

94 mido)methyl)-[1 , T- carboxamide biphenyl]-3- hydrochloride

carboxamide

(R)-N-((2-((N- (benzyloxy)formami

N-(aminomethyl)-3- do)methyl)heptana

(4,5- mido)methyl)-3-

95 521.3 dimethyloxazol-2-

(4,5- yl)benzamide dimethyloxazol-2- yl)benzamide

(R)-N-((2-((N-

N-(aminomethyl)-3- (benzyloxy)formami

(4-methyl-1 H- do)methyl)heptana

96 506.3 pyrazol-1- mido)methyl)-3-(4- yl)benzamide methyl-1 H-pyrazol-

1-yl)benzamide (R)-N-((2-((N- (benzyloxy)formami

N-(aminomethyl)-3- do)methyl)heptana

(2-methyloxazol-5-

97 mido)methyl)-3-(2- 507.2

yl)benzamide methyloxazol-5- yl)benzamide

INTERMEDIATE 98

(R)-N-((2-((N-(benzyloxy)formamido)methyl)heptanamido)methyl )-6-ph

(trifluoromethyl)picolinamide

N-(aminomethyl)-6-phenyl-4-(trifluoromethyl)picolinamide (227 mg, 0.77 mmol), HATU (292 mg, 0.77 mmol) and DIPEA (0.27 ml, 1.54 mmol) were added to a solution of (R)-2-((N-(benzyloxy)formamido)methyl)heptanoic acid (226 mg, 0.77 mmol) in DMF (3.6 ml) and the reaction stirred at room temperature for 18 hours. Water (10 ml) and EtOAc (30 ml) were then added to the reaction and the layers were separated. The organic layer was washed with water, dried over Na 2 S0 4 , filtered and concentrated to give the title compound (378 mg, 86 % yield). MS (m/z) 571.2 (M+H + ).

Intermediates 99-104 were prepared from (R)-2-((N-(benzyloxy)formamido)methyl) heptanoic acid and the indicated amine by methods analogous to those described for

Intermediate 98.

6-phenylpyrazine- 2-carboxamide

(R)-N-((2-((N- (benzyloxy)forma

N-(aminomethyl)- mido)methyl)hept

5-fluoro-6- anamido)methyl)-

100 521.3 phenylpicolinamid

5-fluoro-6- e phenylpicolinamid

e

(R)-N-((2-((N- (benzyloxy)forma

N-(aminomethyl)- mido)methyl)hept

2,2'-difluoro-3'- anamido)methyl)- methoxy-[1 , T-

101 2,2'-difluoro-3'- 568.2

biphenyl]-3- methoxy-[1 , 1 '- carboxamide biphenyl]-3- carboxamide

(R)-N-((2-((N- (benzyloxy)forma

N-(aminomethyl)- mido)methyl)hept

2-fluoro-3'- anamido)methyl)- methoxy-[1 , T- 2-fluoro-3'- 550.3

102 biphenyl]-3- methoxy-[1 , 1 '- carboxamide biphenyl]-3- carboxamide

(R)-N-((2-((N- N-(aminomethyl)- (benzyloxy)forma 2,2'-difluoro-5'- mido)methyl)hept methoxy-[1 , T-

103 568.3

anamido)methyl)- biphenyl]-3- 2,2'-difluoro-5'- carboxamide methoxy-[1 , 1 '-

Intermediate 105 was prepared from (2R,3R)-3-(N-(benzyloxy)formamido)-2- phenethylpentanoic acid and the indicated amine by methods analogous to those described for Intermediate 98.

INTERMEDIATE 106

(R)-N-((2-((N-(benzyloxy)formamido)methyl)heptanamido)methyl )-6-(4- fluorophenyl)picolinamide

To a solution of (R)-N-((2-((N-(benzyloxy)formarnido)methyl)heptanarnido)meth yl)-6- bromopicolinamide (150 mg, 0.3 mmol), (4-fluorophenyl)boronic acid (50 mg, 0.36 mmol) and PdCl 2 (dppf)-CH 2 Cl 2 adduct (8 mg, 9.80 μηιοΙ) in 1 ,4-dioxane (1.8 ml) was added aq. Na 2 C0 3 solution (10 %, 0.95 ml, 0.89 mmol) and the reaction was subjected to microwave irradiation at 100 °C for 5 minutes. The reaction was then partitioned between ethyl acetate (10 ml) and water (1 ml) and the layers separated. The organic phase was washed with brine (1 ml), dried over sodium sulfate and concentrated. The residue was preabsorbed on to silica and purified by flash chromatography (ISCO Combiflash, 12 g ISCO RediSep column, 5- 50 % EtOAc (+ 1 % MeOH)/hexanes) to give the title compound as a colorless oil (103 mg, 60 % yield). MS (m/z) 521.3 (M+H + ).

Intermediates 107-112 were prepared from (R)-N-((2-((N- (benzyloxy)formamido)methyl)heptanamido)methyl)-6-bromopicol inamide and the indicated boronic acid by methods analogous to those described for Intermediate 106.

Intermediates 113-118 were prepared from (R)-N-((3-(N-(benzyloxy)formamido)-2- (cyclopentylmethyl)propanamido)methyl)-3-bromobenzamide and the indicated boronic acid by methods analogous to those described for Intermediate 106.

carboxamide

Intermediate 1 19 was prepared from N-(((R)-2-((R)-1-(N- (benzyloxy)formamido)propyl)heptanamido)methyl)-3-bromobenza mide and the indicated boronate/boronic acid by methods analogous to those described for Intermediate 106.

MS (m/z) Boronate/

Int. Name Structure

(M+H + ) boronic acid

3'-((((R)-2-((R)-1-(N- 3-ethoxy-5- (benzyloxy)formamid (4,4,5,5- o)propyl)heptanamid tetramethyl-

119 o)methyl)carbamoyl)- 618.2 1 ,3,2-

5-ethoxy-[1 , 1 '- dioxaborolan biphenyl]-3- -2-yl)benzoic carboxylic acid acid

Intermediates 120-140 and 142 were prepared from (R)-N-((2-((N- (benzyloxy)formamido)methyl)heptanamido)methyl)-3-bromobenza mide and the indicated boronate/boronic acid by methods analogous to those described for Intermediate 106.

dicarboxamide

Intermediates 143-149 were prepared from (R)-N-((3-(N-(benzyloxy)formamido)-2- (cyclopentylmethyl)propanamido)methyl)-3-bromobenzamide and the indicated boronic acid by methods analogous to those described for Intermediate 106.

carboxamide (R)-N-((3-(N- (benzyloxy)formamido

(5- )-2- methoxypyridin

149 (cyclopentyl methyl) pr H H 1 545.2

-3-yl)boronic opanamido)methyl)-3- acid (5-methoxypyridin-3- yl)benzamide

Intermediates 150-151 were prepared from (R)-N-((2-((N-(benzyloxy)formamido) methyl)-4-phenylbutanamido)methyl)-3-bromobenzamide and the indicated boronic acid by methods analogous to those described for Intermediate 106.

Intermediates 152-154 were prepared from N-(((R)-2-((R)-1-(N- (benzyloxy)formamido)propyl)heptanamido)methyl)-3-bromobenza mide and the indicated boronate/boronic acid by methods analogous to those described for Intermediate 106.

yl)phosphonae Intermediate 155 was prepared from N-(((R)-2-((R)-1-(N- (benzyloxy)formamido)propyl)heptanamido)methyl)-6-bromopicol inamide and the indicated boronate/boronic acid by methods analogous to those described for Intermediate 106.

INTERMEDIATE 156

3-(6-((((R)-2-((R)-1-(N-(benzyloxy)formamido)propyl)heptanam ido)methyl)carbamoyl)pyridin- 2-yl)-5-ethoxybenzoic acid

A mixture of 3-ethoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoic acid

(304 mg, 1.04 mmol), N-(((R)-2-((R)-1-(N-(benzyloxy)formamido)propyl)

heptanamido)methyl)-6-bromopicolinamide (505 mg, 0.95 mmol), PdCI2(dppf)-CH2CI2 adduct (58.0 mg, 0.07 mmol) and aq. Na2C03 (1 M, 2.84 ml, 2.84 mmol) in 1 ,4-dioxane (7.34 ml) was stirred at 70 °C for 2 hours. The reaction was then slowly diluted with water and DCM, the layers were separated and the aqueous phase acidified by addition of HCI and extracted with DCM (3 x). The combined organic extracts were concentrated and the residue purified by flash chromatography (ISCO Rf, 0-20 % MeOH/DCM) to give the title compound as a dark solid (586 mg, 100 % yield). MS (m/z) 619.3 (M+H+).

Intermediates 157-172 and 500-511 were prepared from N-(((R)-2-((R)-1-(N- (benzyloxy)formamido)propyl)heptanamido)methyl)-6-bromopicol inamide and the indicated boronate/boronic acid by methods analogous to those described for Intermediate 156.

do)succinate

mate

tate

do)succinate

Intermediate 173 was prepared from (R)-N-((2-((N-(benzyloxy)formamido)methyl) heptanamido)methyl)-6-bromopicolinamide and the indicated boronate/boronic acid by methods analogous to those described for Intermediate 156.

Intermediates 174-178 were prepared from N-(((R)-2-((R)-1-(N- (benzyloxy)formamido)propyl)heptanamido)methyl)-3-bromobenza mide and the indicated boronate/boronic acid by methods analogous for those described for Intermediate 156.

INTERMEDIATE 179

(S)-2-(3'-((((R)-2-((R)-1-(N-(benzyloxy)formamido)propyl)hep tanamido)methyl)carbamoyl)-5- eth acid

A mixture of (S)-dimethyl 2-(3-ethoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzamido)succinate N-(((R)-2-((R)-1-(N-(benzyloxy)formamido)propyl)

heptanamido)methyl)-3-bromobenzamide (105 mg, 0.2 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (12.1 mg, 0.02 mmol) and Na 2 C0 3 (1 M, 0.59 ml, 0.59 mmol) in 1 ,4-dioxane (1.53 ml) was stirred at 70 °C for 60 minutes. The reaction was then cooled to room temperature and diluted with MeOH and water (10 ml). LiOH (1.74 mmol) was then added and the reaction was stirred for 1 hour. The reaction was then acidified, diluted with water and extracted with EtOAc (3 x). The combined organic extracts were concentrated to give the title compound (145 mg) which was used without further purification or characterization. INTERMEDIATE 180

dimethyl (3-(6-((((R)-2-((R)-1-(N- (benzyloxy)formamido)propyl)heptanamido)methyl)carbamoyl)pyr idin-2-yl)-5-

A mixture of dimethyl (3-ethoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)phosphonate (505 mg, 1.42 mmol), N-(((R)-2-((R)-1-(N- (benzyloxy)formamido)propyl)heptanamido)methyl)-6-bromopicol inamide (687 mg, 1.29 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (79 mg, 0.1 mmol) and Na 2 C0 3 (1 M, 3.86 ml, 3.86 mmol) in 1 ,4-dioxane (9.98 ml) was stirred at 50 °C for 10 minutes. The reaction was then cooled and extracted with DCM. The organic layer was concentrated and the residue purified by flash chromatography (ISCO, 40 g silica gel column, 0-100 % EtOAc/DCM, 5 %

MeOH/DCM) to give the title compound as a brown solid (586 mg, 67 % yield). MS (m/z) 683.0 (M+H + ).

INTERMEDIATE 181

3'-((9H-xanthen-9-yl)thio)-N-(((R)-2-((R)-1-(N- hydroxyformami l]-3-carboxamide

A solution of 3'-((9H-xanthen-9-yl)thio)-[1 , 1 '-biphenyl]-3-carboxylic acid (251 mg,

0.61 mmol), DIPEA ( 0.28 ml, 1.6 mmol), HOBt (107 mg, 0.8 mmol) and EDC (152 mg, 0.8 mmol) in DCM (6 ml) under nitrogen was stirred at room temperature for 15 minutes then added dropwise to a solution of (R)-N-(aminomethyl)-2-((N- hydroxyformamido)methyl)heptanamide (240 mg, 0.78 mmol) in DCM (3 ml) under nitrogen. The reaction was stirred at room temperature overnight. The reaction was then diluted by the addition of DCM and washed with saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated. The residue was purified by flash chromatography (Biotage SP1 , NH column, 0-15 % MeOH/DCM) to give the title compound (165 mg, 43 % yield). MS (m/z) 646 (M+23 + ). INTERMEDIATE 182

dimethyl (3-ethoxy-5-(6-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)he ptanamido) meth nate

Pd/C (299 mg, 0.28 mmol) was added to dimethyl (3-(6-(((R)-2-((R)-1-(N- (benzyloxy)formamido)propyl)heptanamido)methyl)carbamoyl)pyr idine-2-yl)-5- ethoxyphenyl)phosphonate (586 mg, 0.86 mmol) and the reaction was purged with nitrogen. Ethanol (4 ml) was added followed by methanol (70 ml) and the reaction placed under hydrogen atmosphere (balloon) for 4 hours. The reaction was then filtered through Celite® and concentrated. The residue was purified by flash chromatography (ISCO, 40 g silica column, 0-5 % MeOH/DCM: 15 minutes, 5 % MeOH/DCM: 5 minutes) to give the title compound as a sticky brown oil (408 mg, 88 % yield). MS (m/z) 593.0 (M+H + ).

Intermediates 183-185 and 600-608 were prepared from the indicated intermediate by methods analogous to those described for Intermediate 182.

pentanedioate pentanedioate

INTERMEDIATE 186

(4-(6-((((R)-2-((R)-1-(N- (benzyloxy)formamido)propyl)heptanamido)methyl)carbamoyl)pyr idin-2-yl)-2-

To a solution of dimethyl (4-(6-((((R)-2-((R)-1-(N-(benzyloxy)formamido)propyl) heptanamido)methyl)carbamoyl)pyridin-2-yl)-2-ethoxyphenyl)ph osphonate (531 mg, 0.78 mmol) in DCM (7.53 ml) at 0 °C was added bromotrimethylsilane (0.25 ml, 1.94 mmol). The reaction was allowed to warm to room temperature, stirred for 1 hour and then concentrated. The residue was azeotroped twice with DCM to give the title compound (509 mg, 100 % yield) which was used without further purification. MS (m/z) 655.3 (M+H + ).

INTERMEDIATE 188

6-(3-((2-aminoethyl)carbamoyl)-5-ethoxyphenyl)-N-(((R)-2-((R )-1-(N-(benzyloxy)

formamido)propyl)heptanamido)methyl)picolinamide

A suspension of (9H-fluoren-9-yl)methyl (2-(3-(6-((((R)-2-((R)-1-(N- (benzyloxy)formamido)propyl)heptanamido)methyl)carbamoyl)pyr idin-2-yl)-5- ethoxybenzamido) ethyl)carbamate (234 mg, 0.27 mmol) in acetonitrile (4 ml) was treated with pyrrolidine (0.6 ml, 7.26 mmol) and stirred for 2 hours. The reaction was then concentrated and the residue purified by flash chromatography (ISCO, 40 g column; 0-15 % MeOH + 0.1 % TEA/DCM to give the title compound as a tan solid (170 mg) which was used without further purification. MS (m/z) 661.0 (M+H + ).

INTERMEDIATE 189

(S)-dimethyl 2-(3'-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-3-(2-m ethoxy-2-oxoethoxy)-[1 , 1 '- -4-ylcarboxamido)succinate

To a reaction flask, a mixture of (S)-dimethyl 2-(3'-((((R)-2-((R)-1-(N- (benzyloxy)formamido)propyl)heptanamido)methyl)carbamoyl)-3- (2-methoxy-2-oxoethoxy)- [1 , T-biphenyl]-4-ylcarboxamido)succinate (450 mg, 0.45 mmol) and Pd/C (47.6 mg, 0.05 mmol) was flushed with N 2 . Methanol (4.47 ml) was added, and the mixture was evacuated and backfilled with N 2 (3 x). The mixture was then evacuated and backfilled with H 2 (excess). The resulting mixture was hydrogenated for 18 hours and was then evacuated and flushed with N 2 (3 x). The mixture was filtered though a syringe filter under N 2 , with MeOH. The filtrate was concentrated to dryness. The filtrate was resubjected to the previous reaction conditions with the addition of ammonium formate (282 mg, 4.47 mmol) to the reaction mixture. Additional of ammonium formate (282 mg, 4.47 mmol) and Pd/C (47.6 mg, 0.05 mmol) were required for reaction completion. The mixture was filtered under N 2 , washing with MeOH and concentrated. The concentrate was dissolved in DCM, filtered and concentrated. Purification using ISCO RF (0-10 % MeOH/EtOAc) afforded the title compound (133 mg, 0.18 mmol, 39.5 % yield. MS (m/z). 715.4 (M+H + ).

INTERMEDIATE 190

ethyl 5-ethoxy-2-hydroxy-3'-((((R)-2-((R)-1-(N- hydroxyformamido)p henyl]-3-carboxylate

To a reaction flask, ethyl 3'-((((R)-2-((R)-1-(N- (benzyloxy)formamido)propyl)heptanamido)methyl)carbamoyl)-5- ethoxy-2-hydroxy-[1 , 1 '- biphenyl]-3-carboxylate (221 mg, 0.33 mmol), Pd/C (35.5 mg, 0.03 mmol) and DCM (0.500 ml) was added. The mixture was diluted with methanol (2.0 ml) and ammonium formate (105 mg, 1.67 mmol) was added. The reaction mixture stirred at room temperature for 1 hour. The reaction mixture was filtered through a plug of Celite® with methanol (10 ml) and the filtrate was concentrated. The residue was redisolved in ethyl acetate and methanol and the resulting solution was filtered through a phase separator, concentrated and purified by Si0 2 chromatography (ISCO Combiflash Rf and eluted with 0 to 10 % methanol in ethyl acetate over 20 minutes, 25 g column) to provide the titled compound. MS (m/z) 572.2. (M+H + ). Intermediates 191 -195 were prepared from the indicated intermediate by methods analogous to those described for Intermediate 190.

)heptanamid mido)methyl) o)methyl)car carbamoyl)- bamoyl)- 3-ethoxy-

[1 ,1 - [1 ,1 - biphenyl]-4- biphenyl]-4- yl)phosphona yl)phosphon te ate

Intermediates 196-197 were prepared from (R)-N-(aminomethyl)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamide and the indicated acid by methods analogous to those described for Intermediate 87 with slight modifications to the base, solvent and coupling reagent.

INTERMEDIATE 700

dibenzyl ( osphonate

Paraformaldehyde (3.15 g, 105 mmol) and AcOH (1.091 ml, 19.07 mmol) were added to a mixture of triphenylmethanamine (24.97 g, 96 mmol) in toluene (502 ml). The resulting mixture was heated to 80 °C for 1 h. Dibenzyl phosphonate (21.06 ml, 95 mmol) was added and the mixture was stirred at reflux for 3 h. The reaction was cooled to RT, TEA (5.31 ml, 38.1 mmol) was added, and the mixture was concentrated. Purification using ISCO Rf (0-50 % EtOAc/Hex) afforded dibenzy ((tritylamino)methyl)phosphonate (45.83 g, 86 mmol, 90 % yield) as a colorless solid. MS (m/z) 534.3 (M+H + ).

INTERMEDIATE 701

(bis(benzyloxy) minium chloride

To a stirring mixture of dibenzyl ((tritylamino)methyl)phosphonate (17.61 g, 33.0 mmol) in methanol (165 ml) was added HCI (4 M in dioxane) (12.38 ml, 49.5 mmol). The resulting mixture was stirred at RT for 15 min and was then concentrated to dryness to afford

(bis(benzyloxy)phosphoryl)methanaminium chloride (19.66g, 33.0 mmol). The yield is assumed quantitative (55% by weight). Product is a colorless solid. MS (m/z) 292.1 (M+H + ).

INTERMEDIATE 702

dibenzyl ((4-bromo-2-ethoxybenzamido)methyl)phosphonate

To a stirring solution of 4-bromo-2-ethoxybenzoic acid (10.00 g, 40.8 mmol) and HATU (17.07 g, 44.9 mmol) in acetonitrile (102 ml), DIEA (21.38 ml, 122 mmol) was added DIEA (21.38 ml, 122 mmol). The resulting mixture was added to a stirring slurry of

(bis(benzyloxy)phosphoryl)methanaminium chloride (20.06 g, 61.2 mmol) in DMF (102 ml). The resulting mixture was stirred for 1 hr and was then stored in the freezer overnight. Next, water was added followed by EtOAc. The organics were washed with brine (2x). The combined washes were back-extracted using EtOAc. The combined organics were dried over MgS0 4 , filtered, concentrated and purified using ISCO Rf (0-100 % EtOAc/Hex) to afford dibenzyl ((4-bromo-2-ethoxybenzamido)methyl)phosphonate (14.93 g, 28.8 mmol, 70.6 % yield) as a yellow oil. MS (m/z) 518.2 (M+H + ). Intermediates 703-705 were prepared from the indicated intermediate by methods analogous to those described for Intermediate 702.

INTERMEDIATE 706

dibenzyl ((4-(6-((((R)-2-((R)-1-(N- (benzyloxy)formamido)propyl)heptanamido)methyl)carbamoyl)pyr idin-2-yl)-2- ethoxybenzamido)methyl)phosphonate

To a solution of dibenzyl ((4-bromo-2-ethoxybenzamido)methyl)phosphonate (50 mg, 0.096 mmol), bis(pinacolato)diboron (36.7 mg, 0.145 mmol), and potassium acetate (47.3 mg,

0.482 mmol) in 1 ,4-dioxane (0.386 mL) was added PdCI 2 (dppf)-CH 2 Cl 2 adduct (3.94 mg,

4.82 μηιοΙ). Flask was inserted into a pre-heated heating block at 100 °C for 3 h.

N-(((R)-2-((R)-1-(N-(benzyloxy)formamido)propyl)heptanamido) methyl)-6-bromopicolinamide

(61.8 mg, 0.1 16mmol) and water (0.1 mL) were then added and reaction mixture kept stirring at room temperature for 30 min. Additional PdCl 2 (dppf)-CH 2 Cl 2 adduct (3.94 mg, 4.82 μηιοΙ) and K 2 C0 3 (0.289 ml_, 0.289 mmol) was added and the reaction was stirred for 18 h. Reaction mixture was diluted with EtOAc and an EtOAc/H 2 0 extraction carried out. A final brine wash was carried out and the organic layer collected, concentrated in vacuo, and purified via ISCO purification (12 g column, EtOAc/Hexanes, 100 % Hexanes to 100 % EtOAc) to give the title compound as an off white solid (83.7 mg, 32 % yield). MS (m/z) 622 (M+H + ).

Intermediates 707-709 were prepared from the indicated intermediate by methods analogous to those described for Intermediate 706.

phonate

EXAMPLE 1

3-ethoxy-5-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzoic acid

3-(6-((((R)-2-((R)-1-(N-(benzyloxy)formamido)propyl)heptanam ido)methyl)carbamoyl) pyridin-2-yl)-5-ethoxybenzoic acid (600 mg, 0.97 mmol) was dissolved in

ethanol (3.59 ml) and the reaction flushed with nitrogen. Pd/C (155 mg, 0.15 mmol) was then added and the reaction placed under hydrogen atmosphere (balloon) and stirred at room temperature for 5 hours. The reaction was then filtered through Celite®, washing with ethyl acetate. The filtrates were concentrated and purified by reverse phase HPLC (Waters, X- Bridge PrepShield RP C 18 , 5 μΜ, 30 x 150 mm, 10-50 % CH 3 CN/water + 0.1 % NH 4 OH, 14 minute gradient). Fractions containing product were combined, acidified and extracted with DCM and ethyl acetate. The combined organic extracts were concentrated, the resultant solid was suspended in acetonitrile and stirred for 1 hour and then collected by filtration and air dried to give the title compound as an off white solid (180 mg, 35 % yield). Examples 2-43, 45-49 and 200-205 were prepared from the indicated intermediate by methods analogous to those described for Example 1.

namide (R)-N-((2-((N- (R)-N-((2-((N- h y d roxy f o rm a m i d o) (benzyloxy)formamid methyl)heptanamido o)methyl)heptanamid )methyl)-[2,3'- o)methyl)-[2,3'- bipyridine]-6- bipyridine]-6-

carboxamide carboxamide

(R)-N-((2-((N- (R)-N-((2-((N- hydroxyformamido) (benzyloxy)formamid methyl)heptanamido o)methyl)heptanamid

)methyl)-6-(4- o)methyl)-6-(4- (trifluoromethyl)phen (trifluoromethyl)phen

yl)picolinamide yl)picolinamide

(R)-N-((2-((N- (R)-N-((2-((N- hydroxyformamido) (benzyloxy)formamid methyl)heptanamido o)methyl)heptanamid

)methyl)-6-(4- o)methyl)-6-(4- (trifluoromethoxy)ph (trifluoromethoxy)phe enyl)picolinamide nyl)picolinamide

(R)-N-((2-((N- (R)-N-((2-((N- hydroxyformamido) (benzyloxy)formamid methyl)heptanamido o)methyl)heptanamid )methyl)-6- o)methyl)-6- phenylpyrazine-2- phenylpyrazine-2- carboxamide carboxamide

(R)-5-fluoro-N-((2-

(R)-N-((2-((N- ((N- (benzyloxy)formamid hydroxyformamido)

OH o)methyl)heptanamid methyl)heptanamido

o)methyl)-5-fluoro-6-

)methyl)-6- phenylpicolinamide phenylpicolinamide

(R)-N-((2-((N- (R)-N-((2-((N- hydroxyformamido) (benzyloxy)formamid methyl)heptanamido J OH o)methyl)heptanamid )methyl)-6-phenyl-4- CF 3 J o)methyl)-6-phenyl-4- (trifluoromethyl)picoli (trifluoromethyl)picoli

acid acid

acid methoxybenzoic acid

ethoxybenzoic acid 3-ethoxy-3'-((((R)-2- 3'-((((R)-2-((R)-1-(N-

((R)-1-(N- (benzyloxy)formamid hydroxyformamido)p o)propyl)heptanamid ropyl)heptanamido) o)methyl)carbamoyl)- methyl)carbamoyl)- 3-ethoxy-[1 , T- [1 , 1'-biphenyl]-4- biphenyl]-4- carboxylic acid carboxylic acid

(R)-N-((2-((N- (R)-N-((2-((N- hydroxyformamido) (benzyloxy)formamid methyl)heptanamido o)methyl)heptanamid )methyl)-3-((6- o)methyl)-3-((6- methoxypyridin-3- methoxypyridin-3- yl)oxy)benzamide yl)oxy)benzamide

(R)-N-((2-((N- (R)-N-((2-((N- hydroxyformamido) (benzyloxy)formamid methyl)heptanamido o)methyl)heptanamid

)methyl)-[1,r- o)methyl)-[1,r- biphenyl]-3- biphenyl]-3- carboxamide carboxamide

(R)-2-fluoro-N-((2- (R)-N-((2-((N- ((N- (benzyloxy)formamid hydroxyformamido) o)methyl)heptanamid I methyl)heptanamido o)methyl)-2-fluoro-3'- )methyl)-3'-methoxy- methoxy-[1 , 1 '-

[1 , 1'-biphenyl]-3- biphenyl]-3- carboxamide carboxamide

(R)-2,2'-difluoro-N- (R)-N-((2-((N-

((2-((N- (benzyloxy)formamid hydroxyformamido) o)methyl)heptanamid I methyl)heptanamido o)methyl)-2,2'- )methyl)-3'-methoxy- difluoro-3'-methoxy-

[1 , 1'-biphenyl]-3- [1 , 1'-biphenyl]-3- carboxamide carboxamide (R)-2,2'-difluoro-N- (R)-N-((2-((N-

((2-((N- (benzyloxy)formamid hydroxyformamido) o)methyl)heptanamid methyl)heptanamido o)methyl)-2,2'- )methyl)-5'-methoxy- difluoro-5'-methoxy- [1 , 1'-biphenyl]-3- [1 , 1'-biphenyl]-3- carboxamide carboxamide

(R)-3-(4,5- (R)-N-((2-((N- dimethyloxazol-2-yl)- (benzyloxy)formamid

N-((2-((N- o)methyl)heptanamid hydroxyformamido) o)methyl)-3-(4,5- methyl)heptanamido dimethyloxazol-2-

)methyl)benzamide yl)benzamide

(R)-N-((2-((N- (R)-N-((2-((N- hydroxyformamido) _ Ν O o (benzyloxy)formamid methyl)heptanamido o)methyl)heptanamid

)methyl)-3-(4- o)methyl)-3-(4- methyl-1 H-pyrazol- methyl-1 H-pyrazol-1-

1-yl)benzamide yl)benzamide

(R)-N-((2-((N- (R)-N-((2-((N- hydroxyformamido) (benzyloxy)formamid methyl)heptanamido o)methyl)heptanamid

)methyl)-3-(2- o)methyl)-3-(2- methyloxazol-5- methyloxazol-5- yl)benzamide yl)benzamide

(R)-N-((2-((N- (R)-N-((2-((N- hydroxyformamido) (benzyloxy)formamid methyl)heptanamido o)methyl)heptanamid

)methyl)-3-(2- o)methyl)-3-(2- methoxypyrimidin-4- methoxypyrimidin-4- yl)benzamide yl)benzamide methyl)propanamido (cyclopentylmethyl)pr )methyl)-3'-methoxy- opanamido)methyl)- [1 , 1'-biphenyl]-3- 3'-methoxy-[1 , 1 '- carboxamide biphenyl]-3- carboxamide

(R)-N-((3- (R)-N-((3-(N- cyclopentyl-2-((N- (benzyloxy)formamid hydroxyformamido) o)-2- methyl)propanamido (cyclopentylmethyl)pr )methyl)-4'- opanamido)methyl)- (trifluoromethyl)- 4'-(trifluoromethyl)- [1 , 1'-biphenyl]-3- [1 , 1'-biphenyl]-3- carboxamide carboxamide

(R)-N-((3-(N-

(R)-3'-cyano-N-((3- (benzyloxy)formamid cyclopentyl-2-((N- o)-2- hydroxyformamido)

0 0 (cyclopentylmethyl)pr methyl)propanamido

opanamido)methyl)- )methyl)-[1 , 1 '- 3'-cyano-[1 , T- biphenyl]-3- biphenyl]-3- carboxamide

carboxamide

(R)-N-((3- (R)-N-((3-(N- cyclopentyl-2-((N- (benzyloxy)formamid hydroxyformamido) o)-2- methyl)propanamido (cyclopentylmethyl)pr )methyl)-[1 , 1 '- opanamido)methyl)- biphenyl]-3- [1 , 1'-biphenyl]-3- carboxamide carboxamide

(R)-N-((3- (R)-N-((3-(N- cyclopentyl-2-((N- (benzyloxy)formamid hydroxyformamido) o)-2- methyl)propanamido (cyclopentylmethyl)pr )methyl)-3- opanamido)methyl)- ethyl)phosphonic thyl)phosphonate acid

dibenzyl ((2-

((2-hydroxy-4-(6- (benzyloxy)-4-(6- ((((R)-2-((R)-1-(N- hydroxyformamido)p o OH ((((R)-2-((R)-1-(N- yloxy)formamid ropyl)heptanamido) N Y S O O (benz

203 o)propyl)heptanamid methyl)carbamoyl)p

o)methyl)carbamoyl) yridin-2- pyridin-2- yl)benzamido)methyl

yl)benzamido)methyl) )phosphonic acid

phosphonate

(3-hydroxy-5-(6- dibenzyl (3- ((((R)-2-((R)-1-(N- (benzyloxy)-5-(6- hydroxyformamido)p

((((R)-2-((R)-1-(N- ropyl)heptanamido)

(benzyloxy)formamid methyl)carbamoyl)p

204 o)propyl)heptanamid yridin-2- HO OH j J OH

o)methyl)carbamoyl) yl)phenyl)phosphoni

pyridin-2- c acid,

yl)phenyl)phosphonat Trifluoroacetic acid

e salt

(S)-2-(2-fluoro-4-(6-

(S)-di benzyl 2-(4-(6- ((((R)-2-((R)-1-(N- ((((R)-2-((R)-1-(N- hydroxyformamido)p

(benzyloxy)formamid ropyl)heptanamido)

o)propyl)heptanamid

205 methyl)carbamoyl)p

o)methyl)carbamoyl) yridin-2- pyridin-2-yl)-2- yl)benzamido)succin

fluorobenzamido)suc ic acid,

cinate 2 Ammonia salt

EXAMPLE 51 (R)-N-((2-((N-hydroxyformamido)methyl)heptanamido)m

A solution of (R)-N-((2-((N-(benzyloxy)formamido)methyl)heptanamido)methyl )-3-(5- methyloxazol-2-yl)benzamide (61 mg, 0.12 mmol) in methanol (1 ml) was added to

Pearlman's catalyst (8.5 mg, 0.01 mmol) and the mixture purged with nitrogen 3 times and then placed under a hydrogen atmosphere (balloon) and stirred at room temperature for 2 hours. The reaction was then filtered through Celite® and the Celite® washed with methanol. The filtrate was concentrated and DCM added to the residue. The resultant precipitate was collected by filtration to give the title compound as an off white solid (25 mg, 47 % yield).

Example 52 was prepared from the indicated intermediate by methods analogous to those described for Example 51.

EXAMPLE 53

5-ethoxy-3'-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)hepta namido)methyl)carbamoyl)- '-biphenyl]-3-carboxylic acid

To a nitrogen purged vial was added 3'-((((R)-2-((R)-1-(N- (benzyloxy)formamido)propyl)heptanamido)methyl)carbamoyl)-5- ethoxy-[1 , T-biphenyl]-3- carboxylic acid (138 mg, 0.22 mmol) followed by Pd/C, (10 % wt, 15 mg, 0.01 mmol). DCM (0.5 ml) was then added followed by methanol (1.5 ml). Ammonium formate (89 mg, 1.41 mmol) was then added and the reaction was stirred for 3 hours and then overnight. The reaction was then filtered through a plug of Celite® and the Celite® was washed with MeOH (10 ml). The filtrate was concentrated and the residue was purified by reverse phase HPLC (Waters, XBridge Prep Shield RP, C18 5 μηι, ODB 30 X 150 mm column, 20-60%

CH 3 CN/water + 0.1 % NH 4 OH over 15 minutes, 2 injections) to give the title compound as a tan solid (49 mg, 31 % yield). Examples 54-84 were prepared from the indicated intermediate by methods analogous to those described for Example 53.

'-

carboxamide '-

dicarboxamide 3,3'-dicarboxamide

EXAMPLE 85

N-(((R)-2-((R)-1-(N-hydroxyformarnido)propyl)heptanamido)met hyl)-3'-mercapto-[1 , 1 '- -3-carboxamide

A solution of 3'-((9H-xanthen-9-yl)thio)-N-(((R)-2-((R)-1-(N-hydroxyformam ido)propyl) heptanamido)methyl)-[1 , T-biphenyl]-3-carboxamide (0.17 g, 0.27 mmol) in a 98:1 : 1 mixture of DCM/TFA/EtsSiH (26 ml) was stirred under nitrogen at room temperature for 20 minutes. The reaction was then diluted by the addition of DCM and poured into saturated sodium bicarbonate solution and the mixture then acidified to pH 3 by addition of 1 M HCI. The layers were separated and the aqueous phase extracted with DCM (3 x). The combined organic extracts were then washed with brine, dried over Na 2 S0 4 , filtered and concentrated. The residue was purified by reverse phase flash chromatography (C18 column, 0-100 % CH 3 CN/water) to give the title compound (80 mg, 68 % yield). EXAMPLE 86

(S)-2-(3-ethoxy-5-(6-((((R)-2-((R)-1-(N-hydroxyformamido)pro pyl)heptanamido)

methyl) ic acid

To a 20 ml vial was added (S)-dimethyl 2-(3-ethoxy-5-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzamido)succinate (200 mg, 0.3 mmol), methanol (6 ml) and water (2 ml) followed by LiOH (42.8 mg, 1.79 mmol). The mixture was stirred at room temperature for 4 hours then reduced in volume to ~ 4-5 ml under a stream of nitrogen. The remaining solution was then acidified by addition of 1 N HCI. The aqueous was decanted and the solid was dissolved in EtOAc and azeotroped 3 times. The aqueous was extracted twice with EtOAc. The EtOAc layer was separated and combined with the initial EtOAc isolates. The combined EtOAc isolates were then washed with water and the layers separated. The aqueous phase was extracted with additional EtOAc (3 x) and the combined organic extracts were concentrated to give the title compound as a red/brown solid (140 mg, 73 % yield).

Examples 87-97 and 300-308 were prepared from the indicated intermediate by methods analogous to those described for Example 86.

(S)-2-(2-(2- (S)-dimethyl 2-(2- ethoxy-4-(6- (2-ethoxy-4-(6- ((((R)-2-((R)-1-(N- ((((R)-2-((R)-1-(N- hydroxyformamid hydroxyformamido)

88 o)propyl)heptana propyl)heptanamid mido)methyl)carb o)methyl)carbamoyl amoyl)pyridin-2- )pyridin-2-

yl)phenyl)acetami yl)phenyl)acetamid do)succinic acid o)succinate

2-ethoxy-4-(3- Ethyl 2-ethoxy-4-(3- fluoro-6-((((R)-2- fluoro-6-((((R)-2-

((R)-1-(N- ((R)-1-(N- hydroxyformamid hydroxyformamido)

89

o)propyl)heptana propyl)heptanamid

OH

mido)methyl)carb o) amoyl)pyridin-2- methyl)carbamoyl)p yl)benzoic acid yridin-2-yl)benzoate

2-ethoxy-4-(4- ethyl 2-ethoxy-4-(4- ((((R)-2-((R)-1-(N- ((((R)-2-((R)-1-(N- hydroxyformamid hydroxyformamido)

90 o)propyl)heptana propyl)heptanamid mido)methyl)carb OH o)methyl)carbamoyl amoyl)pyrimidin- )pyrimidin-2- 2-yl)benzoic acid yl)benzoate

2-ethoxy-4-(6- ethyl 2-ethoxy-4-(6- ((((R)-2-((R)-1-(N- ((((R)-2-((R)-1-(N- hydroxyformamid hydroxyformamido)

91 o)propyl)heptana propyl)heptanamid mido)methyl)carb o)methyl)carbamoyl amoyl)pyrazin-2- )pyrazin-2- yl)benzoic acid yl)benzoate

Hydrochloride

acid Salt

EXAMPLE 98

(3-ethoxy-5-(6-((((R)-2-((R)-1-(N-hydroxyforrnarnido)propyl) heptanarnido)rnethyl) carbamoyl) robromide

TMSBr (0.38 ml, 2.93 mmol) was added to a solution of dimethyl (3-ethoxy-5-(6- ((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methy l)carbamoyl)pyridin-2- yl)phenyl) phosphonate (0.58 g, 0.99 mmol) in DCM (10 ml) at 0 °C. The reaction was then stirred at room temperature overnight. Additional TMSBr (0.2 ml, 1.54 mmol) and DCM (5 ml) were then added and the reaction stirred for 2 hours. 1 N HCI (5 ml) was then added and the resultant solid collected by filtration and air dried. The solid was then suspended in a mixture of 4: 1 CH 3 CN/EtOAc (6 ml) for 30 minutes and then collected by filtration and air dried to give the title compound as a yellow solid (370 mg, 59 % yield). Examples 99-100 were prepared from the indicated intermediate by methods analogous to those described for Example 98.

EXAMPLE 101

(2-ethoxy-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyrazin -2-yl)phenyl)ph

acid

6-(4-(dimethoxyphosphoryl)-3-ethoxyphenyl)pyrazine-2-carboxy lic acid (134 mg, 0.38 mmol) and (R)-N-(aminomethyl)-2-((R)-1-(N-hydroxyformamido)propyl) heptanamide (99 mg, 0.38 mmol) were dissolved in dry DMF (1.28 ml) and treated with DIPEA (0.13 ml, 0.76 mmol) followed by HATU (159 mg, 0.42 mmol). The reaction was stirred at room

temperature for 2 hours. The reaction was then poured into water and extracted with EtOAc (3 x 50 ml). The combined organic extracts were dried over MgS0 4 , filtered, and

concentrated. The residue was dissolved in DCM (2 ml) and treated with

bromotrimethylsilane (0.11 ml, 0.86 mmol) at 0 °C. The reaction was allowed to warm to room temperature and stirred for 2 hours. The reaction was then quenched with sat. aq. ammonium chloride solution and the precipitate that formed was collected and dissolved in DMSO and purified by reverse phase HPLC (Waters, Sunfire Prep Ci 8 , 35 x 150 mm, 10-50 % CH 3 CN/water (+ 0.1 % TFA), 17 minute run) to give the title compound as a tan foam (47 mg, 22 % yield). Example 102 was prepared from (R)-N-(aminomethyl)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamide and the indicated acid by methods analogous to those described for Example 101.

EXAMPLE 103

5-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)met hyl)carbamoyl)-[1 , 1 '- -3-carboxylic acid

Step 1 : 3-bromo-5-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)benzoic acid

To 3-bromo-5-(methoxycarbonyl)benzoic acid (0.50 g, 1.93 mmol) in DCM (19.3 ml) at 0 °C were added (R)-N-(aminomethyl)-2-((R)-1-(N-hydroxyformamido)

propyl)heptanamide (0.60 g, 2.32 mmol), HATU (0.88 g, 2.32 mmol) and DIPEA (0.34 ml, 1.93 mmol). Ice bath was removed and the reaction was stirred at room temperature.

Dissolution of solids was observed upon warming to room temperature. After 20 min of stirring, DMF (2 ml) was added for solubility. After 1 hour of stirring the reaction was diluted with water, and extracted with DCM and then the layers were separated. The organic layer was washed with water, brine, dried over MgS0 4 and concentrated. The resulting white solid was dissolved in MeOH and 0.30 mg of K 2 C0 3 was added and the mixture was stirred for 1 hour. The mixture was filtered and the filtrate concentrated. The residue was dissolved in EtOAc with stirring, washed with water and brine. The aqueous layer was acidified to pH 3 and the resulting solid was filtered and dried to give the title compound as a white solid (0.17 g, 0.34 mmol, 17.7% yield). MS (m/z) 488.1 (M+2 + ). Step 2: 5-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)met hyl)carbamoyl)-[1 , T- biphenyl]-3-carboxylic Acid A suspension of 3-bromo-5-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)benzoic acid (0.07 g, 0.14 mmol), phenylboronic acid (0.02 g, 0.17 mmol), K 2 C0 3 (0.06 g, 0.43 mmol), Silicat DPP-Pd (0.03 g, 7.20 μηιοΙ) in ethanol (1.6 ml) was heated in microwave at 100 °C for 12 minutes. After 12 minutes of heating, additional phenylboronic acid (0.01 g, 0.09 mmol) and Silicat DPP-Pd (0.01 g, 2.4 μηιοΙ) was added and was heated in microwave at 100 °C for 5 more minutes. The reaction was filtered through a frit rinsing with MeOH and the filtrate was concentrated. The crude material was dissolved in DMSO (3 ml) and purified by reverse phase HPLC (Waters, Sunfire prep C18 OBD, 30x 150 mm, 30 to 70% (CH3CN/water)+0.1 %TFA)). The desired fractions were combined and freeze dried to give the title compound as a white solid (0.004 g, 8.05 mol, 5.60 % yield).

EXAMPLE 104

5-ethoxy-3'-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)hepta namido)methyl)carbamoyl)- '-biphenyl]-3-sulfonic acid

Step 1 : 2-ethylhexyl 3-((3-bromo-5-ethoxyphenyl)thio)propanoate

1-bromo-3-ethoxy-5-iodobenzene (2 g, 6.12 mmol) was dissolved in toluene (16.9 ml) and added to a flask containing Xantphos (0.18 g, 0.31 mmol) and Pd 2 (dba) 3 (0.14 g, 0.15 mmol) in dry toluene (1 ml). Hunig's base (2.14 ml, 12.2 mmol) was added to the reaction followed by 2-ethylhexyl 3-mercaptopropanoate (1.39 ml, 6.12 mmol). The flask was purged with nitrogen, fitted with a condenser, and heated to reflux for 16 hours. The reaction was cooled to room temperature and filtered through Celite®. The residual solid was washed with toluene. The combined organics were concentrated to a brown oil which was purified by flash chromatography (ISCO, 120 g column, 85 ml/min elution, 0-10 % EtOAc/hexanes over 15 minutes followed by a 10 % EtOAc/hexanes hold for 10 minutes, 254 nm detection) to give the title compound as a clear oil. MS (m/z) 418.9 (M+2 + ). Step 2: 3-bromo-5-ethoxybenzenesulfonic acid Sodium (31.2 mg, 1.36 mmol) was cut from the main brick in kerosene, washed in hexanes, and weighed into a vial of hexanes. The solid was then added to ethanol (2 ml). 2- ethylhexyl 3-((3-bromo-5-ethoxyphenyl)thio)propanoate (515 mg, 1.23 mmol) dissolved in ethanol (4.2 ml) was added to the freshly made solution of sodium ethoxide. The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with 1 N HCI and concentrated. The crude oil was partitioned between EtOAc and water. The organics were dried over MgS0 4 , filtered, and concentrated to a pale yellow oil. The oil was dissolved in acetonitrile (7 ml) and treated with hydrogen peroxide (1.26 ml, 12.3 mmol) and

methyltrioxorhenium(VII) (30.8 mg, 0.12 mmol). The reaction was stirred at room

temperature for 3 hours. The reaction was quenched with a catalytic amount of Mn0 2 and then concentrated. The resulting solid was washed with hexanes and dried under vacuum to give the title compound as a tan solid (256 mg, 103 % yield).

Step 3: N-(((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)meth yl)-3-(6-methyl-4,8- dioxo-1 ,3,6,2-dioxazaborocan-2-yl)benzamide

3-(6-methyl-4,8-dioxo-1 ,3,6,2-dioxazaborocan-2-yl)benzoic acid (235 mg, 0.85 mmol) and (R)-N-(aminomethyl)-2-((R)-1-(N-hydroxyformamido)propyl)hept anamide (220 mg, 0.85 mmol) were dissolved in DMF (2.53 ml) and treated with Hunig's base (0.30 ml, 1.70 mmol) and HATU (355 mg, 0.93 mmol). The reaction was stirred at room temperature for 18 hours. The reaction was poured into water. The product was extracted into EtOAc. The organics were dried over MgS0 4 , filtered, and concentrated onto silica gel. The material was purified by flash chromatography using solid loading (ISCO, 40 g column, 40 ml/min elution, 0-100 % EtOAc/hexanes over 30 minutes, 254 nm detection) to give the impure title compound as a white solid (462 mg, 105 % yield) that was carried on to the next step in the reaction sequence. MS (m/z) 519.0 (M+H + ).

Step 4: 5-ethoxy-3'-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 , 1 '-biphenyl]-3-sulfonic acid

To a solution of N-(((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)meth yl)- 3-(6-methyl-4,8-dioxo-1 ,3,6,2-dioxazaborocan-2-yl)benzamide (462 mg, 0.89 mmol) and 3- bromo-5-ethoxybenzenesulfonic acid (223 mg, 0.79 mmol) in 1 ,4-dioxane (3.97 ml) was added a solution of sodium carbonate (252 mg, 2.38 mmol) in water (0.5 ml). PdCI 2 (dppf)- CH 2 CI 2 adduct (64.8 mg, 0.079 mmol) was added to the reaction, and the mixture was heated at 80 °C for 5 hours. The reaction was cooled to room temperature and the reaction solution was decanted away from a solid precipitate that formed. This precipitate was washed with EtOAc. The combined washings and reaction solution were concentrated and purified by flash chromatography (ISCO, 80 g column, 60 ml/min elution, 20 % MeOH/DCM, 254 nm detection) to give the title compound as a tan residue.

EXAMPLE 105

5-ethoxy-5'-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)hepta namido)methyl)carbamoyl)- '-biphenyl]-3,3'-dicarboxylic acid

Step 1 : 3-bromo-5-(methoxycarbonyl)benzoic acid

Sodium hydroxide (0.29 g, 7.32 mmol) was added to a suspension of dimethyl 5- bromoisophthalate (2 g, 7.32 mmol) in acetone (30 ml) and water (15 ml) and the reaction stirred at room temperature for 1 hour. A clear solution was achieved at this point. The reaction was stirred overnight at room temperature. The acetone was removed in vacuu and the residual solution extracted with ethyl acetate. The aqueous was then adjusted to pH4 and extracted twice with ethyl acetate. The organic was then washed with brine, dried and concentrated to give the title compound as a 60 % pure white solid (1.23 g, 2.85 mmol, 38.9 % yield). MS (m/z) 259.0/260.9 (bromine isotopes).

Step 2: methyl 3-bromo-5-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)benzoat e

A suspension of 3-bromo-5-(methoxycarbonyl)benzoic acid (100 mg, 0.39 mmol) in acetonitrile (1.83 ml) was treated with HATU (147 mg, 0.39 mmol) followed by DIPEA (0.20 ml, 1.16 mmol) at 0 °C. A clear solution was obtained a few minutes after DIPEA addition and turned dark brown after 10 minutes. A solution of (R)-N-(aminomethyl)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamide (100 mg, 0.39 mmol) in DMF (1.83 ml) was then added to the reaction. After 2.5 hours the reaction was diluted by the addition of water and the organic layer was separated, washed with sodium bicarbonate, brine and then collected via hydrophobic frit and concentrated. The residue was purified by Si SPE (5 g, DCM, ether, ethyl acetate, acetone) to give the title compound as a 75 % pure yellow oil (93 mg, 0.19 mmol, 48.1 % yield). MS (m/z) 500.0/502.0 (bromine isotope). Step 3: 5-ethoxy-5'-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 , T-biphenyl]-3,3'-di acid

To a mixture of methyl 3-bromo-5-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)benzoat e (90 mg, 0.18 mmol), 3- ethoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoic acid (79 mg, 0.27 mmol) and PdCl 2 (dppf)-CH 2 Cl 2 adduct (14.7 mg, 0.02 mmol) in 1 ,4-dioxane (0.80 ml) was added Na 2 C0 3 (1 M in water) (0.54 ml, 0.54 mmol) and the reaction heated at 100 °C in the microwave for 5 minutes. Reaction was diluted by the addition of DCM and 2 M NaOH. The layers were separated and the aqueous layer was then adjusted to pH4 and extracted with DCM. The organic layer was collected by hydrophobic frit and concentrated to give a dark brown oil which was then re-dissolved in the minimum amount of DCM and purified by Si SPE (5 g, DCM, ether, ethyl acetate, acetone and 10 % methanol in DCM), but no desired product was isolated. The aqueous layer contained some solid which was collected by filtration (3.8 mg). Analysis of material showed that hydrolysis had occurred during work up and di-acid material had formed, but entire sample was used for analysis. Filtrate was concentrated to give 29 mg which was re-purified by Si SPE (1 g, DCM, ether, ethyl acetate, acetone and 10 % methanol in DCM) to give the title compound as a pale orange solid (14 mg, 0.02 mmol, 1 1.6 % yield).

EXAMPLE 400

(S)-2-(2-chloro-4-(6-((((R)-2-((R)-1-N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin -2-yl)benzamido)succinic acid

Pd-C (13.30 mg, 0.125 mmol) was added under a heavy stream of nitrogen to a RT solution containing (S)-di-tert- butyl 2-(4-(6-((((R)-2-((R)-1-(N- (benzyloxy)formamido)propyl)heptanamido)methyl)carbamoyl)pyr idin-2-yl)-2- chlorobenzamido)succinate (209 mg, 0.250 mmol) in ethanol (5 ml). The reaction was purged with a hydrogen needle for 15 min and then stirred under positive hydrogen balloon pressure for 6 h. The reaction mixture was filtered through celite. The celite was washed with methanol. The combined organics were concentrated to a clear, orange film. The film was dissolved in dioxane and concentrated to remove any excess ethanol. The residue was dissolved in 5 ml DCM and treated with trifluoroacetic acid (385 μΙ, 5.00 mmol). The reaction was allowed to stir overnight. The reaction was concentrated, taken up in dioxane (10 ml), and concentrated again to remove any residual TFA. The concentrated crude product was dissolved in 0.5 ml DMSO and was purified via HPLC (Waters Xbridge 30x150 mm

Acetonitrile:Water NH 4 OH 10-50 % Flow Rate: 50 ml/min Gradient time: 26 min).

MS (m/z) 634.3 (M+H + ).

Spectroscopic data for Examples 1-43, 45-49, 51-105, 200-205, 300-308, and 400:

Ή NMR (DMSO-d6) δ: 9.25-9.47 (m, 1 H), 8.83-9.21 (m, 1 H), 8.54 (dd,

J=23.1 , 7.3 Hz, 1 H), 8.34 (dd, J=34.9, 7.3 Hz, 1 H), 8.00-8.16 (m, 2.4H),

444.2 7.82-7.96 (m, 1 H), 7.75 (s, 0.6H), 6.84-7.03 (m, 1 H), 4.50-4.93 (m, 2H), 7.58 a

(M+H + ) 3.99 (s, 3H), 3.17-3.66 (m, 2H), 2.57-2.85 (m, 1 H), 1.20-1.53 (m, 2H),

0.97-1.21 (m, 6H), 0.60-0.78 (m, 3H). H NMR (DMSO-d6) δ: 9.95 (br. s., 0.4H), 9.60 (s, 0.6H), 9.47-9.57 (m,

1 H), 9.16 (d, J=5.0 Hz, 1 H), 8.64-8.71 (m, 1 H), 8.62 (d, J=5.8 Hz, 2H),

414.2 8.22 (s, 0.4H), 7.94 (d, J=4.8 Hz, 1 H), 7.83 (s, 0.6H), 7.47-7.65 (m, 3H), 7.17 a

(M+H + ) 4.59-4.88 (m, 2H), 3.49-3.70 (m, 1 H), 3.34-3.49 (m, 1 H), 2.57-2.79 (m,

1 H), 1.23-1.50 (m, 2H), 0.99-1.24 (m, 6H), 0.69 (m, 3H).

Ή NMR (METHANOL-d4) δ: 8.08-8.18 (m, 2.4H), 7.88-8.00 (m, 3H),

7.77 (s, 0.6H), 7.14 (t, J=8.5 Hz, 2H), 4.67-4.78 (m, 2H), 3.62-3.73 (m,

431.2 0.8H), 3.59 (d, J=6.8 Hz, 0.6H), 3.34 (dd, J=14.1 , 4.8 Hz, 0.6H), 2.65- 2.61

(M+H + ) 2.80 (m, 0.6H), 2.55-2.60 (m, 0.4H), 1 .39-1.56 (m, 1 H), 1 .25-1 .39 (m,

1 H), 1.09-1.23 (m, 3H), 0.95-1 .09 (m, 3H), 0.54-0.69 (m, 3H).

Ή NMR (METHANOL-d4) δ: 8.23 (s, 0.4H), 7.99-8.13 (m, 3H), 7.94 (d,

J=7.8 Hz, 1 H), 7.87 (s, 0.6H), 7.68-7.77 (m, 1 H), 7.23 (dd, J=10.5, 9.0

Hz, 1 H), 4.78-4.88 (m, 2H), 4.05 (s, 3H), 3.78 (dd, J=13.6, 9.5 Hz, 0.8H), 461.2

2.62

3.70 (d, J=6.8 Hz, 0.6H), 3.45 (dd, J=14.2, 4.6 Hz, 0.6H), 2.78-2.93 (m, (M+H + ) 0.6H), 2.65-2.75 (m, 0.4H), 1.49-1.67 (m, 1 H), 1.35-1.49 (m, 1 H), 1.05- 1.35 (m, 6H), 0.66-0.81 (m, 3H). H NMR (DMSO-d6) δ: 9.31 (br. s., 1 H), 9.10-9.24 (m, 1 H), 8.20-8.42

(m, 1 H), 7.88-8.16 (m, 3.3H), 7.67 (s, 0.7H), 7.35-7.52 (m, 1 H), 7.17- 449.2

7.76 a

7.35 (m, 1 H), 4.48-4.91 (m, 2H), 3.44-3.65 (m, 1 H), 3.09-3.29 (m, 1 H), (M+H + ) 2.56-2.87 (m, 1 H), 1.31-1.54 (m, 1 H), 0.98-1.34 (m, 7H), 0.70 (m, 3H).

Ή NMR (DMSO-d6) δ: 10.28 (b.s., 1 H), 9.08 (br. s., 1 H), 8.01-8.12 (m,

2H), 7.90-8.00 (m, 1 H), 7.57-7.67 (m, 1 H), 7.52 (br. s., 1 H), 7.19-7.37 461.2

7.41 a

(m, 2H), 4.51-4.83 (m, 2H), 3.90 (s, 3H), 3.19-3.73 (m, 2H), 2.61-2.86 (M+H + ) (m, 1 H), 1.33-1.53 (m, 1 H), 0.95-1.22 (m, 7H), 0.60-0.78 (m, 3H). H NMR (DMSO-d6) δ: 9.97 (br. s., 0.4H), 9.59 (br. s.,0.6H), 9.52 (s,

1H), 9.31-9.45 (m, 1H), 8.56-8.76 (m, 3H), 8.31 (d, J=7.8 Hz, 1H), 8.22

(s, 0.4H), 8.14 (d, J=7.8 Hz, 1H), 8.06 (d, J=7.5 Hz, 1H), 7.83 (s, 0.6H), 414.2

4.97 a

7.57 (dd, J=7.9, 4.9 Hz, 1H), 4.57-4.87 (m, 2H), 3.50-3.70 (m, 1H), 3.27- (M+H + ) 3.47 (m, 1H), 2.54-2.81 (m, 1H), 1.21-1.50 (m, 2H), 0.94-1.21 (m, 6H),

0.57-0.75 (m, 3H).

Ή NMR (DMSO-d6) δ: 9.29 (t, J=5.8 Hz, 1H), 8.87-9.16 (m, 1H), 8.53

(d, J=8.0 Hz, 1H), 8.47 (d, J=8.3 Hz, 1H), 8.29 (dd, J=22.1, 7.5 Hz, 1H),

481.2 8.02-8.17 (m, 2.4H), 7.81-7.92 (m, 2H), 7.76 (s,0.6H), 4.51-4.92 (m, 2H), 8.2 a

(M+H + ) 3.20-3.66 (m, 2H), 2.57-2.85 (m, 1H), 1.21-1.51 (m, 2H), 0.98-1.21 (m,

6H), 0.68 (t, 3H).

H NMR (DMSO-d6) δ: 9.23-9.34 (m, 1H), 8.88-9.13 (m, 1H), 8.43 (d,

J=8.5 Hz, 1H), 8.38 (d, J=8.8 Hz, 1H), 8.13-8.27 (m, 1.3H), 7.97-8.14

497.2 (m, 2H), 7.75 (s, 0.7H), 7.49 (d, J=8.0 Hz, 2H), 4.52-4.90 (m, 2H), 3.42- 8.38 a

(M+H + ) 3.63 (m, 1H), 3.19-3.42 (m, 1H), 2.58-2.84 (m, 1H), 1.34-1.50 (m, 1H),

1.20-1.35 (m, 1H), 1.01-1.20 (m, 6H), 0.68 (t, 3H).

Ή NMR (DMSO-d6) δ: 9.99 (br. s., 0.4H), 9.55 (br. s., 0.6H), 9.51 (s,

1H), 9.35-9.47 (m, 1H), 9.14 (s, 1H), 8.60-8.77 (m, 1H), 8.31-8.49 (m,

436.2 2H), 8.22 (s, 0.4H), 7.82 (s, 0.6H), 7.50-7.68 (m, 3H), 4.59-4.90 (m, 2H), 6.85 a

(M+23 + ) 3.52-3.70 (m, 1H), 3.28-3.48 (m, 1H), 2.58-2.81 (m, 1H), 1.23-1.52 (m,

2H), 0.98-1.22 (m, 6H), 0.69 (t, 3H).

H NMR (DMSO-d6) δ: 9.97 (br. s., 0.4H), 9.56 (br. s., 0.6H), 9.05-9.20

(m, 1H), 8.59-8.75 (m, 1H), 8.21 (s, 0.4H), 7.96-8.15 (m, 4H), 7.82 (s,

431.2 0.6H), 7.47-7.63 (m, 3H), 4.54-4.85 (m, 2H), 3.51-3.71 (m, 1H), 3.25- 7.65 a

(M+H + ) 3.47 (m, 1H), 2.55-2.76 (m, 1H), 1.25-1.51 (m, 2H), 0.95-1.24 (m, 6H),

0.68 (t, 3H). H NMR (DMSO-d6) δ: 9.94 (s, 0.4H), 9.54 (s, 0.6H), 9.44 (dt, J=11.5,

5.7 Hz, 1H), 8.62-8.73 (m, 1H), 8.57 (s, 1H), 8.38-8.48 (m, 2H), 8.22 (s,

0.4H), 8.18 (s, 1H), 7.82 (s, 0.6H), 7.51-7.62 (m, 3H), 4.81 (m, 1H), 481.2

8.1 d

4.61-4.75 (m, 1H), 3.59 (m, 1H), 3.39-3.44 (m, 0.4H), 3.31-3.36 (m, (M+H + ) 0.6H), 2.71 (br. s., 0.6H), 2.62 (br. s., 0.4H), 1.32-1.38 (m, 2H), 0.97- 1.22 (m, 6H), 0.67 (t, J=7.0 Hz, 3H). H NMR (DMSO-d6) δ: 12.69 (br. s., 1 H), 9.59 (s, 0.3H), 9.28-9.34 (m,

1 H), 9.20-9.26 (m, 0.7H), 8.85-8.91 (m, 0.2H), 8.66-8.73 (m, 0.8H),

8.24-8.33 (m, 1.2H), 8.12 (t, J=7.7 Hz, 1 H), 8.02-8.08 (m, 1 H), 7.84-7.92

529.3 (m, 2H), 7.70-7.80 (m, 1.8H), 4.69-4.81 (m, 1.2H), 4.58-4.68 (m, 0.8H), 6.41 a

(M+H + ) 4.30 (q, J=6.8 Hz, 2H), 3.51-3.61 (m, 1 H), 2.54-2.62 (m, 1 H), 1.46-1.57

(m, 2H), 1.40 (t, J=6.9 Hz, 5H), 0.92-1.17 (m, 6H), 0.72-0.81 (m, 3H),

0.52-0.67 (m, 3H).

Ή NMR (DMSO-d6) δ: 12.04-12.26 (br.s., 1 H), 9.60 (s, 0.3H), 9.19-9.35

(m, 1.7H), 8.86-8.93 (m, 0.3H), 8.70 (t, J=5.0 Hz, 0.7H), 8.27 (s, 0.3H),

8.21 (d, J=7.8 Hz, 1 H), 8.08 (t, J=7.8 Hz, 1 H), 7.97-8.03 (m, 1 H), 7.75

543.3 (br. s., 2.7H), 7.33 (d, J=8.0 Hz, 1 H), 4.69-4.81 (m, 1.2H), 4.58-4.68 (m, 1.2T

(M+H + ) 0.8H), 4.22 (q, J=6.8 Hz, 2H), 3.52-3.63 (m, 3H), 2.54-2.63 (m, 1 H),

1.46-1.58 (m, 2H), 1.32-1.44 (m, 5H), 0.92-1.17 (m, 6H), 0.72-0.82 (m,

3H), 0.53-0.67 (m, 3H). H NMR (DMSO-d6) δ: 12.40 (br. s., 1 H), 9.61 (s, 0.2H), 9.26-9.34 (m,

1 H), 9.16-9.24 (m, 0.7H), 8.82 (br. s., 0.2H), 8.62 (br. s., 0.7H), 8.28 (s,

0.3H), 8.14-8.25 (m, 3H), 8.08 (t, J=7.8 Hz, 1 H), 7.99 (d, J=7.5 Hz, 1 H),

499.3 7.76 (s, 0.7H), 7.42 (d, J=8.0 Hz, 2H), 4.66-4.85 (m, 1.3H), 4.56-4.65 6.04 a

(M+H + ) (m, 0.7H), 3.67 (s, 2H), 3.55-3.64 (m, 1 H), 2.54-2.63 (m, 1 H), 1.45-1.57

(m, 2H), 1.33-1 .44 (m, 2H), 0.97-1.21 (m, 6H), 0.78 (t, J=7.3 Hz, 3H),

0.67 (t, J=6.8 Hz, 1 H), 0.61 (t, 2H).

Ή NMR (DMSO-d6) δ: 12.44 (br. s., 1 H), 9.61 (s, 0.3H), 9.31 (br. s.,

0.7H), 9.23-9.28 (m, 0.3H), 9.14-9.20 (m, 0.7H), 8.80-8.86 (m, 0.3H),

8.60-8.67 (m, 0.7H), 8.27 (s, 0.3H), 8.14-8.23 (m, 3H), 8.08 (t, J=7.7 Hz,

527.3 1 H), 7.97-8.03 (m, 1 H), 7.76 (s, 0.7H), 7.49 (d, J=8.3 Hz, 2H), 4.66-4.85 6.68 a

(M+H + ) (m, 1.2H), 4.57-4.66 (m, 0.8H), 3.55-3.64 (m, 1 H), 2.54-2.63 (m, 1 H),

1.53 (br. s., 8H), 1.36-1.44 (m, 2H), 0.97-1 .17 (m, 6H), 0.78 (t, J=7.2 Hz,

3H), 0.65-0.70 (m, 1 H), 0.58-0.64 (m, 2H). H NMR (DMSO-d6) δ: 12.38 (br. s., 1 H), 9.61 (s, 0.3H), 9.31 (br. s.,

0.7H), 9.22-9.28 (m, 0.3H), 9.17 (t, J=5.9 Hz, 0.7H), 8.80-8.86 (m, 0.3H),

8.60-8.67 (m, 0.7H), 8.28 (s, 0.3H), 8.12-8.21 (m, 3H), 8.08 (t, J=7.7 Hz,

525.3 1 H), 7.97-8.03 (m, 1 H), 7.76 (s, 0.7H), 7.47 (d, J=8.3 Hz, 2H), 4.65-4.84 6.53 a

(M+H + ) (m, 1.3H), 4.56-4.65 (m, 0.7H), 4.18-4.26 (m, 0.3H), 3.55-3.63 (m,

0.7H), 2.55-2.63 (m, 1 H), 1.51 (d, J=2.0 Hz, 4H), 1.35-1.44 (m, 2H),

0.98-1.23 (m, 8H), 0.78 (t, J=7.3 Hz, 3H), 0.67 (t, 1 H), 0.61 (t, 2H). H NMR (METHANOL-d4) δ: 8.15 (s, 0.3H), 8.01 (d, J=7.5 Hz, 1 H),

7.91-7.99 (m, 1 H), 7.75 (d, J=7.5 Hz, 1 H), 7.70 (s, 0.7H), 7.56 (d, J=7.5

499.3 Hz, 1 H), 7.41 (d, J=7.5 Hz, 1 H), 7.27 (t, J=4.0 Hz, 1 H), 4.59-4.74 (m, 6.23 a

(M+H + ) 2H), 3.41-3.62 (m, 1 H), 2.41 -2.67 (m, 1 H), 2.35 (s, 3H), 1.28-1.67 (m,

4H), 1.20-0.90 (m, 6H), 0.70-0.85 (m, 3H), 0.52-0.69 (m, 3H). H NMR (DMSO-d6) δ: 9.01-9.21 (m, 0.7H), 8.89-9.02 (m, 0.3H), 8.79- 8.89 (m, 0.3H), 8.58-8.78 (m, 0.7H), 8.28-8.44 (m, 0.7H), 8.17-8.29 (m,

1 H), 8.15 (s, 0.3H), 8.05-8.13 (m, 1 H), 7.97-8.05 (m, 1 H), 7.85-7.97 (m, 515.2

5.86 a

1.3H), 7.67-7.82 (m, 0.7H), 7.12 (d, J=8.8 Hz, 1 H), 4.47-4.92 (m, 2H), (M+H + ) 4.07-4.27 (m, 0.3H), 3.84 (s, 3H), 3.44-3.68 (m, 0.7H), 2.53-2.67 (m,

1 H), 1.29-1.70 (m, 4H), 0.90-1 .28 (m, 6H), 0.35-0.82 (m, 6H). H NMR (DMSO-d6) δ: 8.95-9.18 (m, 1 H), 8.76-8.86 (m, 0.3H), 8.49- 8.74 (m, 1.7H), 8.28-8.48 (m, 1 H), 8.12-8.23 (m, 1.2H), 8.04-8.13 (m,

1 H), 7.92-8.04 (m, 1 H), 7.73 (br. s., 0.8H), 7.28-7.45 (m, 1 H), 4.48-4.95 503.2

5.93 a

(m, 2H), 4.05-4.27 (m, 0.3H), 3.46-3.67 (m, 0.7H), 2.53-2.66 (m, 1 H), (M+H + ) 1.30-1.64 (m, 4H), 0.93-1.29 (m, 6H), 0.73-0.90 (m, 3H), 0.56-0.73 (m,

3H).

Ή NMR (DMSO-d6) δ: 10.88 (br. s., 1.5H), 9.66 (br. s., 0.2H), 9.32-9.42

(m, 1 H), 9.30 (t, J=6.1 Hz, 0.7H), 8.95 (t, J=5.9 Hz, 0.2H), 8.76 (t, J=5.4

Hz, 0.7H), 8.31 -8.38 (m, 1.3H), 8.15-8.23 (m, 1 H), 8.10-8.15 (m, 1 H),

7.80-7.96 (m, 3.8H), 4.65-4.90 (m, 2H), 4.37 (q, J=7.0 Hz, 2H), 4.25- 565.3

6.4 a

4.33 (m, J=7.0 Hz, 0.3H), 3.59-3.69 (m, 0.8H), 2.62-2.73 (m, J=7.3 Hz, (M+H + ) 1 H), 1.55-1.66 (m, 2H), 1.48 (t, J=6.9 Hz, 5H), 1.15-1.26 (m, 3H), 0.99- 1.15 (m, 3H), 0.80-0.90 (m, 3H), 0.72 (t, J=7.0 Hz, 1 H), 0.62-0.68 (m,

2H). H NMR (DMSO-d6) δ: 9.32 (t, J=6.0 Hz, 0.3H), 9.23 (t, J=5.9 Hz, 0.7H), 8.81-8.87 (m, 0.3H), 8.54-8.68 (m, 1.7H), 8.17-8.30 (m, 2H), 8.12 (t,

J=7.7 Hz, 1 H), 8.02-8.07 (m, 1 H), 7.97 (d, J=13.6 Hz, 1 H), 7.75 (s,

571.0 0.7H), 7.51 (s, 1 H), 4.83-5.16 (br.s., 2H), 4.62-4.82 (m, 2H), 4.22 (q, 6.24 a

(M+H + ) J=6.9 Hz, 2H), 3.53-3.62 (m, 1 H), 3.30-3.42 (m, 2H), 2.72-2.81 (m, 2H),

2.54-2.63 (m, 1 H), 1.47-1.58 (m, 2H), 1.41 (t, J=6.9 Hz, 5H), 1.08-1.18

(m, 3H), 0.98-1 .07 (m, 3H), 0.78 (t, J=7.2 Hz, 3H), 0.58-0.67 (m, 3H).

Ή NMR (DMSO-d6) δ: 13.09-13.30 (m, 0.7H), 9.56 (br. s., 0.5H), 9.17- 9.28 (m, 1 H), 8.66-8.74 (m, 1 H), 8.20-8.26 (m, 2.3H), 8.03-8.13 (m, 3H),

7.82 (s, 0.7H), 7.54 (d, J=1.0 Hz, 1 H), 4.62-4.83 (m, 2H), 4.22 (q, J=7.0 501.2

2.43

Hz, 2H), 3.54-3.69 (m, 1 H), 3.29-3.43 (m, 1 H, excluded by solvent), (M+H + ) 2.57-2.74 (m, 1 H), 1.41 (t, J=6.9 Hz, 4H), 1 .27-1 .36 (m, J=6.8 Hz, 1 H),

1.01-1.20 (m, 6H), 0.65 (t, 3H). H NMR (DMSO-d6) δ: 9.33-9.41 (m, J=6.0 Hz, 1 H), 8.89-8.94 (m,

0.3H), 8.69-8.76 (m, 0.7H), 8.24-8.33 (m, 1.3H), 8.11 (t, 1 H), 8.03-8.08

(m, J=7.5 Hz, 1 H), 7.85-7.92 (m, 2H), 7.77 (s, 0.7H), 7.70 (d, J=8.0 Hz,

563.2 1 H), 7.05-7.16 (m, 3H), 6.94-7.04 (m, J=7.3 Hz, 2H), 4.63-4.89 (m, 2H), 2.46

(M+H + ) 4.26 (q, J=6.8 Hz, 2H), 3.57-3.67 (m, 1 H), 2.58-2.69 (m, 1 H), 2.38-2.47

(m, 2H), 1.63-1 .77 (m, 2H), 1.46-1.59 (m, 2H), 1.36 (t, J=6.8 Hz, 3H),

0.70-0.81 (m, 3H).

Ή NMR (DMSO-d6) δ: 12.49 (br. s., 1 H), 9.59 (s, 0.3H), 9.29-9.37 (m,

0.3H), 9.26 (s, 0.7H), 9.07-9.19 (m, 0.7H), 8.78-8.89 (m, 0.3H), 8.51 - 8.63 (m, 0.7H), 8.29 (s, 0.3H), 8.19 (br. s., 1 H), 7.90 (d, J=6.8 Hz, 2H),

528.3 7.77 (s, 0.7H), 7.75 (d, J=8.0 Hz, 1 H), 7.54-7.63 (m, 1 H), 7.34-7.44 (m, 6.47 a

(M+H + ) 2H), 4.51-4.78 (m, 2H), 4.24 (q, J=6.8 Hz, 2.3H), 3.47-3.65 (m, 0.8H),

2.56-2.68 (m, 1 H), 1.46-1.62 (m, 2H), 1.38 (t, J=7.0 Hz, 5H), 1.03-1.26

(m, 6H), 0.59-0.87 (m, 6H).

Ή NMR (DMSO-d6) δ: 9.97 (br. s., 0.4H), 9.55 (br. s., 0.6H), 9.09-9.20

(m, 1 H), 8.58 (d, J=5.5 Hz, 1 H), 8.21 (s, 0.4H), 8.03 (d, J=3.0 Hz, 1 H),

7.81 (s, 0.6H), 7.62 (d, J=7.8 Hz, 1 H), 7.53 (dd, J=8.9, 2.9 Hz, 1 H), 7.46

459.2 (t, J=7.9 Hz, 1 H), 7.42 (s, 1 H), 7.14-7.20 (m, 1 H), 6.90 (d, J=8.8 Hz, 7.07 a

(M+H + ) 1 H), 4.45-4.67 (m, 2H), 3.87 (s, 3H), 3.49-3.66 (m, 1 H), 3.29-3.41 (m,

1 H), 2.70 (br. s., 0.6H), 2.61 (br. s., 0.4H), 1 .36 (br. s., 1 H), 1.30 (br. s.,

1 H), 1.15 (br. s., 6H), 0.76 (t, J=6.3 Hz, 3H). Ή NMR (DMSO-d6) δ: 9.99 (s, 0.4H), 9.56 (s, 0.6H), 9.28 (d, J=5.8 Hz,

1H), 8.65 (br. s., 1H), 8.22 (s, 0.4H), 8.17 (s, 1H), 7.87 (s, 0.6H), 7.84 (d,

J=9.8 Hz, 2H), 7.75 (d, J=7.8 Hz, 2H), 7.56 (t, J=7.8 Hz, 1H), 7.51 (t, 412.2

7.57 a

J=7.7 Hz, 2H), 7.41 (t, J=7.3 Hz, 1H), 4.53-4.70 (m, 2H), 3.48-3.68 (m, (M+H + ) 1H), 3.41 (m, 1H), 2.68-2.78 (m, 1H), 1.31-1.39 (m, 2H), 1.15 (br. s.,

6H), 0.67-0.81 (m, 3H).

Ή NMR (DMSO-d6) δ: 9.88-10.00 (m, 0.3H), 9.55 (s, 0.7H), 8.86-9.09

(m, 1H), 8.64-8.86 (m, 1H), 8.24 (s, 0.3H), 7.83 (s, 0.7H), 7.50-7.73 (m,

460.2 2H), 7.41 (t, J=7.9 Hz, 1H), 7.34 (t, J=7.7 Hz, 1H), 7.06-7.19 (m, 2H),

2.61 (M+H + ) 7.01 (dd, J=8.2, 1.9 Hz, 1H), 4.46-4.83 (m, 2H), 3.81 (s, 3H), 3.50-3.68

(m, 1H), 3.34 (s, 1H), 2.56-2.79 (m, 1H), 0.98-1.55 (m, 8H), 0.54-0.98

(m, 3H).

Ή NMR (DMSO-d6) δ: 9.94 (s, 0.3H), 9.55 (s, 0.7H), 8.95 (br. s., 1H),

8.72 (d, J=5.5 Hz, 1H), 8.23 (s, 0.3H), 7.82 (s, 0.7H), 7.58-7.71 (m, 1H), 478.2 7.54 (t, J=6.5 Hz, 1H), 7.36 (t, J=7.7 Hz, 1H), 7.16-7.31 (m, 2H), 6.83- 2.57 (M+H + ) 7.07 (m, 1H), 4.58 (dd, J=11.2, 5.4 Hz, 2H), 3.69-4.10 (m, 3H), 3.36- 3.69 (m, 2H), 2.54-2.85 (m, 1H), 0.96-1.59 (m, 8H), 0.49-0.96 (m, 3H).

Ή NMR (DMSO-d6) δ: 9.82-10.11 (m, 0.3H), 9.54 (s, 0.7H), 8.84-9.07

(m, 1H), 8.61-8.84 (m, 1H), 8.14-8.40 (m, 0.3H), 7.82 (s, 0.7H), 7.60 (d, 478.2 J=19.1 Hz, 2H), 7.33-7.43 (m, 1H), 7.27 (t, J=9.3 Hz, 1H), 7.02-7.13 (m, 2.60 (M+H + ) 1H), 6.98 (dd, J=5.9, 3.1 Hz, 1H), 4.41-4.78 (m, 2H), 3.79 (s, 3H), 3.37- 3.67 (m, 2H), 2.56-2.83 (m, 1H), 1.18 (br. s., 8H), 0.56-0.95 (m, 3H).

Ή NMR (DMSO-d6) δ: 9.28-9.39 (m, 1H), 8.61-8.71 (m, 1H), 8.39 (s,

1H), 8.22 (s, 0.4H), 8.03 (d, J=7.8 Hz, 1H), 7.95 (d, J=7.5 Hz, 1H), 7.82 431.2 (s, 0.6H), 7.58 (t, J=7.8 Hz, 1H), 4.53-4.72 (m, 2H), 3.52-3.66 (m, 1H), 2.38 (M+H + ) 3.36-3.46 (m, 1H), 2.60-2.75 (m, 1H), 2.34 (s, 3H), 2.11 (s, 3H), 1.27- 1.45 (m, 2H), 1.12-1.21 (m, 6H), 0.68-0.78 (m, 3H).

Ή NMR (DMSO-d6) δ: 9.94 (s, 0.4H), 9.54 (s, 0.6H), 9.18-9.27 (m, 1H),

8.60-8.69 (m, 1H), 8.32 (s, 1H), 8.26 (s, 1H), 8.21-8.24 (m, 0.4H), 7.92-

416.2 7.96 (m, 1H), 7.83 (s, 0.6H), 7.76 (d, J=7.8 Hz, 1H), 7.60 (s, 1H), 7.54 (t,

2.38 (M+H + ) J=8.0 Hz, 1H), 4.54-4.72 (m, 2H), 3.53-3.71 (m, 1H), 3.35-3.45 (m, 1H),

2.59-2.77 (m, 1H), 2.12 (s, 3H), 1.26-1.44 (m, 2H), 1.08-1.22 (m, 6H),

0.74 (t, J=6.4 Hz, 3H).

Ή NMR (DMSO-d6) δ: 9.90-9.96 (m, 0.4H), 9.49-9.57 (m, 0.6H), 9.23- 9.33 (m, 1H), 8.59-8.69 (m, 1H), 8.40 (s, 1H), 8.21-8.24 (m, 0.4H), 8.10

417.2 (s, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.83 (s, 0.6H), 7.78 (d, J=8.0 Hz, 1H),

2.21 (M+H + ) 7.60 (t, J=7.8 Hz, 1H), 4.52-4.73 (m, 2H), 3.51-3.69 (m, 1H), 3.34-3.46

(m, 1H), 2.58-2.77 (m, 1H), 2.40 (s, 3H), 1.26-1.44 (m, 2H), 1.07-1.22

(m, 6H), 0.74 (t, J=6.8 Hz, 3H). Ή NMR (METHANOL-d4) δ: 8.49-8.57 (m, 2H), 8.27 (d, J=8.0 Hz, 1 H),

8.13 (s, 0.4H), 7.90 (d, J=6.8 Hz, 1 H), 7.75-7.81 (m, 0.6H), 7.49-7.61 444.2 (m, 2H), 4.69 (d, J=5.5 Hz, 2H), 4.02 (s, 3H), 3.52-3.74 (m, 1.4H), 3.35 5.88 a (M+H + ) (dd, J=14.1 , 5.0 Hz, 0.6H), 2.73 (m, 0.6H), 2.59 (br. s., 0.4H), 1 .49 (br.

s., 2H), 1 .11-1.39 (m, 6H), 0.61-0.81 (m, 3H).

Ή NMR (DMSO-d6) δ: 12.16 (s, 1 H), 9.60 (s, 0.3H), 9.21-9.34 (m, 1 H),

9.03-9.17 (m, 0.7H), 8.76-8.90 (m, 0.3H), 8.48-8.64 (m, 0.7H), 8.29 (s,

542.3 0.3H), 8.15 (s, 1 H), 7.85 (d, J=7.8 Hz, 2H), 7.77 (s, 0.7H), 7.49-7.62 (m,

6.53 a (M+H + ) 1 H), 7.18-7.38 (m, 3H), 4.50-4.79 (m, 2H), 4.19-4.27 (m, 0.3H), 4.15 (q,

J=6.9 Hz, 2H), 3.48-3.68 (m, 2.8H), 2.55-2.68 (m, 1 H), 1.30-1.62 (m,

7H), 1.04-1.27 (m, 6H), 0.61-0.86 (m, 6H).

Ή NMR (DMSO-d6) δ: 12.14-13.07 (m, 2H), 9.60 (s, 0.3H), 9.33-9.41

(m, 0.3H), 9.27 (s, 0.7H), 9.16-9.24 (m, 0.7H), 8.90 (br. s., 1 H), 8.79- 8.85 (m, 0.3H), 8.56 (t, J=5.0 Hz, 0.7H), 8.29 (s, 0.3H), 8.20 (s, 1 H),

643.3 7.89 (d, J=7.5 Hz, 2H), 7.79 (br. s., 1 H), 7.77 (s, 0.7H), 7.55-7.63 (m,

5.99 a (M+H + ) 1 H), 7.48 (br. s., 1 H), 7.44 (br. s., 1 H), 4.75-4.85 (m, 1 H), 4.52-4.74 (m,

2H), 4.18 (q, J=7.0 Hz, 2.3H), 3.52-3.64 (m, 0.7H), 2.81-2.95 (m, 1 H),

2.66-2.80 (m, 1 H), 2.57-2.66 (m, 1 H), 1.34-1.62 (m, 7H), 1.04-1.23 (m,

6H), 0.64-0.85 (m, 6H).

Ή NMR (DMSO-d6) δ: 9.29-9.36 (m, 1 H), 8.65-8.72 (m, 1 H), 8.13-8.25

(m, 3H), 7.73-7.91 (m, 4H), 7.57 (t, J=7.7 Hz, 1 H), 7.46 (t, J=7.4 Hz, 490.2 1 H), 7.04-7.22 (m, 5H), 4.60-4.79 (m, 2H), 3.58-3.73 (m, 1 H), 3.38-3.51 2.25 (M+H + ) (m, 1 H), 2.66-2.84 (m, 1 H), 2.5 (2H concealed by DMSO)1.58-1.73 (m,

2H).

Ή NMR (METHANOL-d4) δ: 8.24 (s, 0.4H), 7.95 (s, 1 H), 7.88 (s, 0.6H),

7.77 (d, J=7.8 Hz, 1 H), 7.67-7.73 (m, 1 H), 7.46-7.53 (m, 1 H), 7.30-7.40

(m, 2H), 7.1 1 (d, J=8.3 Hz, 1 H), 7.01-7.08 (m, 1 H), 4.72-4.81 (m, 1 H), 454.2 3.82 (s, 3H), 3.69-3.80 (m, 1 H), 3.42-3.53 (m, 1 H), 3.38-3.41 (1 H, 2.61 (M+H + ) concealed under water peak), 2.84-2.96 (m, 0.6H), 2.71-2.80 (m, 0.4H),

1.80-1.91 (m, 1 H), 1.74 (br. s., 3H), 1.56 (br. s., 2H), 1.28-1.49 (m, 3H),

1.10 (br. s., 2H).

Ή NMR (METHANOL-d4) δ: 8.24 (s, 0.4H), 8.09 (s, 1 H), 7.88 (s, 0.6H),

7.82 (dd, J=7.7, 1.1 Hz, 2H), 7.52-7.61 (m, 1 H), 7.35-7.44 (m, 1 H), 7.21 -

454.2 7.29 (m, 2H), 6.97 (dd, J=8.2, 1.6 Hz, 1 H), 4.72-4.85 (m, 2H), 3.88 (s,

2.54 (M+H + ) 3H), 3.69-3.81 (m, 1 H), 3.46 (dd, J=14.1 , 5.0 Hz, 1 H), 2.83-2.97 (m,

0.6H), 2.71-2.82 (m, 0.4H), 1.81-1.91 (m, 1 H), 1.66-1.79 (m, 3H), 1.47- 1.63 (m, 2H), 1.31-1.47 (m, 3H), 1.02-1.16 (m, 2H).

Ή NMR (METHANOL-d4) δ: 8.23 (s, 0.4H), 8.16 (s, 0.6H), 7.85-7.93

2.85 492.2 (m, 4H), 7.78 (d, J=8.0 Hz, 2H), 7.61 (t, J=7.8 Hz, 1 H), 4.76-4.81 (m, 2H), 3.77 (dd, J=13.9, 8.9 Hz, 1 H), 3.63 (dd, J=14.1 , 5.5 Hz, 0.4H), 3.46 (M+H + ) (dd, J=14.1 , 4.8 Hz, 0.6H), 2.84-2.96 (m, 0.6H), 2.70-2.80 (m, 0.4H),

1.85 (d, J=3.8 Hz, 1 H), 1.65-1.80 (m, 3H), 1.48-1.63 (m, 2H), 1.31-1.48

(m, 3H), 1.08 (dt, J=10.9, 7.5 Hz, 2H).

Ή NMR (METHANOL-d4) δ: 8.24 (s, 0.3H), 8.13 (d, J=13.6 Hz, 1.7H),

8.04 (d, J=7.5 Hz, 0.8H), 7.88 (br. s., 2.2H), 7.83 (br. s., 0.2H), 7.78 (d, 449.2 J=7.5 Hz, 0.8H), 7.66-7.73 (m, 1 H), 7.58-7.66 (m, 1 H), 4.71-4.87 (m, 2.53 (M+H + ) 1 H), 3.59-3.87 (m, 1 H), 3.38-3.55 (m, 2H), 2.67-3.01 (m, 1 H), 1 .64-1.96

(m, 4H), 1.24-1 .62 (m, 5H), 1.09 (br. s., 2H).

Ή NMR (METHANOL-d4) δ: 8.24 (s, 0.4H), 8.10 (s, 1 H), 7.89 (s, 0.6H),

7.80-7.86 (m, 2H), 7.65-7.73 (m, 3H), 7.54-7.61 (m, 2H), 7.48 (t, J=7.5

424.2 Hz, 2H), 7.35-7.44 (m, 1 H), 4.75-4.82 (m, 2H), 3.70-3.81 (m, 1 H), 3.59-

2.62 (M+H + ) 3.69 (m, 0.4H), 3.40-3.52 (m, 0.6H), 2.85-2.95 (m, 0.6H), 2.71-2.81 (m,

0.4H), 1.81-1.92 (m, 1 H), 1.65-1.79 (m, 3H), 1.56 (br. s., 2H), 1.38 (d,

J=5.0 Hz, 3H), 1.03-1.15 (m, 2H).

Ή NMR (DMSO-d6) δ: 9.94 (br. s, 0.4H), 9.54 (br. s, 0.6H), 9.14 (d,

J=5.8 Hz, 1 H), 8.61 (d, J=5.5 Hz, 1 H), 8.21 (s, 0.4H), 7.81 (s, 0.6H),

7.65 (d, J=8.0 Hz, 1 H), 7.45-7.52 (m, 2H), 7.42 (t, J=7.9 Hz, 2H), 7.13- 440.2 7.23 (m, 2H), 7.03 (d, J=7.8 Hz, 2H), 4.45-4.70 (m, 2H), 3.48-3.66 (m, 7.63 a (M+H + ) 1 H), 3.39-3.48 (m, 0.6H), 3.29-3.31 (m, 0.4H), 2.73 (br. s., 0.6H), 2.65

(br. s., 0.4H), 1.73 (br. s., 1 H), 1.60 (br. s., 2H), 1 .38-1 .56 (m, 3H), 1.27- 1.38 (m, 2H), 1.15-1.27 (m, 1 H), 0.88-1.08 (m, 2H).

Ή NMR (DMSO-d6) δ: 12.19-13.84 (m, 1 H), 8.86-9.04 (m, 1 H), 8.59- 8.80 (m, 1 H), 8.11 -8.17 (m, 1 H), 8.04-8.10 (m, 2H), 7.94 (s, 1 H), 7.89 (d, 500.3 J=7.8 Hz, 1 H), 7.82 (d, J=7.3 Hz, 1.4H), 7.56-7.62 (m, 1.5H), 4.47-4.82 6.04 a (M+2H) (m, 2H), 3.72-3.88 (m, 1 H), 2.21-2.44 (m, 3H), 1.21-1 .78 (m, 5H), 0.97- 1.20 (m, J=5.0 Hz, 6H), 0.57-0.84 (m, 6H).

Ή NMR (DMSO-d6) δ: 9.49-10.32 (m, 0.6H), 9.35 (br. s., 1 H), 8.69 (br.

s., 1 H), 8.42 (s, 1 H), 8.21 (s, 0.4H), 8.07 (d, J=7.8 Hz, 1 H), 7.97 (d,

417.2 J=8.0 Hz, 1 H), 7.82 (s, 0.6H), 7.60 (t, J=7.8 Hz, 1 H), 7.04 (d, J=1.0 Hz,

2.34 (M+H + ) 1 H), 4.62 (br. s., 2H), 3.57 (dd, J=13.7, 7.9 Hz, 1 H), 3.39-3.47 (m, 1 H),

2.59-2.83 (m, 1 H), 2.41 (s, 3H), 1.27-1.47 (m, 2H), 1 .03-1 .25 (m, 6H),

0.50-0.84 (m, 3H).

Ή NMR (DMSO-d6) δ: 9.94-10.00 (m, 0.5H), 9.52-9.60 (m, 0.5H), 9.22- 9.31 (m, 1 H), 8.59-8.67 (m, 1 H), 8.54 (s, 1 H), 8.23 (s, 0.4H), 8.15 (d,

404.1 J=7.8 Hz, 1 H), 7.93 (d, J=8.0 Hz, 1 H), 7.84 (s, 0.6H), 7.59 (t, J=7.5 Hz,

2.02 (M+H + ) 1 H), 4.55-4.74 (m, 2H), 3.51 -3.69 (m, 1 H), 3.4 (1 H, concealed under

water peak) 2.60-2.77 (m, 1 H), 1 .30-1 .46 (m, 2H), 1.09-1.21 (m, 6H),

0.68-0.78 (m, 3H). Ή NMR (DMSO-d6) δ: 9.41 (br. s., 0.4H), 9.22 (br. s., 0.7H), 8.86 (br.

s., 0.3H), 8.56-8.66 (m, 0.7H), 8.28 (s, 0.3H), 8.15-8.21 (m, 1 H), 7.84-

528.2 7.92 (m, 3H), 7.76 (s, 0.7H), 7.53-7.61 (m, 1 H), 7.50 (br. s., 1 H), 7.45

2.59 (M+H + ) (br. s., 1 H), 4.51-4.77 (m, 2H), 4.16 (q, J=6.6 Hz, 2H), 3.51-3.63 (m,

1 H), 2.57-2.66 (m, 1 H), 1.46-1.59 (m, 2H), 1.33-1.44 (m, 5H), 1 .03-1.22

(m, 6H), 0.74-0.83 (m, 3H), 0.60-0.73 (m, 3H).

Ή NMR (DMSO-d6) δ: 9.95 (br. s., 0.4H), 9.55 (br. s., 0.6H), 9.28 (d,

J=5.3 Hz, 1 H), 8.64 (d, J=5.8 Hz, 1 H), 8.22 (s, 0.4H), 8.15 (s, 1 H), 7.86- 7.91 (m, 0.6H), 7.85 (s, 1 H), 7.83 (s, 1 H), 7.55 (t, J=7.8 Hz, 1 H), 7.36-

442.2 7.47 (m, 1 H), 7.31 (d, J=7.8 Hz, 1 H), 7.28 (s, 1 H), 6.98 (dd, J=8.2, 1 .9

2.62 (M+H + ) Hz, 1 H), 4.46-4.83 (m, J=11.8, 11.8, 6.1 , 6.1 Hz, 2H), 3.84 (s, 3H), 3.49- 3.70 (m, 1 H), 3.27-3.45 (1 H, concealed under water peak), 2.58-2.80

(m, 1 H), 1.25-1 .50 (m, J=13.9, 8.2 Hz, 2H), 1.05-1.26 (m, 6H), 0.65-0.80

(m, 3H).

Ή NMR (DMSO-d6) δ: 9.92 (br. s., 0.3H), 9.54 (br. s., 0.6H), 9.26 (d,

J=5.3 Hz, 1 H), 8.66 (d, J=5.8 Hz, 1 H), 8.22 (s, 0.3H), 8.13 (s, 1 H), 7.84- 7.88 (m, 1 H), 7.83 (br. s., 1 .7H), 7.54 (t, J=7.8 Hz, 1 H), 7.34-7.46 (m,

468.2 1 H), 7.30-7.33 (m, 0.6H), 7.29 (s, 1.5H), 6.97 (dd, J=7.3, 1.5 Hz, 1 H),

2.74 (M+H + ) 4.52-4.75 (m, 2H), 4.1 1 (q, J=7.0 Hz, 2H), 3.50-3.63 (m, J=6.5 Hz, 1 H),

3.27-3.47 (1 H, concealed under water peak), 2.61-2.86 (m, 1 H), 1.70- 1.83 (m, 1 H), 1.51-1 .71 (m, 3H), 1.40-1.51 (m, 2H), 1.37 (t, J=6.9 Hz,

3H), 1.18-1.33 (m, 3H), 0.89-1.06 (m, 2H).

Ή NMR (DMSO-d6) δ: 9.95 (br. s., 0.4H), 9.58 (br. s., 1.6H), 9.25 (d,

J=5.5 Hz, 1 H), 8.65 (d, J=5.3 Hz, 1 H), 8.22 (s, 0.4H), 8.10 (s, 1 H), 7.84

(br. s., 0.6H), 7.82 (s, 1 H), 7.76 (d, J=7.8 Hz, 1 H), 7.53 (t, J=7.7 Hz, 1 H),

440.2 7.23-7.33 (m, 1 H), 7.15 (d, J=7.8 Hz, 1 H), 7.11 (s, 1 H), 6.81 (dd, J=8.0,

2.36 (M+H + ) 1.3 Hz, 1 H), 4.52-4.75 (m, 2H), 3.56 (dd, J=13.7, 7.4 Hz, 1 H), 3.28-3.47

(1 H, concealed under water peak), 2.59-2.82 (m, 1 H), 1.70-1 .81 (m,

1 H), 1.51-1.70 (m, 3H), 1.38-1.51 (m, 2H), 1.21-1.36 (m, 3H), 0.89-1.06

(m, 2H).

Ή NMR (DMSO-d6) δ: 9.94 (br. s., 0.4H), 9.12-9.36 (m, 1 H), 8.56-8.76

(m, 1 H), 8.21 (s, 0.3H), 8.13 (s, 1 H), 7.79-7.88 (m, 2.5H), 7.57 (s, 1 H),

454.2 7.54 (d, J=7.8 Hz, 2H), 7.41 (t, J=7.5 Hz, 1 H), 7.29 (d, J=7.8 Hz, 1 H),

2.95 (M+H + ) 4.54-4.78 (m, 2H), 3.49-3.66 (m, 1 H), 3.26-3.47 (1 H, concealed under

water peak), 2.99 (dt, J=13.8, 6.9 Hz, 1 H), 2.60-2.80 (m, 1 H), 1.30-1.46

(m, 2H), 1.27 (d, J=7.0 Hz, 6H), 1 .04-1 .23 (m, 6H), 0.64-0.79 (m, 3H).

Ή NMR (DMSO-d6) δ: 9.92 (br. s., 0.4H), 9.54 (br. s., 0.6H), 9.24 (d,

452.2 J=5.3 Hz, 1 H), 8.66 (d, J=5.5 Hz, 1 H), 8.22 (s, 0.4H), 8.13 (s, 1 H), 7.75- 2.84

(M+H + ) 7.90 (m, 2.6H), 7.57 (s, 1 H), 7.54-7.56 (m, 1 H), 7.53 (s, 1 H), 7.41 (t, J=7.7 Hz, 1 H), 7.25 (d, J=7.5 Hz, 1 H), 4.51-4.77 (m, J=6.3 Hz, 2H),

3.49-3.64 (m, 1 H), 3.27-3.47 (1 H, concealed under water peak), 2.74- 2.82 (m, 1 H), 2.70 (q, J=7.5 Hz, 2H), 1.71-1.84 (m, 1 H), 1.50-1.71 (m,

3H), 1.37-1.50 (m, 2H), 1 .28-1 .37 (m, 3H), 1.25 (t, J=7.7 Hz, 3H), 0.89- 1.06 (m, 2H).

Ή NMR (DMSO-d6) δ: 9.98 (br. s., 0.4H), 9.55 (br. s., 0.5H), 9.16 (d,

J=5.8 Hz, 1 H), 8.62 (d, J=4.3 Hz, 1 H), 8.22 (s, 0.4H), 7.95 (s, 1 H), 7.82

(s, 1 H), 7.81 (br. s., 0.6H), 7.66 (d, J=7.8 Hz, 1 H), 7.43-7.54 (m, 1 H), 472.2 7.07 (d, J=9.0 Hz, 1 H), 6.90-6.99 (m, 2H), 4.50-4.74 (m, 2H), 3.76 (s, 2.60 (M+H + ) 3H), 3.70 (s, 3H), 3.50-3.66 (m, 1 H), 3.28-3.44 (1 H, concealed under

water peak), 2.57-2.80 (m, 1 H), 1.26-1.46 (m, 2H), 1.15 (br. s., 6H), 0.74

(t, 3H).

Ή NMR (DMSO-d6) δ: 9.95 (br. s., 0.4H), 9.55 (br. s., 0.6H), 9.28 (d,

J=6.0 Hz, 1 H), 8.69 (d, J=5.8 Hz, 1 H), 8.22 (s, 0.4H), 8.17 (s, 1 H), 7.90

(d, J=8.0 Hz, 2H), 7.82 (br. s., 1 H), 7.79-7.81 (m, 0.6H), 7.76 (br. s., 1 H), 508.2 7.53-7.70 (m, J=8.0, 8.0 Hz, 2H), 7.42 (d, J=8.3 Hz, 1 H), 4.50-4.77 (m, 2.87 (M+H + ) 2H), 3.49-3.65 (m, 1 H), 3.27-3.47 (1 H, concealed under water peak),

2.61-2.85 (m, 1 H), 1.70-1.84 (m, 1 H), 1.50-1.71 (m, 3H), 1.36-1.50 (m,

2H), 1.15-1.36 (m, J=6.8 Hz, 3H), 0.88-1.06 (m, 2H).

Ή NMR (DMSO-d6) δ: 9.93 (s, 0.4H), 9.54 (br. s., 0.5H), 9.24-9.38 (m,

J=5.3 Hz, 1 H), 8.61 -8.77 (m, 1 H), 8.22 (s, 0.4H), 8.19 (s, 1 H), 8.04-8.11

(m, 2H), 7.92 (t, J=9.3 Hz, 2H), 7.82 (s, 0.6H), 7.71-7.81 (m, 2H), 7.61 (t, 492.2 J=7.7 Hz, 1 H), 4.55-4.78 (m, J=4.3 Hz, 2H), 3.49-3.66 (m, 1 H), 3.28- 2.82 (M+H + ) 3.47 (1 H, concealed under water peak), 2.62-2.84 (m, 1 H), 1.70-1.83

(m, 1 H), 1.50-1 .71 (m, 3H), 1.36-1.49 (m, 2H), 1.27 (br. s., 3H), 0.90- 1.04 (m, 2H).

Ή NMR (DMSO-d6) δ: 10.02 (br. s., 0.3H), 9.56 (br. s., 0.4H), 9.25 (d,

J=6.3 Hz, 1 H), 8.67 (d, J=5.3 Hz, 1 H), 8.22 (s, 0.3H), 8.11 (s, 1 H), 7.77- 7.90 (m, 2.5H), 7.54 (t, J=7.7 Hz, 1 H), 6.87 (d, J=2.0 Hz, 2H), 6.55 (t, 484.2 J=1.9 Hz, 1 H), 4.52-4.75 (m, 2H), 3.83 (s, 6H), 3.50-3.63 (m, 1 H), 3.27- 2.63 (M+H + ) 3.48 (1 H, concealed under water peak), 2.64-2.82 (m, 1 H), 1.70-1.81

(m, 1 H), 1.50-1 .70 (m, 3H), 1.38-1.50 (m, 2H), 1.19-1 .35 (m, 3H), 0.89- 1.05 (m, 2H).

Ή NMR (DMSO-d6) δ: 9.95 (br. s., 0.4H), 9.55 (br. s., 0.5H), 9.21 (d,

J=3.8 Hz, 1 H), 8.66 (d, J=6.3 Hz, 1 H), 8.22 (s, 0.4H), 8.11 (s, 1 H), 7.95

474.1 (d, J=7.5 Hz, 1 H), 7.85 (d, J=7.5 Hz, 1 H), 7.82 (br. s., 0.5H), 7.53-7.64

2.27 (M+H + ) (m, 1 H), 7.31-7.42 (m, 1 H), 4.48-4.77 (m, 2H), 4.00 (d, J=3.8 Hz, 6H),

3.49-3.70 (m, 1 H), 3.28-3.46 (1 H, concealed under water peak), 2.57- 2.79 (m, 1 H), 1.25-1 .55 (m, 2H), 1.14 (br. s., 6H), 0.72 (br. s., 3H). Ή NMR (DMSO-d6) δ: 10.03 (br. s., 0.3H), 9.58 (br. s., 0.5H), 9.29 (d,

J=6.0 Hz, 1H), 8.74 (d, J=5.3 Hz, 1H), 8.23 (s, 0.4H), 8.14 (s, 1H), 7.97

(d, J=7.5 Hz, 1H), 7.85-7.88 (m, 0.6H), 7.84 (s, 1H), 7.58 (t, J=7.8 Hz, 508.1 1H), 7.36 (s, 1H), 7.09-7.21 (m, J=7.3 Hz, 3H), 7.07 (d, J=6.8 Hz, 2H), 2.30 (M+H + ) 4.54-4.81 (m, 2H), 4.00 (s, 3H), 3.97 (s, 3H), 3.56-3.74 (m, 1H), 3.37- 3.53 (m, 1H), 2.63-2.87 (m, 1H), 2.39-2.56 (2H, concealed under DMSO

d6 peak), 1.52-1.77 (m, 2H).

Ή NMR (DMSO-d6) δ: 9.96 (br. s., 0.4H), 9.55 (br. s., 0.6H), 9.30 (d,

J=5.3 Hz, 1H), 8.66 (d, J=5.8 Hz, 1H), 8.22 (s, 0.4H), 8.19 (s, 1H), 7.90

430.2 (s, 1H), 7.88 (s, 1H), 7.81-7.85 (m, 0.6H), 7.59-7.68 (m, 2H), 7.50-7.59

2.65 (M+H + ) (m, J=7.8 Hz, 2H), 7.25 (td, J=8.3, 2.1 Hz, 1H), 4.53-4.78 (m, 2H), 3.51- 3.70 (m, 1H), 3.29-3.46 (1H, concealed under water peak), 2.59-2.81

(m, 1H), 1.26-1.52 (m, 2H), 1.14 (br. s., 6H), 0.62-0.79 (m, 3H).

Ή NMR (DMSO-d6) δ: 9.94 (br. s., 0.3H), 9.42-9.68 (m, 1.5H), 9.27 (d,

J=6.5 Hz, 1H), 8.63 (d, J=5.3 Hz, 1H), 8.23 (s, 0.3H), 8.11 (s, 1H), 7.86

(s, 0.6H), 7.81-7.85 (m, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.53 (t, J=7.7 Hz, 428.2 1H), 7.21-7.34 (m, 1H), 7.14 (d, J=7.5 Hz, 1H), 7.11 (s, 1H), 6.80 (dd, 2.37 (M+H + ) J=7.9, 1.9 Hz, 1H), 4.48-4.76 (m, J=12.1, 12.1, 6.3, 6.3 Hz, 2H), 3.49- 3.71 (m, 1H), 3.25-3.47 (1H, concealed under water peak), 2.58-2.82

(m, 1H), 1.25-1.49 (m, 2H), 1.16 (d, J=12.3 Hz, 6H), 0.63-0.80 (m, 3H).

Ή NMR (DMSO-d6) δ: 9.98 (br. s., 0.4H), 9.55 (br. s., 0.5H), 9.30 (d,

J=6.0 Hz, 1H), 8.65 (d, J=4.5 Hz, 1H), 8.18-8.27 (m, 0.3H), 8.14 (s, 1H),

7.87 (s, 0.6H), 7.80-7.85 (m, 2H), 7.54 (t, J=7.8 Hz, 1H), 7.33-7.44 (m, 470.2 1H), 7.22-7.30 (m, J=1.3 Hz, 2H), 6.94-7.01 (m, J=2.0 Hz, 1H), 4.69- 2.82 (M+H + ) 4.77 (m, 1H), 4.64 (dt, J=19.1, 5.9 Hz, 2H), 3.49-3.69 (m, 1H), 3.28-3.45

(1H, concealed under water peak), 2.58-2.80 (m, 1H), 1.33-1.50 (m,

2H), 1.30 (d, J=5.8 Hz, 6H), 1.05-1.22 (m, 6H), 0.68-0.76 (m, 3H).

Ή NMR (DMSO-d6) δ: 9.96 (br. s., 0.3H), 9.54 (br. s., 0.5H), 9.27 (d,

J=4.5 Hz, 1H), 8.64 (d, J=5.0 Hz, 1H), 8.22 (s, 0.4H), 8.14 (s, 1H), 7.75-

430.2 7.90 (m, 4.6H), 7.50-7.61 (m, 1H), 7.34 (t, J=8.8 Hz, 2H), 4.54-4.79 (m,

2.66 (M+H + ) 2H), 3.47-3.71 (m, 1H), 3.28-3.45 (1H, concealed under water peak),

2.59-2.81 (m, 1H), 1.26-1.50 (m, 2H), 1.05-1.23 (m, 6H), 0.66-0.80 (m,

3H).

Ή NMR (DMSO-d6) δ: 9.29 (t, J=4.9 Hz, 0.6H), 9.23 (t, J=4.1 Hz, 0.4H),

8.78 (d, J=4.8 Hz, 1H), 8.58 (s, 1H), 8.42 (s, 1H), 8.33 (d, J=2.5 Hz, 1H),

455.2 8.21 (s, 1H), 8.19 (s, 0.4H), 7.92 (t, J=9.2 Hz, 2H), 7.80 (s, 0.6H), 7.73

1.97 (M+H + ) (br. s., 1H), 7.60 (d, J=15.6 Hz, 1H), 4.53-4.76 (m, J=6.3 Hz, 2H), 3.93

(s, 3H), 3.27-3.61 (2H, concealed underwater peak), 2.62-2.83 (m, 1H),

1.70-1.83 (m, 1H), 1.51-1.70 (m, 3H), 1.37-1.51 (m, 2H), 1.16-1.37 (m, 3H), 0.85-1.10 (m, 2H).

Ή NMR (DMSO-d6) δ: 9.95-10.05 (m, 0.3H), 9.51-9.62 (m, 0.4H), 9.25- 9.33 (m, 1 H), 8.63-8.71 (m, 1 H), 8.58 (d, J=1.3 Hz, 1 H), 8.34 (d, J=2.5

443.2 Hz, 1 H), 8.22 (s, 1.3H), 7.93 (t, J=8.0 Hz, 2H), 7.83 (s, 0.7H), 7.72 (br.

1.97 (M+H + ) s., 1 H), 7.60 (t, J=7.7 Hz, 1 H), 4.55-4.76 (m, 2H), 3.93 (s, 3H), 3.53-3.68

(m, 1 H), 3.33-3.46 (m, 1 H), 2.59-2.79 (m, 1 H), 1.28-1 .50 (m, 2H), 1.08- 1.21 (m, 6H), 0.72 (t, J=6.5 Hz, 3H).

Ή NMR (DMSO-d6) δ: 10.12 (br. s., 0.4H), 9.59 (br. s., 0.5H), 9.10 (d,

J=6.5 Hz, 1 H), 8.65 (t, J=5.4 Hz, 1 H), 8.18-8.29 (m, 1.4H), 8.08 (br. s.,

1 H), 7.92 (s, 1 H), 7.83 (s, 0.6H), 7.72 (dd, J=7.8, 1.5 Hz, 1 H), 7.68 (d, 430.2 J=7.3 Hz, 1 H), 7.39-7.48 (m, 1 H), 4.51-4.74 (m, 2H), 4.17 (q, J=7.3 Hz, 2.25 (M+H + ) 2H), 3.50-3.69 (m, 1 H), 3.28-3.47 (1 H, concealed under water peak),

2.59-2.80 (m, 1 H), 1.42 (t, J=7.3 Hz, 3H), 1.24-1.39 (m, 2H), 1.17 (br. s.,

6H), 0.70-0.80 (m, 3H).

Ή NMR (DMSO-d6) δ: 11.70-13.48 (m, 0.2H), 10.24 (s, 0.1 H), 9.66 (s,

0.2H), 9.22-9.40 (m, 1 H), 8.67 (t, J=5.6 Hz, 1 H), 8.29 (br. s., 1 H), 8.22

456.1 (s, 0.5H), 8.20 (s, 1 H), 7.97 (d, J=7.5 Hz, 1 H), 7.84-7.93 (m, 3H), 7.83

2.29 (M+H + ) (s, 0.6H), 7.51-7.64 (m, 2H), 4.53-4.77 (m, 2H), 3.52-3.69 (m, 1 H), 3.28

-3.47 (1 H, concealed under water peak), 2.61 -2.79 (m, 1 H), 1.28-1.54

(m, 2H), 1.05-1 .21 (m, 6H), 0.71 (t, J=6.7 Hz, 3H).

Ή NMR (DMSO-d6) δ: 9.97 (br. s., 0.5H), 9.55 (br. s., 0.5H), 9.31 (d,

J=6.5 Hz, 1 H), 8.64 (d, J=6.0 Hz, 1 H), 8.21 (t, J=6.8 Hz, 1.6H), 8.17 (s,

491.1 1 H), 7.98 (d, J=7.8 Hz, 1 H), 7.92 (d, J=7.5 Hz, 1 H), 7.81-7.90 (m, 2.6H),

2.18 (M+H + ) 7.67-7.75 (m, 1 H), 7.62 (t, J=7.7 Hz, 1 H), 7.45 (s, 2H), 4.65 (br. s., 2H),

3.52-3.71 (m, 1 H), 3.25-3.47 (1 H, concealed under water peak), 2.59- 2.81 (m, 1 H), 1.26-1 .49 (m, 2H), 1.15 (br. s., 6H), 0.68-0.77 (m, 3H).

Ή NMR (DMSO-d6) δ: 9.95 (br. s., 0.3H), 9.54 (br. s., 0.6H), 9.28 (d,

J=4.3 Hz, 1 H), 8.64 (d, J=5.3 Hz, 1 H), 8.22 (s, 0.4H), 8.17 (s, 1 H), 7.88

510.1 (d, J=4.8 Hz, 2H), 7.83 (s, 0.6H), 7.56 (t, J=7.7 Hz, 1 H), 7.38-7.50 (m,

2.75 (M+H + ) 3H), 7.10 (d, J=7.5 Hz, 1 H), 4.87 (q, J=8.8 Hz, 2H), 4.51-4.75 (m, 2H),

3.50-3.73 (m, 1 H), 3.29-3.46 (1 H, concealed under water peak), 2.58- 2.79 (m, 1 H), 1.26-1 .53 (m, 2H), 1.16 (d, J=14.6 Hz, 6H), 0.72 (t, 3H).

Ή NMR (DMSO-d6) δ: 9.95 (br. s., 0.3H), 9.54 (br. s., 0.5H), 9.23 (d,

J=5.8 Hz, 1 H), 8.62 (d, J=4.5 Hz, 1 H), 8.22 (s, 0.4H), 8.03 (s, 1 H), 7.90

460.1 (d, J=7.8 Hz, 1 H), 7.82 (s, 0.5H), 7.70 (dd, J=7.5, 0.8 Hz, 1 H), 7.52-7.60

2.52 (M+H + ) (m, 1 H), 7.18-7.30 (m, 2H), 7.11 (td, J=6.8, 2.1 Hz, 1 H), 4.48-4.78 (m,

2H), 3.89 (s, 3H), 3.48-3.71 (m, 1 H), 3.27-3.45 (1 H, concealed under

water peak), 2.58-2.81 (m, 1 H), 1.27-1.50 (m, 2H), 1.04-1.22 (m, 6H), 0.61-0.81 (m, 3H).

Ή NMR (DMSO-d6) δ: 9.66-10.11 (m, 1.3H), 9.54 (br. s., 0.6H), 9.25 (d,

J=5.5 Hz, 1 H), 8.63 (d, J=5.5 Hz, 1 H), 8.23 (s, 0.3H), 8.12 (s, 1 H), 7.88

(d, J=7.5 Hz, 1 H), 7.83 (s, 0.6H), 7.77 (d, J=7.8 Hz, 1 H), 7.57 (t, J=7.7 505.0 Hz, 1 H), 7.51 (s, 1 H), 7.47 (d, J=5.8 Hz, 2H), 7.20-7.30 (m, 1 H), 4.50- 2.30 (M+H + ) 4.77 (m, 2H), 3.49-3.72 (m, 1 H), 3.28-3.45 (1 H, concealed under water

peak), 3.04 (s, 3H), 2.59-2.81 (m, 1 H), 1 .26-1 .48 (m, 2H), 1.07-1.23 (m,

6H), 0.67-0.79 (m, 3H).

Ή NMR (DMSO-d6) δ: 10.18 (s, 0.2H), 9.61 (br. s., 0.4H), 9.09-9.31 (m,

1 H), 8.64 (t, J=4.8 Hz, 1 H), 8.22 (s, 0.4H), 8.09 (s, 1 H), 7.83 (s, 0.7H),

455.1 7.74 (t, J=7.3 Hz, 2H), 7.60 (d, J=8.8 Hz, 2H), 7.47 (t, J=7.8 Hz, 1 H),

1.98 (M+H + ) 6.82 (d, J=8.8 Hz, 2H), 4.50-4.78 (m, 2H), 3.51-3.71 (m, 1 H), 3.27-3.47

(1 H, concealed under water peak), 2.96 (s, 6H), 2.58-2.78 (m, 1 H), 1 .26- 1.52 (m, 2H), 1 .05-1 .26 (m, J=8.3 Hz, 6H), 0.66-0.80 (m, 3H).

Ή NMR (DMSO-d6) δ: 9.98 (br. s., 0.3H), 9.55 (br. s., 0.5H), 9.19-9.41

(m, J=5.5 Hz, 1 H), 8.57-8.74 (m, 1 H), 8.25 (br. s., 1 H), 8.23 (br. s.,

490.1 1.4H), 8.12 (d, J=7.8 Hz, 1 H), 7.90-8.01 (m, 3H), 7.75-7.86 (m, J=15.3

2.29 (M+H + ) Hz, 1.6H), 7.62 (t, J=7.8 Hz, 1 H), 4.54-4.79 (m, 2H), 3.50-3.69 (m, 1 H),

3.28-3.45 (1 H, concealed under water peak), 3.31 (s, 3H), 2.59-2.81 (m,

1 H), 1.25-1.48 (m, 2H), 1.07-1 .17 (m, 6H), 0.67-0.77 (m, 3H).

Ή NMR (DMSO-d6) δ: 9.98 (br. s., 0.3H), 9.56 (br. s., 0.5H), 9.25 (d,

J=5.5 Hz, 1 H), 8.64 (br. s., 1 H), 8.23 (s, 0.4H), 8.12 (s, 1 H), 7.83 (s,

442.2 0.7H), 7.79 (t, J=6.8 Hz, 2H), 7.69 (d, J=8.5 Hz, 2H), 7.52 (t, J=7.8 Hz,

2.54 (M+H + ) 1 H), 7.06 (d, J=8.8 Hz, 2H), 4.49-4.78 (m, 2H), 3.81 (s, 3H), 3.50-3.70

(m, 1 H), 3.28-3.46 (1 H, concealed under water peak), 2.59-2.79 (m,

1 H), 1.27-1.50 (m, 2H), 1.05-1 .22 (m, 6H), 0.64-0.79 (m, 3H).

Ή NMR (DMSO-d6) δ: 9.97 (br. s., 0.2H), 9.55 (br. s., 0.4H), 9.24 (d,

J=5.5 Hz, 1 H), 8.65 (br. s., 1 H), 8.22 (s, 0.3H), 8.05 (s, 1 H), 7.90 (d,

430.2 J=7.8 Hz, 1 H), 7.82 (s, 0.6H), 7.72 (d, J=7.5 Hz, 1 H), 7.53-7.65 (m, 2H),

2.56 (M+H + ) 7.42-7.51 (m, 1 H), 7.29-7.39 (m, 2H), 4.48-4.76 (m, 2H), 3.48-3.70 (m,

1 H), 3.28-3.45 (1 H, concealed under water peak), 2.58-2.80 (m, 1 H),

1.25-1.49 (m, 2H), 1.05-1.23 (m, J=3.3 Hz, 6H), 0.66-0.78 (m, 3H).

Ή NMR (DMSO-d6) δ: 9.97 (br. s., 0.3H), 9.55 (br. s., 0.5H), 9.24 (d,

J=5.3 Hz, 1 H), 8.65 (d, J=5.8 Hz, 1 H), 8.22 (s, 0.3H), 8.13 (s, 1 H), 7.80-

460.1 7.90 (m, J=7.8, 1.0 Hz, 2.5H), 7.56 (t, J=7.8 Hz, 1 H), 7.47 (d, J=8.3 Hz,

2.58 (M+H + ) 1 H), 7.26-7.38 (m, 2H), 4.49-4.78 (m, 2H), 3.95 (s, 3H), 3.48-3.70 (m,

1 H), 3.28-3.47 (1 H, concealed under water peak), 2.58-2.81 (m, 1 H),

1.27-1.51 (m, 2H), 1.17 (d, J=10.5 Hz, 6H), 0.65-0.80 (m, 3H). Ή NMR (DMSO-d6) δ: 9.32 (t, J=5.3 Hz, 0.6H), 9.23-9.29 (m, J=5.3 Hz,

0.4H), 8.67 (t, J=5.6 Hz, 1 H), 8.37 (s, 1 H), 8.24 (d, J=5.8 Hz, 2H), 8.21

(s, 0.4H), 8.16 (br. s., 1 H), 7.85-7.94 (m, 4H), 7.82 (s, 0.5H), 7.58 (td, 455.1

82 2.13

J=7.7, 2.9 Hz, 2H), 7.48 (br. s., 1 H), 4.53-4.80 (m, 2H), 3.28-3.63 (2H, (M+H + ) concealed under water peak), 2.60-2.80 (m, 1 H), 1.25-1.49 (m, 2H),

1.15 (dd, J=10.9, 7.2 Hz, 6H), 0.64-0.78 (m, 3H).

Ή NMR (DMSO-d6) δ: 9.97 (br. s., 0.4H), 9.55 (br. s., 0.6H), 9.23 (d,

J=5.0 Hz, 1 H), 8.62 (d, J=5.5 Hz, 1 H), 8.22 (s, 0.5H), 8.11 (s, 1 H), 7.78- 7.89 (m, 2.5H), 7.50-7.58 (m, J=7.5 Hz, 1 H), 7.29 (t, J=7.8 Hz, 1 H), 455.2

83 1.97

6.94-7.03 (m, 2H), 6.77 (dd, J=7.9, 1 .6 Hz, 1 H), 4.50-4.79 (m, 2H), 3.49- (M+H + ) 3.73 (m, 1 H), 3.28-3.46 (1 H, concealed under water peak), 2.97 (s, 6H),

2.58-2.80 (m, 1 H), 1.26-1.47 (m, 2H), 1.06-1.23 (m, 6H), 0.73 (t, 3H).

1 H NMR (DMSO-d6) δ: 9.26-9.61 (m, 1 H), 9.06-9.24 (m, 1 H), 8.67-8.93

(m, 3H), 8.46 (t, J=1.63 Hz, 1 H), 8.08-8.34 (m, 3H), 7.60-7.79 (m, 3H), 592.3

0.96 f

84 4.56-4.88 (m, 2H), 4.44 (q, J=7.19 Hz, 2H), 3.57 (td, J=4.02, 9.91 Hz, (M+H + ) 1 H), 2.58 (ddd, J=4.89, 9.47, 14.24 Hz, 1 H), 1.29-1.62 (m, 7H), 0.89- 1.23 (m, 6H), 0.50-0.86 (m, 6H).

Ή NMR (METHANOL-d4) δ: 8.46 (s, 0.6H), 8.30 (s, 0.4H), 8.07 (s, 1 H),

7.83 (m, 2H), 7.61 (s, 1 H), 7.55 (t, J-8.0 Hz, 1 H), 7.44 (m, 1 H), 7.28-7.36

444.0

85 (m, 2H), 4.78 (m, 2H), 3.77 (m, 1 H), 3.65 (dd, J=6.0, 14.0 Hz, 0.4H), 0.98 d

(M+H + ) 3.45 (dd, J=6.0, 14.0 Hz, 0.6H), 2.85 (m, 0.6H), 2.70 (m, 0.4H), 1.57 (m,

1 H), 1.45 (m, 1 H), 1 .18-1.34 (m, 6H), 0.80 (m, 3H).

Ή NMR (DMSO-d6) δ: 12.02-13.36 (m, 1.6H), 9.60 (s, 0.3H), 9.18-9.38

(m, 1.7H), 8.93 (br. s., 1 H), 8.81-8.88 (m, 0.3H), 8.60-8.67 (m, 0.7H),

8.25 (d, J=6.0 Hz, 1.3H), 8.10-8.20 (m, 2H), 8.05 (d, J=8.3 Hz, 2H), 7.76

644.3

86 (s, 0.7H), 7.52 (s, 1 H), 4.74-4.87 (m, 2H), 4.55-4.74 (m, 1 H), 4.22 (s, 5.95 a

(M+H + ) 2.3H), 3.48-3.64 (m, 0.7H), 2.82-2.96 (m, 1 H), 2.66-2.81 (m, 1 H), 2.54- 2.66 (m, 1 H), 1.46-1 .61 (m, 2H), 1.42 (t, J=6.9 Hz, 5H), 0.92-1.22 (m,

6H), 0.78 (s, 3H), 0.53-0.71 (m, 3H).

Ή NMR (DMSO-d6) δ: 12.20-13.23 (m, 2H), 9.63 (s, 0.3H), 9.15-9.37

(m, 1.7H), 8.95 (d, J=7.5 Hz, 1.3H), 8.71 (br. s., 0.7H), 7.90-8.38 (m,

6.3H), 7.75 (s, 0.7H), 4.57-4.89 (m, 3H), 4.33-4.51 (m, 2H), 4.15-4.28 644.3

87 5.71 a

(m, 0.3H), 4.04 (q, J=7.0 Hz, 1 H), 3.57 (br. s., 0.7H), 2.88-3.00 (m, 1 H), (M+H + ) 2.84 (d, J=5.0 Hz, 1 H), 2.53-2.65 (m, 1 H), 1.22-1.66 (m, 6H), 0.90-1.22

(m, 6H), 0.48-0.90 (m, 6H).

Ή NMR (DMSO-d6) δ: 11.82-13.25 (m, 2H), 9.60 (s, 0.3H), 9.12-9.36

(m, 1.7H), 8.89 (br. s., 0.3H), 8.62-8.75 (m, 0.7H), 8.27 (s, 0.3H), 8.13- 658.3

88 5.85 a

8.23 (m, 2H), 8.07 (t, J=7.8 Hz, 1 H), 7.95-8.02 (m, 1 H), 7.65-7.81 (m, (M+H + ) 2.7H), 7.33 (d, J=8.3 Hz, 1 H), 4.47-4.93 (m, 3H), 4.13-4.31 (m, 2.3H), 3.56 (d, J=4.0 Hz, 0.7H), 3.52 (s, 2H), 2.54-2.80 (m, 3H), 1.46-1.62 (m,

2H), 1.40 (t, J=6.8 Hz, 5H), 0.90-1.15 (m, 6H), 0.71-0.82 (m, 3H), 0.52- 0.69 (m, 3H).

Ή NMR (DMSO-d6) δ: 12.68-12.82 (m, 1 H), 9.56 (s, 0.3H), 9.27 (br. s.,

0.7H), 9.13-9.20 (m, 0.3H), 9.04-9.12 (m, 0.7H), 8.81-8.88 (m, 0.3H),

8.62-8.70 (m, 0.7H), 8.24 (s, 0.3H), 8.11-8.17 (m, 1 H), 8.02-8.09 (m,

1 H), 7.78 (d, J=8.0 Hz, 1 H), 7.73 (d, J=8.5 Hz, 1.7H), 7.66 (d, J=8.0 Hz, 547.0

7.38 a

1 H), 4.66-4.79 (m, 1.3H), 4.57-4.65 (m, 0.7H), 4.25 (q, J=7.1 Hz, 2.3H), (M+H + ) 3.51-3.60 (m, 0.7H), 2.54-2.62 (m, 1 H), 1 .46-1 .57 (m, 2H), 1.40 (t, J=6.9

Hz, 5H), 0.97-1.17 (m, 6H), 0.74-0.81 (m, 3H), 0.67 (t, J=6.8 Hz, 1 H),

0.62 (t, J=6.9 Hz, 2H).

Ή NMR (DMSO-d6) δ: 12.8 (br. s., 1 H), 9.56 (s, 1 H), 9.44-9.50 (m, 1 H),

9.26 (s, 0.3H), 9.18 (d, J=5.02 Hz, 1 H), 8.58-8.66 (m, 0.7H), 8.21-8.29

(m, 1 H), 8.19 (s, 1 H), 7.97 (d, J=5.02 Hz, 1 H), 7.70-7.80 (m, 2H), 4.58- 530.0

2.49

4.85 (m, 2H), 4.26 (q, J=6.69 Hz, 2H), 3.56 (m, 1 H), 2.54-2.63 (m, 1 H), (M+H + ) 1.49-1.59 (m, 3H), 1.41 (t, J=8.0 Hz, 3H), 0.96-1.21 (m, 7H), 0.78 (t,

J=8.0 Hz, 3H), 0.63 (t, J=8.0 Hz, 3H).

Ή NMR (METHANOL-d4) δ: 9.26 (s, 1 H), 9.10 (s, 1 H), 8.17 (s, 0.3H),

7.87-7.95 (m, 2H), 7.77-7.86 (m, 1 .7H), 4.69-4.76 (m, 2H), 4.24 (q,

530.0 J=6.8 Hz, 2H), 3.48-3.54 (m, 1 H), 2.60 (td, J=9.7, 4.4 Hz, 1 H), 1.41-1 .74 2.42

(M+H + ) (m, 4H), 1.49 (t, J=6.78 Hz, 3H), 1.03-1.31 (m, 6H), 0.87 (t, J=7.28 Hz,

3H), 0.69 (t, J=7.03 Hz, 3H).

Ή NMR (DMSO-d6) δ: 12.95 (br. s., 1 H), 12.55 (br. s., 1 H), 9.59 (s,

0.3H), 9.35 (t, J=5.9 Hz, 0.3H), 9.28 (s, 0.7H), 9.15 (t, J=5.8 Hz, 0.7H),

8.91 (d, J=7.8 Hz, 1 H), 8.85 (t, J=5.8 Hz, 0.3H), 8.59 (t, J=5.9 Hz, 0.7H),

643.4 8.28 (s, 0.3H), 8.16-8.24 (m, 1 H), 8.01-8.1 1 (m, 1 H), 7.85-7.98 (m, 2H), 0.83 e

(M+H + ) 7.77 (s, 0.7H), 7.54-7.66 (m, 1 H), 7.40-7.51 (m, 2H), 4.77-4.91 (m, 1 H),

4.52-4.74 (m, 2H), 4.35 (q, J=7.0 Hz, 2H), 4.22 (q, J=7.4 Hz, 0.3H),

3.49-3.64 (m, 0.7H), 2.75-3.02 (m, 2H), 2.55-2.68 (m, 1 H), 1.28-1.64 (m,

7H), 0.95-1.26 (m, 6H), 0.59-0.88 (m, 6H).

Ή NMR (DMSO-d6) δ: 14.10 (br. s., 1 H), 11.43 (br. s., 1 H), 9.1 1-9.71

(m, 2H), 8.78-8.91 (m, 0.2H), 8.59 (t, J=5.9 Hz, 0.7H), 8.27 (s, 0.3H),

8.20 (s, 1 H), 7.83-7.98 (m, 3H), 7.76 (s, 0.7H), 7.52-7.66 (m, 1 H), 7.38 500.2

1.25 h

(s, 1 H), 7.33 (dd, J=8.2, 1.6 Hz, 1 H), 4.47-4.79 (m, 2H), 4.22 (q, J=7.2 (M+H + ) Hz, 0.3H), 3.51 -3.65 (m, 0.7H), 2.56-2.70 (m, 1 H), 1.28-1.63 (m, 4H),

0.97-1.26 (m, 6H), 0.55-0.88 (m, 6H).

Ή NMR (DMSO-d6) δ: 13.66 (br. s., 1 H), 9.32 (br. s., 1 H), 9.11 (t,

564.3 J=6.15 Hz, 1 H), 8.75-8.89 (m, 2H), 8.70 (t, J=5.65 Hz, 1 H), 8.47 (t, 0.82 f

(M+H + ) J=1.63 Hz, 1 H), 8.06-8.34 (m, 3H), 7.57-7.79 (m, 3H), 4.55-4.87 (m, 2H), 3.58 (td, J=4.14, 9.98 Hz, 1 H), 2.53-2.66 (m, 1 H), 1.26-1.64 (m,

4H), 0.91-1.26 (m, 6H), 0.50-0.85 (m, 6H).

Ή NMR (DMSO-d6) δ: 9.27-9.70 (m, 1 H), 9.00-9.25 (m, 1 H), 8.46-8.93

(m, 1 H), 8.29 (s, 0.3H), 8.03 (br. s., 1 H), 7.86 (d, J=7.8 Hz, 1 H), 7.74 (d,

J=7.5 Hz, 1 .7H), 7.37-7.51 (m, 1 H), 7.30 (br. s., 1 H), 6.95 (br. s., 1 H),

95 1.81 h 544.2 4.44-4.80 (m, 2H), 4.21 (br. s., 0.3H), 3.86-4.05 (m, 2H), 3.57 (br. s.,

(M+H + ) 0.7H), 2.68 (br. s., 1 H), 1.24-1.63 (m, 7H), 1.15 (br. s., 6H), 0.76 (d,

J=7.5 Hz, 6H).

Ή NMR (DMSO-d6) δ: 12.10-13.64 (m, 3H), 9.27-9.72 (m, 2H), 9.21 (d,

J=7.8 Hz, 1 H), 8.58-8.95 (m, 1 H), 8.02-8.47 (m, 5H), 7.70-7.98 (m, 2H),

5.00-5.22 (m, 2H), 4.71-4.92 (m, 2H), 4.52-4.73 (m, 1 H), 3.60 (td, 674.7

96 0.75 e

J=10.0, 3.9 Hz, 1 H), 2.68-3.04 (m, 2H), 2.55-2.65 (m, 1 H), 1.31-1.63 (m, (M+H + ) 4H), 1.11 (d, J=3.8 Hz, 4H), 0.89-1 .02 (m, 2H), 0.73-0.82 (m, 3H), 0.64- 0.71 (m, 1 H), 0.54-0.62 (m, 2H).

Ή NMR (DMSO-d6) δ: 13.46 (br. s., 1 H), 12.81 (br. s., 1 H), 12.45 (br.

s., 1 H), 9.59 (s, 0.4H), 9.23-9.40 (m, 0.9H), 9.07-9.19 (m, 1.7H), 8.84 (s,

0.3H), 8.59 (t, J=5.8 Hz, 0.7H), 8.28 (s, 0.3H), 8.21 (s, 1 H), 8.01-8.06

(m, 1 H), 7.94 (d, J=6.5 Hz, 1 H), 7.90 (d, J=8.0 Hz, 1 H), 7.77 (s, 0.7H), 673.3

97 5.55 a

7.56-7.64 (m, 1 H), 7.51 (d, J=8.0 Hz, 1 H), 7.42-7.49 (m, 1 H), 5.04 (s, (M+H + ) 2H), 4.77-4.92 (m, 1 H), 4.53-4.74 (m, 2H), 3.57-3.72 (m, 2H), 2.72-2.96

(m, 2H), 1.26-1 .65 (m, 4H), 1.13 (dd, J=13.3, 6.5 Hz, 6H), 0.60-0.83 (m,

6H).

Ή NMR (DMSO-d6) δ: 9.13 (t, J=5.8 Hz, 1 H), 8.70-8.86 (m, 1.3H), 8.66

(t, J=5.1 Hz, 0.7H), 8.25 (s, 0.3H), 8.08-8.18 (m, 2H), 8.02-8.07 (m, 1 H),

7.91-7.99 (m, 2H), 7.76 (s, 0.7H), 7.29 (d, J=14.3 Hz, 1 H), 4.70-4.83 (m,

565.0

98 1.2H), 4.59-4.69 (m, 0.8H), 4.20 (q, J=6.8 Hz, 2H), 3.52-3.62 (m, 1 H), 6.27 a

(M+H + ) 2.54-2.64 (m, 1 H), 1.53 (d, J=7.0 Hz, 2H), 1.41 (t, J=6.8 Hz, 5H), 0.97- 1.17 (m, 6H), 0.74-0.82 (m, 3H), 0.67 (t, J=6.8 Hz, 1 H), 0.61 (t, J=7.0

Hz, 2H).

Ή NMR (DMSO-d6) 0: 11.14 (br. s., 2H), 9.59 (br. s., 0.2H), 9.38 (t,

J=6.1 Hz, 0.4H), 9.29 (br. s., 0.5H), 9.18 (t, J=5.9 Hz, 0.7H), 8.83 (t,

J=5.9 Hz, 0.3H), 8.56 (t, J=5.9 Hz, 0.7H), 8.26 (s, 0.3H), 8.10-8.17 (m,

564.1 1 H), 7.87 (d, J=7.8 Hz, 1 H), 7.81 (d, J=6.8 Hz, 1 H), 7.74 (s, 0.7H), 7.47- 1.16 h

99 (M+H + ) 7.63 (m, 2H), 7.40 (d, J=1 .8 Hz, 1 H), 7.17 (dd, J=14.3, 1.5 Hz, 1 H),

4.46-4.77 (m, 2H), 4.17 (br. s., 0.3H), 4.13 (q, J=6.8 Hz, 2H), 3.56 (td,

J=9.5, 4.8 Hz, 0.7H), 2.53-2.68 (m, 1 H), 1.44-1.60 (m, 2H), 1 .36 (t,

J=6.9 Hz, 5H), 1 .11 (td, J=11.9, 4.5 Hz, 6H), 0.60-0.83 (m, 6H).

Ή NMR (DMSO-d6) δ: 9.90 (t, J=5.6 Hz, 0.2H), 9.53-9.70 (m, 0.5H),

00 1.08 h 564.1 9.28-9.38 (m, 0.3H), 9.14 (t, J=5.9 Hz, 0.7H), 8.77-8.90 (m, 0.3H), 8.58 (t, J=5.9 Hz, 0.7H), 8.28 (s, 0.4H), 8.12-8.23 (m, 1 H), 7.93-8.03 (m, (M+H + ) 0.6H), 7.89 (d, J=7.5 Hz, 2H), 7.75-7.80 (m, 1 H), 7.50-7.75 (m, 2H),

7.26-7.38 (m, 2H), 4.49-5.31 (m, 2H), 3.91-4.38 (m, 2.4H), 3.57 (td,

J=9.5, 4.4 Hz, 0.6H), 2.57-2.99 (m, 1 H), 1.44-1.59 (m, 2H), 1 .32-1 .42

(m, 5H), 1.04-1 .21 (m, 6H), 0.60-0.81 (m, 6H).

Ή NMR (METHANOL-d4) δ: 9.36 (br. s., 1 H), 9.20 (br. s., 1 H), 8.26 (s,

0.3H), 7.77-7.97 (m, 3.7H), 4.72-4.90 (m, 2H), 4.35 (q, J=6.7 Hz, 2H),

565.9

101 3.60 (m, J=8.5 Hz, 1 H), 2.57-2.77 (m, 1 H), 1 .43-1.75 (m, 4H), 1 .51 (t, 2.15

(M+H + ) J=6.7 Hz, 3H), 1 .03-1 .31 (m, 6H), 0.87 (t, J=7.0 Hz, 3H), 0.69 (t, J=7.0

Hz, 3H).

Ή NMR (DMSO-d6) δ: 9.14 (t, J=4.1 Hz, 1 H), 8.26 (s, 0.3H), 8.07 (d,

J=4.8 Hz, 1 H), 7.94 (d, J=5.0 Hz, 1 H), 7.73 (s, 0.7H), 7.09 (br. s., 1 H), 566.0

102 1.6 C

4.32-5.31 (m, 0.7H), 4.09-4.26 (m, 2.2H), 3.55 (d, J=4.8 Hz, 1 H), 2.54 (M+H + ) (s, 2H), 1.22-1 .61 (m, 7H), 1.13 (br. s., 6H), 0.51-0.85 (m, 6H).

Ή NMR (DMSO-d6) δ: 8.30 (d, J=8.3 Hz, 2H), 8.14-8.25 (m, 1 H), 7.65- 7.76 (m, 2.6H), 7.50 (t, J=7.5 Hz, 2H), 7.37-7.45 (m, 0.4H), 4.42-4.75 484.3

103 6.54 a

(m, 2H), 3.52 (t, J=8.9 Hz, 1 H), 2.55 (br. s., 1 H), 1.25-1.62 (m, 4H), (M+H + ) 0.83-1.14 (m, 6H), 0.72 (t, J=7.3 Hz, 3H), 0.42-0.59 (m, 3H).

Ή NMR (METHANOL-d4) δ: 8.16 (br. s., 1 H), 7.66-8.00 (m, 3H), 7.58

(br. s., 1 H), 7.41 (br. s., 1 H), 7.29 (br. s., 1 H), 4.16 (d, J=4.0 Hz, 1 H),

563.9

104 3.45-3.82 (m, 1 H), 3.15 (br. s., 1 H), 1.77-2.79 (m, 1 H), 1.51-1.73 (m, 5.93 1

(M+) 2H), 1.45 (br. s., 2H), 1.39 (d, J=6.5 Hz, 6H), 1.28-1.37 (m, 3H), 1 .24 (d,

J=10.3 Hz, 3H), 0.73-0.99 (m, 5H).

Ή NMR (DMSO-d6) δ: 13.31 (br. s., 2H), 9.60 (d, J=8.5 Hz, 0.6H), 9.50

(t, J=6.1 Hz, 0.7H), 9.28 (br. s., 0.6H), 8.56-8.94 (m, 1 H), 8.45 (d, J=1.5

Hz, 1 H), 8.40 (s, 0.8H), 8.29-8.35 (m, 1 H), 8.27 (s, 0.2H), 7.87 (s, 1 H),

572.2

105 7.71-7.80 (m, 1 H), 7.55-7.63 (m, 1 H), 7.49 (s, 1 H), 4.46-4.82 (m, 2H), 2.43

(M+H + ) 4.08-4.31 (m, 2.3H), 3.57 (td, J=9.6, 4.4 Hz, 0.7H), 2.54-2.68 (m, 1 H),

1.46-1.60 (m, 2H), 1.30-1.43 (m, 5H), 0.96-1.20 (m, 6H), 0.45-0.84 (m,

6H). H NMR (DMSO-d 6 ) δ: 9.23-9.33 (m, 1 H), 8.88 (t, J=5.4 Hz, 0.3H), 8.69

(t, J=5.5 Hz, 0.7H), 8.45 (d, J=4.8 Hz, 1 H), 8.31 (d, J=7.8 Hz, 1 H), 8.25

622.4

200 (s, 0.3H), 8.03-8.14 (m, 3H), 7.95 (d, J=5.0 Hz, 2H), 7.75 (s, 0.7H), 4.60- 0.71 J

(M+H + ) 4.80 (m, 2H), 4.42 (q, J=6.8 Hz, 2H), 4.21 (d, J=7.5 Hz, 0.3H), 3.52-3.61

(m, 2.6H), 2.53-2.61 (m, 1 H), 1.34-1.56 (m, 7H), 1 .06 (br. s., 3H), 0.93- 1.05 (m, 3H), 0.72-0.87 (m, 3H), 0.54-0.65 (m, 3H).

Ή NMR (DMSO-d6)6: 12.96 (br s, 1 H), 12.74 (br s, 1 H), 9.59 (s, 0.3H),

300 0.84 j 644.5 9.27-9.33 (m, 1 H), 9.18-9.25 (m, 0.7H), 8.81 -8.91 (m, 0.3H), 8.66-8.74 (m, 0.7H), 8.25 (s, 0.3H), 8.13-8.20 (m, 1 H), 8.05-8.1 1 (m, 1 H), 8.01 - (M+H + ) 8.05 (m, 1 H), 7.92-7.95 (m, 0.3H), 7.89-7.92 (m, 0.7H), 7.74 (s, 0.7H),

7.65 (s, 1 H), 6.94 (s, 1 H), 4.73-4.85 (m, J=6.3 Hz, 1 H), 4.64-4.73 (m,

0.3H), 4.54-4.64 (m, J=5.8 Hz, 0.7H), 4.1 1 -4.23 (m, 4H), 4.05 (s, 2H),

3.56 (td, J=9.7, 4.5 Hz, 1 H), 2.53-2.63 (m, 1 H), 1 .43-1 .57 (m, 2H), 1 .38

(t, J=6.9 Hz, 5H), 0.90-1 .19 (m, 6.H), 0.70-0.81 (m, 3H), 0.63 (t, J=7.0

Hz, 1 H), 0.57 ppm (t, J=7.0 Hz, 2H).

Ή NMR (DMSO-d6) δ: 12.70 (br. s., 2H), 9.58 (s, 0.3H),

9.27-9.34 (m, 1 H), 9.24 (t, J=6.3 Hz, 0.7H), 8.87 (t, J=5.6 Hz, 0.3H),

8.68 (t, J=5.6 Hz, 0.7H), 8.21 -8.29 (m, 1 .3H), 8.10 (t, J=7.6 Hz, 1 H),

8.02 (d, J=7.0 Hz, 1 H), 7.79-7.90 (m, 2H), 7.73 (s, 0.7H), 7.22 (d, J=7.8

644.3

301 Hz, 1 H), 4.66-4.81 (m, 1 .3H), 4.57-4.66 (m, 0.7H), 4.07-4.36 (m, 4.3H), 1 .67 c

(M+H + ) 3.92 (s, 2H), 3.55 (td, J=9.6, 4.4 Hz, 0.7H), 2.52-2.62 (m, 1 H), 1 .42-1 .58

(m, 2.3H), 1 .35 (t, J=7.0 Hz, 4.7H), 1 .05-1 .18 (m, 3H), 0.85-1 .05 (m,

3H), 0.70-0.82 (m, 3H), 0.62 (t, J=7.2 Hz, 0.9H), 0.56 (t, J=7.2 Hz,

2.1 H).

Ή NMR (DMSO-d6) δ: 13.20 (br. s, 2H), 9.61 (br. s,

0.3H), 9.37 (br. s, 0.7H), 9.29 (t, J=6.0 Hz, 0.3H), 9.22 (t, J=6.4 Hz,

0.7H), 8.82 (t, J=5.6 Hz, 0.3H), 8.64 (t, J=5.5 Hz, 0.7H), 8.18-8.30 (m,

2.3H), 7.99-8.16 (m, 3H), 7.75 (s, 0.7H), 7.43-7.55 (m, 1 H), 4.84-4.95

559.2

302 (m, 2H), 4.78 (sxt, J=6.2 Hz, 1 H), 4.70 (sxt, J=6.4 Hz, 0.3H), 4.60 (quin, 1 .72 c

(M+H + ) J=6.4 Hz, 0.7H), 4.20 (q, J=7.2 Hz, 0.3H), 3.58 (td, J=10.0, 4.0 Hz,

0.7H), 2.52-2.62 (m, 1 H), 1 .43-1 .58 (m, 2H), 1 .27-1 .43 (m, 2H), 1 .02- 1 .20 (m, 4H), 0.88-1 .02 (m, 2H), 0.69-0.81 (m, 3H), 0.64 (t, J=7.2 Hz,

1 H), 0.57 (t, J=7.2 Hz, 2H).

Ή NMR (DMSO-d6) δ: 12.78-13.76 (m, 2H), 9.60 (s, 0.3H), 9.34 (t,

J=6.0 Hz, 0.3H), 9.29 (s, 0.7H), 9.24 (t, J=6.2 Hz, 0.7H), 8.80 (t, J=5.8

Hz, 0.3H), 8.60 (t, J=5.8 Hz, 0.7H), 8.42-8.55 (m, 2H), 8.28-8.34 (m,

1 H), 8.26 (s, 0.3H), 8.09-8.16 (m, 1 H), 8.04-8.09 (m, 1 H), 7.87 (d, J=7.8

Hz, 1 H), 7.75 (s, 0.7H), 4.81 (sxt, J=6.4 Hz, 0.7H), 4.78 (sxt, J=6.0 Hz, 529.2

303 1 .68 c

0.3H), 4.69 (quin, J=6.2 Hz, 0.3H), 4.60 (quin, J=6.2 Hz, 0.7H), 4.20 (q, (M+H + ) J=7.2 Hz, 0.3H), 3.58 (td, J=9.8, 4.4 Hz, 0.7H), 2.52-2.63 (m, 1 H), 1 .43- 1 .60 (m, 2H), 1 .21 -1 .43 (m, 2H), 0.83-1 .19 (m, 6H), 0.76 (t, J=7.2 Hz,

2.1 H), 0.74 (t, J=7.2 Hz, 0.9H), 0.66 (t, J=7.0 Hz, 0.9H), 0.59 ppm (t,

J=7.0 Hz, 2.1 H).

Ή NMR (DMSO-d6) δ: 12.49 (br. s, 2H), 9.61 (s, 0.3H),

9.33 (t, J=6.2 Hz, 0.3H), 9.25 (t, J=6.1 Hz, 0.7H), 8.90 (d, J=7.8 Hz, 1 H), 600.3

304 0.73 j

8.81 (t, J=5.8 Hz, 0.3H), 8.62 (t, J=5.6 Hz, 0.7H), 8.34-8.44 (m, 1 .7H), (M+H + ) 8.23-8.33 (m, 1 .3H), 8.12 (t, J=7.8 Hz, 0.3H), 8.12 (t, J=7.6 Hz, 0.7H), 8.04 (d, J=7.8 Hz, 1 H), 8.00 (d, J=8.3 Hz, 2H), 7.76 (s, 0.7H), 4.74-4.85

(m, 2H), 4.70 (sxt, J=6.2 Hz, 0.3H), 4.61 (quin, J=6.2 Hz, 0.7H), 4.21 (q,

J=7.3 Hz, 0.3H), 3.58 (td, J=9.6, 4.1 Hz, 0.7H), 2.88 (dd, J=16.4, 5.6 Hz,

1 H), 2.74 (dd, J=16.4, 8.0 Hz, 1 H), 2.53-2.63 (m, 1 H), 1.44-1.61 (m, 2H),

1.38 (d, J=4.3 Hz, 2H), 0.90-1.20 (m, 6H), 0.77 (t, J=7.2 Hz, 2.1 H), 0.74

(t, J=7.2 Hz, 0.9H), 0.65 (t, J=7.0 Hz, 0.9H), 0.58 (t, J=7.2 Hz, 2.1 H).

Ή NMR (DMSO-d6, δ: 12.67 (br. s, 2H), 9.61 (s, 0.3H),

9.30 (s, 0.7H), 9.33 (t, J=6.0 Hz, 0.3H), 9.25 (t, J=6.2 Hz, 0.7H), 8.81 (t,

J=5.8 Hz, 0.3H), 8.61 (t, J=5.8 Hz, 0.7H), 8.35-8.44 (m, 2H), 8.25-8.32

(m, 1.3H), 8.12 (t, J=7.6 Hz, 0.3H), 8.12 (t, J=7.6 Hz, 0.7H), 8.04 (d,

J=7.5 Hz, 1 H), 8.00 (d, J=8.5 Hz, 2H), 7.76 (s, 0.7H), 4.80 (quin, J=6.2

600.3 Hz, 0.7H), 4.79 (quin, J=6.2 Hz, 0.3H), 4.71 (quin, J=6.2 Hz, 1 H), 4.61 0.73 j

(M+H + ) (quin, J=6.2 Hz, 1 H), 4.21 (q, J=7.2 Hz, 0.3H), 3.58 (td, J=9.8, 4.2 Hz,

0.7H), 2.85 (dd, J=16.0, 6.2 Hz, 1 H), 2.65-2.74 (m, 1 H), 2.55-2.62 (m,

1 H), 1.43-1.57 (m, 2H), 1 .31 -1.43 (m, 2H), 0.94-1.20 (m, 6H), 0.77 (t,

J=7.2 Hz, 2.1 H), 0.74 (t, J=7.2 Hz, 0.9H), 0.66 (t, J=7.2 Hz, 0.9H), 0.59

(t, J=7.2 Hz, 2.1 H).

Ή NMR (DMSO-d6, δ: 12.38 (br. s, 2H), 9.61 (s, 0.3H), 9.32 (t, J=6.2

Hz, 0.3H), 9.24 (t, J=6.3 Hz, 0.7H), 8.81 (t, J=5.8 Hz, 0.3H), 8.77 (d,

J=7.5 Hz, 1 H), 8.62 (t, J=5.6 Hz, 0.7H), 8.34-8.43 (m, 1.7H), 8.24-8.32

(m, 1.3H), 8.12 (t, J=7.8 Hz, 0.3H), 8.12 (t, J=7.8 Hz, 0.7H), 8.04 (d,

J=8.4 Hz, 1 H), 8.04 (d, J=7.8 Hz, 2H), 7.76 (s, 0.7H), 4.80 (quin, J=6.3

Hz, 0.7H), 4.77 (quin, J=6.3 Hz, 0.3H), 4.70 (quin, J=6.3 Hz, 0.3H), 4.61 614.4

0.73 j

(quin, J=6.2 Hz, 0.7H), 4.45 (dd, J=9.6, 5.0 Hz, 0.3H), 4.43 (dd, J=9.6, (M+H + ) 5.0 Hz, 0.7H), 4.21 (q, J=7.4 Hz, 0.3H), 3.58 (td, J=9.4, 4.0 Hz, 0.7H),

2.53-2.63 (m, 1 H), 2.39 (t, J=7.5 Hz, 2H), 2.06-2.19 (m, 1 H), 1.90-2.05

(m, 1 H), 1.43-1 .59 (m, 2H), 1.29-1.43 (m, 2H), 0.92-1 .22 (m, 6H), 0.77

(t, J=7.2 Hz, 2.1 H), 0.74 (t, J=7.2 Hz, 0.9H), 0.65 (t, J=7.0 Hz, 0.9H),

0.58 (t, J=7.2 Hz, 2.1 H).

Ή NMR (DMSO-d6) δ: 12.96 (br. s, 1 H), 12.19 (br. s,

1 H), 9.58 (s, 0.3H), 9.30 (t, J=6.0 Hz, 1 H), 9.24 (t, J=6.2 Hz, 0.7H), 8.87

(t, J=6.2 Hz, 0.3H), 8.69 (t, J=6.2 Hz, 0.7H), 8.61 (d, J=7.4 Hz, 1 H), 8.31

(d, J=7.6 Hz, 1 H), 8.24 (s, 0.3H), 8.12 (t, J=7.4 Hz, 1 H), 8.05 (d, J=7.6

Hz, 1 H), 7.94 (s, 3H), 7.74 (s, 0.7H), 4.76 (quin, J=6.2 Hz, 0.7H), 4.71 658.5

0.80 j

(quin, J=6.2 Hz, 0.3H), 4.63 (quin, J=6.2 Hz, 0.7H), 4.51-4.58 (m, 1.3H), (M+H + ) 4.35-4.45 (m, 2H), 4.21 (q, J=7.2 Hz, 0.3H), 3.55 (td, J=9.8, 4.2 Hz,

0.7H), 2.53-2.62 (m, 1 H), 2.25-2.40 (m, 2H), 2.08-2.20 (m, 1 H), 1.89- 2.01 (m, 1 H), 1.50 (t, J=6.9 Hz, 3H), 1.43-1.58 (m, 2H), 1.32-1.43 (m,

2H), 1.05-1.18 (m, 3H), 0.89-1 .05 (m, 3H), 0.77 (t, J=7.2 Hz, 2.1 H), 0.74 (t, J=7.2 Hz, 0.9H), 0.62 (t, J=7.2 Hz, 0.9H), 0.56 (t, J=7.2 Hz, 2.1 H).

Ή NMR (DMSO-d6) δ: 11.07 (br. s, 2H), 9.92 (s, 1 H),

9.37 (br. s, 1 H), 9.00 (t, J=6.0 Hz, 1 H), 8.81 (t, J=6.2 Hz, 0.3H), 8.65 (t,

J=5.8 Hz, 0.7H), 8.23 (s, 0.3H), 8.05-8.12 (m, 1.7H), 7.99-8.05 (m,

1.3H), 7.70-7.86 (m, 2.7H), 7.23 (d, J=15.3 Hz, 1 H), 4.77 (quin, J=6.4

537.2

204 Hz, 0.7H), 4.73 (quin, J=5.4 Hz, 0.3H), 4.61 (quin, J=6.4 Hz, 0.7H), 4.17 1.54 c

(M+H + ) (q, J=7.4 Hz, 0.3H), 3.57 (td, J=9.6, 4.4 Hz, 1 H), 2.53-2.62 (m, 1 H),

1.43-1.60 (m, 2H), 1.30-1.43 (m, 2H), 0.94-1.19 (m, 6H), 0.77 (t, J=7.2

Hz, 2.1 H), 0.75 (t, J=7.2 Hz, 0.9H), 0.67 (t, J=7.2 Hz, 0.9H), 0.61 (t,

J=7.2 Hz, 2.1 H). H NMR (DMSO-d 6 ) δ: 12.54-12.61 (m, 0.9H), 9.62 (s, 0.3H), 9.30 (t,

J=6.1 Hz, 0.3H), 9.20 (t, J=6.3 Hz, 0.7H), 9.03-9.10 (m, 1 H), 8.82 (t,

J=5.6 Hz, 0.3H), 8.63 (t, J=5.8 Hz, 0.7H), 8.27 (s, 0.3H), 8.20-8.26 (m, 594

203 0.66 j

1 H), 8.03-8.13 (m, 3H), 7.76-7.85 (m, 2.8H), 4.68-4.83 (m, 1.3H), 4.57- (M+H + ) 4.64 (m, 0.7H), 4.21 (q, J=7.3 Hz, 0.2H), 3.55-3.67 (m, 2.8H), 2.54-2.62

(m, 1 H), 1.31-1 .60 (m, 4H), 0.94-1.18 (m, 6H), 0.73-0.80 (m, 3H), 0.57- 0.69 (m, 3H).

Ή NMR (DMSO-d6) δ: 9.62 (s, 0.2H), 9.24-9.38 (m, 1.5H), 8.82 (t,

J=5.5 Hz, 0.2H), 8.70-8.77 (m, 1 H), 8.63 (t, J=5.6 Hz, 0.7H), 8.35-8.43

(m, 2H), 8.25-8.33 (m, 1.2H), 8.09-8.16 (m, 1 H), 8.01-8.07 (m, 2.9H),

578.4

201 7.76 (s, 0.7H), 4.56-4.86 (m, 2.2H), 4.22 (q, J=7.4 Hz, 0.4H), 3.54-3.67 0.64 j

(M+H + ) (m, 3.7H), 2.66-2.70 (m, 0.2H), 2.54-2.64 (m, 1 H), 2.31-2.36 (m, 0.2H),

1.30-1.61 (m, 4H), 0.92-1.22 (m, J=6.5 Hz,6.3H), 0.72-0.82 (m, 3H),

0.66 (t, J=7.0 Hz, 0.8H), 0.60 (t, J=1.0 Hz, 2.1 H).

Ή NMR (DMSO-d 6 ) δ: 9.63 (s, 0.3H), 9.42 (t, J=6.1 Hz, 0.4H), 9.33 (t,

J=6.4 Hz, 1.4H), 8.80 (t, J=5.6 Hz, 0.3H), 8.58 (t, J=5.5 Hz, 1.7H), 8.44- 8.49 (m, 1.1 H), 8.27-8.34 (m, 2.4H), 8.09-8.17 (m, 1 H), 8.03-8.09 (m,

834.3

400 1 H), 7.76 (s, 0.7H), 7.60 (d, J=8.0 Hz, 1 H), 7.08 (br. s., 2H), 4.82 (dq, 1.66 h

(M+H + ) J=12.5, 6.0 Hz, 1 H), 4.57-4.75 (m, 1.4H), 4.52 (br. s., 1 .1 H), 4.22 (d,

J=7.0 Hz, 0.3H), 3.51-3.66 (m, 0.9H), 2.67-2.77 (m, 1 H), 2.53-2.62 (m,

1 H), 1.34-1.56 (m, 4H), 0.98-1 .18 (m, 6H), 0.58-0.80 (m, 6H).

Ή NMR (DMSO-d6) δ: 9.61 (s, 0.2H), 9.29 (t, J=1.0 Hz, 0.4H), 9.23 (t,

J=6.1 Hz, 0.8H), 8.84 (t, J=1.0 Hz, 0.2H), 8.64 (t, J=1.0 Hz, 0.7H), 8.46

(t, J=1 .0 Hz, 0.8H), 8.20-8.28 (m, 1.2H), 8.06-8.16 (m, 3H), 8.02 (d, 592.3

202 0.65 j

J=7.5 Hz, 1 H), 7.76 (s, 0.7H), 7.49 (d, J=8.0 Hz, 1 H), 4.57-4.86 (m, (M+H + ) 2.2H), 4.22 (q, J=7.3 Hz, 0.5H), 3.62-3.67 (m, 0.4H), 3.57 (dd, J=11.8,

6.0 Hz, 3H), 2.54-2.64 (m, 1 H), 2.47 (s, 3H), 1.32-1 .59 (m, 4H), 0.93- 1.20 (m, 6.1 H), 0.72-0.82 (m, 3H), 0.66 (t, J=7.0 Hz, 0.8H), 0.60 (t,

J=7.2 Hz, 2H).

Ή NMR (DMSO-d6) δ: 9.61 (s, 0.3H), 9.26-9.34 (m, 1 H), 9.22 (t, J=6.1

Hz, 0.7H), 8.84 (t, J=5.6 Hz, 0.3H), 8.60-8.71 (m, 1.7H), 8.20-8.29 (m,

1.3H), 8.06-8.19 (m, 3H), 7.98-8.06 (m, 1 H), 7.76 (s, 0.7H), 7.45 (d,

J=8.0 Hz, 1 H), 4.67-4.87 (m, 2.3H), 4.62 (dt, J=12.1 , 6.1 Hz, 0.7H), 4.22 614.3

308 0.74 j

(d, J=7.3 Hz, 0.3H), 3.58 (td, J=9.9, 4.4 Hz, 0.7H), (M+H + ) 2.84 (dd, J=16.4, 5.6 Hz, 1 H), 2.69 (dd, J=16.6, 8.0 Hz, 1 H), 2.54-2.64

(m, 1 H), 2.47 (s, 3H), 1.38-1.60 (m, 4H), 0.93-1.23 (m, 6H), 0.70-0.82

(m, 3H), 0.55-0.70 (m, 3H)

Ή NMR (DMSO-d 6 ) d: 9.46 (t, J=6.0 Hz, 0.3H), 9.37 (t, J=6.0 Hz, 0.7H),

8.78 (t, J=5.4 Hz, 0.3H), 8.56 (t, J=4.5 Hz, 0.8H), 8.31-8.45 (m, 2.3H),

8.20-8.30 (m, 2H), 8.11-8.18 (m, 1 H), 8.04-8.10 (m, 1 H), 7.96 (t, J=8.0

Hz, 1 H), 7.77 (s, 0.7H), 7.06 (br. s., 3H), 4.82 (tt, J=12.9, 6.2 Hz, 1 H), 618.3

205 2.31 b

4.56-4.75 (m, 1 H), 4.33 (br. s., 1 H), 4.22 (q, J=7.4 Hz, 0.3H), 3.59 (td, (M+H + ) J=9.5, 4.0 Hz, 0.9H), 2.53-2.67 (m, 3H), 1.25-1.64 (m, 4H), 0.98-1 .20

(m, 6H), 0.73-0.81 (m, 3H), 0.57-0.70 (m, 3H)

Analytical methods: a LCMS Method: Agilent 1 100 Series LC/MSD SL or VL using electrospray positive [ES+ve to give M+H + ] equipped with a Xorbax Eclipse XDB-C8 5.0 μηι column (4.6 mm x 150 mm, i.d.), eluting with 0.05 % TFA in water (solvent A) and 0.05 % TFA in CH 3 CN (solvent B), using the following elution gradient 10-100 % (solvent B) over 10.0 min and holding at 100 % for 1.6 min at a flow rate of 1.0 ml/min. LCMS Method: Agilent 1 100 Series LC/MSD SL or VL using electrospray positive [ES+ve to give M+H + ] equipped with a Sunfire C18 5.0 μηι column (3.0 mm x 50 mm, i.d.), eluting with 0.05 % TFA in water (solvent A) and 0.05 % TFA in CH 3 CN (solvent B), using the following elution gradient: 10-100 % (solvent B) over 2.5 min and holding at 100 % for 1.7 min at a flow rate of 1.0 ml/min. c LCMS Method: Agilent 1200 Series LC/MSD SL or VL using electrospray positive [ES+ve to give M+H + ] equipped with a Sunfire C18 5.0 μηι column (3.0 mm x 50 mm, i.d.), eluting with 0.1 % TFA in water (solvent A) and 0.1 % TFA in CH 3 CN (solvent B), using the following elution gradient: 10-100 % (solvent B) over 2.5 min and holding at 100 % for 1.7 min at a flow rate of 1.0 ml/min. d UPLC Method: Acquity UPLC with SQD MSD using electrospray positive [ES+ve to give M+H + ] equipped with a BEH C18 1.7 μηι column (2.1 mm x 50 mm i.d.) eluting with 0.1 % formic acid in water (solvent A) and 0.1 % formic acid in CH 3 CN (solvent B), using the following elution gradient: 3-100 % (solvent B) over 1.5 min and holding at 100 % for 0.4 min at a flow rate of 1.0 ml/min. e LCMS Method: Shimadzu 10Avp with Sedere Sedex 75C and PE Sciex Single Quadrupole 150EX using electrospray positive [ES+ve to give M+H + ] equipped with a Thermo Hypersil Gold C18 1.9 μηι column (2.1 mm x 20 mm i.d.) eluting with 0.02 % TFA in water (solvent A) and 0.02 % TFA in CH 3 CN (solvent B), using the following elution gradient: 4-95 % (solvent B) over 1.88 min and holding at 4 % for 0.9 min at a flow rate of 1.4 ml/min. f LCMS Method: Shimadzu 10Avp with Sedere Sedex 75C and Waters ZQ Single

Quadrupole using electrospray positive [ES+ve to give M+H + ] equipped with a Thermo Hypersil Gold C18 1.9 μηι column (2.1 mm x 20 mm i.d.) eluting with 0.02 % TFA in water (solvent A) and 0.02 % TFA in CH 3 CN (solvent B), using the following elution gradient: 4-95 % (solvent B) over 1.88 min and holding at 4 % for 0.9 min at a flow rate of 1.4 ml/min.

9 LCMS Method: Agilent 1200 Series LC/MSD SL or VL using electrospray positive [ES+ve to give M+H + ] equipped with a Zorbax C18 5.0 μηι column (4.6 mm x 150 mm, i.d.), eluting with 0.1 % TFA in water (solvent A) and 0.1 % TFA in CH 3 CN (solvent B), using the following elution gradient: 10-100 % (solvent B) over 12.5 min and holding at 100 % for 1.8 min at a flow rate of 1.0 ml/min. h LCMS Method: Agilent 1200 Series LC/MSD SL or VL using electrospray positive [ES+ve to give M+H + ] equipped with a Sunfire C18 2.5 μηι column (2.1 mm x 20 mm, i.d.), eluting with 0.05 % TFA in water (solvent A) and 0.05 % TFA in CH 3 CN (solvent B), using the following elution gradient: 10-100 % (solvent B) over 2.5 min and holding at 100 % for 0.2 min at a flow rate of 1.3 ml/min. 1 LCMS Method: Agilent 1200 Series LC/MSD SL or VL using electrospray positive [ES+ve to give M+H + ] equipped with an Agilent Eclipse XBD-C18 5.0 μηι column (4.6 mm x 250 mm, i.d.), eluting with 0.05 % TFA in water (solvent A) and 0.05 % TFA in CH 3 CN (solvent B), using the following elution gradient: 1-99 % (solvent B) over 10 min at a flow rate of 1.0 ml/min.

jUPLC Method: Acquity UPLC with SQD MSD using electrospray positive [ES+ve to give M+H + ] equipped with a Thermo Hypersil Gold C18 1.9 μηι, (20 mm x 2.1 mm i.d.) eluting with 0.02 % TFA in water (solvent A) and 0.02 % TFA in CH 3 CN (solvent B), using the following elution gradient: 0.5-98 % (solvent B) over 1.9 min at a flow rate of 1.6 mL/min.

Pharmaceutical Compositions

Example A - Tablets are prepared using conventional methods and are formulated as follows:

Example C - Nanosuspensions and micron-sized suspensions are prepared using conventional milling technology such as aqueous bead milling methods and are formulated as follows:

Ingredient Amount per nanosuspension Compound of the invention 50 mg

Polysorbate 20 10 mg

Polyethylene Glycol 4000 20 mg

Mannitol 30 mg

Purified Water qs

Total 110 mg

Example D - Melt Extrudates are prepared using conventional melt extrusion techniques and cryomilling to achieve adequate particle size as follows:

Example E - A lyophilized product is prepared by conventional methods formulated

Biological Assays

Materials:

Buffer components were purchased from Sigma-Aldrich (St. Louis, MO) or an equivalent supplier. The promyostatin peptide substrate was custom synthesized by American Peptide Company (Sunnyvale, CA) using the myostatin protein sequence (Uniprot accession number 014793) surrounding the cleavage site reviewed in Hopkins, D.R., et al., 2007 Matrix Biology, 26, 508-523. The procollagen peptide substrate used in the high enzyme BMP1 cleavage assay was custom synthesized by 21 st Century Biochemicals (Marlboro, MA) using the procollagen la protein sequence (Uniprot accession number P02452) surrounding the cleavage site reviewed in Hopkins, D.R., et al., 2007 Matrix Biology, 26, 508-523. Preparation of Human BMP1 Protein:

The DNA sequence encoding amino acids 23-721 of human BMP1 (NM_001 199.3) with the human RAGE signal sequence (aa1-22 of NM_001136) at the N-terminus and FLAG-6xHis epitope tags at the C-terminus was amplified using PCR technology. The resultant Rgss-BMP1 (23-721 )-FLAG-6xHis fragment was subcloned into pCDN, a mammalian expression vector driven by the CMV promoter and containing the DHFR gene to allow selection in nucleoside-free cell culture media. This construct was electroporated into CHOEI a cells. After selection, conditioned media from individual clones were analyzed using a BMP1 assay for promyostatin-derived peptidase activity (see assay below).

Conditioned media from several clones with the highest activity were analyzed via western blot to confirm expression. The clone with the highest expression and peptidase activity was used for protein expression.

The mature form of human BMP1 (121-721), secreted from the stably transfected CHO cell line, was purified. All purification steps were carried out at 4 °C. 10 1 of conditioned medium was concentrated to 1.2 I with a Watson Marlow diafiltration system (A/G Technology Corpraton, Model # UFP-10-C-55) using a 10 kDa cut off cartridge. A subsequent buffer exchange was carried out on the same system with 5 I of 50 mM Tris buffer, pH 8.0, containing 0.5 M NaCI, 20% glycerol, 1 mM CHAPS, 5 mM CaCI 2 , 10 μΜ ZnCI 2 , and 20 mM imidazole. The diafiltrated medium was subjected to successive nickel NTA superflow chromatography (Qiagen, Valencia, CA) using 50 ml, 30 ml, and 15 ml resin volumes, each overnight at 4°C, and the unbound fraction containing most of the BMP1 was retained. 100 ml of this unbound fraction was diluted into 1000 ml of 50 mM Tris buffer, pH 8.0, containing 20% glycerol, 10 mM NaCI, 5 mM CaCI 2 , 10 μΜ ZnCI 2 , and 1 mM CHAPS and applied to 20 ml of Q Sepharose Fast Flow (GE Healthcare Life Sciences). The Q Sepharose unbound fraction, which contains BMP1 , was further concentrated on a Viva Spin, 10 kDa cut off cartridge (Viviproducts, Littleton, MA).

Preparation of Human TLL1 Protein:

The DNA sequence encoding a natural variant of full length native human TLL1 (NM_012464.4) containing three amino acid substitutions 1156V, N221 S, V284A was amplified from human heart and brain cDNA and subcloned into the pCDN expression vector . The plasmid was electroporated into CHOE1A cells. After selection, a clone expressing high levels of TLL1 was scaled and used for protein purification.

All purification steps were carried out at 4 °C. CHO conditioned medium was diluted 3-fold with 5 mM Tris buffer, pH 8.4, and human TLL1 was captured by Source 30 Q resin (GE Healthcare Life Sciences). After an extensive wash with 50 mM Tris buffer, pH 8.0, human TLL1 was eluted with a linear gradient of 0 to 0.5 M NaCI in 50 mM Tris buffer, pH 8.0. Following a 3.6-fold dilution into 20 mM Tris buffer, pH 7.4, human TLL1 from the Source 30Q pool was then captured onto a Macro-prep ceramic hydroxyapatite (HA) type I 40 μηι resin (BioRad, Hercules, CA). The HA resin was washed with 20 mM Tris buffer, pH 7.4, and human TLL1 was eluted with 0.5 M potassium phosphate buffer, pH 7.4, in a linear gradient from wash buffer. Human TLL1 from the HA pool was salt fractionated with 40% ammonium sulfate saturation and resolubilized with 20 mM Tris buffer, pH 7.0, containing 0.25 M NaCI and 7 mM CaCI 2 .

Preparation of Human TLL2 Protein:

The DNA sequence encoding amino acids 26-1015 of human TLL2 (NM_012465) was PCR amplified from DNA template with the human RAGE signal sequence at the N- terminus and Avi-6xHis epitope tags at the C-terminus

(GGLNDIFEAQKIEWHEHHHHHH). The Rgss-TLL2 Avi-6xHis fragment was subcloned into a pCDN expression vector by Gateway™ recombination (Life Technologies, Grand Island, NY). DHFR deficient CHOEI a cells were maintained in MR1 media (Life Technologies) supplemented with nucleosides at 37°C in 5% C02. Linearized plasmid DNA was electroporated into the cells and clones were generated in media without nucleosides. Clones were screened for TLL2 activity in the promyostatin-derived peptidase assay (see below) which allowed identification of clones that expressed optimal levels of the active form of TLL2.

Stably expressing TLL2 CHO cell conditioned medium was concentrated by diafiltration as described for BMP1. 325 ml of concentrated medium was purified by nickel NTA superflow chromatography (20 ml Ni-NTA SF, overnight at 4 °C). The resin was washed with a 15 mM to 100 mM imidazole linear gradient, and protein was eluted with 0.3 M imidazole in buffer A (50 mM Tris, pH 8.0, 0.5 M NaCI, 20% glycerol, 1 mM CHAPS, 5 mM CaCI 2 , 10 μΜ ZnCI 2 ).

Enzyme Inhibition Assay for human BMP1 :

(i) Low enzyme concentration

Inhibition of BMP1 peptidase activity by test compounds of the invention was measured by monitoring cleavage of a promyostatin peptide substrate by recombinant, mature BMP1 protein (BMP1 (121-721)-Flag-His). FRET quenching of dual-labeled peptide ((5-FAM)-ELIDQYDVQRDDSSDGSLED-K(5,6 TAMRA)-CONH 2 ) is relieved by BMP1- catalyzed cleavage. This assay was run as a 10 μΙ endpoint assay in 384-well format where the reaction contains 0.5 nM BMP1 and 0.8 μΜ promyostatin peptide substrate in 25 mM HEPES buffer, pH 7.5, containing 0.01 % Brij-35 detergent, 5 mM CaCI 2 , and 1 μΜ ZnCI 2 . The assay was run by adding 5 μΙ enzyme solution to a black, low volume assay plate (Greiner 784076) pre-dispensed with 100 nl test compound solutions in DMSO. After 10 minutes, 5 μΙ substrate were added and the reaction was incubated at ambient temperature for an additional 60 minutes. The reaction was quenched with 5 μΙ of 0.5 M EDTA and the plate was read on a ViewLux (PerkinElmer) multilabel plate reader using a 480 nm excitation filter and 540 nm emission filter. The test compounds were prepared in neat DMSO at a concentration of 10 mM. For inhibition curves, compounds were diluted in DMSO using a three-fold serial dilution and tested at 1 1 concentrations (100 μΜ - 1.7 nM, final 1 % DMSO). Responses were normalized to the uninhibited and no-enzyme controls within each plate. Dose-response curves were analyzed using a four-parameter logistic fit in ActivityBase and results are expressed as plC 50 values.

The compounds of Examples 1-43, 45-49, 51-105, 200-205, 300-308 and 400 were tested and exhibited a plC 50 > 6.9 according to this assay.

(ii) High enzyme concentration

Use of a high enzyme concentration assay may be useful, e.g., as discussed in Habig, M., et al., Journal of Biomolecular Screening, 2009, 14, 679-689.

This assay was run as a 10 μΙ endpoint assay in 384-well format where the reaction contains 50 nM BMP1 enzyme and 6 μΜ procollagen I peptide substrate ((5-FAM)- DGGRYYRADDANVVRD-K(5,6-TAMRA)-CONH 2 ) in 25 mM HEPES buffer, pH 7.5, containing 0.01 % Brij-35 detergent, 5 mM CaCI 2 , and 1 μΜ ZnCI 2 . The assay was run by adding 5 μΙ enzyme solution to a black, low volume assay plate (Greiner 784076) pre- dispensed with 100 nl test compound solutions in DMSO. After 10 minutes, 5 μΙ substrate were added and the reaction was incubated at ambient temperature for an additional 30 minutes. The reaction was quenched with 5 μΙ of 0.5 M EDTA and the plate was read on a ViewLux (Perkin Elmer) multilabel plate reader using a 480 nm excitation filter and 540 nm emission filter. Data fitting and compound preparations were performed as described above for the low enzyme concentration.

The compounds of Examples 1-43, 45-49, 51-105, 200-205, 300-308 and 400 were tested and exhibited a plC 50 > 6.6 according to this assay.

Enzyme Inhibition Assay for human TLL1 and TLL2:

Inhibition of human TLL1 and TLL2 recombinant enzymes was measured in 10 ul endpoint assays in 384-well format using the same promyostatin peptide substrate employed in the above Enzyme Inhibition Assay for human BMP1. The TLL1 reaction contained 2 nM TLL1 and 0.8 μΜ promyostatin peptide substrate in 25 mM HEPES buffer, pH 7.5, containing 0.01 % Brij-35 detergent, 5 mM CaCI 2 , and 1 μΜ ZnCI 2 . The TLL1 assay was run by adding 5 μΙ enzyme solution to a black, low volume assay plate (Greiner 784076) pre- dispensed with 100 nl test compound solutions in DMSO. Following a 10 minute

preincubation of enzyme with inhibitor, 5 μΙ of substrate solution were added. TLL1 reactions were incubated at ambient temperature for an additional 60 minutes. The TLL2 reaction contained 18 nM TLL2 and 5 μΜ promyostatin peptide substrate in 25 mM HEPES buffer, pH 7.5, containing 0.01 % Brij-35 detergent, 5 mM CaCI 2 , and 1 μΜ ZnCI 2 . The TLL2 assay was run without an enzyme-inhibitor preincubation by adding 5 μΙ enzyme and 5 μΙ substrate solutions to a black, low volume assay plate (Greiner 784076) pre-dispensed with 100 nl compound solutions in DMSO. TLL2 reactions were incubated at ambient temperature for 60 minutes. TLL1 and TLL2 reactions were quenched with 5 μΙ of 0.5 M EDTA and plates were read on a ViewLux (Perkin Elmer) multilabel plate reader using a 480 nm excitation filter and 540 nm emission filter. Data fitting and compound preparations were performed as described above for the Enzyme Inhibition Assay for human BMP1.

The compounds of Examples 1-25, 27, 29-43, 45-49, 51-104, 200-205, 300-308 and 400 were tested in the TLL1 enzyme inhibition assay and exhibited a plC 50 > 6.4 according to this assay.

The compounds of Examples 1-25, 27, 29-43, 45-49, 51-104, 200-205, 300-308 and

400 were tested in the TLL2 enzyme inhibition assay and exhibited a plC 50 > 6.2 according to this assay.

The above enzyme assay results indicate that the tested compounds are potent inhibitors of one or more of BMP1 , TLL1 and TLL2 enzymatic activity. The tested compounds inhibited one or more of these metalloproteases in biochemical assays using isolated enzymes and peptide substrates.

Cell-based Inhibition Assay of Generation of Procollagen I C-terminal Propeptide (PICP) and Mature Collagen:

An adaptation of the collagen deposition assay described by Chen, C.Z.C., et al.,

British Journal of Pharmacology, 2009, 158, 1 196-1209 was used to examine effect of compounds on procollagen I processing and collagen deposition. In the adapted assay, human cardiac fibroblasts were utilized. Processing of procollagen I was determined by a PICP ELISA assay and deposition of mature collagen was determined by immunostaining.

Human cardiac fibroblasts were cultured and maintained until passage 6 in FGM-3 media (Lonza, #CC-3132) in a 37 °C humidified incubator with 5% C0 2 . They were then seeded in 96-well black wall, clear bottom plates at 10,000 to 15,000 cells per well in eagle's minimum essential media (EMEM, ATCC # 30-2003) containing 10% fetal bovine serum (FBS, Life Technologies # 10082147), 1 % Glutamax (Life Technologies #35050061) and 1 % Penicillin and Streptomycin (Life Technologies # 15070063) . These cultures were placed in 37 °C incubator. The next day, media were removed by aspiration and cells were rinsed with phosphate buffered saline. Crowding media (also called ficoll media) was prepared by adding 1 12.5 mg/ml of ficoll70 and 75 mg/ml ficoll400 (GE healthcare # 17-0310-10 and 17- 0300-10, respectively), 100 μΜ ascorbic acid, 1 % Glutamax and 1 % Penicillin and

Streptomycin to EMEM media. Test compounds (dissolved in DMSO) were diluted into crowding media and then added to the cells. Final concentration of DMSO in crowding media was less than 0.3%. Cells were treated for 24 to 48 hr in a 37 °C incubator. At the end of the treatment period, cell media were collected. The level of PICP in the media were determined by a PICP ELISA assay (Quidel #8003) following the manufacturer's protocol. Potencies of test compounds were calculated by fitting PICP levels, relative to untreated controls, to log (inhibitor) vs. response equation using Graphpad Prism software 6.0 and expressed as plC 50 .

For some compounds, deposition of mature collagen was measured by

immunostaining in addition to PICP levels. At the end of the treatment period, cells on culture plate were fixed with 100% methanol (prechilled to -20 °C) for 10 min. Then the cells were immunostained with mouse anti-mature collagen I antibody (1 :500 dilution,

Sigma#C2456), anti-mouse secondary antibody Alexa647 (1 :500 dilution,

lnvitrogen#A21236) and Hoechst (for nuclei, 2 μg/ml, lnvitrogen#H3596). Fluorescent image acquisition was done using the Operetta High Content Imaging system (Perkin Elmer). For each image field, the intensity of mature collagen staining was normalized with the number of nuclei. Normalized collagen levels were used to calculate the potency of test compounds with Graphpad Prism software, as described above.

The compounds of Examples 1-43, 45-49, 51-105, 200-205, 300-308 and 400 were tested in the PICP cellular inhibition assay and exhibited a plC 50 > 4.7 in this assay.

The compounds of Examples 1 , 26, 28, 39, 87, 88, 90, 94, 101 , 102 were tested in the mature collagen cellular inhibition assay and exhibited a plC 50 > 5.8 in this assay.

The above cellular assay results demonstrate that the tested compounds inhibit the processing of procollagen substrate by native enzyme produced by the fibroblast, the cell type that drives fibrosis in vivo.

In view of the above, compounds of the invention should have benefit as anti-fibrotic agents across a wide variety of diseases driven by pathological fibrosis, and diseases related to other in vivo substrates for these enzymes, e.g., where muscle function or muscle mass is diminished.