NZ756220B2 - Macrocyclic broad spectrum antibiotics - Google Patents
Macrocyclic broad spectrum antibiotics Download PDFInfo
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- NZ756220B2 NZ756220B2 NZ756220A NZ75622018A NZ756220B2 NZ 756220 B2 NZ756220 B2 NZ 756220B2 NZ 756220 A NZ756220 A NZ 756220A NZ 75622018 A NZ75622018 A NZ 75622018A NZ 756220 B2 NZ756220 B2 NZ 756220B2
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Abstract
Provided herein are antibacterial compounds of formula (I), wherein the compounds in some embodiments have broad spectrum bioactivity. In various embodiments, the compounds act by inhibition of bacterial type 1 signal peptidase (SpsB), an essential protein in bacteria. Pharmaceutical compositions and methods for treatment using the compounds described herein are also provided. d methods for treatment using the compounds described herein are also provided.
Description
MACROCYCLIC BROAD SPECTRUM ANTIBIOTICS
CROSS-REFERENCE
This patent application claims the benefit of PCT Application No. , filed
February 15, 2017; and PCT Application No. , filed May 19, 2017; each of which is
incorporated herein by reference in their entirety.
BACKGROUND OF THE INVENTION
Antibiotic resistance is a serious and growing phenomenon in contemporary medicine and has
emerged as a major public health concern of the 21st century. Therefore, novel classes of broad-spectrum
antibiotics, especially those that target novel mechanisms of action, are needed to treat multidrug-resistant
pathogens.
SUMMARY OF THE INVENTION
[0002] Described herein are novel macrocyclic compounds for the treatment of microbial infections, such
as for the treatment of bacterial infections. In various embodiments, the present disclosure provides
lipopeptide macrocyclic compounds for the treatment of bacterial infections. In various embodiments, the
present disclosure provides classes and subclasses of chemical compounds structurally related to
arylomycin for the treatment of bacterial infections. In various embodiments, the macrocyclic compounds
act by inhibition of bacterial type 1 signal peptidase (SpsB), an essential protein in bacteria. In some
embodiments, the signal peptidase is a Gram-negative signal peptidase. In some embodiments, the signal
peptidase is LepB.
In one aspect described herein is a compound of Formula (I):
(R )
27 6
(R ) R
18 16
O CN
Z X N
17 9
11 12
Formula (I);
wherein:
1 2 23
R and R are each independently H, -(C -C )alkyl, -(C -C )alkyl-OR , -CH CH(OH)CH NH , -
1 6 1 6 2 2 2
CH CH(heterocycloalkyl)CH NH , -CH C(O)NH , -CH C(O)N(H)CH CN, -(C -C )alkyl-C(O)OR , -
2 2 2 2 2 2 2 1 6
21 22 25 26 23 21 22
(C -C )alkyl-NR R , -(C -C )alkyl-C(O)NR R , -(C -C )alkyl-N(R )C(O)(C -C )alkylNR R , -
1 6 1 6 1 6 1 6
23 23
(C -C )alkyl-N(R )C(O)(C -C )alkyl, -(C -C )alkyl-C(O)N(R )(C -C )alkyl, -(C -C )alkyl-
1 6 1 6 1 6 1 6 1 6
18253141_1 (GHMatters) P111789.NZ
23 23 21 22
C(O)N(R )(C -C )alkyl-heterocycloalkyl, -(C -C )alkyl-NR C(=NH)NR R , -(C -C )alkyl-
1 6 1 6 1 6
23 23 21 22
NR C(=NH)R , -(C -C )alkyl-[(C -C )alkyl-NR R ] , -(C -C )heteroalkyl, or optionally substituted
1 6 1 6 2 1 6
heterocycloalkyl;
or R and R and the atoms to which they are attached form an optionally substituted heterocycloalkyl ring;
R is H or –(C -C )alkyl;
R is H, -(C -C )alkyl, -(C -C )alkyl-OH, -(C -C )cycloalkyl, or –C(O)NH ;
1 6 1 6 3 6 2
or R and R are combined to form a heterocycloalkyl ring;
R is H or –(C -C )alkyl;
or R and R and the carbon atom to which they are attached form a cyclopropyl ring;
6 7 8
R , R , and R are each independently H, fluoro, hydroxyl, amino, optionally substituted alkyl,optionally
substituted heteroalkyl, or –(C -C )alkyl;
R is H, -(C -C )alkyl, -(C -C )haloalkyl, or –(C -C )cycloalkyl;
1 6 1 6 3 6
R is H, -(C -C )alkyl, -(C -C )haloalkyl, or –(C -C )cycloalkyl;
1 6 1 6 3 6
9 10
or R and R are combined to form a heterocycloalkyl or cycloalkyl ring
11 12 23 23
R and R are each independently H, -NH , -(C -C )alkyl, -(C -C )alkyl-OR , -(C -C )alkyl-SR , -(C -
2 1 6 1 6 1 6 1
23 21 22 23 23
C )alkyl-C(O)OR , -(C -C )alkyl-NR R , -(C -C )alkyl-NR OR , -(C -C )alkyl-
6 1 6 1 6 1 6
23 23 25 26
NHC(O)NR OR , -(C -C )alkyl-O-(C -C )alkyl-NR R , -(C -C )alkyl-CN, -(C -C )alkyl-
1 6 1 6 1 6 1 6
23 23 25 26
NR C(O)R , -(C -C )alkyl-C(O)NR R , -(C -C )heteroalkyl-CO H, -(C -C )alkyl-S(O)(C -C )alkyl,
1 6 1 6 2 1 6 1 6
-(C -C )alkyl-N(H)CH=NH, -(C -C )alkyl-C(NH )=NH, -(C -C )alkyl-N(H)C(=NH)NH , -(C -
1 6 1 6 2 1 6 2 1
26 25 26
C )alkyl-N(H)S(O) NR R , -(C -C )alkyl-N(H)S(O) (C -C )alkyl, -(C -C )alkyl-N(H)-C(O)NR R ,
6 2 1 6 2 1 6 1 6
-(C -C )alkylC(O)N(H)[optionally substituted(C -C )alkyl]-OR , -(C -C )alkylN(H)C(O)(C -
1 6 2 6 1 6 1
23 25 26
C )alkyl-OR , -(C -C )alkylC(O)N(H)heterocycloalkyl, -(C -C )alkylC(O)NR R , -(C -C )alkyl-
6 1 6 1 6 1 6
26 25 26
-C )alkyl-NR R , -(C -C )alkyl-N(H)-(C -C )alkylC(O)NR R , -(C -C )alkyl-
N(H)-C(O)-(C
1 6 1 6 1 6 1 6
heterocycloalkyl, optionally substituted –(C -C )alkyl-N(H)heterocycloalkyl, or –(C -C )alkyl-
1 6 1 6
heteroaryl;
11 18 12
or R and R are combined to form an optionally substituted heterocycloalkyl ring; and R is H;
16 17 18 23
R , R , R , and R are each independently H, -(C -C )alkyl, -(C -C )cycloalkyl, -(C -C )alkyl-OR , -
1 6 3 6 1 6
23 21 22
(C -C )alkyl-C(O)OR , or –(C -C )alkyl-NR R ;
1 6 1 6
X is optionally substituted –(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, optionally substituted –(C -
1 6 2 6 2 6 3
C )cycloalkyl-, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally
24 24
substituted heteroaryl, -O-(C -C )alkyl-, -N(R )(C -C )alkyl-, -N(R )(C -C )aryl-, or –SO (C -
1 6 1 6 6 10 2 1
C )alkyl-;
Y is a bond, -O-, -S-, optionally substituted –(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, -(C -
1 6 2 6 2 6 1
24 24 24
C )alkyl-N(R )(C -C )alkyl-, -O-(C -C )alkyl-, -Oaryl-, -N(R )(C -C )alkyl-, -N(R )SO (C -
6 1 6 1 6 1 6 2 1
C )alkyl-, -N(R )C(O)(C -C )alkyl-, -C(O)(C -C )alkyl-, -S(C -C )alkyl-, -SO (C -C )alkyl-, -
6 1 6 1 6 1 6 2 1 6
C(O)NH(C -C )alkyl-, optionally substituted –(C -C )cycloalkyl-, optionally substituted –
1 6 3 7
18253141_1 (GHMatters) P111789.NZ
24 24 24
C(O)N(R )aryl-, optionally substituted –N(R )C(O)aryl-, optionally substituted –N(R )SO aryl-,
optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Z is H, halogen, -NH , -CN, -CF , -CO H, -(C -C )alkyl, -(C -C )alkenyl, -CH=((C -C )cycloalkyl), -
2 3 2 1 12 2 12 3 7
26
(C -C )alkynyl, -C(O)NR R , -O-(C -C )alkyl, -S-(C -C )alkyl, -O-(C -C )[optionally substituted
2 12 1 12 1 12 3 10
23 23
(C -C )cycloalkyl], -O-(C -C )alkyl-OR , -(C -C )alkyl-OR , -(C -C )alkyl-CN, -S-(C -C )alkyl, -
3 7 1 6 1 12 1 12 1 12
24 24
N(R )(C -C )alkyl, -N(R )C(O)(C -C )alkyl, optionally substituted –(C -C )cycloalkyl, -(C -
1 12 1 12 3 7 1
C )alkyl-(C -C )cycloalkyl, -(C -C )alkyl-heterocycloalkyl, optionally substituted heterocycloalkyl,
6 3 7 1 6
optionally substituted aryl, or optionally substituted heteroaryl;
21 22
each R and R is independently H, -(C -C )alkyl, -(C -C )heteroalkyl, -(C -C )alkyl-CO H, -C(O)(C -
1 6 1 6 1 6 2 1
C )alkyl, -C(O)O(C -C )alkyl, -C(O)O(C -C )haloalkyl, -C(=NH)(C -C )alkyl, -C(=NH)N(R ) , -
6 1 6 1 6 1 6 2
31 31 21 22
C(O)N(R ) , or –SO N(R ) ; or R and R and the nitrogen atom to which they are attached form a
2 2 2
heterocycloalkyl ring;
31 31
each R is independently H or –(C -C )alkyl; or two R and the nitrogen atom to which they are attached
form a heterocycloalkyl ring;
each R is independently H or –(C -C )alkyl;
each R is independently H or –(C -C )alkyl;
26
each R and R is independently H or optionally substituted –(C -C )alkyl;
26
or R and R and the nitrogen atom to which they are attached form a heterocycloalkyl ring;
27 23 24 23 23 24
each R is independently halogen, -NR R , -NHC(O)R , -NHC(O)NR R , nitro, hydroxyl, optionally
substituted –(C -C )alkyl, optionally substituted –(C -C )heteroalkyl, optionally substituted -(C -
1 6 1 6 1
C )heteroalkyloxy, optionally substituted -(C -C )heteroalkylamino, -(C -C )alkoxy, -C(O)(C -
6 1 6 1 6 1
C )alkyl, or –S(O) (C -C )alkyl;
6 2 1 6
1 27
or R and R and the atoms to which they are attached form an optionally substituted 5- or 6-membered
heterocycloalkyl ring;
28 23 24 23 23 24
each R is independently halogen, -NR R , -NHC(O)R , -NHC(O)NR R , nitro, hydroxyl, optionally
substituted –(C -C )alkyl, optionally substituted –(C -C )heteroalkyl, optionally substituted -(C -
1 6 1 6 1
C )heteroalkyloxy, optionally substituted -(C -C )heteroalkylamino, -(C -C )alkoxy, -C(O)(C -
6 1 6 1 6 1
C )alkyl, or –S(O) (C -C )alkyl;
6 2 1 6
2 28
or R and R and the atoms to which they are attached form an optionally substituted 5- or 6-membered
heterocycloalkyl ring;
p is 0, 1, or 2; and
q is 0, 1, or 2;
or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
[0003a] In another aspect, there is provided a compound of Formula (I):
18253141_1 (GHMatters) P111789.NZ
(R )
(R )
18 16
R R N
O CN
Z X N
17 9 R
11 12
Formula (I);
wherein:
1 2 23
R and R are each independently H, -(C -C )alkyl, -(C -C )alkyl-OR , -CH CH(OH)CH NH , -
1 6 1 6 2 2 2
CH CH(heterocycloalkyl)CH NH , -CH C(O)NH , -CH C(O)N(H)CH CN, -(C -C )alkyl-C(O)OR , -
2 2 2 2 2 2 2 1 6
21 22 25 26 23 21 22
(C -C )alkyl-NR R , -(C -C )alkyl-C(O)NR R , -(C -C )alkyl-N(R )C(O)(C -C )alkylNR R , -
1 6 1 6 1 6 1 6
23 23
(C -C )alkyl-N(R )C(O)(C -C )alkyl, -(C -C )alkyl-C(O)N(R )(C -C )alkyl, -(C -C )alkyl-
1 6 1 6 1 6 1 6 1 6
23 23 21 22
C(O)N(R )(C -C )alkyl-heterocycloalkyl, -(C -C )alkyl-NR C(=NH)NR R , -(C -C )alkyl-
1 6 1 6 1 6
23 23 21 22
NR C(=NH)R , -(C -C )alkyl-[(C -C )alkyl-NR R ] , -(C -C )heteroalkyl, or optionally substituted
1 6 1 6 2 1 6
heterocycloalkyl;
or R and R and the atoms to which they are attached form an optionally substituted heterocycloalkyl ring;
R is H or -(C -C )alkyl;
R is H, -(C -C )alkyl, -(C -C )alkyl-OH, -(C -C )cycloalkyl, or -C(O)NH ;
1 6 1 6 3 6 2
or R and R are combined to form a heterocycloalkyl ring;
R is H or -(C -C )alkyl;
or R and R and the carbon atom to which they are attached form a cyclopropyl ring;
6 7 8
R , R , and R are each independently H, fluoro, hydroxyl, amino, optionally substituted alkyl, optionally
substituted heteroalkyl, or -(C -C )alkyl;
R is H, -(C -C )alkyl, -(C -C )haloalkyl, or -(C -C )cycloalkyl;
1 6 1 6 3 6
R is H, -(C -C )alkyl, -(C -C )haloalkyl, or -(C -C )cycloalkyl;
1 6 1 6 3 6
9 10
or R and R are combined to form a heterocycloalkyl or cycloalkyl ring
11 12 23 23
R and R are each independently H, -NH , -(C -C )alkyl, -(C -C )alkyl-OR , -(C -C )alkyl-SR , -(C -
2 1 6 1 6 1 6 1
23 21 22 23 23
C )alkyl-C(O)OR , -(C -C )alkyl-NR R , -(C -C )alkyl-NR OR , -(C -C )alkyl-
6 1 6 1 6 1 6
23 23 25 26
NHC(O)NR OR , -(C -C )alkyl-O-(C -C )alkyl-NR R , -(C -C )alkyl-CN, -(C -C )alkyl-
1 6 1 6 1 6 1 6
23 23 25 26
NR C(O)R , -(C -C )alkyl-C(O)NR R , -(C -C )heteroalkyl-CO H, -(C -C )alkyl-S(O)(C -C )alkyl,
1 6 1 6 2 1 6 1 6
-(C -C )alkyl-N(H)CH=NH, -(C -C )alkyl-C(NH )=NH, -(C -C )alkyl-N(H)C(=NH)NH , -(C -
1 6 1 6 2 1 6 2 1
26 25 26
C )alkyl-N(H)S(O) NR R , -(C -C )alkyl-N(H)S(O) (C -C )alkyl, -(C -C )alkyl-N(H)-C(O)NR R ,
6 2 1 6 2 1 6 1 6
-(C -C )alkylC(O)N(H)[optionally substituted(C -C )alkyl]-OR , -(C -C )alkylN(H)C(O)(C -
1 6 2 6 1 6 1
23 25 26
C )alkyl-OR , -(C -C )alkylC(O)N(H)heterocycloalkyl, -(C -C )alkylC(O)NR R , -(C -C )alkyl-
6 1 6 1 6 1 6
26 25 26
N(H)-C(O)-(C -C )alkyl-NR R , -(C -C )alkyl-N(H)-(C -C )alkylC(O)NR R , -(C -C )alkyl-
1 6 1 6 1 6 1 6
18253141_1 (GHMatters) P111789.NZ
heterocycloalkyl, optionally substituted -(C -C )alkyl-N(H)heterocycloalkyl, or -(C -C )alkyl-
1 6 1 6
heteroaryl;
11 18 12
or R and R are combined to form an optionally substituted heterocycloalkyl ring; and R is H;
16 17 18 23
R , R , R , and R are each independently H, -(C -C )alkyl, -(C -C )cycloalkyl, -(C -C )alkyl-OR , -
1 6 3 6 1 6
23 21 22
(C -C )alkyl-C(O)OR , or -(C -C )alkyl-NR R ;
1 6 1 6
X is optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, optionally substituted -(C -
1 6 2 6 2 6 3
C )cycloalkyl-, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally
24 24
substituted heteroaryl, -O-(C -C )alkyl-, -N(R )(C -C )alkyl-, -N(R )(C -C )aryl-, or -SO (C -
1 6 1 6 6 10 2 1
C )alkyl-;
Y is a bond, -O-, -S-, optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, -(C -
1 6 2 6 2 6 1
24 24 24
C )alkyl-N(R )(C -C )alkyl-, -O-(C -C )alkyl-, -Oaryl-, -N(R )(C -C )alkyl-, -N(R )SO (C -
6 1 6 1 6 1 6 2 1
C )alkyl-, -N(R )C(O)(C -C )alkyl-, -C(O)(C -C )alkyl-, -S(C -C )alkyl-, -SO (C -C )alkyl-, -
6 1 6 1 6 1 6 2 1 6
C(O)NH(C -C )alkyl-, optionally substituted -(C -C )cycloalkyl-, optionally substituted -
1 6 3 7
24 24 24
C(O)N(R )aryl-, optionally substituted -N(R )C(O)aryl-, optionally substituted -N(R )SO aryl-,
optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Z is H, halogen, -NH , -CN, -CF , -CO H, -(C -C )alkyl, -(C -C )alkenyl, -CH=((C -C )cycloalkyl), -
2 3 2 1 12 2 12 3 7
26
(C -C )alkynyl, -C(O)NR R , -O-(C -C )alkyl, -S-(C -C )alkyl, -O-(C -C )[optionally substituted
2 12 1 12 1 12 3 10
23 23
(C -C )cycloalkyl], -O-(C -C )alkyl-OR , -(C -C )alkyl-OR , -(C -C )alkyl-CN, -S-(C -C )alkyl, -
3 7 1 6 1 12 1 12 1 12
24 24
N(R )(C -C )alkyl, -N(R )C(O)(C -C )alkyl, optionally substituted -(C -C )cycloalkyl, -(C -
1 12 1 12 3 7 1
C )alkyl-(C -C )cycloalkyl, -(C -C )alkyl-heterocycloalkyl, optionally substituted heterocycloalkyl,
6 3 7 1 6
optionally substituted aryl, or optionally substituted heteroaryl;
21 22
each R and R is independently H, -(C -C )alkyl, -(C -C )heteroalkyl, -(C -C )alkyl-CO H, -C(O)(C -
1 6 1 6 1 6 2 1
)alkyl, -C(O)O(C -C )alkyl, -C(O)O(C -C )haloalkyl, -C(=NH)(C -C )alkyl, -C(=NH)N(R ) , -
6 1 6 1 6 1 6 2
31 31 21 22
C(O)N(R ) , or -SO N(R ) ; or R and R and the nitrogen atom to which they are attached form a
2 2 2
heterocycloalkyl ring;
31 31
each R is independently H or -(C -C )alkyl; or two R and the nitrogen atom to which they are attached
form a heterocycloalkyl ring;
each R is independently H or -(C -C )alkyl;
each R is independently H or -(C -C )alkyl;
26
each R and R is independently H or optionally substituted -(C -C )alkyl;
26
or R and R and the nitrogen atom to which they are attached form a heterocycloalkyl ring;
27 23 24 23 23 24
each R is independently halogen, -NR R , -NHC(O)R , -NHC(O)NR R , nitro, hydroxyl, optionally
substituted -(C -C )alkyl, optionally substituted -(C -C )heteroalkyl, optionally substituted -(C -
1 6 1 6 1
C )heteroalkyloxy, optionally substituted -(C -C )heteroalkylamino, -(C -C )alkoxy, -C(O)(C -
6 1 6 1 6 1
C )alkyl, or -S(O) (C -C )alkyl;
6 2 1 6
1 27
or R and R and the atoms to which they are attached form an optionally substituted 5- or 6-membered
heterocycloalkyl ring;
18253141_1 (GHMatters) P111789.NZ
28 23 24 23 23 24
each R is independently halogen, -NR R , -NHC(O)R , -NHC(O)NR R , nitro, hydroxyl, optionally
substituted -(C -C )alkyl, optionally substituted -(C -C )heteroalkyl, optionally substituted -(C -
1 6 1 6 1
C )heteroalkyloxy, optionally substituted -(C -C )heteroalkylamino, -(C -C )alkoxy, -C(O)(C -
6 1 6 1 6 1
C )alkyl, or -S(O) (C -C )alkyl;
6 2 1 6
2 28
or R and R and the atoms to which they are attached form an optionally substituted 5- or 6-membered
heterocycloalkyl ring;
p is 1 or 2 and q is 0, 1, or 2; or q is 1 or 2 and p is 0, 1, or 2; and
wherein the optional substituents, in each instance, are selected from the group consisting of -(C -
C )alkyl, halogen, hydroxy, amine, carboxylic acid, and -O-(C -C )alkyl-;
1 6
or a pharmaceutically acceptable salt or solvate thereof.
[0003b] In another aspect, there is provided a compound of Formula (II):
(R )
(R )
13 14 N
18 16
O R R
Z X N
17 9 R
11 12
Formula (II);
wherein:
1 2 23
R and R are each independently H, -(C -C )alkyl, -(C -C )alkyl-OR , -CH CH(OH)CH NH , -
1 6 1 6 2 2 2
CH CH(heterocycloalkyl)CH NH , -CH C(O)NH , -CH C(O)N(H)CH CN, -(C -C )alkyl-C(O)OR , -
2 2 2 2 2 2 2 1 6
21 22 25 26 23 21 22
(C -C )alkyl-NR R , -(C -C )alkyl-C(O)NR R , -(C -C )alkyl-N(R )C(O)(C -C )alkylNR R , -
1 6 1 6 1 6 1 6
23 23
(C -C )alkyl-N(R )C(O)(C -C )alkyl, -(C -C )alkyl-C(O)N(R )(C -C )alkyl, -(C -C )alkyl-
1 6 1 6 1 6 1 6 1 6
23 23 21 22
)(C -C )alkyl-heterocycloalkyl, -(C -C )alkyl-NR C(=NH)NR R , -(C -C )alkyl-
C(O)N(R
1 6 1 6 1 6
23 23 21 22
NR C(=NH)R , -(C -C )alkyl-[(C -C )alkyl-NR R ] , -(C -C )heteroalkyl, or optionally substituted
1 6 1 6 2 1 6
heterocycloalkyl;
or R and R and the atoms to which they are attached form an optionally substituted heterocycloalkyl ring;
R is H or -(C -C )alkyl;
R is H, -(C -C )alkyl, -(C -C )alkyl-OH, -(C -C )cycloalkyl, or -C(O)NH ;
1 6 1 6 3 6 2
or R and R are combined to form a heterocycloalkyl ring;
R is H or -(C -C )alkyl;
or R and R and the carbon atom to which they are attached form a cyclopropyl ring;
6 7 8
R , R , and R are each independently H or -(C -C )alkyl;
R is H, -(C -C )alkyl, -(C -C )haloalkyl, or -(C -C )cycloalkyl;
1 6 1 6 3 6
18253141_1 (GHMatters) P111789.NZ
R is H or -(C -C )alkyl;
11 12 23 23
R and R are each independently H, -NH , -(C -C )alkyl, -(C -C )alkyl-OR , -(C -C )alkyl-SR , -(C -
2 1 6 1 6 1 6 1
23 21 22 23 23
C )alkyl-C(O)OR , -(C -C )alkyl-NR R , -(C -C )alkyl-NR OR , -(C -C )alkyl-
6 1 6 1 6 1 6
23 23 25 26
NHC(O)NR OR , -(C -C )alkyl-O-(C -C )alkyl-NR R , -(C -C )alkyl-CN, -(C -C )alkyl-
1 6 1 6 1 6 1 6
23 23 25 26
NR C(O)R , -(C -C )alkyl-C(O)NR R , -(C -C )heteroalkyl-CO H, -(C -C )alkyl-S(O)(C -C )alkyl,
1 6 1 6 2 1 6 1 6
-(C -C )alkyl-N(H)CH=NH, -(C -C )alkyl-C(NH )=NH, -(C -C )alkyl-N(H)C(=NH)NH , -(C -
1 6 1 6 2 1 6 2 1
26 25 26
C )alkyl-N(H)S(O) NR R , -(C -C )alkyl-N(H)S(O) (C -C )alkyl, -(C -C )alkyl-N(H)-C(O)NR R ,
6 2 1 6 2 1 6 1 6
-(C -C )alkylC(O)N(H)[optionally substituted(C -C )alkyl]-OR , -(C -C )alkylN(H)C(O)(C -
1 6 2 6 1 6 1
23 25 26
C )alkyl-OR , -(C -C )alkylC(O)N(H)heterocycloalkyl, -(C -C )alkylC(O)NR R , -(C -C )alkyl-
6 1 6 1 6 1 6
26 25 26
N(H)-C(O)-(C -C )alkyl-NR R , -(C -C )alkyl-N(H)-(C -C )alkylC(O)NR R , -(C -C )alkyl-
1 6 1 6 1 6 1 6
heterocycloalkyl, optionally substituted -(C -C )alkyl-N(H)heterocycloalkyl, or -(C -C )alkyl-
1 6 1 6
heteroaryl;
13 14 23 23
R and R are each independently H, -NH , -(C -C )alkyl, -(C -C )alkyl-OR , -(C -C )alkyl-SR , -(C -
2 1 6 1 6 1 6 1
23 21 22 25 26
C )alkyl-C(O)OR , -(C -C )alkyl-NR R , -(C -C )alkyl-CN, -(C -C )alkyl-C(O)NR R , -(C -
6 1 6 1 6 1 6 1
C )alkyl-N(H)C(NH)NH , -(C -C )alkyl-heterocycloalkyl, or -(C -C )alkyl-heteroaryl;
6 2 1 6 1 6
13 19 14
or R and R are combined to form an optionally substituted heterocycloalkyl ring; and R is H;
16 17 18 19
R , R , R , R , and R are each independently H, -(C -C )alkyl, -(C -C )cycloalkyl, -(C -C )alkyl-
1 6 3 6 1 6
23 23 21 22
OR , -(C -C )alkyl-C(O)OR , or -(C -C )alkyl-NR R ;
1 6 1 6
X is optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, optionally substituted -(C -
1 6 2 6 2 6 3
C )cycloalkyl-, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally
24 24
substituted heteroaryl, -O-(C -C )alkyl-, -N(R )(C -C )alkyl-, -N(R )(C -C )aryl-, or -SO (C -
1 6 1 6 6 10 2 1
C )alkyl-;
-C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, -(C -
Y is a bond, -O-, -S-, optionally substituted -(C
1 6 2 6 2 6 1
24 24
C )alkyl-N(R )(C -C )alkyl-, -O-(C -C )alkyl-, -O(C -C )aryl-, -N(R )(C -C )alkyl-, -
6 1 6 1 6 6 10 1 6
24 24
N(R )SO (C -C )alkyl-, -N(R )C(O)(C -C )alkyl-, -C(O)(C -C )alkyl-, -S(C -C )alkyl-, -SO (C -
2 1 6 1 6 1 6 1 6 2 1
C )alkyl-, -C(O)NH(C -C )alkyl-, optionally substituted -(C -C )cycloalkyl-, optionally substituted -
6 1 6 3 7
24 24 24
C(O)N(R )aryl-, optionally substituted -N(R )C(O)aryl-, optionally substituted -N(R )SO aryl-,
optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Z is H, halogen, -NH , -CN, -CF , -CO H, -(C -C )alkyl, -(C -C )alkenyl, -CH=((C -C )cycloalkyl), -
2 3 2 1 12 2 12 3 7
26
(C -C )alkynyl, -C(O)NR R , -O-(C -C )alkyl, -S-(C -C )alkyl, -O-(C -C )[optionally substituted
2 12 1 12 1 12 3 10
23 23
(C -C )cycloalkyl], -O-(C -C )alkyl-OR , -(C -C )alkyl-OR , -(C -C )alkyl-CN, -S-(C -C )alkyl, -
3 7 1 6 1 12 1 12 1 12
24 24
N(R )(C -C )alkyl, -N(R )C(O)(C -C )alkyl, optionally substituted -(C -C )cycloalkyl, -(C -
1 12 1 12 3 7 1
C )alkyl-(C -C )cycloalkyl, -(C -C )alkyl-heterocycloalkyl, optionally substituted heterocycloalkyl,
6 3 7 1 6
optionally substituted aryl, or optionally substituted heteroaryl;
21 22
each R and R is independently H, -(C -C )alkyl, -(C -C )heteroalkyl, -(C -C )alkyl-CO H, -C(O)(C -
1 6 1 6 1 6 2 1
31 31 21 22
C )alkyl, -C(O)N(R ) , or -SO N(R ) ; or R and R and the nitrogen atom to which they are
6 2 2 2
attached form a heterocycloalkyl ring;
18253141_1 (GHMatters) P111789.NZ
31 31
each R is independently H or -(C -C )alkyl; or two R and the nitrogen atom to which they are attached
form a heterocycloalkyl ring;
each R is independently H or -(C -C )alkyl;
each R is independently H or -(C -C )alkyl;
26
each R and R is independently H or optionally substituted -(C -C )alkyl;
26
or R and R and the nitrogen atom to which they are attached form a heterocycloalkyl ring;
27 23 24 23 23 24
each R is independently halogen, -NR R , -NHC(O)R , -NHC(O)NR R , nitro, hydroxyl, optionally
substituted -(C -C )alkyl, optionally substituted -(C -C )heteroalkyl, optionally substituted -(C -
1 6 1 6 1
C )heteroalkyloxy, optionally substituted -(C -C )heteroalkylamino, -(C -C )alkoxy, -C(O)(C -
6 1 6 1 6 1
C )alkyl, or -S(O) (C -C )alkyl;
6 2 1 6
1 27
or R and R and the atoms to which they are attached form an optionally substituted 5- or 6-membered
heterocycloalkyl ring;
28 23 24 23 23 24
each R is independently halogen, -NR R , -NHC(O)R , -NHC(O)NR R , nitro, hydroxyl, optionally
substituted -(C -C )alkyl, optionally substituted -(C -C )heteroalkyl, optionally substituted -(C -
1 6 1 6 1
C )heteroalkyloxy, optionally substituted -(C -C )heteroalkylamino, -(C -C )alkoxy, -C(O)(C -
6 1 6 1 6 1
C )alkyl, or -S(O) (C -C )alkyl;
6 2 1 6
2 28
or R and R and the atoms to which they are attached form an optionally substituted 5- or 6-membered
heterocycloalkyl ring;
n is 0 or 1;
p is 1 or 2 and q is 0, 1, or 2; or q is 1 or 2 and p is 0, 1, or 2; and
wherein the optional substituents, in each instance, are selected from the group consisting of -(C -
C )alkyl, halogen, hydroxy, amine, carboxylic acid, and -O-(C -C )alkyl-;
1 6
or a pharmaceutically acceptable salt or solvate thereof.
[0003c] In another aspect, there is provided a pharmaceutical composition comprising the compound as
defined herein, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, and a
pharmaceutically acceptable excipient.
[0003d] In another aspect, there is provided a use of a compound as defined herein, or a
pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, for preparation of a
medicament for treatment of a bacterial infection in a patient.
[0003e] In another aspect, there is provided a use of a compound as defined herein, or a
pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, for preparation of a
medicament for treatment of a lepB-mediated infection in a mammal.
18253141_1 (GHMatters) P111789.NZ
In another embodiment is a compound of Formula (I) having the structure of Formula (Ia):
(R )
27 6
(R )
R R N
O CN
Z X N
17 9
O R R
11 12
Formula (Ia).
6 7 8
In another embodiment is a compound of Formula (I) or (Ia) wherein R , R , and R are H. In
16
another embodiment is a compound of Formula (I) or (Ia) wherein R and R are H. In another
embodiment is a compound of Formula (I) or (Ia) having the structure of Formula (Ib):
Z X N O
O R O
Formula (Ib).
In another embodiment is a compound of Formula (I), (Ia), or (Ib) wherein R is -CH . In another
embodiment is a compound of Formula (I), (Ia), or (Ib) wherein R is H. In another embodiment is a
compound of Formula (I), (Ia), or (Ib) wherein R is H. In another embodiment is a compound of Formula
(I), (Ia), or (Ib) wherein R is H. In another embodiment is a compound of Formula (I), (Ia), or (Ib)
wherein R is -(C -C )alkyl. In another embodiment is a compound of Formula (I), (Ia), or (Ib) wherein R
is -(C -C )cycloalkyl. In another embodiment is a compound of Formula (I), (Ia), or (Ib) wherein R and R
and the carbon atom to which they are attached form a cyclopropyl ring. In another embodiment is a
compound of Formula (I), (Ia), or (Ib) wherein R is -(C -C )alkyl. In another embodiment is a compound
of Formula (I), (Ia), or (Ib) wherein R is -CH . In another embodiment is a compound of Formula (I), (Ia),
or (Ib) having the structure of Formula (Ic):
18253141_1 (GHMatters) P111789.NZ
Z X N
Formula (Ic).
In another embodiment is a compound of Formula (I) or (Ia)-(Ic) wherein R is -(C -C )alkyl-
23 11
OR . In another embodiment is a compound of Formula (I) or (Ia)-(Ic) wherein R is -CH CH OH. In
another embodiment is a compound of Formula (I) or (Ia)-(Ic) wherein R is -(C -C )alkyl. In another
11 21 22
embodiment is a compound of Formula (I) or (Ia)-(Ic) wherein R is -(C -C )alkyl-NR R . In another
embodiment is a compound of Formula (I) or (Ia)-(Ic) wherein R is -(C -C )alkyl-NH . In another
1 6 2
embodiment is a compound of Formula (I) or (Ia)-(Ic) wherein R is -CH NH . In another embodiment is
a compound of Formula (I) or (Ia)-(Ic) wherein R is -CH CH NH . In another embodiment is a
2 2 2
compound of Formula (I) or (Ia)-(Ic) wherein R is -CH CH CH NH . In another embodiment is a
2 2 2 2
compound of Formula (I) or (Ia)-(Ic) wherein R is -CH CH CH CH NH . In another embodiment is a
2 2 2 2 2
compound of Formula (I) or (Ia)-(Ic) wherein R and R are each independently H or -(C -C )alkyl-
21 22 1 2
NR R . In another embodiment is a compound of Formula (I) or (Ia)-(Ic) wherein R and R are each
21 22
independently -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (I) or (Ia)-(Ic)
wherein R and R are each -CH CH NH . In another embodiment is a compound of Formula (I) or (Ia)-
2 2 2
1 21 22 2
(Ic) wherein R is -(C -C )alkyl-NR R and R is H. In another embodiment is a compound of Formula
(I) or (Ia)-(Ic) wherein R is -CH CH NH and R is H. In another embodiment is a compound of Formula
2 2 2
1 2 21 22
(I) or (Ia)-(Ic) wherein R is H and R is -(C -C )alkyl-NR R . In another embodiment is a compound of
Formula (I) or (Ia)-(Ic) wherein R is H and R is -CH CH NH . In another embodiment is a compound of
2 2 2
Formula (I) or (Ia)-(Ic) wherein R is H and R is H. In another embodiment is a compound of Formula (I)
or (Ia)-(Ic) having the structure of Formula (Id):
18253141_1 (GHMatters) P111789.NZ
Z X N
Formula (Id);
wherein R is -CH CH NH or -CH CH CH NH .
2 2 2 2 2 2 2
In one aspect described herein is a compound of Formula (II):
(R )
(R )
13 14 N
O R R 18 16
O CN
Z X N
17 9 R
11 12
Formula (II);
wherein:
1 2 23
R and R are each independently H, -(C -C )alkyl, -(C -C )alkyl-OR , -CH CH(OH)CH NH , -
1 6 1 6 2 2 2
CH CH(heterocycloalkyl)CH NH , -CH C(O)NH , -CH C(O)N(H)CH CN, -(C -C )alkyl-C(O)OR , -
2 2 2 2 2 2 2 1 6
21 22 25 26 23 21 22
(C -C )alkyl-NR R , -(C -C )alkyl-C(O)NR R , -(C -C )alkyl-N(R )C(O)(C -C )alkylNR R , -
1 6 1 6 1 6 1 6
23 23
(C -C )alkyl-N(R )C(O)(C -C )alkyl, -(C -C )alkyl-C(O)N(R )(C -C )alkyl, -(C -C )alkyl-
1 6 1 6 1 6 1 6 1 6
23 23 21 22
C(O)N(R )(C -C )alkyl-heterocycloalkyl, -(C -C )alkyl-NR C(=NH)NR R , -(C -C )alkyl-
1 6 1 6 1 6
23 23 21 22
NR C(=NH)R , -(C -C )alkyl-[(C -C )alkyl-NR R ] , -(C -C )heteroalkyl, or optionally substituted
1 6 1 6 2 1 6
heterocycloalkyl;
and R and the atoms to which they are attached form an optionally substituted heterocycloalkyl ring;
or R
R is H or -(C -C )alkyl;
R is H, -(C -C )alkyl, -(C -C )alkyl-OH, -(C -C )cycloalkyl, or -C(O)NH ;
1 6 1 6 3 6 2
or R and R are combined to form a heterocycloalkyl ring;
R is H or -(C -C )alkyl;
or R and R and the carbon atom to which they are attached form a cyclopropyl ring;
18253141_1 (GHMatters) P111789.NZ
6 7 8
R , R , and R are each independently H or -(C -C )alkyl;
R is H, -(C -C )alkyl, -(C -C )haloalkyl, or -(C -C )cycloalkyl;
1 6 1 6 3 6
R is H or -(C -C )alkyl;
11 12 23 23
R and R are each independently H, -NH , -(C -C )alkyl, -(C -C )alkyl-OR , -(C -C )alkyl-SR , -(C -
2 1 6 1 6 1 6 1
23 21 22 23 23
C )alkyl-C(O)OR , -(C -C )alkyl-NR R , -(C -C )alkyl-NR OR , -(C -C )alkyl-
6 1 6 1 6 1 6
23 23 25 26
NHC(O)NR OR , -(C -C )alkyl-O-(C -C )alkyl-NR R , -(C -C )alkyl-CN, -(C -C )alkyl-
1 6 1 6 1 6 1 6
23 23 25 26
NR C(O)R , -(C -C )alkyl-C(O)NR R , -(C -C )heteroalkyl-CO H, -(C -C )alkyl-S(O)(C -C )alkyl,
1 6 1 6 2 1 6 1 6
-(C -C )alkyl-N(H)CH=NH, -(C -C )alkyl-C(NH )=NH, -(C -C )alkyl-N(H)C(=NH)NH , -(C -
1 6 1 6 2 1 6 2 1
26 25 26
C )alkyl-N(H)S(O) NR R , -(C -C )alkyl-N(H)S(O) (C -C )alkyl, -(C -C )alkyl-N(H)-C(O)NR R ,
6 2 1 6 2 1 6 1 6
-(C -C )alkylC(O)N(H)[optionally substituted(C -C )alkyl]-OR , -(C -C )alkylN(H)C(O)(C -
1 6 2 6 1 6 1
23 25 26
C )alkyl-OR , -(C -C )alkylC(O)N(H)heterocycloalkyl, -(C -C )alkylC(O)NR R , -(C -C )alkyl-
6 1 6 1 6 1 6
26 25 26
N(H)-C(O)-(C -C )alkyl-NR R , -(C -C )alkyl-N(H)-(C -C )alkylC(O)NR R , -(C -C )alkyl-
1 6 1 6 1 6 1 6
heterocycloalkyl, optionally substituted -(C -C )alkyl-N(H)heterocycloalkyl, or -(C -C )alkyl-
1 6 1 6
heteroaryl;
13 14 23 23
R and R are each independently H, -NH , -(C -C )alkyl, -(C -C )alkyl-OR , -(C -C )alkyl-SR , -(C -
2 1 6 1 6 1 6 1
23 21 22 25 26
C )alkyl-C(O)OR , -(C -C )alkyl-NR R , -(C -C )alkyl-CN, -(C -C )alkyl-C(O)NR R , -(C -
6 1 6 1 6 1 6 1
C )alkyl-N(H)C(NH)NH , -(C -C )alkyl-heterocycloalkyl, or -(C -C )alkyl-heteroaryl;
6 2 1 6 1 6
13 19 14
or R and R are combined to form an optionally substituted heterocycloalkyl ring; and R is H;
16 17 18 19
R , R , R , R , and R are each independently H, -(C -C )alkyl, -(C -C )cycloalkyl, -(C -C )alkyl-
1 6 3 6 1 6
23 23 21 22
OR , -(C -C )alkyl-C(O)OR , or -(C -C )alkyl-NR R ;
1 6 1 6
X is optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, optionally substituted -(C -
1 6 2 6 2 6 3
C )cycloalkyl-, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally
24 24
-C )alkyl-, -N(R )(C -C )alkyl-, -N(R )(C -C )aryl-, or -SO (C -
substituted heteroaryl, -O-(C
1 6 1 6 6 10 2 1
C )alkyl-;
Y is a bond, -O-, -S-, optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, -(C -
1 6 2 6 2 6 1
24 24
C )alkyl-N(R )(C -C )alkyl-, -O-(C -C )alkyl-, -O(C -C )aryl-, -N(R )(C -C )alkyl-, -
6 1 6 1 6 6 10 1 6
24 24
N(R )SO (C -C )alkyl-, -N(R )C(O)(C -C )alkyl-, -C(O)(C -C )alkyl-, -S(C -C )alkyl-, -SO (C -
2 1 6 1 6 1 6 1 6 2 1
C )alkyl-, -C(O)NH(C -C )alkyl-, optionally substituted -(C -C )cycloalkyl-, optionally substituted -
6 1 6 3 7
24 24 24
C(O)N(R )aryl-, optionally substituted -N(R )C(O)aryl-, optionally substituted -N(R )SO aryl-,
optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Z is H, halogen, -NH , -CN, -CF , -CO H, -(C -C )alkyl, -(C -C )alkenyl, -CH=((C -C )cycloalkyl), -
2 3 2 1 12 2 12 3 7
26
(C -C )alkynyl, -C(O)NR R , -O-(C -C )alkyl, -S-(C -C )alkyl, -O-(C -C )[optionally substituted
2 12 1 12 1 12 3 10
23 23
(C -C )cycloalkyl], -O-(C -C )alkyl-OR , -(C -C )alkyl-OR , -(C -C )alkyl-CN, -S-(C -C )alkyl, -
3 7 1 6 1 12 1 12 1 12
24 24
N(R )(C -C )alkyl, -N(R )C(O)(C -C )alkyl, optionally substituted -(C -C )cycloalkyl, -(C -
1 12 1 12 3 7 1
C )alkyl-(C -C )cycloalkyl, -(C -C )alkyl-heterocycloalkyl, optionally substituted heterocycloalkyl,
6 3 7 1 6
optionally substituted aryl, or optionally substituted heteroaryl;
18253141_1 (GHMatters) P111789.NZ
21 22
each R and R is independently H, -(C -C )alkyl, -(C -C )heteroalkyl, -(C -C )alkyl-CO H, -C(O)(C -
1 6 1 6 1 6 2 1
31 31 21 22
C )alkyl, -C(O)N(R ) , or -SO N(R ) ; or R and R and the nitrogen atom to which they are
6 2 2 2
attached form a heterocycloalkyl ring;
31 31
each R is independently H or -(C -C )alkyl; or two R and the nitrogen atom to which they are attached
form a heterocycloalkyl ring;
each R is independently H or -(C -C )alkyl;
each R is independently H or -(C -C )alkyl;
26
each R and R is independently H or optionally substituted -(C -C )alkyl;
26
or R and R and the nitrogen atom to which they are attached form a heterocycloalkyl ring;
27 23 24 23 23 24
each R is independently halogen, -NR R , -NHC(O)R , -NHC(O)NR R , nitro, hydroxyl, optionally
substituted -(C -C )alkyl, optionally substituted -(C -C )heteroalkyl, optionally substituted -(C -
1 6 1 6 1
C )heteroalkyloxy, optionally substituted -(C -C )heteroalkylamino, -(C -C )alkoxy, -C(O)(C -
6 1 6 1 6 1
C )alkyl, or -S(O) (C -C )alkyl;
6 2 1 6
1 27
or R and R and the atoms to which they are attached form an optionally substituted 5- or 6-membered
heterocycloalkyl ring;
28 23 24 23 23 24
each R is independently halogen, -NR R , -NHC(O)R , -NHC(O)NR R , nitro, hydroxyl, optionally
substituted -(C -C )alkyl, optionally substituted -(C -C )heteroalkyl, optionally substituted -(C -
1 6 1 6 1
C )heteroalkyloxy, optionally substituted -(C -C )heteroalkylamino, -(C -C )alkoxy, -C(O)(C -
6 1 6 1 6 1
C )alkyl, or -S(O) (C -C )alkyl;
6 2 1 6
2 28
or R and R and the atoms to which they are attached form an optionally substituted 5- or 6-membered
heterocycloalkyl ring;
n is 0 or 1;
p is 0, 1, or 2; and
q is 0, 1, or 2;
or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
In another embodiment is a compound of Formula (II) having the structure of Formula (IIa):
13 14 N
18 16
O R R
Z X N
R 10
17 9 R
11 12
Formula (IIa).
18253141_1 (GHMatters) P111789.NZ
6 7 8
In another embodiment is a compound of Formula (II) or (IIa) wherein R , R , and R are H. In
16
another embodiment is a compound of Formula (II) or (IIa) wherein R and R are H. In another
embodiment is a compound of Formula (II) or (IIa) having the structure of Formula (IIb):
O R 18
Z X N
Formula (IIb).
In another embodiment is a compound of Formula (II), (IIa), or (IIb) wherein R is H. In another
embodiment is a compound of Formula (II), (IIa), or (IIb) wherein R is H. In another embodiment is a
compound of Formula (II), (IIa), or (IIb) wherein R is -CH . In another embodiment is a compound of
Formula (II), (IIa), or (IIb) wherein R is H. In another embodiment is a compound of Formula (II), (IIa),
or (IIb) wherein R is H. In another embodiment is a compound of Formula (II), (IIa), or (IIb) wherein R
is -(C -C )alkyl. In another embodiment is a compound of Formula (II), (IIa), or (IIb) wherein R is -(C -
1 6 3
C )cycloalkyl. In another embodiment is a compound of Formula (II), (IIa), or (IIb) wherein R and R and
the carbon atom to which they are attached form a cyclopropyl ring. In another embodiment is a compound
of Formula (II), (IIa), or (IIb) wherein R is -(C -C )alkyl. In another embodiment is a compound of
Formula (II), (IIa), or (IIb) wherein R is -CH . In another embodiment is a compound of Formula (II),
(IIa), or (IIb) having the structure of Formula (IIc):
O CN
Z X N
Formula (IIc);
wherein R and R are each independently H or -CH CH NH .
2 2 2
[0012] In another embodiment is a compound of Formula (II) or (IIa)-(IIc) wherein R is -(C -C )alkyl-
23 11
OR . In another embodiment is a compound of Formula (II) or (IIa)-(IIc) wherein R is -CH CH OH. In
another embodiment is a compound of Formula (II) or (IIa)-(IIc) wherein R is -(C -C )alkyl. In another
11 21 22
embodiment is a compound of Formula (II) or (IIa)-(IIc) wherein R is -(C -C )alkyl-NR R . In another
18253141_1 (GHMatters) P111789.NZ
embodiment is a compound of Formula (II) or (IIa)-(IIc) wherein R is -(C -C )alkyl-NH . In another
1 6 2
embodiment is a compound of Formula (II) or (IIa)-(IIc) wherein R is -CH NH . In another embodiment
is a compound of Formula (II) or (IIa)-(IIc) wherein R is -CH CH NH . In another embodiment is a
2 2 2
compound of Formula (II) or (IIa)-(IIc) wherein R is -CH CH CH NH . In another embodiment is a
2 2 2 2
compound of Formula (II) or (IIa)-(IIc) wherein R is -CH CH CH CH NH . In another embodiment is a
2 2 2 2 2
13 23
compound of Formula (II) or (IIa)-(IIc) wherein R is -(C -C )alkyl-OR . In another embodiment is a
compound of Formula (II) or (IIa)-(IIc) wherein R is -CH OH. In another embodiment is a compound of
Formula (II) or (IIa)-(IIc) wherein R is -CH CH OH. In another embodiment is a compound of Formula
(II) or (IIa)-(IIc) having the structure of Formula (IId):
X N O
Formula (IId).
In another embodiment is a compound of Formula (II) or (IIa)-(IId) wherein R is -CH . In
another embodiment is a compound of Formula (II) or (IIa)-(IId) wherein R is H. In another embodiment
is a compound of Formula (II) or (IIa)-(IId) wherein R is H. In another embodiment is a compound of
Formula (II) or (IIa)-(IId) wherein R is -(C -C )alkyl. In another embodiment is a compound of Formula
(II) or (IIa)-(IId) wherein R is -(C -C )cycloalkyl. In another embodiment is a compound of Formula (II)
or (IIa)-(IId) wherein R and R and the carbon atom to which they are attached form a cyclopropyl ring. In
another embodiment is a compound of Formula (II) or (IIa)-(IId) wherein R is -(C -C )alkyl. In another
embodiment is a compound of Formula (II) or (IIa)-(IId) wherein R is -CH . In another embodiment is a
compound of Formula (II) or (IIa)-(IId) wherein R and R are each independently H or -(C -C )alkyl-
21 22 1 2
NR R . In another embodiment is a compound of Formula (II) or (IIa)-(IId) wherein R and R are each
21 22
independently -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (II) or (IIa)-(IId)
wherein R and R are each -CH CH NH . In another embodiment is a compound of Formula (II) or (IIa)-
2 2 2
1 21 22 2
(IId) wherein R is -(C -C )alkyl-NR R and R is H. In another embodiment is a compound of Formula
(II) or (IIa)-(IId) wherein R is -CH CH NH and R is H. In another embodiment is a compound of
2 2 2
1 2 21 22
Formula (II) or (IIa)-(IId) wherein R is H and R is -(C -C )alkyl-NR R . In another embodiment is a
compound of Formula (II) or (IIa)-(IId) wherein R is H and R is -CH CH NH . In another embodiment is
2 2 2
a compound of Formula (II) or (IIa)-(IId) having the structure of Formula (IIe):
18253141_1 (GHMatters) P111789.NZ
O CN
X N O
Formula (IIe);
wherein R and R are each independently H or -CH CH NH .
2 2 2
In another embodiment is a compound of Formula (I), (Ia)-(Id), (II), or (IIa)-(IIe) wherein X is
optionally substituted aryl. In another embodiment is a compound of Formula (I), (Ia)-(Id), (II), or (IIa)-
(IIe) wherein X is optionally substituted phenyl. In another embodiment is a compound of Formula (I),
(Ia)-(Id), (II), or (IIa)-(IIe) wherein X is optionally substituted heteroaryl. In another embodiment is a
compound of Formula (I), (Ia)-(Id), (II), or (IIa)-(IIe) wherein X is disubstituted heteroaryl. In another
embodiment is a compound of Formula (I), (Ia)-(Id), (II), or (IIa)-(IIe) wherein X is heteroaryl
disubstituted with substituents each independently selected from halogen, -CN, optionally substituted -(C -
23 25 26
C )alkyl, optionally substituted -O-(C -C )alkyl, OR , -NR R , and -NO . In another embodiment is a
6 1 6 2
compound of Formula (I), (Ia)-(Id), (II), or (IIa)-(IIe) wherein X is heteroaryl disubstituted with
substituents each independently selected from -(C -C )alkyl. In another embodiment is a compound of
Formula (I), (Ia)-(Id), (II), or (IIa)-(IIe) wherein X is heteroaryl disubstituted with methyl. In another
embodiment is a compound of Formula (I), (Ia)-(Id), (II), or (IIa)-(IIe) wherein X is pyridinyl disubstituted
with substituents each independently selected from halogen, -CN, optionally substituted -(C -C )alkyl,
23 25 26
optionally substituted -O-(C -C )alkyl, OR , -NR R , or -NO . In another embodiment is a compound of
1 6 2
Formula (I), (Ia)-(Id), (II), or (IIa)-(IIe) wherein X is pyridinyl disubstituted with substituents each
independently selected from -(C -C )alkyl. In another embodiment is a compound of Formula (I), (Ia)-(Id),
(II), or (IIa)-(IIe) wherein X is pyridinyl disubstituted with methyl. In another embodiment is a compound
of Formula (I), (Ia)-(Id), (II), or (IIa)-(IIe) wherein X is pyrimidinyl disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
23 25 26
(C -C )alkyl, OR , -NR R , or -NO . In another embodiment is a compound of Formula (I), (Ia)-(Id),
1 6 2
(II), or (IIa)-(IIe) wherein X is pyrimidinyl disubstituted with substituents each independently selected
from -(C -C )alkyl. In another embodiment is a compound of Formula (I), (Ia)-(Id), (II), or (IIa)-(IIe)
wherein X is pyrimidinyl disubstituted with methyl. In another embodiment is a compound of Formula (I),
(Ia)-(Id), (II), or (IIa)-(IIe) wherein X is optionally substituted -(C -C )alkyl-. In another embodiment is a
compound of Formula (I), (Ia)-(Id), (II), or (IIa)-(IIe) wherein Y is optionally substituted aryl. In another
embodiment is a compound of Formula (I), (Ia)-(Id), (II), or (IIa)-(IIe) wherein Y is optionally substituted
phenyl. In another embodiment is a compound of Formula (I), (Ia)-(Id), (II), or (IIa)-(IIe) wherein Y is
optionally substituted heteroaryl. In another embodiment is a compound of Formula (I), (Ia)-(Id), (II), or
18253141_1 (GHMatters) P111789.NZ
(IIa)-(IIe) wherein Y is optionally substituted -(C -C )alkyl-. In another embodiment is a compound of
Formula (I), (Ia)-(Id), (II), or (IIa)-(IIe) wherein Y is optionally substituted (C -C )cycloalkyl-. In another
embodiment is a compound of Formula (I), (Ia)-(Id), (II), or (IIa)-(IIe) wherein Y is optionally substituted
heterocycloalkyl. In another embodiment is a compound of Formula (I), (Ia)-(Id), (II), or (IIa)-(IIe)
wherein Y is -O-. In another embodiment is a compound of Formula (I), (Ia)-(Id), (II), or (IIa)-(IIe)
wherein Y is -(C -C )alkynyl. In another embodiment is a compound of Formula (I), (Ia)-(Id), (II), or (IIa)-
(IIe) wherein Y is -O-(C -C )alkyl-. In another embodiment is a compound of Formula (I), (Ia)-(Id), (II), or
(IIa)-(IIe) wherein Y is a bond. In another embodiment is a compound of Formula (I), (Ia)-(Id), (II), or
(IIa)-(IIe) wherein Z is -(C -C )alkyl. In another embodiment is a compound of Formula (I), (Ia)-(Id), (II),
1 12
or (IIa)-(IIe) wherein Z is n-butyl, isobutyl, or tert-butyl. In another embodiment is a compound of
Formula (I), (Ia)-(Id), (II), or (IIa)-(IIe) wherein Z is -O-(C -C )alkyl. In another embodiment is a
1 12
compound of Formula (I), (Ia)-(Id), (II), or (IIa)-(IIe) wherein Z is -O-(C -C )cycloalkyl. In another
embodiment is a compound of Formula (I), (Ia)-(Id), (II), or (IIa)-(IIe) wherein Z is -(C -C )alkenyl. In
2 12
another embodiment is a compound of Formula (I), (Ia)-(Id), (II), or (IIa)-(IIe) wherein Z is optionally
substituted aryl. In another embodiment is a compound of Formula (I), (Ia)-(Id), (II), or (IIa)-(IIe) wherein
Z is optionally substituted phenyl. In another embodiment is a compound of Formula (I), (Ia)-(Id), (II), or
(IIa)-(IIe) wherein Z is phenyl monsubstituted or disubstituted with a substituent independently selected
from -(C -C )alkyl. In another embodiment is a compound of Formula (I), (Ia)-(Id), (II), or (IIa)-(IIe)
wherein Z is phenyl monosubstituted with n-butyl, isobutyl, or tert-butyl. In another embodiment is a
compound of Formula (I), (Ia)-(Id), (II), or (IIa)-(IIe) wherein Z is phenyl monosubstituted with n-butyl. In
another embodiment is a compound of Formula (I), (Ia)-(Id), (II), or (IIa)-(IIe) wherein Z is phenyl
monosubstituted with isobutyl. In another embodiment is a compound of Formula (I), (Ia)-(Id), (II), or
(IIa)-(IIe) wherein Z is phenyl monosubstituted with tert-butyl. In another embodiment is a compound of
Formula (I), (Ia)-(Id), (II), or (IIa)-(IIe) wherein Z is optionally substituted heteroaryl. In another
embodiment is a compound of Formula (I), (Ia)-(Id), (II), or (IIa)-(IIe) wherein Z is optionally substituted -
(C -C )cycloalkyl. In another embodiment is a compound of Formula (I), (Ia)-(Id), (II), or (IIa)-(IIe)
wherein Z is optionally substituted heterocycloalkyl. In another embodiment is a compound of Formula (I),
(Ia)-(Id), (II), or (IIa)-(IIe) wherein Z is halogen. In another embodiment is a compound of Formula (I),
(Ia)-(Id), (II), or (IIa)-(IIe) wherein Z-Y-X- is not . In another embodiment is a
compound of Formula (I), (Ia)-(Id), (II), or (IIa)-(IIe) wherein the compound is selected from any of the
compounds in table 1 or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
In one aspect described herein is a pharmaceutical composition comprising the compound
disclosed herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or
pharmaceutically acceptable prodrug thereof, and a pharmaceutically acceptable excipient.
18253141_1 (GHMatters) P111789.NZ
In one aspect described herein is a use of a compound disclosed herein, or a pharmaceutically
acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof, for
preparation of a medicament for treatment of a bacterial infection in a patient.
In one aspect described herein is a method of treatment of a bacterial infection in a mammal,
comprising administering to the mammal an effective amount of a compound disclosed herein, or a
pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable
prodrug thereof, to the mammal at a frequency and for a duration sufficient to provide a beneficial effect to
the mammal.
In one aspect described herein is a method of treatment of a lepB-mediated infection in a mammal,
comprising administering to the mammal an effective amount of a compound disclosed herein, or a
pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable
prodrug thereof, to the mammal at a frequency and for a duration sufficient to provide a beneficial effect to
the mammal.
INCORPORATION BY REFERENCE
All publications, patents, and patent applications mentioned in this specification are herein
incorporated by reference to the same extent as if each individual publication, patent, or patent application
was specifically and individually indicated to be incorporated by reference.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
As used in the specification and the appended claims, the singular forms “a,” “an” and “the”
include plural referents unless the context clearly dictates otherwise.
[0021] The term “about” as used herein, when referring to a numerical value or range, allows for a degree
of variability in the value or range, for example, within 10%, or within 5% of a stated value or of a stated
limit of a range.
All percent compositions are given as weight-percentages, unless otherwise stated.
All average molecular weights of polymers are weight-average molecular weights, unless
otherwise specified.
As used herein, “individual” (as in the subject of the treatment) means both mammals and
non-mammals. Mammals include, for example, humans; non-human primates, e.g. apes and monkeys; and
non-primates, e.g. dogs, cats, cattle, horses, sheep, and goats. Non-mammals include, for example, fish and
birds.
[0025] The term “disease” or “disorder” or “malcondition” are used interchangeably, and are used to refer
to diseases or conditions wherein a bacterial SPase plays a role in the biochemical mechanisms involved in
18253141_1 (GHMatters) P111789.NZ
the disease or malcondition such that a therapeutically beneficial effect can be achieved by acting on the
enzyme. “Acting on” SPase can include binding to SPase and/or inhibiting the bioactivity of an SPase.
The expression “effective amount”, when used to describe therapy to an individual suffering from
a disorder, refers to the amount of a compound described herein that is effective to inhibit or otherwise act
on SPase in the individual’s tissues wherein SPase involved in the disorder is active, wherein such
inhibition or other action occurs to an extent sufficient to produce a beneficial therapeutic effect.
“Substantially” as the term is used herein means completely or almost completely; for example, a
composition that is “substantially free” of a component either has none of the component or contains such
a trace amount that any relevant functional property of the composition is unaffected by the presence of the
trace amount, or a compound is “substantially pure” is there are only negligible traces of impurities
present.
“Treating” or “treatment” within the meaning herein refers to an alleviation of symptoms
associated with a disorder or disease, or inhibition of further progression or worsening of those symptoms,
or prevention or prophylaxis of the disease or disorder, or curing the disease or disorder. Similarly, as
used herein, an “effective amount” or a “therapeutically effective amount” of a compound refers to an
amount of the compound that alleviates, in whole or in part, symptoms associated with the disorder or
condition, or halts or slows further progression or worsening of those symptoms, or prevents or provides
prophylaxis for the disorder or condition. In particular, a “therapeutically effective amount” refers to an
amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A
therapeutically effective amount is also one in which any toxic or detrimental effects of compounds
described herein are outweighed by the therapeutically beneficial effects.
By “chemically feasible” is meant a bonding arrangement or a compound where the generally
understood rules of organic structure are not violated; for example a structure within a definition of a claim
that would contain in certain situations a pentavalent carbon atom that would not exist in nature would be
understood to not be within the claim. The structures disclosed herein, in all of their embodiments are
intended to include only “chemically feasible” structures, and any recited structures that are not chemically
feasible, for example in a structure shown with variable atoms or groups, are not intended to be disclosed
or claimed herein.
When a substituent is specified to be an atom or atoms of specified identity, “or a bond”, a
configuration is referred to when the substituent is “a bond” that the groups that are immediately adjacent
to the specified substituent are directly connected to each other in a chemically feasible bonding
configuration.
All chiral, diastereomeric, racemic forms of a structure are intended, unless a particular
stereochemistry or isomeric form is specifically indicated. Compounds described herein can include
enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions, at
any degree of enrichment. Both racemic and diastereomeric mixtures, as well as the individual optical
18253141_1 (GHMatters) P111789.NZ
isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric
partners, and these are all within the scope of the invention.
The inclusion of an isotopic form of one or more atoms in a molecule that is different from the
naturally occurring isotopic distribution of the atom in nature is referred to as an “isotopically labeled
form” of the molecule. All isotopic forms of atoms are included as options in the composition of any
molecule, unless a specific isotopic form of an atom is indicated. For example, any hydrogen atom or set
thereof in a molecule can be any of the isotopic forms of hydrogen, i.e., protium ( H), deuterium ( H), or
tritium ( H) in any combination. Similarly, any carbon atom or set thereof in a molecule can be any of the
11 12 13 14
isotopic form of carbons, such as C, C, C, or C, or any nitrogen atom or set thereof in a molecule can
13 14 15
be any of the isotopic forms of nitrogen, such as N, N, or N. A molecule can include any combination
of isotopic forms in the component atoms making up the molecule, the isotopic form of every atom
forming the molecule being independently selected. In a multi-molecular sample of a compound, not every
individual molecule necessarily has the same isotopic composition. For example, a sample of a compound
can include molecules containing various different isotopic compositions, such as in a tritium or C
radiolabeled sample where only some fraction of the set of molecules making up the macroscopic sample
contains a radioactive atom. It is also understood that many elements that are not artificially isotopically
14 15 32 34
enriched themselves are mixtures of naturally occurring isotopic forms, such as N and N, S and S,
and so forth. A molecule as recited herein is defined as including isotopic forms of all its constituent
elements at each position in the molecule. As is well known in the art, isotopically labeled compounds can
be prepared by the usual methods of chemical synthesis, except substituting an isotopically labeled
precursor molecule. The isotopes, radiolabeled or stable, can be obtained by any method known in the art,
such as generation by neutron absorption of a precursor nuclide in a nuclear reactor, by cyclotron
reactions, or by isotopic separation such as by mass spectrometry. The isotopic forms are incorporated into
14 3
precursors as required for use in any particular synthetic route. For example, C and H can be prepared
14 3
using neutrons generated in a nuclear reactor. Following nuclear transformation, C and H are
incorporated into precursor molecules, followed by further elaboration as needed.
The term “amino protecting group” or “N-protected” as used herein refers to those groups intended
to protect an amino group against undesirable reactions during synthetic procedures and which can later be
removed to reveal the amine. Commonly used amino protecting groups are disclosed in Protective Groups
in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition,
1999). Amino protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-
butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, α-
chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups
such as benzenesulfonyl, p-toluenesulfonyl and the like; alkoxy- or aryloxy-carbonyl groups (which form
urethanes with the protected amine) such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl,
p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,
p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-
18253141_1 (GHMatters) P111789.NZ
dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl,
3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)methylethoxycarbonyl, α,α-dimethyl-3,5-
dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl (Boc),
diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl
(Alloc), 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethyloxycarbonyl (Teoc), phenoxycarbonyl, 4-
nitrophenoxycarbonyl, fluorenylmethoxycarbonyl (Fmoc), cyclopentyloxycarbonyl,
adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; aralkyl groups such as
benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like.
Amine protecting groups also include cyclic amino protecting groups such as phthaloyl and
dithiosuccinimidyl, which incorporate the amino nitrogen into a heterocycle. Typically, amino protecting
groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, Alloc, Teoc, benzyl, Fmoc,
Boc and Cbz. It is well within the skill of the ordinary artisan to select and use the appropriate amino
protecting group for the synthetic task at hand.
The term “hydroxyl protecting group” or “O-protected” as used herein refers to those groups
intended to protect an OH group against undesirable reactions during synthetic procedures and which can
later be removed to reveal the amine. Commonly used hydroxyl protecting groups are disclosed in
Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York,
NY, (3rd Edition, 1999). Hydroxyl protecting groups include acyl groups such as formyl, acetyl,
propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl,
o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and
the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; acyloxy groups (which
form urethanes with the protected amine) such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl,
p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,
p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-
dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl,
3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)methylethoxycarbonyl, α,α-dimethyl-3,5-
dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl (Boc),
diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl
(Alloc), 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethyloxycarbonyl (Teoc), phenoxycarbonyl, 4-
nitrophenoxycarbonyl, fluorenylmethoxycarbonyl (Fmoc), cyclopentyloxycarbonyl,
adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; aralkyl groups such as
benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like.
It is well within the skill of the ordinary artisan to select and use the appropriate hydroxyl protecting group
for the synthetic task at hand.
[0035] In general, “substituted” refers to an organic group as defined herein in which one or more bonds
to a hydrogen atom contained therein are replaced by one or more bonds to a non-hydrogen atom such as,
but not limited to, a halogen (i.e., F, Cl, Br, and I); an oxygen atom in groups such as hydroxyl groups,
18253141_1 (GHMatters) P111789.NZ
alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including
carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl
and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a
nitrogen atom in groups such as amines, hydroxylamines, nitriles, nitro groups, N-oxides, hydrazides,
azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of
substituents that can be bonded to a substituted carbon (or other) atom include F, Cl, Br, I, OR’,
OC(O)N(R’) , CN, NO, NO , ONO , azido, CF , OCF , R’, O (oxo), S (thiono), C(O), S(O),
2 2 2 3 3
methylenedioxy, ethylenedioxy, N(R’) , SR’, SOR’, SO R’, SO N(R’) , SO R’, C(O)R’, C(O)C(O)R’,
2 2 2 2 3
C(O)CH C(O)R’, C(S)R’, C(O)OR’, OC(O)R’, C(O)N(R’) , OC(O)N(R’) , C(S)N(R’) , (CH )
2 2 2 2 2 0-
N(R’)C(O)R’, (CH ) N(R’)N(R’) , N(R’)N(R’)C(O)R’, N(R’)N(R’)C(O)OR’, N(R’)N(R’)CON(R’) ,
2 2 0-2 2 2
N(R’)SO R’, N(R’)SO N(R’) , N(R’)C(O)OR’, N(R’)C(O)R’, N(R’)C(S)R’, N(R’)C(O)N(R’) ,
2 2 2 2
N(R’)C(S)N(R’) , N(COR’)COR’, N(OR’)R’, C(=NH)N(R’) , C(O)N(OR’)R’, or C(=NOR’)R’ wherein
R’ can be hydrogen or a carbon-based moiety, and wherein the carbon-based moiety can itself be further
substituted.
[0036] When a substituent is monovalent, such as, for example, F or Cl, it is bonded to the atom it is
substituting by a single bond. When a substituent is more than monovalent, such as O, which is divalent, it
can be bonded to the atom it is substituting by more than one bond, i.e., a divalent substituent is bonded by
a double bond; for example, a C substituted with O forms a carbonyl group, C=O, which can also be
written as “CO”, “C(O)”, or “C(=O)”, wherein the C and the O are double bonded. When a carbon atom is
substituted with a double-bonded oxygen (=O) group, the oxygen substituent is termed an “oxo” group.
When a divalent substituent such as NR is double-bonded to a carbon atom, the resulting C(=NR) group is
termed an “imino” group. When a divalent substituent such as S is double-bonded to a carbon atom, the
results C(=S) group is termed a “thiocarbonyl” group.
Alternatively, a divalent substituent such as O, S, C(O), S(O), or S(O) can be connected by two
single bonds to two different carbon atoms. For example, O, a divalent substituent, can be bonded to each
of two adjacent carbon atoms to provide an epoxide group, or the O can form a bridging ether group,
termed an “oxy” group, between adjacent or non-adjacent carbon atoms, for example bridging the 1,4-
carbons of a cyclohexyl group to form a [2.2.1]-oxabicyclo system. Further, any substituent can be bonded
to a carbon or other atom by a linker, such as (CH ) or (CR’ ) wherein n is 1, 2, 3, or more, and each R’
2 n 2 n
is independently selected.
C(O) and S(O) groups can be bound to one or two heteroatoms, such as nitrogen, rather than to a
carbon atom. For example, when a C(O) group is bound to one carbon and one nitrogen atom, the resulting
group is called an “amide” or “carboxamide.” When a C(O) group is bound to two nitrogen atoms, the
functional group is termed a urea. When a S(O) group is bound to one carbon and one nitrogen atom, the
resulting unit is termed a “sulfonamide.” When a S(O) group is bound to two nitrogen atoms, the resulting
unit is termed a “sulfamate.”
18253141_1 (GHMatters) P111789.NZ
Substituted alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groups as well as other substituted
groups also include groups in which one or more bonds to a hydrogen atom are replaced by one or more
bonds, including double or triple bonds, to a carbon atom, or to a heteroatom such as, but not limited to,
oxygen in carbonyl (oxo), carboxyl, ester, amide, imide, urethane, and urea groups; and nitrogen in imines,
hydroxyimines, oximes, hydrazones, amidines, guanidines, and nitriles.
Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups
also include rings and fused ring systems in which a bond to a hydrogen atom is replaced with a bond to a
carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups can also be
substituted with alkyl, alkenyl, and alkynyl groups as defined herein.
[0041] By a “ring system” as the term is used herein is meant a moiety comprising one, two, three or
more rings, which can be substituted with non-ring groups or with other ring systems, or both, which can
be fully saturated, partially unsaturated, fully unsaturated, or aromatic, and when the ring system includes
more than a single ring, the rings can be fused, bridging, or spirocyclic. By “spirocyclic” is meant the class
of structures wherein two rings are fused at a single tetrahedral carbon atom, as is well known in the art.
[0042] As to any of the groups described herein, which contain one or more substituents, it is understood,
of course, that such groups do not contain any substitution or substitution patterns which are sterically
impractical and/or synthetically non–feasible. In addition, the compounds of this disclosed subject matter
include all stereochemical isomers arising from the substitution of these compounds.
Selected substituents within the compounds described herein are present to a recursive degree. In
this context, “recursive substituent” means that a substituent may recite another instance of itself or of
another substituent that itself recites the first substituent. Because of the recursive nature of such
substituents, theoretically, a large number may be present in any given claim. One of ordinary skill in the
art of medicinal chemistry and organic chemistry understands that the total number of such substituents is
reasonably limited by the desired properties of the compound intended. Such properties include, by of
example and not limitation, physical properties such as molecular weight, solubility or log P, application
properties such as activity against the intended target, and practical properties such as ease of synthesis.
Recursive substituents are an intended aspect of the disclosed subject matter. One of ordinary skill
in the art of medicinal and organic chemistry understands the versatility of such substituents. To the degree
that recursive substituents are present in a claim of the disclosed subject matter, the total number should be
determined as set forth above.
Alkyl groups include straight chain and branched alkyl groups and cycloalkyl groups having from
1 to about 20 carbon atoms, and typically from 1 to 12 carbons or, in some embodiments, from 1 to 8
carbon atoms. Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as
methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched
alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl,
and 2,2-dimethylpropyl groups. As used herein, the term “alkyl” encompasses n-alkyl, isoalkyl, and
anteisoalkyl groups as well as other branched chain forms of alkyl. Representative substituted alkyl groups
18253141_1 (GHMatters) P111789.NZ
can be substituted one or more times with any of the groups listed above, for example, amino, hydroxy,
cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
The term “alkylene” means a linear saturated divalent hydrocarbon radical of one to six carbon
atoms or a branched saturated divalent hydrocarbon radical of one to six carbon atoms unless otherwise
stated, such as methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene,
pentylene, and the like.
The term “carbonyl” means C=O.
The terms “carboxy” and “hydroxycarbonyl” mean COOH.
Cycloalkyl groups are cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group
can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms
range from 3 to 4, 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but
not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused
rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are
substituted with straight or branched chain alkyl groups as defined above. Representative substituted
cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-,
2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbornyl or
cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro,
thio, alkoxy, and halogen groups. The term “cycloalkenyl” alone or in combination denotes a cyclic
alkenyl group.
The terms “carbocyclic,” “carbocyclyl,” and “carbocycle” denote a ring structure wherein the
atoms of the ring are carbon, such as a cycloalkyl group or an aryl group. In some embodiments, the
carbocycle has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms is 4,
, 6, or 7. Unless specifically indicated to the contrary, the carbocyclic ring can be substituted with as
many as N-1 substituents wherein N is the size of the carbocyclic ring with, for example, alkyl, alkenyl,
alkynyl, amino, aryl, hydroxy, cyano, carboxy, heteroaryl, heterocyclyl, nitro, thio, alkoxy, and halogen
groups, or other groups as are listed above. A carbocyclyl ring can be a cycloalkyl ring, a cycloalkenyl
ring, or an aryl ring. A carbocyclyl can be monocyclic or polycyclic, and if polycyclic each ring can be
independently be a cycloalkyl ring, a cycloalkenyl ring, or an aryl ring.
[0051] (Cycloalkyl)alkyl groups, also denoted cycloalkylalkyl, are alkyl groups as defined above in which
a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkyl group as defined
above.
Alkenyl groups include straight and branched chain and cyclic alkyl groups as defined above,
except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to
about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon
atoms. Examples include, but are not limited to
18253141_1 (GHMatters) P111789.NZ
vinyl, -CH=CH(CH ), -CH=C(CH ) , -C(CH )=CH , -C(CH )=CH(CH ), -C(CH CH )=CH ,
3 3 2 3 2 3 3 2 3 2
cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others.
Cycloalkenyl groups include cycloalkyl groups having at least one double bond between 2
carbons. Thus for example, cycloalkenyl groups include but are not limited to cyclohexenyl,
cyclopentenyl, and cyclohexadienyl groups. Cycloalkenyl groups can have from 3 to about 8-12 ring
members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 6, or 7.
Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl,
adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited
to, decalinyl, and the like, provided they include at least one double bond within a ring. Cycloalkenyl
groups also include rings that are substituted with straight or branched chain alkyl groups as defined
above.
(Cycloalkenyl)alkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond
of the alkyl group is replaced with a bond to a cycloalkenyl group as defined above.
Alkynyl groups include straight and branched chain alkyl groups, except that at least one triple
bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to about 20 carbon atoms, and
typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but
are not limited to –C≡CH, -C≡C(CH ), -C≡C(CH CH ), -CH C≡CH, -CH C≡C(CH ),
3 2 3 2 2 3
C≡C(CH CH ) among others.
and -CH
2 2 3
The term “heteroalkyl” by itself or in combination with another term means, unless otherwise
stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and
one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and
sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The
heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the
heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon
atom in the heteroalkyl group. Examples
include: -O-CH -CH -CH , -CH -CH CH -OH, -CH -CH -NH-CH , -CH -S-CH -CH , -CH CH -S(=O)-C
2 2 3 2 2 2 2 2 3 2 2 3 2 2
H , and -CH CH -O-CH CH -O-CH . Up to two heteroatoms may be consecutive, such as, for
3 2 2 2 2 3
example, -CH -NH-OCH , or –CH -CH -S-S-CH .
2 3 2 2 3
A “heterocycloalkyl” ring is a cycloalkyl ring containing at least one heteroatom. A
heterocycloalkyl ring can also be termed a “heterocyclyl,” described below.
The term “heteroalkenyl” by itself or in combination with another term means, unless otherwise
stated, a stable straight or branched chain monounsaturated or di-unsaturated hydrocarbon group consisting
of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O,
N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen
heteroatom may optionally be quaternized. Up to two heteroatoms may be placed consecutively. Examples
include -CH=CH-O-CH , -CH=CH-CH -OH, -CH -CH=N-OCH , -CH=CH-N(CH )-CH , -CH -CH=CH-
3 2 2 3 3 3 2
CH -SH, and and -CH=CH-O-CH CH -O-CH .
2 2 2 3
18253141_1 (GHMatters) P111789.NZ
Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms in the ring. Thus
aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl,
phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl
groups. In some embodiments, aryl groups contain about 6 to about 14 carbons in the ring portions of the
groups. Aryl groups can be unsubstituted or substituted, as defined above. Representative substituted aryl
groups can be mono-substituted or substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-, or
6-substituted phenyl or 2-8 substituted naphthyl groups, which can be substituted with carbon or non-
carbon groups such as those listed above.
Aralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl
group is replaced with a bond to an aryl group as defined above. Representative aralkyl groups include
benzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. Aralkenyl
group are alkenyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is
replaced with a bond to an aryl group as defined above.
Heterocyclyl groups or the term “heterocyclyl” includes aromatic and non-aromatic ring
compounds containing 3 or more ring members, of which, one or more is a heteroatom such as, but not
limited to, N, O, and S. Thus a heterocyclyl can be a heterocycloalkyl, or a heteroaryl, or if polycyclic, any
combination thereof. In some embodiments, heterocyclyl groups include 3 to about 20 ring members,
whereas other such groups have 3 to about 15 ring members. A heterocyclyl group designated as a C -
heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms
and four heteroatoms and so forth. Likewise a C -heterocyclyl can be a 5-ring with one heteroatom, a 6-
ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms
sums up to equal the total number of ring atoms. A heterocyclyl ring can also include one or more double
bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase “heterocyclyl group”
includes fused ring species including those comprising fused aromatic and non-aromatic groups. For
example, a dioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both
heterocyclyl groups within the meaning herein. The phrase also includes polycyclic ring systems
containing a heteroatom such as, but not limited to, quinuclidyl. Heterocyclyl groups can be unsubstituted,
or can be substituted as discussed above. Heterocyclyl groups include, but are not limited to, pyrrolidinyl,
piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,
thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl,
dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl,
benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl,
guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.
Representative substituted heterocyclyl groups can be mono-substituted or substituted more than once,
such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or
disubstituted with groups such as those listed above.
18253141_1 (GHMatters) P111789.NZ
Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one
or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroaryl rings can have 5 to
about 8-12 ring members. A heteroaryl group is a variety of a heterocyclyl group that possesses an
aromatic electronic structure. A heteroaryl group designated as a C -heteroaryl can be a 5-ring with two
carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth.
Likewise a C -heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth.
The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring
atoms. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl,
tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl,
azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl,
benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl,
guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.
Heteroaryl groups can be unsubstituted, or can be substituted with groups as is discussed above.
Representative substituted heteroaryl groups can be substituted one or more times with groups such as
those listed above.
Additional examples of aryl and heteroaryl groups include but are not limited to phenyl, biphenyl,
indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl,
N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl (2-thienyl, 3-
thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl,
isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-
imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazolyl, 1,2,3-triazolyl 1,2,3-
triazolyl, 1,2,4-triazolyl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4-
thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl,
-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3- pyridazinyl, 4-pyridazinyl, 5-pyridazinyl),
quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-
isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl),
benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl,
6-benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-
(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-
dihydro-benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl (2-benzo[b]thiophenyl, 3-
benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-
benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3-dihydro-benzo[b]thiophenyl), 3-(2,3-
dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl), 6-
(2,3-dihydro-benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl,
3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-
indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-
benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl
18253141_1 (GHMatters) P111789.NZ
(1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl,
-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-
carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepinyl, 5H-dibenz[b,f]azepineyl,
5H-dibenz[b,f]azepineyl, 5H-dibenz[b,f]azepineyl, 5H-dibenz[b,f]azepineyl), 10,11-dihydro-5H-
dibenz[b,f]azepine (10,11-dihydro-5H-dibenz[b,f]azepineyl, 10,11-dihydro-5H-dibenz[b,f]azepineyl,
,11-dihydro-5H-dibenz[b,f]azepineyl, 10,11-dihydro-5H-dibenz[b,f]azepineyl, 10,11-dihydro-5H-
dibenz[b,f]azepineyl), and the like.
Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of
an alkyl group as defined above is replaced with a bond to a heterocyclyl group as defined above.
Representative heterocyclyl alkyl groups include, but are not limited to, furanyl methyl, furanyl
methyl, pyridineyl methyl, tetrahydrofuranyl ethyl, and indolyl propyl.
Heteroarylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of
an alkyl group is replaced with a bond to a heteroaryl group as defined above.
The term “alkoxy” refers to an oxygen atom connected to an alkyl group, including a cycloalkyl
group, as are defined above. Examples of linear alkoxy groups include but are not limited to methoxy,
ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy include but are
not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of
cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,
cyclohexyloxy, and the like. An alkoxy group can include one to about 12-20 carbon atoms bonded to the
oxygen atom, and can further include double or triple bonds, and can also include heteroatoms. For
example, an allyloxy group is an alkoxy group within the meaning herein. A methoxyethoxy group is also
an alkoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent
atoms of a structures are substituted therewith.
The term “thioalkoxy” refers to an alkyl group previously defined attached to the parent molecular
moiety through a sulfur atom.
The term “glycosyloxyoxy” refers to a glycoside attached to the parent molecular moiety through
an oxygen atom.
The term “alkoxycarbonyl” represents as ester group; i.e. an alkoxy group, attached to the parent
molecular moiety through a carbonyl group such as methoxycarbonyl, ethoxycarbonyl, and the like.
[0070] The terms “halo” or “halogen” or “halide” by themselves or as part of another substituent mean,
unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or
bromine.
A “haloalkyl” group includes mono-halo alkyl groups, poly-halo alkyl groups wherein all halo
atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by
halogen atoms, such as fluoro. Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-
dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, perfluorobutyl, and the like.
18253141_1 (GHMatters) P111789.NZ
A “haloalkoxy” group includes mono-halo alkoxy groups, poly-halo alkoxy groups wherein all
halo atoms can be the same or different, and per-halo alkoxy groups, wherein all hydrogen atoms are
replaced by halogen atoms, such as fluoro. Examples of haloalkoxy include trifluoromethoxy, 1,1-
dichloroethoxy, 1,2-dichloroethoxy, 1,3-dibromo-3,3-difluoropropoxy, perfluorobutoxy, and the like.
[0073] The term “(C -C )perfluoroalkyl,” wherein x < y, means an alkyl group with a minimum of x
carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine
atoms. Preferred is -(C -C )perfluoroalkyl, more preferred is -(C -C )perfluoroalkyl, most preferred is –
1 6 1 3
CF .
The term “(C -C )perfluoroalkylene,” wherein x < y, means an alkyl group with a minimum of x
carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine
atoms. Preferred is -(C -C )perfluoroalkylene, more preferred is -(C -C )perfluoroalkylene, most preferred
1 6 1 3
is –CF –.
The terms “aryloxy” and “arylalkoxy” refer to, respectively, an aryl group bonded to an oxygen
atom and an aralkyl group bonded to the oxygen atom at the alkyl moiety. Examples include but are not
limited to phenoxy, naphthyloxy, and benzyloxy.
An “acyl” group as the term is used herein refers to a group containing a carbonyl moiety wherein
the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is also bonded to another
carbon atom, which can be part of an alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like. In the special case wherein the carbonyl
carbon atom is bonded to a hydrogen, the group is a “formyl” group, an acyl group as the term is defined
herein. An acyl group can include 0 to about 12-20 additional carbon atoms bonded to the carbonyl group.
An acyl group can include double or triple bonds within the meaning herein. An acryloyl group is an
example of an acyl group. An acyl group can also include heteroatoms within the meaning here. A
nicotinoyl group (pyridylcarbonyl) group is an example of an acyl group within the meaning herein.
Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and
the like. When the group containing the carbon atom that is bonded to the carbonyl carbon atom contains a
halogen, the group is termed a “haloacyl” group. An example is a trifluoroacetyl group.
The term “amine” includes primary, secondary, and tertiary amines having, e.g., the formula
N(group) wherein each group can independently be H or non-H, such as alkyl, aryl, and the like. Amines
include but are not limited to R-NH , for example, alkylamines, arylamines, alkylarylamines; R NH
wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines,
heterocyclylamines and the like; and R N wherein each R is independently selected, such as
trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like. The term “amine” also
includes ammonium ions as used herein.
[0078] An “amino” group is a substituent of the form -NH , -NHR, -NR , -NR , wherein each R is
2 2 3
independently selected, and protonated forms of each, except for -NR , which cannot be protonated.
Accordingly, any compound substituted with an amino group can be viewed as an amine. An “amino
18253141_1 (GHMatters) P111789.NZ
group” within the meaning herein can be a primary, secondary, tertiary or quaternary amino group. An
“alkylamino” group includes a monoalkylamino, dialkylamino, and trialkylamino group.
An “ammonium” ion includes the unsubstituted ammonium ion NH , but unless otherwise
specified, it also includes any protonated or quaternarized forms of amines. Thus, trimethylammonium
hydrochloride and tetramethylammonium chloride are both ammonium ions, and amines, within the
meaning herein.
The term “amide” (or “amido”) includes C- and N-amide groups, i.e., -C(O)NR , and –NRC(O)R
groups, respectively. Amide groups therefore include but are not limited to primary carboxamide groups (-
C(O)NH ) and formamide groups (-NHC(O)H). A “carboxamido” or “aminocarbonyl” group is a group of
the formula C(O)NR , wherein R can be H, alkyl, aryl, etc.
The term “azido” refers to an N group. An “azide” can be an organic azide or can be a salt of the
azide (N ) anion. The term “nitro” refers to an NO group bonded to an organic moiety. The term
“nitroso” refers to an NO group bonded to an organic moiety. The term nitrate refers to an ONO group
bonded to an organic moiety or to a salt of the nitrate (NO ) anion.
[0082] The term “urethane” (“carbamoyl” or “carbamyl”) includes N- and O-urethane groups,
i.e., -NRC(O)OR and –OC(O)NR groups, respectively.
The term “sulfonamide” (or “sulfonamido”) includes S- and N-sulfonamide groups, i.e., -SO NR
and –NRSO R groups, respectively. Sulfonamide groups therefore include but are not limited to sulfamoyl
groups (-SO NH ). An organosulfur structure represented by the formula –S(O)(NR)– is understood to
refer to a sulfoximine, wherein both the oxygen and the nitrogen atoms are bonded to the sulfur atom,
which is also bonded to two carbon atoms.
The term “amidine” or “amidino” includes groups of the formula -C(NR)NR . Typically, an
amidino group is –C(NH)NH .
The term “guanidine” or “guanidino” includes groups of the formula -NRC(NR)NR . Typically, a
guanidino group is –NHC(NH)NH .
The term “ring derived from a sugar” refers to a compound that forms a ring by removing the
hydrogen atoms from two hydroxyl groups of any sugar.
A “salt” as is well known in the art includes an organic compound such as a carboxylic acid, a
sulfonic acid, or an amine, in ionic form, in combination with a counterion. For example, acids in their
anionic form can form salts with cations such as metal cations, for example sodium, potassium, and the
like; with ammonium salts such as NH or the cations of various amines, including tetraalkyl ammonium
salts such as tetramethylammonium, or other cations such as trimethylsulfonium, and the like. A
“pharmaceutically acceptable” or “pharmacologically acceptable” salt is a salt formed from an ion that has
been approved for human consumption and is generally non-toxic, such as a chloride salt or a sodium salt.
A “zwitterion” is an internal salt such as can be formed in a molecule that has at least two ionizable
groups, one forming an anion and the other a cation, which serve to balance each other. For example,
amino acids such as glycine can exist in a zwitterionic form. A “zwitterion” is a salt within the meaning
18253141_1 (GHMatters) P111789.NZ
herein. The compounds described herein may take the form of salts. The term “salts” embraces addition
salts of free acids or free bases which are compounds described herein. Salts can be “pharmaceutically-
acceptable salts.” The term “pharmaceutically-acceptable salt” refers to salts which possess toxicity
profiles within a range that affords utility in pharmaceutical applications. Pharmaceutically unacceptable
salts may nonetheless possess properties such as high crystallinity, which have utility in the practice of the
present disclosure, such as for example utility in process of synthesis, purification or formulation of
compounds of the present disclosure.
Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid
or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric,
carbonic, sulfuric, and phosphoric acids. Appropriate organic acids may be selected from aliphatic,
cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids,
examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric,
citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic,
4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic,
benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic,
sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic, galactaric and
galacturonic acid. Examples of pharmaceutically unacceptable acid addition salts include, for example,
perchlorates and tetrafluoroborates.
Suitable pharmaceutically acceptable base addition salts of compounds of the present disclosure
include, for example, metallic salts including alkali metal, alkaline earth metal and transition metal salts
such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable
base addition salts also include organic salts made from basic amines such as, for example,
N,N’-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine
(N-methylglucamine) and procaine. Examples of pharmaceutically unacceptable base addition salts
include lithium salts and cyanate salts. Although pharmaceutically unacceptable salts are not generally
useful as medicaments, such salts may be useful, for example as intermediates in the synthesis of Formula
(I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc) compounds, for
example in their purification by recrystallization. All of these salts may be prepared by conventional means
from the corresponding compound according to Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc),
(IV), (IVa)-(IVc), (V), or (Va)-(Vc) by reacting, for example, the appropriate acid or base with the
compound according to Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or
(Va)-(Vc). The term “pharmaceutically acceptable salts” refers to nontoxic inorganic or organic acid
and/or base addition salts, see, for example, Lit et al., Salt Selection for Basic Drugs (1986), Int J. Pharm.,
33, 201-217, incorporated by reference herein.
[0090] A “hydrate” is a compound that exists in a composition with water molecules. The composition
can include water in stoichiometic quantities, such as a monohydrate or a dihydrate, or can include water
18253141_1 (GHMatters) P111789.NZ
in random amounts. As the term is used herein a “hydrate” refers to a solid form, i.e., a compound in
water solution, while it may be hydrated, is not a hydrate as the term is used herein.
A “solvate” is a similar composition except that a solvent other that water replaces the water. For
example, methanol or ethanol can form an “alcoholate”, which can again be stoichiometic or non-
stoichiometric. As the term is used herein a “solvate” refers to a solid form, i.e., a compound in solution in
a solvent, while it may be solvated, is not a solvate as the term is used herein.
A “prodrug” as is well known in the art is a substance that can be administered to a patient where
the substance is converted in vivo by the action of biochemicals within the patients body, such as enzymes,
to the active pharmaceutical ingredient. Examples of prodrugs include esters of carboxylic acid groups,
which can be hydrolyzed by endogenous esterases as are found in the bloodstream of humans and other
mammals. Further examples examples of prodrugs include boronate esters which can be hydrolyzed under
physiological conditions to afford the corresponding boronic acid. Conventional procedures for the
selection and preparation of suitable prodrug derivatives are described, for example, in “Design of
Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.
[0093] In addition, where features or aspects of the present disclosure are described in terms of Markush
groups, those skilled in the art will recognize that the presently described compounds is also thereby
described in terms of any individual member or subgroup of members of the Markush group. For example,
if X is described as selected from the group consisting of bromine, chlorine, and iodine, claims for X being
bromine and claims for X being bromine and chlorine are fully described. Moreover, where features or
aspects of the present disclosure are described in terms of Markush groups, those skilled in the art will
recognize that the present disclosure is also thereby described in terms of any combination of individual
members or subgroups of members of Markush groups. Thus, for example, if X is described as selected
from the group consisting of bromine, chlorine, and iodine, and Y is described as selected from the group
consisting of methyl, ethyl, and propyl, claims for X being bromine and Y being methyl are fully
described.
If a value of a variable that is necessarily an integer, e.g., the number of carbon atoms in an alkyl
group or the number of substituents on a ring, is described as a range, e.g., 0-4, what is meant is that the
value can be any integer between 0 and 4 inclusive, i.e., 0, 1, 2, 3, or 4.
In various embodiments, the compound or set of compounds, such as are used in the inventive
methods, can be any one of any of the combinations and/or sub-combinations of the above-listed
embodiments.
In various embodiments, a compound as shown in any of the Examples, or among the exemplary
compounds, is provided.
Provisos may apply to any of the disclosed categories or embodiments wherein any one or more of
the other above disclosed embodiments or species may be excluded from such categories or embodiments.
The present disclosure further embraces isolated compounds according to Formula (I), (Ia)-(If),
(II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc). The expression “isolated
18253141_1 (GHMatters) P111789.NZ
compound” refers to a preparation of a compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-
(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc), or a mixture of compounds according to Formula (I), (Ia)-(If),
(II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc), wherein the isolated compound has
been separated from the reagents used, and/or byproducts formed, in the synthesis of the compound or
compounds. “Isolated” does not mean that the preparation is technically pure (homogeneous), but it is
sufficiently pure to compound in a form in which it can be used therapeutically. Preferably an “isolated
compound” refers to a preparation of a compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-
(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc) or a mixture of compounds according to Formula (I), (Ia)-(If),
(II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc), which contains the named
compound or mixture of compounds according to Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc),
(IV), (IVa)-(IVc), (V), or (Va)-(Vc) in an amount of at least 10 percent by weight of the total weight.
Preferably the preparation contains the named compound or mixture of compounds in an amount of at least
50 percent by weight of the total weight; more preferably at least 80 percent by weight of the total weight;
and most preferably at least 90 percent, at least 95 percent or at least 98 percent by weight of the total
weight of the preparation.
The compounds described herein and intermediates may be isolated from their reaction mixtures
and purified by standard techniques such as filtration, liquid-liquid extraction, solid phase extraction,
distillation, recrystallization or chromatography, including flash column chromatography, or HPLC.
Isomerism and Tautomerism in Compounds Described Herein
Tautomerism
Within the present disclosure it is to be understood that a compound of Formula (I), (Ia)-(If),
(II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc) or a salt thereof may exhibit the
phenomenon of tautomerism whereby two chemical compounds that are capable of facile interconversion
by exchanging a hydrogen atom between two atoms, to either of which it forms a covalent bond. Since the
tautomeric compounds exist in mobile equilibrium with each other they may be regarded as different
isomeric forms of the same compound. It is to be understood that the formulae drawings within this
specification can represent only one of the possible tautomeric forms. However, it is also to be understood
that the present disclosure encompasses any tautomeric form, and is not to be limited merely to any one
tautomeric form utilized within the formulae drawings. The formulae drawings within this specification
can represent only one of the possible tautomeric forms and it is to be understood that the specification
encompasses all possible tautomeric forms of the compounds drawn not just those forms which it has been
convenient to show graphically herein. For example, tautomerism may be exhibited by a pyrazolyl group
bonded as indicated by the wavy line. While both substituents would be termed a 4-pyrazolyl group, it is
evident that a different nitrogen atom bears the hydrogen atom in each structure.
18253141_1 (GHMatters) P111789.NZ
Such tautomerism can also occur with substituted pyrazoles such as 3-methyl, 5-methyl, or 3,5-
dimethylpyrazoles, and the like. Another example of tautomerism is amido-imido (lactam-lactim when
cyclic) tautomerism, such as is seen in heterocyclic compounds bearing a ring oxygen atom adjacent to a
ring nitrogen atom. For example, the equilibrium:
O OH
HN N
is an example of tautomerism. Accordingly, a structure depicted
herein as one tautomer is intended to also include the other tautomer.
Optical Isomerism
It will be understood that when compounds of the present disclosure contain one or more chiral
centers, the compounds may exist in, and may be isolated as pure enantiomeric or diastereomeric forms or
as racemic mixtures. The present disclosure therefore includes any possible enantiomers, diastereomers,
racemates or mixtures thereof of the compounds described herein.
The isomers resulting from the presence of a chiral center comprise a pair of
non-superimposable isomers that are called “enantiomers.” Single enantiomers of a pure compound are
optically active, i.e., they are capable of rotating the plane of plane polarized light. Single enantiomers are
designated according to the Cahn-Ingold-Prelog system. The priority of substituents is ranked based on
atomic weights, a higher atomic weight, as determined by the systematic procedure, having a higher
priority ranking. Once the priority ranking of the four groups is determined, the molecule is oriented so
that the lowest ranking group is pointed away from the viewer. Then, if the descending rank order of the
other groups proceeds clockwise, the molecule is designated (R) and if the descending rank of the other
groups proceeds counterclockwise, the molecule is designated (S). In the example below, the
Cahn-Ingold-Prelog ranking is A > B > C > D. The lowest ranking atom, D is oriented away from the
viewer.
(R) configuration (S) configuration
[00104] The present disclosure is meant to encompass diastereomers as well as their racemic and
resolved, diastereomerically and enantiomerically pure forms and salts thereof. Diastereomeric pairs may
be resolved by known separation techniques including normal and reverse phase chromatography, and
crystallization.
“Isolated optical isomer” means a compound which has been substantially purified from the
corresponding optical isomer(s) of the same formula. Preferably, the isolated isomer is at least about 80%,
more preferably at least 90% pure, even more preferably at least 98% pure, most preferably at least about
99% pure, by weight.
18253141_1 (GHMatters) P111789.NZ
Isolated optical isomers may be purified from racemic mixtures by well-known chiral separation
techniques. According to one such method, a racemic mixture of a compound described herein, or a chiral
intermediate thereof, is separated into 99% wt.% pure optical isomers by HPLC using a suitable chiral
column, such as a member of the series of DAICEL CHIRALPAK family of columns (Daicel Chemical
Industries, Ltd., Tokyo, Japan). The column is operated according to the manufacturer’s instructions.
Rotational Isomerism
It is understood that due to chemical properties (i.e., resonance lending some double bond
character to the C-N bond) of restricted rotation about the amide bond linkage (as illustrated below) it is
possible to observe separate rotamer species and even, under some circumstances, to isolate such species
(see below). It is further understood that certain structural elements, including steric bulk or substituents on
the amide nitrogen, may enhance the stability of a rotamer to the extent that a compound may be isolated
as, and exist indefinitely, as a single stable rotamer. The present disclosure therefore includes any possible
stable rotamers of formula (I) which are biologically active in the treatment of cancer or other proliferative
disease states.
hindered rotation
Regioisomerism
In some embodiments, the compounds described herein have a particular spatial arrangement of
substituents on the aromatic rings, which is related to the structure activity relationship demonstrated by
the compound class. Often such substitution arrangement is denoted by a numbering system; however,
numbering systems are often not consistent between different ring systems. In six-membered aromatic
systems, the spatial arrangements are specified by the common nomenclature “para” for 1,4-substitution,
“meta” for 1,3-substitution and “ortho” for 1,2-substitution as shown below.
"para-" "meta-" "ortho-"
[00109] In various embodiments, the compound or set of compounds, such as are among the inventive
compounds or are used in the inventive methods, can be any one of any of the combinations and/or sub-
combinations of the above-listed embodiments.
Compounds
In one aspect described herein are compounds of Formula (I):
18253141_1 (GHMatters) P111789.NZ
(R )
(R )
18 16
R R N
O CN
Z X N
17 9 R
11 12
Formula (I);
wherein:
1 2 23
R and R are each independently H, -(C -C )alkyl, -(C -C )alkyl-OR , -CH CH(OH)CH NH , -
1 6 1 6 2 2 2
CH CH(heterocycloalkyl)CH NH , -CH C(O)NH , -CH C(O)N(H)CH CN, -(C -C )alkyl-C(O)OR , -
2 2 2 2 2 2 2 1 6
21 22 25 26 23 21 22
(C -C )alkyl-NR R , -(C -C )alkyl-C(O)NR R , -(C -C )alkyl-N(R )C(O)(C -C )alkylNR R , -
1 6 1 6 1 6 1 6
23 23
(C -C )alkyl-N(R )C(O)(C -C )alkyl, -(C -C )alkyl-C(O)N(R )(C -C )alkyl, -(C -C )alkyl-
1 6 1 6 1 6 1 6 1 6
23 23 21 22
C(O)N(R )(C -C )alkyl-heterocycloalkyl, -(C -C )alkyl-NR C(=NH)NR R , -(C -C )alkyl-
1 6 1 6 1 6
23 23 21 22
NR C(=NH)R , -(C -C )alkyl-[(C -C )alkyl-NR R ] , -(C -C )heteroalkyl, or optionally substituted
1 6 1 6 2 1 6
heterocycloalkyl;
or R and R and the atoms to which they are attached form an optionally substituted heterocycloalkyl ring;
R is H or -(C -C )alkyl;
R is H, -(C -C )alkyl, -(C -C )alkyl-OH, -(C -C )cycloalkyl, or -C(O)NH ;
1 6 1 6 3 6 2
or R and R are combined to form a heterocycloalkyl ring;
R is H or -(C -C )alkyl;
or R and R and the carbon atom to which they are attached form a cyclopropyl ring;
6 7 8
R , R , and R are each independently H, fluoro, hydroxyl, amino, optionally substituted alkyl, optionally
substituted heteroalkyl, or -(C -C )alkyl;
R is H, -(C -C )alkyl, -(C -C )haloalkyl, or -(C -C )cycloalkyl;
1 6 1 6 3 6
R is H, -(C -C )alkyl, -(C -C )haloalkyl, or -(C -C )cycloalkyl;
1 6 1 6 3 6
9 10
or R and R are combined to form a heterocycloalkyl or cycloalkyl ring
11 12 23 23
R and R are each independently H, -NH , -(C -C )alkyl, -(C -C )alkyl-OR , -(C -C )alkyl-SR , -(C -
2 1 6 1 6 1 6 1
23 21 22 23 23
C )alkyl-C(O)OR , -(C -C )alkyl-NR R , -(C -C )alkyl-NR OR , -(C -C )alkyl-
6 1 6 1 6 1 6
23 23 25 26
NHC(O)NR OR , -(C -C )alkyl-O-(C -C )alkyl-NR R , -(C -C )alkyl-CN, -(C -C )alkyl-
1 6 1 6 1 6 1 6
23 23 25 26
NR C(O)R , -(C -C )alkyl-C(O)NR R , -(C -C )heteroalkyl-CO H, -(C -C )alkyl-S(O)(C -C )alkyl,
1 6 1 6 2 1 6 1 6
-(C -C )alkyl-N(H)CH=NH, -(C -C )alkyl-C(NH )=NH, -(C -C )alkyl-N(H)C(=NH)NH , -(C -
1 6 1 6 2 1 6 2 1
26 25 26
C )alkyl-N(H)S(O) NR R , -(C -C )alkyl-N(H)S(O) (C -C )alkyl, -(C -C )alkyl-N(H)-C(O)NR R ,
6 2 1 6 2 1 6 1 6
-(C -C )alkylC(O)N(H)[optionally substituted(C -C )alkyl]-OR , -(C -C )alkylN(H)C(O)(C -
1 6 2 6 1 6 1
23 25 26
C )alkyl-OR , -(C -C )alkylC(O)N(H)heterocycloalkyl, -(C -C )alkylC(O)NR R , -(C -C )alkyl-
6 1 6 1 6 1 6
26 25 26
N(H)-C(O)-(C -C )alkyl-NR R , -(C -C )alkyl-N(H)-(C -C )alkylC(O)NR R , -(C -C )alkyl-
1 6 1 6 1 6 1 6
18253141_1 (GHMatters) P111789.NZ
heterocycloalkyl, optionally substituted -(C -C )alkyl-N(H)heterocycloalkyl, or -(C -C )alkyl-
1 6 1 6
heteroaryl;
11 18 12
or R and R are combined to form an optionally substituted heterocycloalkyl ring; and R is H;
16 17 18 23
R , R , R , and R are each independently H, -(C -C )alkyl, -(C -C )cycloalkyl, -(C -C )alkyl-OR , -
1 6 3 6 1 6
23 21 22
(C -C )alkyl-C(O)OR , or -(C -C )alkyl-NR R ;
1 6 1 6
X is optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, optionally substituted -(C -
1 6 2 6 2 6 3
C )cycloalkyl-, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally
24 24
substituted heteroaryl, -O-(C -C )alkyl-, -N(R )(C -C )alkyl-, -N(R )(C -C )aryl-, or -SO (C -
1 6 1 6 6 10 2 1
C )alkyl-;
Y is a bond, -O-, -S-, optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, -(C -
1 6 2 6 2 6 1
24 24 24
C )alkyl-N(R )(C -C )alkyl-, -O-(C -C )alkyl-, -O(C -C )aryl-, -N(R )(C -C )alkyl-, -N(R )SO (C -
6 1 6 1 6 6 10 1 6 2 1
C )alkyl-, -N(R )C(O)(C -C )alkyl-, -C(O)(C -C )alkyl-, -S(C -C )alkyl-, -SO (C -C )alkyl-, -
6 1 6 1 6 1 6 2 1 6
C(O)NH(C -C )alkyl-, optionally substituted -(C -C )cycloalkyl-, optionally substituted -
1 6 3 7
24 24 24
C(O)N(R )aryl-, optionally substituted -N(R )C(O)aryl-, optionally substituted -N(R )SO aryl-,
optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Z is H, halogen, -NH , -CN, -CF , -CO H, -(C -C )alkyl, -(C -C )alkenyl, -CH=((C -C )cycloalkyl), -
2 3 2 1 12 2 12 3 7
26
(C -C )alkynyl, -C(O)NR R , -O-(C -C )alkyl, -S-(C -C )alkyl, -O-(C -C )[optionally substituted
2 12 1 12 1 12 3 10
23 23
(C -C )cycloalkyl], -O-(C -C )alkyl-OR , -(C -C )alkyl-OR , -(C -C )alkyl-CN, -S-(C -C )alkyl, -
3 7 1 6 1 12 1 12 1 12
24 24
N(R )(C -C )alkyl, -N(R )C(O)(C -C )alkyl, optionally substituted -(C -C )cycloalkyl, -(C -
1 12 1 12 3 7 1
C )alkyl-(C -C )cycloalkyl, -(C -C )alkyl-heterocycloalkyl, optionally substituted heterocycloalkyl,
6 3 7 1 6
optionally substituted aryl, or optionally substituted heteroaryl;
21 22
each R and R is independently H, -(C -C )alkyl, -(C -C )heteroalkyl, -(C -C )alkyl-CO H, -C(O)(C -
1 6 1 6 1 6 2 1
)alkyl, -C(O)O(C -C )alkyl, -C(O)O(C -C )haloalkyl, -C(=NH)(C -C )alkyl, -C(=NH)N(R ) , -
6 1 6 1 6 1 6 2
31 31 21 22
C(O)N(R ) , or -SO N(R ) ; or R and R and the nitrogen atom to which they are attached form a
2 2 2
heterocycloalkyl ring;
31 31
each R is independently H or -(C -C )alkyl; or two R and the nitrogen atom to which they are attached
form a heterocycloalkyl ring;
each R is independently H or -(C -C )alkyl;
each R is independently H or -(C -C )alkyl;
26
each R and R is independently H or optionally substituted -(C -C )alkyl;
26
or R and R and the nitrogen atom to which they are attached form a heterocycloalkyl ring;
27 23 24 23 23 24
each R is independently halogen, -NR R , -NHC(O)R , -NHC(O)NR R , nitro, hydroxyl, optionally
substituted -(C -C )alkyl, optionally substituted -(C -C )heteroalkyl, optionally substituted -(C -
1 6 1 6 1
C )heteroalkyloxy, optionally substituted -(C -C )heteroalkylamino, -(C -C )alkoxy, -C(O)(C -
6 1 6 1 6 1
C )alkyl, or -S(O) (C -C )alkyl;
6 2 1 6
1 27
or R and R and the atoms to which they are attached form an optionally substituted 5- or 6-membered
heterocycloalkyl ring;
18253141_1 (GHMatters) P111789.NZ
28 23 24 23 23 24
each R is independently halogen, -NR R , -NHC(O)R , -NC(O)NR R , nitro, hydroxyl, optionally
substituted -(C -C )alkyl, optionally substituted -(C -C )heteroalkyl, optionally substituted -(C -
1 6 1 6 1
C )heteroalkyloxy, optionally substituted -(C -C )heteroalkylamino, -(C -C )alkoxy, -C(O)(C -
6 1 6 1 6 1
C )alkyl, or -S(O) (C -C )alkyl;
6 2 1 6
2 28
or R and R and the atoms to which they are attached form an optionally substituted 5- or 6-membered
heterocycloalkyl ring;
p is 0, 1, or 2; and
q is 0, 1, or 2;
or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
6 7 8
[00111] In one embodiment is a compound of Formula (I) wherein R , R , and R are H.
16
In another embodiment is a compound of Formula (I) wherein R and R are H.
In one embodiment is a compound of Formula (I) wherein R is -(C -C )alkyl. In another
embodiment is a compound of Formula (I) wherein R is -CH . In another embodiment is a compound of
17 17
Formula (I) wherein R is -CH CH . In another embodiment is a compound of Formula (I) wherein R is
-(C -C )cycloalkyl. In another embodiment is a compound of Formula (I) wherein R is cyclopropyl. In
17 23
another embodiment is a compound of Formula (I) wherein R is -(C -C )alkyl-C(O)OR . In another
embodiment is a compound of Formula (I) wherein R is -CH CH OH. In another embodiment is a
17 21 22
compound of Formula (I) wherein R is -(C -C )alkyl-NR R . In another embodiment is a compound of
Formula (I) wherein R is -CH CH NH . In another embodiment is a compound of Formula (I) wherein
2 2 2
R is H.
In another embodiment is a compound of Formula (I) wherein R is H.
In another embodiment is a compound of Formula (I) wherein R is H.
In another embodiment is a compound of Formula (I) wherein R is H.
In another embodiment is a compound of Formula (I) wherein R is H. In another embodiment is
a compound of Formula (I) wherein R is -(C -C )alkyl. In another embodiment is a compound of Formula
(I) wherein R is -CH . In another embodiment is a compound of Formula (I) wherein R is -CH CH . In
3 2 3
another embodiment is a compound of Formula (I) wherein R is -(C -C )alkyl-OH. In another
embodiment is a compound of Formula (I) wherein R is -CH OH. In another embodiment is a compound
of Formula (I) wherein R is -(C -C )cycloalkyl. In another embodiment is a compound of Formula (I)
wherein R is cyclopropyl. In another embodiment is a compound of Formula (I) wherein R is -C(O)NH .
3 4 5
In another embodiment is a compound of Formula (I) wherein R , R , and R are H.
In another embodiment is a compound of Formula (I) wherein R and R and the carbon atom to
which they are attached form a cyclopropyl ring.
In another embodiment is a compound of Formula (I) wherein R is H.
9
[00121] In another embodiment is a compound of Formula (I) wherein R is H and R is -(C -C )alkyl.
9
In another embodiment is a compound of Formula (I) wherein R is H and R is -CH . In another
9
embodiment is a compound of Formula (I) wherein R is H and R is -CH CH . In another embodiment is
18253141_1 (GHMatters) P111789.NZ
9
a compound of Formula (I) wherein R is H and R is -(C -C )haloalkyl. In another embodiment is a
9
compound of Formula (I) wherein R is H and R is -CH F. In another embodiment is a compound of
9
Formula (I) wherein R is H and R is -CHF . In another embodiment is a compound of Formula (I)
9
wherein R is H and R is -(C -C )cycloalkyl. In another embodiment is a compound of Formula (I)
9 10
wherein R is H and R is cyclopropyl. In another embodiment is a compound of Formula (I) wherein R
is H and R is H.
In another embodiment is a compound of Formula (I) wherein R is H.
12 11
In another embodiment is a compound of Formula (I) wherein R is H and R is -(C -C )alkyl.
12 11
In another embodiment is a compound of Formula (I) wherein R is H and R is -CH . In another
12 11 23
embodiment is a compound of Formula (I) wherein R is H and R is -(C -C )alkyl-OR . In another
12 11
embodiment is a compound of Formula (I) wherein R is H and R is -CH OH. In another embodiment is
12 11
a compound of Formula (I) wherein R is H and R is -CH CH OH. In another embodiment is a
12 11
compound of Formula (I) wherein R is H and R is -(C -C )alkyl. In another embodiment is a compound
12 11 21 22
of Formula (I) wherein R is H and R is -(C -C )alkyl-NR R . In another embodiment is a compound
12 11
of Formula (I) wherein R is H and R is -(C -C )alkyl-NH . In another embodiment is a compound of
1 6 2
12 11
Formula (I) wherein R is H and R is -CH NH . In another embodiment is a compound of Formula (I)
12 11
wherein R is H and R is -CH CH NH . In another embodiment is a compound of Formula (I) wherein
2 2 2
12 11 12
is H and R is -CH CH CH NH . In another embodiment is a compound of Formula (I) wherein R is
2 2 2 2
11 12
H and R is -CH CH CH CH NH . In another embodiment is a compound of Formula (I) wherein R is H
2 2 2 2 2
11 12
and R is -(C -C )alkyl-CN. In another embodiment is a compound of Formula (I) wherein R is H and
11 12 11
R is -CH CN. In another embodiment is a compound of Formula (I) wherein R is H and R is -(C -
26 12 11
C )alkyl-C(O)NR R . In another embodiment is a compound of Formula (I) wherein R is H and R is -
12 11
CH C(O)NH . In another embodiment is a compound of Formula (I) wherein R is H and R is -
12 11
CH CH C(O)NH . In another embodiment is a compound of Formula (I) wherein R is H and R is -(C -
2 2 2 1
12 11
C )alkyl-heteroaryl. In another embodiment is a compound of Formula (I) wherein R is H and R is -(C -
26 12
C )alkyl-N(H)S(O) NR R . In another embodiment is a compound of Formula (I) wherein R is H and
11 12 11
R is -CH N(H)S(O) NH . In another embodiment is a compound of Formula (I) wherein R is H and R
2 2 2
is H.
11 18
In another embodiment is a compound of Formula (I) wherein R and R are combined to form
an optionally substituted heterocycloalkyl ring and R is H.
In another embodiment is a compound of Formula (I) wherein p is 1 and R is halogen. In
another embodiment is a compound of Formula (I) wherein p is 1 and R is optionally substituted -(C -
C )alkyl. In another embodiment is a compound of Formula (I) wherein q is 0, p is 1 and R is halogen. In
another embodiment is a compound of Formula (I) wherein q is 0, p is 1 and R is optionally substituted -
(C -C )alkyl. In another embodiment is a compound of Formula (I) wherein q is 1 and R is halogen. In
another embodiment is a compound of Formula (I) wherein q is 1 and R is optionally substituted -(C -
C )alkyl. In another embodiment is a compound of Formula (I) wherein p is 0, q is 1 and R is halogen. In
18253141_1 (GHMatters) P111789.NZ
another embodiment is a compound of Formula (I) wherein p is 0, q is 1 and R is optionally substituted -
(C -C )alkyl.
In another embodiment is a compound of Formula (I) wherein p is 0, and q is 0.
In another embodiment is a compound of Formula (I) wherein R and R are each independently
21 22 1 2
H or -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (I) wherein R and R are
each H. In another embodiment is a compound of Formula (I) wherein R and R are each independently -
21 22 1 2
(C -C )alkyl-NR R . In another embodiment is a compound of Formula (I) wherein R is H, and R is -
21 22 1
(C -C )alkyl-NR R . In another embodiment is a compound of Formula (I) wherein R is -(C -C )alkyl-
1 6 1 6
21 22 2 1 2
NR R , and R is H. In another embodiment is a compound of Formula (I) wherein R is H, and R is -
CH CH NH . In another embodiment is a compound of Formula (I) wherein R is -CH CH NH , and R is
2 2 2 2 2 2
H. In another embodiment is a compound of Formula (I) wherein R and R are each -CH CH NH . In a
2 2 2
1 21 22 2
further embodiment is a compound of Formula (I) wherein R is -(C -C )alkyl-NR R and R is H. In a
further embodiment is a compound of Formula (I) wherein R is -CH CH NH and R is H. In a further
2 2 2
1 2 21 22
embodiment is a compound of Formula (I) wherein R is H and R is -(C -C )alkyl-NR R . In a further
embodiment is a compound of Formula (I) wherein R is H and R is -CH CH NH . In a further
2 2 2
embodiment is a compound of Formula (I) wherein R and R and the atoms to which they are attached
form an optionally substituted heterocycloalkyl ring. In another embodiment is a compound of Formula (I)
1 2 21 22
wherein R and R are each independently H, -(C -C )alkyl-NR R , or -CH CH(OH)CH NH . In another
1 6 2 2 2
embodiment is a compound of Formula (I) wherein R and R are each independently -
CH CH(OH)CH NH . In another embodiment is a compound of Formula (I) wherein R is H, and R is -
2 2 2
CH CH(OH)CH NH . In another embodiment is a compound of Formula (I) wherein R is -
2 2 2
CH CH(OH)CH NH , and R is H.
2 2 2
In another embodiment is a compound of Formula (I) wherein X is optionally substituted aryl. In
a further embodiment is a compound of Formula (I) wherein X is optionally substituted phenyl. In another
embodiment is a compound of Formula (I) wherein X is optionally substituted heteroaryl. In a further
embodiment is a compound of Formula (I) wherein X is disubstituted heteroaryl. In a further embodiment
is a compound of Formula (I) wherein X is heteroaryl disubstituted with substituents each independently
selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-(C -C )alkyl,
1 6 1 6
23 25 26
OR , -NR R , and -NO . In a further embodiment is a compound of Formula (I) wherein X is heteroaryl
disubstituted with substituents each independently selected from -(C -C )alkyl. In a further embodiment is
a compound of Formula (I) wherein X is heteroaryl disubstituted with methyl. In a further embodiment is a
compound of Formula (I) wherein X is pyridinyl disubstituted with substituents each independently
selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-(C -C )alkyl,
1 6 1 6
23 25 26
OR , -NR R , or -NO . In a further embodiment is a compound of Formula (I) wherein X is pyridinyl
disubstituted with substituents each independently selected from -(C -C )alkyl. In a further embodiment is
a compound of Formula (I) wherein X is pyridinyl disubstituted with methyl. In a further embodiment is a
compound of Formula (I) wherein X is pyrimidinyl disubstituted with substituents each independently
18253141_1 (GHMatters) P111789.NZ
selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-(C -C )alkyl,
1 6 1 6
23 25 26
OR , -NR R , or -NO . In a further embodiment is a compound of Formula (I) wherein X is pyrimidinyl
disubstituted with substituents each independently selected from -(C -C )alkyl. In a further embodiment is
a compound of Formula (I) wherein X is pyrimidinyl disubstituted with methyl. In another embodiment is
a compound of Formula (I) wherein X is optionally substituted -(C -C )alkyl-.
In another embodiment is a compound of Formula (I) wherein Y is optionally substituted aryl. In
a further embodiment is a compound of Formula (I) wherein Y is optionally substituted phenyl. In another
embodiment is a compound of Formula (I) wherein Y is optionally substituted heteroaryl. In another
embodiment is a compound of Formula (I) wherein Y is optionally substituted -(C -C )alkyl-. In another
embodiment is a compound of Formula (I) wherein Y is optionally substituted (C -C )cycloalkyl-. In
another embodiment is a compound of Formula (I) wherein Y is optionally substituted heterocycloalkyl. In
another embodiment is a compound of Formula (I) wherein Y is -O-. In another embodiment is a
compound of Formula (I) wherein Y is -(C -C )alkynyl. In another embodiment is a compound of Formula
(I) wherein Y is -O-(C -C )alkyl-. In another embodiment is a compound of Formula (I) wherein Y is a
bond.
In another embodiment is a compound of Formula (I) wherein Z is -(C -C )alkyl. In a further
1 12
embodiment is a compound of Formula (I) wherein Z is n-butyl, isobutyl, or tert-butyl. In another
-C )alkyl. In another embodiment is a
embodiment is a compound of Formula (I) wherein Z is -O-(C
1 12
compound of Formula (I) wherein Z is -O-(C -C )cycloalkyl. In another embodiment is a compound of
Formula (I) wherein Z is -(C -C )alkenyl. In another embodiment is a compound of Formula (I) wherein Z
2 12
is optionally substituted aryl. In a further embodiment is a compound of Formula (I) wherein Z is
optionally substituted phenyl. In a further embodiment is a compound of Formula (I) wherein Z is phenyl
monsubstituted or disubstituted with a substituent independently selected from -(C -C )alkyl. In a further
embodiment is a compound of Formula (I) wherein Z is phenyl monosubstituted with n-butyl, isobutyl, or
tert-butyl. In a further embodiment is a compound of Formula (I) wherein Z is phenyl monosubstituted
with n-butyl. In a further embodiment is a compound of Formula (I) wherein Z is phenyl monosubstituted
with isobutyl. In a further embodiment is a compound of Formula (I) wherein Z is phenyl monosubstituted
with tert-butyl. In another embodiment is a compound of Formula (I) wherein Z is optionally substituted
heteroaryl. In another embodiment is a compound of Formula (I) wherein Z is optionally substituted -(C -
C )cycloalkyl. In another embodiment is a compound of Formula (I) wherein Z is optionally substituted
heterocycloalkyl. In another embodiment is a compound of Formula (I) wherein Z is halogen.
In another embodiment is a compound of Formula (I) wherein Z-Y-X- is not .
18253141_1 (GHMatters) P111789.NZ
In another embodiment is a compound of Formula (I) having the structure of Formula (Ia):
(R )
27 6
(R )
R R N
O CN
Z X N
17 9
O R R
11 12
Formula (Ia);
wherein:
1 2 23
R and R are each independently H, -(C -C )alkyl, -(C -C )alkyl-OR , -CH CH(OH)CH NH , -
1 6 1 6 2 2 2
CH CH(heterocycloalkyl)CH NH , -CH C(O)NH , -CH C(O)N(H)CH CN, -(C -C )alkyl-C(O)OR , -
2 2 2 2 2 2 2 1 6
21 22 25 26 23 21 22
(C -C )alkyl-NR R , -(C -C )alkyl-C(O)NR R , -(C -C )alkyl-N(R )C(O)(C -C )alkylNR R , -
1 6 1 6 1 6 1 6
23 23
(C -C )alkyl-N(R )C(O)(C -C )alkyl, -(C -C )alkyl-C(O)N(R )(C -C )alkyl, -(C -C )alkyl-
1 6 1 6 1 6 1 6 1 6
23 23 21 22
C(O)N(R )(C -C )alkyl-heterocycloalkyl, -(C -C )alkyl-NR C(=NH)NR R , -(C -C )alkyl-
1 6 1 6 1 6
23 23 21 22
NR C(=NH)R , -(C -C )alkyl-[(C -C )alkyl-NR R ] , -(C -C )heteroalkyl, or optionally substituted
1 6 1 6 2 1 6
heterocycloalkyl;
or R and R and the atoms to which they are attached form an optionally substituted heterocycloalkyl ring;
R is H or -(C -C )alkyl;
R is H, -(C -C )alkyl, -(C -C )alkyl-OH, -(C -C )cycloalkyl, or -C(O)NH ;
1 6 1 6 3 6 2
or R and R are combined to form a heterocycloalkyl ring;
R is H or -(C -C )alkyl;
or R and R and the carbon atom to which they are attached form a cyclopropyl ring;
6 7 8
R , R , and R are each independently H, fluoro, hydroxyl, amino, optionally substituted alkyl, heteroalkyl,
or -(C -C )alkyl;
R is H, -(C -C )alkyl, -(C -C )haloalkyl, or -(C -C )cycloalkyl;
1 6 1 6 3 6
R is H, -(C -C )alkyl, -(C -C )haloalkyl, or -(C -C )cycloalkyl;
1 6 1 6 3 6
9 10
or R and R are combined to form a heterocycloalkyl or cycloalkyl ring
11 12 23 23
R and R are each independently H, -NH , -(C -C )alkyl, -(C -C )alkyl-OR , -(C -C )alkyl-SR , -(C -
2 1 6 1 6 1 6 1
23 21 22 23 23
C )alkyl-C(O)OR , -(C -C )alkyl-NR R , -(C -C )alkyl-NR OR , -(C -C )alkyl-
6 1 6 1 6 1 6
23 23 25 26
NHC(O)NR OR , -(C -C )alkyl-O-(C -C )alkyl-NR R , -(C -C )alkyl-CN, -(C -C )alkyl-
1 6 1 6 1 6 1 6
23 23 25 26
NR C(O)R , -(C -C )alkyl-C(O)NR R , -(C -C )heteroalkyl-CO H, -(C -C )alkyl-S(O)(C -C )alkyl,
1 6 1 6 2 1 6 1 6
-(C -C )alkyl-N(H)CH=NH, -(C -C )alkyl-C(NH )=NH, -(C -C )alkyl-N(H)C(=NH)NH , -(C -
1 6 1 6 2 1 6 2 1
26 25 26
C )alkyl-N(H)S(O) NR R , -(C -C )alkyl-N(H)S(O) (C -C )alkyl, -(C -C )alkyl-N(H)-C(O)NR R ,
6 2 1 6 2 1 6 1 6
-(C -C )alkylC(O)N(H)[optionally substituted(C -C )alkyl]-OR , -(C -C )alkylN(H)C(O)(C -
1 6 2 6 1 6 1
23 25 26
C )alkyl-OR , -(C -C )alkylC(O)N(H)heterocycloalkyl, -(C -C )alkylC(O)NR R , -(C -C )alkyl-
6 1 6 1 6 1 6
18253141_1 (GHMatters) P111789.NZ
26 25 26
N(H)-C(O)-(C -C )alkyl-NR R , -(C -C )alkyl-N(H)-(C -C )alkylC(O)NR R , -(C -C )alkyl-
1 6 1 6 1 6 1 6
heterocycloalkyl, optionally substituted -(C -C )alkyl-N(H)heterocycloalkyl, or -(C -C )alkyl-
1 6 1 6
heteroaryl;
11 18 12
or R and R are combined to form an optionally substituted heterocycloalkyl ring; and R is H;
16 17 18 23
R , R , R , and R are each independently H, -(C -C )alkyl, -(C -C )cycloalkyl, -(C -C )alkyl-OR , -
1 6 3 6 1 6
23 21 22
(C -C )alkyl-C(O)OR , or -(C -C )alkyl-NR R ;
1 6 1 6
X is optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, optionally substituted -(C -
1 6 2 6 2 6 3
C )cycloalkyl-, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally
24 24
substituted heteroaryl, -O-(C -C )alkyl-, -N(R )(C -C )alkyl-, -N(R )(C -C )aryl-, or -SO (C -
1 6 1 6 6 10 2 1
C )alkyl-;
Y is a bond, -O-, -S-, optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, -(C -
1 6 2 6 2 6 1
24 24 24
C )alkyl-N(R )(C -C )alkyl-, -O-(C -C )alkyl-, -O(C -C )aryl-, -N(R )(C -C )alkyl-, -N(R )SO (C -
6 1 6 1 6 6 10 1 6 2 1
C )alkyl-, -N(R )C(O)(C -C )alkyl-, -C(O)(C -C )alkyl-, -S(C -C )alkyl-, -SO (C -C )alkyl-, -
6 1 6 1 6 1 6 2 1 6
C(O)NH(C -C )alkyl-, optionally substituted -(C -C )cycloalkyl-, optionally substituted -
1 6 3 7
24 24 24
C(O)N(R )aryl-, optionally substituted -N(R )C(O)aryl-, optionally substituted -N(R )SO aryl-,
optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Z is H, halogen, -NH , -CN, -CF , -CO H, -(C -C )alkyl, -(C -C )alkenyl, -CH=((C -C )cycloalkyl), -
2 3 2 1 12 2 12 3 7
26
(C -C )alkynyl, -C(O)NR R , -O-(C -C )alkyl, -S-(C -C )alkyl, -O-(C -C )[optionally substituted
2 12 1 12 1 12 3 10
23 23
(C -C )cycloalkyl], -O-(C -C )alkyl-OR , -(C -C )alkyl-OR , -(C -C )alkyl-CN, -S-(C -C )alkyl, -
3 7 1 6 1 12 1 12 1 12
24 24
N(R )(C -C )alkyl, -N(R )C(O)(C -C )alkyl, optionally substituted -(C -C )cycloalkyl, -(C -
1 12 1 12 3 7 1
C )alkyl-(C -C )cycloalkyl, -(C -C )alkyl-heterocycloalkyl, optionally substituted heterocycloalkyl,
6 3 7 1 6
optionally substituted aryl, or optionally substituted heteroaryl;
21 22
each R and R is independently H, -(C -C )alkyl, -(C -C )heteroalkyl, -(C -C )alkyl-CO H, -C(O)(C -
1 6 1 6 1 6 2 1
C )alkyl, -C(O)O(C -C )alkyl, -C(O)O(C -C )haloalkyl, -C(=NH)(C -C )alkyl, -C(=NH)N(R ) , -
6 1 6 1 6 1 6 2
31 31 21 22
C(O)N(R ) , or -SO N(R ) ; or R and R and the nitrogen atom to which they are attached form a
2 2 2
heterocycloalkyl ring;
31 31
each R is independently H or -(C -C )alkyl; or two R and the nitrogen atom to which they are attached
form a heterocycloalkyl ring;
each R is independently H or -(C -C )alkyl;
each R is independently H or -(C -C )alkyl;
26
each R and R is independently H or optionally substituted -(C -C )alkyl;
26
or R and R and the nitrogen atom to which they are attached form a heterocycloalkyl ring;
27 23 24 23 23 24
each R is independently halogen, -NR R , -NHC(O)R , -NHC(O)NR R , nitro, hydroxyl, optionally
substituted -(C -C )alkyl, optionally substituted -(C -C )heteroalkyl, optionally substituted -(C -
1 6 1 6 1
C )heteroalkyloxy, optionally substituted -(C -C )heteroalkylamino, -(C -C )alkoxy, -C(O)(C -
6 1 6 1 6 1
C )alkyl, or -S(O) (C -C )alkyl;
6 2 1 6
18253141_1 (GHMatters) P111789.NZ
1 27
or R and R and the atoms to which they are attached form an optionally substituted 5- or 6-membered
heterocycloalkyl ring;
28 23 24 23 23 24
each R is independently halogen, -NR R , -NHC(O)R , -NHC(O)NR R , nitro, hydroxyl, optionally
substituted -(C -C )alkyl, optionally substituted -(C -C )heteroalkyl, optionally substituted -(C -
1 6 1 6 1
C )heteroalkyloxy, optionally substituted -(C -C )heteroalkylamino, -(C -C )alkoxy, -C(O)(C -
6 1 6 1 6 1
C )alkyl, or -S(O) (C -C )alkyl;
6 2 1 6
2 28
or R and R and the atoms to which they are attached form an optionally substituted 5- or 6-membered
heterocycloalkyl ring;
p is 0, 1, or 2; and
q is 0, 1, or 2;
or a pharmaceutically acceptable salt, solvate, or prodrug thereof.In one embodiment is a
6 7 8
compound of Formula (Ia) wherein R , R , and R are H.
16
In another embodiment is a compound of Formula (Ia) wherein R and R are H.
In one embodiment is a compound of Formula (Ia) wherein R is -(C -C )alkyl. In another
embodiment is a compound of Formula (Ia) wherein R is -CH . In another embodiment is a compound of
17 17
Formula (Ia) wherein R is -CH CH . In another embodiment is a compound of Formula (Ia) wherein R
is -(C -C )cycloalkyl. In another embodiment is a compound of Formula (Ia) wherein R is cyclopropyl.
17 23
In another embodiment is a compound of Formula (Ia) wherein R is -(C -C )alkyl-C(O)OR . In another
embodiment is a compound of Formula (Ia) wherein R is -CH CH OH. In another embodiment is a
17 21 22
compound of Formula (Ia) wherein R is -(C -C )alkyl-NR R . In another embodiment is a compound of
Formula (Ia) wherein R is -CH CH NH . In another embodiment is a compound of Formula (Ia) wherein
2 2 2
R is H.
In another embodiment is a compound of Formula (Ia) wherein R is H.
In another embodiment is a compound of Formula (Ia) wherein R is H.
[00138] In another embodiment is a compound of Formula (Ia) wherein R is H.
In another embodiment is a compound of Formula (Ia) wherein R is H. In another embodiment
is a compound of Formula (Ia) wherein R is -(C -C )alkyl. In another embodiment is a compound of
Formula (Ia) wherein R is -CH . In another embodiment is a compound of Formula (Ia) wherein R is -
CH CH . In another embodiment is a compound of Formula (Ia) wherein R is -(C -C )alkyl-OH. In
2 3 1 6
another embodiment is a compound of Formula (Ia) wherein R is -CH OH. In another embodiment is a
compound of Formula (Ia) wherein R is -(C -C )cycloalkyl. In another embodiment is a compound of
Formula (Ia) wherein R is cyclopropyl. In another embodiment is a compound of Formula (Ia) wherein R
is -C(O)NH .
In another embodiment is a compound of Formula (Ia) wherein R and R and the carbon atom
to which they are attached form a cyclopropyl ring.
3 4 5
In another embodiment is a compound of Formula (Ia) wherein R , R , and R are H.
In another embodiment is a compound of Formula (Ia) wherein R is H.
18253141_1 (GHMatters) P111789.NZ
9
In another embodiment is a compound of Formula (Ia) wherein R is H and R is -(C -C )alkyl.
9
In another embodiment is a compound of Formula (Ia) wherein R is H and R is -CH . In another
9
embodiment is a compound of Formula (Ia) wherein R is H and R is -CH CH . In another embodiment
9
is a compound of Formula (Ia) wherein R is H and R is -(C -C )haloalkyl. In another embodiment is a
9
compound of Formula (Ia) wherein R is H and R is -CH F. In another embodiment is a compound of
9
Formula (Ia) wherein R is H and R is -CHF . In another embodiment is a compound of Formula (Ia)
9
wherein R is H and R is -(C -C )cycloalkyl. In another embodiment is a compound of Formula (Ia)
9 10
wherein R is H and R is cyclopropyl. In another embodiment is a compound of Formula (Ia) wherein R
is H and R is H.
[00144] In another embodiment is a compound of Formula (Ia) wherein R is H.
12 11
In another embodiment is a compound of Formula (Ia) wherein R is H and R is -(C -C )alkyl.
12 11
In another embodiment is a compound of Formula (Ia) wherein R is H and R is -CH . In another
12 11 23
embodiment is a compound of Formula (Ia) wherein R is H and R is -(C -C )alkyl-OR . In another
12 11
embodiment is a compound of Formula (Ia) wherein R is H and R is -CH OH. In another embodiment
12 11
is a compound of Formula (Ia) wherein R is H and R is -CH CH OH. In another embodiment is a
12 11
compound of Formula (Ia) wherein R is H and R is -(C -C )alkyl. In another embodiment is a
12 11 21 22
compound of Formula (Ia) wherein R is H and R is -(C -C )alkyl-NR R . In another embodiment is a
12 11
compound of Formula (Ia) wherein R is H and R is -(C -C )alkyl-NH . In another embodiment is a
1 6 2
12 11
compound of Formula (Ia) wherein R is H and R is -CH NH . In another embodiment is a compound of
12 11
Formula (Ia) wherein R is H and R is -CH CH NH . In another embodiment is a compound of Formula
2 2 2
12 11
(Ia) wherein R is H and R is -CH CH CH NH . In another embodiment is a compound of Formula (Ia)
2 2 2 2
12 11
wherein R is H and R is -CH CH CH CH NH . In another embodiment is a compound of Formula (Ia)
2 2 2 2 2
12 11
wherein R is H and R is -(C -C )alkyl-CN. In another embodiment is a compound of Formula (Ia)
12 11 12
wherein R is H and R is -CH CN. In another embodiment is a compound of Formula (Ia) wherein R is
11 25 26
H and R is -(C -C )alkyl-C(O)NR R . In another embodiment is a compound of Formula (Ia) wherein
12 11 12
R is H and R is -CH C(O)NH . In another embodiment is a compound of Formula (Ia) wherein R is H
11 12
and R is -CH CH C(O)NH . In another embodiment is a compound of Formula (Ia) wherein R is H and
2 2 2
11 12
R is -(C -C )alkyl-heteroaryl. In another embodiment is a compound of Formula (Ia) wherein R is H
11 25 26
and R is -(C -C )alkyl-N(H)S(O) NR R . In another embodiment is a compound of Formula (Ia)
1 6 2
12 11
wherein R is H and R is -CH N(H)S(O) NH . In another embodiment is a compound of Formula (Ia)
2 2 2
12 11
wherein R is H and R is H.
11 18
In another embodiment is a compound of Formula (Ia) wherein R and R are combined to
form an optionally substituted heterocycloalkyl ring and R is H.
In another embodiment is a compound of Formula (Ia) wherein p is 1 and R is halogen. In
another embodiment is a compound of Formula (Ia) wherein p is 1 and R is optionally substituted -(C -
C )alkyl. In another embodiment is a compound of Formula (Ia) wherein q is 0, p is 1 and R is halogen.
In another embodiment is a compound of Formula (Ia) wherein q is 0, p is 1 and R is optionally
18253141_1 (GHMatters) P111789.NZ
substituted -(C -C )alkyl. In another embodiment is a compound of Formula (Ia) wherein q is 1 and R is
halogen. In another embodiment is a compound of Formula (Ia) wherein q is 1 and R is optionally
substituted -(C -C )alkyl. In another embodiment is a compound of Formula (Ia) wherein p is 0, q is 1 and
28 28
R is halogen. In another embodiment is a compound of Formula (Ia) wherein p is 0, q is 1 and R is
optionally substituted -(C -C )alkyl.
In another embodiment is a compound of Formula (Ia) wherein p is 0, and q is 0.
In another embodiment is a compound of Formula (Ia) wherein R and R are each
21 22
independently H or -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (Ia) wherein
1 2 1 2
R and R are each H. In another embodiment is a compound of Formula (Ia) wherein R and R are each
21 22 1
independently -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (Ia) wherein R is
2 21 22 1
H, and R is -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (Ia) wherein R is -
21 22 2 1
(C -C )alkyl-NR R , and R is H. In another embodiment is a compound of Formula (Ia) wherein R is H,
and R is -CH CH NH . In another embodiment is a compound of Formula (Ia) wherein R is -
2 2 2
2 1 2
CH CH NH , and R is H. In another embodiment is a compound of Formula (Ia) wherein R and R are
2 2 2
each -CH CH NH . In a further embodiment is a compound of Formula (Ia) wherein R is -(C -C )alkyl-
2 2 2 1 6
21 22 2 1
NR R and R is H. In a further embodiment is a compound of Formula (Ia) wherein R is -CH CH NH
2 2 2
2 1 2
and R is H. In a further embodiment is a compound of Formula (Ia) wherein R is H and R is -(C -
21 22 1 2
)alkyl-NR R . In a further embodiment is a compound of Formula (Ia) wherein R is H and R is -
CH CH NH . In another embodiment is a compound of Formula (Ia) wherein R and R are each
2 2 2
21 22
independently H, -(C -C )alkyl-NR R , or -CH CH(OH)CH NH . In another embodiment is a compound
1 6 2 2 2
of Formula (Ia) wherein R and R are each independently -CH CH(OH)CH NH . In another embodiment
2 2 2
is a compound of Formula (Ia) wherein R is H, and R is -CH CH(OH)CH NH . In another embodiment
2 2 2
is a compound of Formula (Ia) wherein R is -CH CH(OH)CH NH , and R is H.
2 2 2
In a further embodiment is a compound of Formula (Ia) wherein R and R and the atoms to
which they are attached form an optionally substituted heterocycloalkyl ring.
In another embodiment is a compound of Formula (Ia) wherein X is optionally substituted aryl.
In a further embodiment is a compound of Formula (Ia) wherein X is optionally substituted phenyl. In
another embodiment is a compound of Formula (Ia) wherein X is optionally substituted heteroaryl. In a
further embodiment is a compound of Formula (Ia) wherein X is disubstituted heteroaryl. In a further
embodiment is a compound of Formula (Ia) wherein X is heteroaryl disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
23 25 26
(C -C )alkyl, OR , -NR R , and -NO . In a further embodiment is a compound of Formula (Ia) wherein
1 6 2
X is heteroaryl disubstituted with substituents each independently selected from -(C -C )alkyl. In a further
embodiment is a compound of Formula (Ia) wherein X is heteroaryl disubstituted with methyl. In a further
embodiment is a compound of Formula (Ia) wherein X is pyridinyl disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
23 25 26
(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound of Formula (Ia) wherein X
1 6 2
18253141_1 (GHMatters) P111789.NZ
is pyridinyl disubstituted with substituents each independently selected from -(C -C )alkyl. In a further
embodiment is a compound of Formula (Ia) wherein X is pyridinyl disubstituted with methyl. In a further
embodiment is a compound of Formula (Ia) wherein X is pyrimidinyl disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
23 25 26
(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound of Formula (Ia) wherein X
1 6 2
is pyrimidinyl disubstituted with substituents each independently selected from -(C -C )alkyl. In a further
embodiment is a compound of Formula (Ia) wherein X is pyrimidinyl disubstituted with methyl. In another
embodiment is a compound of Formula (Ia) wherein X is optionally substituted -(C -C )alkyl-.
In another embodiment is a compound of Formula (Ia) wherein Y is optionally substituted aryl.
In a further embodiment is a compound of Formula (Ia) wherein Y is optionally substituted phenyl. In
another embodiment is a compound of Formula (Ia) wherein Y is optionally substituted heteroaryl. In
another embodiment is a compound of Formula (Ia) wherein Y is optionally substituted -(C -C )alkyl-. In
another embodiment is a compound of Formula (Ia) wherein Y is optionally substituted (C -C )cycloalkyl-.
In another embodiment is a compound of Formula (Ia) wherein Y is optionally substituted
heterocycloalkyl. In another embodiment is a compound of Formula (Ia) wherein Y is -O-. In another
embodiment is a compound of Formula (Ia) wherein Y is -(C -C )alkynyl. In another embodiment is a
compound of Formula (Ia) wherein Y is -O-(C -C )alkyl-. In another embodiment is a compound of
Formula (Ia) wherein Y is a bond.
In another embodiment is a compound of Formula (Ia) wherein Z is -(C -C )alkyl. In a further
1 12
embodiment is a compound of Formula (Ia) wherein Z is n-butyl, isobutyl, or tert-butyl. In another
embodiment is a compound of Formula (Ia) wherein Z is -O-(C -C )alkyl. In another embodiment is a
1 12
compound of Formula (Ia) wherein Z is -O-(C -C )cycloalkyl. In another embodiment is a compound of
Formula (Ia) wherein Z is -(C -C )alkenyl. In another embodiment is a compound of Formula (Ia)
2 12
wherein Z is optionally substituted aryl. In a further embodiment is a compound of Formula (Ia) wherein Z
is optionally substituted phenyl. In a further embodiment is a compound of Formula (Ia) wherein Z is
phenyl monsubstituted or disubstituted with a substituent independently selected from -(C -C )alkyl. In a
further embodiment is a compound of Formula (Ia) wherein Z is phenyl monosubstituted with n-butyl,
isobutyl, or tert-butyl. In a further embodiment is a compound of Formula (Ia) wherein Z is phenyl
monosubstituted with n-butyl. In a further embodiment is a compound of Formula (Ia) wherein Z is phenyl
monosubstituted with isobutyl. In a further embodiment is a compound of Formula (Ia) wherein Z is
phenyl monosubstituted with tert-butyl. In another embodiment is a compound of Formula (Ia) wherein Z
is optionally substituted heteroaryl. In another embodiment is a compound of Formula (Ia) wherein Z is
optionally substituted -(C -C )cycloalkyl. In another embodiment is a compound of Formula (Ia) wherein
Z is optionally substituted heterocycloalkyl. In another embodiment is a compound of Formula (Ia)
wherein Z is halogen.
18253141_1 (GHMatters) P111789.NZ
In another embodiment is a compound of Formula (Ia) wherein Z-Y-X- is not
In another embodiment is a compound of Formula (I) having the structure of Formula (Ib):
Z X N O
O R O
Formula (Ib);
wherein:
1 2 23
R and R are each independently H, -(C -C )alkyl, -(C -C )alkyl-OR , -CH CH(OH)CH NH , -
1 6 1 6 2 2 2
CH CH(heterocycloalkyl)CH NH , -CH C(O)NH , -CH C(O)N(H)CH CN, -(C -C )alkyl-C(O)OR , -
2 2 2 2 2 2 2 1 6
21 22 25 26 23 21 22
(C -C )alkyl-NR R , -(C -C )alkyl-C(O)NR R , -(C -C )alkyl-N(R )C(O)(C -C )alkylNR R , -
1 6 1 6 1 6 1 6
23 23
(C -C )alkyl-N(R )C(O)(C -C )alkyl, -(C -C )alkyl-C(O)N(R )(C -C )alkyl, -(C -C )alkyl-
1 6 1 6 1 6 1 6 1 6
23 23 21 22
C(O)N(R )(C -C )alkyl-heterocycloalkyl, -(C -C )alkyl-NR C(=NH)NR R , -(C -C )alkyl-
1 6 1 6 1 6
23 23 21 22
NR C(=NH)R , -(C -C )alkyl-[(C -C )alkyl-NR R ] , -(C -C )heteroalkyl, or optionally substituted
1 6 1 6 2 1 6
heterocycloalkyl;
or R and R and the atoms to which they are attached form an optionally substituted heterocycloalkyl ring;
R is H, -(C -C )alkyl, -(C -C )alkyl-OH, -(C -C )cycloalkyl, or -C(O)NH ;
1 6 1 6 3 6 2
R is H or -(C -C )alkyl;
or R and R and the carbon atom to which they are attached form a cyclopropyl ring;
R is H, -(C -C )alkyl, -(C -C )haloalkyl, or -(C -C )cycloalkyl;
1 6 1 6 3 6
11 23 23 23
R is H, -NH , -(C -C )alkyl, -(C -C )alkyl-OR , -(C -C )alkyl-SR , -(C -C )alkyl-C(O)OR , -(C -
2 1 6 1 6 1 6 1 6 1
21 22 23 23 23 23
C )alkyl-NR R , -(C -C )alkyl-NR OR , -(C -C )alkyl-NHC(O)NR OR , -(C -C )alkyl-O-(C -
6 1 6 1 6 1 6 1
26 23 23 25 26
C )alkyl-NR R , -(C -C )alkyl-CN, -(C -C )alkyl-NR C(O)R , -(C -C )alkyl-C(O)NR R , -(C -
6 1 6 1 6 1 6 1
C )heteroalkyl-CO H, -(C -C )alkyl-S(O)(C -C )alkyl, -(C -C )alkyl-N(H)CH=NH, -(C -C )alkyl-
6 2 1 6 1 6 1 6 1 6
26
C(NH )=NH, -(C -C )alkyl-N(H)C(=NH)NH , -(C -C )alkyl-N(H)S(O) NR R , -(C -C )alkyl-
2 1 6 2 1 6 2 1 6
26
N(H)S(O) (C -C )alkyl, -(C -C )alkyl-N(H)-C(O)NR R , -(C -C )alkylC(O)N(H)[optionally
2 1 6 1 6 1 6
23 23
substituted(C -C )alkyl]-OR , -(C -C )alkylN(H)C(O)(C -C )alkyl-OR , -(C -
2 6 1 6 1 6 1
26
C )alkylC(O)N(H)heterocycloalkyl, -(C -C )alkylC(O)NR R , -(C -C )alkyl-N(H)-C(O)-(C -
6 1 6 1 6 1
26 25 26
C )alkyl-NR R , -(C -C )alkyl-N(H)-(C -C )alkylC(O)NR R , -(C -C )alkyl-heterocycloalkyl,
6 1 6 1 6 1 6
optionally substituted -(C -C )alkyl-N(H)heterocycloalkyl, or -(C -C )alkyl-heteroaryl;
1 6 1 6
18253141_1 (GHMatters) P111789.NZ
11 18 12
or R and R are combined to form an optionally substituted heterocycloalkyl ring; and R is H;
17 18 23
R and R are each independently H, -(C -C )alkyl, -(C -C )cycloalkyl, -(C -C )alkyl-OR , -(C -
1 6 3 6 1 6 1
23 21 22
C )alkyl-C(O)OR , or -(C -C )alkyl-NR R ;
6 1 6
X is optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, optionally substituted -(C -
1 6 2 6 2 6 3
C )cycloalkyl-, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally
24 24
substituted heteroaryl, -O-(C -C )alkyl-, -N(R )(C -C )alkyl-, -N(R )(C -C )aryl-, or -SO (C -
1 6 1 6 6 10 2 1
C )alkyl-;
Y is a bond, -O-, -S-, optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, -(C -
1 6 2 6 2 6 1
24 24 24
C )alkyl-N(R )(C -C )alkyl-, -O-(C -C )alkyl-, -O(C -C )aryl-, -N(R )(C -C )alkyl-, -N(R )SO (C -
6 1 6 1 6 6 10 1 6 2 1
C )alkyl-, -N(R )C(O)(C -C )alkyl-, -C(O)(C -C )alkyl-, -S(C -C )alkyl-, -SO (C -C )alkyl-, -
6 1 6 1 6 1 6 2 1 6
C(O)NH(C -C )alkyl-, optionally substituted -(C -C )cycloalkyl-, optionally substituted -
1 6 3 7
24 24 24
C(O)N(R )aryl-, optionally substituted -N(R )C(O)aryl-, optionally substituted -N(R )SO aryl-,
optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Z is H, halogen, -NH , -CN, -CF , -CO H, -(C -C )alkyl, -(C -C )alkenyl, -CH=((C -C )cycloalkyl), -
2 3 2 1 12 2 12 3 7
26
(C -C )alkynyl, -C(O)NR R , -O-(C -C )alkyl, -S-(C -C )alkyl, -O-(C -C )[optionally substituted
2 12 1 12 1 12 3 10
23 23
(C -C )cycloalkyl], -O-(C -C )alkyl-OR , -(C -C )alkyl-OR , -(C -C )alkyl-CN, -S-(C -C )alkyl, -
3 7 1 6 1 12 1 12 1 12
24 24
N(R )(C -C )alkyl, -N(R )C(O)(C -C )alkyl, optionally substituted -(C -C )cycloalkyl, -(C -
1 12 1 12 3 7 1
C )alkyl-(C -C )cycloalkyl, -(C -C )alkyl-heterocycloalkyl, optionally substituted heterocycloalkyl,
6 3 7 1 6
optionally substituted aryl, or optionally substituted heteroaryl;
21 22
each R and R is independently H, -(C -C )alkyl, -(C -C )heteroalkyl, -(C -C )alkyl-CO H, -C(O)(C -
1 6 1 6 1 6 2 1
C )alkyl, -C(O)O(C -C )alkyl, -C(O)O(C -C )haloalkyl, -C(=NH)(C -C )alkyl, -C(=NH)N(R ) , -
6 1 6 1 6 1 6 2
31 31 21 22
C(O)N(R ) , or -SO N(R ) ; or R and R and the nitrogen atom to which they are attached form a
2 2 2
heterocycloalkyl ring;
31 31
each R is independently H or -(C -C )alkyl; or two R and the nitrogen atom to which they are attached
form a heterocycloalkyl ring;
each R is independently H or -(C -C )alkyl;
each R is independently H or -(C -C )alkyl;
26
each R and R is independently H or optionally substituted -(C -C )alkyl;
26
or R and R and the nitrogen atom to which they are attached form a heterocycloalkyl ring; and
[00156] or a pharmaceutically acceptable salt, solvate, or prodrug thereof.In one embodiment is a
compound of Formula (Ib) wherein R is -(C -C )alkyl. In another embodiment is a compound of Formula
17 17
(Ib) wherein R is -CH . In another embodiment is a compound of Formula (Ib) wherein R is -CH CH .
3 2 3
In another embodiment is a compound of Formula (Ib) wherein R is -(C -C )cycloalkyl. In another
embodiment is a compound of Formula (Ib) wherein R is cyclopropyl. In another embodiment is a
17 23
compound of Formula (Ib) wherein R is -(C -C )alkyl-C(O)OR . In another embodiment is a compound
of Formula (Ib) wherein R is -CH CH OH. In another embodiment is a compound of Formula (Ib)
18253141_1 (GHMatters) P111789.NZ
17 21 22 17
wherein R is -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (Ib) wherein R
is -CH CH NH . In another embodiment is a compound of Formula (Ib) wherein R is H.
2 2 2
In another embodiment is a compound of Formula (Ib) wherein R is H.
In another embodiment is a compound of Formula (Ib) wherein R is H.
[00159] In another embodiment is a compound of Formula (Ib) wherein R is H. In another embodiment
is a compound of Formula (Ib) wherein R is -(C -C )alkyl. In another embodiment is a compound of
Formula (Ib) wherein R is -CH . In another embodiment is a compound of Formula (Ib) wherein R is -
CH CH . In another embodiment is a compound of Formula (Ib) wherein R is -(C -C )alkyl-OH. In
2 3 1 6
another embodiment is a compound of Formula (Ib) wherein R is -CH OH. In another embodiment is a
compound of Formula (Ib) wherein R is -(C -C )cycloalkyl. In another embodiment is a compound of
Formula (Ib) wherein R is cyclopropyl. In another embodiment is a compound of Formula (Ib) wherein R
is -C(O)NH .
In another embodiment is a compound of Formula (Ib) wherein R and R and the carbon atom
to which they are attached form a cyclopropyl ring.
[00161] In another embodiment is a compound of Formula (Ib) wherein R is -(C -C )alkyl. In another
embodiment is a compound of Formula (Ib) wherein R is -CH . In another embodiment is a compound of
Formula (Ib) wherein R is -CH CH . In another embodiment is a compound of Formula (Ib) wherein R is
-(C -C )haloalkyl. In another embodiment is a compound of Formula (Ib) wherein R is -CH F. In another
1 6 2
embodiment is a compound of Formula (Ib) wherein R is -CHF . In another embodiment is a compound
of Formula (Ib) wherein R is -(C -C )cycloalkyl. In another embodiment is a compound of Formula (Ib)
wherein R is cyclopropyl. In another embodiment is a compound of Formula (Ib) wherein R is H.
In another embodiment is a compound of Formula (Ib) wherein R is -(C -C )alkyl. In another
embodiment is a compound of Formula (Ib) wherein R is -CH . In another embodiment is a compound of
11 23
Formula (Ib) wherein R is -(C -C )alkyl-OR . In another embodiment is a compound of Formula (Ib)
11 11
wherein R is -CH OH. In another embodiment is a compound of Formula (Ib) wherein R is -
CH CH OH. In another embodiment is a compound of Formula (Ib) wherein R is -(C -C )alkyl. In
2 2 1 6
11 21 22
another embodiment is a compound of Formula (Ib) wherein R is -(C -C )alkyl-NR R . In another
embodiment is a compound of Formula (Ib) wherein R is -(C -C )alkyl-NH . In another embodiment is a
1 6 2
compound of Formula (Ib) wherein R is -CH NH . In another embodiment is a compound of Formula
11 11
(Ib) wherein R is -CH CH NH . In another embodiment is a compound of Formula (Ib) wherein R is -
2 2 2
CH CH CH NH . In another embodiment is a compound of Formula (Ib) wherein R is -
2 2 2 2
CH CH CH CH NH . In another embodiment is a compound of Formula (Ib) wherein R is -(C -C )alkyl-
2 2 2 2 2 1 6
CN. In another embodiment is a compound of Formula (Ib) wherein R is -CH CN. In another
11 25 26
embodiment is a compound of Formula (Ib) wherein R is -(C -C )alkyl-C(O)NR R . In another
embodiment is a compound of Formula (Ib) wherein R is -CH C(O)NH . In another embodiment is a
compound of Formula (Ib) wherein R is -CH CH C(O)NH . In another embodiment is a compound of
2 2 2
Formula (Ib) wherein R is -(C -C )alkyl-heteroaryl. In another embodiment is a compound of Formula
18253141_1 (GHMatters) P111789.NZ
11 25 26
(Ib) wherein R is -(C -C )alkyl-N(H)S(O) NR R . In another embodiment is a compound of Formula
1 6 2
(Ib) wherein R is -CH N(H)S(O) NH . In another embodiment is a compound of Formula (Ib) wherein
2 2 2
R is H.
11 18
In another embodiment is a compound of Formula (Ib) wherein R and R are combined to
form an optionally substituted heterocycloalkyl ring.
In another embodiment is a compound of Formula (Ib) wherein R and R are each
21 22
independently H or -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (Ib) wherein
1 2 1 2
R and R are each H. In another embodiment is a compound of Formula (Ib) wherein R and R are each
21 22 1
independently -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (Ib) wherein R is
2 21 22 1
H, and R is -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (Ib) wherein R is -
21 22 2 1
(C -C )alkyl-NR R , and R is H. In another embodiment is a compound of Formula (Ib) wherein R is H,
and R is -CH CH NH . In another embodiment is a compound of Formula (Ib) wherein R is -
2 2 2
2 1 2
CH CH NH , and R is H. In another embodiment is a compound of Formula (Ib) wherein R and R are
2 2 2
each -CH CH NH . In a further embodiment is a compound of Formula (Ib) wherein R is -(C -C )alkyl-
2 2 2 1 6
21 22 2 1
NR R and R is H. In a further embodiment is a compound of Formula (Ib) wherein R is -CH CH NH
2 2 2
2 1 2
and R is H. In a further embodiment is a compound of Formula (Ib) wherein R is H and R is -(C -
21 22 1 2
C )alkyl-NR R . In a further embodiment is a compound of Formula (Ib) wherein R is H and R is -
CH NH . In another embodiment is a compound of Formula (Ib) wherein R and R are each
2 2 2
21 22
independently H, -(C -C )alkyl-NR R , or -CH CH(OH)CH NH . In another embodiment is a compound
1 6 2 2 2
of Formula (Ib) wherein R and R are each independently -CH CH(OH)CH NH . In another embodiment
2 2 2
is a compound of Formula (Ib) wherein R is H, and R is -CH CH(OH)CH NH . In another embodiment
2 2 2
is a compound of Formula (Ib) wherein R is -CH CH(OH)CH NH , and R is H.
2 2 2
In a further embodiment is a compound of Formula (Ib) wherein R and R and the atoms to
which they are attached form an optionally substituted heterocycloalkyl ring.
[00166] In another embodiment is a compound of Formula (Ib) wherein X is optionally substituted aryl.
In a further embodiment is a compound of Formula (Ib) wherein X is optionally substituted phenyl. In
another embodiment is a compound of Formula (Ib) wherein X is optionally substituted heteroaryl. In a
further embodiment is a compound of Formula (Ib) wherein X is disubstituted heteroaryl. In a further
embodiment is a compound of Formula (Ib) wherein X is heteroaryl disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
23 25 26
(C -C )alkyl, OR , -NR R , and -NO . In a further embodiment is a compound of Formula (Ib) wherein
1 6 2
X is heteroaryl disubstituted with substituents each independently selected from -(C -C )alkyl. In a further
embodiment is a compound of Formula (Ib) wherein X is heteroaryl disubstituted with methyl. In a further
embodiment is a compound of Formula (Ib) wherein X is pyridinyl disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
23 25 26
(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound of Formula (Ib) wherein X
1 6 2
is pyridinyl disubstituted with substituents each independently selected from -(C -C )alkyl. In a further
18253141_1 (GHMatters) P111789.NZ
embodiment is a compound of Formula (Ib) wherein X is pyridinyl disubstituted with methyl. In a further
embodiment is a compound of Formula (Ib) wherein X is pyrimidinyl disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
23 25 26
(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound of Formula (Ib) wherein X
1 6 2
is pyrimidinyl disubstituted with substituents each independently selected from -(C -C )alkyl. In a further
embodiment is a compound of Formula (Ib) wherein X is pyrimidinyl disubstituted with methyl. In another
embodiment is a compound of Formula (Ib) wherein X is optionally substituted -(C -C )alkyl-.
In another embodiment is a compound of Formula (Ib) wherein Y is optionally substituted aryl.
In a further embodiment is a compound of Formula (Ib) wherein Y is optionally substituted phenyl. In
another embodiment is a compound of Formula (Ib) wherein Y is optionally substituted heteroaryl. In
another embodiment is a compound of Formula (Ib) wherein Y is optionally substituted -(C -C )alkyl-. In
another embodiment is a compound of Formula (Ib) wherein Y is optionally substituted (C -C )cycloalkyl-.
In another embodiment is a compound of Formula (Ib) wherein Y is optionally substituted
heterocycloalkyl. In another embodiment is a compound of Formula (Ib) wherein Y is -O-. In another
embodiment is a compound of Formula (Ib) wherein Y is -(C -C )alkynyl. In another embodiment is a
compound of Formula (Ib) wherein Y is -O-(C -C )alkyl-. In another embodiment is a compound of
Formula (Ib) wherein Y is a bond.
In another embodiment is a compound of Formula (Ib) wherein Z is -(C -C )alkyl. In a further
1 12
embodiment is a compound of Formula (Ib) wherein Z is n-butyl, isobutyl, or tert-butyl. In another
embodiment is a compound of Formula (Ib) wherein Z is -O-(C -C )alkyl. In another embodiment is a
1 12
compound of Formula (Ib) wherein Z is -O-(C -C )cycloalkyl. In another embodiment is a compound of
Formula (Ib) wherein Z is -(C -C )alkenyl. In another embodiment is a compound of Formula (Ib)
2 12
wherein Z is optionally substituted aryl. In a further embodiment is a compound of Formula (Ib) wherein Z
is optionally substituted phenyl. In a further embodiment is a compound of Formula (Ib) wherein Z is
phenyl monsubstituted or disubstituted with a substituent independently selected from -(C -C )alkyl. In a
further embodiment is a compound of Formula (Ib) wherein Z is phenyl monosubstituted with n-butyl,
isobutyl, or tert-butyl. In a further embodiment is a compound of Formula (Ib) wherein Z is phenyl
monosubstituted with n-butyl. In a further embodiment is a compound of Formula (Ib) wherein Z is phenyl
monosubstituted with isobutyl. In a further embodiment is a compound of Formula (Ib) wherein Z is
phenyl monosubstituted with tert-butyl. In another embodiment is a compound of Formula (Ib) wherein Z
is optionally substituted heteroaryl. In another embodiment is a compound of Formula (Ib) wherein Z is
optionally substituted -(C -C )cycloalkyl. In another embodiment is a compound of Formula (Ib) wherein
Z is optionally substituted heterocycloalkyl. In another embodiment is a compound of Formula (Ib)
wherein Z is halogen.
18253141_1 (GHMatters) P111789.NZ
In another embodiment is a compound of Formula (Ib) wherein Z-Y-X- is not
In another embodiment is a compound of Formula (I) having the structure of Formula (Ic):
O CN
Z X N
Formula (Ic);
wherein:
1 2 23
R and R are each independently H, -(C -C )alkyl, -(C -C )alkyl-OR , -CH CH(OH)CH NH , -
1 6 1 6 2 2 2
CH CH(heterocycloalkyl)CH NH , -CH C(O)NH , -CH C(O)N(H)CH CN, -(C -C )alkyl-C(O)OR , -
2 2 2 2 2 2 2 1 6
21 22 25 26 23 21 22
(C -C )alkyl-NR R , -(C -C )alkyl-C(O)NR R , -(C -C )alkyl-N(R )C(O)(C -C )alkylNR R , -
1 6 1 6 1 6 1 6
23 23
(C -C )alkyl-N(R )C(O)(C -C )alkyl, -(C -C )alkyl-C(O)N(R )(C -C )alkyl, -(C -C )alkyl-
1 6 1 6 1 6 1 6 1 6
23 23 21 22
C(O)N(R )(C -C )alkyl-heterocycloalkyl, -(C -C )alkyl-NR C(=NH)NR R , -(C -C )alkyl-
1 6 1 6 1 6
23 23 21 22
NR C(=NH)R , -(C -C )alkyl-[(C -C )alkyl-NR R ] , -(C -C )heteroalkyl, or optionally substituted
1 6 1 6 2 1 6
heterocycloalkyl;
or R and R and the atoms to which they are attached form an optionally substituted heterocycloalkyl ring;
11 23 23 23
R is H, -NH , -(C -C )alkyl, -(C -C )alkyl-OR , -(C -C )alkyl-SR , -(C -C )alkyl-C(O)OR , -(C -
2 1 6 1 6 1 6 1 6 1
21 22 23 23 23 23
C )alkyl-NR R , -(C -C )alkyl-NR OR , -(C -C )alkyl-NHC(O)NR OR , -(C -C )alkyl-O-(C -
6 1 6 1 6 1 6 1
26 23 23 25 26
C )alkyl-NR R , -(C -C )alkyl-CN, -(C -C )alkyl-NR C(O)R , -(C -C )alkyl-C(O)NR R , -(C -
6 1 6 1 6 1 6 1
C )heteroalkyl-CO H, -(C -C )alkyl-S(O)(C -C )alkyl, -(C -C )alkyl-N(H)CH=NH, -(C -C )alkyl-
6 2 1 6 1 6 1 6 1 6
26
C(NH )=NH, -(C -C )alkyl-N(H)C(=NH)NH , -(C -C )alkyl-N(H)S(O) NR R , -(C -C )alkyl-
2 1 6 2 1 6 2 1 6
26
N(H)S(O) (C -C )alkyl, -(C -C )alkyl-N(H)-C(O)NR R , -(C -C )alkylC(O)N(H)[optionally
2 1 6 1 6 1 6
23 23
substituted(C -C )alkyl]-OR , -(C -C )alkylN(H)C(O)(C -C )alkyl-OR , -(C -
2 6 1 6 1 6 1
26
C )alkylC(O)N(H)heterocycloalkyl, -(C -C )alkylC(O)NR R , -(C -C )alkyl-N(H)-C(O)-(C -
6 1 6 1 6 1
26 25 26
C )alkyl-NR R , -(C -C )alkyl-N(H)-(C -C )alkylC(O)NR R , -(C -C )alkyl-heterocycloalkyl,
6 1 6 1 6 1 6
optionally substituted -(C -C )alkyl-N(H)heterocycloalkyl, or -(C -C )alkyl-heteroaryl;
1 6 1 6
X is optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, optionally substituted -(C -
1 6 2 6 2 6 3
C )cycloalkyl-, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally
24 24
substituted heteroaryl, -O-(C -C )alkyl-, -N(R )(C -C )alkyl-, -N(R )(C -C )aryl-, or -SO (C -
1 6 1 6 6 10 2 1
C )alkyl-;
18253141_1 (GHMatters) P111789.NZ
Y is a bond, -O-, -S-, optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, -(C -
1 6 2 6 2 6 1
24 24 24
C )alkyl-N(R )(C -C )alkyl-, -O-(C -C )alkyl-, -O(C -C )aryl-, -N(R )(C -C )alkyl-, -N(R )SO (C -
6 1 6 1 6 6 10 1 6 2 1
C )alkyl-, -N(R )C(O)(C -C )alkyl-, -C(O)(C -C )alkyl-, -S(C -C )alkyl-, -SO (C -C )alkyl-, -
6 1 6 1 6 1 6 2 1 6
C(O)NH(C -C )alkyl-, optionally substituted -(C -C )cycloalkyl-, optionally substituted -
1 6 3 7
24 24 24
C(O)N(R )aryl-, optionally substituted -N(R )C(O)aryl-, optionally substituted -N(R )SO aryl-,
optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Z is H, halogen, -NH , -CN, -CF , -CO H, -(C -C )alkyl, -(C -C )alkenyl, -CH=((C -C )cycloalkyl), -
2 3 2 1 12 2 12 3 7
26
(C -C )alkynyl, -C(O)NR R , -O-(C -C )alkyl, -S-(C -C )alkyl, -O-(C -C )[optionally substituted
2 12 1 12 1 12 3 10
23 23
(C -C )cycloalkyl], -O-(C -C )alkyl-OR , -(C -C )alkyl-OR , -(C -C )alkyl-CN, -S-(C -C )alkyl, -
3 7 1 6 1 12 1 12 1 12
24 24
N(R )(C -C )alkyl, -N(R )C(O)(C -C )alkyl, optionally substituted -(C -C )cycloalkyl, -(C -
1 12 1 12 3 7 1
C )alkyl-(C -C )cycloalkyl, -(C -C )alkyl-heterocycloalkyl, optionally substituted heterocycloalkyl,
6 3 7 1 6
optionally substituted aryl, or optionally substituted heteroaryl;
21 22
each R and R is independently H, -(C -C )alkyl, -(C -C )heteroalkyl, -(C -C )alkyl-CO H, -C(O)(C -
1 6 1 6 1 6 2 1
C )alkyl, -C(O)O(C -C )alkyl, -C(O)O(C -C )haloalkyl, -C(=NH)(C -C )alkyl, -C(=NH)N(R ) , -
6 1 6 1 6 1 6 2
31 31 21 22
C(O)N(R ) , or -SO N(R ) ; or R and R and the nitrogen atom to which they are attached form a
2 2 2
heterocycloalkyl ring;
31 31
each R is independently H or -(C -C )alkyl; or two R and the nitrogen atom to which they are attached
form a heterocycloalkyl ring;
each R is independently H or -(C -C )alkyl;
each R is independently H or -(C -C )alkyl;
26
each R and R is independently H or optionally substituted -(C -C )alkyl;
26
or R and R and the nitrogen atom to which they are attached form a heterocycloalkyl ring; and
or a pharmaceutically acceptable salt, solvate, or prodrug thereof.In another embodiment is a
compound of Formula (Ic) wherein R is -(C -C )alkyl. In another embodiment is a compound of Formula
11 11
(Ic) wherein R is -CH . In another embodiment is a compound of Formula (Ic) wherein R is -(C -
23 11
C )alkyl-OR . In another embodiment is a compound of Formula (Ic) wherein R is -CH OH. In another
embodiment is a compound of Formula (Ic) wherein R is -CH CH OH. In another embodiment is a
compound of Formula (Ic) wherein R is -(C -C )alkyl. In another embodiment is a compound of Formula
11 21 22
(Ic) wherein R is -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (Ic) wherein
11 11
R is -(C -C )alkyl-NH . In another embodiment is a compound of Formula (Ic) wherein R is -CH NH .
1 6 2 2 2
In another embodiment is a compound of Formula (Ic) wherein R is -CH CH NH . In another
2 2 2
embodiment is a compound of Formula (Ic) wherein R is -CH CH CH NH . In another embodiment is a
2 2 2 2
compound of Formula (Ic) wherein R is -CH CH CH CH NH . In another embodiment is a compound of
2 2 2 2 2
Formula (Ic) wherein R is -(C -C )alkyl-CN. In another embodiment is a compound of Formula (Ic)
11 11
wherein R is -CH CN. In another embodiment is a compound of Formula (Ic) wherein R is -(C -
26 11
C )alkyl-C(O)NR R . In another embodiment is a compound of Formula (Ic) wherein R is -
CH C(O)NH . In another embodiment is a compound of Formula (Ic) wherein R is -CH CH C(O)NH .
2 2 2 2 2
18253141_1 (GHMatters) P111789.NZ
In another embodiment is a compound of Formula (Ic) wherein R is -(C -C )alkyl-heteroaryl. In another
11 25 26
embodiment is a compound of Formula (Ic) wherein R is -(C -C )alkyl-N(H)S(O) NR R . In another
1 6 2
embodiment is a compound of Formula (Ic) wherein R is -CH N(H)S(O) NH . In another embodiment is
2 2 2
a compound of Formula (Ic) wherein R is H.
[00172] In another embodiment is a compound of Formula (Ic) wherein R and R are each
21 22
independently H or -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (Ic) wherein
1 2 1 2
R and R are each H. In another embodiment is a compound of Formula (Ic) wherein R and R are each
21 22 1
independently -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (Ic) wherein R is
2 21 22 1
H, and R is -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (Ic) wherein R is -
21 22 2 1
(C -C )alkyl-NR R , and R is H. In another embodiment is a compound of Formula (Ic) wherein R is H,
and R is -CH CH NH . In another embodiment is a compound of Formula (Ic) wherein R is -
2 2 2
2 1 2
CH CH NH , and R is H. In another embodiment is a compound of Formula (Ic) wherein R and R are
2 2 2
each -CH CH NH . In a further embodiment is a compound of Formula (Ic) wherein R is -(C -C )alkyl-
2 2 2 1 6
21 22 2 1
NR R and R is H. In a further embodiment is a compound of Formula (Ic) wherein R is -CH CH NH
2 2 2
2 1 2
and R is H. In a further embodiment is a compound of Formula (Ic) wherein R is H and R is -(C -
21 22 1 2
C )alkyl-NR R . In a further embodiment is a compound of Formula (Ic) wherein R is H and R is -
CH CH NH . In another embodiment is a compound of Formula (Ic) wherein R and R are each
2 2 2
21 22
independently H, -(C -C )alkyl-NR R , or -CH CH(OH)CH NH . In another embodiment is a compound
1 6 2 2 2
of Formula (Ic) wherein R and R are each independently -CH CH(OH)CH NH . In another embodiment
2 2 2
is a compound of Formula (Ic) wherein R is H, and R is -CH CH(OH)CH NH . In another embodiment
2 2 2
is a compound of Formula (Ic) wherein R is -CH CH(OH)CH NH , and R is H.
2 2 2
In a further embodiment is a compound of Formula (Ic) wherein R and R and the atoms to
which they are attached form an optionally substituted heterocycloalkyl ring.
In another embodiment is a compound of Formula (Ic) wherein X is optionally substituted aryl.
In a further embodiment is a compound of Formula (Ic) wherein X is optionally substituted phenyl. In
another embodiment is a compound of Formula (Ic) wherein X is optionally substituted heteroaryl. In a
further embodiment is a compound of Formula (Ic) wherein X is disubstituted heteroaryl. In a further
embodiment is a compound of Formula (Ic) wherein X is heteroaryl disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
23 25 26
(C -C )alkyl, OR , -NR R , and -NO . In a further embodiment is a compound of Formula (Ic) wherein
1 6 2
X is heteroaryl disubstituted with substituents each independently selected from -(C -C )alkyl. In a further
embodiment is a compound of Formula (Ic) wherein X is heteroaryl disubstituted with methyl. In a further
embodiment is a compound of Formula (Ic) wherein X is pyridinyl disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
23 25 26
(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound of Formula (Ic) wherein X
1 6 2
is pyridinyl disubstituted with substituents each independently selected from -(C -C )alkyl. In a further
embodiment is a compound of Formula (Ic) wherein X is pyridinyl disubstituted with methyl. In a further
18253141_1 (GHMatters) P111789.NZ
embodiment is a compound of Formula (Ic) wherein X is pyrimidinyl disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
23 25 26
(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound of Formula (Ic) wherein X
1 6 2
is pyrimidinyl disubstituted with substituents each independently selected from -(C -C )alkyl. In a further
embodiment is a compound of Formula (Ic) wherein X is pyrimidinyl disubstituted with methyl. In another
embodiment is a compound of Formula (Ic) wherein X is optionally substituted -(C -C )alkyl-.
In another embodiment is a compound of Formula (Ic) wherein Y is optionally substituted aryl.
In a further embodiment is a compound of Formula (Ic) wherein Y is optionally substituted phenyl. In
another embodiment is a compound of Formula (Ic) wherein Y is optionally substituted heteroaryl. In
another embodiment is a compound of Formula (Ic) wherein Y is optionally substituted -(C -C )alkyl-. In
another embodiment is a compound of Formula (Ic) wherein Y is optionally substituted (C -C )cycloalkyl-.
In another embodiment is a compound of Formula (Ic) wherein Y is optionally substituted
heterocycloalkyl. In another embodiment is a compound of Formula (Ic) wherein Y is -O-. In another
embodiment is a compound of Formula (Ic) wherein Y is -(C -C )alkynyl. In another embodiment is a
compound of Formula (Ic) wherein Y is -O-(C -C )alkyl-. In another embodiment is a compound of
Formula (Ic) wherein Y is a bond.
In another embodiment is a compound of Formula (Ic) wherein Z is -(C -C )alkyl. In a further
1 12
embodiment is a compound of Formula (Ic) wherein Z is n-butyl, isobutyl, or tert-butyl. In another
embodiment is a compound of Formula (Ic) wherein Z is -O-(C -C )alkyl. In another embodiment is a
1 12
compound of Formula (Ic) wherein Z is -O-(C -C )cycloalkyl. In another embodiment is a compound of
Formula (Ic) wherein Z is -(C -C )alkenyl. In another embodiment is a compound of Formula (Ic)
2 12
wherein Z is optionally substituted aryl. In a further embodiment is a compound of Formula (Ic) wherein Z
is optionally substituted phenyl. In a further embodiment is a compound of Formula (Ic) wherein Z is
phenyl monsubstituted or disubstituted with a substituent independently selected from -(C -C )alkyl. In a
further embodiment is a compound of Formula (Ic) wherein Z is phenyl monosubstituted with n-butyl,
isobutyl, or tert-butyl. In a further embodiment is a compound of Formula (Ic) wherein Z is phenyl
monosubstituted with n-butyl. In a further embodiment is a compound of Formula (Ic) wherein Z is phenyl
monosubstituted with isobutyl. In a further embodiment is a compound of Formula (Ic) wherein Z is
phenyl monosubstituted with tert-butyl. In another embodiment is a compound of Formula (Ic) wherein Z
is optionally substituted heteroaryl. In another embodiment is a compound of Formula (Ic) wherein Z is
optionally substituted -(C -C )cycloalkyl. In another embodiment is a compound of Formula (Ic) wherein
Z is optionally substituted heterocycloalkyl. In another embodiment is a compound of Formula (Ic)
wherein Z is halogen.
In another embodiment is a compound of Formula (Ic) wherein Z-Y-X- is not
.
18253141_1 (GHMatters) P111789.NZ
In another embodiment is a compound of Formula (I) having the structure of Formula (Id):
O CN
Z X N
Formula (Id);
wherein:
R is -CH NH , -CH CH NH or -CH CH CH NH ;
2 2 2 2 , 2 2 2 2
X is optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, optionally substituted -(C -
1 6 2 6 2 6 3
C )cycloalkyl-, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally
24 24
substituted heteroaryl, -O-(C -C )alkyl-, -N(R )(C -C )alkyl-, -N(R )(C -C )aryl-, or -SO (C -
1 6 1 6 6 10 2 1
C )alkyl-;
Y is a bond, -O-, -S-, optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, -(C -
1 6 2 6 2 6 1
24 24 24
C )alkyl-N(R )(C -C )alkyl-, -O-(C -C )alkyl-, -O(C -C )aryl-, -N(R )(C -C )alkyl-, -N(R )SO (C -
6 1 6 1 6 6 10 1 6 2 1
C )alkyl-, -N(R )C(O)(C -C )alkyl-, -C(O)(C -C )alkyl-, -S(C -C )alkyl-, -SO (C -C )alkyl-, -
6 1 6 1 6 1 6 2 1 6
C(O)NH(C -C )alkyl-, optionally substituted -(C -C )cycloalkyl-, optionally substituted -
1 6 3 7
24 24 24
C(O)N(R )aryl-, optionally substituted -N(R )C(O)aryl-, optionally substituted -N(R )SO aryl-,
optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Z is H, halogen, -NH , -CN, -CF , -CO H, -(C -C )alkyl, -(C -C )alkenyl, -CH=((C -C )cycloalkyl), -
2 3 2 1 12 2 12 3 7
26
(C -C )alkynyl, -C(O)NR R , -O-(C -C )alkyl, -S-(C -C )alkyl, -O-(C -C )[optionally substituted
2 12 1 12 1 12 3 10
23 23
(C -C )cycloalkyl], -O-(C -C )alkyl-OR , -(C -C )alkyl-OR , -(C -C )alkyl-CN, -S-(C -C )alkyl, -
3 7 1 6 1 12 1 12 1 12
24 24
N(R )(C -C )alkyl, -N(R )C(O)(C -C )alkyl, optionally substituted -(C -C )cycloalkyl, -(C -
1 12 1 12 3 7 1
C )alkyl-(C -C )cycloalkyl, -(C -C )alkyl-heterocycloalkyl, optionally substituted heterocycloalkyl,
6 3 7 1 6
optionally substituted aryl, or optionally substituted heteroaryl;
each R is independently H or -(C -C )alkyl;
each R is independently H or -(C -C )alkyl;
26
each R and R is independently H or optionally substituted -(C -C )alkyl;
26
or R and R and the nitrogen atom to which they are attached form a heterocycloalkyl ring; and
or a pharmaceutically acceptable salt, solvate, or prodrug thereof.In one embodiment is a
compound of Formula (Id) wherein R is -CH NH . In another embodiment is a compound of Formula
18253141_1 (GHMatters) P111789.NZ
11 11
(Id) wherein R is -CH CH NH . In another embodiment is a compound of Formula (Id) wherein R is -
2 2 2
CH CH CH NH .
2 2 2 2
In another embodiment is a compound of Formula (Id) wherein X is optionally substituted aryl.
In a further embodiment is a compound of Formula (Id) wherein X is optionally substituted phenyl. In
another embodiment is a compound of Formula (Id) wherein X is optionally substituted heteroaryl. In a
further embodiment is a compound of Formula (Id) wherein X is disubstituted heteroaryl. In a further
embodiment is a compound of Formula (Id) wherein X is heteroaryl disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
23 25 26
(C -C )alkyl, OR , -NR R , and -NO . In a further embodiment is a compound of Formula (Id) wherein
1 6 2
X is heteroaryl disubstituted with substituents each independently selected from -(C -C )alkyl. In a further
embodiment is a compound of Formula (Id) wherein X is heteroaryl disubstituted with methyl. In a further
embodiment is a compound of Formula (Id) wherein X is pyridinyl disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
23 25 26
(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound of Formula (Id) wherein X
1 6 2
is pyridinyl disubstituted with substituents each independently selected from -(C -C )alkyl. In a further
embodiment is a compound of Formula (Id) wherein X is pyridinyl disubstituted with methyl. In a further
embodiment is a compound of Formula (Id) wherein X is pyrimidinyl disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
23 25 26
(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound of Formula (Id) wherein X
1 6 2
is pyrimidinyl disubstituted with substituents each independently selected from -(C -C )alkyl. In a further
embodiment is a compound of Formula (Id) wherein X is pyrimidinyl disubstituted with methyl. In another
embodiment is a compound of Formula (Id) wherein X is optionally substituted -(C -C )alkyl-.
In another embodiment is a compound of Formula (Id) wherein Y is optionally substituted aryl.
In a further embodiment is a compound of Formula (Id) wherein Y is optionally substituted phenyl. In
another embodiment is a compound of Formula (Id) wherein Y is optionally substituted heteroaryl. In
another embodiment is a compound of Formula (Id) wherein Y is optionally substituted -(C -C )alkyl-. In
another embodiment is a compound of Formula (Id) wherein Y is optionally substituted (C -C )cycloalkyl-.
In another embodiment is a compound of Formula (Id) wherein Y is optionally substituted
heterocycloalkyl. In another embodiment is a compound of Formula (Id) wherein Y is -O-. In another
embodiment is a compound of Formula (Id) wherein Y is -(C -C )alkynyl. In another embodiment is a
compound of Formula (Id) wherein Y is -O-(C -C )alkyl-. In another embodiment is a compound of
Formula (Id) wherein Y is a bond.
In another embodiment is a compound of Formula (Id) wherein Z is -(C -C )alkyl. In a further
1 12
embodiment is a compound of Formula (Id) wherein Z is n-butyl, isobutyl, or tert-butyl. In another
embodiment is a compound of Formula (Id) wherein Z is -O-(C -C )alkyl. In another embodiment is a
1 12
compound of Formula (Id) wherein Z is -O-(C -C )cycloalkyl. In another embodiment is a compound of
Formula (Id) wherein Z is -(C -C )alkenyl. In another embodiment is a compound of Formula (Id)
2 12
18253141_1 (GHMatters) P111789.NZ
wherein Z is optionally substituted aryl. In a further embodiment is a compound of Formula (Id) wherein Z
is optionally substituted phenyl. In a further embodiment is a compound of Formula (Id) wherein Z is
phenyl monsubstituted or disubstituted with a substituent independently selected from -(C -C )alkyl. In a
further embodiment is a compound of Formula (Id) wherein Z is phenyl monosubstituted with n-butyl,
isobutyl, or tert-butyl. In a further embodiment is a compound of Formula (Id) wherein Z is phenyl
monosubstituted with n-butyl. In a further embodiment is a compound of Formula (Id) wherein Z is phenyl
monosubstituted with isobutyl. In a further embodiment is a compound of Formula (Id) wherein Z is
phenyl monosubstituted with tert-butyl. In another embodiment is a compound of Formula (Id) wherein Z
is optionally substituted heteroaryl. In another embodiment is a compound of Formula (Id) wherein Z is
optionally substituted -(C -C )cycloalkyl. In another embodiment is a compound of Formula (Id) wherein
Z is optionally substituted heterocycloalkyl. In another embodiment is a compound of Formula (Id)
wherein Z is halogen.
In another embodiment is a compound of Formula (Id) wherein Z-Y-X- is not
[00184] In another embodiment is a compound of Formula (I) having the structure of Formula (Ie):
Z X N
O R O
Formula (Ie);
wherein:
2 23
R is H, -(C -C )alkyl, -(C -C )alkyl-OR , -CH CH(OH)CH NH , -CH CH(heterocycloalkyl)CH NH , -
1 6 1 6 2 2 2 2 2 2
23 21 22
CH C(O)NH , -CH C(O)N(H)CH CN, -(C -C )alkyl-C(O)OR , -(C -C )alkyl-NR R , -(C -C )alkyl-
2 2 2 2 1 6 1 6 1 6
26 23 21 22 23
C(O)NR R , -(C -C )alkyl-N(R )C(O)(C -C )alkylNR R , -(C -C )alkyl-N(R )C(O)(C -C )alkyl, -
1 6 1 6 1 6 1 6
23 23
(C -C )alkyl-C(O)N(R )(C -C )alkyl, -(C -C )alkyl-C(O)N(R )(C -C )alkyl-heterocycloalkyl, (C -
1 6 1 6 1 6 1 6 1
C )heteroalkyl, or optionally substituted heterocycloalkyl;
R is H, -(C -C )alkyl, -(C -C )alkyl-OH, -(C -C )cycloalkyl, or -C(O)NH ;
1 6 1 6 3 6 2
R is H or -(C -C )alkyl;
or R and R and the carbon atom to which they are attached form a cyclopropyl ring;
R is H, -(C -C )alkyl, -(C -C )haloalkyl, or -(C -C )cycloalkyl;
1 6 1 6 3 6
18253141_1 (GHMatters) P111789.NZ
11 23 23 23
R is H, -NH , -(C -C )alkyl, -(C -C )alkyl-OR , -(C -C )alkyl-SR , -(C -C )alkyl-C(O)OR , -(C -
2 1 6 1 6 1 6 1 6 1
21 22 23 23 23 23
C )alkyl-NR R , -(C -C )alkyl-NR OR , -(C -C )alkyl-NHC(O)NR OR , -(C -C )alkyl-O-(C -
6 1 6 1 6 1 6 1
26 23 23 25 26
C )alkyl-NR R , -(C -C )alkyl-CN, -(C -C )alkyl-NR C(O)R , -(C -C )alkyl-C(O)NR R , -(C -
6 1 6 1 6 1 6 1
C )heteroalkyl-CO H, -(C -C )alkyl-S(O)(C -C )alkyl, -(C -C )alkyl-N(H)CH=NH, -(C -C )alkyl-
6 2 1 6 1 6 1 6 1 6
26
C(NH )=NH, -(C -C )alkyl-N(H)C(=NH)NH , -(C -C )alkyl-N(H)S(O) NR R , -(C -C )alkyl-
2 1 6 2 1 6 2 1 6
26
N(H)S(O) (C -C )alkyl, -(C -C )alkyl-N(H)-C(O)NR R , -(C -C )alkylC(O)N(H)[optionally
2 1 6 1 6 1 6
23 23
substituted(C -C )alkyl]-OR , -(C -C )alkylN(H)C(O)(C -C )alkyl-OR , -(C -
2 6 1 6 1 6 1
26
C )alkylC(O)N(H)heterocycloalkyl, -(C -C )alkylC(O)NR R , -(C -C )alkyl-N(H)-C(O)-(C -
6 1 6 1 6 1
26 25 26
C )alkyl-NR R , -(C -C )alkyl-N(H)-(C -C )alkylC(O)NR R , -(C -C )alkyl-heterocycloalkyl,
6 1 6 1 6 1 6
optionally substituted -(C -C )alkyl-N(H)heterocycloalkyl, or -(C -C )alkyl-heteroaryl;
1 6 1 6
11 18 12
or R and R are combined to form an optionally substituted heterocycloalkyl ring; and R is H;
17 18 23
R and R are each independently H, -(C -C )alkyl, -(C -C )cycloalkyl, -(C -C )alkyl-OR , -(C -
1 6 3 6 1 6 1
23 21 22
C )alkyl-C(O)OR , or -(C -C )alkyl-NR R ;
6 1 6
X is optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, optionally substituted -(C -
1 6 2 6 2 6 3
C )cycloalkyl-, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally
24 24
substituted heteroaryl, -O-(C -C )alkyl-, -N(R )(C -C )alkyl-, -N(R )(C -C )aryl-, or -SO (C -
1 6 1 6 6 10 2 1
C )alkyl-;
Y is a bond, -O-, -S-, optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, -(C -
1 6 2 6 2 6 1
24 24 24
C )alkyl-N(R )(C -C )alkyl-, -O-(C -C )alkyl-, -O(C -C )aryl-, -N(R )(C -C )alkyl-, -N(R )SO (C -
6 1 6 1 6 6 10 1 6 2 1
C )alkyl-, -N(R )C(O)(C -C )alkyl-, -C(O)(C -C )alkyl-, -S(C -C )alkyl-, -SO (C -C )alkyl-, -
6 1 6 1 6 1 6 2 1 6
C(O)NH(C -C )alkyl-, optionally substituted -(C -C )cycloalkyl-, optionally substituted -
1 6 3 7
24 24 24
C(O)N(R )aryl-, optionally substituted -N(R )C(O)aryl-, optionally substituted -N(R )SO aryl-,
optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Z is H, halogen, -NH , -CN, -CF , -CO H, -(C -C )alkyl, -(C -C )alkenyl, -CH=((C -C )cycloalkyl), -
2 3 2 1 12 2 12 3 7
26
(C -C )alkynyl, -C(O)NR R , -O-(C -C )alkyl, -S-(C -C )alkyl, -O-(C -C )[optionally substituted
2 12 1 12 1 12 3 10
23 23
(C -C )cycloalkyl], -O-(C -C )alkyl-OR , -(C -C )alkyl-OR , -(C -C )alkyl-CN, -S-(C -C )alkyl, -
3 7 1 6 1 12 1 12 1 12
24 24
N(R )(C -C )alkyl, -N(R )C(O)(C -C )alkyl, optionally substituted -(C -C )cycloalkyl, -(C -
1 12 1 12 3 7 1
C )alkyl-(C -C )cycloalkyl, -(C -C )alkyl-heterocycloalkyl, optionally substituted heterocycloalkyl,
6 3 7 1 6
optionally substituted aryl, or optionally substituted heteroaryl;
21 22
each R and R is independently H, -(C -C )alkyl, -(C -C )heteroalkyl, -(C -C )alkyl-CO H, -C(O)(C -
1 6 1 6 1 6 2 1
C )alkyl, -C(O)O(C -C )alkyl, -C(O)O(C -C )haloalkyl, -C(=NH)(C -C )alkyl, -C(=NH)N(R ) , -
6 1 6 1 6 1 6 2
31 31 21 22
C(O)N(R ) , or -SO N(R ) ; or R and R and the nitrogen atom to which they are attached form a
2 2 2
heterocycloalkyl ring;
31 31
each R is independently H or -(C -C )alkyl; or two R and the nitrogen atom to which they are attached
form a heterocycloalkyl ring;
each R is independently H or -(C -C )alkyl;
each R is independently H or -(C -C )alkyl;
18253141_1 (GHMatters) P111789.NZ
26
each R and R is independently H or optionally substituted -(C -C )alkyl;
26
or R and R and the nitrogen atom to which they are attached form a heterocycloalkyl ring; and
or a pharmaceutically acceptable salt, solvate, or prodrug thereof.In one embodiment is a
compound of Formula (Ie) wherein R is -(C -C )alkyl. In another embodiment is a compound of Formula
17 17
(Ie) wherein R is -CH . In another embodiment is a compound of Formula (Ie) wherein R is -CH CH .
3 2 3
In another embodiment is a compound of Formula (Ie) wherein R is -(C -C )cycloalkyl. In another
embodiment is a compound of Formula (Ie) wherein R is cyclopropyl. In another embodiment is a
17 23
compound of Formula (Ie) wherein R is -(C -C )alkyl-C(O)OR . In another embodiment is a compound
of Formula (Ie) wherein R is -CH CH OH. In another embodiment is a compound of Formula (Ie)
17 21 22 17
wherein R is -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (Ie) wherein R
is -CH CH NH . In another embodiment is a compound of Formula (Ie) wherein R is H.
2 2 2
In another embodiment is a compound of Formula (Ie) wherein R is H.
In another embodiment is a compound of Formula (Ie) wherein R is H.
In another embodiment is a compound of Formula (Ie) wherein R is H. In another embodiment
is a compound of Formula (Ie) wherein R is -(C -C )alkyl. In another embodiment is a compound of
Formula (Ie) wherein R is -CH . In another embodiment is a compound of Formula (Ie) wherein R is -
CH CH . In another embodiment is a compound of Formula (Ie) wherein R is -(C -C )alkyl-OH. In
2 3 1 6
another embodiment is a compound of Formula (Ie) wherein R is -CH OH. In another embodiment is a
compound of Formula (Ie) wherein R is -(C -C )cycloalkyl. In another embodiment is a compound of
Formula (Ie) wherein R is cyclopropyl. In another embodiment is a compound of Formula (Ie) wherein R
is -C(O)NH .
In another embodiment is a compound of Formula (Ie) wherein R and R and the carbon atom
to which they are attached form a cyclopropyl ring.
In another embodiment is a compound of Formula (Ie) wherein R is -(C -C )alkyl. In another
embodiment is a compound of Formula (Ie) wherein R is -CH . In another embodiment is a compound of
Formula (Ie) wherein R is -CH CH . In another embodiment is a compound of Formula (Ie) wherein R is
-(C -C )haloalkyl. In another embodiment is a compound of Formula (Ie) wherein R is -CH F. In another
1 6 2
embodiment is a compound of Formula (Ie) wherein R is -CHF . In another embodiment is a compound
of Formula (Ie) wherein R is -(C -C )cycloalkyl. In another embodiment is a compound of Formula (Ie)
wherein R is cyclopropyl. In another embodiment is a compound of Formula (Ie) wherein R is H.
In another embodiment is a compound of Formula (Ie) wherein R is -(C -C )alkyl. In another
embodiment is a compound of Formula (Ie) wherein R is -CH . In another embodiment is a compound of
11 23
Formula (Ie) wherein R is -(C -C )alkyl-OR . In another embodiment is a compound of Formula (Ie)
11 11
wherein R is -CH OH. In another embodiment is a compound of Formula (Ie) wherein R is -
CH CH OH. In another embodiment is a compound of Formula (Ie) wherein R is -(C -C )alkyl. In
2 2 1 6
11 21 22
another embodiment is a compound of Formula (Ie) wherein R is -(C -C )alkyl-NR R . In another
embodiment is a compound of Formula (Ie) wherein R is -(C -C )alkyl-NH . In another embodiment is a
1 6 2
18253141_1 (GHMatters) P111789.NZ
compound of Formula (Ie) wherein R is -CH NH . In another embodiment is a compound of Formula
11 11
(Ie) wherein R is -CH CH NH . In another embodiment is a compound of Formula (Ie) wherein R is -
2 2 2
CH CH CH NH . In another embodiment is a compound of Formula (Ie) wherein R is -
2 2 2 2
CH CH CH CH NH . In another embodiment is a compound of Formula (Ie) wherein R is -(C -C )alkyl-
2 2 2 2 2 1 6
CN. In another embodiment is a compound of Formula (Ie) wherein R is -CH CN. In another
11 25 26
embodiment is a compound of Formula (Ie) wherein R is -(C -C )alkyl-C(O)NR R . In another
embodiment is a compound of Formula (Ie) wherein R is -CH C(O)NH . In another embodiment is a
compound of Formula (Ie) wherein R is -CH CH C(O)NH . In another embodiment is a compound of
2 2 2
Formula (Ie) wherein R is -(C -C )alkyl-heteroaryl. In another embodiment is a compound of Formula
11 25 26
(Ie) wherein R is -(C -C )alkyl-N(H)S(O) NR R . In another embodiment is a compound of Formula
1 6 2
(Ie) wherein R is -CH N(H)S(O) NH . In another embodiment is a compound of Formula (Ie) wherein
2 2 2
R is H.
11 18
In another embodiment is a compound of Formula (Ie) wherein R and R are combined to
form an optionally substituted heterocycloalkyl ring.
[00193] In another embodiment is a compound of Formula (Ie) wherein R is H or -(C -C )alkyl-
21 22 2
NR R . In another embodiment is a compound of Formula (Ie) wherein R is H. In another embodiment
2 21 22
is a compound of Formula (Ie) wherein R is -(C -C )alkyl-NR R . In another embodiment is a
is -CH CH NH . In another embodiment is a compound of Formula
compound of Formula (Ie) wherein R
2 2 2
(Ie) wherein R is -CH CH CH NH . In another embodiment is a compound of Formula (Ie) wherein R is
2 2 2 2
2 21 22
-CH NH . In another embodiment is a compound of Formula (Ie) wherein R is H, -(C -C )alkyl-NR R ,
2 2 1 6
or -CH CH(OH)CH NH . In another embodiment is a compound of Formula (Ie) wherein R is -
2 2 2
CH CH(OH)CH NH .
2 2 2
In another embodiment is a compound of Formula (Ie) wherein X is optionally substituted aryl.
In a further embodiment is a compound of Formula (Ie) wherein X is optionally substituted phenyl. In
another embodiment is a compound of Formula (Ie) wherein X is optionally substituted heteroaryl. In a
further embodiment is a compound of Formula (Ie) wherein X is monosubstituted or disubstituted
heteroaryl. In a further embodiment is a compound of Formula (Ie) wherein X is disubstituted heteroaryl.
In a further embodiment is a compound of Formula (Ie) wherein X is heteroaryl monosubstituted or
disubstituted with substituents each independently selected from halogen, -CN, optionally substituted -(C -
23 25 26
C )alkyl, optionally substituted -O-(C -C )alkyl, OR , -NR R , and -NO . In a further embodiment is a
6 1 6 2
compound of Formula (Ie) wherein X is heteroaryl monosubstituted or disubstituted with substituents each
independently selected from -(C -C )alkyl. In a further embodiment is a compound of Formula (Ie)
wherein X is heteroaryl monosubstituted or disubstituted with methyl. In a further embodiment is a
compound of Formula (Ie) wherein X is pyridinyl monosubstituted or disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
23 25 26
(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound of Formula (Ie) wherein X
1 6 2
is pyridinyl monosubstituted or disubstituted with substituents each independently selected from -(C -
18253141_1 (GHMatters) P111789.NZ
C )alkyl. In a further embodiment is a compound of Formula (Ie) wherein X is pyridinyl monosubstituted
or disubstituted with methyl. In a further embodiment is a compound of Formula (Ie) wherein X is
pyrimidinyl monosubstituted or disubstituted with substituents each independently selected from halogen, -
23 25 26
CN, optionally substituted -(C -C )alkyl, optionally substituted -O-(C -C )alkyl, OR , -NR R , or -NO .
1 6 1 6 2
In a further embodiment is a compound of Formula (Ie) wherein X is pyrimidinyl monosubstituted or
disubstituted with substituents each independently selected from -(C -C )alkyl. In a further embodiment is
a compound of Formula (Ie) wherein X is pyrimidinyl monosubstituted or disubstituted with methyl. In
another embodiment is a compound of Formula (Ie) wherein X is optionally substituted -(C -C )alkyl-.
In another embodiment is a compound of Formula (Ie) wherein Y is optionally substituted aryl.
In a further embodiment is a compound of Formula (Ie) wherein Y is optionally substituted phenyl. In
another embodiment is a compound of Formula (Ie) wherein Y is optionally substituted heteroaryl. In
another embodiment is a compound of Formula (Ie) wherein Y is optionally substituted -(C -C )alkyl-. In
another embodiment is a compound of Formula (Ie) wherein Y is optionally substituted (C -C )cycloalkyl-.
In another embodiment is a compound of Formula (Ie) wherein Y is optionally substituted
heterocycloalkyl. In another embodiment is a compound of Formula (Ie) wherein Y is -O-. In another
embodiment is a compound of Formula (Ie) wherein Y is -(C -C )alkynyl. In another embodiment is a
compound of Formula (Ie) wherein Y is -O-(C -C )alkyl-. In another embodiment is a compound of
Formula (Ie) wherein Y is a bond.
In another embodiment is a compound of Formula (Ie) wherein Z is -(C -C )alkyl. In a further
1 12
embodiment is a compound of Formula (Ie) wherein Z is n-butyl, isobutyl, or tert-butyl. In another
embodiment is a compound of Formula (Ie) wherein Z is -O-(C -C )alkyl. In another embodiment is a
1 12
compound of Formula (Ie) wherein Z is -O-(C -C )cycloalkyl. In another embodiment is a compound of
Formula (Ie) wherein Z is -(C -C )alkenyl. In another embodiment is a compound of Formula (Ie)
2 12
wherein Z is optionally substituted aryl. In a further embodiment is a compound of Formula (Ie) wherein Z
is optionally substituted phenyl. In a further embodiment is a compound of Formula (Ie) wherein Z is
phenyl monsubstituted or disubstituted with a substituent independently selected from -(C -C )alkyl. In a
further embodiment is a compound of Formula (Ie) wherein Z is phenyl monosubstituted with n-butyl,
isobutyl, or tert-butyl. In a further embodiment is a compound of Formula (Ie) wherein Z is phenyl
monosubstituted with n-butyl. In a further embodiment is a compound of Formula (Ie) wherein Z is phenyl
monosubstituted with isobutyl. In a further embodiment is a compound of Formula (Ie) wherein Z is
phenyl monosubstituted with tert-butyl. In another embodiment is a compound of Formula (Ie) wherein Z
is optionally substituted heteroaryl. In another embodiment is a compound of Formula (Ie) wherein Z is
optionally substituted -(C -C )cycloalkyl. In another embodiment is a compound of Formula (Ie) wherein
Z is optionally substituted heterocycloalkyl. In another embodiment is a compound of Formula (Ie)
wherein Z is halogen.
18253141_1 (GHMatters) P111789.NZ
In another embodiment is a compound of Formula (I) having the structure of Formula (If):
Z X N
O R O
Formula (If);
wherein:
1 23
R is H, -(C -C )alkyl, -(C -C )alkyl-OR , -CH CH(OH)CH NH , -CH CH(heterocycloalkyl)CH NH , -
1 6 1 6 2 2 2 2 2 2
23 21 22
CH C(O)NH , -CH C(O)N(H)CH CN, -(C -C )alkyl-C(O)OR , -(C -C )alkyl-NR R , -(C -C )alkyl-
2 2 2 2 1 6 1 6 1 6
26 23 21 22 23
C(O)NR R , -(C -C )alkyl-N(R )C(O)(C -C )alkylNR R , -(C -C )alkyl-N(R )C(O)(C -C )alkyl, -
1 6 1 6 1 6 1 6
23 23
(C -C )alkyl-C(O)N(R )(C -C )alkyl, -(C -C )alkyl-C(O)N(R )(C -C )alkyl-heterocycloalkyl, (C -
1 6 1 6 1 6 1 6 1
C )heteroalkyl, or optionally substituted heterocycloalkyl;
R is H, -(C -C )alkyl, -(C -C )alkyl-OH, -(C -C )cycloalkyl, or -C(O)NH ;
1 6 1 6 3 6 2
R is H or -(C -C )alkyl;
or R and R and the carbon atom to which they are attached form a cyclopropyl ring;
R is H, -(C -C )alkyl, -(C -C )haloalkyl, or -(C -C )cycloalkyl;
1 6 1 6 3 6
11 23 23 23
R is H, -NH , -(C -C )alkyl, -(C -C )alkyl-OR , -(C -C )alkyl-SR , -(C -C )alkyl-C(O)OR , -(C -
2 1 6 1 6 1 6 1 6 1
21 22 23 23 23 23
C )alkyl-NR R , -(C -C )alkyl-NR OR , -(C -C )alkyl-NHC(O)NR OR , -(C -C )alkyl-O-(C -
6 1 6 1 6 1 6 1
26 23 23 25 26
C )alkyl-NR R , -(C -C )alkyl-CN, -(C -C )alkyl-NR C(O)R , -(C -C )alkyl-C(O)NR R , -(C -
6 1 6 1 6 1 6 1
C )heteroalkyl-CO H, -(C -C )alkyl-S(O)(C -C )alkyl, -(C -C )alkyl-N(H)CH=NH, -(C -C )alkyl-
6 2 1 6 1 6 1 6 1 6
26
C(NH )=NH, -(C -C )alkyl-N(H)C(=NH)NH , -(C -C )alkyl-N(H)S(O) NR R , -(C -C )alkyl-
2 1 6 2 1 6 2 1 6
26
N(H)S(O) (C -C )alkyl, -(C -C )alkyl-N(H)-C(O)NR R , -(C -C )alkylC(O)N(H)[optionally
2 1 6 1 6 1 6
23 23
substituted(C -C )alkyl]-OR , -(C -C )alkylN(H)C(O)(C -C )alkyl-OR , -(C -
2 6 1 6 1 6 1
26
C )alkylC(O)N(H)heterocycloalkyl, -(C -C )alkylC(O)NR R , -(C -C )alkyl-N(H)-C(O)-(C -
6 1 6 1 6 1
26 25 26
C )alkyl-NR R , -(C -C )alkyl-N(H)-(C -C )alkylC(O)NR R , -(C -C )alkyl-heterocycloalkyl,
6 1 6 1 6 1 6
optionally substituted -(C -C )alkyl-N(H)heterocycloalkyl, or -(C -C )alkyl-heteroaryl;
1 6 1 6
11 18 12
or R and R are combined to form an optionally substituted heterocycloalkyl ring; and R is H;
17 18 23
R and R are each independently H, -(C -C )alkyl, -(C -C )cycloalkyl, -(C -C )alkyl-OR , -(C -
1 6 3 6 1 6 1
23 21 22
C )alkyl-C(O)OR , or -(C -C )alkyl-NR R ;
6 1 6
X is optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, optionally substituted -(C -
1 6 2 6 2 6 3
C )cycloalkyl-, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally
24 24
-C )alkyl-, -N(R )(C -C )alkyl-, -N(R )(C -C )aryl-, or -SO (C -
substituted heteroaryl, -O-(C
1 6 1 6 6 10 2 1
C )alkyl-;
18253141_1 (GHMatters) P111789.NZ
Y is a bond, -O-, -S-, optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, -(C -
1 6 2 6 2 6 1
24 24 24
C )alkyl-N(R )(C -C )alkyl-, -O-(C -C )alkyl-, -O(C -C )aryl-, -N(R )(C -C )alkyl-, -N(R )SO (C -
6 1 6 1 6 6 10 1 6 2 1
C )alkyl-, -N(R )C(O)(C -C )alkyl-, -C(O)(C -C )alkyl-, -S(C -C )alkyl-, -SO (C -C )alkyl-, -
6 1 6 1 6 1 6 2 1 6
C(O)NH(C -C )alkyl-, optionally substituted -(C -C )cycloalkyl-, optionally substituted -
1 6 3 7
24 24 24
C(O)N(R )aryl-, optionally substituted -N(R )C(O)aryl-, optionally substituted -N(R )SO aryl-,
optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Z is H, halogen, -NH , -CN, -CF , -CO H, -(C -C )alkyl, -(C -C )alkenyl, -CH=((C -C )cycloalkyl), -
2 3 2 1 12 2 12 3 7
26
(C -C )alkynyl, -C(O)NR R , -O-(C -C )alkyl, -S-(C -C )alkyl, -O-(C -C )[optionally substituted
2 12 1 12 1 12 3 10
23 23
(C -C )cycloalkyl], -O-(C -C )alkyl-OR , -(C -C )alkyl-OR , -(C -C )alkyl-CN, -S-(C -C )alkyl, -
3 7 1 6 1 12 1 12 1 12
24 24
N(R )(C -C )alkyl, -N(R )C(O)(C -C )alkyl, optionally substituted -(C -C )cycloalkyl, -(C -
1 12 1 12 3 7 1
C )alkyl-(C -C )cycloalkyl, -(C -C )alkyl-heterocycloalkyl, optionally substituted heterocycloalkyl,
6 3 7 1 6
optionally substituted aryl, or optionally substituted heteroaryl;
21 22
each R and R is independently H, -(C -C )alkyl, -(C -C )heteroalkyl, -(C -C )alkyl-CO H, -C(O)(C -
1 6 1 6 1 6 2 1
C )alkyl, -C(O)O(C -C )alkyl, -C(O)O(C -C )haloalkyl, -C(=NH)(C -C )alkyl, -C(=NH)N(R ) , -
6 1 6 1 6 1 6 2
31 31 21 22
C(O)N(R ) , or -SO N(R ) ; or R and R and the nitrogen atom to which they are attached form a
2 2 2
heterocycloalkyl ring;
31 31
each R is independently H or -(C -C )alkyl; or two R and the nitrogen atom to which they are attached
form a heterocycloalkyl ring;
each R is independently H or -(C -C )alkyl;
each R is independently H or -(C -C )alkyl;
26
each R and R is independently H or optionally substituted -(C -C )alkyl;
26
or R and R and the nitrogen atom to which they are attached form a heterocycloalkyl ring; and
or a pharmaceutically acceptable salt, solvate, or prodrug thereof.In one embodiment is a
compound of Formula (If) wherein R is -(C -C )alkyl. In another embodiment is a compound of Formula
17 17
(If) wherein R is -CH . In another embodiment is a compound of Formula (If) wherein R is -CH CH .
3 2 3
In another embodiment is a compound of Formula (If) wherein R is -(C -C )cycloalkyl. In another
embodiment is a compound of Formula (If) wherein R is cyclopropyl. In another embodiment is a
17 23
compound of Formula (If) wherein R is -(C -C )alkyl-C(O)OR . In another embodiment is a compound
of Formula (If) wherein R is -CH CH OH. In another embodiment is a compound of Formula (If)
17 21 22 17
wherein R is -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (If) wherein R
is -CH CH NH . In another embodiment is a compound of Formula (If) wherein R is H.
2 2 2
In another embodiment is a compound of Formula (If) wherein R is H.
In another embodiment is a compound of Formula (If) wherein R is H.
In another embodiment is a compound of Formula (If) wherein R is H. In another embodiment
is a compound of Formula (If) wherein R is -(C -C )alkyl. In another embodiment is a compound of
Formula (If) wherein R is -CH . In another embodiment is a compound of Formula (If) wherein R is -
CH CH . In another embodiment is a compound of Formula (If) wherein R is -(C -C )alkyl-OH. In
2 3 1 6
18253141_1 (GHMatters) P111789.NZ
another embodiment is a compound of Formula (If) wherein R is -CH OH. In another embodiment is a
compound of Formula (If) wherein R is -(C -C )cycloalkyl. In another embodiment is a compound of
Formula (If) wherein R is cyclopropyl. In another embodiment is a compound of Formula (If) wherein R
is -C(O)NH .
[00202] In another embodiment is a compound of Formula (If) wherein R and R and the carbon atom to
which they are attached form a cyclopropyl ring.
In another embodiment is a compound of Formula (If) wherein R is -(C -C )alkyl. In another
embodiment is a compound of Formula (If) wherein R is -CH . In another embodiment is a compound of
Formula (If) wherein R is -CH CH . In another embodiment is a compound of Formula (If) wherein R is
-(C -C )haloalkyl. In another embodiment is a compound of Formula (If) wherein R is -CH F. In another
1 6 2
embodiment is a compound of Formula (If) wherein R is -CHF . In another embodiment is a compound of
Formula (If) wherein R is -(C -C )cycloalkyl. In another embodiment is a compound of Formula (If)
wherein R is cyclopropyl. In another embodiment is a compound of Formula (If) wherein R is H.
In another embodiment is a compound of Formula (If) wherein R is -(C -C )alkyl. In another
embodiment is a compound of Formula (If) wherein R is -CH . In another embodiment is a compound of
11 23
Formula (If) wherein R is -(C -C )alkyl-OR . In another embodiment is a compound of Formula (If)
11 11
wherein R is -CH OH. In another embodiment is a compound of Formula (If) wherein R is -
CH CH OH. In another embodiment is a compound of Formula (If) wherein R is -(C -C )alkyl. In
2 2 1 6
11 21 22
another embodiment is a compound of Formula (If) wherein R is -(C -C )alkyl-NR R . In another
embodiment is a compound of Formula (If) wherein R is -(C -C )alkyl-NH . In another embodiment is a
1 6 2
compound of Formula (If) wherein R is -CH NH . In another embodiment is a compound of Formula (If)
11 11
wherein R is -CH CH NH . In another embodiment is a compound of Formula (If) wherein R is -
2 2 2
CH CH CH NH . In another embodiment is a compound of Formula (If) wherein R is -
2 2 2 2
CH CH CH CH NH . In another embodiment is a compound of Formula (If) wherein R is -(C -C )alkyl-
2 2 2 2 2 1 6
CN. In another embodiment is a compound of Formula (If) wherein R is -CH CN. In another
11 25 26
embodiment is a compound of Formula (If) wherein R is -(C -C )alkyl-C(O)NR R . In another
embodiment is a compound of Formula (If) wherein R is -CH C(O)NH . In another embodiment is a
compound of Formula (If) wherein R is -CH CH C(O)NH . In another embodiment is a compound of
2 2 2
Formula (If) wherein R is -(C -C )alkyl-heteroaryl. In another embodiment is a compound of Formula
11 25 26
(If) wherein R is -(C -C )alkyl-N(H)S(O) NR R . In another embodiment is a compound of Formula
1 6 2
11 11
(If) wherein R is -CH N(H)S(O) NH . In another embodiment is a compound of Formula (If) wherein R
2 2 2
is H.
11 18
In another embodiment is a compound of Formula (If) wherein R and R are combined to
form an optionally substituted heterocycloalkyl ring.
[00206] In another embodiment is a compound of Formula (If) wherein R is H or -(C -C )alkyl-
21 22 1
NR R . In another embodiment is a compound of Formula (If) wherein R is H. In another embodiment is
1 21 22
a compound of Formula (If) wherein R is -(C -C )alkyl-NR R . In another embodiment is a compound
18253141_1 (GHMatters) P111789.NZ
of Formula (If) wherein R is -CH CH NH . In another embodiment is a compound of Formula (If)
2 2 2
wherein R is -CH CH CH NH . In another embodiment is a compound of Formula (If) wherein R is -
2 2 2 2
1 21 22
CH NH . In another embodiment is a compound of Formula (If) wherein R is H, -(C -C )alkyl-NR R ,
2 2 1 6
or -CH CH(OH)CH NH . In another embodiment is a compound of Formula (If) wherein R is -
2 2 2
CH CH(OH)CH NH .
2 2 2
In another embodiment is a compound of Formula (If) wherein X is optionally substituted aryl.
In a further embodiment is a compound of Formula (If) wherein X is optionally substituted phenyl. In
another embodiment is a compound of Formula (If) wherein X is optionally substituted heteroaryl. In a
further embodiment is a compound of Formula (If) wherein X is monosubstituted or disubstituted
heteroaryl. In a further embodiment is a compound of Formula (If) wherein X is disubstituted heteroaryl.
In a further embodiment is a compound of Formula (If) wherein X is heteroaryl monosubstituted or
disubstituted with substituents each independently selected from halogen, -CN, optionally substituted -(C -
23 25 26
C )alkyl, optionally substituted -O-(C -C )alkyl, OR , -NR R , and -NO . In a further embodiment is a
6 1 6 2
compound of Formula (If) wherein X is heteroaryl monosubstituted or disubstituted with substituents each
independently selected from -(C -C )alkyl. In a further embodiment is a compound of Formula (If)
wherein X is heteroaryl monosubstituted or disubstituted with methyl. In a further embodiment is a
compound of Formula (If) wherein X is pyridinyl monosubstituted or disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
23 25 26
(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound of Formula (If) wherein X
1 6 2
is pyridinyl monosubstituted or disubstituted with substituents each independently selected from -(C -
C )alkyl. In a further embodiment is a compound of Formula (If) wherein X is pyridinyl monosubstituted
or disubstituted with methyl. In a further embodiment is a compound of Formula (If) wherein X is
pyrimidinyl monosubstituted or disubstituted with substituents each independently selected from halogen, -
23 25 26
CN, optionally substituted -(C -C )alkyl, optionally substituted -O-(C -C )alkyl, OR , -NR R , or -NO .
1 6 1 6 2
In a further embodiment is a compound of Formula (If) wherein X is pyrimidinyl monosubstituted or
disubstituted with substituents each independently selected from -(C -C )alkyl. In a further embodiment is
a compound of Formula (If) wherein X is pyrimidinyl monosubstituted or disubstituted with methyl. In
another embodiment is a compound of Formula (If) wherein X is optionally substituted -(C -C )alkyl-.
In another embodiment is a compound of Formula (If) wherein Y is optionally substituted aryl.
In a further embodiment is a compound of Formula (If) wherein Y is optionally substituted phenyl. In
another embodiment is a compound of Formula (If) wherein Y is optionally substituted heteroaryl. In
another embodiment is a compound of Formula (If) wherein Y is optionally substituted -(C -C )alkyl-. In
another embodiment is a compound of Formula (If) wherein Y is optionally substituted (C -C )cycloalkyl-.
In another embodiment is a compound of Formula (If) wherein Y is optionally substituted heterocycloalkyl.
In another embodiment is a compound of Formula (If) wherein Y is -O-. In another embodiment is a
compound of Formula (If) wherein Y is -(C -C )alkynyl. In another embodiment is a compound of
18253141_1 (GHMatters) P111789.NZ
Formula (If) wherein Y is -O-(C -C )alkyl-. In another embodiment is a compound of Formula (If)
wherein Y is a bond.
In another embodiment is a compound of Formula (If) wherein Z is -(C -C )alkyl. In a further
1 12
embodiment is a compound of Formula (If) wherein Z is n-butyl, isobutyl, or tert-butyl. In another
embodiment is a compound of Formula (If) wherein Z is -O-(C -C )alkyl. In another embodiment is a
1 12
compound of Formula (If) wherein Z is -O-(C -C )cycloalkyl. In another embodiment is a compound of
Formula (If) wherein Z is -(C -C )alkenyl. In another embodiment is a compound of Formula (If) wherein
2 12
Z is optionally substituted aryl. In a further embodiment is a compound of Formula (If) wherein Z is
optionally substituted phenyl. In a further embodiment is a compound of Formula (If) wherein Z is phenyl
monsubstituted or disubstituted with a substituent independently selected from -(C -C )alkyl. In a further
embodiment is a compound of Formula (If) wherein Z is phenyl monosubstituted with n-butyl, isobutyl, or
tert-butyl. In a further embodiment is a compound of Formula (If) wherein Z is phenyl monosubstituted
with n-butyl. In a further embodiment is a compound of Formula (If) wherein Z is phenyl monosubstituted
with isobutyl. In a further embodiment is a compound of Formula (If) wherein Z is phenyl
monosubstituted with tert-butyl. In another embodiment is a compound of Formula (If) wherein Z is
optionally substituted heteroaryl. In another embodiment is a compound of Formula (If) wherein Z is
optionally substituted -(C -C )cycloalkyl. In another embodiment is a compound of Formula (If) wherein Z
is optionally substituted heterocycloalkyl. In another embodiment is a compound of Formula (If) wherein
Z is halogen.
[00210] In another aspect described herein is a compound of Formula (II):
(R )
27 6
(R ) R
13 14 N
18 16
O R R
Z X N
17 9
O R O R
11 12
Formula (II);
wherein:
1 2 23
R and R are each independently H, -(C -C )alkyl, -(C -C )alkyl-OR , -CH CH(OH)CH NH , -
1 6 1 6 2 2 2
CH CH(heterocycloalkyl)CH NH , -CH C(O)NH , -CH C(O)N(H)CH CN, -(C -C )alkyl-C(O)OR , -
2 2 2 2 2 2 2 1 6
21 22 25 26 23 21 22
(C -C )alkyl-NR R , -(C -C )alkyl-C(O)NR R , -(C -C )alkyl-N(R )C(O)(C -C )alkylNR R , -
1 6 1 6 1 6 1 6
23 23
(C -C )alkyl-N(R )C(O)(C -C )alkyl, -(C -C )alkyl-C(O)N(R )(C -C )alkyl, -(C -C )alkyl-
1 6 1 6 1 6 1 6 1 6
23 23 21 22
C(O)N(R )(C -C )alkyl-heterocycloalkyl, -(C -C )alkyl-NR C(=NH)NR R , -(C -C )alkyl-
1 6 1 6 1 6
18253141_1 (GHMatters) P111789.NZ
23 23 21 22
NR C(=NH)R , -(C -C )alkyl-[(C -C )alkyl-NR R ] , -(C -C )heteroalkyl, or optionally substituted
1 6 1 6 2 1 6
heterocycloalkyl;
or R and R and the atoms to which they are attached form an optionally substituted heterocycloalkyl ring;
R is H or -(C -C )alkyl;
R is H, -(C -C )alkyl, -(C -C )alkyl-OH, -(C -C )cycloalkyl, or -C(O)NH ;
1 6 1 6 3 6 2
or R and R are combined to form a heterocycloalkyl ring;
R is H or -(C -C )alkyl;
or R and R and the carbon atom to which they are attached form a cyclopropyl ring;
6 7 8
R , R , and R are each independently H or -(C -C )alkyl;
R is H, -(C -C )alkyl, -(C -C )haloalkyl, or -(C -C )cycloalkyl;
1 6 1 6 3 6
R is H or -(C -C )alkyl;
11 12 23 23
R and R are each independently H, -NH , -(C -C )alkyl, -(C -C )alkyl-OR , -(C -C )alkyl-SR , -(C -
2 1 6 1 6 1 6 1
23 21 22 23 23
C )alkyl-C(O)OR , -(C -C )alkyl-NR R , -(C -C )alkyl-NR OR , -(C -C )alkyl-
6 1 6 1 6 1 6
23 23 25 26
NHC(O)NR OR , -(C -C )alkyl-O-(C -C )alkyl-NR R , -(C -C )alkyl-CN, -(C -C )alkyl-
1 6 1 6 1 6 1 6
23 23 25 26
NR C(O)R , -(C -C )alkyl-C(O)NR R , -(C -C )heteroalkyl-CO H, -(C -C )alkyl-S(O)(C -C )alkyl,
1 6 1 6 2 1 6 1 6
-(C -C )alkyl-N(H)CH=NH, -(C -C )alkyl-C(NH )=NH, -(C -C )alkyl-N(H)C(=NH)NH , -(C -
1 6 1 6 2 1 6 2 1
26 25 26
C )alkyl-N(H)S(O) NR R , -(C -C )alkyl-N(H)S(O) (C -C )alkyl, -(C -C )alkyl-N(H)-C(O)NR R ,
6 2 1 6 2 1 6 1 6
-(C -C )alkylC(O)N(H)[optionally substituted(C -C )alkyl]-OR , -(C -C )alkylN(H)C(O)(C -
1 6 2 6 1 6 1
23 25 26
C )alkyl-OR , -(C -C )alkylC(O)N(H)heterocycloalkyl, -(C -C )alkylC(O)NR R , -(C -C )alkyl-
6 1 6 1 6 1 6
26 25 26
N(H)-C(O)-(C -C )alkyl-NR R , -(C -C )alkyl-N(H)-(C -C )alkylC(O)NR R , -(C -C )alkyl-
1 6 1 6 1 6 1 6
heterocycloalkyl, optionally substituted -(C -C )alkyl-N(H)heterocycloalkyl, or -(C -C )alkyl-
1 6 1 6
heteroaryl;
13 14 23 23
R and R are each independently H, -NH , -(C -C )alkyl, -(C -C )alkyl-OR , -(C -C )alkyl-SR , -(C -
2 1 6 1 6 1 6 1
23 21 22 25 26
C )alkyl-C(O)OR , -(C -C )alkyl-NR R , -(C -C )alkyl-CN, -(C -C )alkyl-C(O)NR R , -(C -
6 1 6 1 6 1 6 1
C )alkyl-N(H)C(NH)NH , -(C -C )alkyl-heterocycloalkyl, or -(C -C )alkyl-heteroaryl;
6 2 1 6 1 6
13 19 14
or R and R are combined to form an optionally substituted heterocycloalkyl ring; and R is H;
16 17 18 19
R , R , R , R , and R are each independently H, -(C -C )alkyl, -(C -C )cycloalkyl, -(C -C )alkyl-
1 6 3 6 1 6
23 23 21 22
OR , -(C -C )alkyl-C(O)OR , or -(C -C )alkyl-NR R ;
1 6 1 6
X is optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, optionally substituted -(C -
1 6 2 6 2 6 3
C )cycloalkyl-, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally
24 24
substituted heteroaryl, -O-(C -C )alkyl-, -N(R )(C -C )alkyl-, -N(R )(C -C )aryl-, or -SO (C -
1 6 1 6 6 10 2 1
C )alkyl-;
Y is a bond, -O-, -S-, optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, -(C -
1 6 2 6 2 6 1
24 24
C )alkyl-N(R )(C -C )alkyl-, -O-(C -C )alkyl-, -O(C -C )aryl-, -N(R )(C -C )alkyl-, -
6 1 6 1 6 6 10 1 6
24 24
N(R )SO (C -C )alkyl-, -N(R )C(O)(C -C )alkyl-, -C(O)(C -C )alkyl-, -S(C -C )alkyl-, -SO (C -
2 1 6 1 6 1 6 1 6 2 1
C )alkyl-, -C(O)NH(C -C )alkyl-, optionally substituted -(C -C )cycloalkyl-, optionally substituted -
6 1 6 3 7
18253141_1 (GHMatters) P111789.NZ
24 24 24
C(O)N(R )aryl-, optionally substituted -N(R )C(O)aryl-, optionally substituted -N(R )SO aryl-,
optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Z is H, halogen, -NH , -CN, -CF , -CO H, -(C -C )alkyl, -(C -C )alkenyl, -CH=((C -C )cycloalkyl), -
2 3 2 1 12 2 12 3 7
26
(C -C )alkynyl, -C(O)NR R , -O-(C -C )alkyl, -S-(C -C )alkyl, -O-(C -C )[optionally substituted
2 12 1 12 1 12 3 10
23 23
(C -C )cycloalkyl], -O-(C -C )alkyl-OR , -(C -C )alkyl-OR , -(C -C )alkyl-CN, -S-(C -C )alkyl, -
3 7 1 6 1 12 1 12 1 12
24 24
N(R )(C -C )alkyl, -N(R )C(O)(C -C )alkyl, optionally substituted -(C -C )cycloalkyl, -(C -
1 12 1 12 3 7 1
C )alkyl-(C -C )cycloalkyl, -(C -C )alkyl-heterocycloalkyl, optionally substituted heterocycloalkyl,
6 3 7 1 6
optionally substituted aryl, or optionally substituted heteroaryl;
21 22
each R and R is independently H, -(C -C )alkyl, -(C -C )heteroalkyl, -(C -C )alkyl-CO H, -C(O)(C -
1 6 1 6 1 6 2 1
31 31 21 22
C )alkyl, -C(O)N(R ) , or -SO N(R ) ; or R and R and the nitrogen atom to which they are
6 2 2 2
attached form a heterocycloalkyl ring;
31 31
each R is independently H or -(C -C )alkyl; or two R and the nitrogen atom to which they are attached
form a heterocycloalkyl ring;
each R is independently H or -(C -C )alkyl;
each R is independently H or -(C -C )alkyl;
26
each R and R is independently H or optionally substituted -(C -C )alkyl;
26
or R and R and the nitrogen atom to which they are attached form a heterocycloalkyl ring;
27 23 24 23 23 24
each R is independently halogen, -NR R , -NHC(O)R , -NHC(O)NR R , nitro, hydroxyl, optionally
substituted -(C -C )alkyl, optionally substituted -(C -C )heteroalkyl, optionally substituted -(C -
1 6 1 6 1
C )heteroalkyloxy, optionally substituted -(C -C )heteroalkylamino, -(C -C )alkoxy, -C(O)(C -
6 1 6 1 6 1
C )alkyl, or -S(O) (C -C )alkyl;
6 2 1 6
1 27
or R and R and the atoms to which they are attached form an optionally substituted 5- or 6-membered
heterocycloalkyl ring;
28 23 24 23 23 24
each R is independently halogen, -NR R , -NHC(O)R , -NHC(O)NR R , nitro, hydroxyl, optionally
substituted -(C -C )alkyl, optionally substituted -(C -C )heteroalkyl, optionally substituted -(C -
1 6 1 6 1
C )heteroalkyloxy, optionally substituted -(C -C )heteroalkylamino, -(C -C )alkoxy, -C(O)(C -
6 1 6 1 6 1
C )alkyl, or -S(O) (C -C )alkyl;
6 2 1 6
2 28
or R and R and the atoms to which they are attached form an optionally substituted 5- or 6-membered
heterocycloalkyl ring;
n is 0 or 1;
p is 0, 1, or 2; and
q is 0, 1, or 2;
or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
In one embodiment is a compound of Formula (II) wherein n is 0. In another embodiment is a
compound of Formula (II) wherein n is 1.
6 7 8
In another embodiment is a compound of Formula (II) wherein R , R , and R are H.
16
In another embodiment is a compound of Formula (II) wherein R and R are H.
18253141_1 (GHMatters) P111789.NZ
In one embodiment is a compound of Formula (II) wherein R is -(C -C )alkyl. In another
embodiment is a compound of Formula (II) wherein R is -CH . In another embodiment is a compound of
17 17
Formula (II) wherein R is -CH CH . In another embodiment is a compound of Formula (II) wherein R
is -(C -C )cycloalkyl. In another embodiment is a compound of Formula (II) wherein R is cyclopropyl. In
17 23
another embodiment is a compound of Formula (II) wherein R is -(C -C )alkyl-C(O)OR . In another
embodiment is a compound of Formula (II) wherein R is -CH CH OH. In another embodiment is a
17 21 22
compound of Formula (II) wherein R is -(C -C )alkyl-NR R . In another embodiment is a compound of
Formula (II) wherein R is -CH CH NH . In another embodiment is a compound of Formula (II) wherein
2 2 2
R is H.
[00215] In another embodiment is a compound of Formula (II) wherein R is H.
In another embodiment is a compound of Formula (II) wherein R is H.
In another embodiment is a compound of Formula (II) wherein R is H.
In another embodiment is a compound of Formula (II) wherein R is H.
In another embodiment is a compound of Formula (II) wherein R is H. In another embodiment
is a compound of Formula (II) wherein R is -(C -C )alkyl. In another embodiment is a compound of
Formula (II) wherein R is -CH . In another embodiment is a compound of Formula (II) wherein R is -
CH CH . In another embodiment is a compound of Formula (II) wherein R is -(C -C )alkyl-OH. In
2 3 1 6
another embodiment is a compound of Formula (II) wherein R is -CH OH. In another embodiment is a
compound of Formula (II) wherein R is -(C -C )cycloalkyl. In another embodiment is a compound of
Formula (II) wherein R is cyclopropyl. In another embodiment is a compound of Formula (II) wherein R
is -C(O)NH .
3 4 5
In another embodiment is a compound of Formula (II) wherein R , R , and R are H.
In another embodiment is a compound of Formula (II) wherein R and R and the carbon atom to
which they are attached form a cyclopropyl ring.
[00222] In another embodiment is a compound of Formula (II) wherein R is H.
9
In another embodiment is a compound of Formula (II) wherein R is H and R is -(C -C )alkyl.
9
In another embodiment is a compound of Formula (II) wherein R is H and R is -CH . In another
9
embodiment is a compound of Formula (II) wherein R is H and R is -CH CH . In another embodiment is
9
a compound of Formula (II) wherein R is H and R is -(C -C )haloalkyl. In another embodiment is a
9
compound of Formula (II) wherein R is H and R is -CH F. In another embodiment is a compound of
9
Formula (II) wherein R is H and R is -CHF . In another embodiment is a compound of Formula (II)
9
wherein R is H and R is -(C -C )cycloalkyl. In another embodiment is a compound of Formula (II)
9 10
wherein R is H and R is cyclopropyl. In another embodiment is a compound of Formula (II) wherein R
is H and R is H.
[00224] In another embodiment is a compound of Formula (II) wherein R is H.
12 11
In another embodiment is a compound of Formula (II) wherein R is H and R is -(C -C )alkyl.
12 11
In another embodiment is a compound of Formula (II) wherein R is H and R is -CH . In another
18253141_1 (GHMatters) P111789.NZ
12 11 23
embodiment is a compound of Formula (II) wherein R is H and R is -(C -C )alkyl-OR . In another
embodiment is a compound of Formula (II) wherein R is -CH OH. In another embodiment is a
12 11
compound of Formula (II) wherein R is H and R is -CH CH OH. In another embodiment is a
12 11
compound of Formula (II) wherein R is H and R is -(C -C )alkyl. In another embodiment is a
12 11 21 22
compound of Formula (II) wherein R is H and R is -(C -C )alkyl-NR R . In another embodiment is a
12 11
compound of Formula (II) wherein R is H and R is -(C -C )alkyl-NH . In another embodiment is a
1 6 2
12 11
compound of Formula (II) wherein R is H and R is -CH NH . In another embodiment is a compound of
12 11
Formula (II) wherein R is H and R is -CH CH NH . In another embodiment is a compound of Formula
2 2 2
12 11
(II) wherein R is H and R is -CH CH CH NH . In another embodiment is a compound of Formula (II)
2 2 2 2
12 11
wherein R is H and R is -CH CH CH CH NH . In another embodiment is a compound of Formula (II)
2 2 2 2 2
12 11
wherein R is H and R is -(C -C )alkyl-CN. In another embodiment is a compound of Formula (II)
12 11 12
wherein R is H and R is -CH CN. In another embodiment is a compound of Formula (II) wherein R is
11 25 26
H and R is -(C -C )alkyl-C(O)NR R . In another embodiment is a compound of Formula (II) wherein
12 11 12
R is H and R is -CH C(O)NH . In another embodiment is a compound of Formula (II) wherein R is H
11 12
and R is -CH CH C(O)NH . In another embodiment is a compound of Formula (II) wherein R is H and
2 2 2
11 12
R is -(C -C )alkyl-heteroaryl. In another embodiment is a compound of Formula (II) wherein R is H
11 25 26
and R is -(C -C )alkyl-N(H)S(O) NR R . In another embodiment is a compound of Formula (II)
1 6 2
12 11
wherein R is H and R is -CH N(H)S(O) NH . In another embodiment is a compound of Formula (II)
2 2 2
12 11
wherein R is H and R is H.
11 18
[00226] In another embodiment is a compound of Formula (II) wherein R and R are combined to
form an optionally substituted heterocycloalkyl ring and R is H.
In another embodiment is a compound of Formula (II) wherein R is H.
14 13
In another embodiment is a compound of Formula (II) wherein R is H and R is -(C -C )alkyl.
14 13
In another embodiment is a compound of Formula (II) wherein R is H and R is -CH . In another
14 13 23
embodiment is a compound of Formula (II) wherein R is H and R is -(C -C )alkyl-OR . In another
14 13
embodiment is a compound of Formula (II) wherein R is H and R is -CH OH. In another embodiment
14 13
is a compound of Formula (II) wherein R is H and R is -CH CH OH. In another embodiment is a
14 13
compound of Formula (II) wherein R is H and R is -(C -C )alkyl. In another embodiment is a
14 13 21 22
compound of Formula (II) wherein R is H and R is -(C -C )alkyl-NR R . In another embodiment is a
14 13
compound of Formula (II) wherein R is H and R is -(C -C )alkyl-NH . In another embodiment is a
1 6 2
14 13
compound of Formula (II) wherein R is H and R is -CH NH . In another embodiment is a compound of
14 13
Formula (II) wherein R is H and R is -CH CH NH . In another embodiment is a compound of Formula
2 2 2
14 13
(II) wherein R is H and R is -CH CH CH NH . In another embodiment is a compound of Formula (II)
2 2 2 2
14 13
wherein R is H and R is -CH CH CH CH NH . In another embodiment is a compound of Formula (II)
2 2 2 2 2
14 13
wherein R is H and R is -(C -C )alkyl-CN. In another embodiment is a compound of Formula (II)
14 13 14
wherein R is H and R is -CH CN. In another embodiment is a compound of Formula (II) wherein R is
13 25 26
H and R is -(C -C )alkyl-C(O)NR R . In another embodiment is a compound of Formula (II) wherein
18253141_1 (GHMatters) P111789.NZ
14 13 14
R is H and R is -CH C(O)NH . In another embodiment is a compound of Formula (II) wherein R is H
13 14
and R is -CH CH C(O)NH . In another embodiment is a compound of Formula (II) wherein R is H and
2 2 2
13 14
R is -(C -C )alkyl-heteroaryl. In another embodiment is a compound of Formula (II) wherein R is H
and R is H.
13 19
[00229] In another embodiment is a compound of Formula (II) wherein R and R are combined to
form an optionally substituted heterocycloalkyl ring and R is H.
In another embodiment is a compound of Formula (II) wherein p is 1 and R is halogen. In
another embodiment is a compound of Formula (II) wherein p is 1 and R is optionally substituted -(C -
C )alkyl. In another embodiment is a compound of Formula (II) wherein q is 0, p is 1 and R is halogen.
In another embodiment is a compound of Formula (II) wherein q is 0, p is 1 and R is optionally
substituted -(C -C )alkyl. In another embodiment is a compound of Formula (II) wherein q is 1 and R is
halogen. In another embodiment is a compound of Formula (II) wherein q is 1 and R is optionally
substituted -(C -C )alkyl. In another embodiment is a compound of Formula (II) wherein p is 0, q is 1 and
28 28
R is halogen. In another embodiment is a compound of Formula (II) wherein p is 0, q is 1 and R is
optionally substituted -(C -C )alkyl.
In another embodiment is a compound of Formula (II) wherein p is 0, and q is 0.
In another embodiment is a compound of Formula (II) wherein R and R are each independently
21 22 1 2
H or -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (II) wherein R and R are
each H. In another embodiment is a compound of Formula (II) wherein R and R are each independently -
21 22 1 2
(C -C )alkyl-NR R . In another embodiment is a compound of Formula (II) wherein R is H, and R is -
21 22 1
(C -C )alkyl-NR R . In another embodiment is a compound of Formula (II) wherein R is -(C -C )alkyl-
1 6 1 6
21 22 2 1 2
NR R , and R is H. In another embodiment is a compound of Formula (II) wherein R is H, and R is -
CH CH NH . In another embodiment is a compound of Formula (II) wherein R is -CH CH NH , and R is
2 2 2 2 2 2
H. In another embodiment is a compound of Formula (II) wherein R and R are each -CH CH NH . In
2 2 2
another embodiment is a compound of Formula (II) wherein R and R are each independently H, -(C -
21 22
C )alkyl-NR R , or -CH CH(OH)CH NH . In another embodiment is a compound of Formula (II)
6 2 2 2
wherein R and R are each independently -CH CH(OH)CH NH . In another embodiment is a compound
2 2 2
of Formula (II) wherein R is H, and R is -CH CH(OH)CH NH . In another embodiment is a compound
2 2 2
of Formula (II) wherein R is -CH CH(OH)CH NH , and R is H. In a further embodiment is a compound
2 2 2
of Formula (II) wherein R and R and the atoms to which they are attached form an optionally substituted
heterocycloalkyl ring.
In another embodiment is a compound of Formula (II) wherein X is optionally substituted aryl.
In a further embodiment is a compound of Formula (II) wherein X is optionally substituted phenyl. In
another embodiment is a compound of Formula (II) wherein X is optionally substituted heteroaryl. In a
further embodiment is a compound of Formula (II) wherein X is disubstituted heteroaryl. In a further
embodiment is a compound of Formula (II) wherein X is heteroaryl disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
18253141_1 (GHMatters) P111789.NZ
23 25 26
(C -C )alkyl, OR , -NR R , and -NO . In a further embodiment is a compound of Formula (II) wherein
1 6 2
X is heteroaryl disubstituted with substituents each independently selected from -(C -C )alkyl. In a further
embodiment is a compound of Formula (II) wherein X is heteroaryl disubstituted with methyl. In a further
embodiment is a compound of Formula (II) wherein X is pyridinyl disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
23 25 26
(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound of Formula (II) wherein X
1 6 2
is pyridinyl disubstituted with substituents each independently selected from -(C -C )alkyl. In a further
embodiment is a compound of Formula (II) wherein X is pyridinyl disubstituted with methyl. In a further
embodiment is a compound of Formula (II) wherein X is pyrimidinyl disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
23 25 26
(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound of Formula (II) wherein X
1 6 2
is pyrimidinyl disubstituted with substituents each independently selected from -(C -C )alkyl. In a further
embodiment is a compound of Formula (II) wherein X is pyrimidinyl disubstituted with methyl. In another
embodiment is a compound of Formula (II) wherein X is optionally substituted -(C -C )alkyl-.
[00234] In another embodiment is a compound of Formula (II) wherein Y is optionally substituted aryl.
In a further embodiment is a compound of Formula (II) wherein Y is optionally substituted phenyl. In
another embodiment is a compound of Formula (II) wherein Y is optionally substituted heteroaryl. In
another embodiment is a compound of Formula (II) wherein Y is optionally substituted -(C -C )alkyl-. In
another embodiment is a compound of Formula (II) wherein Y is optionally substituted (C -C )cycloalkyl-.
In another embodiment is a compound of Formula (II) wherein Y is optionally substituted heterocycloalkyl.
In another embodiment is a compound of Formula (II) wherein Y is -O-. In another embodiment is a
compound of Formula (II) wherein Y is -(C -C )alkynyl. In another embodiment is a compound of
Formula (II) wherein Y is -O-(C -C )alkyl-. In another embodiment is a compound of Formula (II)
wherein Y is a bond.
[00235] In another embodiment is a compound of Formula (II) wherein Z is -(C -C )alkyl. In a further
1 12
embodiment is a compound of Formula (II) wherein Z is n-butyl, isobutyl, or tert-butyl. In another
embodiment is a compound of Formula (II) wherein Z is -O-(C -C )alkyl. In another embodiment is a
1 12
compound of Formula (II) wherein Z is -O-(C -C )cycloalkyl. In another embodiment is a compound of
Formula (II) wherein Z is -(C -C )alkenyl. In another embodiment is a compound of Formula (II) wherein
2 12
Z is optionally substituted aryl. In a further embodiment is a compound of Formula (II) wherein Z is
optionally substituted phenyl. In a further embodiment is a compound of Formula (II) wherein Z is phenyl
monsubstituted or disubstituted with a substituent independently selected from -(C -C )alkyl. In a further
embodiment is a compound of Formula (II) wherein Z is phenyl monosubstituted with n-butyl, isobutyl, or
tert-butyl. In a further embodiment is a compound of Formula (II) wherein Z is phenyl monosubstituted
with n-butyl. In a further embodiment is a compound of Formula (II) wherein Z is phenyl monosubstituted
with isobutyl. In a further embodiment is a compound of Formula (II) wherein Z is phenyl
monosubstituted with tert-butyl. In another embodiment is a compound of Formula (II) wherein Z is
18253141_1 (GHMatters) P111789.NZ
optionally substituted heteroaryl. In another embodiment is a compound of Formula (II) wherein Z is
optionally substituted -(C -C )cycloalkyl. In another embodiment is a compound of Formula (II) wherein Z
is optionally substituted heterocycloalkyl. In another embodiment is a compound of Formula (II) wherein
Z is halogen.
[00236] In another embodiment described herein is a compound of Formula (II) having the structure of
Formula (IIa):
(R )
(R )
13 14 N
O R R 18 16
Z X N
R 10
17 9 R
11 12
Formula (IIa);
wherein:
1 2 23
R and R are each independently H, -(C -C )alkyl, -(C -C )alkyl-OR , -CH CH(OH)CH NH , -
1 6 1 6 2 2 2
CH CH(heterocycloalkyl)CH NH , -CH C(O)NH , -CH C(O)N(H)CH CN, -(C -C )alkyl-C(O)OR , -
2 2 2 2 2 2 2 1 6
21 22 25 26 23 21 22
(C -C )alkyl-NR R , -(C -C )alkyl-C(O)NR R , -(C -C )alkyl-N(R )C(O)(C -C )alkylNR R , -
1 6 1 6 1 6 1 6
23 23
(C -C )alkyl-N(R )C(O)(C -C )alkyl, -(C -C )alkyl-C(O)N(R )(C -C )alkyl, -(C -C )alkyl-
1 6 1 6 1 6 1 6 1 6
23 23 21 22
C(O)N(R )(C -C )alkyl-heterocycloalkyl, -(C -C )alkyl-NR C(=NH)NR R , -(C -C )alkyl-
1 6 1 6 1 6
23 23 21 22
NR C(=NH)R , -(C -C )alkyl-[(C -C )alkyl-NR R ] , -(C -C )heteroalkyl, or optionally substituted
1 6 1 6 2 1 6
heterocycloalkyl;
or R and R and the atoms to which they are attached form an optionally substituted heterocycloalkyl ring;
R is H or -(C -C )alkyl;
R is H, -(C -C )alkyl, -(C -C )alkyl-OH, -(C -C )cycloalkyl, or -C(O)NH ;
1 6 1 6 3 6 2
or R and R are combined to form a heterocycloalkyl ring;
R is H or -(C -C )alkyl;
or R and R and the carbon atom to which they are attached form a cyclopropyl ring;
6 7 8
R , R , and R are each independently H or -(C -C )alkyl;
R is H, -(C -C )alkyl, -(C -C )haloalkyl, or -(C -C )cycloalkyl;
1 6 1 6 3 6
R is H or -(C -C )alkyl;
11 12 23 23
R and R are each independently H, -NH , -(C -C )alkyl, -(C -C )alkyl-OR , -(C -C )alkyl-SR , -(C -
2 1 6 1 6 1 6 1
23 21 22 23 23
C )alkyl-C(O)OR , -(C -C )alkyl-NR R , -(C -C )alkyl-NR OR , -(C -C )alkyl-
6 1 6 1 6 1 6
23 23 25 26
NHC(O)NR OR , -(C -C )alkyl-O-(C -C )alkyl-NR R , -(C -C )alkyl-CN, -(C -C )alkyl-
1 6 1 6 1 6 1 6
23 23 25 26
NR C(O)R , -(C -C )alkyl-C(O)NR R , -(C -C )heteroalkyl-CO H, -(C -C )alkyl-S(O)(C -C )alkyl,
1 6 1 6 2 1 6 1 6
18253141_1 (GHMatters) P111789.NZ
-(C -C )alkyl-N(H)CH=NH, -(C -C )alkyl-C(NH )=NH, -(C -C )alkyl-N(H)C(=NH)NH , -(C -
1 6 1 6 2 1 6 2 1
26 25 26
C )alkyl-N(H)S(O) NR R , -(C -C )alkyl-N(H)S(O) (C -C )alkyl, -(C -C )alkyl-N(H)-C(O)NR R ,
6 2 1 6 2 1 6 1 6
-(C -C )alkylC(O)N(H)[optionally substituted(C -C )alkyl]-OR , -(C -C )alkylN(H)C(O)(C -
1 6 2 6 1 6 1
23 25 26
C )alkyl-OR , -(C -C )alkylC(O)N(H)heterocycloalkyl, -(C -C )alkylC(O)NR R , -(C -C )alkyl-
6 1 6 1 6 1 6
26 25 26
N(H)-C(O)-(C -C )alkyl-NR R , -(C -C )alkyl-N(H)-(C -C )alkylC(O)NR R , -(C -C )alkyl-
1 6 1 6 1 6 1 6
heterocycloalkyl, optionally substituted -(C -C )alkyl-N(H)heterocycloalkyl, or -(C -C )alkyl-
1 6 1 6
heteroaryl;
13 14 23 23
R and R are each independently H, -NH , -(C -C )alkyl, -(C -C )alkyl-OR , -(C -C )alkyl-SR , -(C -
2 1 6 1 6 1 6 1
23 21 22 25 26
C )alkyl-C(O)OR , -(C -C )alkyl-NR R , -(C -C )alkyl-CN, -(C -C )alkyl-C(O)NR R , -(C -
6 1 6 1 6 1 6 1
C )alkyl-N(H)C(NH)NH , -(C -C )alkyl-heterocycloalkyl, or -(C -C )alkyl-heteroaryl;
6 2 1 6 1 6
13 19 14
or R and R are combined to form an optionally substituted heterocycloalkyl ring; and R is H;
16 17 18 19
R , R , R , R , and R are each independently H, -(C -C )alkyl, -(C -C )cycloalkyl, -(C -C )alkyl-
1 6 3 6 1 6
23 23 21 22
OR , -(C -C )alkyl-C(O)OR , or -(C -C )alkyl-NR R ;
1 6 1 6
X is optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, optionally substituted -(C -
1 6 2 6 2 6 3
C )cycloalkyl-, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally
24 24
substituted heteroaryl, -O-(C -C )alkyl-, -N(R )(C -C )alkyl-, -N(R )(C -C )aryl-, or -SO (C -
1 6 1 6 6 10 2 1
C )alkyl-;
Y is a bond, -O-, -S-, optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, -(C -
1 6 2 6 2 6 1
24 24
C )alkyl-N(R )(C -C )alkyl-, -O-(C -C )alkyl-, -O(C -C )aryl-, -N(R )(C -C )alkyl-, -
6 1 6 1 6 6 10 1 6
24 24
N(R )SO (C -C )alkyl-, -N(R )C(O)(C -C )alkyl-, -C(O)(C -C )alkyl-, -S(C -C )alkyl-, -SO (C -
2 1 6 1 6 1 6 1 6 2 1
C )alkyl-, -C(O)NH(C -C )alkyl-, optionally substituted -(C -C )cycloalkyl-, optionally substituted -
6 1 6 3 7
24 24 24
C(O)N(R )aryl-, optionally substituted -N(R )C(O)aryl-, optionally substituted -N(R )SO aryl-,
optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Z is H, halogen, -NH , -CN, -CF , -CO H, -(C -C )alkyl, -(C -C )alkenyl, -CH=((C -C )cycloalkyl), -
2 3 2 1 12 2 12 3 7
26
(C -C )alkynyl, -C(O)NR R , -O-(C -C )alkyl, -S-(C -C )alkyl, -O-(C -C )[optionally substituted
2 12 1 12 1 12 3 10
23 23
(C -C )cycloalkyl], -O-(C -C )alkyl-OR , -(C -C )alkyl-OR , -(C -C )alkyl-CN, -S-(C -C )alkyl, -
3 7 1 6 1 12 1 12 1 12
24 24
N(R )(C -C )alkyl, -N(R )C(O)(C -C )alkyl, optionally substituted -(C -C )cycloalkyl, -(C -
1 12 1 12 3 7 1
C )alkyl-(C -C )cycloalkyl, -(C -C )alkyl-heterocycloalkyl, optionally substituted heterocycloalkyl,
6 3 7 1 6
optionally substituted aryl, or optionally substituted heteroaryl;
21 22
each R and R is independently H, -(C -C )alkyl, -(C -C )heteroalkyl, -(C -C )alkyl-CO H, -C(O)(C -
1 6 1 6 1 6 2 1
31 31 21 22
C )alkyl, -C(O)N(R ) , or -SO N(R ) ; or R and R and the nitrogen atom to which they are
6 2 2 2
attached form a heterocycloalkyl ring;
31 31
each R is independently H or -(C -C )alkyl; or two R and the nitrogen atom to which they are attached
form a heterocycloalkyl ring;
each R is independently H or -(C -C )alkyl;
each R is independently H or -(C -C )alkyl;
26
each R and R is independently H or optionally substituted -(C -C )alkyl;
18253141_1 (GHMatters) P111789.NZ
26
or R and R and the nitrogen atom to which they are attached form a heterocycloalkyl ring;
27 23 24 23 23 24
each R is independently halogen, -NR R , -NHC(O)R , -NHC(O)NR R , nitro, hydroxyl, optionally
substituted -(C -C )alkyl, optionally substituted -(C -C )heteroalkyl, optionally substituted -(C -
1 6 1 6 1
C )heteroalkyloxy, optionally substituted -(C -C )heteroalkylamino, -(C -C )alkoxy, -C(O)(C -
6 1 6 1 6 1
C )alkyl, or -S(O) (C -C )alkyl;
6 2 1 6
1 27
or R and R and the atoms to which they are attached form an optionally substituted 5- or 6-membered
heterocycloalkyl ring;
28 23 24 23 23 24
each R is independently halogen, -NR R , -NHC(O)R , -NHC(O)NR R , nitro, hydroxyl, optionally
substituted -(C -C )alkyl, optionally substituted -(C -C )heteroalkyl, optionally substituted -(C -
1 6 1 6 1
C )heteroalkyloxy, optionally substituted -(C -C )heteroalkylamino, -(C -C )alkoxy, -C(O)(C -
6 1 6 1 6 1
C )alkyl, or -S(O) (C -C )alkyl;
6 2 1 6
2 28
or R and R and the atoms to which they are attached form an optionally substituted 5- or 6-membered
heterocycloalkyl ring;
n is 0 or 1;
p is 0, 1, or 2; and
q is 0, 1, or 2;
or a pharmaceutically acceptable salt, solvate, or prodrug thereof.In one embodiment is a
compound of Formula (IIa) wherein n is 0. In another embodiment is a compound of Formula (IIa)
wherein n is 1.
6 7 8
[00238] In another embodiment is a compound of Formula (IIa) wherein R , R , and R are H.
16
In another embodiment is a compound of Formula (IIa) wherein R and R are H.
In one embodiment is a compound of Formula (IIa) wherein R is -(C -C )alkyl. In another
embodiment is a compound of Formula (IIa) wherein R is -CH . In another embodiment is a compound
of Formula (IIa) wherein R is -CH CH . In another embodiment is a compound of Formula (IIa) wherein
17 17
R is -(C -C )cycloalkyl. In another embodiment is a compound of Formula (IIa) wherein R is
cyclopropyl. In another embodiment is a compound of Formula (IIa) wherein R is -(C -C )alkyl-
23 17
C(O)OR . In another embodiment is a compound of Formula (IIa) wherein R is -CH CH OH. In another
17 21 22
embodiment is a compound of Formula (IIa) wherein R is -(C -C )alkyl-NR R . In another embodiment
is a compound of Formula (IIa) wherein R is -CH CH NH . In another embodiment is a compound of
2 2 2
Formula (IIa) wherein R is H.
In another embodiment is a compound of Formula (IIa) wherein R is H.
In another embodiment is a compound of Formula (IIa) wherein R is H.
In another embodiment is a compound of Formula (IIa) wherein R is H.
In another embodiment is a compound of Formula (IIa) wherein R is H.
[00245] In another embodiment is a compound of Formula (IIa) wherein R is H. In another embodiment
is a compound of Formula (IIa) wherein R is -(C -C )alkyl. In another embodiment is a compound of
Formula (IIa) wherein R is -CH . In another embodiment is a compound of Formula (IIa) wherein R is -
18253141_1 (GHMatters) P111789.NZ
CH CH . In another embodiment is a compound of Formula (IIa) wherein R is -(C -C )alkyl-OH. In
2 3 1 6
another embodiment is a compound of Formula (IIa) wherein R is -CH OH. In another embodiment is a
compound of Formula (IIa) wherein R is -(C -C )cycloalkyl. In another embodiment is a compound of
Formula (IIa) wherein R is cyclopropyl. In another embodiment is a compound of Formula (IIa) wherein
R is -C(O)NH .
3 4 5
In another embodiment is a compound of Formula (IIa) wherein R , R , and R are H.
In another embodiment is a compound of Formula (IIa) wherein R and R and the carbon atom
to which they are attached form a cyclopropyl ring.
In another embodiment is a compound of Formula (IIa) wherein R is H.
9
[00249] In another embodiment is a compound of Formula (IIa) wherein R is H and R is -(C -C )alkyl.
9
In another embodiment is a compound of Formula (IIa) wherein R is H and R is -CH . In another
9
embodiment is a compound of Formula (IIa) wherein R is H and R is -CH CH . In another embodiment
9
is H and R is -(C -C )haloalkyl. In another embodiment is a
is a compound of Formula (IIa) wherein R
9
compound of Formula (IIa) wherein R is H and R is -CH F. In another embodiment is a compound of
9
Formula (IIa) wherein R is H and R is -CHF . In another embodiment is a compound of Formula (IIa)
9
wherein R is H and R is -(C -C )cycloalkyl. In another embodiment is a compound of Formula (IIa)
9
wherein R is H and R is cyclopropyl. In another embodiment is a compound of Formula (IIa) wherein
9
R is H and R is H.
In another embodiment is a compound of Formula (IIa) wherein R is H.
12 11
[00251] In another embodiment is a compound of Formula (IIa) wherein R is H and R is -(C -
12 11
C )alkyl. In another embodiment is a compound of Formula (IIa) wherein R is H and R is -CH . In
12 11 23
another embodiment is a compound of Formula (IIa) wherein R is H and R is -(C -C )alkyl-OR . In
another embodiment is a compound of Formula (IIa) wherein R is -CH OH. In another embodiment is a
12 11
compound of Formula (IIa) wherein R is H and R is -CH CH OH. In another embodiment is a
12 11
compound of Formula (IIa) wherein R is H and R is -(C -C )alkyl. In another embodiment is a
12 11 21 22
compound of Formula (IIa) wherein R is H and R is -(C -C )alkyl-NR R . In another embodiment is a
12 11
compound of Formula (IIa) wherein R is H and R is -(C -C )alkyl-NH . In another embodiment is a
1 6 2
12 11
compound of Formula (IIa) wherein R is H and R is -CH NH . In another embodiment is a compound
12 11
of Formula (IIa) wherein R is H and R is -CH CH NH . In another embodiment is a compound of
2 2 2
12 11
Formula (IIa) wherein R is H and R is -CH CH CH NH . In another embodiment is a compound of
2 2 2 2
12 11
Formula (IIa) wherein R is H and R is -CH CH CH CH NH . In another embodiment is a compound of
2 2 2 2 2
12 11
Formula (IIa) wherein R is H and R is -(C -C )alkyl-CN. In another embodiment is a compound of
12 11
Formula (IIa) wherein R is H and R is -CH CN. In another embodiment is a compound of Formula (IIa)
12 11 25 26
wherein R is H and R is -(C -C )alkyl-C(O)NR R . In another embodiment is a compound of Formula
12 11
(IIa) wherein R is H and R is -CH C(O)NH . In another embodiment is a compound of Formula (IIa)
12 11
wherein R is H and R is -CH CH C(O)NH . In another embodiment is a compound of Formula (IIa)
2 2 2
12 11
wherein R is H and R is -(C -C )alkyl-heteroaryl. In another embodiment is a compound of Formula
18253141_1 (GHMatters) P111789.NZ
12 11 25 26
(IIa) wherein R is H and R is -(C -C )alkyl-N(H)S(O) NR R . In another embodiment is a compound
1 6 2
12 11
of Formula (IIa) wherein R is H and R is -CH N(H)S(O) NH . In another embodiment is a compound
2 2 2
12 11
of Formula (IIa) wherein R is H and R is H.
11 18
In another embodiment is a compound of Formula (IIa) wherein R and R are combined to
form an optionally substituted heterocycloalkyl ring and R is H.
In another embodiment is a compound of Formula (IIa) wherein R is H.
14 13
In another embodiment is a compound of Formula (IIa) wherein R is H and R is -(C -
14 13
C )alkyl. In another embodiment is a compound of Formula (IIa) wherein R is H and R is -CH . In
14 13 23
another embodiment is a compound of Formula (IIa) wherein R is H and R is -(C -C )alkyl-OR . In
14 13
another embodiment is a compound of Formula (IIa) wherein R is H and R is -CH OH. In another
14 13
embodiment is a compound of Formula (IIa) wherein R is H and R is -CH CH OH. In another
14 13
embodiment is a compound of Formula (IIa) wherein R is H and R is -(C -C )alkyl. In another
14 13 21 22
embodiment is a compound of Formula (IIa) wherein R is H and R is -(C -C )alkyl-NR R . In another
14 13
embodiment is a compound of Formula (IIa) wherein R is H and R is -(C -C )alkyl-NH . In another
1 6 2
14 13
embodiment is a compound of Formula (IIa) wherein R is H and R is -CH NH . In another embodiment
14 13
is a compound of Formula (IIa) wherein R is H and R is -CH CH NH . In another embodiment is a
2 2 2
14 13
compound of Formula (IIa) wherein R is H and R is -CH CH CH NH . In another embodiment is a
2 2 2 2
14 13
compound of Formula (IIa) wherein R is H and R is -CH CH CH CH NH . In another embodiment is a
2 2 2 2 2
14 13
compound of Formula (IIa) wherein R is H and R is -(C -C )alkyl-CN. In another embodiment is a
14 13
compound of Formula (IIa) wherein R is H and R is -CH CN. In another embodiment is a compound of
14 13 25 26
Formula (IIa) wherein R is H and R is -(C -C )alkyl-C(O)NR R . In another embodiment is a
14 13
compound of Formula (IIa) wherein R is H and R is -CH C(O)NH . In another embodiment is a
14 13
compound of Formula (IIa) wherein R is H and R is -CH CH C(O)NH . In another embodiment is a
2 2 2
14 13
compound of Formula (IIa) wherein R is H and R is -(C -C )alkyl-heteroaryl. In another embodiment is
14 13
a compound of Formula (IIa) wherein R is H and R is H.
13 19
In another embodiment is a compound of Formula (IIa) wherein R and R are combined to
form an optionally substituted heterocycloalkyl ring and R is H.
In another embodiment is a compound of Formula (IIa) wherein p is 1 and R is halogen. In
another embodiment is a compound of Formula (IIa) wherein p is 1 and R is optionally substituted -(C -
C )alkyl. In another embodiment is a compound of Formula (IIa) wherein q is 0, p is 1 and R is halogen.
In another embodiment is a compound of Formula (IIa) wherein q is 0, p is 1 and R is optionally
substituted -(C -C )alkyl. In another embodiment is a compound of Formula (IIa) wherein q is 1 and R is
halogen. In another embodiment is a compound of Formula (IIa) wherein q is 1 and R is optionally
substituted -(C -C )alkyl. In another embodiment is a compound of Formula (IIa) wherein p is 0, q is 1 and
28 28
R is halogen. In another embodiment is a compound of Formula (IIa) wherein p is 0, q is 1 and R is
optionally substituted -(C -C )alkyl.
In another embodiment is a compound of Formula (IIa) wherein p is 0, and q is 0.
18253141_1 (GHMatters) P111789.NZ
In another embodiment is a compound of Formula (IIa) wherein R and R are each
21 22
independently H or -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (IIa)
1 2 1 2
wherein R and R are each H. In another embodiment is a compound of Formula (IIa) wherein R and R
21 22
are each independently -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (IIa)
1 2 21 22
wherein R is H, and R is -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (IIa)
1 21 22 2
wherein R is -(C -C )alkyl-NR R , and R is H. In another embodiment is a compound of Formula (IIa)
wherein R is H, and R is -CH CH NH . In another embodiment is a compound of Formula (IIa) wherein
2 2 2
1 2 1
R is -CH CH NH , and R is H. In another embodiment is a compound of Formula (IIa) wherein R and
2 2 2
2 1 2
R are each -CH CH NH . In another embodiment is a compound of Formula (IIa) wherein R and R are
2 2 2
21 22
each independently H, -(C -C )alkyl-NR R , or -CH CH(OH)CH NH . In another embodiment is a
1 6 2 2 2
compound of Formula (IIa) wherein R and R are each independently -CH CH(OH)CH NH . In another
2 2 2
embodiment is a compound of Formula (IIa) wherein R is H, and R is -CH CH(OH)CH NH . In another
2 2 2
embodiment is a compound of Formula (IIa) wherein R is -CH CH(OH)CH NH , and R is H. In a further
2 2 2
embodiment is a compound of Formula (IIa) wherein R and R and the atoms to which they are attached
form an optionally substituted heterocycloalkyl ring.
In another embodiment is a compound of Formula (IIa) wherein X is optionally substituted aryl.
In a further embodiment is a compound of Formula (IIa) wherein X is optionally substituted phenyl. In
another embodiment is a compound of Formula (IIa) wherein X is optionally substituted heteroaryl. In a
further embodiment is a compound of Formula (IIa) wherein X is disubstituted heteroaryl. In a further
embodiment is a compound of Formula (IIa) wherein X is heteroaryl disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
23 25 26
(C -C )alkyl, OR , -NR R , and -NO . In a further embodiment is a compound of Formula (IIa) wherein
1 6 2
X is heteroaryl disubstituted with substituents each independently selected from -(C -C )alkyl. In a further
embodiment is a compound of Formula (IIa) wherein X is heteroaryl disubstituted with methyl. In a further
embodiment is a compound of Formula (IIa) wherein X is pyridinyl disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
23 25 26
(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound of Formula (IIa) wherein X
1 6 2
is pyridinyl disubstituted with substituents each independently selected from -(C -C )alkyl. In a further
embodiment is a compound of Formula (IIa) wherein X is pyridinyl disubstituted with methyl. In a further
embodiment is a compound of Formula (IIa) wherein X is pyrimidinyl disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
23 25 26
(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound of Formula (IIa) wherein X
1 6 2
is pyrimidinyl disubstituted with substituents each independently selected from -(C -C )alkyl. In a further
embodiment is a compound of Formula (IIa) wherein X is pyrimidinyl disubstituted with methyl. In
another embodiment is a compound of Formula (IIa) wherein X is optionally substituted -(C -C )alkyl-.
In another embodiment is a compound of Formula (IIa) wherein Y is optionally substituted aryl.
In a further embodiment is a compound of Formula (IIa) wherein Y is optionally substituted phenyl. In
18253141_1 (GHMatters) P111789.NZ
another embodiment is a compound of Formula (IIa) wherein Y is optionally substituted heteroaryl. In
another embodiment is a compound of Formula (IIa) wherein Y is optionally substituted -(C -C )alkyl-. In
another embodiment is a compound of Formula (IIa) wherein Y is optionally substituted (C -
C )cycloalkyl-. In another embodiment is a compound of Formula (IIa) wherein Y is optionally substituted
heterocycloalkyl. In another embodiment is a compound of Formula (IIa) wherein Y is -O-. In another
embodiment is a compound of Formula (IIa) wherein Y is -(C -C )alkynyl. In another embodiment is a
compound of Formula (IIa) wherein Y is -O-(C -C )alkyl-. In another embodiment is a compound of
Formula (IIa) wherein Y is a bond.
In another embodiment is a compound of Formula (IIa) wherein Z is -(C -C )alkyl. In a further
1 12
embodiment is a compound of Formula (IIa) wherein Z is n-butyl, isobutyl, or tert-butyl. In another
embodiment is a compound of Formula (IIa) wherein Z is -O-(C -C )alkyl. In another embodiment is a
1 12
compound of Formula (IIa) wherein Z is -O-(C -C )cycloalkyl. In another embodiment is a compound of
Formula (IIa) wherein Z is -(C -C )alkenyl. In another embodiment is a compound of Formula (IIa)
2 12
wherein Z is optionally substituted aryl. In a further embodiment is a compound of Formula (IIa) wherein
Z is optionally substituted phenyl. In a further embodiment is a compound of Formula (IIa) wherein Z is
phenyl monsubstituted or disubstituted with a substituent independently selected from -(C -C )alkyl. In a
further embodiment is a compound of Formula (IIa) wherein Z is phenyl monosubstituted with n-butyl,
isobutyl, or tert-butyl. In a further embodiment is a compound of Formula (IIa) wherein Z is phenyl
monosubstituted with n-butyl. In a further embodiment is a compound of Formula (IIa) wherein Z is
phenyl monosubstituted with isobutyl. In a further embodiment is a compound of Formula (IIa) wherein Z
is phenyl monosubstituted with tert-butyl. In another embodiment is a compound of Formula (IIa) wherein
Z is optionally substituted heteroaryl. In another embodiment is a compound of Formula (IIa) wherein Z is
optionally substituted -(C -C )cycloalkyl. In another embodiment is a compound of Formula (IIa) wherein
Z is optionally substituted heterocycloalkyl. In another embodiment is a compound of Formula (IIa)
wherein Z is halogen.
In another embodiment described herein is a compound of Formula (II) having the structure of
Formula (IIb):
13 N
Z X N
Formula (IIb);
wherein:
18253141_1 (GHMatters) P111789.NZ
1 2 23
R and R are each independently H, -(C -C )alkyl, -(C -C )alkyl-OR , -CH CH(OH)CH NH , -
1 6 1 6 2 2 2
CH CH(heterocycloalkyl)CH NH , -CH C(O)NH , -CH C(O)N(H)CH CN, -(C -C )alkyl-C(O)OR , -
2 2 2 2 2 2 2 1 6
21 22 25 26 23 21 22
(C -C )alkyl-NR R , -(C -C )alkyl-C(O)NR R , -(C -C )alkyl-N(R )C(O)(C -C )alkylNR R , -
1 6 1 6 1 6 1 6
23 23
(C -C )alkyl-N(R )C(O)(C -C )alkyl, -(C -C )alkyl-C(O)N(R )(C -C )alkyl, -(C -C )alkyl-
1 6 1 6 1 6 1 6 1 6
23 23 21 22
C(O)N(R )(C -C )alkyl-heterocycloalkyl, -(C -C )alkyl-NR C(=NH)NR R , -(C -C )alkyl-
1 6 1 6 1 6
23 23 21 22
NR C(=NH)R , -(C -C )alkyl-[(C -C )alkyl-NR R ] , -(C -C )heteroalkyl, or optionally substituted
1 6 1 6 2 1 6
heterocycloalkyl;
or R and R and the atoms to which they are attached form an optionally substituted heterocycloalkyl ring;
R is H, -(C -C )alkyl, -(C -C )alkyl-OH, -(C -C )cycloalkyl, or -C(O)NH ;
1 6 1 6 3 6 2
R is H or -(C -C )alkyl;
or R and R and the carbon atom to which they are attached form a cyclopropyl ring;
R is H, -(C -C )alkyl, -(C -C )haloalkyl, or -(C -C )cycloalkyl;
1 6 1 6 3 6
11 23 23 23
R is H, -NH , -(C -C )alkyl, -(C -C )alkyl-OR , -(C -C )alkyl-SR , -(C -C )alkyl-C(O)OR , -(C -
2 1 6 1 6 1 6 1 6 1
21 22 23 23 23 23
C )alkyl-NR R , -(C -C )alkyl-NR OR , -(C -C )alkyl-NHC(O)NR OR , -(C -C )alkyl-O-(C -
6 1 6 1 6 1 6 1
26 23 23 25 26
C )alkyl-NR R , -(C -C )alkyl-CN, -(C -C )alkyl-NR C(O)R , -(C -C )alkyl-C(O)NR R , -(C -
6 1 6 1 6 1 6 1
C )heteroalkyl-CO H, -(C -C )alkyl-S(O)(C -C )alkyl, -(C -C )alkyl-N(H)CH=NH, -(C -C )alkyl-
6 2 1 6 1 6 1 6 1 6
26
C(NH )=NH, -(C -C )alkyl-N(H)C(=NH)NH , -(C -C )alkyl-N(H)S(O) NR R , -(C -C )alkyl-
2 1 6 2 1 6 2 1 6
26
N(H)S(O) (C -C )alkyl, -(C -C )alkyl-N(H)-C(O)NR R , -(C -C )alkylC(O)N(H)[optionally
2 1 6 1 6 1 6
23 23
substituted(C -C )alkyl]-OR , -(C -C )alkylN(H)C(O)(C -C )alkyl-OR , -(C -
2 6 1 6 1 6 1
26
C )alkylC(O)N(H)heterocycloalkyl, -(C -C )alkylC(O)NR R , -(C -C )alkyl-N(H)-C(O)-(C -
6 1 6 1 6 1
26 25 26
C )alkyl-NR R , -(C -C )alkyl-N(H)-(C -C )alkylC(O)NR R , -(C -C )alkyl-heterocycloalkyl,
6 1 6 1 6 1 6
optionally substituted -(C -C )alkyl-N(H)heterocycloalkyl, or -(C -C )alkyl-heteroaryl;
1 6 1 6
13 23 23 23
R is H, -NH , -(C -C )alkyl, -(C -C )alkyl-OR , -(C -C )alkyl-SR , -(C -C )alkyl-C(O)OR , -(C -
2 1 6 1 6 1 6 1 6 1
21 22 25 26
C )alkyl-NR R , -(C -C )alkyl-CN, -(C -C )alkyl-C(O)NR R , -(C -C )alkyl-N(H)C(NH)NH , -(C -
6 1 6 1 6 1 6 2 1
C )alkyl-heterocycloalkyl, or -(C -C )alkyl-heteroaryl;
6 1 6
13 19 14
or R and R are combined to form an optionally substituted heterocycloalkyl ring; and R is H;
17 18 19 23
R , R , and R are each independently H, -(C -C )alkyl, -(C -C )cycloalkyl, -(C -C )alkyl-OR , -(C -
1 6 3 6 1 6 1
23 21 22
C )alkyl-C(O)OR , or -(C -C )alkyl-NR R ;
6 1 6
X is optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, optionally substituted -(C -
1 6 2 6 2 6 3
C )cycloalkyl-, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally
24 24
substituted heteroaryl, -O-(C -C )alkyl-, -N(R )(C -C )alkyl-, -N(R )(C -C )aryl-, or -SO (C -
1 6 1 6 6 10 2 1
C )alkyl-;
Y is a bond, -O-, -S-, optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, -(C -
1 6 2 6 2 6 1
24 24
C )alkyl-N(R )(C -C )alkyl-, -O-(C -C )alkyl-, -O(C -C )aryl-, -N(R )(C -C )alkyl-, -
6 1 6 1 6 6 10 1 6
24 24
N(R )SO (C -C )alkyl-, -N(R )C(O)(C -C )alkyl-, -C(O)(C -C )alkyl-, -S(C -C )alkyl-, -SO (C -
2 1 6 1 6 1 6 1 6 2 1
C )alkyl-, -C(O)NH(C -C )alkyl-, optionally substituted -(C -C )cycloalkyl-, optionally substituted -
6 1 6 3 7
18253141_1 (GHMatters) P111789.NZ
24 24 24
C(O)N(R )aryl-, optionally substituted -N(R )C(O)aryl-, optionally substituted -N(R )SO aryl-,
optionally substituted heterocycloalkyl,optionally substituted aryl, or optionally substituted heteroaryl;
Z is H, halogen, -NH , -CN, -CF , -CO H, -(C -C )alkyl, -(C -C )alkenyl, -CH=((C -C )cycloalkyl), -
2 3 2 1 12 2 12 3 7
26
(C -C )alkynyl, -C(O)NR R , -O-(C -C )alkyl, -S-(C -C )alkyl, -O-(C -C )[optionally substituted
2 12 1 12 1 12 3 10
23 23
(C -C )cycloalkyl], -O-(C -C )alkyl-OR , -(C -C )alkyl-OR , -(C -C )alkyl-CN, -S-(C -C )alkyl, -
3 7 1 6 1 12 1 12 1 12
24 24
N(R )(C -C )alkyl, -N(R )C(O)(C -C )alkyl, optionally substituted -(C -C )cycloalkyl, -(C -
1 12 1 12 3 7 1
C )alkyl-(C -C )cycloalkyl, -(C -C )alkyl-heterocycloalkyl, optionally substituted heterocycloalkyl,
6 3 7 1 6
optionally substituted aryl, or optionally substituted heteroaryl;
21 22
each R and R is independently H, -(C -C )alkyl, -(C -C )heteroalkyl, -(C -C )alkyl-CO H, -C(O)(C -
1 6 1 6 1 6 2 1
31 31 21 22
C )alkyl, -C(O)N(R ) , or -SO N(R ) ; or R and R and the nitrogen atom to which they are
6 2 2 2
attached form a heterocycloalkyl ring;
31 31
each R is independently H or -(C -C )alkyl; or two R and the nitrogen atom to which they are attached
form a heterocycloalkyl ring;
each R is independently H or -(C -C )alkyl;
each R is independently H or -(C -C )alkyl;
26
each R and R is independently H or optionally substituted -(C -C )alkyl; and
26
or R and R and the nitrogen atom to which they are attached form a heterocycloalkyl ring;
or a pharmaceutically acceptable salt, solvate, or prodrug thereof.In one embodiment is a
compound of Formula (IIb) wherein R is -(C -C )alkyl. In another embodiment is a compound of
17 17
Formula (IIb) wherein R is -CH . In another embodiment is a compound of Formula (IIb) wherein R is
-CH CH . In another embodiment is a compound of Formula (IIb) wherein R is -(C -C )cycloalkyl. In
2 3 3 6
another embodiment is a compound of Formula (IIb) wherein R is cyclopropyl. In another embodiment is
17 23
a compound of Formula (IIb) wherein R is -(C -C )alkyl-C(O)OR . In another embodiment is a
compound of Formula (IIb) wherein R is -CH CH OH. In another embodiment is a compound of
17 21 22
Formula (IIb) wherein R is -(C -C )alkyl-NR R . In another embodiment is a compound of Formula
17 17
(IIb) wherein R is -CH CH NH . In another embodiment is a compound of Formula (IIb) wherein R is
2 2 2
In another embodiment is a compound of Formula (IIb) wherein R is H.
In another embodiment is a compound of Formula (IIb) wherein R is H.
[00266] In another embodiment is a compound of Formula (IIb) wherein R is H.
In another embodiment is a compound of Formula (IIb) wherein R is H. In another embodiment
is a compound of Formula (IIb) wherein R is -(C -C )alkyl. In another embodiment is a compound of
Formula (IIb) wherein R is -CH . In another embodiment is a compound of Formula (IIb) wherein R is -
CH CH . In another embodiment is a compound of Formula (IIb) wherein R is -(C -C )alkyl-OH. In
2 3 1 6
another embodiment is a compound of Formula (IIb) wherein R is -CH OH. In another embodiment is a
compound of Formula (IIb) wherein R is -(C -C )cycloalkyl. In another embodiment is a compound of
18253141_1 (GHMatters) P111789.NZ
Formula (IIb) wherein R is cyclopropyl. In another embodiment is a compound of Formula (IIb) wherein
R is -C(O)NH .
In another embodiment is a compound of Formula (IIb) wherein R and R are H.
In another embodiment is a compound of Formula (IIb) wherein R and R and the carbon atom
to which they are attached form a cyclopropyl ring.
In another embodiment is a compound of Formula (IIb) wherein R is -(C -C )alkyl. In another
embodiment is a compound of Formula (IIb) wherein R is -CH . In another embodiment is a compound of
Formula (IIb) wherein R is -CH CH . In another embodiment is a compound of Formula (IIb) wherein R
is -(C -C )haloalkyl. In another embodiment is a compound of Formula (IIb) wherein R is -CH F. In
1 6 2
another embodiment is a compound of Formula (IIb) wherein R is -CHF . In another embodiment is a
compound of Formula (IIb) wherein R is -(C -C )cycloalkyl. In another embodiment is a compound of
Formula (IIb) wherein R is cyclopropyl. In another embodiment is a compound of Formula (IIb) wherein
R is H.
In another embodiment is a compound of Formula (IIb) wherein R is -(C -C )alkyl. In another
embodiment is a compound of Formula (IIb) wherein R is -CH . In another embodiment is a compound
11 23
of Formula (IIb) wherein R is -(C -C )alkyl-OR . In another embodiment is a compound of Formula
11 11
(IIb) wherein R is -CH OH. In another embodiment is a compound of Formula (IIb) wherein R is -
CH CH OH. In another embodiment is a compound of Formula (IIb) wherein R is -(C -C )alkyl. In
2 2 1 6
11 21 22
another embodiment is a compound of Formula (IIb) wherein R is -(C -C )alkyl-NR R . In another
embodiment is a compound of Formula (IIb) wherein R is -(C -C )alkyl-NH . In another embodiment is a
1 6 2
compound of Formula (IIb) wherein R is -CH NH . In another embodiment is a compound of Formula
11 11
(IIb) wherein R is -CH CH NH . In another embodiment is a compound of Formula (IIb) wherein R is -
2 2 2
CH CH CH NH . In another embodiment is a compound of Formula (IIb) wherein R is -
2 2 2 2
CH CH CH CH NH . In another embodiment is a compound of Formula (IIb) wherein R is -(C -
2 2 2 2 2 1
C )alkyl-CN. In another embodiment is a compound of Formula (IIb) wherein R is -CH CN. In another
11 25 26
embodiment is a compound of Formula (IIb) wherein R is -(C -C )alkyl-C(O)NR R . In another
embodiment is a compound of Formula (IIb) wherein R is -CH C(O)NH . In another embodiment is a
compound of Formula (IIb) wherein R is -CH CH C(O)NH . In another embodiment is a compound of
2 2 2
Formula (IIb) wherein R is -(C -C )alkyl-heteroaryl. In another embodiment is a compound of Formula
11 25 26
(IIb) wherein R is -(C -C )alkyl-N(H)S(O) NR R . In another embodiment is a compound of Formula
1 6 2
(IIb) wherein R is -CH N(H)S(O) NH . In another embodiment is a compound of Formula (IIb) wherein
2 2 2
R is H.
11 18
In another embodiment is a compound of Formula (IIb) wherein R and R are combined to
form an optionally substituted heterocycloalkyl ring and R is H.
[00273] In another embodiment is a compound of Formula (IIb) wherein R is -(C -C )alkyl. In another
embodiment is a compound of Formula (IIb) wherein R is -CH . In another embodiment is a compound
13 23
of Formula (IIb) wherein R is -(C -C )alkyl-OR . In another embodiment is a compound of Formula
18253141_1 (GHMatters) P111789.NZ
13 13
(IIb) wherein R is -CH OH. In another embodiment is a compound of Formula (IIb) wherein R is -
CH CH OH. In another embodiment is a compound of Formula (IIb) wherein R is -(C -C )alkyl. In
2 2 1 6
13 21 22
another embodiment is a compound of Formula (IIb) wherein R is -(C -C )alkyl-NR R . In another
embodiment is a compound of Formula (IIb) wherein R is -(C -C )alkyl-NH . In another embodiment is a
1 6 2
compound of Formula (IIb) wherein R is -CH NH . In another embodiment is a compound of Formula
13 13
(IIb) wherein R is -CH CH NH . In another embodiment is a compound of Formula (IIb) wherein R is -
2 2 2
CH CH CH NH . In another embodiment is a compound of Formula (IIb) wherein R is -
2 2 2 2
CH CH CH CH NH . In another embodiment is a compound of Formula (IIb) wherein R is -(C -
2 2 2 2 2 1
C )alkyl-CN. In another embodiment is a compound of Formula (IIb) wherein R is -CH CN. In another
13 25 26
embodiment is a compound of Formula (IIb) wherein R is -(C -C )alkyl-C(O)NR R . In another
embodiment is a compound of Formula (IIb) wherein R is -CH C(O)NH . In another embodiment is a
compound of Formula (IIb) wherein R is -CH CH C(O)NH . In another embodiment is a compound of
2 2 2
Formula (IIb) wherein R is -(C -C )alkyl-heteroaryl. In another embodiment is a compound of Formula
(IIb) wherein R is H.
13 19
[00274] In another embodiment is a compound of Formula (IIb) wherein R and R are combined to
form an optionally substituted heterocycloalkyl ring and R is H.
In another embodiment is a compound of Formula (IIb) wherein R and R are each
21 22
-C )alkyl-NR R . In another embodiment is a compound of Formula (IIb)
independently H, or -(C
1 2 1 2
wherein R and R are each H. In another embodiment is a compound of Formula (IIb) wherein R and R
21 22
are each independently -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (IIb)
1 2 21 22
wherein R is H, and R is -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (IIb)
1 21 22 2
wherein R is -(C -C )alkyl-NR R , and R is H. In another embodiment is a compound of Formula (IIb)
wherein R is H, and R is -CH CH NH . In another embodiment is a compound of Formula (IIb) wherein
2 2 2
1 2 1
R is -CH CH NH , and R is H. In another embodiment is a compound of Formula (IIb) wherein R and
2 2 2
2 1 2
R are each -CH CH NH . In another embodiment is a compound of Formula (IIb) wherein R and R are
2 2 2
21 22
each independently H, -(C -C )alkyl-NR R , or -CH CH(OH)CH NH . In another embodiment is a
1 6 2 2 2
compound of Formula (IIb) wherein R and R are each independently -CH CH(OH)CH NH . In another
2 2 2
embodiment is a compound of Formula (IIb) wherein R is H, and R is -CH CH(OH)CH NH . In another
2 2 2
embodiment is a compound of Formula (IIb) wherein R is -CH CH(OH)CH NH , and R is H. In a further
2 2 2
embodiment is a compound of Formula (IIb) wherein R and R and the atoms to which they are attached
form an optionally substituted heterocycloalkyl ring.
In another embodiment is a compound of Formula (IIb) wherein X is optionally substituted aryl.
In a further embodiment is a compound of Formula (IIb) wherein X is optionally substituted phenyl. In
another embodiment is a compound of Formula (IIb) wherein X is optionally substituted heteroaryl. In a
further embodiment is a compound of Formula (IIb) wherein X is disubstituted heteroaryl. In a further
embodiment is a compound of Formula (IIb) wherein X is heteroaryl disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
18253141_1 (GHMatters) P111789.NZ
23 25 26
(C -C )alkyl, OR , -NR R , and -NO . In a further embodiment is a compound of Formula (IIb) wherein
1 6 2
X is heteroaryl disubstituted with substituents each independently selected from -(C -C )alkyl. In a further
embodiment is a compound of Formula (IIb) wherein X is heteroaryl disubstituted with methyl. In a
further embodiment is a compound of Formula (IIb) wherein X is pyridinyl disubstituted with substituents
each independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted
23 25 26
-O-(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound of Formula (IIb)
1 6 2
wherein X is pyridinyl disubstituted with substituents each independently selected from -(C -C )alkyl. In a
further embodiment is a compound of Formula (IIb) wherein X is pyridinyl disubstituted with methyl. In a
further embodiment is a compound of Formula (IIb) wherein X is pyrimidinyl disubstituted with
substituents each independently selected from halogen, -CN, optionally substituted -(C -C )alkyl,
23 25 26
optionally substituted -O-(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound
1 6 2
of Formula (IIb) wherein X is pyrimidinyl disubstituted with substituents each independently selected from
-(C -C )alkyl. In a further embodiment is a compound of Formula (IIb) wherein X is pyrimidinyl
disubstituted with methyl. In another embodiment is a compound of Formula (IIb) wherein X is optionally
substituted -(C -C )alkyl-.
In another embodiment is a compound of Formula (IIb) wherein Y is optionally substituted aryl.
In a further embodiment is a compound of Formula (IIb) wherein Y is optionally substituted phenyl. In
another embodiment is a compound of Formula (IIb) wherein Y is optionally substituted heteroaryl. In
another embodiment is a compound of Formula (IIb) wherein Y is optionally substituted -(C -C )alkyl-. In
another embodiment is a compound of Formula (IIb) wherein Y is optionally substituted (C -
C )cycloalkyl-. In another embodiment is a compound of Formula (IIb) wherein Y is optionally substituted
heterocycloalkyl. In another embodiment is a compound of Formula (IIb) wherein Y is -O-. In another
embodiment is a compound of Formula (IIb) wherein Y is -(C -C )alkynyl. In another embodiment is a
compound of Formula (IIb) wherein Y is -O-(C -C )alkyl-. In another embodiment is a compound of
Formula (IIb) wherein Y is a bond.
In another embodiment is a compound of Formula (IIb) wherein Z is -(C -C )alkyl. In a further
1 12
embodiment is a compound of Formula (IIb) wherein Z is n-butyl, isobutyl, or tert-butyl. In another
embodiment is a compound of Formula (IIb) wherein Z is -O-(C -C )alkyl. In another embodiment is a
1 12
compound of Formula (IIb) wherein Z is -O-(C -C )cycloalkyl. In another embodiment is a compound of
Formula (IIb) wherein Z is -(C -C )alkenyl. In another embodiment is a compound of Formula (IIb)
2 12
wherein Z is optionally substituted aryl. In a further embodiment is a compound of Formula (IIb) wherein
Z is optionally substituted phenyl. In a further embodiment is a compound of Formula (IIb) wherein Z is
phenyl monsubstituted or disubstituted with a substituent independently selected from -(C -C )alkyl. In a
further embodiment is a compound of Formula (IIb) wherein Z is phenyl monosubstituted with n-butyl,
isobutyl, or tert-butyl. In a further embodiment is a compound of Formula (IIb) wherein Z is phenyl
monosubstituted with n-butyl. In a further embodiment is a compound of Formula (IIb) wherein Z is
phenyl monosubstituted with isobutyl. In a further embodiment is a compound of Formula (IIb) wherein Z
18253141_1 (GHMatters) P111789.NZ
is phenyl monosubstituted with tert-butyl. In another embodiment is a compound of Formula (IIb) wherein
Z is optionally substituted heteroaryl. In another embodiment is a compound of Formula (IIb) wherein Z is
optionally substituted -(C -C )cycloalkyl. In another embodiment is a compound of Formula (IIb) wherein
Z is optionally substituted heterocycloalkyl. In another embodiment is a compound of Formula (IIb)
wherein Z is halogen.
In another embodiment described herein is a compound of Formula (II) having the structure of
Formula (IIc):
Z X N
Formula (IIc);
wherein:
R and R are each independently H or -CH CH NH ;
2 2 2
11 23 23 23
R is H, -NH , -(C -C )alkyl, -(C -C )alkyl-OR , -(C -C )alkyl-SR , -(C -C )alkyl-C(O)OR , -(C -
2 1 6 1 6 1 6 1 6 1
21 22 23 23 23 23
C )alkyl-NR R , -(C -C )alkyl-NR OR , -(C -C )alkyl-NHC(O)NR OR , -(C -C )alkyl-O-(C -
6 1 6 1 6 1 6 1
26 23 23 25 26
C )alkyl-NR R , -(C -C )alkyl-CN, -(C -C )alkyl-NR C(O)R , -(C -C )alkyl-C(O)NR R , -(C -
6 1 6 1 6 1 6 1
C )heteroalkyl-CO H, -(C -C )alkyl-S(O)(C -C )alkyl, -(C -C )alkyl-N(H)CH=NH, -(C -C )alkyl-
6 2 1 6 1 6 1 6 1 6
26
C(NH )=NH, -(C -C )alkyl-N(H)C(=NH)NH , -(C -C )alkyl-N(H)S(O) NR R , -(C -C )alkyl-
2 1 6 2 1 6 2 1 6
26
N(H)S(O) (C -C )alkyl, -(C -C )alkyl-N(H)-C(O)NR R , -(C -C )alkylC(O)N(H)[optionally
2 1 6 1 6 1 6
23 23
substituted(C -C )alkyl]-OR , -(C -C )alkylN(H)C(O)(C -C )alkyl-OR , -(C -
2 6 1 6 1 6 1
26
C )alkylC(O)N(H)heterocycloalkyl, -(C -C )alkylC(O)NR R , -(C -C )alkyl-N(H)-C(O)-(C -
6 1 6 1 6 1
26 25 26
C )alkyl-NR R , -(C -C )alkyl-N(H)-(C -C )alkylC(O)NR R , -(C -C )alkyl-heterocycloalkyl,
6 1 6 1 6 1 6
optionally substituted -(C -C )alkyl-N(H)heterocycloalkyl, or -(C -C )alkyl-heteroaryll;
1 6 1 6
13 23 23 23
R is H, -NH , -(C -C )alkyl, -(C -C )alkyl-OR , -(C -C )alkyl-SR , -(C -C )alkyl-C(O)OR , -(C -
2 1 6 1 6 1 6 1 6 1
21 22 25 26
C )alkyl-NR R , -(C -C )alkyl-CN, -(C -C )alkyl-C(O)NR R , -(C -C )alkyl-N(H)C(NH)NH , -(C -
6 1 6 1 6 1 6 2 1
C )alkyl-heterocycloalkyl, or -(C -C )alkyl-heteroaryl;
6 1 6
X is optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, optionally substituted -(C -
1 6 2 6 2 6 3
C )cycloalkyl-, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally
24 24
substituted heteroaryl, -O-(C -C )alkyl-, -N(R )(C -C )alkyl-, -N(R )(C -C )aryl-, or -SO (C -
1 6 1 6 6 10 2 1
C )alkyl-;
Y is a bond, -O-, -S-, optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, -(C -
1 6 2 6 2 6 1
24 24
C )alkyl-N(R )(C -C )alkyl-, -O-(C -C )alkyl-, -O(C -C )aryl-, -N(R )(C -C )alkyl-, -
6 1 6 1 6 6 10 1 6
18253141_1 (GHMatters) P111789.NZ
24 24
N(R )SO (C -C )alkyl-, -N(R )C(O)(C -C )alkyl-, -C(O)(C -C )alkyl-, -S(C -C )alkyl-, -SO (C -
2 1 6 1 6 1 6 1 6 2 1
C )alkyl-, -C(O)NH(C -C )alkyl-, optionally substituted -(C -C )cycloalkyl-, optionally substituted -
6 1 6 3 7
24 24 24
C(O)N(R )aryl-, optionally substituted -N(R )C(O)aryl-, optionally substituted -N(R )SO aryl-,
optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Z is H, halogen, -NH , -CN, -CF , -CO H, -(C -C )alkyl, -(C -C )alkenyl, -CH=((C -C )cycloalkyl), -
2 3 2 1 12 2 12 3 7
26
(C -C )alkynyl, -C(O)NR R , -O-(C -C )alkyl, -S-(C -C )alkyl, -O-(C -C )[optionally substituted
2 12 1 12 1 12 3 10
23 23
(C -C )cycloalkyl], -O-(C -C )alkyl-OR , -(C -C )alkyl-OR , -(C -C )alkyl-CN, -S-(C -C )alkyl, -
3 7 1 6 1 12 1 12 1 12
24 24
N(R )(C -C )alkyl, -N(R )C(O)(C -C )alkyl, optionally substituted -(C -C )cycloalkyl, -(C -
1 12 1 12 3 7 1
C )alkyl-(C -C )cycloalkyl, -(C -C )alkyl-heterocycloalkyl, optionally substituted heterocycloalkyl,
6 3 7 1 6
optionally substituted aryl, or optionally substituted heteroaryl;
21 22
each R and R is independently H, -(C -C )alkyl, -(C -C )heteroalkyl, -(C -C )alkyl-CO H, -C(O)(C -
1 6 1 6 1 6 2 1
31 31 21 22
C )alkyl, -C(O)N(R ) , or -SO N(R ) ; or R and R and the nitrogen atom to which they are
6 2 2 2
attached form a heterocycloalkyl ring;
31 31
each R is independently H or -(C -C )alkyl; or two R and the nitrogen atom to which they are attached
form a heterocycloalkyl ring;
each R is independently H or -(C -C )alkyl;
each R is independently H or -(C -C )alkyl;
26
each R and R is independently H or optionally substituted -(C -C )alkyl; and
26
or R and R and the nitrogen atom to which they are attached form a heterocycloalkyl ring;
[00280] or a pharmaceutically acceptable salt, solvate, or prodrug thereof.In another embodiment is a
compound of Formula (IIc) wherein R is -(C -C )alkyl. In another embodiment is a compound of
11 11
Formula (IIc) wherein R is -CH . In another embodiment is a compound of Formula (IIc) wherein R is -
23 11
(C -C )alkyl-OR . In another embodiment is a compound of Formula (IIc) wherein R is -CH OH. In
1 6 2
another embodiment is a compound of Formula (IIc) wherein R is -CH CH OH. In another embodiment
is a compound of Formula (IIc) wherein R is -(C -C )alkyl. In another embodiment is a compound of
11 21 22
Formula (IIc) wherein R is -(C -C )alkyl-NR R . In another embodiment is a compound of Formula
(IIc) wherein R is -(C -C )alkyl-NH . In another embodiment is a compound of Formula (IIc) wherein
1 6 2
11 11
R is -CH NH . In another embodiment is a compound of Formula (IIc) wherein R is -CH CH NH . In
2 2 2 2 2
another embodiment is a compound of Formula (IIc) wherein R is -CH CH CH NH . In another
2 2 2 2
embodiment is a compound of Formula (IIc) wherein R is -CH CH CH CH NH . In another embodiment
2 2 2 2 2
is a compound of Formula (IIc) wherein R is -(C -C )alkyl-CN. In another embodiment is a compound of
11 11
Formula (IIc) wherein R is -CH CN. In another embodiment is a compound of Formula (IIc) wherein R
26 11
is -(C -C )alkyl-C(O)NR R . In another embodiment is a compound of Formula (IIc) wherein R is -
CH C(O)NH . In another embodiment is a compound of Formula (IIc) wherein R is -CH CH C(O)NH .
2 2 2 2 2
In another embodiment is a compound of Formula (IIc) wherein R is -(C -C )alkyl-heteroaryl. In another
11 25 26
embodiment is a compound of Formula (IIc) wherein R is -(C -C )alkyl-N(H)S(O) NR R . In another
1 6 2
18253141_1 (GHMatters) P111789.NZ
embodiment is a compound of Formula (IIc) wherein R is -CH N(H)S(O) NH . In another embodiment
2 2 2
is a compound of Formula (IIc) wherein R is H.
In another embodiment is a compound of Formula (IIc) wherein R is -(C -C )alkyl. In another
embodiment is a compound of Formula (IIc) wherein R is -CH . In another embodiment is a compound
13 23
of Formula (IIc) wherein R is -(C -C )alkyl-OR . In another embodiment is a compound of Formula
13 13
(IIc) wherein R is -CH OH. In another embodiment is a compound of Formula (IIc) wherein R is -
CH CH OH. In another embodiment is a compound of Formula (IIc) wherein R is -(C -C )alkyl. In
2 2 1 6
13 21 22
another embodiment is a compound of Formula (IIc) wherein R is -(C -C )alkyl-NR R . In another
embodiment is a compound of Formula (IIc) wherein R is -(C -C )alkyl-NH . In another embodiment is a
1 6 2
compound of Formula (IIc) wherein R is -CH NH . In another embodiment is a compound of Formula
13 13
(IIc) wherein R is -CH CH NH . In another embodiment is a compound of Formula (IIc) wherein R is -
2 2 2
CH CH CH NH . In another embodiment is a compound of Formula (IIc) wherein R is -
2 2 2 2
CH CH CH CH NH . In another embodiment is a compound of Formula (IIc) wherein R is -(C -
2 2 2 2 2 1
C )alkyl-CN. In another embodiment is a compound of Formula (IIc) wherein R is -CH CN. In another
13 25 26
embodiment is a compound of Formula (IIc) wherein R is -(C -C )alkyl-C(O)NR R . In another
embodiment is a compound of Formula (IIc) wherein R is -CH C(O)NH . In another embodiment is a
compound of Formula (IIc) wherein R is -CH CH C(O)NH . In another embodiment is a compound of
2 2 2
Formula (IIc) wherein R is -(C -C )alkyl-heteroaryl. In another embodiment is a compound of Formula
(IIc) wherein R is H.
[00282] In another embodiment is a compound of Formula (IIc) wherein R and R are each H. In
another embodiment is a compound of Formula (IIc) wherein R is H, and R is -CH CH NH . In another
2 2 2
embodiment is a compound of Formula (IIc) wherein R is -CH CH NH , and R is H. In another
2 2 2
embodiment is a compound of Formula (IIc) wherein R and R are each -CH CH NH . In a further
2 2 2
embodiment is a compound of Formula (IIc) wherein R and R and the atoms to which they are attached
form an optionally substituted heterocycloalkyl ring.
In another embodiment is a compound of Formula (IIc) wherein X is optionally substituted aryl.
In a further embodiment is a compound of Formula (IIc) wherein X is optionally substituted phenyl. In
another embodiment is a compound of Formula (IIc) wherein X is optionally substituted heteroaryl. In a
further embodiment is a compound of Formula (IIc) wherein X is disubstituted heteroaryl. In a further
embodiment is a compound of Formula (IIc) wherein X is heteroaryl disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
23 25 26
(C -C )alkyl, OR , -NR R , and -NO . In a further embodiment is a compound of Formula (IIc) wherein
1 6 2
X is heteroaryl disubstituted with substituents each independently selected from -(C -C )alkyl. In a further
embodiment is a compound of Formula (IIc) wherein X is heteroaryl disubstituted with methyl. In a further
embodiment is a compound of Formula (IIc) wherein X is pyridinyl disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
23 25 26
(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound of Formula (IIc) wherein X
1 6 2
18253141_1 (GHMatters) P111789.NZ
is pyridinyl disubstituted with substituents each independently selected from -(C -C )alkyl. In a further
embodiment is a compound of Formula (IIc) wherein X is pyridinyl disubstituted with methyl. In a further
embodiment is a compound of Formula (IIc) wherein X is pyrimidinyl disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
23 25 26
(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound of Formula (IIc) wherein X
1 6 2
is pyrimidinyl disubstituted with substituents each independently selected from -(C -C )alkyl. In a further
embodiment is a compound of Formula (IIc) wherein X is pyrimidinyl disubstituted with methyl. In
another embodiment is a compound of Formula (IIc) wherein X is optionally substituted -(C -C )alkyl-.
In another embodiment is a compound of Formula (IIc) wherein Y is optionally substituted aryl.
In a further embodiment is a compound of Formula (IIc) wherein Y is optionally substituted phenyl. In
another embodiment is a compound of Formula (IIc) wherein Y is optionally substituted heteroaryl. In
another embodiment is a compound of Formula (IIc) wherein Y is optionally substituted -(C -C )alkyl-. In
another embodiment is a compound of Formula (IIc) wherein Y is optionally substituted (C -
C )cycloalkyl-. In another embodiment is a compound of Formula (IIc) wherein Y is optionally substituted
heterocycloalkyl. In another embodiment is a compound of Formula (IIc) wherein Y is -O-. In another
embodiment is a compound of Formula (IIc) wherein Y is -(C -C )alkynyl. In another embodiment is a
compound of Formula (IIc) wherein Y is -O-(C -C )alkyl-. In another embodiment is a compound of
Formula (IIc) wherein Y is a bond.
In another embodiment is a compound of Formula (IIc) wherein Z is -(C -C )alkyl. In a further
1 12
embodiment is a compound of Formula (IIc) wherein Z is n-butyl, isobutyl, or tert-butyl. In another
embodiment is a compound of Formula (IIc) wherein Z is -O-(C -C )alkyl. In another embodiment is a
1 12
compound of Formula (IIc) wherein Z is -O-(C -C )cycloalkyl. In another embodiment is a compound of
Formula (IIc) wherein Z is -(C -C )alkenyl. In another embodiment is a compound of Formula (IIc)
2 12
wherein Z is optionally substituted aryl. In a further embodiment is a compound of Formula (IIc) wherein
Z is optionally substituted phenyl. In a further embodiment is a compound of Formula (IIc) wherein Z is
phenyl monsubstituted or disubstituted with a substituent independently selected from -(C -C )alkyl. In a
further embodiment is a compound of Formula (IIc) wherein Z is phenyl monosubstituted with n-butyl,
isobutyl, or tert-butyl. In a further embodiment is a compound of Formula (IIc) wherein Z is phenyl
monosubstituted with n-butyl. In a further embodiment is a compound of Formula (IIc) wherein Z is
phenyl monosubstituted with isobutyl. In a further embodiment is a compound of Formula (IIc) wherein Z
is phenyl monosubstituted with tert-butyl. In another embodiment is a compound of Formula (IIc) wherein
Z is optionally substituted heteroaryl. In another embodiment is a compound of Formula (IIc) wherein Z is
optionally substituted -(C -C )cycloalkyl. In another embodiment is a compound of Formula (IIc) wherein
Z is optionally substituted heterocycloalkyl. In another embodiment is a compound of Formula (IIc)
wherein Z is halogen.
In another embodiment described herein are compounds of Formula (II) having the structure of
Formula (IId):
18253141_1 (GHMatters) P111789.NZ
X N O
Formula (IId);
wherein:
1 2 23
R and R are each independently H, -(C -C )alkyl, -(C -C )alkyl-OR , -CH CH(OH)CH NH , -
1 6 1 6 2 2 2
CH CH(heterocycloalkyl)CH NH , -CH C(O)NH , -CH C(O)N(H)CH CN, -(C -C )alkyl-C(O)OR , -
2 2 2 2 2 2 2 1 6
21 22 25 26 23 21 22
(C -C )alkyl-NR R , -(C -C )alkyl-C(O)NR R , -(C -C )alkyl-N(R )C(O)(C -C )alkylNR R , -
1 6 1 6 1 6 1 6
23 23
(C -C )alkyl-N(R )C(O)(C -C )alkyl, -(C -C )alkyl-C(O)N(R )(C -C )alkyl, -(C -C )alkyl-
1 6 1 6 1 6 1 6 1 6
23 23 21 22
C(O)N(R )(C -C )alkyl-heterocycloalkyl, -(C -C )alkyl-NR C(=NH)NR R , -(C -C )alkyl-
1 6 1 6 1 6
23 23 21 22
NR C(=NH)R , -(C -C )alkyl-[(C -C )alkyl-NR R ] , -(C -C )heteroalkyl, or optionally substituted
1 6 1 6 2 1 6
heterocycloalkyl;
or R and R and the atoms to which they are attached form an optionally substituted heterocycloalkyl ring;
R is H, -(C -C )alkyl, -(C -C )alkyl-OH, -(C -C )cycloalkyl, or -C(O)NH ;
1 6 1 6 3 6 2
R is H or -(C -C )alkyl;
or R and R and the carbon atom to which they are attached form a cyclopropyl ring;
R is H, -(C -C )alkyl, -(C -C )haloalkyl, or -(C -C )cycloalkyl;
1 6 1 6 3 6
17 23 23
R is H, -(C -C )alkyl, -(C -C )cycloalkyl, -(C -C )alkyl-OR , -(C -C )alkyl-C(O)OR , or -(C -C )alkyl-
1 6 3 6 1 6 1 6 1 6
21 22
NR R ;
X is optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, optionally substituted -(C -
1 6 2 6 2 6 3
C )cycloalkyl-, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally
24 24
substituted heteroaryl, -O-(C -C )alkyl-, -N(R )(C -C )alkyl-, -N(R )(C -C )aryl-, or -SO (C -
1 6 1 6 6 10 2 1
C )alkyl-;
Y is a bond, -O-, -S-, optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, -(C -
1 6 2 6 2 6 1
24 24
C )alkyl-N(R )(C -C )alkyl-, -O-(C -C )alkyl-, -O(C -C )aryl-, -N(R )(C -C )alkyl-, -
6 1 6 1 6 6 10 1 6
24 24
N(R )SO (C -C )alkyl-, -N(R )C(O)(C -C )alkyl-, -C(O)(C -C )alkyl-, -S(C -C )alkyl-, -SO (C -
2 1 6 1 6 1 6 1 6 2 1
C )alkyl-, -C(O)NH(C -C )alkyl-, optionally substituted -(C -C )cycloalkyl-, optionally substituted -
6 1 6 3 7
24 24 24
C(O)N(R )aryl-, optionally substituted -N(R )C(O)aryl-, optionally substituted -N(R )SO aryl-,
optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Z is H, halogen, -NH , -CN, -CF , -CO H, -(C -C )alkyl, -(C -C )alkenyl, -CH=((C -C )cycloalkyl), -
2 3 2 1 12 2 12 3 7
26
(C -C )alkynyl, -C(O)NR R , -O-(C -C )alkyl, -S-(C -C )alkyl, -O-(C -C )[optionally substituted
2 12 1 12 1 12 3 10
23 23
(C -C )cycloalkyl], -O-(C -C )alkyl-OR , -(C -C )alkyl-OR , -(C -C )alkyl-CN, -S-(C -C )alkyl, -
3 7 1 6 1 12 1 12 1 12
24 24
N(R )(C -C )alkyl, -N(R )C(O)(C -C )alkyl, optionally substituted -(C -C )cycloalkyl, -(C -
1 12 1 12 3 7 1
18253141_1 (GHMatters) P111789.NZ
C )alkyl-(C -C )cycloalkyl, -(C -C )alkyl-heterocycloalkyl, optionally substituted heterocycloalkyl,
6 3 7 1 6
optionally substituted aryl, or optionally substituted heteroaryl;
21 22
each R and R is independently H, -(C -C )alkyl, -(C -C )heteroalkyl, -(C -C )alkyl-CO H, -C(O)(C -
1 6 1 6 1 6 2 1
31 31 21 22
C )alkyl, -C(O)N(R ) , or -SO N(R ) ; or R and R and the nitrogen atom to which they are
6 2 2 2
attached form a heterocycloalkyl ring;
31 31
each R is independently H or -(C -C )alkyl; or two R and the nitrogen atom to which they are attached
form a heterocycloalkyl ring;
each R is independently H or -(C -C )alkyl;
each R is independently H or -(C -C )alkyl;
26
each R and R is independently H or optionally substituted -(C -C )alkyl; and
26
or R and R and the nitrogen atom to which they are attached form a heterocycloalkyl ring;
or a pharmaceutically acceptable salt, solvate, or prodrug thereof.In one embodiment is a
compound of Formula (IId) wherein R is -(C -C )alkyl. In another embodiment is a compound of
17 17
Formula (IId) wherein R is -CH . In another embodiment is a compound of Formula (IId) wherein R is
-CH CH . In another embodiment is a compound of Formula (IId) wherein R is -(C -C )cycloalkyl. In
2 3 3 6
another embodiment is a compound of Formula (IId) wherein R is cyclopropyl. In another embodiment is
17 23
a compound of Formula (IId) wherein R is -(C -C )alkyl-C(O)OR . In another embodiment is a
compound of Formula (IId) wherein R is -CH CH OH. In another embodiment is a compound of
17 21 22
Formula (IId) wherein R is -(C -C )alkyl-NR R . In another embodiment is a compound of Formula
17 17
(IId) wherein R is -CH CH NH . In another embodiment is a compound of Formula (IId) wherein R is
2 2 2
In another embodiment is a compound of Formula (IId) wherein R is H.
In another embodiment is a compound of Formula (IId) wherein R is H. In another embodiment
is a compound of Formula (IId) wherein R is -(C -C )alkyl. In another embodiment is a compound of
Formula (IId) wherein R is -CH . In another embodiment is a compound of Formula (IId) wherein R is -
CH CH . In another embodiment is a compound of Formula (IId) wherein R is -(C -C )alkyl-OH. In
2 3 1 6
another embodiment is a compound of Formula (IId) wherein R is -CH OH. In another embodiment is a
compound of Formula (IId) wherein R is -(C -C )cycloalkyl. In another embodiment is a compound of
Formula (IId) wherein R is cyclopropyl. In another embodiment is a compound of Formula (IId) wherein
R is -C(O)NH .
In another embodiment is a compound of Formula (IId) wherein R and R are H.
In another embodiment is a compound of Formula (IId) wherein R and R and the carbon atom
to which they are attached form a cyclopropyl ring.
In another embodiment is a compound of Formula (IId) wherein R is -(C -C )alkyl. In another
embodiment is a compound of Formula (IId) wherein R is -CH . In another embodiment is a compound of
Formula (IId) wherein R is -CH CH . In another embodiment is a compound of Formula (IId) wherein R
is -(C -C )haloalkyl. In another embodiment is a compound of Formula (IId) wherein R is -CH F. In
1 6 2
18253141_1 (GHMatters) P111789.NZ
another embodiment is a compound of Formula (IId) wherein R is -CHF . In another embodiment is a
compound of Formula (IId) wherein R is -(C -C )cycloalkyl. In another embodiment is a compound of
Formula (IId) wherein R is cyclopropyl. In another embodiment is a compound of Formula (IId) wherein
R is H.
[00293] In another embodiment is a compound of Formula (IId) wherein R and R are each
21 22
independently H or -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (IId)
1 2 1 2
wherein R and R are each H. In another embodiment is a compound of Formula (IId) wherein R and R
21 22
are each independently -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (IId)
1 2 21 22
wherein R is H, and R is -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (IId)
1 21 22 2
wherein R is -(C -C )alkyl-NR R , and R is H. In another embodiment is a compound of Formula (IId)
wherein R is H, and R is -CH CH NH . In another embodiment is a compound of Formula (IId) wherein
2 2 2
1 2 1
R is -CH CH NH , and R is H. In another embodiment is a compound of Formula (IId) wherein R and
2 2 2
2 1 2
R are each -CH CH NH . In another embodiment is a compound of Formula (IId) wherein R and R are
2 2 2
21 22
each independently H, -(C -C )alkyl-NR R , or -CH CH(OH)CH NH . In another embodiment is a
1 6 2 2 2
compound of Formula (IId) wherein R and R are each independently -CH CH(OH)CH NH . In another
2 2 2
embodiment is a compound of Formula (IId) wherein R is H, and R is -CH CH(OH)CH NH . In another
2 2 2
embodiment is a compound of Formula (IId) wherein R is -CH CH(OH)CH NH , and R is H. In a further
2 2 2
embodiment is a compound of Formula (IId) wherein R and R and the atoms to which they are attached
form an optionally substituted heterocycloalkyl ring.
[00294] In another embodiment is a compound of Formula (IId) wherein X is optionally substituted aryl.
In a further embodiment is a compound of Formula (IId) wherein X is optionally substituted phenyl. In
another embodiment is a compound of Formula (IId) wherein X is optionally substituted heteroaryl. In a
further embodiment is a compound of Formula (IId) wherein X is disubstituted heteroaryl. In a further
embodiment is a compound of Formula (IId) wherein X is heteroaryl disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
23 25 26
(C -C )alkyl, OR , -NR R , and -NO . In a further embodiment is a compound of Formula (IId) wherein
1 6 2
X is heteroaryl disubstituted with substituents each independently selected from -(C -C )alkyl. In a further
embodiment is a compound of Formula (IId) wherein X is heteroaryl disubstituted with methyl. In a
further embodiment is a compound of Formula (IId) wherein X is pyridinyl disubstituted with substituents
each independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted
23 25 26
-O-(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound of Formula (IId)
1 6 2
wherein X is pyridinyl disubstituted with substituents each independently selected from -(C -C )alkyl. In a
further embodiment is a compound of Formula (IId) wherein X is pyridinyl disubstituted with methyl. In a
further embodiment is a compound of Formula (IId) wherein X is pyrimidinyl disubstituted with
substituents each independently selected from halogen, -CN, optionally substituted -(C -C )alkyl,
23 25 26
optionally substituted -O-(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound
1 6 2
of Formula (IId) wherein X is pyrimidinyl disubstituted with substituents each independently selected from
18253141_1 (GHMatters) P111789.NZ
-(C -C )alkyl. In a further embodiment is a compound of Formula (IId) wherein X is pyrimidinyl
disubstituted with methyl. In another embodiment is a compound of Formula (IId) wherein X is optionally
substituted -(C -C )alkyl-.
In another embodiment is a compound of Formula (IId) wherein Y is optionally substituted aryl.
In a further embodiment is a compound of Formula (IId) wherein Y is optionally substituted phenyl. In
another embodiment is a compound of Formula (IId) wherein Y is optionally substituted heteroaryl. In
another embodiment is a compound of Formula (IId) wherein Y is optionally substituted -(C -C )alkyl-. In
another embodiment is a compound of Formula (IId) wherein Y is optionally substituted (C -
C )cycloalkyl-. In another embodiment is a compound of Formula (IId) wherein Y is optionally substituted
heterocycloalkyl. In another embodiment is a compound of Formula (IId) wherein Y is -O-. In another
embodiment is a compound of Formula (IId) wherein Y is -(C -C )alkynyl. In another embodiment is a
compound of Formula (IId) wherein Y is -O-(C -C )alkyl-. In another embodiment is a compound of
Formula (IId) wherein Y is a bond.
In another embodiment is a compound of Formula (IId) wherein Z is -(C -C )alkyl. In a further
1 12
embodiment is a compound of Formula (IId) wherein Z is n-butyl, isobutyl, or tert-butyl. In another
embodiment is a compound of Formula (IId) wherein Z is -O-(C -C )alkyl. In another embodiment is a
1 12
compound of Formula (IId) wherein Z is -O-(C -C )cycloalkyl. In another embodiment is a compound of
-C )alkenyl. In another embodiment is a compound of Formula (IId)
Formula (IId) wherein Z is -(C
2 12
wherein Z is optionally substituted aryl. In a further embodiment is a compound of Formula (IId) wherein
Z is optionally substituted phenyl. In a further embodiment is a compound of Formula (IId) wherein Z is
phenyl monsubstituted or disubstituted with a substituent independently selected from -(C -C )alkyl. In a
further embodiment is a compound of Formula (IId) wherein Z is phenyl monosubstituted with n-butyl,
isobutyl, or tert-butyl. In a further embodiment is a compound of Formula (IId) wherein Z is phenyl
monosubstituted with n-butyl. In a further embodiment is a compound of Formula (IId) wherein Z is
phenyl monosubstituted with isobutyl. In a further embodiment is a compound of Formula (IId) wherein Z
is phenyl monosubstituted with tert-butyl. In another embodiment is a compound of Formula (IId) wherein
Z is optionally substituted heteroaryl. In another embodiment is a compound of Formula (IId) wherein Z is
optionally substituted -(C -C )cycloalkyl. In another embodiment is a compound of Formula (IId) wherein
Z is optionally substituted heterocycloalkyl. In another embodiment is a compound of Formula (IId)
wherein Z is halogen.
In another embodiment described herein are compounds of Formula (II) having the structure of
Formula (IIe):
18253141_1 (GHMatters) P111789.NZ
O CN
X N O
Formula (IIe);
wherein:
R and R are each independently H or -CH CH NH ;
2 2 2
X is optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, optionally substituted -(C -
1 6 2 6 2 6 3
C )cycloalkyl-, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally
24 24
substituted heteroaryl, -O-(C -C )alkyl-, -N(R )(C -C )alkyl-, -N(R )(C -C )aryl-, or -SO (C -
1 6 1 6 6 10 2 1
C )alkyl-;
Y is a bond, -O-, -S-, optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, -(C -
1 6 2 6 2 6 1
24 24
C )alkyl-N(R )(C -C )alkyl-, -O-(C -C )alkyl-, -O(C -C )aryl-, -N(R )(C -C )alkyl-, -
6 1 6 1 6 6 10 1 6
24 24
N(R )SO (C -C )alkyl-, -N(R )C(O)(C -C )alkyl-, -C(O)(C -C )alkyl-, -S(C -C )alkyl-, -SO (C -
2 1 6 1 6 1 6 1 6 2 1
C )alkyl-, -C(O)NH(C -C )alkyl-, optionally substituted -(C -C )cycloalkyl-, optionally substituted -
6 1 6 3 7
24 24 24
C(O)N(R )aryl-, optionally substituted -N(R )C(O)aryl-, optionally substituted -N(R )SO aryl-,
optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Z is H, halogen, -NH , -CN, -CF , -CO H, -(C -C )alkyl, -(C -C )alkenyl, -CH=((C -C )cycloalkyl), -
2 3 2 1 12 2 12 3 7
26
(C -C )alkynyl, -C(O)NR R , -O-(C -C )alkyl, -S-(C -C )alkyl, -O-(C -C )[optionally substituted
2 12 1 12 1 12 3 10
23 23
(C -C )cycloalkyl], -O-(C -C )alkyl-OR , -(C -C )alkyl-OR , -(C -C )alkyl-CN, -S-(C -C )alkyl, -
3 7 1 6 1 12 1 12 1 12
24 24
N(R )(C -C )alkyl, -N(R )C(O)(C -C )alkyl, optionally substituted -(C -C )cycloalkyl, -(C -
1 12 1 12 3 7 1
C )alkyl-(C -C )cycloalkyl, -(C -C )alkyl-heterocycloalkyl, optionally substituted heterocycloalkyl,
6 3 7 1 6
optionally substituted aryl, or optionally substituted heteroaryl;
each R is independently H or -(C -C )alkyl;
each R is independently H or -(C -C )alkyl;
26
each R and R is independently H or optionally substituted -(C -C )alkyl; and
26
or R and R and the nitrogen atom to which they are attached form a heterocycloalkyl ring;
or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
In one embodiment is a compound of Formula (IIe) wherein R and R are each H. In another
embodiment is a compound of Formula (IIe) wherein R is H, and R is -CH CH NH . In another
2 2 2
embodiment is a compound of Formula (IIe) wherein R is -CH CH NH , and R is H. In another
2 2 2
embodiment is a compound of Formula (IIe) wherein R and R are each -CH CH NH .
2 2 2
[00299] In another embodiment is a compound of Formula (IIe) wherein X is optionally substituted aryl.
In a further embodiment is a compound of Formula (IIe) wherein X is optionally substituted phenyl. In
18253141_1 (GHMatters) P111789.NZ
another embodiment is a compound of Formula (IIe) wherein X is optionally substituted heteroaryl. In a
further embodiment is a compound of Formula (IIe) wherein X is disubstituted heteroaryl. In a further
embodiment is a compound of Formula (IIe) wherein X is heteroaryl disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
23 25 26
(C -C )alkyl, OR , -NR R , and -NO . In a further embodiment is a compound of Formula (IIe) wherein
1 6 2
X is heteroaryl disubstituted with substituents each independently selected from -(C -C )alkyl. In a further
embodiment is a compound of Formula (IIe) wherein X is heteroaryl disubstituted with methyl. In a further
embodiment is a compound of Formula (IIe) wherein X is pyridinyl disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
23 25 26
(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound of Formula (IIe) wherein X
1 6 2
is pyridinyl disubstituted with substituents each independently selected from -(C -C )alkyl. In a further
embodiment is a compound of Formula (IIe) wherein X is pyridinyl disubstituted with methyl. In a further
embodiment is a compound of Formula (IIe) wherein X is pyrimidinyl disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
23 25 26
(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound of Formula (IIe) wherein X
1 6 2
is pyrimidinyl disubstituted with substituents each independently selected from -(C -C )alkyl. In a further
embodiment is a compound of Formula (IIe) wherein X is pyrimidinyl disubstituted with methyl. In
another embodiment is a compound of Formula (IIe) wherein X is optionally substituted -(C -C )alkyl-.
In another embodiment is a compound of Formula (IIe) wherein Y is optionally substituted aryl.
In a further embodiment is a compound of Formula (IIe) wherein Y is optionally substituted phenyl. In
another embodiment is a compound of Formula (IIe) wherein Y is optionally substituted heteroaryl. In
another embodiment is a compound of Formula (IIe) wherein Y is optionally substituted -(C -C )alkyl-. In
another embodiment is a compound of Formula (IIe) wherein Y is optionally substituted (C -
C )cycloalkyl-. In another embodiment is a compound of Formula (IIe) wherein Y is optionally substituted
heterocycloalkyl. In another embodiment is a compound of Formula (IIe) wherein Y is -O-. In another
embodiment is a compound of Formula (IIe) wherein Y is -(C -C )alkynyl. In another embodiment is a
compound of Formula (IIe) wherein Y is -O-(C -C )alkyl-. In another embodiment is a compound of
Formula (IIe) wherein Y is a bond.
In another embodiment is a compound of Formula (IIe) wherein Z is -(C -C )alkyl. In a further
1 12
embodiment is a compound of Formula (IIe) wherein Z is n-butyl, isobutyl, or tert-butyl. In another
embodiment is a compound of Formula (IIe) wherein Z is -O-(C -C )alkyl. In another embodiment is a
1 12
compound of Formula (IIe) wherein Z is -O-(C -C )cycloalkyl. In another embodiment is a compound of
Formula (IIe) wherein Z is -(C -C )alkenyl. In another embodiment is a compound of Formula (IIe)
2 12
wherein Z is optionally substituted aryl. In a further embodiment is a compound of Formula (IIe) wherein
Z is optionally substituted phenyl. In a further embodiment is a compound of Formula (IIe) wherein Z is
phenyl monsubstituted or disubstituted with a substituent independently selected from -(C -C )alkyl. In a
further embodiment is a compound of Formula (IIe) wherein Z is phenyl monosubstituted with n-butyl,
18253141_1 (GHMatters) P111789.NZ
isobutyl, or tert-butyl. In a further embodiment is a compound of Formula (IIe) wherein Z is phenyl
monosubstituted with n-butyl. In a further embodiment is a compound of Formula (IIe) wherein Z is
phenyl monosubstituted with isobutyl. In a further embodiment is a compound of Formula (IIe) wherein Z
is phenyl monosubstituted with tert-butyl. In another embodiment is a compound of Formula (IIe) wherein
Z is optionally substituted heteroaryl. In another embodiment is a compound of Formula (IIe) wherein Z is
optionally substituted -(C -C )cycloalkyl. In another embodiment is a compound of Formula (IIe) wherein
Z is optionally substituted heterocycloalkyl. In another embodiment is a compound of Formula (IIe)
wherein Z is halogen.
In one aspect described herein are compounds of Formula (III):
(R )
(R )
18 16
Z X N
17 9 R
O R O R
11 12
Formula (III);
wherein:
1 2 23
R and R are each independently H, -(C -C )alkyl, -(C -C )alkyl-OR , -CH CH(OH)CH NH , -
1 6 1 6 2 2 2
CH CH(heterocycloalkyl)CH NH , -CH C(O)NH , -CH C(O)N(H)CH CN, -(C -C )alkyl-C(O)OR , -
2 2 2 2 2 2 2 1 6
21 22 25 26 23 21 22
(C -C )alkyl-NR R , -(C -C )alkyl-C(O)NR R , -(C -C )alkyl-N(R )C(O)(C -C )alkylNR R , -
1 6 1 6 1 6 1 6
23 23
(C -C )alkyl-N(R )C(O)(C -C )alkyl, -(C -C )alkyl-C(O)N(R )(C -C )alkyl, -(C -C )alkyl-
1 6 1 6 1 6 1 6 1 6
23 23 21 22
C(O)N(R )(C -C )alkyl-heterocycloalkyl, -(C -C )alkyl-NR C(=NH)NR R , -(C -C )alkyl-
1 6 1 6 1 6
23 23 21 22
NR C(=NH)R , -(C -C )alkyl-[(C -C )alkyl-NR R ] , -(C -C )heteroalkyl, or optionally substituted
1 6 1 6 2 1 6
heterocycloalkyl;
or R and R and the atoms to which they are attached form an optionally substituted heterocycloalkyl ring;
R is H or -(C -C )alkyl;
R is H, -(C -C )alkyl, -(C -C )alkyl-OH, -(C -C )cycloalkyl, or -C(O)NH ;
1 6 1 6 3 6 2
or R and R are combined to form a heterocycloalkyl ring;
R is H or -(C -C )alkyl;
or R and R and the carbon atom to which they are attached form a cyclopropyl ring;
6 7 8
R , R , and R are each independently H, fluoro, hydroxyl, amino, optionally substituted alkyl, heteroalkyl,
or -(C -C )alkyl;
R is H, -(C -C )alkyl, -(C -C )haloalkyl, or -(C -C )cycloalkyl;
1 6 1 6 3 6
is H, -(C -C )alkyl, -(C -C )haloalkyl, or -(C -C )cycloalkyl;
1 6 1 6 3 6
9 10
or R and R are combined to form a heterocycloalkyl or cycloalkyl ring
18253141_1 (GHMatters) P111789.NZ
11 12 23 23
R and R are each independently H, -NH , -(C -C )alkyl, -(C -C )alkyl-OR , -(C -C )alkyl-SR , -(C -
2 1 6 1 6 1 6 1
23 21 22 23 23
C )alkyl-C(O)OR , -(C -C )alkyl-NR R , -(C -C )alkyl-NR OR , -(C -C )alkyl-
6 1 6 1 6 1 6
23 23 25 26
NHC(O)NR OR , -(C -C )alkyl-O-(C -C )alkyl-NR R , -(C -C )alkyl-CN, -(C -C )alkyl-
1 6 1 6 1 6 1 6
23 23 25 26
NR C(O)R , -(C -C )alkyl-C(O)NR R , -(C -C )heteroalkyl-CO H, -(C -C )alkyl-S(O)(C -C )alkyl,
1 6 1 6 2 1 6 1 6
-(C -C )alkyl-N(H)CH=NH, -(C -C )alkyl-C(NH )=NH, -(C -C )alkyl-N(H)C(=NH)NH , -(C -
1 6 1 6 2 1 6 2 1
26 25 26
C )alkyl-N(H)S(O) NR R , -(C -C )alkyl-N(H)S(O) (C -C )alkyl, -(C -C )alkyl-N(H)-C(O)NR R ,
6 2 1 6 2 1 6 1 6
-(C -C )alkylC(O)N(H)[optionally substituted(C -C )alkyl]-OR , -(C -C )alkylN(H)C(O)(C -
1 6 2 6 1 6 1
23 25 26
C )alkyl-OR , -(C -C )alkylC(O)N(H)heterocycloalkyl, -(C -C )alkylC(O)NR R , -(C -C )alkyl-
6 1 6 1 6 1 6
26 25 26
N(H)-C(O)-(C -C )alkyl-NR R , -(C -C )alkyl-N(H)-(C -C )alkylC(O)NR R , -(C -C )alkyl-
1 6 1 6 1 6 1 6
heterocycloalkyl, optionally substituted -(C -C )alkyl-N(H)heterocycloalkyl, or -(C -C )alkyl-
1 6 1 6
heteroaryl;
11 18 12
or R and R are combined to form an optionally substituted heterocycloalkyl ring; and R is H;
16 17 18 23
R , R , R , and R are each independently H, -(C -C )alkyl, -(C -C )cycloalkyl, -(C -C )alkyl-OR , -
1 6 3 6 1 6
23 21 22
(C -C )alkyl-C(O)OR , or -(C -C )alkyl-NR R ;
1 6 1 6
X is disubstituted heteroaryl;
Y is a bond, -O-, -S-, optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, -(C -
1 6 2 6 2 6 1
24 24 24
C )alkyl-N(R )(C -C )alkyl-, -O-(C -C )alkyl-, -O(C -C )aryl-, -N(R )(C -C )alkyl-, -N(R )SO (C -
6 1 6 1 6 6 10 1 6 2 1
C )alkyl-, -N(R )C(O)(C -C )alkyl-, -C(O)(C -C )alkyl-, -S(C -C )alkyl-, -SO (C -C )alkyl-, -
6 1 6 1 6 1 6 2 1 6
C(O)NH(C -C )alkyl-, optionally substituted -(C -C )cycloalkyl-, optionally substituted -
1 6 3 7
24 24 24
C(O)N(R )aryl-, optionally substituted -N(R )C(O)aryl-, optionally substituted -N(R )SO aryl-,
optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Z is H, halogen, -NH , -CN, -CF , -CO H, -(C -C )alkyl, -(C -C )alkenyl, -CH=((C -C )cycloalkyl), -
2 3 2 1 12 2 12 3 7
26
-C )alkynyl, -C(O)NR R , -O-(C -C )alkyl, -S-(C -C )alkyl, -O-(C -C )[optionally substituted
2 12 1 12 1 12 3 10
23 23
(C -C )cycloalkyl], -O-(C -C )alkyl-OR , -(C -C )alkyl-OR , -(C -C )alkyl-CN, -S-(C -C )alkyl, -
3 7 1 6 1 12 1 12 1 12
24 24
N(R )(C -C )alkyl, -N(R )C(O)(C -C )alkyl, optionally substituted -(C -C )cycloalkyl, -(C -
1 12 1 12 3 7 1
C )alkyl-(C -C )cycloalkyl, -(C -C )alkyl-heterocycloalkyl, optionally substituted heterocycloalkyl,
6 3 7 1 6
optionally substituted aryl, or optionally substituted heteroaryl;
21 22
each R and R is independently H, -(C -C )alkyl, -(C -C )heteroalkyl, -(C -C )alkyl-CO H, -C(O)(C -
1 6 1 6 1 6 2 1
C )alkyl, -C(O)O(C -C )alkyl, -C(O)O(C -C )haloalkyl, -C(=NH)(C -C )alkyl, -C(=NH)N(R ) , -
6 1 6 1 6 1 6 2
31 31 21 22
C(O)N(R ) , or -SO N(R ) ; or R and R and the nitrogen atom to which they are attached form a
2 2 2
heterocycloalkyl ring;
31 31
each R is independently H or -(C -C )alkyl; or two R and the nitrogen atom to which they are attached
form a heterocycloalkyl ring;
each R is independently H or -(C -C )alkyl;
each R is independently H or -(C -C )alkyl;
26
each R and R is independently H or optionally substituted -(C -C )alkyl;
26
or R and R and the nitrogen atom to which they are attached form a heterocycloalkyl ring;
18253141_1 (GHMatters) P111789.NZ
27 23 24 23 23 24
each R is independently halogen, -NR R , -NHC(O)R , -NHC(O)NR R , nitro, hydroxyl, optionally
substituted -(C -C )alkyl, optionally substituted -(C -C )heteroalkyl, optionally substituted -(C -
1 6 1 6 1
C )heteroalkyloxy, optionally substituted -(C -C )heteroalkylamino, -(C -C )alkoxy, -C(O)(C -
6 1 6 1 6 1
C )alkyl, or -S(O) (C -C )alkyl;
6 2 1 6
1 27
or R and R and the atoms to which they are attached form an optionally substituted 5- or 6-membered
heterocycloalkyl ring;
28 23 24 23 23 24
each R is independently halogen, -NR R , -NHC(O)R , -NHC(O)NR R , nitro, hydroxyl, optionally
substituted -(C -C )alkyl, optionally substituted -(C -C )heteroalkyl, optionally substituted -(C -
1 6 1 6 1
C )heteroalkyloxy, optionally substituted -(C -C )heteroalkylamino, -(C -C )alkoxy, -C(O)(C -
6 1 6 1 6 1
C )alkyl, or -S(O) (C -C )alkyl;
6 2 1 6
2 28
or R and R and the atoms to which they are attached form an optionally substituted 5- or 6-membered
heterocycloalkyl ring;
p is 0, 1, or 2; and
q is 0, 1, or 2;
or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
6 7 8
In one embodiment is a compound of Formula (III) wherein R , R , and R are H.
16
In another embodiment is a compound of Formula (III) wherein R and R are H.
In one embodiment is a compound of Formula (III) wherein R is -(C -C )alkyl. In another
embodiment is a compound of Formula (III) wherein R is -CH . In another embodiment is a compound
of Formula (III) wherein R is -CH CH . In another embodiment is a compound of Formula (III) wherein
17 17
R is -(C -C )cycloalkyl. In another embodiment is a compound of Formula (III) wherein R is
cyclopropyl. In another embodiment is a compound of Formula (III) wherein R is -(C -C )alkyl-
23 17
C(O)OR . In another embodiment is a compound of Formula (III) wherein R is -CH CH OH. In another
17 21 22
embodiment is a compound of Formula (III) wherein R is -(C -C )alkyl-NR R . In another embodiment
is a compound of Formula (III) wherein R is -CH CH NH . In another embodiment is a compound of
2 2 2
Formula (III) wherein R is H.
In another embodiment is a compound of Formula (III) wherein R is H.
In another embodiment is a compound of Formula (III) wherein R is H.
In another embodiment is a compound of Formula (III) wherein R is H.
[00309] In another embodiment is a compound of Formula (III) wherein R is H. In another embodiment
is a compound of Formula (III) wherein R is -(C -C )alkyl. In another embodiment is a compound of
Formula (III) wherein R is -CH . In another embodiment is a compound of Formula (III) wherein R is -
CH CH . In another embodiment is a compound of Formula (III) wherein R is -(C -C )alkyl-OH. In
2 3 1 6
another embodiment is a compound of Formula (III) wherein R is -CH OH. In another embodiment is a
compound of Formula (III) wherein R is -(C -C )cycloalkyl. In another embodiment is a compound of
Formula (III) wherein R is cyclopropyl. In another embodiment is a compound of Formula (III) wherein
R is -C(O)NH .
18253141_1 (GHMatters) P111789.NZ
3 4 5
In another embodiment is a compound of Formula (III) wherein R , R , and R are H.
In another embodiment is a compound of Formula (III) wherein R and R and the carbon atom
to which they are attached form a cyclopropyl ring.
In another embodiment is a compound of Formula (III) wherein R is H.
9
[00313] In another embodiment is a compound of Formula (III) wherein R is H and R is -(C -C )alkyl.
9
In another embodiment is a compound of Formula (III) wherein R is H and R is -CH . In another
9
embodiment is a compound of Formula (III) wherein R is H and R is -CH CH . In another embodiment
9
is a compound of Formula (III) wherein R is H and R is -(C -C )haloalkyl. In another embodiment is a
9
compound of Formula (III) wherein R is H and R is -CH F. In another embodiment is a compound of
9
Formula (III) wherein R is H and R is -CHF . In another embodiment is a compound of Formula (III)
9
wherein R is H and R is -(C -C )cycloalkyl. In another embodiment is a compound of Formula (III)
9
wherein R is H and R is cyclopropyl. In another embodiment is a compound of Formula (III) wherein
9
is H and R is H.
In another embodiment is a compound of Formula (III) wherein R is H.
12 11
[00315] In another embodiment is a compound of Formula (III) wherein R is H and R is -(C -
12 11
C )alkyl. In another embodiment is a compound of Formula (III) wherein R is H and R is -CH . In
12 11 23
another embodiment is a compound of Formula (III) wherein R is H and R is -(C -C )alkyl-OR . In
12 11
another embodiment is a compound of Formula (III) wherein R is H and R is -CH OH. In another
12 11
embodiment is a compound of Formula (III) wherein R is H and R is -CH CH OH. In another
12 11
embodiment is a compound of Formula (III) wherein R is H and R is -(C -C )alkyl. In another
12 11 21 22
embodiment is a compound of Formula (III) wherein R is H and R is -(C -C )alkyl-NR R . In another
12 11
embodiment is a compound of Formula (III) wherein R is H and R is -(C -C )alkyl-NH . In another
1 6 2
12 11
embodiment is a compound of Formula (III) wherein R is H and R is -CH NH . In another embodiment
12 11
is a compound of Formula (III) wherein R is H and R is -CH CH NH . In another embodiment is a
2 2 2
12 11
compound of Formula (III) wherein R is H and R is -CH CH CH NH . In another embodiment is a
2 2 2 2
12 11
compound of Formula (III) wherein R is H and R is -CH CH CH CH NH . In another embodiment is a
2 2 2 2 2
12 11
compound of Formula (III) wherein R is H and R is -(C -C )alkyl-CN. In another embodiment is a
12 11
compound of Formula (III) wherein R is H and R is -CH CN. In another embodiment is a compound of
12 11 25 26
Formula (III) wherein R is H and R is -(C -C )alkyl-C(O)NR R . In another embodiment is a
12 11
compound of Formula (III) wherein R is H and R is -CH C(O)NH . In another embodiment is a
12 11
compound of Formula (III) wherein R is H and R is -CH CH C(O)NH . In another embodiment is a
2 2 2
12 11
compound of Formula (III) wherein R is H and R is -(C -C )alkyl-heteroaryl. In another embodiment is
12 11 25 26
a compound of Formula (III) wherein R is H and R is -(C -C )alkyl-N(H)S(O) NR R . In another
1 6 2
12 11
embodiment is a compound of Formula (III) wherein R is H and R is -CH N(H)S(O) NH . In another
2 2 2
12 11
embodiment is a compound of Formula (III) wherein R is H and R is H.
11 18
In another embodiment is a compound of Formula (III) wherein R and R are combined to
form an optionally substituted heterocycloalkyl ring and R is H.
18253141_1 (GHMatters) P111789.NZ
In another embodiment is a compound of Formula (III) wherein p is 1 and R is halogen. In
another embodiment is a compound of Formula (III) wherein p is 1 and R is optionally substituted -(C -
C )alkyl. In another embodiment is a compound of Formula (III) wherein q is 0, p is 1 and R is halogen.
In another embodiment is a compound of Formula (III) wherein q is 0, p is 1 and R is optionally
substituted -(C -C )alkyl. In another embodiment is a compound of Formula (III) wherein q is 1 and R is
halogen. In another embodiment is a compound of Formula (III) wherein q is 1 and R is optionally
substituted -(C -C )alkyl. In another embodiment is a compound of Formula (III) wherein p is 0, q is 1 and
28 28
R is halogen. In another embodiment is a compound of Formula (III) wherein p is 0, q is 1 and R is
optionally substituted -(C -C )alkyl.
[00318] In another embodiment is a compound of Formula (III) wherein p is 0, and q is 0.
In another embodiment is a compound of Formula (III) wherein R and R are each
21 22
independently H or -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (III)
1 2 1 2
wherein R and R are each H. In another embodiment is a compound of Formula (III) wherein R and R
21 22
are each independently -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (III)
1 2 21 22
wherein R is H, and R is -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (III)
1 21 22 2
wherein R is -(C -C )alkyl-NR R , and R is H. In another embodiment is a compound of Formula (III)
wherein R is H, and R is -CH CH NH . In another embodiment is a compound of Formula (III) wherein
2 2 2
1 2 1 2
R is -CH CH NH , and R is H. In another embodiment is a compound of Formula (III) wherein R and R
2 2 2
are each -CH CH NH . In a further embodiment is a compound of Formula (III) wherein R is -(C -
2 2 2 1
21 22 2 1
C )alkyl-NR R and R is H. In a further embodiment is a compound of Formula (III) wherein R is -
2 1 2
CH CH NH and R is H. In a further embodiment is a compound of Formula (III) wherein R is H and R
2 2 2
21 22 1 2
is -(C -C )alkyl-NR R . In a further embodiment is a compound of Formula (III) wherein R is H and R
is -CH CH NH . In another embodiment is a compound of Formula (III) wherein R and R are each
2 2 2
21 22
independently H, -(C -C )alkyl-NR R , or -CH CH(OH)CH NH . In another embodiment is a compound
1 6 2 2 2
of Formula (III) wherein R and R are each independently -CH CH(OH)CH NH . In another embodiment
2 2 2
is a compound of Formula (III) wherein R is H, and R is -CH CH(OH)CH NH . In another embodiment
2 2 2
is a compound of Formula (III) wherein R is -CH CH(OH)CH NH , and R is H. In a further embodiment
2 2 2
is a compound of Formula (III) wherein R and R and the atoms to which they are attached form an
optionally substituted heterocycloalkyl ring.
[00320] In another embodiment is a compound of Formula (III) wherein X is heteroaryl disubstituted
with substituents each independently selected from halogen, -CN, optionally substituted -(C -C )alkyl,
23 25 26
optionally substituted -O-(C -C )alkyl, OR , -NR R , and -NO . In a further embodiment is a compound
1 6 2
of Formula (III) wherein X is heteroaryl disubstituted with substituents each independently selected from -
(C -C )alkyl. In a further embodiment is a compound of Formula (III) wherein X is heteroaryl
disubstituted with methyl. In a further embodiment is a compound of Formula (III) wherein X is pyridinyl
disubstituted with substituents each independently selected from halogen, -CN, optionally substituted -(C -
23 25 26
C )alkyl, optionally substituted -O-(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a
6 1 6 2
18253141_1 (GHMatters) P111789.NZ
compound of Formula (III) wherein X is pyridinyl disubstituted with substituents each independently
selected from -(C -C )alkyl. In a further embodiment is a compound of Formula (III) wherein X is
pyridinyl disubstituted with methyl. In a further embodiment is a compound of Formula (III) wherein X is
pyrimidinyl disubstituted with substituents each independently selected from halogen, -CN, optionally
23 25 26
substituted -(C -C )alkyl, optionally substituted -O-(C -C )alkyl, OR , -NR R , or -NO . In a further
1 6 1 6 2
embodiment is a compound of Formula (III) wherein X is pyrimidinyl disubstituted with substituents each
independently selected from -(C -C )alkyl. In a further embodiment is a compound of Formula (III)
wherein X is pyrimidinyl disubstituted with methyl.
In another embodiment is a compound of Formula (III) wherein Y is optionally substituted aryl.
In a further embodiment is a compound of Formula (III) wherein Y is optionally substituted phenyl. In
another embodiment is a compound of Formula (III) wherein Y is optionally substituted heteroaryl. In
another embodiment is a compound of Formula (III) wherein Y is optionally substituted -(C -C )alkyl-. In
another embodiment is a compound of Formula (III) wherein Y is optionally substituted (C -C )cycloalkyl-.
In another embodiment is a compound of Formula (III) wherein Y is optionally substituted
heterocycloalkyl. In another embodiment is a compound of Formula (III) wherein Y is -O-. In another
embodiment is a compound of Formula (III) wherein Y is -(C -C )alkynyl. In another embodiment is a
compound of Formula (III) wherein Y is -O-(C -C )alkyl-. In another embodiment is a compound of
Formula (III) wherein Y is a bond.
In another embodiment is a compound of Formula (III) wherein Z is -(C -C )alkyl. In a further
1 12
embodiment is a compound of Formula (III) wherein Z is n-butyl, isobutyl, or tert-butyl. In another
embodiment is a compound of Formula (III) wherein Z is -O-(C -C )alkyl. In another embodiment is a
1 12
compound of Formula (III) wherein Z is -O-(C -C )cycloalkyl. In another embodiment is a compound of
Formula (III) wherein Z is -(C -C )alkenyl. In another embodiment is a compound of Formula (III)
2 12
wherein Z is optionally substituted aryl. In a further embodiment is a compound of Formula (III) wherein
Z is optionally substituted phenyl. In a further embodiment is a compound of Formula (III) wherein Z is
phenyl monsubstituted or disubstituted with a substituent independently selected from -(C -C )alkyl. In a
further embodiment is a compound of Formula (III) wherein Z is phenyl monosubstituted with n-butyl,
isobutyl, or tert-butyl. In a further embodiment is a compound of Formula (III) wherein Z is phenyl
monosubstituted with n-butyl. In a further embodiment is a compound of Formula (III) wherein Z is
phenyl monosubstituted with isobutyl. In a further embodiment is a compound of Formula (III) wherein Z
is phenyl monosubstituted with tert-butyl. In another embodiment is a compound of Formula (III) wherein
Z is optionally substituted heteroaryl. In another embodiment is a compound of Formula (III) wherein Z is
optionally substituted -(C -C )cycloalkyl. In another embodiment is a compound of Formula (III) wherein
Z is optionally substituted heterocycloalkyl. In another embodiment is a compound of Formula (III)
wherein Z is halogen.
18253141_1 (GHMatters) P111789.NZ
In another embodiment is a compound of Formula (III) wherein Z-Y-X- is not
In another embodiment is a compound of Formula (III) having the structure of Formula (IIIa):
(R )
(R )
18 16
Z X N
17 9 R
11 12
Formula (IIIa);
wherein:
1 2 23
R and R are each independently H, -(C -C )alkyl, -(C -C )alkyl-OR , -CH CH(OH)CH NH , -
1 6 1 6 2 2 2
CH CH(heterocycloalkyl)CH NH , -CH C(O)NH , -CH C(O)N(H)CH CN, -(C -C )alkyl-C(O)OR , -
2 2 2 2 2 2 2 1 6
21 22 25 26 23 21 22
(C -C )alkyl-NR R , -(C -C )alkyl-C(O)NR R , -(C -C )alkyl-N(R )C(O)(C -C )alkylNR R , -
1 6 1 6 1 6 1 6
23 23
(C -C )alkyl-N(R )C(O)(C -C )alkyl, -(C -C )alkyl-C(O)N(R )(C -C )alkyl, -(C -C )alkyl-
1 6 1 6 1 6 1 6 1 6
23 23 21 22
C(O)N(R )(C -C )alkyl-heterocycloalkyl, -(C -C )alkyl-NR C(=NH)NR R , -(C -C )alkyl-
1 6 1 6 1 6
23 23 21 22
NR C(=NH)R , -(C -C )alkyl-[(C -C )alkyl-NR R ] , -(C -C )heteroalkyl, or optionally substituted
1 6 1 6 2 1 6
heterocycloalkyl;
or R and R and the atoms to which they are attached form an optionally substituted heterocycloalkyl ring;
R is H or -(C -C )alkyl;
R is H, -(C -C )alkyl, -(C -C )alkyl-OH, -(C -C )cycloalkyl, or -C(O)NH ;
1 6 1 6 3 6 2
or R and R are combined to form a heterocycloalkyl ring;
R is H or -(C -C )alkyl;
or R and R and the carbon atom to which they are attached form a cyclopropyl ring;
6 7 8
R , R , and R are each independently H, fluoro, hydroxyl, amino, optionally substituted alkyl, heteroalkyl,
or -(C -C )alkyl;
R is H, -(C -C )alkyl, -(C -C )haloalkyl, or -(C -C )cycloalkyl;
1 6 1 6 3 6
R is H, -(C -C )alkyl, -(C -C )haloalkyl, or -(C -C )cycloalkyl;
1 6 1 6 3 6
9 10
or R and R are combined to form a heterocycloalkyl or cycloalkyl ring
11 12 23 23
R and R are each independently H, -NH , -(C -C )alkyl, -(C -C )alkyl-OR , -(C -C )alkyl-SR , -(C -
2 1 6 1 6 1 6 1
23 21 22 23 23
C )alkyl-C(O)OR , -(C -C )alkyl-NR R , -(C -C )alkyl-NR OR , -(C -C )alkyl-
6 1 6 1 6 1 6
23 23 25 26
NHC(O)NR OR , -(C -C )alkyl-O-(C -C )alkyl-NR R , -(C -C )alkyl-CN, -(C -C )alkyl-
1 6 1 6 1 6 1 6
23 23 25 26
NR C(O)R , -(C -C )alkyl-C(O)NR R , -(C -C )heteroalkyl-CO H, -(C -C )alkyl-S(O)(C -C )alkyl,
1 6 1 6 2 1 6 1 6
18253141_1 (GHMatters) P111789.NZ
-(C -C )alkyl-N(H)CH=NH, -(C -C )alkyl-C(NH )=NH, -(C -C )alkyl-N(H)C(=NH)NH , -(C -
1 6 1 6 2 1 6 2 1
26 25 26
C )alkyl-N(H)S(O) NR R , -(C -C )alkyl-N(H)S(O) (C -C )alkyl, -(C -C )alkyl-N(H)-C(O)NR R ,
6 2 1 6 2 1 6 1 6
-(C -C )alkylC(O)N(H)[optionally substituted(C -C )alkyl]-OR , -(C -C )alkylN(H)C(O)(C -
1 6 2 6 1 6 1
23 25 26
C )alkyl-OR , -(C -C )alkylC(O)N(H)heterocycloalkyl, -(C -C )alkylC(O)NR R , -(C -C )alkyl-
6 1 6 1 6 1 6
26 25 26
N(H)-C(O)-(C -C )alkyl-NR R , -(C -C )alkyl-N(H)-(C -C )alkylC(O)NR R , -(C -C )alkyl-
1 6 1 6 1 6 1 6
heterocycloalkyl, optionally substituted -(C -C )alkyl-N(H)heterocycloalkyl, or -(C -C )alkyl-
1 6 1 6
heteroaryl;
11 18 12
or R and R are combined to form an optionally substituted heterocycloalkyl ring; and R is H;
16 17 18 23
R , R , R , and R are each independently H, -(C -C )alkyl, -(C -C )cycloalkyl, -(C -C )alkyl-OR , -
1 6 3 6 1 6
23 21 22
(C -C )alkyl-C(O)OR , or -(C -C )alkyl-NR R ;
1 6 1 6
X is disubstituted heteroaryl;
Y is a bond, -O-, -S-, optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, -(C -
1 6 2 6 2 6 1
24 24 24
C )alkyl-N(R )(C -C )alkyl-, -O-(C -C )alkyl-, -O(C -C )aryl-, -N(R )(C -C )alkyl-, -N(R )SO (C -
6 1 6 1 6 6 10 1 6 2 1
C )alkyl-, -N(R )C(O)(C -C )alkyl-, -C(O)(C -C )alkyl-, -S(C -C )alkyl-, -SO (C -C )alkyl-, -
6 1 6 1 6 1 6 2 1 6
C(O)NH(C -C )alkyl-, optionally substituted -(C -C )cycloalkyl-, optionally substituted -
1 6 3 7
24 24 24
C(O)N(R )aryl-, optionally substituted -N(R )C(O)aryl-, optionally substituted -N(R )SO aryl-,
optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Z is H, halogen, -NH , -CN, -CF , -CO H, -(C -C )alkyl, -(C -C )alkenyl, -CH=((C -C )cycloalkyl), -
2 3 2 1 12 2 12 3 7
26
(C -C )alkynyl, -C(O)NR R , -O-(C -C )alkyl, -S-(C -C )alkyl, -O-(C -C )[optionally substituted
2 12 1 12 1 12 3 10
23 23
(C -C )cycloalkyl], -O-(C -C )alkyl-OR , -(C -C )alkyl-OR , -(C -C )alkyl-CN, -S-(C -C )alkyl, -
3 7 1 6 1 12 1 12 1 12
24 24
N(R )(C -C )alkyl, -N(R )C(O)(C -C )alkyl, optionally substituted -(C -C )cycloalkyl, -(C -
1 12 1 12 3 7 1
C )alkyl-(C -C )cycloalkyl, -(C -C )alkyl-heterocycloalkyl, optionally substituted heterocycloalkyl,
6 3 7 1 6
optionally substituted aryl, or optionally substituted heteroaryl;
21 22
each R and R is independently H, -(C -C )alkyl, -(C -C )heteroalkyl, -(C -C )alkyl-CO H, -C(O)(C -
1 6 1 6 1 6 2 1
C )alkyl, -C(O)O(C -C )alkyl, -C(O)O(C -C )haloalkyl, -C(=NH)(C -C )alkyl, -C(=NH)N(R ) , -
6 1 6 1 6 1 6 2
31 31 21 22
C(O)N(R ) , or -SO N(R ) ; or R and R and the nitrogen atom to which they are attached form a
2 2 2
heterocycloalkyl ring;
31 31
each R is independently H or -(C -C )alkyl; or two R and the nitrogen atom to which they are attached
form a heterocycloalkyl ring;
each R is independently H or -(C -C )alkyl;
each R is independently H or -(C -C )alkyl;
26
each R and R is independently H or optionally substituted -(C -C )alkyl;
26
or R and R and the nitrogen atom to which they are attached form a heterocycloalkyl ring;
27 23 24 23 23 24
each R is independently halogen, -NR R , -NHC(O)R , -NHC(O)NR R , nitro, hydroxyl, optionally
substituted -(C -C )alkyl, optionally substituted -(C -C )heteroalkyl, optionally substituted -(C -
1 6 1 6 1
C )heteroalkyloxy, optionally substituted -(C -C )heteroalkylamino, -(C -C )alkoxy, -C(O)(C -
6 1 6 1 6 1
C )alkyl, or -S(O) (C -C )alkyl;
6 2 1 6
18253141_1 (GHMatters) P111789.NZ
1 27
or R and R and the atoms to which they are attached form an optionally substituted 5- or 6-membered
heterocycloalkyl ring;
28 23 24 23 23 24
each R is independently halogen, -NR R , -NHC(O)R , -NHC(O)NR R , nitro, hydroxyl, optionally
substituted -(C -C )alkyl, optionally substituted -(C -C )heteroalkyl, optionally substituted -(C -
1 6 1 6 1
C )heteroalkyloxy, optionally substituted -(C -C )heteroalkylamino, -(C -C )alkoxy, -C(O)(C -
6 1 6 1 6 1
C )alkyl, or -S(O) (C -C )alkyl;
6 2 1 6
2 28
or R and R and the atoms to which they are attached form an optionally substituted 5- or 6-membered
heterocycloalkyl ring;
p is 0, 1, or 2; and
q is 0, 1, or 2;
or a pharmaceutically acceptable salt, solvate, or prodrug thereof.In one embodiment is a
6 7 8
compound of Formula (IIIa) wherein R , R , and R are H.
16
In another embodiment is a compound of Formula (IIIa) wherein R and R are H.
In one embodiment is a compound of Formula (IIIa) wherein R is -(C -C )alkyl. In another
embodiment is a compound of Formula (IIIa) wherein R is -CH . In another embodiment is a compound
of Formula (IIIa) wherein R is -CH CH . In another embodiment is a compound of Formula (IIIa)
17 17
wherein R is -(C -C )cycloalkyl. In another embodiment is a compound of Formula (IIIa) wherein R is
cyclopropyl. In another embodiment is a compound of Formula (IIIa) wherein R is -(C -C )alkyl-
23 17
C(O)OR . In another embodiment is a compound of Formula (IIIa) wherein R is -CH CH OH. In
17 21 22
another embodiment is a compound of Formula (IIIa) wherein R is -(C -C )alkyl-NR R . In another
embodiment is a compound of Formula (IIIa) wherein R is -CH CH NH . In another embodiment is a
2 2 2
compound of Formula (IIIa) wherein R is H.
In another embodiment is a compound of Formula (IIIa) wherein R is H.
In another embodiment is a compound of Formula (IIIa) wherein R is H.
[00330] In another embodiment is a compound of Formula (IIIa) wherein R is H.
In another embodiment is a compound of Formula (IIIa) wherein R is H. In another
embodiment is a compound of Formula (IIIa) wherein R is -(C -C )alkyl. In another embodiment is a
compound of Formula (IIIa) wherein R is -CH . In another embodiment is a compound of Formula (IIIa)
wherein R is -CH CH . In another embodiment is a compound of Formula (IIIa) wherein R is -(C -
2 3 1
C )alkyl-OH. In another embodiment is a compound of Formula (IIIa) wherein R is -CH OH. In another
embodiment is a compound of Formula (IIIa) wherein R is -(C -C )cycloalkyl. In another embodiment is
a compound of Formula (IIIa) wherein R is cyclopropyl. In another embodiment is a compound of
Formula (IIIa) wherein R is -C(O)NH .
In another embodiment is a compound of Formula (IIIa) wherein R and R and the carbon atom
to which they are attached form a cyclopropyl ring.
3 4 5
In another embodiment is a compound of Formula (IIIa) wherein R , R , and R are H.
In another embodiment is a compound of Formula (IIIa) wherein R is H.
18253141_1 (GHMatters) P111789.NZ
9
In another embodiment is a compound of Formula (IIIa) wherein R is H and R is -(C -
9
C )alkyl. In another embodiment is a compound of Formula (IIIa) wherein R is H and R is -CH . In
9
another embodiment is a compound of Formula (IIIa) wherein R is H and R is -CH CH . In another
9
embodiment is a compound of Formula (IIIa) wherein R is H and R is -(C -C )haloalkyl. In another
9
embodiment is a compound of Formula (IIIa) wherein R is H and R is -CH F. In another embodiment is
9
a compound of Formula (IIIa) wherein R is H and R is -CHF . In another embodiment is a compound of
9
Formula (IIIa) wherein R is H and R is -(C -C )cycloalkyl. In another embodiment is a compound of
9
Formula (IIIa) wherein R is H and R is cyclopropyl. In another embodiment is a compound of Formula
9
(IIIa) wherein R is H and R is H.
[00336] In another embodiment is a compound of Formula (IIIa) wherein R is H.
12 11
In another embodiment is a compound of Formula (IIIa) wherein R is H and R is -(C -
12 11
C )alkyl. In another embodiment is a compound of Formula (IIIa) wherein R is H and R is -CH . In
12 11 23
another embodiment is a compound of Formula (IIIa) wherein R is H and R is -(C -C )alkyl-OR . In
12 11
another embodiment is a compound of Formula (IIIa) wherein R is H and R is -CH OH. In another
12 11
embodiment is a compound of Formula (IIIa) wherein R is H and R is -CH CH OH. In another
12 11
embodiment is a compound of Formula (IIIa) wherein R is H and R is -(C -C )alkyl. In another
12 11 21 22
embodiment is a compound of Formula (IIIa) wherein R is H and R is -(C -C )alkyl-NR R . In
12 11
another embodiment is a compound of Formula (IIIa) wherein R is H and R is -(C -C )alkyl-NH . In
1 6 2
12 11
another embodiment is a compound of Formula (IIIa) wherein R is H and R is -CH NH . In another
12 11
embodiment is a compound of Formula (IIIa) wherein R is H and R is -CH CH NH . In another
2 2 2
12 11
embodiment is a compound of Formula (IIIa) wherein R is H and R is -CH CH CH NH . In another
2 2 2 2
12 11
embodiment is a compound of Formula (IIIa) wherein R is H and R is -CH CH CH CH NH . In
2 2 2 2 2
12 11
another embodiment is a compound of Formula (IIIa) wherein R is H and R is -(C -C )alkyl-CN. In
12 11
another embodiment is a compound of Formula (IIIa) wherein R is H and R is -CH CN. In another
12 11 25 26
embodiment is a compound of Formula (IIIa) wherein R is H and R is -(C -C )alkyl-C(O)NR R . In
12 11
another embodiment is a compound of Formula (IIIa) wherein R is H and R is -CH C(O)NH . In
12 11
another embodiment is a compound of Formula (IIIa) wherein R is H and R is -CH CH C(O)NH . In
2 2 2
12 11
another embodiment is a compound of Formula (IIIa) wherein R is H and R is -(C -C )alkyl-heteroaryl.
12 11
In another embodiment is a compound of Formula (IIIa) wherein R is H and R is -(C -C )alkyl-
26 12 11
N(H)S(O) NR R . In another embodiment is a compound of Formula (IIIa) wherein R is H and R is -
12 11
CH N(H)S(O) NH . In another embodiment is a compound of Formula (IIIa) wherein R is H and R is
2 2 2
11 18
In another embodiment is a compound of Formula (IIIa) wherein R and R are combined to
form an optionally substituted heterocycloalkyl ring and R is H.
[00339] In another embodiment is a compound of Formula (IIIa) wherein p is 1 and R is halogen. In
another embodiment is a compound of Formula (IIIa) wherein p is 1 and R is optionally substituted -(C -
C )alkyl. In another embodiment is a compound of Formula (IIIa) wherein q is 0, p is 1 and R is halogen.
18253141_1 (GHMatters) P111789.NZ
In another embodiment is a compound of Formula (IIIa) wherein q is 0, p is 1 and R is optionally
substituted -(C -C )alkyl. In another embodiment is a compound of Formula (IIIa) wherein q is 1 and R is
halogen. In another embodiment is a compound of Formula (IIIa) wherein q is 1 and R is optionally
substituted -(C -C )alkyl. In another embodiment is a compound of Formula (IIIa) wherein p is 0, q is 1
28 28
and R is halogen. In another embodiment is a compound of Formula (IIIa) wherein p is 0, q is 1 and R
is optionally substituted -(C -C )alkyl.
In another embodiment is a compound of Formula (IIIa) wherein p is 0, and q is 0.
In another embodiment is a compound of Formula (IIIa) wherein R and R are each
21 22
independently H or -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (IIIa)
1 2 1 2
wherein R and R are each H. In another embodiment is a compound of Formula (IIIa) wherein R and R
21 22
are each independently -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (IIIa)
1 2 21 22
wherein R is H, and R is -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (IIIa)
1 21 22 2
wherein R is -(C -C )alkyl-NR R , and R is H. In another embodiment is a compound of Formula (IIIa)
wherein R is H, and R is -CH CH NH . In another embodiment is a compound of Formula (IIIa) wherein
2 2 2
1 2 1
R is -CH CH NH , and R is H. In another embodiment is a compound of Formula (IIIa) wherein R and
2 2 2
R are each -CH CH NH . In a further embodiment is a compound of Formula (IIIa) wherein R is -(C -
2 2 2 1
21 22 2 1
C )alkyl-NR R and R is H. In a further embodiment is a compound of Formula (IIIa) wherein R is -
2 1 2
CH NH and R is H. In a further embodiment is a compound of Formula (IIIa) wherein R is H and R
2 2 2
21 22 1 2
is -(C -C )alkyl-NR R . In a further embodiment is a compound of Formula (IIIa) wherein R is H and R
is -CH CH NH . In another embodiment is a compound of Formula (IIIa) wherein R and R are each
2 2 2
21 22
independently H, -(C -C )alkyl-NR R , or -CH CH(OH)CH NH . In another embodiment is a compound
1 6 2 2 2
of Formula (IIIa) wherein R and R are each independently -CH CH(OH)CH NH . In another
2 2 2
embodiment is a compound of Formula (IIIa) wherein R is H, and R is -CH CH(OH)CH NH . In another
2 2 2
embodiment is a compound of Formula (IIIa) wherein R is -CH CH(OH)CH NH , and R is H. In a
2 2 2
further embodiment is a compound of Formula (IIIa) wherein R and R and the atoms to which they are
attached form an optionally substituted heterocycloalkyl ring.
In another embodiment is a compound of Formula (IIIa) wherein X is heteroaryl disubstituted
with substituents each independently selected from halogen, -CN, optionally substituted -(C -C )alkyl,
23 25 26
optionally substituted -O-(C -C )alkyl, OR , -NR R , and -NO . In a further embodiment is a compound
1 6 2
of Formula (IIIa) wherein X is heteroaryl disubstituted with substituents each independently selected from
-(C -C )alkyl. In a further embodiment is a compound of Formula (IIIa) wherein X is heteroaryl
disubstituted with methyl. In a further embodiment is a compound of Formula (IIIa) wherein X is pyridinyl
disubstituted with substituents each independently selected from halogen, -CN, optionally substituted -(C -
23 25 26
C )alkyl, optionally substituted -O-(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a
6 1 6 2
compound of Formula (IIIa) wherein X is pyridinyl disubstituted with substituents each independently
selected from -(C -C )alkyl. In a further embodiment is a compound of Formula (IIIa) wherein X is
pyridinyl disubstituted with methyl. In a further embodiment is a compound of Formula (IIIa) wherein X is
18253141_1 (GHMatters) P111789.NZ
pyrimidinyl disubstituted with substituents each independently selected from halogen, -CN, optionally
23 25 26
substituted -(C -C )alkyl, optionally substituted -O-(C -C )alkyl, OR , -NR R , or -NO . In a further
1 6 1 6 2
embodiment is a compound of Formula (IIIa) wherein X is pyrimidinyl disubstituted with substituents each
independently selected from -(C -C )alkyl. In a further embodiment is a compound of Formula (IIIa)
wherein X is pyrimidinyl disubstituted with methyl.
In another embodiment is a compound of Formula (IIIa) wherein Y is optionally substituted aryl.
In a further embodiment is a compound of Formula (IIIa) wherein Y is optionally substituted phenyl. In
another embodiment is a compound of Formula (IIIa) wherein Y is optionally substituted heteroaryl. In
another embodiment is a compound of Formula (IIIa) wherein Y is optionally substituted -(C -C )alkyl-. In
another embodiment is a compound of Formula (IIIa) wherein Y is optionally substituted (C -
C )cycloalkyl-. In another embodiment is a compound of Formula (IIIa) wherein Y is optionally
substituted heterocycloalkyl. In another embodiment is a compound of Formula (IIIa) wherein Y is -O-. In
another embodiment is a compound of Formula (IIIa) wherein Y is -(C -C )alkynyl. In another
embodiment is a compound of Formula (IIIa) wherein Y is -O-(C -C )alkyl-. In another embodiment is a
compound of Formula (IIIa) wherein Y is a bond.
In another embodiment is a compound of Formula (IIIa) wherein Z is -(C -C )alkyl. In a further
1 12
embodiment is a compound of Formula (IIIa) wherein Z is n-butyl, isobutyl, or tert-butyl. In another
-C )alkyl. In another embodiment is a
embodiment is a compound of Formula (IIIa) wherein Z is -O-(C
1 12
compound of Formula (IIIa) wherein Z is -O-(C -C )cycloalkyl. In another embodiment is a compound of
Formula (IIIa) wherein Z is -(C -C )alkenyl. In another embodiment is a compound of Formula (IIIa)
2 12
wherein Z is optionally substituted aryl. In a further embodiment is a compound of Formula (IIIa) wherein
Z is optionally substituted phenyl. In a further embodiment is a compound of Formula (IIIa) wherein Z is
phenyl monsubstituted or disubstituted with a substituent independently selected from -(C -C )alkyl. In a
further embodiment is a compound of Formula (IIIa) wherein Z is phenyl monosubstituted with n-butyl,
isobutyl, or tert-butyl. In a further embodiment is a compound of Formula (IIIa) wherein Z is phenyl
monosubstituted with n-butyl. In a further embodiment is a compound of Formula (IIIa) wherein Z is
phenyl monosubstituted with isobutyl. In a further embodiment is a compound of Formula (IIIa) wherein Z
is phenyl monosubstituted with tert-butyl. In another embodiment is a compound of Formula (IIIa)
wherein Z is optionally substituted heteroaryl. In another embodiment is a compound of Formula (IIIa)
wherein Z is optionally substituted -(C -C )cycloalkyl. In another embodiment is a compound of Formula
(IIIa) wherein Z is optionally substituted heterocycloalkyl. In another embodiment is a compound of
Formula (IIIa) wherein Z is halogen.
In another embodiment is a compound of Formula (IIIa) wherein Z-Y-X- is not
18253141_1 (GHMatters) P111789.NZ
In another embodiment is a compound of Formula (III) having the structure of Formula (IIIb):
O CN
Z X N
Formula (IIIb);
wherein:
1 2 23
R and R are each independently H, -(C -C )alkyl, -(C -C )alkyl-OR , -CH CH(OH)CH NH , -
1 6 1 6 2 2 2
CH CH(heterocycloalkyl)CH NH , -CH C(O)NH , -CH C(O)N(H)CH CN, -(C -C )alkyl-C(O)OR , -
2 2 2 2 2 2 2 1 6
21 22 25 26 23 21 22
(C -C )alkyl-NR R , -(C -C )alkyl-C(O)NR R , -(C -C )alkyl-N(R )C(O)(C -C )alkylNR R , -
1 6 1 6 1 6 1 6
23 23
(C -C )alkyl-N(R )C(O)(C -C )alkyl, -(C -C )alkyl-C(O)N(R )(C -C )alkyl, -(C -C )alkyl-
1 6 1 6 1 6 1 6 1 6
23 23 21 22
C(O)N(R )(C -C )alkyl-heterocycloalkyl, -(C -C )alkyl-NR C(=NH)NR R , -(C -C )alkyl-
1 6 1 6 1 6
23 23 21 22
NR C(=NH)R , -(C -C )alkyl-[(C -C )alkyl-NR R ] , -(C -C )heteroalkyl, or optionally substituted
1 6 1 6 2 1 6
heterocycloalkyl;
or R and R and the atoms to which they are attached form an optionally substituted heterocycloalkyl ring;
R is H, -(C -C )alkyl, -(C -C )alkyl-OH, -(C -C )cycloalkyl, or -C(O)NH ;
1 6 1 6 3 6 2
R is H or -(C -C )alkyl;
or R and R and the carbon atom to which they are attached form a cyclopropyl ring;
R is H, -(C -C )alkyl, -(C -C )haloalkyl, or -(C -C )cycloalkyl;
1 6 1 6 3 6
11 23 23 23
R is H, -NH , -(C -C )alkyl, -(C -C )alkyl-OR , -(C -C )alkyl-SR , -(C -C )alkyl-C(O)OR , -(C -
2 1 6 1 6 1 6 1 6 1
21 22 23 23 23 23
C )alkyl-NR R , -(C -C )alkyl-NR OR , -(C -C )alkyl-NHC(O)NR OR , -(C -C )alkyl-O-(C -
6 1 6 1 6 1 6 1
26 23 23 25 26
C )alkyl-NR R , -(C -C )alkyl-CN, -(C -C )alkyl-NR C(O)R , -(C -C )alkyl-C(O)NR R , -(C -
6 1 6 1 6 1 6 1
C )heteroalkyl-CO H, -(C -C )alkyl-S(O)(C -C )alkyl, -(C -C )alkyl-N(H)CH=NH, -(C -C )alkyl-
6 2 1 6 1 6 1 6 1 6
26
C(NH )=NH, -(C -C )alkyl-N(H)C(=NH)NH , -(C -C )alkyl-N(H)S(O) NR R , -(C -C )alkyl-
2 1 6 2 1 6 2 1 6
26
(C -C )alkyl, -(C -C )alkyl-N(H)-C(O)NR R , -(C -C )alkylC(O)N(H)[optionally
N(H)S(O)
2 1 6 1 6 1 6
23 23
substituted(C -C )alkyl]-OR , -(C -C )alkylN(H)C(O)(C -C )alkyl-OR , -(C -
2 6 1 6 1 6 1
26
C )alkylC(O)N(H)heterocycloalkyl, -(C -C )alkylC(O)NR R , -(C -C )alkyl-N(H)-C(O)-(C -
6 1 6 1 6 1
26 25 26
C )alkyl-NR R , -(C -C )alkyl-N(H)-(C -C )alkylC(O)NR R , -(C -C )alkyl-heterocycloalkyl,
6 1 6 1 6 1 6
optionally substituted -(C -C )alkyl-N(H)heterocycloalkyl, or -(C -C )alkyl-heteroaryl;
1 6 1 6
11 18 12
or R and R are combined to form an optionally substituted heterocycloalkyl ring; and R is H;
17 18 23
R and R are each independently H, -(C -C )alkyl, -(C -C )cycloalkyl, -(C -C )alkyl-OR , -(C -
1 6 3 6 1 6 1
23 21 22
C )alkyl-C(O)OR , or -(C -C )alkyl-NR R ;
6 1 6
X is disubstituted heteroaryl;
18253141_1 (GHMatters) P111789.NZ
Y is a bond, -O-, -S-, optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, -(C -
1 6 2 6 2 6 1
24 24 24
C )alkyl-N(R )(C -C )alkyl-, -O-(C -C )alkyl-, -O(C -C )aryl-, -N(R )(C -C )alkyl-, -N(R )SO (C -
6 1 6 1 6 6 10 1 6 2 1
C )alkyl-, -N(R )C(O)(C -C )alkyl-, -C(O)(C -C )alkyl-, -S(C -C )alkyl-, -SO (C -C )alkyl-, -
6 1 6 1 6 1 6 2 1 6
C(O)NH(C -C )alkyl-, optionally substituted -(C -C )cycloalkyl-, optionally substituted -
1 6 3 7
24 24 24
C(O)N(R )aryl-, optionally substituted -N(R )C(O)aryl-, optionally substituted -N(R )SO aryl-,
optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Z is H, halogen, -NH , -CN, -CF , -CO H, -(C -C )alkyl, -(C -C )alkenyl, -CH=((C -C )cycloalkyl), -
2 3 2 1 12 2 12 3 7
26
(C -C )alkynyl, -C(O)NR R , -O-(C -C )alkyl, -S-(C -C )alkyl, -O-(C -C )[optionally substituted
2 12 1 12 1 12 3 10
23 23
(C -C )cycloalkyl], -O-(C -C )alkyl-OR , -(C -C )alkyl-OR , -(C -C )alkyl-CN, -S-(C -C )alkyl, -
3 7 1 6 1 12 1 12 1 12
24 24
N(R )(C -C )alkyl, -N(R )C(O)(C -C )alkyl, optionally substituted -(C -C )cycloalkyl, -(C -
1 12 1 12 3 7 1
C )alkyl-(C -C )cycloalkyl, -(C -C )alkyl-heterocycloalkyl, optionally substituted heterocycloalkyl,
6 3 7 1 6
optionally substituted aryl, or optionally substituted heteroaryl;
21 22
each R and R is independently H, -(C -C )alkyl, -(C -C )heteroalkyl, -(C -C )alkyl-CO H, -C(O)(C -
1 6 1 6 1 6 2 1
C )alkyl, -C(O)O(C -C )alkyl, -C(O)O(C -C )haloalkyl, -C(=NH)(C -C )alkyl, -C(=NH)N(R ) , -
6 1 6 1 6 1 6 2
31 31 21 22
C(O)N(R ) , or -SO N(R ) ; or R and R and the nitrogen atom to which they are attached form a
2 2 2
heterocycloalkyl ring;
31 31
each R is independently H or -(C -C )alkyl; or two R and the nitrogen atom to which they are attached
form a heterocycloalkyl ring;
each R is independently H or -(C -C )alkyl;
each R is independently H or -(C -C )alkyl;
26
each R and R is independently H or optionally substituted -(C -C )alkyl;
26
or R and R and the nitrogen atom to which they are attached form a heterocycloalkyl ring; and
or a pharmaceutically acceptable salt, solvate, or prodrug thereof.In one embodiment is a
compound of Formula (IIIb) wherein R is -(C -C )alkyl. In another embodiment is a compound of
17 17
Formula (IIIb) wherein R is -CH . In another embodiment is a compound of Formula (IIIb) wherein R
is -CH CH . In another embodiment is a compound of Formula (IIIb) wherein R is -(C -C )cycloalkyl. In
2 3 3 6
another embodiment is a compound of Formula (IIIb) wherein R is cyclopropyl. In another embodiment
17 23
is a compound of Formula (IIIb) wherein R is -(C -C )alkyl-C(O)OR . In another embodiment is a
compound of Formula (IIIb) wherein R is -CH CH OH. In another embodiment is a compound of
17 21 22
Formula (IIIb) wherein R is -(C -C )alkyl-NR R . In another embodiment is a compound of Formula
17 17
(IIIb) wherein R is -CH CH NH . In another embodiment is a compound of Formula (IIIb) wherein R is
2 2 2
In another embodiment is a compound of Formula (IIIb) wherein R is H.
In another embodiment is a compound of Formula (IIIb) wherein R is H.
[00350] In another embodiment is a compound of Formula (IIIb) wherein R is H. In another
embodiment is a compound of Formula (IIIb) wherein R is -(C -C )alkyl. In another embodiment is a
compound of Formula (IIIb) wherein R is -CH . In another embodiment is a compound of Formula (IIIb)
18253141_1 (GHMatters) P111789.NZ
wherein R is -CH CH . In another embodiment is a compound of Formula (IIIb) wherein R is -(C -
2 3 1
C )alkyl-OH. In another embodiment is a compound of Formula (IIIb) wherein R is -CH OH. In another
embodiment is a compound of Formula (IIIb) wherein R is -(C -C )cycloalkyl. In another embodiment is
a compound of Formula (IIIb) wherein R is cyclopropyl. In another embodiment is a compound of
Formula (IIIb) wherein R is -C(O)NH .
In another embodiment is a compound of Formula (IIIb) wherein R and R and the carbon atom
to which they are attached form a cyclopropyl ring.
In another embodiment is a compound of Formula (IIIb) wherein R is -(C -C )alkyl. In another
embodiment is a compound of Formula (IIIb) wherein R is -CH . In another embodiment is a compound
of Formula (IIIb) wherein R is -CH CH . In another embodiment is a compound of Formula (IIIb)
wherein R is -(C -C )haloalkyl. In another embodiment is a compound of Formula (IIIb) wherein R is -
CH F. In another embodiment is a compound of Formula (IIIb) wherein R is -CHF . In another
embodiment is a compound of Formula (IIIb) wherein R is -(C -C )cycloalkyl. In another embodiment is
a compound of Formula (IIIb) wherein R is cyclopropyl. In another embodiment is a compound of
Formula (IIIb) wherein R is H.
In another embodiment is a compound of Formula (IIIb) wherein R is -(C -C )alkyl. In another
embodiment is a compound of Formula (IIIb) wherein R is -CH . In another embodiment is a compound
11 23
of Formula (IIIb) wherein R is -(C -C )alkyl-OR . In another embodiment is a compound of Formula
11 11
(IIIb) wherein R is -CH OH. In another embodiment is a compound of Formula (IIIb) wherein R is -
CH CH OH. In another embodiment is a compound of Formula (IIIb) wherein R is -(C -C )alkyl. In
2 2 1 6
11 21 22
another embodiment is a compound of Formula (IIIb) wherein R is -(C -C )alkyl-NR R . In another
embodiment is a compound of Formula (IIIb) wherein R is -(C -C )alkyl-NH . In another embodiment is
1 6 2
a compound of Formula (IIIb) wherein R is -CH NH . In another embodiment is a compound of Formula
11 11
(IIIb) wherein R is -CH CH NH . In another embodiment is a compound of Formula (IIIb) wherein R is
2 2 2
-CH CH CH NH . In another embodiment is a compound of Formula (IIIb) wherein R is -
2 2 2 2
CH CH CH CH NH . In another embodiment is a compound of Formula (IIIb) wherein R is -(C -
2 2 2 2 2 1
C )alkyl-CN. In another embodiment is a compound of Formula (IIIb) wherein R is -CH CN. In another
11 25 26
embodiment is a compound of Formula (IIIb) wherein R is -(C -C )alkyl-C(O)NR R . In another
embodiment is a compound of Formula (IIIb) wherein R is -CH C(O)NH . In another embodiment is a
compound of Formula (IIIb) wherein R is -CH CH C(O)NH . In another embodiment is a compound of
2 2 2
Formula (IIIb) wherein R is -(C -C )alkyl-heteroaryl. In another embodiment is a compound of Formula
11 25 26
(IIIb) wherein R is -(C -C )alkyl-N(H)S(O) NR R . In another embodiment is a compound of Formula
1 6 2
(IIIb) wherein R is -CH N(H)S(O) NH . In another embodiment is a compound of Formula (IIIb)
2 2 2
wherein R is H.
11 18
[00354] In another embodiment is a compound of Formula (IIIb) wherein R and R are combined to
form an optionally substituted heterocycloalkyl ring.
18253141_1 (GHMatters) P111789.NZ
In another embodiment is a compound of Formula (IIIb) wherein R and R are each
21 22
independently H or -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (IIIb)
1 2 1 2
wherein R and R are each H. In another embodiment is a compound of Formula (IIIb) wherein R and R
21 22
are each independently -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (IIIb)
1 2 21 22
wherein R is H, and R is -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (IIIb)
1 21 22 2
wherein R is -(C -C )alkyl-NR R , and R is H. In another embodiment is a compound of Formula (IIIb)
wherein R is H, and R is -CH CH NH . In another embodiment is a compound of Formula (IIIb) wherein
2 2 2
1 2 1
R is -CH CH NH , and R is H. In another embodiment is a compound of Formula (IIIb) wherein R and
2 2 2
R are each -CH CH NH . In a further embodiment is a compound of Formula (IIIb) wherein R is -(C -
2 2 2 1
21 22 2 1
C )alkyl-NR R and R is H. In a further embodiment is a compound of Formula (IIIb) wherein R is -
CH CH NH and R is H. In a further embodiment is a compound of Formula (IIIb) wherein R is H and
2 2 2
2 21 22 1
R is -(C -C )alkyl-NR R . In a further embodiment is a compound of Formula (IIIb) wherein R is H and
2 1 2
R is -CH CH NH . In another embodiment is a compound of Formula (IIIb) wherein R and R are each
2 2 2
21 22
independently H, -(C -C )alkyl-NR R , or -CH CH(OH)CH NH . In another embodiment is a compound
1 6 2 2 2
of Formula (IIIb) wherein R and R are each independently -CH CH(OH)CH NH . In another
2 2 2
embodiment is a compound of Formula (IIIb) wherein R is H, and R is -CH CH(OH)CH NH . In another
2 2 2
embodiment is a compound of Formula (IIIb) wherein R is -CH CH(OH)CH NH , and R is H. In a
2 2 2
further embodiment is a compound of Formula (IIIb) wherein R and R and the atoms to which they are
attached form an optionally substituted heterocycloalkyl ring.
[00356] In another embodiment is a compound of Formula (IIIb) wherein X is heteroaryl disubstituted
with substituents each independently selected from halogen, -CN, optionally substituted -(C -C )alkyl,
23 25 26
optionally substituted -O-(C -C )alkyl, OR , -NR R , and -NO . In a further embodiment is a compound
1 6 2
of Formula (IIIb) wherein X is heteroaryl disubstituted with substituents each independently selected from
-(C -C )alkyl. In a further embodiment is a compound of Formula (IIIb) wherein X is heteroaryl
disubstituted with methyl. In a further embodiment is a compound of Formula (IIIb) wherein X is pyridinyl
disubstituted with substituents each independently selected from halogen, -CN, optionally substituted -(C -
23 25 26
C )alkyl, optionally substituted -O-(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a
6 1 6 2
compound of Formula (IIIb) wherein X is pyridinyl disubstituted with substituents each independently
selected from -(C -C )alkyl. In a further embodiment is a compound of Formula (IIIb) wherein X is
pyridinyl disubstituted with methyl. In a further embodiment is a compound of Formula (IIIb) wherein X is
pyrimidinyl disubstituted with substituents each independently selected from halogen, -CN, optionally
23 25 26
substituted -(C -C )alkyl, optionally substituted -O-(C -C )alkyl, OR , -NR R , or -NO . In a further
1 6 1 6 2
embodiment is a compound of Formula (IIIb) wherein X is pyrimidinyl disubstituted with substituents
each independently selected from -(C -C )alkyl. In a further embodiment is a compound of Formula (IIIb)
wherein X is pyrimidinyl disubstituted with methyl.
In another embodiment is a compound of Formula (IIIb) wherein Y is optionally substituted aryl.
In a further embodiment is a compound of Formula (IIIb) wherein Y is optionally substituted phenyl. In
18253141_1 (GHMatters) P111789.NZ
another embodiment is a compound of Formula (IIIb) wherein Y is optionally substituted heteroaryl. In
another embodiment is a compound of Formula (IIIb) wherein Y is optionally substituted -(C -C )alkyl-. In
another embodiment is a compound of Formula (IIIb) wherein Y is optionally substituted (C -
C )cycloalkyl-. In another embodiment is a compound of Formula (IIIb) wherein Y is optionally
substituted heterocycloalkyl. In another embodiment is a compound of Formula (IIIb) wherein Y is -O-. In
another embodiment is a compound of Formula (IIIb) wherein Y is -(C -C )alkynyl. In another
embodiment is a compound of Formula (IIIb) wherein Y is -O-(C -C )alkyl-. In another embodiment is a
compound of Formula (IIIb) wherein Y is a bond.
In another embodiment is a compound of Formula (IIIb) wherein Z is -(C -C )alkyl. In a further
1 12
embodiment is a compound of Formula (IIIb) wherein Z is n-butyl, isobutyl, or tert-butyl. In another
embodiment is a compound of Formula (IIIb) wherein Z is -O-(C -C )alkyl. In another embodiment is a
1 12
compound of Formula (IIIb) wherein Z is -O-(C -C )cycloalkyl. In another embodiment is a compound of
Formula (IIIb) wherein Z is -(C -C )alkenyl. In another embodiment is a compound of Formula (IIIb)
2 12
wherein Z is optionally substituted aryl. In a further embodiment is a compound of Formula (IIIb) wherein
Z is optionally substituted phenyl. In a further embodiment is a compound of Formula (IIIb) wherein Z is
phenyl monsubstituted or disubstituted with a substituent independently selected from -(C -C )alkyl. In a
further embodiment is a compound of Formula (IIIb) wherein Z is phenyl monosubstituted with n-butyl,
isobutyl, or tert-butyl. In a further embodiment is a compound of Formula (IIIb) wherein Z is phenyl
monosubstituted with n-butyl. In a further embodiment is a compound of Formula (IIIb) wherein Z is
phenyl monosubstituted with isobutyl. In a further embodiment is a compound of Formula (IIIb) wherein Z
is phenyl monosubstituted with tert-butyl. In another embodiment is a compound of Formula (IIIb)
wherein Z is optionally substituted heteroaryl. In another embodiment is a compound of Formula (IIIb)
wherein Z is optionally substituted -(C -C )cycloalkyl. In another embodiment is a compound of Formula
(IIIb) wherein Z is optionally substituted heterocycloalkyl. In another embodiment is a compound of
Formula (IIIb) wherein Z is halogen.
In another embodiment is a compound of Formula (IIIb) wherein Z-Y-X- is not
In another embodiment is a compound of Formula (III) having the structure of Formula (IIIc):
18253141_1 (GHMatters) P111789.NZ
Z X N
Formula (IIIc);
wherein:
1 2 23
R and R are each independently H, -(C -C )alkyl, -(C -C )alkyl-OR , -CH CH(OH)CH NH , -
1 6 1 6 2 2 2
CH CH(heterocycloalkyl)CH NH , -CH C(O)NH , -CH C(O)N(H)CH CN, -(C -C )alkyl-C(O)OR , -
2 2 2 2 2 2 2 1 6
21 22 25 26 23 21 22
(C -C )alkyl-NR R , -(C -C )alkyl-C(O)NR R , -(C -C )alkyl-N(R )C(O)(C -C )alkylNR R , -
1 6 1 6 1 6 1 6
23 23
(C -C )alkyl-N(R )C(O)(C -C )alkyl, -(C -C )alkyl-C(O)N(R )(C -C )alkyl, -(C -C )alkyl-
1 6 1 6 1 6 1 6 1 6
23 23 21 22
C(O)N(R )(C -C )alkyl-heterocycloalkyl, -(C -C )alkyl-NR C(=NH)NR R , -(C -C )alkyl-
1 6 1 6 1 6
23 23 21 22
NR C(=NH)R , -(C -C )alkyl-[(C -C )alkyl-NR R ] , -(C -C )heteroalkyl, or optionally substituted
1 6 1 6 2 1 6
heterocycloalkyl;
or R and R and the atoms to which they are attached form an optionally substituted heterocycloalkyl ring;
11 23 23 23
R is H, -NH , -(C -C )alkyl, -(C -C )alkyl-OR , -(C -C )alkyl-SR , -(C -C )alkyl-C(O)OR , -(C -
2 1 6 1 6 1 6 1 6 1
21 22 23 23 23 23
C )alkyl-NR R , -(C -C )alkyl-NR OR , -(C -C )alkyl-NHC(O)NR OR , -(C -C )alkyl-O-(C -
6 1 6 1 6 1 6 1
26 23 23 25 26
C )alkyl-NR R , -(C -C )alkyl-CN, -(C -C )alkyl-NR C(O)R , -(C -C )alkyl-C(O)NR R , -(C -
6 1 6 1 6 1 6 1
C )heteroalkyl-CO H, -(C -C )alkyl-S(O)(C -C )alkyl, -(C -C )alkyl-N(H)CH=NH, -(C -C )alkyl-
6 2 1 6 1 6 1 6 1 6
26
C(NH )=NH, -(C -C )alkyl-N(H)C(=NH)NH , -(C -C )alkyl-N(H)S(O) NR R , -(C -C )alkyl-
2 1 6 2 1 6 2 1 6
26
N(H)S(O) (C -C )alkyl, -(C -C )alkyl-N(H)-C(O)NR R , -(C -C )alkylC(O)N(H)[optionally
2 1 6 1 6 1 6
23 23
substituted(C -C )alkyl]-OR , -(C -C )alkylN(H)C(O)(C -C )alkyl-OR , -(C -
2 6 1 6 1 6 1
26
C )alkylC(O)N(H)heterocycloalkyl, -(C -C )alkylC(O)NR R , -(C -C )alkyl-N(H)-C(O)-(C -
6 1 6 1 6 1
26 25 26
C )alkyl-NR R , -(C -C )alkyl-N(H)-(C -C )alkylC(O)NR R , -(C -C )alkyl-heterocycloalkyl,
6 1 6 1 6 1 6
optionally substituted -(C -C )alkyl-N(H)heterocycloalkyl, or -(C -C )alkyl-heteroaryl;
1 6 1 6
X is disubstituted heteroaryl;
Y is a bond, -O-, -S-, optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, -(C -
1 6 2 6 2 6 1
24 24 24
C )alkyl-N(R )(C -C )alkyl-, -O-(C -C )alkyl-, -O(C -C )aryl-, -N(R )(C -C )alkyl-, -N(R )SO (C -
6 1 6 1 6 6 10 1 6 2 1
C )alkyl-, -N(R )C(O)(C -C )alkyl-, -C(O)(C -C )alkyl-, -S(C -C )alkyl-, -SO (C -C )alkyl-, -
6 1 6 1 6 1 6 2 1 6
C(O)NH(C -C )alkyl-, optionally substituted -(C -C )cycloalkyl-, optionally substituted -
1 6 3 7
24 24 24
C(O)N(R )aryl-, optionally substituted -N(R )C(O)aryl-, optionally substituted -N(R )SO aryl-,
optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Z is H, halogen, -NH , -CN, -CF , -CO H, -(C -C )alkyl, -(C -C )alkenyl, -CH=((C -C )cycloalkyl), -
2 3 2 1 12 2 12 3 7
26
(C -C )alkynyl, -C(O)NR R , -O-(C -C )alkyl, -S-(C -C )alkyl, -O-(C -C )[optionally substituted
2 12 1 12 1 12 3 10
18253141_1 (GHMatters) P111789.NZ
23 23
(C -C )cycloalkyl], -O-(C -C )alkyl-OR , -(C -C )alkyl-OR , -(C -C )alkyl-CN, -S-(C -C )alkyl, -
3 7 1 6 1 12 1 12 1 12
24 24
N(R )(C -C )alkyl, -N(R )C(O)(C -C )alkyl, optionally substituted -(C -C )cycloalkyl, -(C -
1 12 1 12 3 7 1
C )alkyl-(C -C )cycloalkyl, -(C -C )alkyl-heterocycloalkyl, optionally substituted heterocycloalkyl,
6 3 7 1 6
optionally substituted aryl, or optionally substituted heteroaryl;
21 22
each R and R is independently H, -(C -C )alkyl, -(C -C )heteroalkyl, -(C -C )alkyl-CO H, -C(O)(C -
1 6 1 6 1 6 2 1
C )alkyl, -C(O)O(C -C )alkyl, -C(O)O(C -C )haloalkyl, -C(=NH)(C -C )alkyl, -C(=NH)N(R ) , -
6 1 6 1 6 1 6 2
31 31 21 22
C(O)N(R ) , or -SO N(R ) ; or R and R and the nitrogen atom to which they are attached form a
2 2 2
heterocycloalkyl ring;
31 31
each R is independently H or -(C -C )alkyl; or two R and the nitrogen atom to which they are attached
form a heterocycloalkyl ring;
each R is independently H or -(C -C )alkyl;
each R is independently H or -(C -C )alkyl;
26
each R and R is independently H or optionally substituted -(C -C )alkyl;
26
or R and R and the nitrogen atom to which they are attached form a heterocycloalkyl ring; and
[00361] or a pharmaceutically acceptable salt, solvate, or prodrug thereof.In another embodiment is a
compound of Formula (IIIc) wherein R is -(C -C )alkyl. In another embodiment is a compound of
11 11
Formula (IIIc) wherein R is -CH . In another embodiment is a compound of Formula (IIIc) wherein R is
23 11
-(C -C )alkyl-OR . In another embodiment is a compound of Formula (IIIc) wherein R is -CH OH. In
1 6 2
another embodiment is a compound of Formula (IIIc) wherein R is -CH CH OH. In another embodiment
is a compound of Formula (IIIc) wherein R is -(C -C )alkyl. In another embodiment is a compound of
11 21 22
Formula (IIIc) wherein R is -(C -C )alkyl-NR R . In another embodiment is a compound of Formula
(IIIc) wherein R is -(C -C )alkyl-NH . In another embodiment is a compound of Formula (IIIc) wherein
1 6 2
11 11
R is -CH NH . In another embodiment is a compound of Formula (IIIc) wherein R is -CH CH NH . In
2 2 2 2 2
another embodiment is a compound of Formula (IIIc) wherein R is -CH CH CH NH . In another
2 2 2 2
embodiment is a compound of Formula (IIIc) wherein R is -CH CH CH CH NH . In another
2 2 2 2 2
embodiment is a compound of Formula (IIIc) wherein R is -(C -C )alkyl-CN. In another embodiment is a
compound of Formula (IIIc) wherein R is -CH CN. In another embodiment is a compound of Formula
11 25 26
(IIIc) wherein R is -(C -C )alkyl-C(O)NR R . In another embodiment is a compound of Formula (IIIc)
11 11
wherein R is -CH C(O)NH . In another embodiment is a compound of Formula (IIIc) wherein R is -
CH CH C(O)NH . In another embodiment is a compound of Formula (IIIc) wherein R is -(C -C )alkyl-
2 2 2 1 6
heteroaryl. In another embodiment is a compound of Formula (IIIc) wherein R is -(C -C )alkyl-
26 11
N(H)S(O) NR R . In another embodiment is a compound of Formula (IIIc) wherein R is -
CH N(H)S(O) NH . In another embodiment is a compound of Formula (IIIc) wherein R is H.
2 2 2
In another embodiment is a compound of Formula (IIIc) wherein R and R are each
21 22
independently H or -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (IIIc)
1 2 1 2
wherein R and R are each H. In another embodiment is a compound of Formula (IIIc) wherein R and R
21 22
are each independently -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (IIIc)
18253141_1 (GHMatters) P111789.NZ
1 2 21 22
wherein R is H, and R is -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (IIIc)
1 21 22 2
wherein R is -(C -C )alkyl-NR R , and R is H. In another embodiment is a compound of Formula (IIIc)
wherein R is H, and R is -CH CH NH . In another embodiment is a compound of Formula (IIIc) wherein
2 2 2
1 2 1
R is -CH CH NH , and R is H. In another embodiment is a compound of Formula (IIIc) wherein R and
2 2 2
R are each -CH CH NH . In a further embodiment is a compound of Formula (IIIc) wherein R is -(C -
2 2 2 1
21 22 2 1
C )alkyl-NR R and R is H. In a further embodiment is a compound of Formula (IIIc) wherein R is -
2 1 2
CH CH NH and R is H. In a further embodiment is a compound of Formula (IIIc) wherein R is H and R
2 2 2
21 22 1 2
is -(C -C )alkyl-NR R . In a further embodiment is a compound of Formula (IIIc) wherein R is H and R
is -CH CH NH . In another embodiment is a compound of Formula (IIIc) wherein R and R are each
2 2 2
21 22
independently H, -(C -C )alkyl-NR R , or -CH CH(OH)CH NH . In another embodiment is a compound
1 6 2 2 2
of Formula (IIIc) wherein R and R are each independently -CH CH(OH)CH NH . In another
2 2 2
embodiment is a compound of Formula (IIIc) wherein R is H, and R is -CH CH(OH)CH NH . In another
2 2 2
embodiment is a compound of Formula (IIIc) wherein R is -CH CH(OH)CH NH , and R is H. In a
2 2 2
further embodiment is a compound of Formula (IIIc) wherein R and R and the atoms to which they are
attached form an optionally substituted heterocycloalkyl ring.
In another embodiment is a compound of Formula (IIIc) wherein X is heteroaryl disubstituted
with substituents each independently selected from halogen, -CN, optionally substituted -(C -C )alkyl,
23 25 26
optionally substituted -O-(C -C )alkyl, OR , -NR R , and -NO . In a further embodiment is a compound
1 6 2
of Formula (IIIc) wherein X is heteroaryl disubstituted with substituents each independently selected from
-(C -C )alkyl. In a further embodiment is a compound of Formula (IIIc) wherein X is heteroaryl
disubstituted with methyl. In a further embodiment is a compound of Formula (IIIc) wherein X is pyridinyl
disubstituted with substituents each independently selected from halogen, -CN, optionally substituted -(C -
23 25 26
C )alkyl, optionally substituted -O-(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a
6 1 6 2
compound of Formula (IIIc) wherein X is pyridinyl disubstituted with substituents each independently
selected from -(C -C )alkyl. In a further embodiment is a compound of Formula (IIIc) wherein X is
pyridinyl disubstituted with methyl. In a further embodiment is a compound of Formula (IIIc) wherein X is
pyrimidinyl disubstituted with substituents each independently selected from halogen, -CN, optionally
23 25 26
substituted -(C -C )alkyl, optionally substituted -O-(C -C )alkyl, OR , -NR R , or -NO . In a further
1 6 1 6 2
embodiment is a compound of Formula (IIIc) wherein X is pyrimidinyl disubstituted with substituents each
independently selected from -(C -C )alkyl. In a further embodiment is a compound of Formula (IIIc)
wherein X is pyrimidinyl disubstituted with methyl.
In another embodiment is a compound of Formula (IIIc) wherein Y is optionally substituted aryl.
In a further embodiment is a compound of Formula (IIIc) wherein Y is optionally substituted phenyl. In
another embodiment is a compound of Formula (IIIc) wherein Y is optionally substituted heteroaryl. In
another embodiment is a compound of Formula (IIIc) wherein Y is optionally substituted -(C -C )alkyl-. In
another embodiment is a compound of Formula (IIIc) wherein Y is optionally substituted (C -
C )cycloalkyl-. In another embodiment is a compound of Formula (IIIc) wherein Y is optionally
18253141_1 (GHMatters) P111789.NZ
substituted heterocycloalkyl. In another embodiment is a compound of Formula (IIIc) wherein Y is -O-. In
another embodiment is a compound of Formula (IIIc) wherein Y is -(C -C )alkynyl. In another
embodiment is a compound of Formula (IIIc) wherein Y is -O-(C -C )alkyl-. In another embodiment is a
compound of Formula (IIIc) wherein Y is a bond.
[00365] In another embodiment is a compound of Formula (IIIc) wherein Z is -(C -C )alkyl. In a further
1 12
embodiment is a compound of Formula (IIIc) wherein Z is n-butyl, isobutyl, or tert-butyl. In another
embodiment is a compound of Formula (IIIc) wherein Z is -O-(C -C )alkyl. In another embodiment is a
1 12
compound of Formula (IIIc) wherein Z is -O-(C -C )cycloalkyl. In another embodiment is a compound of
Formula (IIIc) wherein Z is -(C -C )alkenyl. In another embodiment is a compound of Formula (IIIc)
2 12
wherein Z is optionally substituted aryl. In a further embodiment is a compound of Formula (IIIc) wherein
Z is optionally substituted phenyl. In a further embodiment is a compound of Formula (IIIc) wherein Z is
phenyl monsubstituted or disubstituted with a substituent independently selected from -(C -C )alkyl. In a
further embodiment is a compound of Formula (IIIc) wherein Z is phenyl monosubstituted with n-butyl,
isobutyl, or tert-butyl. In a further embodiment is a compound of Formula (IIIc) wherein Z is phenyl
monosubstituted with n-butyl. In a further embodiment is a compound of Formula (IIIc) wherein Z is
phenyl monosubstituted with isobutyl. In a further embodiment is a compound of Formula (IIIc) wherein Z
is phenyl monosubstituted with tert-butyl. In another embodiment is a compound of Formula (IIIc)
wherein Z is optionally substituted heteroaryl. In another embodiment is a compound of Formula (IIIc)
wherein Z is optionally substituted -(C -C )cycloalkyl. In another embodiment is a compound of Formula
(IIIc) wherein Z is optionally substituted heterocycloalkyl. In another embodiment is a compound of
Formula (IIIc) wherein Z is halogen.
In another embodiment is a compound of Formula (IIIc) wherein Z-Y-X- is not
In one aspect described herein are compounds of Formula (IV):
(R )
(R )
18 16
R R N
O CN
Z X N
17 9 R
11 12
Formula (IV);
wherein:
18253141_1 (GHMatters) P111789.NZ
1 2 23
R and R are each independently H, -(C -C )alkyl, -(C -C )alkyl-OR , -CH CH(OH)CH NH , -
1 6 1 6 2 2 2
CH CH(heterocycloalkyl)CH NH , -CH C(O)NH , -CH C(O)N(H)CH CN, -(C -C )alkyl-C(O)OR , -
2 2 2 2 2 2 2 1 6
21 22 25 26 23 21 22
(C -C )alkyl-NR R , -(C -C )alkyl-C(O)NR R , -(C -C )alkyl-N(R )C(O)(C -C )alkylNR R , -
1 6 1 6 1 6 1 6
23 23
(C -C )alkyl-N(R )C(O)(C -C )alkyl, -(C -C )alkyl-C(O)N(R )(C -C )alkyl, -(C -C )alkyl-
1 6 1 6 1 6 1 6 1 6
23 23 21 22
C(O)N(R )(C -C )alkyl-heterocycloalkyl, -(C -C )alkyl-NR C(=NH)NR R , -(C -C )alkyl-
1 6 1 6 1 6
23 23 21 22
NR C(=NH)R , -(C -C )alkyl-[(C -C )alkyl-NR R ] , -(C -C )heteroalkyl, or optionally substituted
1 6 1 6 2 1 6
heterocycloalkyl;
or R and R and the atoms to which they are attached form an optionally substituted heterocycloalkyl ring;
R is H or -(C -C )alkyl;
R is H, -(C -C )alkyl, -(C -C )alkyl-OH, -(C -C )cycloalkyl, or -C(O)NH ;
1 6 1 6 3 6 2
or R and R are combined to form a heterocycloalkyl ring;
R is H or -(C -C )alkyl;
or R and R and the carbon atom to which they are attached form a cyclopropyl ring;
6 7 8
R , R , and R are each independently H, fluoro, hydroxyl, amino, optionally substituted alkyl, optionally
substituted heteroalkyl, or -(C -C )alkyl;
R is H, -(C -C )alkyl, -(C -C )haloalkyl, or -(C -C )cycloalkyl;
1 6 1 6 3 6
R is H, -(C -C )alkyl, -(C -C )haloalkyl, or -(C -C )cycloalkyl;
1 6 1 6 3 6
9 10
or R and R are combined to form a heterocycloalkyl or cycloalkyl ring
11 12 25 26
R and R are each independently H or -(C -C )alkyl-N(H)S(O) NR R ;
1 6 2
16 17 18 23
R , R , R , and R are each independently H, -(C -C )alkyl, -(C -C )cycloalkyl, -(C -C )alkyl-OR , -
1 6 3 6 1 6
23 21 22
(C -C )alkyl-C(O)OR , or -(C -C )alkyl-NR R ;
1 6 1 6
X is optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, optionally substituted -(C -
1 6 2 6 2 6 3
)cycloalkyl-, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally
24 24
substituted heteroaryl, -O-(C -C )alkyl-, -N(R )(C -C )alkyl-, -N(R )(C -C )aryl-, or -SO (C -
1 6 1 6 6 10 2 1
C )alkyl-;
Y is a bond, -O-, -S-, optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, -(C -
1 6 2 6 2 6 1
24 24 24
C )alkyl-N(R )(C -C )alkyl-, -O-(C -C )alkyl-, -O(C -C )aryl-, -N(R )(C -C )alkyl-, -N(R )SO (C -
6 1 6 1 6 6 10 1 6 2 1
C )alkyl-, -N(R )C(O)(C -C )alkyl-, -C(O)(C -C )alkyl-, -S(C -C )alkyl-, -SO (C -C )alkyl-, -
6 1 6 1 6 1 6 2 1 6
C(O)NH(C -C )alkyl-, optionally substituted -(C -C )cycloalkyl-, optionally substituted -
1 6 3 7
24 24 24
C(O)N(R )aryl-, optionally substituted -N(R )C(O)aryl-, optionally substituted -N(R )SO aryl-,
optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Z is H, halogen, -NH , -CN, -CF , -CO H, -(C -C )alkyl, -(C -C )alkenyl, -CH=((C -C )cycloalkyl), -
2 3 2 1 12 2 12 3 7
26
(C -C )alkynyl, -C(O)NR R , -O-(C -C )alkyl, -S-(C -C )alkyl, -O-(C -C )[optionally substituted
2 12 1 12 1 12 3 10
23 23
(C -C )cycloalkyl], -O-(C -C )alkyl-OR , -(C -C )alkyl-OR , -(C -C )alkyl-CN, -S-(C -C )alkyl, -
3 7 1 6 1 12 1 12 1 12
24 24
N(R )(C -C )alkyl, -N(R )C(O)(C -C )alkyl, optionally substituted -(C -C )cycloalkyl, -(C -
1 12 1 12 3 7 1
C )alkyl-(C -C )cycloalkyl, -(C -C )alkyl-heterocycloalkyl, optionally substituted heterocycloalkyl,
6 3 7 1 6
optionally substituted aryl, or optionally substituted heteroaryl;
18253141_1 (GHMatters) P111789.NZ
21 22
each R and R is independently H, -(C -C )alkyl, -(C -C )heteroalkyl, -(C -C )alkyl-CO H, -C(O)(C -
1 6 1 6 1 6 2 1
C )alkyl, -C(O)O(C -C )alkyl, -C(O)O(C -C )haloalkyl, -C(=NH)(C -C )alkyl, -C(=NH)N(R ) , -
6 1 6 1 6 1 6 2
31 31 21 22
C(O)N(R ) , or -SO N(R ) ; or R and R and the nitrogen atom to which they are attached form a
2 2 2
heterocycloalkyl ring;
31 31
each R is independently H or -(C -C )alkyl; or two R and the nitrogen atom to which they are attached
form a heterocycloalkyl ring;
each R is independently H or -(C -C )alkyl;
each R is independently H or -(C -C )alkyl;
26
each R and R is independently H or optionally substituted -(C -C )alkyl;
26
or R and R and the nitrogen atom to which they are attached form a heterocycloalkyl ring;
27 23 24 23 23 24
each R is independently halogen, -NR R , -NHC(O)R , -NHC(O)NR R , nitro, hydroxyl, optionally
substituted -(C -C )alkyl, optionally substituted -(C -C )heteroalkyl, optionally substituted -(C -
1 6 1 6 1
C )heteroalkyloxy, optionally substituted -(C -C )heteroalkylamino, -(C -C )alkoxy, -C(O)(C -
6 1 6 1 6 1
C )alkyl, or -S(O) (C -C )alkyl;
6 2 1 6
1 27
or R and R and the atoms to which they are attached form an optionally substituted 5- or 6-membered
heterocycloalkyl ring;
28 23 24 23 23 24
each R is independently halogen, -NR R , -NHC(O)R , -NC(O)NR R , nitro, hydroxyl, optionally
substituted -(C -C )alkyl, optionally substituted -(C -C )heteroalkyl, optionally substituted -(C -
1 6 1 6 1
C )heteroalkyloxy, optionally substituted -(C -C )heteroalkylamino, -(C -C )alkoxy, -C(O)(C -
6 1 6 1 6 1
C )alkyl, or -S(O) (C -C )alkyl;
6 2 1 6
2 28
or R and R and the atoms to which they are attached form an optionally substituted 5- or 6-membered
heterocycloalkyl ring;
p is 0, 1, or 2; and
q is 0, 1, or 2;
or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
6 7 8
In one embodiment is a compound of Formula (IV) wherein R , R , and R are H.
16
In another embodiment is a compound of Formula (IV) wherein R and R are H.
In one embodiment is a compound of Formula (IV) wherein R is -(C -C )alkyl. In another
embodiment is a compound of Formula (IV) wherein R is -CH . In another embodiment is a compound
of Formula (IV) wherein R is -CH CH . In another embodiment is a compound of Formula (IV) wherein
17 17
R is -(C -C )cycloalkyl. In another embodiment is a compound of Formula (IV) wherein R is
cyclopropyl. In another embodiment is a compound of Formula (IV) wherein R is -(C -C )alkyl-
23 17
C(O)OR . In another embodiment is a compound of Formula (IV) wherein R is -CH CH OH. In another
17 21 22
embodiment is a compound of Formula (IV) wherein R is -(C -C )alkyl-NR R . In another embodiment
is a compound of Formula (IV) wherein R is -CH CH NH . In another embodiment is a compound of
2 2 2
Formula (IV) wherein R is H.
In another embodiment is a compound of Formula (IV) wherein R is H.
18253141_1 (GHMatters) P111789.NZ
In another embodiment is a compound of Formula (IV) wherein R is H.
In another embodiment is a compound of Formula (IV) wherein R is H.
In another embodiment is a compound of Formula (IV) wherein R is H. In another embodiment
is a compound of Formula (IV) wherein R is -(C -C )alkyl. In another embodiment is a compound of
Formula (IV) wherein R is -CH . In another embodiment is a compound of Formula (IV) wherein R is -
CH CH . In another embodiment is a compound of Formula (IV) wherein R is -(C -C )alkyl-OH. In
2 3 1 6
another embodiment is a compound of Formula (IV) wherein R is -CH OH. In another embodiment is a
compound of Formula (IV) wherein R is -(C -C )cycloalkyl. In another embodiment is a compound of
Formula (IV) wherein R is cyclopropyl. In another embodiment is a compound of Formula (IV) wherein
R is -C(O)NH .
3 4 5
In another embodiment is a compound of Formula (IV) wherein R , R , and R are H.
In another embodiment is a compound of Formula (IV) wherein R and R and the carbon atom
to which they are attached form a cyclopropyl ring.
In another embodiment is a compound of Formula (IV) wherein R is H.
9
[00378] In another embodiment is a compound of Formula (IV) wherein R is H and R is -(C -C )alkyl.
9
In another embodiment is a compound of Formula (IV) wherein R is H and R is -CH . In another
9
embodiment is a compound of Formula (IV) wherein R is H and R is -CH CH . In another embodiment
9
is a compound of Formula (IV) wherein R is H and R is -(C -C )haloalkyl. In another embodiment is a
9
compound of Formula (IV) wherein R is H and R is -CH F. In another embodiment is a compound of
9
Formula (IV) wherein R is H and R is -CHF . In another embodiment is a compound of Formula (IV)
9
wherein R is H and R is -(C -C )cycloalkyl. In another embodiment is a compound of Formula (IV)
9
wherein R is H and R is cyclopropyl. In another embodiment is a compound of Formula (IV) wherein
9
R is H and R is H.
In another embodiment is a compound of Formula (IV) wherein R is H.
12 11
[00380] In another embodiment is a compound of Formula (IV) wherein R is H and R is -(C -
26 12
C )alkyl-N(H)S(O) NR R . In another embodiment is a compound of Formula (IV) wherein R is H and
R is -CH N(H)S(O) NH .
2 2 2
In another embodiment is a compound of Formula (IV) wherein p is 1 and R is halogen. In
another embodiment is a compound of Formula (IV) wherein p is 1 and R is optionally substituted -(C -
C )alkyl. In another embodiment is a compound of Formula (IV) wherein q is 0, p is 1 and R is halogen.
In another embodiment is a compound of Formula (IV) wherein q is 0, p is 1 and R is optionally
substituted -(C -C )alkyl. In another embodiment is a compound of Formula (IV) wherein q is 1 and R is
halogen. In another embodiment is a compound of Formula (IV) wherein q is 1 and R is optionally
substituted -(C -C )alkyl. In another embodiment is a compound of Formula (IV) wherein p is 0, q is 1 and
28 28
is halogen. In another embodiment is a compound of Formula (IV) wherein p is 0, q is 1 and R is
optionally substituted -(C -C )alkyl.
In another embodiment is a compound of Formula (IV) wherein p is 0, and q is 0.
18253141_1 (GHMatters) P111789.NZ
In another embodiment is a compound of Formula (IV) wherein R and R are each
21 22
independently H or -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (IV)
1 2 1 2
wherein R and R are each H. In another embodiment is a compound of Formula (IV) wherein R and R
21 22
are each independently -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (IV)
1 2 21 22
wherein R is H, and R is -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (IV)
1 21 22 2
wherein R is -(C -C )alkyl-NR R , and R is H. In another embodiment is a compound of Formula (IV)
wherein R is H, and R is -CH CH NH . In another embodiment is a compound of Formula (IV) wherein
2 2 2
1 2 1
R is -CH CH NH , and R is H. In another embodiment is a compound of Formula (IV) wherein R and
2 2 2
R are each -CH CH NH . In a further embodiment is a compound of Formula (IV) wherein R is -(C -
2 2 2 1
21 22 2 1
C )alkyl-NR R and R is H. In a further embodiment is a compound of Formula (IV) wherein R is -
2 1 2
CH CH NH and R is H. In a further embodiment is a compound of Formula (IV) wherein R is H and R
2 2 2
21 22 1 2
is -(C -C )alkyl-NR R . In a further embodiment is a compound of Formula (IV) wherein R is H and R
is -CH CH NH . In another embodiment is a compound of Formula (IV) wherein R and R are each
2 2 2
21 22
independently H, -(C -C )alkyl-NR R , or -CH CH(OH)CH NH . In another embodiment is a compound
1 6 2 2 2
of Formula (IV) wherein R and R are each independently -CH CH(OH)CH NH . In another embodiment
2 2 2
is a compound of Formula (IV) wherein R is H, and R is -CH CH(OH)CH NH . In another embodiment
2 2 2
is a compound of Formula (IV) wherein R is -CH CH(OH)CH NH , and R is H. In a further embodiment
2 2 2
is a compound of Formula (IV) wherein R and R and the atoms to which they are attached form an
optionally substituted heterocycloalkyl ring.
[00384] In another embodiment is a compound of Formula (IV) wherein X is optionally substituted aryl.
In a further embodiment is a compound of Formula (IV) wherein X is optionally substituted phenyl. In
another embodiment is a compound of Formula (IV) wherein X is optionally substituted heteroaryl. In a
further embodiment is a compound of Formula (IV) wherein X is disubstituted heteroaryl. In a further
embodiment is a compound of Formula (IV) wherein X is heteroaryl disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
23 25 26
(C -C )alkyl, OR , -NR R , and -NO . In a further embodiment is a compound of Formula (IV) wherein
1 6 2
X is heteroaryl disubstituted with substituents each independently selected from -(C -C )alkyl. In a further
embodiment is a compound of Formula (IV) wherein X is heteroaryl disubstituted with methyl. In a further
embodiment is a compound of Formula (IV) wherein X is pyridinyl disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
23 25 26
(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound of Formula (IV) wherein X
1 6 2
is pyridinyl disubstituted with substituents each independently selected from -(C -C )alkyl. In a further
embodiment is a compound of Formula (IV) wherein X is pyridinyl disubstituted with methyl. In a further
embodiment is a compound of Formula (IV) wherein X is pyrimidinyl disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
23 25 26
(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound of Formula (IV) wherein X
1 6 2
is pyrimidinyl disubstituted with substituents each independently selected from -(C -C )alkyl. In a further
18253141_1 (GHMatters) P111789.NZ
embodiment is a compound of Formula (IV) wherein X is pyrimidinyl disubstituted with methyl. In
another embodiment is a compound of Formula (IV) wherein X is optionally substituted -(C -C )alkyl-.
In another embodiment is a compound of Formula (IV) wherein Y is optionally substituted aryl.
In a further embodiment is a compound of Formula (IV) wherein Y is optionally substituted phenyl. In
another embodiment is a compound of Formula (IV) wherein Y is optionally substituted heteroaryl. In
another embodiment is a compound of Formula (IV) wherein Y is optionally substituted -(C -C )alkyl-. In
another embodiment is a compound of Formula (IV) wherein Y is optionally substituted (C -
C )cycloalkyl-. In another embodiment is a compound of Formula (IV) wherein Y is optionally substituted
heterocycloalkyl. In another embodiment is a compound of Formula (IV) wherein Y is -O-. In another
embodiment is a compound of Formula (IV) wherein Y is -(C -C )alkynyl. In another embodiment is a
compound of Formula (IV) wherein Y is -O-(C -C )alkyl-. In another embodiment is a compound of
Formula (IV) wherein Y is a bond.
In another embodiment is a compound of Formula (IV) wherein Z is -(C -C )alkyl. In a further
1 12
embodiment is a compound of Formula (IV) wherein Z is n-butyl, isobutyl, or tert-butyl. In another
embodiment is a compound of Formula (IV) wherein Z is -O-(C -C )alkyl. In another embodiment is a
1 12
compound of Formula (IV) wherein Z is -O-(C -C )cycloalkyl. In another embodiment is a compound of
Formula (IV) wherein Z is -(C -C )alkenyl. In another embodiment is a compound of Formula (IV)
2 12
wherein Z is optionally substituted aryl. In a further embodiment is a compound of Formula (IV) wherein
Z is optionally substituted phenyl. In a further embodiment is a compound of Formula (IV) wherein Z is
phenyl monsubstituted or disubstituted with a substituent independently selected from -(C -C )alkyl. In a
further embodiment is a compound of Formula (IV) wherein Z is phenyl monosubstituted with n-butyl,
isobutyl, or tert-butyl. In a further embodiment is a compound of Formula (IV) wherein Z is phenyl
monosubstituted with n-butyl. In a further embodiment is a compound of Formula (IV) wherein Z is
phenyl monosubstituted with isobutyl. In a further embodiment is a compound of Formula (IV) wherein Z
is phenyl monosubstituted with tert-butyl. In another embodiment is a compound of Formula (IV) wherein
Z is optionally substituted heteroaryl. In another embodiment is a compound of Formula (IV) wherein Z is
optionally substituted -(C -C )cycloalkyl. In another embodiment is a compound of Formula (IV) wherein
Z is optionally substituted heterocycloalkyl. In another embodiment is a compound of Formula (IV)
wherein Z is halogen.
[00387] In another embodiment is a compound of Formula (IV) having the structure of Formula (IVa):
18253141_1 (GHMatters) P111789.NZ
(R )
27 6
(R )
R R N
O CN
Z X N
17 9
O R R
11 12
Formula (IVa);
wherein:
1 2 23
R and R are each independently H, -(C -C )alkyl, -(C -C )alkyl-OR , -CH CH(OH)CH NH , -
1 6 1 6 2 2 2
CH CH(heterocycloalkyl)CH NH , -CH C(O)NH , -CH C(O)N(H)CH CN, -(C -C )alkyl-C(O)OR , -
2 2 2 2 2 2 2 1 6
21 22 25 26 23 21 22
(C -C )alkyl-NR R , -(C -C )alkyl-C(O)NR R , -(C -C )alkyl-N(R )C(O)(C -C )alkylNR R , -
1 6 1 6 1 6 1 6
23 23
(C -C )alkyl-N(R )C(O)(C -C )alkyl, -(C -C )alkyl-C(O)N(R )(C -C )alkyl, -(C -C )alkyl-
1 6 1 6 1 6 1 6 1 6
23 23 21 22
C(O)N(R )(C -C )alkyl-heterocycloalkyl, -(C -C )alkyl-NR C(=NH)NR R , -(C -C )alkyl-
1 6 1 6 1 6
23 23 21 22
NR C(=NH)R , -(C -C )alkyl-[(C -C )alkyl-NR R ] , -(C -C )heteroalkyl, or optionally substituted
1 6 1 6 2 1 6
heterocycloalkyl;
or R and R and the atoms to which they are attached form an optionally substituted heterocycloalkyl ring;
R is H or -(C -C )alkyl;
is H, -(C -C )alkyl, -(C -C )alkyl-OH, -(C -C )cycloalkyl, or -C(O)NH ;
1 6 1 6 3 6 2
or R and R are combined to form a heterocycloalkyl ring;
R is H or -(C -C )alkyl;
or R and R and the carbon atom to which they are attached form a cyclopropyl ring;
6 7 8
R , R , and R are each independently H, fluoro, hydroxyl, amino, optionally substituted alkyl, heteroalkyl,
or -(C -C )alkyl;
R is H, -(C -C )alkyl, -(C -C )haloalkyl, or -(C -C )cycloalkyl;
1 6 1 6 3 6
R is H, -(C -C )alkyl, -(C -C )haloalkyl, or -(C -C )cycloalkyl;
1 6 1 6 3 6
9 10
or R and R are combined to form a heterocycloalkyl or cycloalkyl ring
11 12 25 26
R and R are each independently H and -(C -C )alkyl-N(H)S(O) NR R ;
1 6 2
16 17 18 23
R , R , R , and R are each independently H, -(C -C )alkyl, -(C -C )cycloalkyl, -(C -C )alkyl-OR , -
1 6 3 6 1 6
23 21 22
(C -C )alkyl-C(O)OR , or -(C -C )alkyl-NR R ;
1 6 1 6
X is optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, optionally substituted -(C -
1 6 2 6 2 6 3
C )cycloalkyl-, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally
24 24
substituted heteroaryl, -O-(C -C )alkyl-, -N(R )(C -C )alkyl-, -N(R )(C -C )aryl-, or -SO (C -
1 6 1 6 6 10 2 1
C )alkyl-;
Y is a bond, -O-, -S-, optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, -(C -
1 6 2 6 2 6 1
24 24 24
C )alkyl-N(R )(C -C )alkyl-, -O-(C -C )alkyl-, -O(C -C )aryl-, -N(R )(C -C )alkyl-, -N(R )SO (C -
6 1 6 1 6 6 10 1 6 2 1
18253141_1 (GHMatters) P111789.NZ
C )alkyl-, -N(R )C(O)(C -C )alkyl-, -C(O)(C -C )alkyl-, -S(C -C )alkyl-, -SO (C -C )alkyl-, -
6 1 6 1 6 1 6 2 1 6
C(O)NH(C -C )alkyl-, optionally substituted -(C -C )cycloalkyl-, optionally substituted -
1 6 3 7
24 24 24
C(O)N(R )aryl-, optionally substituted -N(R )C(O)aryl-, optionally substituted -N(R )SO aryl-,
optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Z is H, halogen, -NH , -CN, -CF , -CO H, -(C -C )alkyl, -(C -C )alkenyl, -CH=((C -C )cycloalkyl), -
2 3 2 1 12 2 12 3 7
26
(C -C )alkynyl, -C(O)NR R , -O-(C -C )alkyl, -S-(C -C )alkyl, -O-(C -C )[optionally substituted
2 12 1 12 1 12 3 10
23 23
(C -C )cycloalkyl], -O-(C -C )alkyl-OR , -(C -C )alkyl-OR , -(C -C )alkyl-CN, -S-(C -C )alkyl, -
3 7 1 6 1 12 1 12 1 12
24 24
N(R )(C -C )alkyl, -N(R )C(O)(C -C )alkyl, optionally substituted -(C -C )cycloalkyl, -(C -
1 12 1 12 3 7 1
C )alkyl-(C -C )cycloalkyl, -(C -C )alkyl-heterocycloalkyl, optionally substituted heterocycloalkyl,
6 3 7 1 6
optionally substituted aryl, or optionally substituted heteroaryl;
21 22
each R and R is independently H, -(C -C )alkyl, -(C -C )heteroalkyl, -(C -C )alkyl-CO H, -C(O)(C -
1 6 1 6 1 6 2 1
C )alkyl, -C(O)O(C -C )alkyl, -C(O)O(C -C )haloalkyl, -C(=NH)(C -C )alkyl, -C(=NH)N(R ) , -
6 1 6 1 6 1 6 2
31 31 21 22
C(O)N(R ) , or -SO N(R ) ; or R and R and the nitrogen atom to which they are attached form a
2 2 2
heterocycloalkyl ring;
31 31
each R is independently H or -(C -C )alkyl; or two R and the nitrogen atom to which they are attached
form a heterocycloalkyl ring;
each R is independently H or -(C -C )alkyl;
each R is independently H or -(C -C )alkyl;
26
each R and R is independently H or optionally substituted -(C -C )alkyl;
26
or R and R and the nitrogen atom to which they are attached form a heterocycloalkyl ring;
27 23 24 23 23 24
each R is independently halogen, -NR R , -NHC(O)R , -NHC(O)NR R , nitro, hydroxyl, optionally
substituted -(C -C )alkyl, optionally substituted -(C -C )heteroalkyl, optionally substituted -(C -
1 6 1 6 1
)heteroalkyloxy, optionally substituted -(C -C )heteroalkylamino, -(C -C )alkoxy, -C(O)(C -
6 1 6 1 6 1
C )alkyl, or -S(O) (C -C )alkyl;
6 2 1 6
1 27
or R and R and the atoms to which they are attached form an optionally substituted 5- or 6-membered
heterocycloalkyl ring;
28 23 24 23 23 24
each R is independently halogen, -NR R , -NHC(O)R , -NHC(O)NR R , nitro, hydroxyl, optionally
substituted -(C -C )alkyl, optionally substituted -(C -C )heteroalkyl, optionally substituted -(C -
1 6 1 6 1
C )heteroalkyloxy, optionally substituted -(C -C )heteroalkylamino, -(C -C )alkoxy, -C(O)(C -
6 1 6 1 6 1
C )alkyl, or -S(O) (C -C )alkyl;
6 2 1 6
2 28
or R and R and the atoms to which they are attached form an optionally substituted 5- or 6-membered
heterocycloalkyl ring;
p is 0, 1, or 2; and
q is 0, 1, or 2;
[00388] or a pharmaceutically acceptable salt, solvate, or prodrug thereof.In one embodiment is a
6 7 8
compound of Formula (IVa) wherein R , R , and R are H.
16
In another embodiment is a compound of Formula (IVa) wherein R and R are H.
18253141_1 (GHMatters) P111789.NZ
In one embodiment is a compound of Formula (IVa) wherein R is -(C -C )alkyl. In another
embodiment is a compound of Formula (IVa) wherein R is -CH . In another embodiment is a compound
of Formula (IVa) wherein R is -CH CH . In another embodiment is a compound of Formula (IVa)
17 17
wherein R is -(C -C )cycloalkyl. In another embodiment is a compound of Formula (IVa) wherein R is
cyclopropyl. In another embodiment is a compound of Formula (IVa) wherein R is -(C -C )alkyl-
23 17
C(O)OR . In another embodiment is a compound of Formula (IVa) wherein R is -CH CH OH. In
17 21 22
another embodiment is a compound of Formula (IVa) wherein R is -(C -C )alkyl-NR R . In another
embodiment is a compound of Formula (IVa) wherein R is -CH CH NH . In another embodiment is a
2 2 2
compound of Formula (IVa) wherein R is H.
[00391] In another embodiment is a compound of Formula (IVa) wherein R is H.
In another embodiment is a compound of Formula (IVa) wherein R is H.
In another embodiment is a compound of Formula (IVa) wherein R is H.
In another embodiment is a compound of Formula (IVa) wherein R is H. In another
embodiment is a compound of Formula (IVa) wherein R is -(C -C )alkyl. In another embodiment is a
compound of Formula (IVa) wherein R is -CH . In another embodiment is a compound of Formula (IVa)
wherein R is -CH CH . In another embodiment is a compound of Formula (IVa) wherein R is -(C -
2 3 1
C )alkyl-OH. In another embodiment is a compound of Formula (IVa) wherein R is -CH OH. In another
embodiment is a compound of Formula (IVa) wherein R is -(C -C )cycloalkyl. In another embodiment is
a compound of Formula (IVa) wherein R is cyclopropyl. In another embodiment is a compound of
Formula (IVa) wherein R is -C(O)NH .
In another embodiment is a compound of Formula (IVa) wherein R and R and the carbon atom
to which they are attached form a cyclopropyl ring.
3 4 5
In another embodiment is a compound of Formula (IVa) wherein R , R , and R are H.
In another embodiment is a compound of Formula (IVa) wherein R is H.
9
[00398] In another embodiment is a compound of Formula (IVa) wherein R is H and R is -(C -
9
C )alkyl. In another embodiment is a compound of Formula (IVa) wherein R is H and R is -CH . In
9
another embodiment is a compound of Formula (IVa) wherein R is H and R is -CH CH . In another
9
embodiment is a compound of Formula (IVa) wherein R is H and R is -(C -C )haloalkyl. In another
9
embodiment is a compound of Formula (IVa) wherein R is H and R is -CH F. In another embodiment is
9
a compound of Formula (IVa) wherein R is H and R is -CHF . In another embodiment is a compound of
9
Formula (IVa) wherein R is H and R is -(C -C )cycloalkyl. In another embodiment is a compound of
9
Formula (IVa) wherein R is H and R is cyclopropyl. In another embodiment is a compound of Formula
9
(IVa) wherein R is H and R is H.
In another embodiment is a compound of Formula (IVa) wherein R is H.
12 11
[00400] In another embodiment is a compound of Formula (IVa) wherein R is H and R is -(C -
26 12
C )alkyl-N(H)S(O) NR R . In another embodiment is a compound of Formula (IVa) wherein R is H
and R is –CH N(H)S(O) NH .
2 2 2
18253141_1 (GHMatters) P111789.NZ
In another embodiment is a compound of Formula (IVa) wherein p is 1 and R is halogen. In
another embodiment is a compound of Formula (IVa) wherein p is 1 and R is optionally substituted -(C -
C )alkyl. In another embodiment is a compound of Formula (IVa) wherein q is 0, p is 1 and R is halogen.
In another embodiment is a compound of Formula (IVa) wherein q is 0, p is 1 and R is optionally
substituted -(C -C )alkyl. In another embodiment is a compound of Formula (IVa) wherein q is 1 and R
is halogen. In another embodiment is a compound of Formula (IVa) wherein q is 1 and R is optionally
substituted -(C -C )alkyl. In another embodiment is a compound of Formula (IVa) wherein p is 0, q is 1
28 28
and R is halogen. In another embodiment is a compound of Formula (IVa) wherein p is 0, q is 1 and R
is optionally substituted -(C -C )alkyl.
[00402] In another embodiment is a compound of Formula (IVa) wherein p is 0, and q is 0.
In another embodiment is a compound of Formula (IVa) wherein R and R are each
21 22
independently H or -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (IVa)
1 2 1 2
wherein R and R are each H. In another embodiment is a compound of Formula (IVa) wherein R and R
21 22
are each independently -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (IVa)
1 2 21 22
wherein R is H, and R is -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (IVa)
1 21 22 2
wherein R is -(C -C )alkyl-NR R , and R is H. In another embodiment is a compound of Formula (IVa)
wherein R is H, and R is -CH CH NH . In another embodiment is a compound of Formula (IVa) wherein
2 2 2
1 2 1
R is -CH CH NH , and R is H. In another embodiment is a compound of Formula (IVa) wherein R and
2 2 2
R are each -CH CH NH . In a further embodiment is a compound of Formula (IVa) wherein R is -(C -
2 2 2 1
21 22 2 1
C )alkyl-NR R and R is H. In a further embodiment is a compound of Formula (IVa) wherein R is -
CH CH NH and R is H. In a further embodiment is a compound of Formula (IVa) wherein R is H and
2 2 2
2 21 22 1
R is -(C -C )alkyl-NR R . In a further embodiment is a compound of Formula (IVa) wherein R is H and
2 1 2
R is -CH CH NH . In another embodiment is a compound of Formula (IVa) wherein R and R are each
2 2 2
21 22
independently H, -(C -C )alkyl-NR R , or -CH CH(OH)CH NH . In another embodiment is a compound
1 6 2 2 2
of Formula (IVa) wherein R and R are each independently -CH CH(OH)CH NH . In another
2 2 2
embodiment is a compound of Formula (IVa) wherein R is H, and R is -CH CH(OH)CH NH . In another
2 2 2
embodiment is a compound of Formula (IVa) wherein R is -CH CH(OH)CH NH , and R is H. In a
2 2 2
further embodiment is a compound of Formula (IVa) wherein R and R and the atoms to which they are
attached form an optionally substituted heterocycloalkyl ring.
[00404] In another embodiment is a compound of Formula (IVa) wherein X is optionally substituted aryl.
In a further embodiment is a compound of Formula (IVa) wherein X is optionally substituted phenyl. In
another embodiment is a compound of Formula (IVa) wherein X is optionally substituted heteroaryl. In a
further embodiment is a compound of Formula (IVa) wherein X is disubstituted heteroaryl. In a further
embodiment is a compound of Formula (IVa) wherein X is heteroaryl disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
23 25 26
(C -C )alkyl, OR , -NR R , and -NO . In a further embodiment is a compound of Formula (IVa) wherein
1 6 2
X is heteroaryl disubstituted with substituents each independently selected from -(C -C )alkyl. In a further
18253141_1 (GHMatters) P111789.NZ
embodiment is a compound of Formula (IVa) wherein X is heteroaryl disubstituted with methyl. In a
further embodiment is a compound of Formula (IVa) wherein X is pyridinyl disubstituted with substituents
each independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted
23 25 26
-O-(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound of Formula (IVa)
1 6 2
wherein X is pyridinyl disubstituted with substituents each independently selected from -(C -C )alkyl. In a
further embodiment is a compound of Formula (IVa) wherein X is pyridinyl disubstituted with methyl. In a
further embodiment is a compound of Formula (IVa) wherein X is pyrimidinyl disubstituted with
substituents each independently selected from halogen, -CN, optionally substituted -(C -C )alkyl,
23 25 26
optionally substituted -O-(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound
1 6 2
of Formula (IVa) wherein X is pyrimidinyl disubstituted with substituents each independently selected
from -(C -C )alkyl. In a further embodiment is a compound of Formula (IVa) wherein X is pyrimidinyl
disubstituted with methyl. In another embodiment is a compound of Formula (IVa) wherein X is optionally
substituted -(C -C )alkyl-.
In another embodiment is a compound of Formula (IVa) wherein Y is optionally substituted aryl.
In a further embodiment is a compound of Formula (IVa) wherein Y is optionally substituted phenyl. In
another embodiment is a compound of Formula (IVa) wherein Y is optionally substituted heteroaryl. In
another embodiment is a compound of Formula (IVa) wherein Y is optionally substituted -(C -C )alkyl-. In
another embodiment is a compound of Formula (IVa) wherein Y is optionally substituted (C -
C )cycloalkyl-. In another embodiment is a compound of Formula (IVa) wherein Y is optionally
substituted heterocycloalkyl. In another embodiment is a compound of Formula (IVa) wherein Y is -O-. In
another embodiment is a compound of Formula (IVa) wherein Y is -(C -C )alkynyl. In another
embodiment is a compound of Formula (IVa) wherein Y is -O-(C -C )alkyl-. In another embodiment is a
compound of Formula (IVa) wherein Y is a bond.
In another embodiment is a compound of Formula (IVa) wherein Z is -(C -C )alkyl. In a further
1 12
embodiment is a compound of Formula (IVa) wherein Z is n-butyl, isobutyl, or tert-butyl. In another
embodiment is a compound of Formula (IVa) wherein Z is -O-(C -C )alkyl. In another embodiment is a
1 12
compound of Formula (IVa) wherein Z is -O-(C -C )cycloalkyl. In another embodiment is a compound of
Formula (IVa) wherein Z is -(C -C )alkenyl. In another embodiment is a compound of Formula (IVa)
2 12
wherein Z is optionally substituted aryl. In a further embodiment is a compound of Formula (IVa) wherein
Z is optionally substituted phenyl. In a further embodiment is a compound of Formula (IVa) wherein Z is
phenyl monsubstituted or disubstituted with a substituent independently selected from -(C -C )alkyl. In a
further embodiment is a compound of Formula (IVa) wherein Z is phenyl monosubstituted with n-butyl,
isobutyl, or tert-butyl. In a further embodiment is a compound of Formula (IVa) wherein Z is phenyl
monosubstituted with n-butyl. In a further embodiment is a compound of Formula (IVa) wherein Z is
phenyl monosubstituted with isobutyl. In a further embodiment is a compound of Formula (IVa) wherein Z
is phenyl monosubstituted with tert-butyl. In another embodiment is a compound of Formula (IVa)
wherein Z is optionally substituted heteroaryl. In another embodiment is a compound of Formula (IVa)
18253141_1 (GHMatters) P111789.NZ
wherein Z is optionally substituted -(C -C )cycloalkyl. In another embodiment is a compound of Formula
(IVa) wherein Z is optionally substituted heterocycloalkyl. In another embodiment is a compound of
Formula (IVa) wherein Z is halogen.
In another embodiment is a compound of Formula (IV) having the structure of Formula (IVb):
Z X N
Formula (IVb);
wherein:
1 2 23
R and R are each independently H, -(C -C )alkyl, -(C -C )alkyl-OR , -CH CH(OH)CH NH , -
1 6 1 6 2 2 2
CH CH(heterocycloalkyl)CH NH , -CH C(O)NH , -CH C(O)N(H)CH CN, -(C -C )alkyl-C(O)OR , -
2 2 2 2 2 2 2 1 6
21 22 25 26 23 21 22
(C -C )alkyl-NR R , -(C -C )alkyl-C(O)NR R , -(C -C )alkyl-N(R )C(O)(C -C )alkylNR R , -
1 6 1 6 1 6 1 6
23 23
(C -C )alkyl-N(R )C(O)(C -C )alkyl, -(C -C )alkyl-C(O)N(R )(C -C )alkyl, -(C -C )alkyl-
1 6 1 6 1 6 1 6 1 6
23 23 21 22
C(O)N(R )(C -C )alkyl-heterocycloalkyl, -(C -C )alkyl-NR C(=NH)NR R , -(C -C )alkyl-
1 6 1 6 1 6
23 23 21 22
NR C(=NH)R , -(C -C )alkyl-[(C -C )alkyl-NR R ] , -(C -C )heteroalkyl, or optionally substituted
1 6 1 6 2 1 6
heterocycloalkyl;
or R and R and the atoms to which they are attached form an optionally substituted heterocycloalkyl ring;
R is H, -(C -C )alkyl, -(C -C )alkyl-OH, -(C -C )cycloalkyl, or -C(O)NH ;
1 6 1 6 3 6 2
R is H or -(C -C )alkyl;
or R and R and the carbon atom to which they are attached form a cyclopropyl ring;
R is H, -(C -C )alkyl, -(C -C )haloalkyl, or -(C -C )cycloalkyl;
1 6 1 6 3 6
11 25 26
R is -(C -C )alkyl-N(H)S(O) NR R ;
1 6 2
17 18 23
R and R are each independently H, -(C -C )alkyl, -(C -C )cycloalkyl, -(C -C )alkyl-OR , -(C -
1 6 3 6 1 6 1
23 21 22
)alkyl-C(O)OR , or -(C -C )alkyl-NR R ;
6 1 6
X is optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, optionally substituted -(C -
1 6 2 6 2 6 3
C )cycloalkyl-, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally
24 24
substituted heteroaryl, -O-(C -C )alkyl-, -N(R )(C -C )alkyl-, -N(R )(C -C )aryl-, or -SO (C -
1 6 1 6 6 10 2 1
C )alkyl-;
Y is a bond, -O-, -S-, optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, -(C -
1 6 2 6 2 6 1
24 24 24
C )alkyl-N(R )(C -C )alkyl-, -O-(C -C )alkyl-, -O(C -C )aryl-, -N(R )(C -C )alkyl-, -N(R )SO (C -
6 1 6 1 6 6 10 1 6 2 1
C )alkyl-, -N(R )C(O)(C -C )alkyl-, -C(O)(C -C )alkyl-, -S(C -C )alkyl-, -SO (C -C )alkyl-, -
6 1 6 1 6 1 6 2 1 6
C(O)NH(C -C )alkyl-, optionally substituted -(C -C )cycloalkyl-, optionally substituted -
1 6 3 7
18253141_1 (GHMatters) P111789.NZ
24 24 24
C(O)N(R )aryl-, optionally substituted -N(R )C(O)aryl-, optionally substituted -N(R )SO aryl-,
optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Z is H, halogen, -NH , -CN, -CF , -CO H, -(C -C )alkyl, -(C -C )alkenyl, -CH=((C -C )cycloalkyl), -
2 3 2 1 12 2 12 3 7
26
(C -C )alkynyl, -C(O)NR R , -O-(C -C )alkyl, -S-(C -C )alkyl, -O-(C -C )[optionally substituted
2 12 1 12 1 12 3 10
23 23
(C -C )cycloalkyl], -O-(C -C )alkyl-OR , -(C -C )alkyl-OR , -(C -C )alkyl-CN, -S-(C -C )alkyl, -
3 7 1 6 1 12 1 12 1 12
24 24
N(R )(C -C )alkyl, -N(R )C(O)(C -C )alkyl, optionally substituted -(C -C )cycloalkyl, -(C -
1 12 1 12 3 7 1
C )alkyl-(C -C )cycloalkyl, -(C -C )alkyl-heterocycloalkyl, optionally substituted heterocycloalkyl,
6 3 7 1 6
optionally substituted aryl, or optionally substituted heteroaryl;
21 22
each R and R is independently H, -(C -C )alkyl, -(C -C )heteroalkyl, -(C -C )alkyl-CO H, -C(O)(C -
1 6 1 6 1 6 2 1
C )alkyl, -C(O)O(C -C )alkyl, -C(O)O(C -C )haloalkyl, -C(=NH)(C -C )alkyl, -C(=NH)N(R ) , -
6 1 6 1 6 1 6 2
31 31 21 22
C(O)N(R ) , or -SO N(R ) ; or R and R and the nitrogen atom to which they are attached form a
2 2 2
heterocycloalkyl ring;
31 31
each R is independently H or -(C -C )alkyl; or two R and the nitrogen atom to which they are attached
form a heterocycloalkyl ring;
each R is independently H or -(C -C )alkyl;
each R is independently H or -(C -C )alkyl;
26
each R and R is independently H or optionally substituted -(C -C )alkyl;
26
or R and R and the nitrogen atom to which they are attached form a heterocycloalkyl ring; and
or a pharmaceutically acceptable salt, solvate, or prodrug thereof.In one embodiment is a
compound of Formula (IVb) wherein R is -(C -C )alkyl. In another embodiment is a compound of
17 17
Formula (IVb) wherein R is -CH . In another embodiment is a compound of Formula (IVb) wherein R
is -CH CH . In another embodiment is a compound of Formula (IVb) wherein R is -(C -C )cycloalkyl. In
2 3 3 6
another embodiment is a compound of Formula (IVb) wherein R is cyclopropyl. In another embodiment
17 23
is a compound of Formula (IVb) wherein R is -(C -C )alkyl-C(O)OR . In another embodiment is a
compound of Formula (IVb) wherein R is -CH CH OH. In another embodiment is a compound of
17 21 22
Formula (IVb) wherein R is -(C -C )alkyl-NR R . In another embodiment is a compound of Formula
17 17
(IVb) wherein R is -CH CH NH . In another embodiment is a compound of Formula (IVb) wherein R
2 2 2
is H.
In another embodiment is a compound of Formula (IVb) wherein R is H.
[00410] In another embodiment is a compound of Formula (IVb) wherein R is H.
In another embodiment is a compound of Formula (IVb) wherein R is H. In another
embodiment is a compound of Formula (IVb) wherein R is -(C -C )alkyl. In another embodiment is a
compound of Formula (IVb) wherein R is -CH . In another embodiment is a compound of Formula (IVb)
wherein R is -CH CH . In another embodiment is a compound of Formula (IVb) wherein R is -(C -
2 3 1
C )alkyl-OH. In another embodiment is a compound of Formula (IVb) wherein R is -CH OH. In another
embodiment is a compound of Formula (IVb) wherein R is -(C -C )cycloalkyl. In another embodiment is
18253141_1 (GHMatters) P111789.NZ
a compound of Formula (IVb) wherein R is cyclopropyl. In another embodiment is a compound of
Formula (IVb) wherein R is -C(O)NH .
In another embodiment is a compound of Formula (IVb) wherein R and R and the carbon atom
to which they are attached form a cyclopropyl ring.
[00413] In another embodiment is a compound of Formula (IVb) wherein R is -(C -C )alkyl. In another
embodiment is a compound of Formula (IVb) wherein R is -CH . In another embodiment is a compound
of Formula (IVb) wherein R is -CH CH . In another embodiment is a compound of Formula (IVb)
wherein R is -(C -C )haloalkyl. In another embodiment is a compound of Formula (IVb) wherein R is -
CH F. In another embodiment is a compound of Formula (IVb) wherein R is -CHF . In another
embodiment is a compound of Formula (IVb) wherein R is -(C -C )cycloalkyl. In another embodiment is
a compound of Formula (IVb) wherein R is cyclopropyl. In another embodiment is a compound of
Formula (IVb) wherein R is H.
In another embodiment is a compound of Formula (IVb) wherein R is -(C -C )alkyl-
26 11
N(H)S(O) NR R . In another embodiment is a compound of Formula (IVb) wherein R is –
CH N(H)S(O) NH .
2 2 2
In another embodiment is a compound of Formula (IVb) wherein R and R are each
21 22
independently H or -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (IVb)
1 2 1 2
wherein R and R are each H. In another embodiment is a compound of Formula (IVb) wherein R and R
21 22
are each independently -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (IVb)
1 2 21 22
wherein R is H, and R is -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (IVb)
1 21 22 2
wherein R is -(C -C )alkyl-NR R , and R is H. In another embodiment is a compound of Formula (IVb)
wherein R is H, and R is -CH CH NH . In another embodiment is a compound of Formula (IVb) wherein
2 2 2
1 2 1
R is -CH CH NH , and R is H. In another embodiment is a compound of Formula (IVb) wherein R and
2 2 2
R are each -CH CH NH . In a further embodiment is a compound of Formula (IVb) wherein R is -(C -
2 2 2 1
21 22 2 1
C )alkyl-NR R and R is H. In a further embodiment is a compound of Formula (IVb) wherein R is -
CH CH NH and R is H. In a further embodiment is a compound of Formula (IVb) wherein R is H and
2 2 2
2 21 22 1
R is -(C -C )alkyl-NR R . In a further embodiment is a compound of Formula (IVb) wherein R is H and
2 1 2
R is -CH CH NH . In another embodiment is a compound of Formula (IVb) wherein R and R are each
2 2 2
21 22
independently H, -(C -C )alkyl-NR R , or -CH CH(OH)CH NH . In another embodiment is a compound
1 6 2 2 2
of Formula (IVb) wherein R and R are each independently -CH CH(OH)CH NH . In another
2 2 2
embodiment is a compound of Formula (IVb) wherein R is H, and R is -CH CH(OH)CH NH . In another
2 2 2
embodiment is a compound of Formula (IVb) wherein R is -CH CH(OH)CH NH , and R is H. In a
2 2 2
further embodiment is a compound of Formula (IVb) wherein R and R and the atoms to which they are
attached form an optionally substituted heterocycloalkyl ring.
[00416] In another embodiment is a compound of Formula (IVb) wherein X is optionally substituted aryl.
In a further embodiment is a compound of Formula (IVb) wherein X is optionally substituted phenyl. In
another embodiment is a compound of Formula (IVb) wherein X is optionally substituted heteroaryl. In a
18253141_1 (GHMatters) P111789.NZ
further embodiment is a compound of Formula (IVb) wherein X is disubstituted heteroaryl. In a further
embodiment is a compound of Formula (IVb) wherein X is heteroaryl disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
23 25 26
(C -C )alkyl, OR , -NR R , and -NO . In a further embodiment is a compound of Formula (IVb) wherein
1 6 2
X is heteroaryl disubstituted with substituents each independently selected from -(C -C )alkyl. In a further
embodiment is a compound of Formula (IVb) wherein X is heteroaryl disubstituted with methyl. In a
further embodiment is a compound of Formula (IVb) wherein X is pyridinyl disubstituted with substituents
each independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted
23 25 26
-O-(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound of Formula (IVb)
1 6 2
wherein X is pyridinyl disubstituted with substituents each independently selected from -(C -C )alkyl. In a
further embodiment is a compound of Formula (IVb) wherein X is pyridinyl disubstituted with methyl. In
a further embodiment is a compound of Formula (IVb) wherein X is pyrimidinyl disubstituted with
substituents each independently selected from halogen, -CN, optionally substituted -(C -C )alkyl,
23 25 26
optionally substituted -O-(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound
1 6 2
of Formula (IVb) wherein X is pyrimidinyl disubstituted with substituents each independently selected
from -(C -C )alkyl. In a further embodiment is a compound of Formula (IVb) wherein X is pyrimidinyl
disubstituted with methyl. In another embodiment is a compound of Formula (IVb) wherein X is optionally
substituted -(C -C )alkyl-.
In another embodiment is a compound of Formula (IVb) wherein Y is optionally substituted aryl.
In a further embodiment is a compound of Formula (IVb) wherein Y is optionally substituted phenyl. In
another embodiment is a compound of Formula (IVb) wherein Y is optionally substituted heteroaryl. In
another embodiment is a compound of Formula (IVb) wherein Y is optionally substituted -(C -C )alkyl-.
In another embodiment is a compound of Formula (IVb) wherein Y is optionally substituted (C -
C )cycloalkyl-. In another embodiment is a compound of Formula (IVb) wherein Y is optionally
substituted heterocycloalkyl. In another embodiment is a compound of Formula (IVb) wherein Y is -O-. In
another embodiment is a compound of Formula (IVb) wherein Y is -(C -C )alkynyl. In another
embodiment is a compound of Formula (IVb) wherein Y is -O-(C -C )alkyl-. In another embodiment is a
compound of Formula (IVb) wherein Y is a bond.
In another embodiment is a compound of Formula (IVb) wherein Z is -(C -C )alkyl. In a further
1 12
embodiment is a compound of Formula (IVb) wherein Z is n-butyl, isobutyl, or tert-butyl. In another
embodiment is a compound of Formula (IVb) wherein Z is -O-(C -C )alkyl. In another embodiment is a
1 12
compound of Formula (IVb) wherein Z is -O-(C -C )cycloalkyl. In another embodiment is a compound of
Formula (IVb) wherein Z is -(C -C )alkenyl. In another embodiment is a compound of Formula (IVb)
2 12
wherein Z is optionally substituted aryl. In a further embodiment is a compound of Formula (IVb) wherein
Z is optionally substituted phenyl. In a further embodiment is a compound of Formula (IVb) wherein Z is
phenyl monsubstituted or disubstituted with a substituent independently selected from -(C -C )alkyl. In a
further embodiment is a compound of Formula (IVb) wherein Z is phenyl monosubstituted with n-butyl,
18253141_1 (GHMatters) P111789.NZ
isobutyl, or tert-butyl. In a further embodiment is a compound of Formula (IVb) wherein Z is phenyl
monosubstituted with n-butyl. In a further embodiment is a compound of Formula (IVb) wherein Z is
phenyl monosubstituted with isobutyl. In a further embodiment is a compound of Formula (IVb) wherein Z
is phenyl monosubstituted with tert-butyl. In another embodiment is a compound of Formula (IVb)
wherein Z is optionally substituted heteroaryl. In another embodiment is a compound of Formula (IVb)
wherein Z is optionally substituted -(C -C )cycloalkyl. In another embodiment is a compound of Formula
(IVb) wherein Z is optionally substituted heterocycloalkyl. In another embodiment is a compound of
Formula (IVb) wherein Z is halogen.
In another embodiment is a compound of Formula (IV) having the structure of Formula (IVc):
O CN
Z X N
Formula (IVc);
wherein:
1 2 23
R and R are each independently H, -(C -C )alkyl, -(C -C )alkyl-OR , -CH CH(OH)CH NH , -
1 6 1 6 2 2 2
CH CH(heterocycloalkyl)CH NH , -CH C(O)NH , -CH C(O)N(H)CH CN, -(C -C )alkyl-C(O)OR , -
2 2 2 2 2 2 2 1 6
21 22 25 26 23 21 22
(C -C )alkyl-NR R , -(C -C )alkyl-C(O)NR R , -(C -C )alkyl-N(R )C(O)(C -C )alkylNR R , -
1 6 1 6 1 6 1 6
23 23
(C -C )alkyl-N(R )C(O)(C -C )alkyl, -(C -C )alkyl-C(O)N(R )(C -C )alkyl, -(C -C )alkyl-
1 6 1 6 1 6 1 6 1 6
23 23 21 22
C(O)N(R )(C -C )alkyl-heterocycloalkyl, -(C -C )alkyl-NR C(=NH)NR R , -(C -C )alkyl-
1 6 1 6 1 6
23 23 21 22
NR C(=NH)R , -(C -C )alkyl-[(C -C )alkyl-NR R ] , -(C -C )heteroalkyl, or optionally substituted
1 6 1 6 2 1 6
heterocycloalkyl;
or R and R and the atoms to which they are attached form an optionally substituted heterocycloalkyl ring;
11 25 26
R is -(C -C )alkyl-N(H)S(O) NR R ;
1 6 2
-C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, optionally substituted -(C -
X is optionally substituted -(C
1 6 2 6 2 6 3
C )cycloalkyl-, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally
24 24
substituted heteroaryl, -O-(C -C )alkyl-, -N(R )(C -C )alkyl-, -N(R )(C -C )aryl-, or -SO (C -
1 6 1 6 6 10 2 1
C )alkyl-;
Y is a bond, -O-, -S-, optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, -(C -
1 6 2 6 2 6 1
24 24 24
C )alkyl-N(R )(C -C )alkyl-, -O-(C -C )alkyl-, -O(C -C )aryl-, -N(R )(C -C )alkyl-, -N(R )SO (C -
6 1 6 1 6 6 10 1 6 2 1
C )alkyl-, -N(R )C(O)(C -C )alkyl-, -C(O)(C -C )alkyl-, -S(C -C )alkyl-, -SO (C -C )alkyl-, -
6 1 6 1 6 1 6 2 1 6
C(O)NH(C -C )alkyl-, optionally substituted -(C -C )cycloalkyl-, optionally substituted -
1 6 3 7
18253141_1 (GHMatters) P111789.NZ
24 24 24
C(O)N(R )aryl-, optionally substituted -N(R )C(O)aryl-, optionally substituted -N(R )SO aryl-,
optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Z is H, halogen, -NH , -CN, -CF , -CO H, -(C -C )alkyl, -(C -C )alkenyl, -CH=((C -C )cycloalkyl), -
2 3 2 1 12 2 12 3 7
26
(C -C )alkynyl, -C(O)NR R , -O-(C -C )alkyl, -S-(C -C )alkyl, -O-(C -C )[optionally substituted
2 12 1 12 1 12 3 10
23 23
(C -C )cycloalkyl], -O-(C -C )alkyl-OR , -(C -C )alkyl-OR , -(C -C )alkyl-CN, -S-(C -C )alkyl, -
3 7 1 6 1 12 1 12 1 12
24 24
N(R )(C -C )alkyl, -N(R )C(O)(C -C )alkyl, optionally substituted -(C -C )cycloalkyl, -(C -
1 12 1 12 3 7 1
C )alkyl-(C -C )cycloalkyl, -(C -C )alkyl-heterocycloalkyl, optionally substituted heterocycloalkyl,
6 3 7 1 6
optionally substituted aryl, or optionally substituted heteroaryl;
21 22
each R and R is independently H, -(C -C )alkyl, -(C -C )heteroalkyl, -(C -C )alkyl-CO H, -C(O)(C -
1 6 1 6 1 6 2 1
C )alkyl, -C(O)O(C -C )alkyl, -C(O)O(C -C )haloalkyl, -C(=NH)(C -C )alkyl, -C(=NH)N(R ) , -
6 1 6 1 6 1 6 2
31 31 21 22
C(O)N(R ) , or -SO N(R ) ; or R and R and the nitrogen atom to which they are attached form a
2 2 2
heterocycloalkyl ring;
31 31
each R is independently H or -(C -C )alkyl; or two R and the nitrogen atom to which they are attached
form a heterocycloalkyl ring;
each R is independently H or -(C -C )alkyl;
each R is independently H or -(C -C )alkyl;
26
each R and R is independently H or optionally substituted -(C -C )alkyl;
26
or R and R and the nitrogen atom to which they are attached form a heterocycloalkyl ring; and
or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
[00421] In another embodiment is a compound of Formula (IVc) wherein R is -(C -C )alkyl-
26 11
N(H)S(O) NR R . In another embodiment is a compound of Formula (IVc) wherein R is –
CH N(H)S(O) NH .
2 2 2
In another embodiment is a compound of Formula (IVc) wherein R and R are each
21 22
independently H or -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (IVc)
1 2 1 2
wherein R and R are each H. In another embodiment is a compound of Formula (IVc) wherein R and R
21 22
are each independently -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (IVc)
1 2 21 22
wherein R is H, and R is -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (IVc)
1 21 22 2
wherein R is -(C -C )alkyl-NR R , and R is H. In another embodiment is a compound of Formula (IVc)
wherein R is H, and R is -CH CH NH . In another embodiment is a compound of Formula (IVc) wherein
2 2 2
1 2 1
R is -CH CH NH , and R is H. In another embodiment is a compound of Formula (IVc) wherein R and
2 2 2
R are each -CH CH NH . In a further embodiment is a compound of Formula (IVc) wherein R is -(C -
2 2 2 1
21 22 2 1
C )alkyl-NR R and R is H. In a further embodiment is a compound of Formula (IVc) wherein R is -
CH CH NH and R is H. In a further embodiment is a compound of Formula (IVc) wherein R is H and
2 2 2
2 21 22 1
R is -(C -C )alkyl-NR R . In a further embodiment is a compound of Formula (IVc) wherein R is H and
2 1 2
R is -CH CH NH . In another embodiment is a compound of Formula (IVc) wherein R and R are each
2 2 2
21 22
independently H, -(C -C )alkyl-NR R , or -CH CH(OH)CH NH . In another embodiment is a compound
1 6 2 2 2
18253141_1 (GHMatters) P111789.NZ
of Formula (IVc) wherein R and R are each independently -CH CH(OH)CH NH . In another
2 2 2
embodiment is a compound of Formula (IVc) wherein R is H, and R is -CH CH(OH)CH NH . In another
2 2 2
embodiment is a compound of Formula (IVc) wherein R is -CH CH(OH)CH NH , and R is H. In a
2 2 2
further embodiment is a compound of Formula (IVc) wherein R and R and the atoms to which they are
attached form an optionally substituted heterocycloalkyl ring.
In another embodiment is a compound of Formula (IVc) wherein X is optionally substituted aryl.
In a further embodiment is a compound of Formula (IVc) wherein X is optionally substituted phenyl. In
another embodiment is a compound of Formula (IVc) wherein X is optionally substituted heteroaryl. In a
further embodiment is a compound of Formula (IVc) wherein X is disubstituted heteroaryl. In a further
embodiment is a compound of Formula (IVc) wherein X is heteroaryl disubstituted with substituents each
independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted -O-
23 25 26
(C -C )alkyl, OR , -NR R , and -NO . In a further embodiment is a compound of Formula (IVc) wherein
1 6 2
X is heteroaryl disubstituted with substituents each independently selected from -(C -C )alkyl. In a further
embodiment is a compound of Formula (IVc) wherein X is heteroaryl disubstituted with methyl. In a
further embodiment is a compound of Formula (IVc) wherein X is pyridinyl disubstituted with substituents
each independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally substituted
23 25 26
-O-(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound of Formula (IVc)
1 6 2
wherein X is pyridinyl disubstituted with substituents each independently selected from -(C -C )alkyl. In a
further embodiment is a compound of Formula (IVc) wherein X is pyridinyl disubstituted with methyl. In a
further embodiment is a compound of Formula (IVc) wherein X is pyrimidinyl disubstituted with
substituents each independently selected from halogen, -CN, optionally substituted -(C -C )alkyl,
23 25 26
optionally substituted -O-(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound
1 6 2
of Formula (IVc) wherein X is pyrimidinyl disubstituted with substituents each independently selected
from -(C -C )alkyl. In a further embodiment is a compound of Formula (IVc) wherein X is pyrimidinyl
disubstituted with methyl. In another embodiment is a compound of Formula (IVc) wherein X is optionally
substituted -(C -C )alkyl-.
In another embodiment is a compound of Formula (IVc) wherein Y is optionally substituted aryl.
In a further embodiment is a compound of Formula (IVc) wherein Y is optionally substituted phenyl. In
another embodiment is a compound of Formula (IVc) wherein Y is optionally substituted heteroaryl. In
another embodiment is a compound of Formula (IVc) wherein Y is optionally substituted -(C -C )alkyl-. In
another embodiment is a compound of Formula (IVc) wherein Y is optionally substituted (C -
C )cycloalkyl-. In another embodiment is a compound of Formula (IVc) wherein Y is optionally
substituted heterocycloalkyl. In another embodiment is a compound of Formula (IVc) wherein Y is -O-. In
another embodiment is a compound of Formula (IVc) wherein Y is -(C -C )alkynyl. In another
embodiment is a compound of Formula (IVc) wherein Y is -O-(C -C )alkyl-. In another embodiment is a
compound of Formula (IVc) wherein Y is a bond.
18253141_1 (GHMatters) P111789.NZ
In another embodiment is a compound of Formula (IVc) wherein Z is -(C -C )alkyl. In a further
1 12
embodiment is a compound of Formula (IVc) wherein Z is n-butyl, isobutyl, or tert-butyl. In another
embodiment is a compound of Formula (IVc) wherein Z is -O-(C -C )alkyl. In another embodiment is a
1 12
compound of Formula (IVc) wherein Z is -O-(C -C )cycloalkyl. In another embodiment is a compound of
Formula (IVc) wherein Z is -(C -C )alkenyl. In another embodiment is a compound of Formula (IVc)
2 12
wherein Z is optionally substituted aryl. In a further embodiment is a compound of Formula (IVc) wherein
Z is optionally substituted phenyl. In a further embodiment is a compound of Formula (IVc) wherein Z is
phenyl monsubstituted or disubstituted with a substituent independently selected from -(C -C )alkyl. In a
further embodiment is a compound of Formula (IVc) wherein Z is phenyl monosubstituted with n-butyl,
isobutyl, or tert-butyl. In a further embodiment is a compound of Formula (IVc) wherein Z is phenyl
monosubstituted with n-butyl. In a further embodiment is a compound of Formula (IVc) wherein Z is
phenyl monosubstituted with isobutyl. In a further embodiment is a compound of Formula (IVc) wherein Z
is phenyl monosubstituted with tert-butyl. In another embodiment is a compound of Formula (IVc)
wherein Z is optionally substituted heteroaryl. In another embodiment is a compound of Formula (IVc)
wherein Z is optionally substituted -(C -C )cycloalkyl. In another embodiment is a compound of Formula
(IVc) wherein Z is optionally substituted heterocycloalkyl. In another embodiment is a compound of
Formula (IVc) wherein Z is halogen.
In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa),
(IIb), (IIc), (IId), (IIe), (III), (IIIa), (IIIb), (IIIc), (IV), (IVa), (IVb), and (IVc) is selected from a compound
in table 1 or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
Table 1
Cp. # Name Structure
201 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[4-[3-(4-
butylphenyl)pyrazolyl]methyl- O
N N O
benzoyl]amino]butanoyl]amino]- N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
202 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-methyl[4-
(pentafluoro-lambda6-
O HN
sulfanyl)phenyl]benzoyl]amino]buta N N O
noyl]amino]-10,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
203 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S) O
amino[[4-(4-tert-butylphenyl)
methyl-
O HN
benzoyl]amino]butanoyl]amino]-
N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
204 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[4-(2-hexylpyrimidin
O HN
yl)methyl- H
N N O
benzoyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
205 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S) O
amino[[2-methyl(4-
pentylphenyl)pyridine
O HN
carbonyl]amino]butanoyl]amino]-
N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
206 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[6-(4-tert-butylphenyl)
methyl-pyridine
O HN
carbonyl]amino]butanoyl]amino]- N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
207 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[6-(4-butylphenyl)
methyl-pyridine
N N O
carbonyl]amino]butanoyl]amino]- N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
208 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[2-methyl(4-
propylphenyl)pyridine O HN
N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
209 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[2-methyl(2- H N
N N N
O HN
pentylpyrimidinyl)pyridine H
N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
210 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[6-(4-tert-butylmethyl-
N N CN
phenyl)methyl-pyridine
O HN
carbonyl]amino]butanoyl]amino]- N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
211 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-methyl[4-[1-
N N CN
(trifluoromethyl)cyclopropyl]phenyl
O HN
N N O
]pyridine
carbonyl]amino]butanoyl]amino]- O O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
212 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-methyl[4-(1-
N N CN
methylcyclopropyl)phenyl]pyridine-
O HN
3-carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
213 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S) O
amino[[6-(3,3-dimethylbut
ynyl)methyl-pyridine N N CN
O HN
carbonyl]amino]butanoyl]amino]-
N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
214 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[6-(2-cyclohexylethynyl)-
O HN
2-methyl-pyridine
N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
215 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[6-(4-tert-butylphenyl)
methyl-pyridine N N CN
O HN
carbonyl]amino]butanoyl]amino]-
N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
216 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[(4-methyltetralinyl-
N N CN
pyrimidine
O HN
carbonyl)amino]butanoyl]amino]- N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
217 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[2-[4-
(cyclobutylmethyl)phenyl]
N N N O
methyl-pyrimidine (S)
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
218 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[2-[4-
N N CN
O HN
(cyclopentylmethyl)phenyl]
N N N O
methyl-pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12- 2
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
219 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[4-methyl[4-[1-
N N CN
(trifluoromethyl)cyclopropyl]phenyl
O HN
N N (S) N O
]pyrimidine
carbonyl]amino]butanoyl]amino]- O O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
220 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[2-(4-isopentylphenyl)
N N CN
O HN
methyl-pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
221 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[2-(4-ethylnaphthyl)
N N CN
methyl-pyrimidine
O HN
N N N O
carbonyl]amino]butanoyl]amino]- (S)
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
222 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[4-methyl(2-methyl
N N CN
propyl-phenyl)pyrimidine
O HN
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
223 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[2-(4-butylmethyl-
N N CN
O HN
phenyl)methyl-pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa- 2
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
224 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[4-methyl[4-(1-
N N CN
methylcyclopropyl)phenyl]pyrimidin
O HN
N N N O
e (S)
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
225 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[4-methyl[4-
N N CN
(pentafluoro-lambda6-
O HN
N N (S) N O
sulfanyl)phenyl]pyrimidine
carbonyl]amino]butanoyl]amino]- O O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
226 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[4-(2,2- 2
dimethylpropyl)phenyl]methyl-
pyrimidine
N CN
carbonyl]amino]butanoyl]amino]- H H
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
227 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[4-methyl(4-pent
N N CN
O HN
ynylphenyl)pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
228 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[2-(3,3-dimethylbut
N N CN
O HN
ynyl)methyl-pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]- N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
229 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[4-methyl(3-methylbut-
N N CN
O HN
1-ynyl)pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa- 2
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
230 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[2-(4-cyclopentylphenyl)-
N N CN
4-methyl-pyrimidine O HN
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12- O
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
231 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[4-methyl(4-
N N CN
tetrahydropyran
O HN
N N N O
ylphenyl)pyrimidine (S)
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
232 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[2-(4-tert-
N N N
O HN
butylphenyl)pyrimidinyl]
N N N O
methyl-pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
233 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-cyclohexylphenyl)-
O HN
4-methyl-pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]- N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
234 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(1,1-dimethylindan
yl)methyl-pyrimidine
O HN
N N N
carbonyl]amino]butanoyl]amino]- O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
235 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-butylchloro-
O HN
phenyl)methyl-pyrimidine
N N N
carbonyl]amino]butanoyl]amino]- N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
236 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[4-methyl[4-(1-methyl- N
O HN
1-phenyl-ethyl)phenyl]pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
237 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(3-tert-butylphenyl)
methyl-pyrimidine
O HN
carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo-9,12- N O
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
238 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[4-methyl[4-(3-
methyloxetan
O HN
N N N
yl)phenyl]pyrimidine O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
239 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)[[2-
[4-(2-adamantyl)phenyl]methyl-
O HN
pyrimidinecarbonyl]amino]
N N N O
amino-butanoyl]amino]-10,13- N O
dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
240 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-heptylphenyl) N N
O HN
methyl-pyrimidine N N N
carbonyl]amino]butanoyl]amino]- O O
,13-dioxo-9,12- 2
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
241 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[4-methyl(4-
O HN
pentoxyphenyl)pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
242 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-butoxymethyl- N
O HN
phenyl)methyl-pyrimidine
N N N
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
243 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-butoxy-3,5-
O HN
dimethyl-phenyl)methyl-
N N N O
pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
244 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-butoxyfluoro-
N N CN
phenyl)methyl-pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
245 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-isopentyloxyphenyl)-
N N CN
O HN
4-methyl-pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]- O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
246 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-isopropoxyphenyl)-
N N CN
4-methyl-pyrimidine
O HN
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
247 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
Cl O
methyl[methyl-[rac-(2S)
amino[[2-(4-butoxychloro-
N N CN
O HN
phenyl)methyl-pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
248 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-hexoxyphenyl)
N N CN
O HN
methyl-pyrimidine N N N
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
249 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(2,2-dimethylchroman-
N N CN
O HN
6-yl)methyl-pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]- N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
250 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-tert-butoxyphenyl)-
N N CN
4-methyl-pyrimidine
O HN
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
251 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S) O O
amino[[2-(3-isopropoxyphenyl)-
4-methyl-pyrimidine N N
O HN
carbonyl]amino]butanoyl]amino]- H H
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene- 2
8-carboxamide
252 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[4-(2,2-
N N CN
O HN
dimethylpropoxy)phenyl]methyl-
N N N O
pyrimidine N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
253 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S) O
amino[[2-(4-tert-butylphenyl)-
N N CN
4,6-dimethyl-pyrimidine
carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
H N HO
254 rac-(8S,11S,14S)(2-
aminoethoxy)-N-(cyanomethyl)
hydroxymethyl[methyl-[rac- N N
(2S)amino[[2-(4-tert-
N N N O
butylphenyl)-4,6-dimethyl-
pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
255 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-butylphenyl)-4,6- H
N N CN
O HN
dimethyl-pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
256 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-heptylphenyl)-4,6- N N CN
O HN
dimethyl-pyrimidine N N N O
carbonyl]amino]butanoyl]amino]- O O
,13-dioxo-9,12- 2
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
257 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[4,6-dimethyl(4-
trimethylsilylphenyl)pyrimidine N N CN
O HN
carbonyl]amino]butanoyl]amino]-
N N N
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
258 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-isobutylphenyl)-4,6-
N N CN
O HN
dimethyl-pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]- N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
259 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[(4,6-dimethyltetralin
yl-pyrimidine
O HN
N N N O
carbonyl)amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
260 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-ethylphenyl)-4,6-
dimethyl-pyrimidine
O HN
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
261 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[4-(1,1-
N N CN
O HN
dimethylpropyl)phenyl]-4,6-
N N N O
dimethyl-pyrimidine N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
262 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-isopentylphenyl)-
N N CN
O HN
4,6-dimethyl-pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
263 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(3-tert-butylphenyl)-
4,6-dimethyl-pyrimidine H N
carbonyl]amino]butanoyl]amino]- O
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
264 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S) O
amino[[2-[4-(1-cyanomethyl-
N N N
ethyl)phenyl]-4,6-dimethyl-
O HN
pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
265 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[4,6-dimethyl(4-
vinylphenyl)pyrimidine N N
O HN
carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
266 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S) H N
amino[[2-(4-isopropenylphenyl)-
4,6-dimethyl-pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
O HN
N N N O
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
267 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[4-(1-methoxy
methyl-ethyl)phenyl]-4,6-dimethyl-
N N N O
pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
268 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(3,4-dibutylphenyl)-4,6-
dimethyl-pyrimidine
O HN
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12- O O
diazatricyclo[13.3.1.12,6]icosa- NH
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
269 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(1,1-dimethylindan
yl)-4,6-dimethyl-pyrimidine N N
O HN
carbonyl]amino]butanoyl]amino]-
N N N
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
270 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(1,1-dimethyltetralin
yl)-4,6-dimethyl-pyrimidine
O HN
carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
271 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4,4-dimethylchroman-
7-yl)-4,6-dimethyl-pyrimidine
O O HN
carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
272 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S) O
amino[[2-[4-(1,2-dimethylprop
enyl)phenyl]-4,6-dimethyl-
pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
273 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[4,6-dimethyl[4-(2-
methylprop
O HN
enyl)phenyl]pyrimidine N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
274 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[4-
(cyclopentylidenemethyl)phenyl]-
O HN
N N N O
4,6-dimethyl-pyrimidine
carbonyl]amino]butanoyl]amino]- O O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
275 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[4-
O HN
(cyclopentylmethyl)phenyl]-4,6-
N N N
dimethyl-pyrimidine N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
276 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[4-(2-ethylbut
enyl)phenyl]-4,6-dimethyl-
O HN
N N N O
pyrimidine
carbonyl]amino]butanoyl]amino]- O O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
277 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[4-(2-
ethylbutyl)phenyl]-4,6-dimethyl-
N N N O
pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
8-carboxamide
278 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[4,6-dimethyl[4-[rac- H
O HN
(E)-pentenyl]phenyl]pyrimidine- H H
N N N O
-carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
279 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[4,6-dimethyl[4-[rac-
O HN
(E)-butenyl]phenyl]pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]- N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
280 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S) O
amino[[4,6-dimethyl[4-(1-
methylcyclopropyl)phenyl]pyrimidin
e N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
281 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[4-(1-
ethylcyclopropyl)phenyl]-4,6-
O HN
N N N
dimethyl-pyrimidine
carbonyl]amino]butanoyl]amino]- O O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
282 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[4,6-dimethyl[4-(1-
O HN
propylcyclopropyl)phenyl]pyrimidin
N N N O
e
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
283 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[4-(1- H
butylcyclopropyl)phenyl]-4,6- H H
N N N O
dimethyl-pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
284 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S) O
amino[(4,6-dimethyl
spiro[cyclopropane-1,1’-indane]-5’- N N
O HN
yl-pyrimidine
N N N O
carbonyl)amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
285 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[(4,6-dimethyl
spiro[chromane-4,1’-cyclopropane]-
N N N O
7-yl-pyrimidine
carbonyl)amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
286 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[4-(1-
cyclopentylcyclopropyl)phenyl]-4,6- O HN
N N N O
dimethyl-pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12- NH
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
287 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[(4-tert-
butylphenyl)methyl]-4,6-dimethyl-
O HN
N N N O
pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
8-carboxamide
288 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[1-(4-tert-butylphenyl)-
1-methyl-ethyl]-4,6-dimethyl-
O HN
N N N
pyrimidine O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
289 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[(4-tert-butylphenyl)-
difluoro-methyl]-4,6-dimethyl-
N N N O
pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
290 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(1,1-
dimethylisochromanyl)-4,6-
O HN
dimethyl-pyrimidine N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
291 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(2,2-dimethyl-3H-
benzofuranyl)-4,6-dimethyl- N N
pyrimidine
N N N
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
292 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(3,3-dimethyl-2H-
O N N
benzofuranyl)-4,6-dimethyl-
O HN
N N N
pyrimidine O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
293 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(5-butylpyridyl)-4,6-
dimethyl-pyrimidine N O HN
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa- 2
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
294 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S) F
amino[[2-[4-(1,1-
difluorobutyl)phenyl]-4,6-dimethyl-
O HN
N N N O
pyrimidine
carbonyl]amino]butanoyl]amino]- O O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
295 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-tert-
butylcyclohexenyl)-4,6-dimethyl-
O HN
pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
296 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-tert-
butylcyclohexyl)-4,6-dimethyl- N N
pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
297 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-tert-
butylcyclohexyl)-4,6-dimethyl-
O HN
pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
298 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S) O
amino[[2-(4-tert-butylhydroxy-
phenyl)-4,6-dimethyl-pyrimidine N N
O HN
carbonyl]amino]butanoyl]amino]-
OH N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
299 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S) O
amino[[2-(4-tert-butylfluoro-
phenyl)-4,6-dimethyl-pyrimidine N N
O HN
carbonyl]amino]butanoyl]amino]-
F N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
300 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-cyclopropylphenyl)-
4,6-dimethyl-pyrimidine
O HN
carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
301 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S) O
amino[[2-(4-cyclobutylphenyl)-
4,6-dimethyl-pyrimidine
O HN
carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
302 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S) O
amino[[2-(4-cyclopentylphenyl)-
4,6-dimethyl-pyrimidine
O HN
carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
303 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[4-(cyclohexen
yl)phenyl]-4,6-dimethyl-pyrimidine-
O HN
-carbonyl]amino]butanoyl]amino]- N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
304 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-cyclohexylphenyl)-
4,6-dimethyl-pyrimidine
O HN
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
305 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-cycloheptylphenyl)-
4,6-dimethyl-pyrimidine
O HN
carbonyl]amino]butanoyl]amino]- N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
306 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(3,3-dimethylbut
ynyl)-4,6-dimethyl-pyrimidine N N
O HN
carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
307 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[2-(4-
ethylphenyl)ethynyl]-4,6-dimethyl- O HN
N N N O
pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
308 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[2-(4-
O HN
butylphenyl)ethynyl]-4,6-dimethyl-
N N N O
pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
309 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[4,6-dimethyl(2-
phenylethynyl)pyrimidine
O HN
carbonyl]amino]butanoyl]amino]- N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
310 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[4,6-dimethyl[2-(4-
O HN
vinylphenyl)ethynyl]pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
311 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[2-(4-tert-
butylphenyl)ethynyl]-4,6-dimethyl- O HN
N N N O
pyrimidine N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
312 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[2-[4-(1,2-
dimethylprop
N N N O
enyl)phenyl]ethynyl]-4,6-dimethyl-
pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
313 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[4,6-dimethyl[2-[4-(2-
O HN
methylprop
N N N O
enyl)phenyl]ethynyl]pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
314 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[2-(4-
isopropenylphenyl)ethynyl]-4,6-
O HN
N N N O
dimethyl-pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
315 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S) O
amino[[2-(4-tert-butyl
piperidyl)-4,6-dimethyl-pyrimidine- N N N
O HN
-carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
316 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(3-tert-butylazetidin
yl)-4,6-dimethyl-pyrimidine
N N N
O HN
carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
317 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[4,6-dimethyl(4-
N N N
pentoxypiperidyl)pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
318 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[4-(4-tert-
N N N
O HN
butylphenyl)piperazinyl]-4,6-
N N N O
dimethyl-pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
319 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-tert-butyloxo
pyridyl)-4,6-dimethyl-pyrimidine
N N N
O HN
carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
320 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[4-(4-tert-butyl
O HN
piperidyl)phenyl]-4,6-dimethyl-
N N N O
pyrimidine N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
321 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[4,6-dimethyl(4-
pyrrolidinylphenyl)pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
322 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[4-(4,4-difluoro
O HN
piperidyl)phenyl]-4,6-dimethyl-
N N N O
pyrimidine O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
323 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[4-(azetidin
yl)phenyl]-4,6-dimethyl-pyrimidine-
-carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
324 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[4,6-dimethyl[4-(1-
piperidyl)phenyl]pyrimidine
O HN
carbonyl]amino]butanoyl]amino]- N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
325 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[4-(azepan
yl)phenyl]-4,6-dimethyl-pyrimidine-
O HN
-carbonyl]amino]butanoyl]amino]- N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
326 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[4-(azocan
yl)phenyl]-4,6-dimethyl-pyrimidine-
N N N O
-carbonyl]amino]butanoyl]amino]- N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
327 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[4,6-dimethyl[4-[rac-
O HN
(3S,5R)-3,5-dimethyl
N N N O
piperidyl]phenyl]pyrimidine N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
328 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[4,6-dimethyl(4-
O HN
pentoxyphenyl)pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
329 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-isopentyloxyphenyl)- H
4,6-dimethyl-pyrimidine H H
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
330 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[4,6-dimethyl(4-
O HN
propoxyphenyl)pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
331 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-butoxyphenyl)-4,6-
O HN
dimethyl-pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
332 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-hexoxyphenyl)-4,6-
O HN
dimethyl-pyrimidine N N N
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12- NH
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
333 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[4-(2- H
methoxyethoxy)phenyl]-4,6- H H
N N N O
dimethyl-pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
334 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(2,3-dihydro-1,4-
benzodioxinyl)-4,6-dimethyl-
O O HN
N N N O
pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
335 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[4-
O HN
(cyclobutoxy)phenyl]-4,6-dimethyl-
N N N
pyrimidine N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
336 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[4-
(cyclopentoxy)phenyl]-4,6-
O HN
N N N O
dimethyl-pyrimidine
carbonyl]amino]butanoyl]amino]- O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
337 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[4-
O HN
(cyclohexoxy)phenyl]-4,6-dimethyl-
N N N O
pyrimidine N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
8-carboxamide
338 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[4-(3,3-
O HN
dimethylbutoxy)phenyl]-4,6-
N N N O
dimethyl-pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
339 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[4-(1-
O HN
ethylpropoxy)phenyl]-4,6-dimethyl-
N N N O
pyrimidine N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
340 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[4-
O HN
(cycloheptoxy)phenyl]-4,6-
N N N O
dimethyl-pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
341 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[4,6-dimethyl[4-(1- H
propylbutoxy)phenyl]pyrimidine H H
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
342 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-tert-butoxyphenyl)-
4,6-dimethyl-pyrimidine O HN
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa- NH
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
343 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[4-(tert-
O HN
butoxymethyl)phenyl]-4,6-dimethyl-
N N N O
pyrimidine N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
344 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[4,6-dimethyl[4-(1-
methylcyclopropoxy)phenyl]pyrimid
O HN
N N N
ine O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
345 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[4-(1-
ethylcyclopropoxy)phenyl]-4,6- O HN
N N N
dimethyl-pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12- 2
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
346 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[4,6-dimethyl[4-(1-
O HN
propylcyclopropoxy)phenyl]pyrimid
N N N O
ine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
347 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[4-(1-
O HN
butylcyclopropoxy)phenyl]-4,6-
N N N O
dimethyl-pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
8-carboxamide
348 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[4-(4,4- N N
O HN
N N N O
dimethylcyclohexoxy)phenyl]-4,6-
dimethyl-pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
349 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[4,6-dimethyl[4-[[rac- H N
O HN
(3aR,7aS)-2,3,3a,4,5,6,7,7a-
N N N O
octahydro-1H-inden
yl]oxy]phenyl]pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
350 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[4,6-dimethyl[4-[rac- H
(1S,4R)-norbornan H H
N N N O
yl]oxyphenyl]pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
351 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-butoxy-2,3,5,6- H N
F O HN
tetrafluoro-phenyl)-4,6-dimethyl-
F N N N O
pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
352 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[4,6-dimethyl(4- H
O HN
pentylsulfanylphenyl)pyrimidine H H
N N N
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
353 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-tert-butylphenoxy)-
O N N
4,6-dimethyl-pyrimidine
N N N
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
354 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-butylphenoxy)-4,6- H N
O N N
O HN
dimethyl-pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
355 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(3,4-dibutylphenoxy)- N
O N N
O HN
4,6-dimethyl-pyrimidine H H
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
356 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[4-(4,4-
dimethylpentoxy)phenyl]-4,6-
O HN
N N N
dimethyl-pyrimidine
carbonyl]amino]butanoyl]amino]- O O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
357 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[4-(5,5-
O HN
dimethylhexoxy)phenyl]-4,6-
N N N O
dimethyl-pyrimidine N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
358 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S) O
amino[[6-(4-tert-butylphenyl)-
2,4-dimethyl-pyridine
O HN
carbonyl]amino]butanoyl]amino]-
N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
359 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[6-[4-(2,2-
O HN
dimethylpropoxy)phenyl]-2,4-
N N O
dimethyl-pyridine N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
360 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[6-(4-isopropoxyphenyl)-
2,4-dimethyl-pyridine
O HN
N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa- NH
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
361 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S) O
amino[[6-(1,1-dimethylindan
yl)-2,4-dimethyl-pyridine N N
O HN
carbonyl]amino]butanoyl]amino]-
N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
362 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2,4-dimethyl(4-
O HN
pentoxyphenyl)pyridine
N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
363 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S) O
amino[[6-(4-tert-butylfluoro-
phenyl)-2,4-dimethyl-pyridine
O HN
carbonyl]amino]butanoyl]amino]- F N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
364 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[6-[4-
(cyclohexoxy)phenyl]-2,4-dimethyl- O HN
N N O
pyridine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
365 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[6-(5-butylpyridyl)-2,4-
dimethyl-pyridine O HN
N N O
carbonyl]amino]butanoyl]amino]- N
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
366 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[6-(4-butylphenyl)-2,4-
dimethyl-pyridine
carbonyl]amino]butanoyl]amino]-
O HN
,13-dioxo-9,12-
N N O
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
367 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[6-(4-butoxy-2,3,5,6-
F O HN
tetrafluoro-phenyl)-2,4-dimethyl-
F N N O
pyridine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
368 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S) O
amino[[6-(4-tert-butylnitro-
phenyl)-2,4-dimethyl-pyridine
O HN
carbonyl]amino]butanoyl]amino]-
N N N O
O O N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
369 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S) O
amino[[6-(2-aminotert-butyl-
phenyl)-2,4-dimethyl-pyridine
O HN
carbonyl]amino]butanoyl]amino]- NH N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
370 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[4-(4-tert-butylphenyl)-
2,6-dimethyl-
N CN
O HN
benzoyl]amino]butanoyl]amino]- H
N (S) N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
371 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[4-(4-tert-butylphenyl)
chloro-
N CN
benzoyl]amino]butanoyl]amino]- H
N (S) N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
372 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[2-amino(4-tert-
butylphenyl)benzoyl]amino]butanoy NH N CN
O HN
l]amino]-10,13-dioxo-9,12-
N N O
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
373 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[2-amino(4-tert-
butylphenyl)methyl-
NH N CN
O HN
benzoyl]amino]butanoyl]amino]- H
N (S) N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
374 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[4-(4-tert-butylphenoxy)-
2,3-dimethyl-
O HN
benzoyl]amino]butanoyl]amino]- N (S) N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
375 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[4-(4-tert-butylphenoxy)-
2,6-dimethyl-
O HN
benzoyl]amino]butanoyl]amino]- N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
376 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[4-(4-tert-butylphenoxy)-
O Cl N
2-chloro-
O HN
benzoyl]amino]butanoyl]amino]- N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
377 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[4-(4-butylphenoxy)
O Cl N
O HN
chloro- H
benzoyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
378 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[2-chloro(3,4-
O Cl N
O HN
dibutylphenoxy)benzoyl]amino]buta H
noyl]amino]-10,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
379 2-[5-heptyl[[rac-(1S)amino
[methyl-[rac-(7S,10S,13S)-3,18-
H N O
bis(2-aminoethoxy)
(cyanomethylcarbamoyl)methyl-
O HN
8,11-dioxo-9,12-
N N O
diazatricyclo[13.3.1.12,6]icosa- O
1(19),2,4,6(20),15,17-hexaen
yl]carbamoyl]propyl]carbamoyl]phe
noxy]acetic acid
380 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[4-[5-(4-
hexoxyphenyl)isoxazol
O HN
yl]benzoyl]amino]butanoyl]amino]- H
N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
381 4-methyl(4-pentylphenyl)-N-[rac-
(1S)amino[methyl-[rac-
H N O
(7S,10S,13S)-3,18-bis(2-
aminoethoxy)
(cyanomethylcarbamoyl)methyl- N
O O HN
8,11-dioxo-9,12- N
N (S) N O
diazatricyclo[13.3.1.12,6]icosa-
1(19),2,4,6(20),15,17-hexaen
yl]carbamoyl]propyl]oxazole
carboxamide
382 4-methyl(4-pentylphenyl)-N-[rac-
(1R)amino[methyl-[rac-
(7S,10S,13S)-3,18-bis(2-
aminoethoxy)
(cyanomethylcarbamoyl)methyl-
N CN
O O HN
8,11-dioxo-9,12-
N (R) N O
diazatricyclo[13.3.1.12,6]icosa-
1(19),2,4,6(20),15,17-hexaen
yl]carbamoyl]propyl]oxazole
carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
383 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[1-(4-tert-butylphenyl)
oxo-pyridine N O HN
N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa- 2
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
384 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S) O
amino[[1-(4-tert-butylphenyl)
oxo-pyridazine
N O HN
carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
385 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[3-(4-tert-butylphenyl)
methyl-1,2,4-triazine
N HN
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
386 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[5-(4-tert-butylphenyl)
methyloxo-pyrazine N
O HN
carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
387 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[1-(4-tert-butylphenyl)
methyloxo-pyridazine
N O HN
carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
388 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(difluoromethyl)(2-
F O HN
hexylpyrimidin
N N O
yl)benzoyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
389 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[1-(4-tert-
butylphenyl)piperidine
N HN
N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
390 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[4-(4-tert-
butylphenyl)piperidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
391 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[4-(4-tert-
butylphenyl)cyclohexanecarbonyl]a N
O HN
mino]butanoyl]amino]-10,13-dioxo-
N N O
9,12-diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
392 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[4-(4-tert-
butylphenyl)cyclohexanecarbonyl]a
O HN
mino]butanoyl]amino]-10,13-dioxo-
N N O
9,12-diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide 2
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
393 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[7-(4-tert-butylphenyl)
methyl-imidazo[1,2-a]pyridine N
O HN
carbonyl]amino]butanoyl]amino]- N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
394 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[(7-hexylmethyl-
quinoline
carbonyl)amino]butanoyl]amino]- N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
395 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[(6-hexylmethyl-
quinoline
O HN
N N O
carbonyl)amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa- NH
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
396 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[(6-hexoxymethyl-
H N O
quinoline
carbonyl)amino]butanoyl]amino]-
O HN
,13-dioxo-9,12-
N N O
diazatricyclo[13.3.1.12,6]icosa-
O N O
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
397 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[6-(4-tert-butylphenoxy)- H N
O HN
2-methyl-quinoline H
N N O
O N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
398 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[(7-hexylmethyl-1,5-
naphthyridine
carbonyl)amino]butanoyl]amino]- N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
399 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[(6-hexyl-2,4-dimethyl- N
quinoline H
N N O
carbonyl)amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
400 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[(7-hexylmethyl- N
naphthalene H
N N O
carbonyl)amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
401 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
H N O
methyl[methyl-[rac-(2S) O
amino[[5-bromo(4-tert-
butylphenyl)methyl-pyridine
O HN
O HN
carbonyl]amino]butanoyl]amino]-
N N O
N N O
Br N O
Br N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
402 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[6-(4-tert-butylphenyl)-
2,5-dimethyl-pyridine
O HN
carbonyl]amino]butanoyl]amino]- N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
403 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[6-(4-tert-butylphenyl)
methoxymethyl-pyridine N N
O HN
carbonyl]amino]butanoyl]amino]-
N N O
MeO N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
404 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[6-(4-tert-butylphenyl)
hydroxymethyl-pyridine N N
O HN
carbonyl]amino]butanoyl]amino]-
N N O
HO N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
405 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[5-amino(4-tert-
butylphenyl)methyl-pyridine N N
O HN
carbonyl]amino]butanoyl]amino]-
N N O
H N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
406 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[6-(4-tert-butylphenyl)
methylnitro-pyridine
O HN
carbonyl]amino]butanoyl]amino]-
N N O
O N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
407 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S) 2
amino[[6-(4-tert-butylphenyl)
chloromethyl-pyridine
O HN
carbonyl]amino]butanoyl]amino]-
N N O
,13-dioxo-9,12- Cl N O
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
408 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[6-(4-tert-butylphenyl)
(dimethylamino)methyl-pyridine-
O HN
3-carbonyl]amino]butanoyl]amino]- H
N N O
N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
409 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[6-(4-tert-butylphenyl)
methyl(methylamino)pyridine
carbonyl]amino]butanoyl]amino]- H
N N O
N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
410 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S) O
amino[[6-(4-tert-butylphenyl)
cyanomethyl-pyridine N N
O HN
carbonyl]amino]butanoyl]amino]-
N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
411 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S) O
amino[[4-amino(4-tert-
NH N
butylphenyl)pyridine
O HN
carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
412 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S) O
amino[[2-amino(4-tert-
butylphenyl)pyridine N NH N
O HN
carbonyl]amino]butanoyl]amino]-
N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
413 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[4-amino(4-tert-
butylphenyl)methyl-pyridine NH N
O HN
carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
414 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S) O
amino[[2-amino(4-tert-
N NH
butylphenyl)methyl-pyridine 2
carbonyl]amino]butanoyl]amino]-
N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
415 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[2-amino(4-tert-
N NH N
butylphenyl)nitro-pyridine
O HN
carbonyl]amino]butanoyl]amino]-
N N O
O N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
416 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S) O
amino[[2,5-diamino(4-tert-
N NH N
butylphenyl)pyridine 2
O HN
carbonyl]amino]butanoyl]amino]-
N N O
H N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
417 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[4-ethyl(4-
isobutylphenyl)pyrimidine
O HN
carbonyl]amino]butanoyl]amino]- N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
418 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[4-(difluoromethyl)(4-
N CHF N
isobutylphenyl)pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]- N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
419 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S) O
amino[[2-(4-tert-butylphenyl)
N OH N
hydroxy-pyrimidine
O HN
carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
420 2-[2-(4-tert-butylphenyl)[[rac-
(1S)amino[methyl-[rac-
H N O
(7S,10S,13S)-3,18-bis(2- O
HOOC
aminoethoxy)
N O N CN
(cyanomethylcarbamoyl)methyl-
8,11-dioxo-9,12- N N N O
diazatricyclo[13.3.1.12,6]icosa-
1(19),2,4,6(20),15,17-hexaen
yl]carbamoyl]propyl]carbamoyl]pyri
midinyl]oxyacetic acid
421 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S) O
amino[[2-(4-tert-butylphenyl)
N Cl N
chloromethyl-pyrimidine
O HN
carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
422 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S) O
amino[[2-(4-tert-butylphenyl)
N OMe N
methoxymethyl-pyrimidine
carbonyl]amino]butanoyl]amino]- N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
423 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-tert-butylphenyl)
N OH N
hydroxymethyl-pyrimidine
O HN
carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
424 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S) O
amino[[2-(4-tert-butylphenyl)
N NMe N
(dimethylamino)methyl-
O HN
pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
425 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[2-(4-tert-butylphenyl)
N NHMe N
methyl(methylamino)pyrimidine-
O HN
N N N O
-carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
426 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S) O
amino[[4-amino(4-tert-
butylphenyl)methyl-pyrimidine- N NH
-carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
427 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[4-amino[4-(3,3-
N NH N
O HN
dimethylbutoxy)phenyl]methyl-
N N N O
pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
428 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S) O
amino[[2-(4-tert-butylphenyl)
methyl 3
(trifluoromethyl)pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
429 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S) O
amino[[4,6-diamino(4-tert-
N NH N CN
butylphenyl)pyrimidine
O HN
carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
430 rac-(8S,11S,14S)-N-(cyanomethyl)-
3,18-dihydroxymethyl
[methyl-[rac-(2S)amino[[6-(4- N N
O HN
isobutylphenyl)methyl-pyridine-
N N O
3-carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
431 rac-(8S,11S,14S)-N-(cyanomethyl)-
3,18-dihydroxymethyl
[methyl-[rac-(2S)amino[[2-(4-
O HN
tert-butylphenyl)methyl- N N N O
pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
432 rac-(8S,11S,14S)-N-(cyanomethyl)-
3,18-dihydroxymethyl
O HN
[methyl-[rac-(2S)amino[[4-
N N N O
methyl(4-
pentylphenyl)pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
433 rac-(8S,11S,14S)-3,18-bis(3-
aminopropoxy)-N-(cyanomethyl)- H N
11-methyl[methyl-[rac-(2S)
amino[[2-(4-tert-butylphenyl) N N
O HN
methyl-pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
434 rac-(8S,11S,14S)-3,18-bis(3-
aminopropoxy)-N-(cyanomethyl)- 2
11-methyl[methyl-[rac-(2S)
amino[[2-(4-tert-butylphenyl)-
O HN
N N N O
4,6-dimethyl-pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12- 2
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
435 rac-(8S,11S,14S)-3,18-bis(3-
H N O
aminopropoxy)-N-(cyanomethyl)-
11-methyl[methyl-[rac-(2S)
O HN
amino[[4,6-dimethyl(4-
N N N O
pentoxyphenyl)pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
436 rac-(8S,11S,14S)-3,18-bis(3-
aminopropoxy)-N-(cyanomethyl)-
11-methyl[methyl-[rac-(2S)
N NH N
O HN
amino[[4-amino[4-(3,3-
N N N O
dimethylbutoxy)phenyl]methyl-
pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
437 rac-(8S,11S,14S)-3,18-bis(4-
H N O
aminobutoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-tert-butylphenyl)- N N
O HN
4,6-dimethyl-pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
438 rac-(8S,11S,14S)-N-(cyanomethyl)-
H N (S)
11-methyl[methyl-[rac-(2S)
amino[[2-(4-tert-butylphenyl)
methyl-pyrimidine
carbonyl]amino]butanoyl]amino]- N N
O HN
,13-dioxo-3,18-bis[rac-(2S)
N N N O
aminopropoxy]-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
439 rac-(8S,11S,14S)-3,18-bis(3-amino-
2-hydroxy-propoxy)-N-
(cyanomethyl)methyl
H N O
[methyl-[rac-(2S)amino[[2-(4-
tert-butylphenyl)-4,6-dimethyl-
O HN
pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]- N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
N N CN
N N N O
441 rac-(8S,11S,14S)-N-(cyanomethyl)-
HN NH
11-methyl-3,18-bis[2-[(N-
methylcarbamimidoyl)amino]ethoxy
HN N
][methyl-[rac-(2S)amino
[[2-(4-tert-butylphenyl)-4,6-
dimethyl-pyrimidine
N N CN
O HN
carbonyl]amino]butanoyl]amino]-
N N O
,13-dioxo-9,12- N O
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
442 rac-(8S,11S,14S)-N-(cyanomethyl)-
3,18-bis[2-(dimethylamino)ethoxy]-
11-methyl[methyl-[rac-(2S)
amino[[2-(4-tert-butylphenyl)
methyl-pyrimidine
N N CN
O HN
carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
443 rac-(2S)-N,N’-dimethyl[(2-
methyloctyl-benzoyl)amino]-N-
[rac-(7S,10S,13S)-3,18-bis(2-
aminoethoxy) N
O HN
(cyanomethylcarbamoyl)methyl- H
8,11-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(19),2,4,6(20),15,17-hexaen
yl]butanediamide
444 rac-(2S)-N,N’,N’-trimethyl[(2-
methyloctyl-benzoyl)amino]-N-
[rac-(7S,10S,13S)-3,18-bis(2-
aminoethoxy) N
O HN
(cyanomethylcarbamoyl)methyl- H
8,11-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(19),2,4,6(20),15,17-hexaen
yl]pentanediamide
445 rac-(2S)-N’-ethyl-N-methyl[(2-
methyloctyl-benzoyl)amino]-N-
[rac-(7S,10S,13S)-3,18-bis(2-
aminoethoxy) N
(cyanomethylcarbamoyl)methyl- H
8,11-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(19),2,4,6(20),15,17-hexaen
yl]pentanediamide
446 rac-(2S)-N’-(2-hydroxyethyl)-N-
methyl[(2-methyloctyl-
benzoyl)amino]-N-[rac-
(7S,10S,13S)-3,18-bis(2- H N
aminoethoxy) H
(cyanomethylcarbamoyl)methyl-
8,11-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(19),2,4,6(20),15,17-hexaen
yl]pentanediamide
447 rac-(2S)-N-methyl[(2-methyl
octyl-benzoyl)amino]-N’-(oxetan
yl)-N-[rac-(7S,10S,13S)-3,18-bis(2-
aminoethoxy) N
O HN
(cyanomethylcarbamoyl)methyl- H
8,11-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(19),2,4,6(20),15,17-hexaen
yl]pentanediamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
448 rac-(2S)-N’-[2-hydroxy
(hydroxymethyl)ethyl]-N-methyl
[(2-methyloctyl-benzoyl)amino]-
N-[rac-(7S,10S,13S)-3,18-bis(2- N
aminoethoxy) H
(cyanomethylcarbamoyl)methyl-
8,11-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(19),2,4,6(20),15,17-hexaen
yl]pentanediamide
449 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)[(2- H N O
methyloctyl-benzoyl)amino]
(sulfamoylamino)butanoyl]amino]-
H N CN
8 17
,13-dioxo-9,12-
O HN
N N O
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
450 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)[(2-
methyloctyl-benzoyl)amino]
N CN
ureido-pentanoyl]amino]-10,13-
O HN
N N O
dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
N NH
8-carboxamide
451 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)[[4-
methyl(4-
N N CN
O HN
pentylphenyl)pyrimidine H
N N N O
carbonyl]amino]ureido-
butanoyl]amino]-10,13-dioxo-9,12-
HN NH
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
452 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)[[2-
(4-tert-butylphenyl)methyl-
N N CN
pyrimidinecarbonyl]amino]
O HN
N N N O
ureido-butanoyl]amino]-10,13- (S)
dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
HN NH
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
453 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)[(4-
heptylmethyl-benzoyl)amino]
N CN
O NH
(methylamino)propanoyl]amino]-
N NH O
,13-dioxo-9,12- O
diazatricyclo[13.3.1.12,6]icosa- NH
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
454 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2R)[(4-
heptylmethyl-benzoyl)amino]
sulfanyl-propanoyl]amino]-10,13-
C H N CN
7 15
O HN
dioxo-9,12-
N N O
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
N CN
O HN
N N O
456 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2R)
amino[(4-heptylmethyl-
N CN
O HN
benzoyl)amino]butanoyl]amino]-
N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
457 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-tert-butylphenyl)
methyl-pyrimidine
N N CN
O HN
carbonyl]amino]propanoyl]amino]-
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa- 2
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
458 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S) O
hydroxy[[2-(4-isobutylphenyl)
N N CN
methyl-pyrimidine
O HN
carbonyl]amino]butanoyl]amino]- N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
8-carboxamide
459 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)[[2-
(4-tert-butylphenyl)methyl-
N CN
O HN
pyrimidinecarbonyl]amino] H
N N N O
hydroxy-butanoyl]amino]-10,13-
dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
460 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)[[2- O
(4-tert-butylphenyl)methyl-
pyrimidinecarbonyl]amino]
N N CN
O HN
(methoxyamino)butanoyl]amino]- H H
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
461 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S,4R)
H N O
(aminomethyl)(4-hexylmethyl-
benzoyl)pyrrolidine
carbonyl]amino]-10,13-dioxo-9,12- O
N CN
O HN
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
462 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)[[2-
(4-tert-butylphenyl)methyl-
pyrimidinecarbonyl]amino]
N CN
O HN
guanidino-propanoyl]amino]-10,13-
N N N O
dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
HN NH
8-carboxamide
OH N
O O HN
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
464 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[rac-(2S)[[2-(4-tert- H
butylphenyl)-4,6-dimethyl- H H
N N O
N N O
pyrimidine
carbonyl]amino]propanoyl]amino]bu
tanoyl]amino]-10,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
465 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[rac-(2S)[[2-(4-tert-
O O HN
butylphenyl)-4,6-dimethyl-
N N N O
pyrimidinecarbonyl]amino]
hydroxy-
propanoyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
466 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S) 2
amino[[rac-(2S)tert-butoxy O
[[2-(4-tert-butylphenyl)-4,6-
dimethyl-pyrimidine
Ot-Bu N
O O HN
carbonyl]amino]propanoyl]amino]bu
N N O
N N N O
tanoyl]amino]-10,13-dioxo-9,12- H
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
467 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[rac-(2R)[[2-(4-tert-
O O HN
butylphenyl)-4,6-dimethyl-
N N O
N N N O
pyrimidinecarbonyl]amino]
hydroxy-
propanoyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
468 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[rac-(2R)tert-butoxy H N
Ot-Bu
O O HN
[[2-(4-tert-butylphenyl)-4,6- H H
N N O
N N N O
dimethyl-pyrimidine
carbonyl]amino]propanoyl]amino]bu
tanoyl]amino]-10,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
469 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[rac-(2S)[[2-(4-tert- H N
O O HN
butylphenyl)-4,6-dimethyl-
N N O
N N N O
pyrimidine
carbonyl]amino]pentanoyl]amino]bu
tanoyl]amino]-10,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
470 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-[[2-(4-tert- H
O O HN
butylphenyl)-4,6-dimethyl- H H
N N N O
pyrimidine
carbonyl]amino]acetyl]amino]butan
oyl]amino]-10,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
471 rac-(8S,11S,14S)-N-(cyanomethyl)-
3,18-dihydroxymethyl-10,13-
dioxo[[rac-(2S)amino[(4-
C CH
6 13 3
O HN
hexylmethyl- H H
N N O
benzoyl)amino]butanoyl]amino]-
O O CH
9,12-diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene- NH
8-carboxamide
472 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl-10,13-dioxo[[rac-(2S)
amino[[2-(4-tert-butylphenyl)
O HN
methyl-pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
O O CH
9,12-diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
473 rac-(8S,11S,14S)-N-(cyanomethyl)-
14-[ethyl-[rac-(2S)amino[(4-
hexylmethyl-
benzoyl)amino]butanoyl]amino]-
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
3,18-dihydroxymethyl-10,13-
dioxo-9,12-
CH N
diazatricyclo[13.3.1.12,6]icosa- 3
O HN
1(18),2(20),3,5,15(19),16-hexaene- N N O
8-carboxamide
O O CH
474 rac-(8S,11S,14S)[2-aminoethyl-
[rac-(2S)amino[(4-hexyl
CH N
methyl-
N N O
benzoyl)amino]butanoyl]amino]-N-
(cyanomethyl)-3,18-dihydroxy
O O CH
methyl-10,13-dioxo-9,12-
NH NH
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
475 rac-(8S,11S,14S)-N-(cyanomethyl)-
3,18-dihydroxy[2-hydroxyethyl-
[rac-(2S)amino[(4-hexyl 3
methyl- N N
CH N O
benzoyl)amino]butanoyl]amino]
O O CH
methyl-10,13-dioxo-9,12-
NH OH
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
476 rac-(8S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
[methyl-[rac-(2S)amino[[2-(4-
tert-butylphenyl)methyl-
pyrimidine
O HN
N N N
carbonyl]amino]butanoyl]amino]- O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
(hydroxymethyl)[methyl-[rac-
(2S)amino[[2-(4-tert-
butylphenyl)methyl-pyrimidine-
O HN
N N N
-carbonyl]amino]butanoyl]amino]- O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
478 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
cyclopropyl[methyl-[rac-(2S) O
amino[(4-heptylmethyl-
benzoyl)amino]butanoyl]amino]- N
O HN
,13-dioxo-9,12-
N N O
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
479 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
ethyl[methyl-[rac-(2S)amino-
2-[(4-heptylmethyl-
benzoyl)amino]butanoyl]amino]- N
O HN
,13-dioxo-9,12-
N N O
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
480 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
ethyl-10,13-dioxo[[rac-(2S)
amino[(4-heptylmethyl-
benzoyl)amino]butanoyl]amino]-
O HN
9,12-diazatricyclo[13.3.1.12,6]icosa-
N N O
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
481 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)[[4-amino(4-
hexylmethyl-benzoyl)pyrrolidine-
2-carbonyl]-methyl-amino]-N-
(cyanomethyl)methyl-10,13-
O HN
dioxo-9,12-
N N O
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
482 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)[(4-amino
tetradecanoyl-pyrrolidine
H N O
carbonyl)-methyl-amino]-N-
(cyanomethyl)methyl-10,13-
dioxo-9,12- O N
O HN
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
483 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)[(4-amino
H N O
tetradecanoyl-pyrrolidine
carbonyl)-methyl-amino]-N-
(cyanomethyl)methyl-10,13-
dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa- H N
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
H N O
O HN
N N O
N N N O
O HN
N N N O
O HN
N N N O
O HN
N N O
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
O HN
N N N O
NH O O
O HN
N N N
491 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)[(2-
aminoacetyl)amino][[2-(4-tert-
butylphenyl)methyl-pyrimidine- N N
O HN
N N N O
carbonyl]amino]propanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
492 (8S,11S,14S)[[(2S)amino 2
[[2-(4-tert-butylphenyl)-4,6-
dimethyl-pyrimidine
carbonyl]amino]methyl-
pentanoyl]-methyl-amino]-3,18-
bis(2-aminoethoxy)-N-
N N N O
(cyanomethyl)methyl-10,13-
dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
493 rac-(8S,11S,14S)-3,18-bis(2- 2
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)[(2-
aminooxo-ethyl)amino][[2-(4-
tert-butylphenyl)methyl- N N
pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
O NH
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
494 rac-(8S,11S,14S)-3,18-bis(2- 2
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)[[2-
(4-tert-butylphenyl)methyl-
pyrimidinecarbonyl]amino] N N
O HN
formamido-butanoyl]amino]-10,13-
N N N O
dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
495 rac-(8S,11S,14S)-3,18-bis(2- 2
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)(2-
aminoethoxy)[[2-(4-tert-
butylphenyl)-4,6-dimethyl-
O HN
pyrimidine
N N N O
carbonyl]amino]propanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
496 (8S,11S,14S)[[(2S)
acetamido[[2-[4-
(cyclohexoxy)phenyl]-4,6-dimethyl-
pyrimidine
N N CN
carbonyl]amino]butanoyl]-methyl-
O HN
N N N O
amino]-3,18-bis(2-aminoethoxy)-N-
(cyanomethyl)methyl-10,13-
dioxo-9,12- HN O
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
497 (8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
[[(2S)[[2-[4-
(cyclohexoxy)phenyl]-4,6-dimethyl-
pyrimidinecarbonyl]amino]
O HN
N N N O
(methanesulfonamido)butanoyl]-
methyl-amino]methyl-10,13-
dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
498 (8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
[[(2S)[[2-[4- O
(cyclohexoxy)phenyl]-4,6-dimethyl-
pyrimidinecarbonyl]amino]
O HN
N N N O
ureido-butanoyl]-methyl-amino]
methyl-10,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
HN O
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
499 (8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
[[(2S)[[2-[4-
(cyclohexoxy)phenyl]-4,6-dimethyl-
O HN
pyrimidinecarbonyl]amino]
N N N O
ureido-propanoyl]-methyl-amino]- N O
11-methyl-10,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
O NH
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
500 (8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
[[(2S)[[2-[4-
(cyclohexoxy)phenyl]-4,6-dimethyl-
pyrimidinecarbonyl]amino]
O HN
N N N O
(sulfamoylamino)butanoyl]-methyl-
amino]methyl-10,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene- O
8-carboxamide
501 (8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
[[(2S)[[2-[4-
(cyclohexoxy)phenyl]-4,6-dimethyl-
O HN
pyrimidinecarbonyl]amino]
N N N O
ureido-pentanoyl]-methyl-amino]-
11-methyl-10,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa- NH
1(18),2(20),3,5,15(19),16-hexaene-
O NH
8-carboxamide
502 (8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
[[(2S)[[2-[4-
(cyclohexoxy)phenyl]-4,6-dimethyl-
pyrimidinecarbonyl]amino] O HN
N N N O
(sulfamoylamino)propanoyl]-
methyl-amino]methyl-10,13-
dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
503 (8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
[[(2S)[[2-[4-
(cyclohexoxy)phenyl]-4,6-dimethyl-
pyrimidinecarbonyl]amino]
N N N O
(sulfamoylamino)pentanoyl]-methyl-
amino]methyl-10,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
O S O
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
504 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)[[2- O
[4-(cyclohexoxy)phenyl]-4,6-
dimethyl-pyrimidine
O HN
N N N O
carbonyl]amino]formamido-
butanoyl]amino]-10,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa- HN
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
505 rac-(2S)[[2-[4-
(cyclohexoxy)phenyl]-4,6-dimethyl-
pyrimidinecarbonyl]amino]-N-
methyl-N-[rac-(7S,10S,13S)-3,18-
bis(2-aminoethoxy)
O HN
N N N O
(cyanomethylcarbamoyl)methyl-
8,11-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
H N O
1(19),2,4,6(20),15,17-hexaen
yl]pentanediamide
506 (2S)-N-[(7S,10S,13S)-3,18-bis(2-
aminoethoxy)
(cyanomethylcarbamoyl)methyl-
8,11-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
O HN
N N N O
1(19),2,4,6(20),15,17-hexaenyl]-
2-[[2-[4-(cyclohexoxy)phenyl]-4,6-
dimethyl-pyrimidine
carbonyl]amino]-N-methyl-
butanediamide
507 (8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
[[(2S)[[2-[4-
(cyclohexoxy)phenyl]-4,6-dimethyl-
pyrimidinecarbonyl]amino] O HN
N N N O
hydroxy-propanoyl]-methyl-amino]-
11-methyl-10,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
508 (8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
[[(2R)[[2-[4-
(cyclohexoxy)phenyl]-4,6-dimethyl-
pyrimidinecarbonyl]amino] O HN
N N N O
hydroxy-propanoyl]-methyl-amino]-
11-methyl-10,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
509 (8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
[[(2S)[[2-[4- O
(cyclohexoxy)phenyl]-4,6-dimethyl-
pyrimidinecarbonyl]amino]
O HN
N N N O
hydroxy-butanoyl]-methyl-amino]-
11-methyl-10,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
510 (8S,11S,14S)[[(2S)amino
[[(2S)[[2-[4-
(cyclohexoxy)phenyl]-4,6-dimethyl-
pyrimidine
N CN
O O HN
carbonyl]amino]butanoyl]amino]but
N N O
N N O
anoyl]-methyl-amino]-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl-10,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
511 (8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
[[(2S)[[2-[4-
(cyclohexoxy)phenyl]-4,6-dimethyl-
pyrimidinecarbonyl]amino][(2-
O HN
N N N
hydroxyacetyl)amino]butanoyl]-
methyl-amino]methyl-10,13-
dioxo-9,12-
HN O
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
512 (8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
[[(2S)[[2-[4-
(cyclohexoxy)phenyl]-4,6-dimethyl-
O HN
pyrimidinecarbonyl]amino]
N N N O
(hydroxycarbamoylamino)butanoyl]- N O
methyl-amino]methyl-10,13-
dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa- HN
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
513 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[4,6-dimethyl(4-
N N CN
O HN
pentylphenyl)pyrimidine
N N N
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
514 rac-(8S,11S,14S)(2-
aminoethoxy)-N-(cyanomethyl)
hydroxymethyl[methyl-[rac-
(2S)amino[[4,6-dimethyl(4-
trimethylsilylphenyl)pyrimidine H H
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa- 2
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
516 rac-(8S,11S,14S)(2-
aminoethoxy)-N-(cyanomethyl)
hydroxymethyl[methyl-[rac-
(2S)amino[[2-(4-ethylphenyl)-
4,6-dimethyl-pyrimidine H H
N N N
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
517 rac-(8S,11S,14S)(2-
acetamidoethoxy)(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-tert-butylphenyl)-
4,6-dimethyl-pyrimidine
O HN
carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
518 rac-(8S,11S,14S)(2-
aminoethoxy)-N-(cyanomethyl) HO
hydroxymethyl[methyl-[rac-
(2S)amino[[4,6-dimethyl(4- N
pentoxyphenyl)pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
519 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl-10,13-dioxo[[rac-(2S)
amino[[2-[4-
(cyclohexoxy)phenyl]-4,6-dimethyl- O HN
N N N O
pyrimidine
carbonyl]amino]butanoyl]amino]-
9,12-diazatricyclo[13.3.1.12,6]icosa- 2
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
520 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2,4-diamino(4-tert-
butylphenyl)pyridine
N NH N
O HN
carbonyl]amino]butanoyl]amino]-
N N O
,13-dioxo-9,12-
NH O O
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
521 rac-(8S,11S,14S)(2-
aminoethoxy)-N-(cyanomethyl)
hydroxymethyl[methyl-[rac-
(2S)amino[[4,6-dimethyl(4-
pentylphenyl)pyrimidine N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
522 rac-(8S,11S,14S)(2-
aminoethoxy)-N-(cyanomethyl)
hydroxymethyl[methyl-[rac-
(2S)amino[[2-[4-
O HN
(cyclohexoxy)phenyl]-4,6-dimethyl-
N N N O
pyrimidine N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
523 rac-(8S,11S,14S)(2-
aminoethoxy)-N-(cyanomethyl)
hydroxymethyl[methyl-[rac- N N
O HN
(2S)amino[[2-(4-tert-
N N N O
butylphenyl)methyl-pyrimidine-
-carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
524 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[2-(4-hydroxyphenyl)
methyl-pyrimidine
O HN
carbonyl]amino]butanoyl]amino]-
N N N
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene- 2
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
H N HO
525 rac-(8S,11S,14S)(2- O
aminoethoxy)-N-(cyanomethyl)
hydroxymethyl[methyl-[rac-
O HN
(2S)amino[[6-(4- N N N O
isobutylphenyl)methyl-pyridine-
3-carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
H N HO
526 rac-(8S,11S,14S)(2-
aminoethoxy)-N-(cyanomethyl)
hydroxymethyl[methyl-[rac- N N
(2S)amino[[6-(4-tert-
N N O
butylphenyl)methyl-pyridine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
527 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[2-[4-(3,3-
N N N
O HN
dimethylbutoxy)piperidyl]-4,6-
N N N O
dimethyl-pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
528 rac-(8S,11S,14S)(2-
aminoethoxy)-N-(cyanomethyl)
hydroxymethyl[methyl-[rac-
(2S)amino[[2-[4-(3,3-
O HN
dimethylbutoxy)phenyl]-4,6-
N N N O
dimethyl-pyrimidine N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
529 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[4-amino(5-butyl
pyridyl)methyl-pyridine O HN
N N O
carbonyl]amino]butanoyl]amino]-
NH O O
,13-dioxo-9,12- 2
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
530 rac-(8S,11S,14S)(2-
aminoethoxy)-N-(cyanomethyl)
hydroxymethyl[methyl-[rac-
(2S)amino[[6-(4-tert-
HN N
butylphenyl)-2,4-dimethyl-pyridine-
3-carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
531 rac-(8S,11S,14S)(2-
aminoethoxy)-N-(cyanomethyl)
hydroxymethyl[methyl-[rac-
(2S)amino[[2-(1,1-
dimethylindanyl)-4,6-dimethyl-
N N N O
pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
532 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[4-amino[4-
N NH N
(cycloheptoxy)phenyl]methyl-
O HN
N N N O
pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
533 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)[[5-
acetamido(4-tert-butylphenyl)
methyl-pyridinecarbonyl]amino]-
4-amino-butanoyl]amino]-10,13-
N N O
HN N O
dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
534 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[4-amino[5-(3,3-
N NH N
dimethylbutoxy)pyridyl] N O HN
N N N O
methyl-pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12- 2
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
H N HO
535 rac-(8S,11S,14S)(2-
aminoethoxy)-N-(cyanomethyl)
hydroxymethyl[methyl-[rac- N N
O HN
(2S)amino[[2-[4-(1,1-
N N N O
dimethylpropyl)phenyl]methyl-
pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
536 rac-(8S,11S,14S)(2-
aminoethoxy)-N-(cyanomethyl)
hydroxymethyl[methyl-[rac-
(2S)amino[[4,6-dimethyl(4- N
O HN
pentoxyphenyl)pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
537 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[6-(4-tert-butylphenyl)
methyl(trifluoromethyl)pyridine-
3-carbonyl]amino]butanoyl]amino]-
F N N O
,13-dioxo-9,12-
F O O
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
538 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[4-amino[4-(3,3-
NH N
O HN
dimethylbutoxy)phenyl]methyl-
N N N O
pyridine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
H N HO
539 rac-(8S,11S,14S)(2- O
aminoethoxy)-N-(cyanomethyl)
hydroxymethyl[methyl-[rac-
O HN
N N N O
(2S)amino[[2-[4-(3,3-
dimethylbutoxy)phenyl]-4,6-
dimethyl-pyrimidine 2
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
540 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[2-(2-tert-butylpyrimidin- N
-yl)-4,6-dimethyl-pyrimidine
N N N
carbonyl]amino]butanoyl]amino]- H H
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
H N HO
541 rac-(8S,11S,14S)(2-
aminoethoxy)-N-(cyanomethyl)
hydroxymethyl[methyl-[rac-
O HN
(2S)amino[[4-(4-tert-
N N O
butylphenyl)-2,6-dimethyl-
benzoyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
542 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S) O
amino[[2-(4-hydroxyphenyl)-4,6-
dimethyl-pyrimidine
O HN
carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
543 rac-(8S,11S,14S)(2-
aminoethoxy)-N-(cyanomethyl)
hydroxymethyl[methyl-[rac-
(2S)amino[[4,6-dimethyl[4-
O HN
N N N O
methylcyclopropyl)phenyl]pyrimidin N O
e
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
544 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[4-amino[4-
NH N
O HN
(cyclohexoxy)phenyl]methyl-
N N N O
pyridine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
545 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
amino[[4-amino[4-
NH N
(cycloheptoxy)phenyl]methyl- O HN
N N N O
pyridine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12- 2
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
546 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[4-amino(4-tert-
butylphenyl)ethyl-pyridine
O HN
carbonyl]amino]butanoyl]amino]-
N N O
,13-dioxo-9,12-
NH O O
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene- 2
8-carboxamide
547 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[4-amino[4-
N NH N
(cyclohexoxy)phenyl]methyl-
N N N O
pyrimidine
carbonyl]amino]butanoyl]amino]- H OH
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
H N HO
548 rac-(8S,11S,14S)(2-
aminoethoxy)-N-(cyanomethyl)
hydroxymethyl[methyl-[rac-
N NH N
O HN
(2S)amino[[4-amino(4-tert-
N N N O
butylphenyl)methyl-pyrimidine-
-carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
549 rac-(8S,11S,14S)(2- 2
aminoethoxy)-N-(cyanomethyl)
hydroxymethyl[methyl-[rac-
(2S)amino[[2-(4-tert-
O HN
butylphenyl)methyl-pyrimidine-
N N N O
-carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
550 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[2-[2-(3,3-
O HN
dimethylbutoxy)pyrimidinyl]-4,6-
N N N O
dimethyl-pyrimidine O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
551 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[4-(2-aminooxo- 2
ethoxy)(4-tert-butylphenyl) O HN
N N N O
methyl-pyridine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12- 2
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
552 rac-(8S,11S,14S)(2-
aminoethoxy)-N-(cyanomethyl)
hydroxymethyl[methyl-[rac-
(2S)amino[[2-(4- N N
isopropoxyphenyl)-4,6-dimethyl-
N N N O
pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
553 rac-(8S,11S,14S)(2-
aminoethoxy)-N-(cyanomethyl)
hydroxymethyl[methyl-[rac-
(2S)amino[[2-(4-tert-
butylphenyl)-4,6-dimethyl-
pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
554 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S) O
amino[[4-amino(4-tert-
butylphenyl)chloro-pyridine N Cl N
O HN
carbonyl]amino]butanoyl]amino]-
N N O
,13-dioxo-9,12-
NH O O
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
555 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S) O
amino[[4,6-dimethyl[4-[rac-
(2R,6S)-2,6-dimethyl
piperidyl]phenyl]pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
H N HO
556 rac-(8S,11S,14S)(2-
aminoethoxy)-N-(cyanomethyl)
hydroxymethyl[methyl-[rac- N N
(2S)amino[[4-amino(4-tert-
N N O
butylphenyl)methyl-pyridine
NH O O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
557 rac-(8S,11S,14S)(2-
aminoethoxy)-N-(cyanomethyl)
hydroxymethyl[methyl-[rac-
(2S)amino[[4-amino(4-tert-
butylphenyl)methyl-pyridine
NH N
O HN
carbonyl]amino]butanoyl]amino]- H H
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
558 rac-(8S,11S,14S)(2-
aminoethoxy)-N-(cyanomethyl)
methoxymethyl[methyl-
[rac-(2S)amino[[2-(4-tert-
butylphenyl)methyl-pyrimidine-
O HN
-carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo-9,12- N O
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
559 rac-(8S,11S,14S)acetamido
(2-aminoethoxy)-N-(cyanomethyl)-
H N HO
3-hydroxymethyl[methyl-
[rac-(2S)amino[[2-(4-tert-
butylphenyl)-4,6-dimethyl-
O HN
pyrimidine H H
N N N
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa- 2
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
560 rac-(8S,11S,14S)(2-
H N HO
aminoethoxy)-N-(cyanomethyl)
fluorohydroxymethyl
[methyl-[rac-(2S)amino[[2-(4-
O HN
tert-butylphenyl)-4,6-dimethyl-
N N N O
pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
561 rac-(8S,11S,14S)(2-
aminoethoxy)-N-(cyanomethyl)-
3,18-dihydroxymethyl
[methyl-[rac-(2S)amino[[2-(4-
tert-butylphenyl)-4,6-dimethyl-
pyrimidine HN
N N N
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2,4,6(20),15(19),16-hexaene-
8-carboxamide
562 rac-(8S,11S,14S)-4,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
hydroxymethyl[methyl-[rac- HO
(2S)amino[[2-(4-tert-
butylphenyl)-4,6-dimethyl- H N
pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2,4,6(20),15(19),16-hexaene-
8-carboxamide
564 rac-(8S,11S,14S)-3,18-bis(3-
aminopropoxy)-N-(cyanomethyl)-
H N O
11-methyl[methyl-[rac-(2S)
amino[[4-amino[4- NH N CN
O HN
(cycloheptoxy)phenyl]methyl-
N N N
pyridine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
565 rac-(8S,11S,14S)-3,18-bis(3-
aminopropoxy)-N-(cyanomethyl)-
H N O
11-methyl[methyl-[rac-(2S)
amino[[4-amino[4-
NH N CN
O HN
(cyclohexoxy)phenyl]methyl-
N N N O
pyridine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
8-carboxamide
566 rac-(8S,11S,14S)-3,18-bis(3-
aminopropoxy)-N-(cyanomethyl)-
H N O
11-methyl[methyl-[rac-(2S) O
amino[[4-amino[4-
N NH N CN
O HN
(cycloheptoxy)phenyl]methyl-
N N O
N (S)
pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
567 rac-(8S,11S,14S)-N-(cyanomethyl)-
11-methyl[methyl-[rac-(2S)
amino[[2-(4-tert-butylphenyl)-
H N O
4,6-dimethyl-pyrimidine
carbonyl]amino]butanoyl]amino]-
N N CN
,13-dioxo-3,18-bis[rac-(2R) HN
N N N O
aminohydroxy-propoxy]-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
568 rac-(8S,11S,14S)-N-(cyanomethyl)-
11-methyl[methyl-[rac-(2S)
amino[[2-[4- R
H N O
(cyclohexoxy)phenyl]-4,6-dimethyl- O OH
pyrimidine
N N CN
O HN
carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo-3,18-bis[rac-(2R)
aminohydroxy-propoxy]-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
569 rac-(8S,11S,14S)-N-(cyanomethyl)-
11-methyl[methyl-[rac-(2S)
amino[[2-(4-isopropoxyphenyl)- O
H N O
4,6-dimethyl-pyrimidine
carbonyl]amino]butanoyl]amino]- H
N N CN
O HN
,13-dioxo-3,18-bis[rac-(2R)
N N N O
aminohydroxy-propoxy]-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
570 rac-(8S,11S,14S)-N-(cyanomethyl)-
11-methyl[methyl-[rac-(2S)
amino[[2-(4-tert-butylphenyl)-
H N O
4,6-dimethyl-pyrimidine
carbonyl]amino]butanoyl]amino]-
N N CN
,13-dioxo-3,18-bis[rac-(2S) O HN
N N N O
aminohydroxy-propoxy]-9,12- S S
( ) ( )
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
571 rac-(8S,11S,14S)(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
H N O
amino[[2-(4-tert-butylphenyl)-
4,6-dimethyl-pyrimidine
N N CN
O HN
carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo[rac-(2R)amino-
2-hydroxy-propoxy]-9,12-
diazatricyclo[13.3.1.12,6]icosa- 2
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
572 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)[[2-
(4-tert-butylphenyl)-4,6-dimethyl-
pyrimidinecarbonyl]amino]
N N CN
O HN
(sulfamoylamino)propanoyl]amino]- H
N N N O
(S) (S)
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene- O S O
8-carboxamide
573 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl-10,13-dioxo[[rac-(2S)
[[2-[4-(cyclohexoxy)phenyl]-4,6-
dimethyl-pyrimidine
O HN
N N N O
carbonyl]amino]
(sulfamoylamino)propanoyl]amino]-
9,12-diazatricyclo[13.3.1.12,6]icosa- NH
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
574 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)[[2-
(4-tert-butylphenyl)-4,6-dimethyl-
pyrimidinecarbonyl]amino]
N N CN
O HN
(sulfamoylamino)butanoyl]amino]-
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
HN NH
1(18),2(20),3,5,15(19),16-hexaene- 2
8-carboxamide
575 rac-(8S,11S,14S)-3,18-bis(3-
aminopropoxy)-N-(cyanomethyl)- O
11-methyl[methyl-[rac-(2S)
[[2-(4-tert-butylphenyl)-4,6- H
N N CN
O HN
dimethyl-pyrimidine
N N N O
carbonyl]amino]
(sulfamoylamino)propanoyl]amino]- O O
,13-dioxo-9,12-
O S NH
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
576 rac-(8S,11S,14S)-3,18-bis(3-
aminopropoxy)-N-(cyanomethyl)-
11-methyl[methyl-[rac-(2S)
H N O
[[2-[4-(cyclohexoxy)phenyl]-4,6-
dimethyl-pyrimidine
N N CN
O HN
carbonyl]amino]
N N N O
(S) (S)
(sulfamoylamino)propanoyl]amino]-
,13-dioxo-9,12-
O S O
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
577 rac-(8S,11S,14S)-N-(cyanomethyl)-
11-methyl[methyl-[rac-(2S)
[[2-(4-tert-butylphenyl)-4,6-
H N O
dimethyl-pyrimidine
carbonyl]amino]
N N CN
O HN
(sulfamoylamino)propanoyl]amino]-
N N N O
,13-dioxo-3,18-bis[rac-(2R)
aminohydroxy-propoxy]-9,12- O O
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene- O
8-carboxamide
578 rac-(8S,11S,14S)-N-(cyanomethyl)-
11-methyl[methyl-[rac-(2S) OH
[[2-[4-(cyclohexoxy)phenyl]-4,6-
H N O
O OH
dimethyl-pyrimidine
carbonyl]amino] N N CN
(sulfamoylamino)propanoyl]amino]-
N N N O
,13-dioxo-3,18-bis[rac-(2R)
aminohydroxy-propoxy]-9,12-
O S NH
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
579 rac-(8S,11S,14S)-N-(cyanomethyl)-
11-methyl[methyl-[rac-(2S)
[[2-(4-isopropoxyphenyl)-4,6- (R)
H N O
dimethyl-pyrimidine
O OH
carbonyl]amino]
N N CN
O HN
(sulfamoylamino)propanoyl]amino]-
N N N O
,13-dioxo-3,18-bis[rac-(2R)
aminohydroxy-propoxy]-9,12-
H N S O
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
580 rac-(8S,11S,14S)-N-(cyanomethyl)-
11-methyl[methyl-[rac-(2S)
[[2-(4-tert-butylphenyl)-4,6- O
H N O
dimethyl-pyrimidine
carbonyl]amino]
N N CN
(sulfamoylamino)butanoyl]amino]-
N N N O
,13-dioxo-3,18-bis[rac-(2R) N O
aminohydroxy-propoxy]-9,12-
diazatricyclo[13.3.1.12,6]icosa- HN
1(18),2(20),3,5,15(19),16-hexaene- O O
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
8-carboxamide
581 rac-(8S,11S,14S)-N-(cyanomethyl)-
11-methyl[methyl-[rac-(2S)
[[2-(4-tert-butylphenyl)-4,6-
H N O
dimethyl-pyrimidine
carbonyl]amino] H
N N CN
O HN
(sulfamoylamino)propanoyl]amino]-
N N N O
,13-dioxo-3,18-bis[rac-(2S)
aminohydroxy-propoxy]-9,12-
diazatricyclo[13.3.1.12,6]icosa-
H N S O
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
582 rac-(8S,11S,14S)-N-(cyanomethyl)-
H N NH
18-hydroxymethyl[methyl- (R)
[rac-(2S)[[2-(4-tert-butylphenyl)-
HO OH
4,6-dimethyl-pyrimidine O
carbonyl]amino]
N N CN
(sulfamoylamino)propanoyl]amino]- H
N N N O
,13-dioxo-3,17-bis[rac-(2R)
aminohydroxy-propoxy]-9,12-
O S NH
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
583 (8S,11S,14S)[[(2S)amino
[[2-(4-tert-butylphenyl)-4,6-
dimethyl-pyrimidine
carbonyl]amino]butanoyl]-methyl- O
amino]-3,17-bis(2-aminoethoxy)-N-
N N CN
O HN
(cyanomethyl)hydroxy H
N N N O
methyl-10,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
584 rac-(8S,11S,14S)-3,17-bis(2-
aminoethoxy)-N-(cyanomethyl)
hydroxymethyl[methyl-[rac-
(2S)[[2-(4-tert-butylphenyl)-4,6-
N N CN
O HN
dimethyl-pyrimidine
N N N O
carbonyl]amino]
(sulfamoylamino)propanoyl]amino]-
O S NH
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
585 rac-(8S,11S,14S)-3,17-bis(2-
aminoethoxy)-N-(cyanomethyl)
methoxymethyl[methyl-
[rac-(2S)[[2-(4-tert-butylphenyl)-
N N CN
O HN
4,6-dimethyl-pyrimidine
N N N O
carbonyl]amino]
(sulfamoylamino)propanoyl]amino]- O O
,13-dioxo-9,12-
O S NH
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
8-carboxamide
586 rac-(8S,11S,14S)-N-(cyanomethyl)-
H N NH
18-methoxymethyl[methyl-
[rac-(2S)amino[[2-(4-tert-
butylphenyl)-4,6-dimethyl-
pyrimidine
N N CN
O HN
carbonyl]amino]butanoyl]amino]- H
N N N O
,13-dioxo-3,17-bis[rac-(2R)
aminohydroxy-propoxy]-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
587 rac-(8S,11S,14S)(2-
aminoethoxy)-N-(cyanomethyl)
hydroxymethyl[methyl-[rac-
(2S)amino[[2-(4-tert-
butylphenyl)-4,6-dimethyl- 2
N N CN
pyrimidine
O HN
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo[rac-(2R)amino
hydroxy-propoxy]-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
588 rac-(8S,11S,14S)(2-
aminoethoxy)-N-(cyanomethyl)
hydroxymethyl[methyl-[rac-
HO OH
(2S)amino[[2-(4-tert-
butylphenyl)-4,6-dimethyl- N N CN
O HN
pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo[rac-(2R)amino-
2-hydroxy-propoxy]-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
589 rac-(8S,11S,14S)(2-
aminoethoxy)(2-
aminoethylamino)-N-(cyanomethyl)-
18-hydroxymethyl[methyl-
N N CN
[rac-(2S)amino[[2-(4-tert- H
N N N O
butylphenyl)-4,6-dimethyl-
pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
590 rac-(8S,11S,14S)(2- 2
aminoethoxy)-N-(cyanomethyl)
H N NH OH
(2-guanidinoethoxy)hydroxy O
methyl[methyl-[rac-(2S)[[2-
N N CN
O HN
(4-tert-butylphenyl)-4,6-dimethyl-
N N N O
pyrimidinecarbonyl]amino]
(sulfamoylamino)propanoyl]amino]-
O S NH
,13-dioxo-9,12- 2
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
2 (R)
591 rac-(8S,11S,14S)-N-(cyanomethyl)-
O NH
O OH
3,18-dimethoxymethyl
HO O
[methyl-[rac-(2S)amino[[2-(4-
tert-butylphenyl)-4,6-dimethyl-
N N CN
O HN
pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]- N O
,13-dioxo-4,17-bis[rac-(2R)
aminohydroxy-propoxy]-9,12- NH
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
592 rac-(8S,11S,14S)-4,17-bis(2-
NH O
aminoethoxy)-N-(cyanomethyl)-
3,18-dimethoxymethyl
[methyl-[rac-(2S)amino[[2-(4-
N N CN
O HN
tert-butylphenyl)-4,6-dimethyl- H
N N N O
pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12- 2
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
593 rac-(8S,11S,14S)-N-(cyanomethyl)-
O NH
O OH
3,18-dimethoxymethyl
HO O
[methyl-[rac-(2S)[[2-(4-tert-
butylphenyl)-4,6-dimethyl-
pyrimidinecarbonyl]amino] H
N N N O
(sulfamoylamino)propanoyl]amino]-
,13-dioxo-4,17-bis[rac-(2R)
O S O
aminohydroxy-propoxy]-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
594 rac-(8S,11S,14S)(2-
aminoethoxy)-N-(cyanomethyl)
H N O
hydroxymethyl[methyl-[rac-
(2S)amino[[2-(4-tert-
N N CN
butylphenyl)-4,6-dimethyl-
N N N O
pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo[rac-(2R)amino-
2-hydroxy-propoxy]-9,12-
diazatricyclo[13.3.1.12,6]icosa-
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
HN NH
595 rac-(8S,11S,14S)-N-(cyanomethyl)-
18-(2-guanidinoethoxy)hydroxy- HN HO
11-methyl[methyl-[rac-(2S)
amino[[2-(4-tert-butylphenyl)-
N N CN
O HN
4,6-dimethyl-pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
596 rac-(8S,11S,14S)-N-(cyanomethyl)-
H N N O
18-(3-guanidinopropoxy)
hydroxymethyl[methyl-[rac-
N N CN
(2S)amino[[2-(4-tert-
O HN
butylphenyl)-4,6-dimethyl- N N N
pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
597 rac-(8S,11S,14S)(3-
aminopropoxy)-N-(cyanomethyl)-
18-hydroxymethyl[methyl-
[rac-(2S)amino[[2-(4-tert-
O NH
butylphenyl)-4,6-dimethyl-
N NH NH O
pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12- NH
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
H N O
598 rac-(8S,11S,14S)(3-
aminopropoxy)-N-(cyanomethyl)
hydroxymethyl[methyl-[rac- HN
N N N O
(2S)amino[[4,6-dimethyl(4-
pentoxyphenyl)pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
599 rac-(8S,11S,14S)[2-
[carbamimidoyl(methyl)amino]ethox
y]-N-(cyanomethyl)hydroxy
methyl[methyl-[rac-(2S)
amino[[2-(4-tert-butylphenyl)-
O HN
4,6-dimethyl-pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
8-carboxamide
600 rac-(8S,11S,14S)-N-(cyanomethyl)-
N HO
3-hydroxymethyl[2-
(methylamino)ethoxy][methyl-
N N CN
[rac-(2S)amino[[2-(4-tert- O
N N N O
butylphenyl)-4,6-dimethyl-
pyrimidine O O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
601 rac-(8S,11S,14S)[2-(2-
H N O
aminoethylamino)ethoxy]-N-
(cyanomethyl)hydroxy
N N CN
O HN
methyl[methyl-[rac-(2S)
N N N O
amino[[2-(4-tert-butylphenyl)-
4,6-dimethyl-pyrimidine O O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
602 rac-(8S,11S,14S)[2-(3-
H N N HO
aminopropylamino)ethoxy]-N-
(cyanomethyl)hydroxy
N N CN
methyl[methyl-[rac-(2S)
O HN
N N N O
amino[[2-(4-tert-butylphenyl)-
4,6-dimethyl-pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
HN N HO
603 rac-(8S,11S,14S)-N-(cyanomethyl)-
18-[2-(ethanimidoylamino)ethoxy]-
3-hydroxymethyl[methyl- H
O HN
[rac-(2S)amino[[2-(4-tert-
N N N O
butylphenyl)-4,6-dimethyl- O
pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
604 rac-(8S,11S,14S)(azetidin
yloxy)-N-(cyanomethyl)hydroxy-
11-methyl[methyl-[rac-(2S)
N N CN
amino[[2-(4-tert-butylphenyl)-
O HN
N N N O
4,6-dimethyl-pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
8-carboxamide
605 rac-(8S,11S,14S)(azetidin
yloxy)-N-(cyanomethyl)
hydroxymethyl[methyl-[rac-
(2S)amino[[2-(4-tert-
butylphenyl)-4,6-dimethyl-
N N CN
O HN
pyrimidine H
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
606 rac-(8S,11S,14S)(2-amino
methyl-ethoxy)-N-(cyanomethyl)-
18-hydroxymethyl[methyl-
[rac-(2S)amino[[2-(4-tert-
N N CN
butylphenyl)-4,6-dimethyl-
O HN
pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
607 rac-(8S,11S,14S)(2-amino
H N HO
methyl-ethoxy)-N-(cyanomethyl)
hydroxymethyl[methyl-[rac-
(2S)amino[[2-(4-tert- N N CN
O HN
butylphenyl)-4,6-dimethyl-
N N N O
pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
608 rac-(8S,11S,14S)-N-(cyanomethyl)-
3-hydroxymethyl[methyl-
[rac-(2S)amino[[2-(4-tert-
butylphenyl)-4,6-dimethyl-
N N CN
O HN
pyrimidine H
N N N
carbonyl]amino]butanoyl]amino]-
,13-dioxo(4-piperidyloxy)-
9,12-diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
609 rac-(8S,11S,14S)-N-(cyanomethyl)-
18-hydroxymethyl[methyl-
[rac-(2S)amino[[2-(4-tert-
butylphenyl)-4,6-dimethyl-
pyrimidine
N N CN
carbonyl]amino]butanoyl]amino]-
O HN
N N N O
,13-dioxo(4-piperidyloxy)- (S)
9,12-diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
610 rac-(8S,11S,14S)[3-amino
(aminomethyl)propoxy]-N- 2
(cyanomethyl)hydroxy
methyl[methyl-[rac-(2S)
amino[[2-(4-tert-butylphenyl)- H
N N CN
O HN
4,6-dimethyl-pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
611 rac-(8S,11S,14S)[3-amino
H N O
(aminomethyl)propoxy]-N-
(cyanomethyl)hydroxy
N N CN
O HN
methyl[methyl-[rac-(2S) H
N N N O
amino[[2-(4-tert-butylphenyl)-
4,6-dimethyl-pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
612 rac-(8S,11S,14S)-N-(cyanomethyl)-
18-hydroxymethyl[methyl-
[rac-(2S)amino[[2-(4-tert-
butylphenyl)-4,6-dimethyl-
pyrimidine
carbonyl]amino]butanoyl]amino]-
O HN
N N N O
,13-dioxo[rac-(2R)amino
hydroxy-propoxy]-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
613 rac-(8S,11S,14S)-N-(cyanomethyl)-
18-hydroxymethyl[methyl-
[rac-(2S)amino[[2-(4-tert-
butylphenyl)-4,6-dimethyl-
pyrimidine
N N CN
carbonyl]amino]butanoyl]amino]-
,13-dioxo[rac-(2S)amino
N N N O
hydroxy-propoxy]-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
614 rac-(8S,11S,14S)-N-(cyanomethyl)-
18-hydroxymethyl[methyl- (R)
[rac-(2S)amino[[2-(4-tert-
butylphenyl)-4,6-dimethyl-
pyrimidine
N N CN
O HN
carbonyl]amino]butanoyl]amino]-
N N N
,13-dioxo[rac-(2R)amino N O
hydroxy-propoxy]-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
8-carboxamide
H N HO
615 rac-(8S,11S,14S)(2-
aminoethoxy)-N-(cyanomethyl)
hydroxymethyl[methyl-[rac- CN
O HN
(2S)[[2-[4-(cyclohexoxy)phenyl]-
N N N O
4,6-dimethyl-pyrimidine
carbonyl]amino]
(sulfamoylamino)butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
616 rac-(8S,11S,14S)(2-
aminoethoxy)-N-(cyanomethyl)
hydroxymethyl[methyl-[rac- OH
(2S)[[2-[4-(cyclohexoxy)phenyl]-
N N CN
4,6-dimethyl-pyrimidine
O HN
carbonyl]amino] N N N
(sulfamoylamino)propanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
617 rac-(8S,11S,14S)-N-(cyanomethyl)-
H N O
3-hydroxymethyl[methyl-
[rac-(2S)amino[[2-(4-tert-
N N CN
O HN
butylphenyl)-4,6-dimethyl- H H
N N N O
pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo[rac-(2R)amino-
2-hydroxy-propoxy]-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
618 rac-(8S,11S,14S)(2-
HN NH
aminoethoxy)-N-(cyanomethyl)
hydroxymethyl[methyl-[rac- O
(2S)amino[[2-(4-tert-
butylphenyl)-4,6-dimethyl- N N CN
O HN
pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxoureido-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
NH O
619 rac-(8S,11S,14S)-3,18-bis(2-
HN NH
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
amino[[2-(4-tert-butylphenyl)-
4,6-dimethyl-pyrimidine
O HN
carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxoureido-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene218-
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
8-carboxamide
620 rac-(8S,11S,14S)acetamido
(2-aminoethoxy)-N-(cyanomethyl)-
18-hydroxymethyl[methyl-
[rac-(2S)amino[[2-(4-tert-
butylphenyl)-4,6-dimethyl-
N O N CN
O HN
pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
621 rac-(8S,11S,14S)(2-
aminoethoxy)-N-(cyanomethyl)
hydroxymethyl[methyl-[rac-
H N N
(2S)amino[[2-(4-tert-
butylphenyl)-4,6-dimethyl-
N O CN
O HN
pyrimidine
N N N O
carbonyl]amino]butanoyl]amino]-
,13-dioxoureido-9,12-
diazatricyclo[13.3.1.12,6]icosa- 2
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
622 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N O
methyl[methyl-[rac-(2S)
H N N
amino[[2-(4-tert-butylphenyl)-
4,6-dimethyl-pyrimidine
N O N CN
O HN
carbonyl]amino]butanoyl]amino]- H
N N N O
,13-dioxoureido-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
N N CN
O HN
N N N O
H N H N
624 rac-(8S,11S,14S)amino(2-
aminoethoxy)-N-(cyanomethyl)
methyl[methyl-[rac-(2S)
N N CN
O HN
amino[[2-(4-tert-butylphenyl)- H
N N N O
4,6-dimethyl-pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
H N MeO OH
625 rac-(8S,11S,14S)(2-
aminoethoxy)-N-(cyanomethyl)
hydroxymethoxymethyl
N N CN
O HN
[methyl-[rac-(2S)amino[[2-(4-
N N N O
tert-butylphenyl)-4,6-dimethyl-
pyrimidine
carbonyl]amino]butanoyl]amino]- 2
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
626 rac-(8S,11S,14S)(2-
H N HO
aminoethoxy)(aminomethyl)-N-
(cyanomethyl)hydroxy
N CN
methyl[methyl-[rac-(2S)
O HN
amino[[2-(4-tert-butylphenyl)-
N N N O
4,6-dimethyl-pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
627 rac-(8S,11S,14S)-5,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N MeO
methoxymethyl[methyl-
[rac-(2S)[[2-(4-tert-butylphenyl)-
N N CN
4,6-dimethyl-pyrimidine
O HN
carbonyl]amino]
N N N O
(sulfamoylamino)propanoyl]amino]-
,13-dioxo-9,12-
O S NH
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
628 rac-(8S,11S,14S)-5,18-bis(2-
aminoethoxy)-N-(cyanomethyl)
H N HO O
hydroxymethyl[methyl-[rac-
(2S)[[2-(4-tert-butylphenyl)-4,6-
N N CN
dimethyl-pyrimidine
O HN
carbonyl]amino] N N N O
(sulfamoylamino)propanoyl]amino]-
,13-dioxo-9,12-
O S NH
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
629 rac-(8S,11S,14S)(2- 2
aminoethoxy)(aminomethyl)-N-
(cyanomethyl)hydroxy
methyl[methyl-[rac-(2S)[[2-
N CN
O HN
(4-tert-butylphenyl)-4,6-dimethyl-
N N N O
pyrimidinecarbonyl]amino]
(sulfamoylamino)propanoyl]amino]- NH
O S NH
,13-dioxo-9,12- 2
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
8-carboxamide
630 (8S,11S,14S)[[(2S)amino
[[2-(4-tert-butylphenyl)-4,6-
Chiral
dimethyl-pyrimidine
carbonyl]amino]butanoyl]-methyl-
O HN
amino](2-aminoethylamino)-N-
N N N O
(cyanomethyl)hydroxy
methoxymethyl-10,13-dioxo-
9,12-diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
H N HO
631 (8S,11S,14S)amino[[(2S)
Chiral
amino[[2-(4-tert-butylphenyl)-
4,6-dimethyl-pyrimidine
O HN
carbonyl]amino]butanoyl]-methyl-
N N N O
amino](2-aminoethoxy)-N-
(cyanomethyl)hydroxy
methyl-10,13-dioxo-9,12- 2
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
632 (8S,11S,14S)[[(2S)amino
[[2-(4-tert-butylphenyl)-4,6-
Chiral
dimethyl-pyrimidine
carbonyl]amino]butanoyl]-methyl-
O HN
amino](2-aminoethoxy)-N-
N N N O
(cyanomethyl)-3,18-dihydroxy
methyl-10,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
H N HO
633 (8S,11S,14S)[[(2S)amino
Chiral
[[2-(4-tert-butylphenyl)-4,6-
dimethyl-pyrimidine
O HN
carbonyl]amino]butanoyl]-methyl-
N N N O
amino]-17,18-bis(2-aminoethoxy)-
N-(cyanomethyl)hydroxy
methyl-10,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
634 rac-(8S,11S,14S)(2-
aminoethoxy)(aminomethyl)-N-
(cyanomethyl)methyl
[methyl-[rac-(2S)amino[[2-(4-
tert-butylphenyl)-4,6-dimethyl-
O HN
pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa- 2
1(18),2,4,6(20),15(19),16-hexaene-
8-carboxamide
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
635 rac-(8S,11S,14S)(2- 2
aminoethoxy)(aminomethyl)-N-
(cyanomethyl)hydroxy
methyl[methyl-[rac-(2S)
O HN
amino[[2-(4-tert-butylphenyl)-
N N N
4,6-dimethyl-pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
636 rac-(8S,11S,14S)(2- 2
aminoethoxy)(3-aminopropyl)-
N-(cyanomethyl)hydroxy
methyl[methyl-[rac-(2S)
O HN
amino[[2-(4-tert-butylphenyl)-
N N N O
4,6-dimethyl-pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12- 2
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
637 rac-(8S,11S,14S)(2-
aminoethoxy)(3-aminopropyl)-
N-(cyanomethyl)hydroxy
methyl[methyl-[rac-(2S)[[2-
(4-tert-butylphenyl)-4,6-dimethyl-
N N N O
pyrimidinecarbonyl]amino]
(sulfamoylamino)propanoyl]amino]- NH
O S NH
,13-dioxo-9,12- 2
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxamide
In one aspect described herein are compounds of Formula (V):
(R )q
27 6
(R )
18 16
Z X N
17 9
O R R
11 12
Formula (V);
wherein:
18253141_1 (GHMatters) P111789.NZ
1 2 23
R and R are each independently H, -(C -C )alkyl, -(C -C )alkyl-OR , -CH CH(OH)CH NH , -
1 6 1 6 2 2 2
CH CH(heterocycloalkyl)CH NH , -CH C(O)NH , -CH C(O)N(H)CH CN, -(C -C )alkyl-C(O)OR , -
2 2 2 2 2 2 2 1 6
21 22 25 26 23 21 22
(C -C )alkyl-NR R , -(C -C )alkyl-C(O)NR R , -(C -C )alkyl-N(R )C(O)(C -C )alkylNR R , -
1 6 1 6 1 6 1 6
23 23
(C -C )alkyl-N(R )C(O)(C -C )alkyl, -(C -C )alkyl-C(O)N(R )(C -C )alkyl, -(C -C )alkyl-
1 6 1 6 1 6 1 6 1 6
23 23 21 22
C(O)N(R )(C -C )alkyl-heterocycloalkyl, -(C -C )alkyl-NR C(=NH)NR R , -(C -C )alkyl-
1 6 1 6 1 6
23 23 21 22
NR C(=NH)R , -(C -C )alkyl-[(C -C )alkyl-NR R ] , -(C -C )heteroalkyl, or optionally substituted
1 6 1 6 2 1 6
heterocycloalkyl;
or R and R and the atoms to which they are attached form an optionally substituted heterocycloalkyl ring;
6 7 8
R , R , and R are each independently H, fluoro, hydroxyl, amino, optionally substituted alkyl,heteroalkyl,
or -(C -C )alkyl;
R is H, -(C -C )alkyl, -(C -C )haloalkyl, or -(C -C )cycloalkyl;
1 6 1 6 3 6
R is H, -(C -C )alkyl, -(C -C )haloalkyl, or -(C -C )cycloalkyl;
1 6 1 6 3 6
9 10
or R and R are combined to form a heterocycloalkyl or cycloalkyl ring
11 12 23 23
R and R are each independently H, -NH , -(C -C )alkyl, -(C -C )alkyl-OR , -(C -C )alkyl-SR , -(C -
2 1 6 1 6 1 6 1
23 21 22 23 23
C )alkyl-C(O)OR , -(C -C )alkyl-NR R , -(C -C )alkyl-NR OR , -(C -C )alkyl-
6 1 6 1 6 1 6
23 23 25 26
NHC(O)NR OR , -(C -C )alkyl-O-(C -C )alkyl-NR R , -(C -C )alkyl-CN, -(C -C )alkyl-
1 6 1 6 1 6 1 6
23 23 25 26
NR C(O)R , -(C -C )alkyl-C(O)NR R , -(C -C )heteroalkyl-CO H, -(C -C )alkyl-S(O)(C -C )alkyl,
1 6 1 6 2 1 6 1 6
-(C -C )alkyl-N(H)CH=NH, -(C -C )alkyl-C(NH )=NH, -(C -C )alkyl-N(H)C(=NH)NH , -(C -
1 6 1 6 2 1 6 2 1
26 25 26
C )alkyl-N(H)S(O) NR R , -(C -C )alkyl-N(H)S(O) (C -C )alkyl, -(C -C )alkyl-N(H)-C(O)NR R ,
6 2 1 6 2 1 6 1 6
-(C -C )alkylC(O)N(H)[optionally substituted(C -C )alkyl]-OR , -(C -C )alkylN(H)C(O)(C -
1 6 2 6 1 6 1
23 25 26
C )alkyl-OR , -(C -C )alkylC(O)N(H)heterocycloalkyl, -(C -C )alkylC(O)NR R , -(C -C )alkyl-
6 1 6 1 6 1 6
26 25 26
N(H)-C(O)-(C -C )alkyl-NR R , -(C -C )alkyl-N(H)-(C -C )alkylC(O)NR R , -(C -C )alkyl-
1 6 1 6 1 6 1 6
-C )alkyl-N(H)heterocycloalkyl, or -(C -C )alkyl-
heterocycloalkyl, optionally substituted -(C
1 6 1 6
heteroaryl;
11 18 12
or R and R are combined to form an optionally substituted heterocycloalkyl ring; and R is H;
16 17 18 23
R , R , R , and R are each independently H, -(C -C )alkyl, -(C -C )cycloalkyl, -(C -C )alkyl-OR , -
1 6 3 6 1 6
23 21 22
(C -C )alkyl-C(O)OR , or -(C -C )alkyl-NR R ;
1 6 1 6
X is optionally substituted heteroaryl;
Y is a bond, -O-, -S-, optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, -(C -
1 6 2 6 2 6 1
24 24 24
C )alkyl-N(R )(C -C )alkyl-, -O-(C -C )alkyl-, -O(C -C )aryl-, -N(R )(C -C )alkyl-, -N(R )SO (C -
6 1 6 1 6 6 10 1 6 2 1
C )alkyl-, -N(R )C(O)(C -C )alkyl-, -C(O)(C -C )alkyl-, -S(C -C )alkyl-, -SO (C -C )alkyl-, -
6 1 6 1 6 1 6 2 1 6
C(O)NH(C -C )alkyl-, optionally substituted -(C -C )cycloalkyl-, optionally substituted -
1 6 3 7
24 24 24
C(O)N(R )aryl-, optionally substituted -N(R )C(O)aryl-, optionally substituted -N(R )SO aryl-,
optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Z is H, halogen, -NH , -CN, -CF , -CO H, -(C -C )alkyl, -(C -C )alkenyl, -CH=((C -C )cycloalkyl), -
2 3 2 1 12 2 12 3 7
26
(C -C )alkynyl, -C(O)NR R , -O-(C -C )alkyl, -S-(C -C )alkyl, -O-(C -C )[optionally substituted
2 12 1 12 1 12 3 10
23 23
(C -C )cycloalkyl], -O-(C -C )alkyl-OR , -(C -C )alkyl-OR , -(C -C )alkyl-CN, -S-(C -C )alkyl, -
3 7 1 6 1 12 1 12 1 12
18253141_1 (GHMatters) P111789.NZ
24 24
N(R )(C -C )alkyl, -N(R )C(O)(C -C )alkyl, optionally substituted -(C -C )cycloalkyl, -(C -
1 12 1 12 3 7 1
C )alkyl-(C -C )cycloalkyl, -(C -C )alkyl-heterocycloalkyl, optionally substituted heterocycloalkyl,
6 3 7 1 6
optionally substituted aryl, or optionally substituted heteroaryl;
21 22
each R and R is independently H, -(C -C )alkyl, -(C -C )heteroalkyl, -(C -C )alkyl-CO H, -C(O)(C -
1 6 1 6 1 6 2 1
C )alkyl, -C(O)O(C -C )alkyl, -C(O)O(C -C )haloalkyl, -C(=NH)(C -C )alkyl, -C(=NH)N(R ) , -
6 1 6 1 6 1 6 2
31 31 21 22
C(O)N(R ) , or -SO N(R ) ; or R and R and the nitrogen atom to which they are attached form a
2 2 2
heterocycloalkyl ring;
31 31
each R is independently H or -(C -C )alkyl; or two R and the nitrogen atom to which they are attached
form a heterocycloalkyl ring;
each R is independently H or -(C -C )alkyl;
each R is independently H or -(C -C )alkyl;
26
each R and R is independently H or optionally substituted -(C -C )alkyl;
26
or R and R and the nitrogen atom to which they are attached form a heterocycloalkyl ring;
27 23 24 23 23 24
each R is independently halogen, -NR R , -NHC(O)R , -NHC(O)NR R , nitro, hydroxyl, optionally
substituted -(C -C )alkyl, optionally substituted -(C -C )heteroalkyl, optionally substituted -(C -
1 6 1 6 1
C )heteroalkyloxy, optionally substituted -(C -C )heteroalkylamino, -(C -C )alkoxy, -C(O)(C -
6 1 6 1 6 1
C )alkyl, or -S(O) (C -C )alkyl;
6 2 1 6
1 27
or R and R and the atoms to which they are attached form an optionally substituted 5- or 6-membered
heterocycloalkyl ring;
28 23 24 23 23 24
each R is independently halogen, -NR R , -NHC(O)R , -NHC(O)NR R , nitro, hydroxyl, optionally
substituted -(C -C )alkyl, optionally substituted -(C -C )heteroalkyl, optionally substituted -(C -
1 6 1 6 1
C )heteroalkyloxy, optionally substituted -(C -C )heteroalkylamino, -(C -C )alkoxy, -C(O)(C -
6 1 6 1 6 1
)alkyl, or -S(O) (C -C )alkyl;
6 2 1 6
2 28
or R and R and the atoms to which they are attached form an optionally substituted 5- or 6-membered
heterocycloalkyl ring;
p is 0, 1, or 2; and
q is 0, 1, or 2;
or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
6 7 8
In one embodiment is a compound of Formula (V) wherein R , R , and R are H.
16
[00430] In another embodiment is a compound of Formula (V) wherein R and R are H.
In one embodiment is a compound of Formula (V) wherein R is -(C -C )alkyl. In another
embodiment is a compound of Formula (V) wherein R is -CH . In another embodiment is a compound of
17 17
Formula (V) wherein R is -CH CH . In another embodiment is a compound of Formula (V) wherein R
is -(C -C )cycloalkyl. In another embodiment is a compound of Formula (V) wherein R is cyclopropyl.
17 23
In another embodiment is a compound of Formula (V) wherein R is -(C -C )alkyl-C(O)OR . In another
embodiment is a compound of Formula (V) wherein R is -CH CH OH. In another embodiment is a
17 21 22
compound of Formula (V) wherein R is -(C -C )alkyl-NR R . In another embodiment is a compound of
18253141_1 (GHMatters) P111789.NZ
Formula (V) wherein R is -CH CH NH . In another embodiment is a compound of Formula (V) wherein
2 2 2
R is H.
In another embodiment is a compound of Formula (V) wherein R is H.
In another embodiment is a compound of Formula (V) wherein R is H.
9
[00434] In another embodiment is a compound of Formula (V) wherein R is H and R is -(C -C )alkyl.
9
In another embodiment is a compound of Formula (V) wherein R is H and R is -CH . In another
9
embodiment is a compound of Formula (V) wherein R is H and R is -CH CH . In another embodiment
9
is a compound of Formula (V) wherein R is H and R is -(C -C )haloalkyl. In another embodiment is a
9
compound of Formula (V) wherein R is H and R is -CH F. In another embodiment is a compound of
9
Formula (V) wherein R is H and R is -CHF . In another embodiment is a compound of Formula (V)
9
wherein R is H and R is -(C -C )cycloalkyl. In another embodiment is a compound of Formula (V)
9 10
wherein R is H and R is cyclopropyl. In another embodiment is a compound of Formula (V) wherein R
is H and R is H.
In another embodiment is a compound of Formula (V) wherein R is H.
12 11
[00436] In another embodiment is a compound of Formula (V) wherein R is H and R is -(C -C )alkyl.
12 11
In another embodiment is a compound of Formula (V) wherein R is H and R is -CH . In another
12 11 23
embodiment is a compound of Formula (V) wherein R is H and R is -(C -C )alkyl-OR . In another
12 11
embodiment is a compound of Formula (V) wherein R is H and R is -CH OH. In another embodiment
12 11
is a compound of Formula (V) wherein R is H and R is -CH CH OH. In another embodiment is a
12 11
compound of Formula (V) wherein R is H and R is -(C -C )alkyl. In another embodiment is a
12 11 21 22
compound of Formula (V) wherein R is H and R is -(C -C )alkyl-NR R . In another embodiment is a
12 11
compound of Formula (V) wherein R is H and R is -(C -C )alkyl-NH . In another embodiment is a
1 6 2
12 11
compound of Formula (V) wherein R is H and R is -CH NH . In another embodiment is a compound of
12 11
Formula (V) wherein R is H and R is -CH CH NH . In another embodiment is a compound of Formula
2 2 2
12 11
(V) wherein R is H and R is -CH CH CH NH . In another embodiment is a compound of Formula (V)
2 2 2 2
12 11
wherein R is H and R is -CH CH CH CH NH . In another embodiment is a compound of Formula (V)
2 2 2 2 2
12 11
wherein R is H and R is -(C -C )alkyl-CN. In another embodiment is a compound of Formula (V)
12 11 12
wherein R is H and R is -CH CN. In another embodiment is a compound of Formula (V) wherein R is
11 25 26
H and R is -(C -C )alkyl-C(O)NR R . In another embodiment is a compound of Formula (V) wherein
12 11 12
R is H and R is -CH C(O)NH . In another embodiment is a compound of Formula (V) wherein R is H
11 12
and R is -CH CH C(O)NH . In another embodiment is a compound of Formula (V) wherein R is H and
2 2 2
11 25 26
R is -(C -C )alkyl-N(H)S(O) NR R . In another embodiment is a compound of Formula (V) wherein
1 6 2
12 11
R is H and R is –CH N(H)S(O) NH . In another embodiment is a compound of Formula (V) wherein
2 2 2
12 11
R is H and R is -(C -C )alkyl-heteroaryl.
12 11
[00437] In another embodiment is a compound of Formula (V) wherein R is H and R is H.
11 18
In another embodiment is a compound of Formula (V) wherein R and R are combined to
form an optionally substituted heterocycloalkyl ring and R is H.
18253141_1 (GHMatters) P111789.NZ
In another embodiment is a compound of Formula (V) wherein p is 1 and R is halogen. In
another embodiment is a compound of Formula (V) wherein p is 1 and R is optionally substituted -(C -
C )alkyl. In another embodiment is a compound of Formula (V) wherein q is 0, p is 1 and R is halogen.
In another embodiment is a compound of Formula (V) wherein q is 0, p is 1 and R is optionally
substituted -(C -C )alkyl. In another embodiment is a compound of Formula (V) wherein q is 1 and R is
halogen. In another embodiment is a compound of Formula (V) wherein q is 1 and R is optionally
substituted -(C -C )alkyl. In another embodiment is a compound of Formula (V) wherein p is 0, q is 1 and
28 28
R is halogen. In another embodiment is a compound of Formula (V) wherein p is 0, q is 1 and R is
optionally substituted -(C -C )alkyl.
[00440] In another embodiment is a compound of Formula (V) wherein p is 0, and q is 0.
In another embodiment is a compound of Formula (V) wherein R and R are each
21 22
independently H or -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (V) wherein
1 2 1 2
R and R are each H. In another embodiment is a compound of Formula (V) wherein R and R are each
21 22 1
independently -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (V) wherein R is
2 21 22 1
H, and R is -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (V) wherein R is -
21 22 2 1
(C -C )alkyl-NR R , and R is H. In another embodiment is a compound of Formula (V) wherein R is H,
and R is -CH CH NH . In another embodiment is a compound of Formula (V) wherein R is -
2 2 2
2 1 2
CH CH NH , and R is H. In another embodiment is a compound of Formula (V) wherein R and R are
2 2 2
each -CH CH NH . In a further embodiment is a compound of Formula (V) wherein R is -(C -C )alkyl-
2 2 2 1 6
21 22 2 1
NR R and R is H. In a further embodiment is a compound of Formula (V) wherein R is -CH CH NH
2 2 2
2 1 2
and R is H. In a further embodiment is a compound of Formula (V) wherein R is H and R is -(C -
21 22 1 2
C )alkyl-NR R . In a further embodiment is a compound of Formula (V) wherein R is H and R is -
CH CH NH . In another embodiment is a compound of Formula (V) wherein R and R are each
2 2 2
21 22
independently H, -(C -C )alkyl-NR R , or -CH CH(OH)CH NH . In another embodiment is a compound
1 6 2 2 2
of Formula (V) wherein R and R are each independently -CH CH(OH)CH NH . In another embodiment
2 2 2
is a compound of Formula (V) wherein R is H, and R is -CH CH(OH)CH NH . In another embodiment is
2 2 2
a compound of Formula (V) wherein R is -CH CH(OH)CH NH , and R is H. In a further embodiment is
2 2 2
a compound of Formula (V) wherein R and R and the atoms to which they are attached form an
optionally substituted heterocycloalkyl ring.
[00442] In another embodiment is a compound of Formula (V) wherein X is optionally substituted
heteroaryl. In a further embodiment is a compound of Formula (V) wherein X is monosubstituted or
disubstituted heteroaryl. In a further embodiment is a compound of Formula (V) wherein X is heteroaryl
monosubstituted or disubstituted with a substituent independently selected from halogen, -CN, optionally
23 25 26
substituted -(C -C )alkyl, optionally substituted -O-(C -C )alkyl, OR , -NR R , and -NO . In a further
1 6 1 6 2
embodiment is a compound of Formula (V) wherein X is heteroaryl monosubstituted or disubstituted with
a substituent independently selected from -(C -C )alkyl.In a further embodiment is a compound of
Formula (V) wherein X is heteroaryl monosubstituted or disubstituted with methyl. In a further
18253141_1 (GHMatters) P111789.NZ
embodiment is a compound of Formula (V) wherein X is pyridinyl monosubstituted or disubstituted with a
substituent independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally
23 25 26
substituted -O-(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound of Formula
1 6 2
(V) wherein X is pyridinyl monosubstituted or disubstituted with a substituent independently selected from
-(C -C )alkyl. In a further embodiment is a compound of Formula (V) wherein X is pyridinyl
monosubstituted or disubstituted with methyl. In a further embodiment is a compound of Formula (V) X is
pyrimidinyl monosubstituted or disubstituted with a substituent independently selected from halogen, -CN,
23 25 26
optionally substituted -(C -C )alkyl, optionally substituted -O-(C -C )alkyl, OR , -NR R , or -NO . In a
1 6 1 6 2
further embodiment is a compound of Formula (V) X is pyrimidinyl monosubstituted or disubstituted with
a substituent independently selected from -(C -C )alkyl. In a further embodiment is a compound of
Formula (V) X is pyrimidinyl monosubstituted or disubstituted with methyl.
In another embodiment is a compound of Formula (V) wherein Y is optionally substituted aryl.
In a further embodiment is a compound of Formula (V) wherein Y is optionally substituted phenyl. In
another embodiment is a compound of Formula (V) wherein Y is optionally substituted heteroaryl. In
another embodiment is a compound of Formula (V) wherein Y is optionally substituted -(C -C )alkyl-. In
another embodiment is a compound of Formula (V) wherein Y is optionally substituted (C -C )cycloalkyl-.
In another embodiment is a compound of Formula (V) wherein Y is optionally substituted heterocycloalkyl.
In another embodiment is a compound of Formula (V) wherein Y is -O-. In another embodiment is a
compound of Formula (V) wherein Y is -(C -C )alkynyl. In another embodiment is a compound of
Formula (V) wherein Y is -O-(C -C )alkyl-. In another embodiment is a compound of Formula (V)
wherein Y is a bond.
In another embodiment is a compound of Formula (V) wherein Z is -(C -C )alkyl. In a further
1 12
embodiment is a compound of Formula (V) wherein Z is n-butyl, isobutyl, or tert-butyl. In another
embodiment is a compound of Formula (V) wherein Z is -O-(C -C )alkyl. In another embodiment is a
1 12
compound of Formula (V) wherein Z is -O-(C -C )cycloalkyl. In another embodiment is a compound of
Formula (V) wherein Z is -(C -C )alkenyl. In another embodiment is a compound of Formula (V) wherein
2 12
Z is optionally substituted aryl. In a further embodiment is a compound of Formula (V) wherein Z is
optionally substituted phenyl. In a further embodiment is a compound of Formula (V) wherein Z is phenyl
monsubstituted or disubstituted with a substituent independently selected from -(C -C )alkyl. In a further
embodiment is a compound of Formula (V) wherein Z is phenyl monosubstituted with n-butyl, isobutyl, or
tert-butyl. In a further embodiment is a compound of Formula (V) wherein Z is phenyl monosubstituted
with n-butyl. In a further embodiment is a compound of Formula (V) wherein Z is phenyl monosubstituted
with isobutyl. In a further embodiment is a compound of Formula (V) wherein Z is phenyl
monosubstituted with tert-butyl. In another embodiment is a compound of Formula (V) wherein Z is
optionally substituted heteroaryl. In another embodiment is a compound of Formula (V) wherein Z is
optionally substituted -(C -C )cycloalkyl. In another embodiment is a compound of Formula (V) wherein
18253141_1 (GHMatters) P111789.NZ
Z is optionally substituted heterocycloalkyl. In another embodiment is a compound of Formula (V)
wherein Z is halogen.
In another embodiment is a compound of Formula (V) having the structure of Formula (Va):
(R )q
(R )
18 16
Z X N
17 9
O R O R
11 12
Formula (Va);
wherein:
1 2 23
R and R are each independently H, -(C -C )alkyl, -(C -C )alkyl-OR , -CH CH(OH)CH NH , -
1 6 1 6 2 2 2
CH CH(heterocycloalkyl)CH NH , -CH C(O)NH , -CH C(O)N(H)CH CN, -(C -C )alkyl-C(O)OR , -
2 2 2 2 2 2 2 1 6
21 22 25 26 23 21 22
(C -C )alkyl-NR R , -(C -C )alkyl-C(O)NR R , -(C -C )alkyl-N(R )C(O)(C -C )alkylNR R , -
1 6 1 6 1 6 1 6
23 23
(C -C )alkyl-N(R )C(O)(C -C )alkyl, -(C -C )alkyl-C(O)N(R )(C -C )alkyl, -(C -C )alkyl-
1 6 1 6 1 6 1 6 1 6
23 23 21 22
C(O)N(R )(C -C )alkyl-heterocycloalkyl, -(C -C )alkyl-NR C(=NH)NR R , -(C -C )alkyl-
1 6 1 6 1 6
23 23 21 22
NR C(=NH)R , -(C -C )alkyl-[(C -C )alkyl-NR R ] , -(C -C )heteroalkyl, or optionally substituted
1 6 1 6 2 1 6
heterocycloalkyl;
or R and R and the atoms to which they are attached form an optionally substituted heterocycloalkyl ring;
6 7 8
R , R , and R are each independently H, fluoro, hydroxyl, amino, optionally substituted alkyl, optionally
substituted heteroalkyl, or -(C -C )alkyl;
R is H, -(C -C )alkyl, -(C -C )haloalkyl, or -(C -C )cycloalkyl;
1 6 1 6 3 6
R is H, -(C -C )alkyl, -(C -C )haloalkyl, or -(C -C )cycloalkyl;
1 6 1 6 3 6
9 10
or R and R are combined to form a heterocycloalkyl or cycloalkyl ring
11 12 23 23
R and R are each independently H, -NH , -(C -C )alkyl, -(C -C )alkyl-OR , -(C -C )alkyl-SR , -(C -
2 1 6 1 6 1 6 1
23 21 22 23 23
C )alkyl-C(O)OR , -(C -C )alkyl-NR R , -(C -C )alkyl-NR OR , -(C -C )alkyl-
6 1 6 1 6 1 6
23 23 25 26
NHC(O)NR OR , -(C -C )alkyl-O-(C -C )alkyl-NR R , -(C -C )alkyl-CN, -(C -C )alkyl-
1 6 1 6 1 6 1 6
23 23 25 26
C(O)R , -(C -C )alkyl-C(O)NR R , -(C -C )heteroalkyl-CO H, -(C -C )alkyl-S(O)(C -C )alkyl,
1 6 1 6 2 1 6 1 6
-(C -C )alkyl-N(H)CH=NH, -(C -C )alkyl-C(NH )=NH, -(C -C )alkyl-N(H)C(=NH)NH , -(C -
1 6 1 6 2 1 6 2 1
26 25 26
C )alkyl-N(H)S(O) NR R , -(C -C )alkyl-N(H)S(O) (C -C )alkyl, -(C -C )alkyl-N(H)-C(O)NR R ,
6 2 1 6 2 1 6 1 6
-(C -C )alkylC(O)N(H)[optionally substituted(C -C )alkyl]-OR , -(C -C )alkylN(H)C(O)(C -
1 6 2 6 1 6 1
23 25 26
C )alkyl-OR , -(C -C )alkylC(O)N(H)heterocycloalkyl, -(C -C )alkylC(O)NR R , -(C -C )alkyl-
6 1 6 1 6 1 6
26 25 26
N(H)-C(O)-(C -C )alkyl-NR R , -(C -C )alkyl-N(H)-(C -C )alkylC(O)NR R , -(C -C )alkyl-
1 6 1 6 1 6 1 6
heterocycloalkyl, optionally substituted -(C -C )alkyl-N(H)heterocycloalkyl, or -(C -C )alkyl-
1 6 1 6
heteroaryl;
18253141_1 (GHMatters) P111789.NZ
11 18 12
or R and R are combined to form an optionally substituted heterocycloalkyl ring; and R is H;
16 17 18 23
R , R , R , and R are each independently H, -(C -C )alkyl, -(C -C )cycloalkyl, -(C -C )alkyl-OR , -
1 6 3 6 1 6
23 21 22
(C -C )alkyl-C(O)OR , or -(C -C )alkyl-NR R ;
1 6 1 6
X is optionally substituted heteroaryl;
Y is a bond, -O-, -S-, optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, -(C -
1 6 2 6 2 6 1
24 24 24
C )alkyl-N(R )(C -C )alkyl-, -O-(C -C )alkyl-, -O(C -C )aryl-, -N(R )(C -C )alkyl-, -N(R )SO (C -
6 1 6 1 6 6 10 1 6 2 1
C )alkyl-, -N(R )C(O)(C -C )alkyl-, -C(O)(C -C )alkyl-, -S(C -C )alkyl-, -SO (C -C )alkyl-, -
6 1 6 1 6 1 6 2 1 6
C(O)NH(C -C )alkyl-, optionally substituted -(C -C )cycloalkyl-, optionally substituted -
1 6 3 7
24 24 24
C(O)N(R )aryl-, optionally substituted -N(R )C(O)aryl-, optionally substituted -N(R )SO aryl-,
optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Z is H, halogen, -NH , -CN, -CF , -CO H, -(C -C )alkyl, -(C -C )alkenyl, -CH=((C -C )cycloalkyl), -
2 3 2 1 12 2 12 3 7
26
(C -C )alkynyl, -C(O)NR R , -O-(C -C )alkyl, -S-(C -C )alkyl, -O-(C -C )[optionally substituted
2 12 1 12 1 12 3 10
23 23
(C -C )cycloalkyl], -O-(C -C )alkyl-OR , -(C -C )alkyl-OR , -(C -C )alkyl-CN, -S-(C -C )alkyl, -
3 7 1 6 1 12 1 12 1 12
24 24
N(R )(C -C )alkyl, -N(R )C(O)(C -C )alkyl, optionally substituted -(C -C )cycloalkyl, -(C -
1 12 1 12 3 7 1
C )alkyl-(C -C )cycloalkyl, -(C -C )alkyl-heterocycloalkyl, optionally substituted heterocycloalkyl,
6 3 7 1 6
optionally substituted aryl, or optionally substituted heteroaryl;
21 22
each R and R is independently H, -(C -C )alkyl, -(C -C )heteroalkyl, -(C -C )alkyl-CO H, -C(O)(C -
1 6 1 6 1 6 2 1
C )alkyl, -C(O)O(C -C )alkyl, -C(O)O(C -C )haloalkyl, -C(=NH)(C -C )alkyl, -C(=NH)N(R ) , -
6 1 6 1 6 1 6 2
31 31 21 22
C(O)N(R ) , or -SO N(R ) ; or R and R and the nitrogen atom to which they are attached form a
2 2 2
heterocycloalkyl ring;
31 31
each R is independently H or -(C -C )alkyl; or two R and the nitrogen atom to which they are attached
form a heterocycloalkyl ring;
each R is independently H or -(C -C )alkyl;
each R is independently H or -(C -C )alkyl;
26
each R and R is independently H or optionally substituted -(C -C )alkyl;
26
or R and R and the nitrogen atom to which they are attached form a heterocycloalkyl ring;
27 23 24 23 23 24
each R is independently halogen, -NR R , -NHC(O)R , -NHC(O)NR R , nitro, hydroxyl, optionally
substituted -(C -C )alkyl, optionally substituted -(C -C )heteroalkyl, optionally substituted -(C -
1 6 1 6 1
C )heteroalkyloxy, optionally substituted -(C -C )heteroalkylamino, -(C -C )alkoxy, -C(O)(C -
6 1 6 1 6 1
C )alkyl, or -S(O) (C -C )alkyl;
6 2 1 6
1 27
or R and R and the atoms to which they are attached form an optionally substituted 5- or 6-membered
heterocycloalkyl ring;
28 23 24 23 23 24
each R is independently halogen, -NR R , -NHC(O)R , -NHC(O)NR R , nitro, hydroxyl, optionally
substituted -(C -C )alkyl, optionally substituted -(C -C )heteroalkyl, optionally substituted -(C -
1 6 1 6 1
C )heteroalkyloxy, optionally substituted -(C -C )heteroalkylamino, -(C -C )alkoxy, -C(O)(C -
6 1 6 1 6 1
C )alkyl, or -S(O) (C -C )alkyl;
6 2 1 6
18253141_1 (GHMatters) P111789.NZ
2 28
or R and R and the atoms to which they are attached form an optionally substituted 5- or 6-membered
heterocycloalkyl ring;
p is 0, 1, or 2; and
q is 0, 1, or 2;
[00446] or a pharmaceutically acceptable salt, solvate, or prodrug thereof.In one embodiment is a
6 7 8
compound of Formula (Va) wherein R , R , and R are H.
16
In another embodiment is a compound of Formula (Va) wherein R and R are H.
In one embodiment is a compound of Formula (Va) wherein R is -(C -C )alkyl. In another
embodiment is a compound of Formula (Va) wherein R is -CH . In another embodiment is a compound
of Formula (Va) wherein R is -CH CH . In another embodiment is a compound of Formula (Va) wherein
17 17
R is -(C -C )cycloalkyl. In another embodiment is a compound of Formula (Va) wherein R is
cyclopropyl. In another embodiment is a compound of Formula (Va) wherein R is -(C -C )alkyl-
23 17
C(O)OR . In another embodiment is a compound of Formula (Va) wherein R is -CH CH OH. In another
17 21 22
embodiment is a compound of Formula (Va) wherein R is -(C -C )alkyl-NR R . In another embodiment
is a compound of Formula (Va) wherein R is -CH CH NH . In another embodiment is a compound of
2 2 2
Formula (Va) wherein R is H.
In another embodiment is a compound of Formula (Va) wherein R is H.
In another embodiment is a compound of Formula (Va) wherein R is H.
9
In another embodiment is a compound of Formula (Va) wherein R is H and R is -(C -C )alkyl.
9
In another embodiment is a compound of Formula (Va) wherein R is H and R is -CH . In another
9
embodiment is a compound of Formula (Va) wherein R is H and R is -CH CH . In another embodiment
9
is a compound of Formula (Va) wherein R is H and R is -(C -C )haloalkyl. In another embodiment is a
9
compound of Formula (Va) wherein R is H and R is -CH F. In another embodiment is a compound of
9
Formula (Va) wherein R is H and R is -CHF . In another embodiment is a compound of Formula (Va)
9
wherein R is H and R is -(C -C )cycloalkyl. In another embodiment is a compound of Formula (Va)
9
wherein R is H and R is cyclopropyl. In another embodiment is a compound of Formula (Va) wherein
9
R is H and R is H.
In another embodiment is a compound of Formula (Va) wherein R is H.
12 11
In another embodiment is a compound of Formula (Va) wherein R is H and R is -(C -
12 11
C )alkyl. In another embodiment is a compound of Formula (Va) wherein R is H and R is -CH . In
12 11 23
another embodiment is a compound of Formula (Va) wherein R is H and R is -(C -C )alkyl-OR . In
12 11
another embodiment is a compound of Formula (Va) wherein R is H and R is -CH OH. In another
12 11
embodiment is a compound of Formula (Va) wherein R is H and R is -CH CH OH. In another
12 11
embodiment is a compound of Formula (Va) wherein R is H and R is -(C -C )alkyl. In another
12 11 21 22
embodiment is a compound of Formula (Va) wherein R is H and R is -(C -C )alkyl-NR R . In another
12 11
embodiment is a compound of Formula (Va) wherein R is H and R is -(C -C )alkyl-NH . In another
1 6 2
12 11
embodiment is a compound of Formula (Va) wherein R is H and R is -CH NH . In another embodiment
18253141_1 (GHMatters) P111789.NZ
12 11
is a compound of Formula (Va) wherein R is H and R is -CH CH NH . In another embodiment is a
2 2 2
12 11
compound of Formula (Va) wherein R is H and R is -CH CH CH NH . In another embodiment is a
2 2 2 2
12 11
compound of Formula (Va) wherein R is H and R is -CH CH CH CH NH . In another embodiment is a
2 2 2 2 2
12 11
compound of Formula (Va) wherein R is H and R is -(C -C )alkyl-CN. In another embodiment is a
12 11
compound of Formula (Va) wherein R is H and R is -CH CN. In another embodiment is a compound of
12 11 25 26
Formula (Va) wherein R is H and R is -(C -C )alkyl-C(O)NR R . In another embodiment is a
12 11
compound of Formula (Va) wherein R is H and R is -CH C(O)NH . In another embodiment is a
12 11
compound of Formula (Va) wherein R is H and R is -CH CH C(O)NH . In another embodiment is a
2 2 2
12 11
compound of Formula (Va) wherein R is H and R is -(C -C )alkyl-heteroaryl. In another embodiment is
12 11 25 26
a compound of Formula (Va) wherein R is H and R is -(C -C )alkyl-N(H)S(O) NR R . In another
1 6 2
12 11
embodiment is a compound of Formula (Va) wherein R is H and R is –CH N(H)S(O) NH . In another
2 2 2
12 11
embodiment is a compound of Formula (Va) wherein R is H and R is H.
11 18
In another embodiment is a compound of Formula (Va) wherein R and R are combined to
form an optionally substituted heterocycloalkyl ring and R is H.
[00455] In another embodiment is a compound of Formula (Va) wherein p is 1 and R is halogen. In
another embodiment is a compound of Formula (Va) wherein p is 1 and R is optionally substituted -(C -
C )alkyl. In another embodiment is a compound of Formula (Va) wherein q is 0, p is 1 and R is halogen.
is optionally
In another embodiment is a compound of Formula (Va) wherein q is 0, p is 1 and R
substituted -(C -C )alkyl. In another embodiment is a compound of Formula (Va) wherein q is 1 and R is
halogen. In another embodiment is a compound of Formula (Va) wherein q is 1 and R is optionally
substituted -(C -C )alkyl. In another embodiment is a compound of Formula (Va) wherein p is 0, q is 1 and
28 28
R is halogen. In another embodiment is a compound of Formula (Va) wherein p is 0, q is 1 and R is
optionally substituted -(C -C )alkyl.
In another embodiment is a compound of Formula (Va) wherein p is 0, and q is 0.
[00457] In another embodiment is a compound of Formula (Va) wherein R and R are each
21 22
independently H or -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (Va)
1 2 1 2
wherein R and R are each H. In another embodiment is a compound of Formula (Va) wherein R and R
21 22
are each independently -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (Va)
1 2 21 22
wherein R is H, and R is -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (Va)
1 21 22 2
wherein R is -(C -C )alkyl-NR R , and R is H. In another embodiment is a compound of Formula (Va)
wherein R is H, and R is -CH CH NH . In another embodiment is a compound of Formula (Va) wherein
2 2 2
1 2 1
R is -CH CH NH , and R is H. In another embodiment is a compound of Formula (Va) wherein R and
2 2 2
R are each -CH CH NH . In a further embodiment is a compound of Formula (Va) wherein R is -(C -
2 2 2 1
21 22 2 1
C )alkyl-NR R and R is H. In a further embodiment is a compound of Formula (Va) wherein R is -
2 1 2
CH CH NH and R is H. In a further embodiment is a compound of Formula (Va) wherein R is H and R
2 2 2
21 22 1 2
is -(C -C )alkyl-NR R . In a further embodiment is a compound of Formula (Va) wherein R is H and R
is -CH CH NH . In another embodiment is a compound of Formula (Va) wherein R and R are each
2 2 2
18253141_1 (GHMatters) P111789.NZ
21 22
independently H, -(C -C )alkyl-NR R , or -CH CH(OH)CH NH . In another embodiment is a compound
1 6 2 2 2
of Formula (Va) wherein R and R are each independently -CH CH(OH)CH NH . In another embodiment
2 2 2
is a compound of Formula (Va) wherein R is H, and R is -CH CH(OH)CH NH . In another embodiment
2 2 2
is a compound of Formula (Va) wherein R is -CH CH(OH)CH NH , and R is H. In a further embodiment
2 2 2
is a compound of Formula (Va) wherein R and R and the atoms to which they are attached form an
optionally substituted heterocycloalkyl ring.
In another embodiment is a compound of Formula (Va) wherein X is optionally substituted
heteroaryl. In a further embodiment is a compound of Formula (Va) wherein X is monosubstituted or
disubstituted heteroaryl. In a further embodiment is a compound of Formula (Va) wherein X is heteroaryl
monosubstituted or disubstituted with a substituent independently selected from halogen, -CN, optionally
23 25 26
substituted -(C -C )alkyl, optionally substituted -O-(C -C )alkyl, OR , -NR R , and -NO . In a further
1 6 1 6 2
embodiment is a compound of Formula (Va) wherein X is heteroaryl monosubstituted or disubstituted with
a substituent independently selected from -(C -C )alkyl.In a further embodiment is a compound of
Formula (Va) wherein X is heteroaryl monosubstituted or disubstituted with methyl. In a further
embodiment is a compound of Formula (Va) wherein X is pyridinyl monosubstituted or disubstituted with
a substituent independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally
23 25 26
substituted -O-(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound of Formula
1 6 2
(Va) wherein X is pyridinyl monosubstituted or disubstituted with a substituent independently selected
from -(C -C )alkyl. In a further embodiment is a compound of Formula (Va) wherein X is pyridinyl
monosubstituted or disubstituted with methyl. In a further embodiment is a compound of Formula (Va) X
is pyrimidinyl monosubstituted or disubstituted with a substituent independently selected from halogen, -
23 25 26
CN, optionally substituted -(C -C )alkyl, optionally substituted -O-(C -C )alkyl, OR , -NR R , or -NO .
1 6 1 6 2
In a further embodiment is a compound of Formula (Va) X is pyrimidinyl monosubstituted or disubstituted
with a substituent independently selected from -(C -C )alkyl. In a further embodiment is a compound of
Formula (Va) X is pyrimidinyl monosubstituted or disubstituted with methyl.
In another embodiment is a compound of Formula (Va) wherein Y is optionally substituted aryl.
In a further embodiment is a compound of Formula (Va) wherein Y is optionally substituted phenyl. In
another embodiment is a compound of Formula (Va) wherein Y is optionally substituted heteroaryl. In
another embodiment is a compound of Formula (Va) wherein Y is optionally substituted -(C -C )alkyl-. In
another embodiment is a compound of Formula (Va) wherein Y is optionally substituted (C -
C )cycloalkyl-. In another embodiment is a compound of Formula (Va) wherein Y is optionally substituted
heterocycloalkyl. In another embodiment is a compound of Formula (Va) wherein Y is -O-. In another
embodiment is a compound of Formula (Va) wherein Y is -(C -C )alkynyl. In another embodiment is a
compound of Formula (Va) wherein Y is -O-(C -C )alkyl-. In another embodiment is a compound of
Formula (Va) wherein Y is a bond.
In another embodiment is a compound of Formula (Va) wherein Z is -(C -C )alkyl. In a further
1 12
embodiment is a compound of Formula (Va) wherein Z is n-butyl, isobutyl, or tert-butyl. In another
18253141_1 (GHMatters) P111789.NZ
embodiment is a compound of Formula (Va) wherein Z is -O-(C -C )alkyl. In another embodiment is a
1 12
compound of Formula (Va) wherein Z is -O-(C -C )cycloalkyl. In another embodiment is a compound of
Formula (Va) wherein Z is -(C -C )alkenyl. In another embodiment is a compound of Formula (Va)
2 12
wherein Z is optionally substituted aryl. In a further embodiment is a compound of Formula (Va) wherein
Z is optionally substituted phenyl. In a further embodiment is a compound of Formula (Va) wherein Z is
phenyl monsubstituted or disubstituted with a substituent independently selected from -(C -C )alkyl. In a
further embodiment is a compound of Formula (Va) wherein Z is phenyl monosubstituted with n-butyl,
isobutyl, or tert-butyl. In a further embodiment is a compound of Formula (Va) wherein Z is phenyl
monosubstituted with n-butyl. In a further embodiment is a compound of Formula (Va) wherein Z is
phenyl monosubstituted with isobutyl. In a further embodiment is a compound of Formula (Va) wherein Z
is phenyl monosubstituted with tert-butyl. In another embodiment is a compound of Formula (Va) wherein
Z is optionally substituted heteroaryl. In another embodiment is a compound of Formula (Va) wherein Z is
optionally substituted -(C -C )cycloalkyl. In another embodiment is a compound of Formula (Va) wherein
Z is optionally substituted heterocycloalkyl. In another embodiment is a compound of Formula (Va)
wherein Z is halogen.
In another embodiment is a compound of Formula (V) having the structure of Formula (Vb):
Z X N
O R O
Formula (Vb);
wherein:
1 2 23
R and R are each independently H, -(C -C )alkyl, -(C -C )alkyl-OR , -CH CH(OH)CH NH , -
1 6 1 6 2 2 2
CH CH(heterocycloalkyl)CH NH , -CH C(O)NH , -CH C(O)N(H)CH CN, -(C -C )alkyl-C(O)OR , -
2 2 2 2 2 2 2 1 6
21 22 25 26 23 21 22
(C -C )alkyl-NR R , -(C -C )alkyl-C(O)NR R , -(C -C )alkyl-N(R )C(O)(C -C )alkylNR R , -
1 6 1 6 1 6 1 6
23 23
(C -C )alkyl-N(R )C(O)(C -C )alkyl, -(C -C )alkyl-C(O)N(R )(C -C )alkyl, -(C -C )alkyl-
1 6 1 6 1 6 1 6 1 6
23 23 21 22
C(O)N(R )(C -C )alkyl-heterocycloalkyl, -(C -C )alkyl-NR C(=NH)NR R , -(C -C )alkyl-
1 6 1 6 1 6
23 23 21 22
NR C(=NH)R , -(C -C )alkyl-[(C -C )alkyl-NR R ] , -(C -C )heteroalkyl, or optionally substituted
1 6 1 6 2 1 6
heterocycloalkyl;
or R and R and the atoms to which they are attached form an optionally substituted heterocycloalkyl ring;
R is H, -(C -C )alkyl, -(C -C )haloalkyl, or -(C -C )cycloalkyl;
1 6 1 6 3 6
11 23 23 23
R is H, -NH , -(C -C )alkyl, -(C -C )alkyl-OR , -(C -C )alkyl-SR , -(C -C )alkyl-C(O)OR , -(C -
2 1 6 1 6 1 6 1 6 1
21 22 23 23 23 23
C )alkyl-NR R , -(C -C )alkyl-NR OR , -(C -C )alkyl-NHC(O)NR OR , -(C -C )alkyl-O-(C -
6 1 6 1 6 1 6 1
18253141_1 (GHMatters) P111789.NZ
26 23 23 25 26
C )alkyl-NR R , -(C -C )alkyl-CN, -(C -C )alkyl-NR C(O)R , -(C -C )alkyl-C(O)NR R , -(C -
6 1 6 1 6 1 6 1
C )heteroalkyl-CO H, -(C -C )alkyl-S(O)(C -C )alkyl, -(C -C )alkyl-N(H)CH=NH, -(C -C )alkyl-
6 2 1 6 1 6 1 6 1 6
26
C(NH )=NH, -(C -C )alkyl-N(H)C(=NH)NH , -(C -C )alkyl-N(H)S(O) NR R , -(C -C )alkyl-
2 1 6 2 1 6 2 1 6
26
N(H)S(O) (C -C )alkyl, -(C -C )alkyl-N(H)-C(O)NR R , -(C -C )alkylC(O)N(H)[optionally
2 1 6 1 6 1 6
23 23
substituted(C -C )alkyl]-OR , -(C -C )alkylN(H)C(O)(C -C )alkyl-OR , -(C -
2 6 1 6 1 6 1
26
C )alkylC(O)N(H)heterocycloalkyl, -(C -C )alkylC(O)NR R , -(C -C )alkyl-N(H)-C(O)-(C -
6 1 6 1 6 1
26 25 26
C )alkyl-NR R , -(C -C )alkyl-N(H)-(C -C )alkylC(O)NR R , -(C -C )alkyl-heterocycloalkyl,
6 1 6 1 6 1 6
optionally substituted -(C -C )alkyl-N(H)heterocycloalkyl, or -(C -C )alkyl-heteroaryl;
1 6 1 6
11 18 12
or R and R are combined to form an optionally substituted heterocycloalkyl ring; and R is H;
17 18 23
R and R are each independently H, -(C -C )alkyl, -(C -C )cycloalkyl, -(C -C )alkyl-OR , -(C -
1 6 3 6 1 6 1
23 21 22
C )alkyl-C(O)OR , or -(C -C )alkyl-NR R ;
6 1 6
X is optionally substituted heteroaryl;
Y is a bond, -O-, -S-, optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, -(C -
1 6 2 6 2 6 1
24 24 24
C )alkyl-N(R )(C -C )alkyl-, -O-(C -C )alkyl-, -O(C -C )aryl-, -N(R )(C -C )alkyl-, -N(R )SO (C -
6 1 6 1 6 6 10 1 6 2 1
C )alkyl-, -N(R )C(O)(C -C )alkyl-, -C(O)(C -C )alkyl-, -S(C -C )alkyl-, -SO (C -C )alkyl-, -
6 1 6 1 6 1 6 2 1 6
C(O)NH(C -C )alkyl-, optionally substituted -(C -C )cycloalkyl-, optionally substituted -
1 6 3 7
24 24 24
C(O)N(R )aryl-, optionally substituted -N(R )C(O)aryl-, optionally substituted -N(R )SO aryl-,
optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Z is H, halogen, -NH , -CN, -CF , -CO H, -(C -C )alkyl, -(C -C )alkenyl, -CH=((C -C )cycloalkyl), -
2 3 2 1 12 2 12 3 7
26
(C -C )alkynyl, -C(O)NR R , -O-(C -C )alkyl, -S-(C -C )alkyl, -O-(C -C )[optionally substituted
2 12 1 12 1 12 3 10
23 23
(C -C )cycloalkyl], -O-(C -C )alkyl-OR , -(C -C )alkyl-OR , -(C -C )alkyl-CN, -S-(C -C )alkyl, -
3 7 1 6 1 12 1 12 1 12
24 24
N(R )(C -C )alkyl, -N(R )C(O)(C -C )alkyl, optionally substituted -(C -C )cycloalkyl, -(C -
1 12 1 12 3 7 1
)alkyl-(C -C )cycloalkyl, -(C -C )alkyl-heterocycloalkyl, optionally substituted heterocycloalkyl,
6 3 7 1 6
optionally substituted aryl, or optionally substituted heteroaryl;
21 22
each R and R is independently H, -(C -C )alkyl, -(C -C )heteroalkyl, -(C -C )alkyl-CO H, -C(O)(C -
1 6 1 6 1 6 2 1
C )alkyl, -C(O)O(C -C )alkyl, -C(O)O(C -C )haloalkyl, -C(=NH)(C -C )alkyl, -C(=NH)N(R ) , -
6 1 6 1 6 1 6 2
31 31 21 22
C(O)N(R ) , or -SO N(R ) ; or R and R and the nitrogen atom to which they are attached form a
2 2 2
heterocycloalkyl ring;
31 31
each R is independently H or -(C -C )alkyl; or two R and the nitrogen atom to which they are attached
form a heterocycloalkyl ring;
each R is independently H or -(C -C )alkyl;
each R is independently H or -(C -C )alkyl;
26
each R and R is independently H or optionally substituted -(C -C )alkyl;
26
or R and R and the nitrogen atom to which they are attached form a heterocycloalkyl ring; and
[00462] or a pharmaceutically acceptable salt, solvate, or prodrug thereof.In one embodiment is a
compound of Formula (Vb) wherein R is -(C -C )alkyl. In another embodiment is a compound of
17 17
Formula (Vb) wherein R is -CH . In another embodiment is a compound of Formula (Vb) wherein R is
18253141_1 (GHMatters) P111789.NZ
-CH CH . In another embodiment is a compound of Formula (Vb) wherein R is -(C -C )cycloalkyl. In
2 3 3 6
another embodiment is a compound of Formula (Vb) wherein R is cyclopropyl. In another embodiment is
17 23
a compound of Formula (Vb) wherein R is -(C -C )alkyl-C(O)OR . In another embodiment is a
compound of Formula (Vb) wherein R is -CH CH OH. In another embodiment is a compound of
17 21 22
Formula (Vb) wherein R is -(C -C )alkyl-NR R . In another embodiment is a compound of Formula
17 17
(Vb) wherein R is -CH CH NH . In another embodiment is a compound of Formula (Vb) wherein R is
2 2 2
In another embodiment is a compound of Formula (Vb) wherein R is H.
In another embodiment is a compound of Formula (Vb) wherein R is -(C -C )alkyl. In another
embodiment is a compound of Formula (Vb) wherein R is -CH . In another embodiment is a compound of
Formula (Vb) wherein R is -CH CH . In another embodiment is a compound of Formula (Vb) wherein R
is -(C -C )haloalkyl. In another embodiment is a compound of Formula (Vb) wherein R is -CH F. In
1 6 2
another embodiment is a compound of Formula (Vb) wherein R is -CHF . In another embodiment is a
compound of Formula (Vb) wherein R is -(C -C )cycloalkyl. In another embodiment is a compound of
Formula (Vb) wherein R is cyclopropyl. In another embodiment is a compound of Formula (Vb) wherein
R is H.
In another embodiment is a compound of Formula (Vb) wherein R is -(C -C )alkyl. In another
embodiment is a compound of Formula (Vb) wherein R is -CH . In another embodiment is a compound
11 23
of Formula (Vb) wherein R is -(C -C )alkyl-OR . In another embodiment is a compound of Formula
11 11
(Vb) wherein R is -CH OH. In another embodiment is a compound of Formula (Vb) wherein R is -
CH CH OH. In another embodiment is a compound of Formula (Vb) wherein R is -(C -C )alkyl. In
2 2 1 6
11 21 22
another embodiment is a compound of Formula (Vb) wherein R is -(C -C )alkyl-NR R . In another
embodiment is a compound of Formula (Vb) wherein R is -(C -C )alkyl-NH . In another embodiment is
1 6 2
a compound of Formula (Vb) wherein R is -CH NH . In another embodiment is a compound of Formula
11 11
(Vb) wherein R is -CH CH NH . In another embodiment is a compound of Formula (Vb) wherein R is -
2 2 2
CH CH CH NH . In another embodiment is a compound of Formula (Vb) wherein R is -
2 2 2 2
CH CH CH CH NH . In another embodiment is a compound of Formula (Vb) wherein R is -(C -
2 2 2 2 2 1
C )alkyl-CN. In another embodiment is a compound of Formula (Vb) wherein R is -CH CN. In another
11 25 26
embodiment is a compound of Formula (Vb) wherein R is -(C -C )alkyl-C(O)NR R . In another
embodiment is a compound of Formula (Vb) wherein R is -CH C(O)NH . In another embodiment is a
compound of Formula (Vb) wherein R is -CH CH C(O)NH . In another embodiment is a compound of
2 2 2
Formula (Vb) wherein R is -(C -C )alkyl-heteroaryl. In another embodiment is a compound of Formula
11 25 26
(Vb) wherein R is -(C -C )alkyl-N(H)S(O) NR R . In another embodiment is a compound of Formula
1 6 2
(Vb) wherein R is –CH N(H)S(O) NH . In another embodiment is a compound of Formula (Vb) wherein
2 2 2
R is H.
11 18
In another embodiment is a compound of Formula (Vb) wherein R and R are combined to
form an optionally substituted heterocycloalkyl ring.
18253141_1 (GHMatters) P111789.NZ
In another embodiment is a compound of Formula (Vb) wherein R and R are each
21 22
independently H or -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (Vb)
1 2 1 2
wherein R and R are each H. In another embodiment is a compound of Formula (Vb) wherein R and R
21 22
are each independently -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (Vb)
1 2 21 22
wherein R is H, and R is -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (Vb)
1 21 22 2
wherein R is -(C -C )alkyl-NR R , and R is H. In another embodiment is a compound of Formula (Vb)
wherein R is H, and R is -CH CH NH . In another embodiment is a compound of Formula (Vb) wherein
2 2 2
1 2 1
R is -CH CH NH , and R is H. In another embodiment is a compound of Formula (Vb) wherein R and
2 2 2
R are each -CH CH NH . In a further embodiment is a compound of Formula (Vb) wherein R is -(C -
2 2 2 1
21 22 2 1
C )alkyl-NR R and R is H. In a further embodiment is a compound of Formula (Vb) wherein R is -
2 1 2
CH CH NH and R is H. In a further embodiment is a compound of Formula (Vb) wherein R is H and R
2 2 2
21 22 1 2
is -(C -C )alkyl-NR R . In a further embodiment is a compound of Formula (Vb) wherein R is H and R
is -CH CH NH . In another embodiment is a compound of Formula (Vb) wherein R and R are each
2 2 2
21 22
independently H, -(C -C )alkyl-NR R , or -CH CH(OH)CH NH . In another embodiment is a compound
1 6 2 2 2
of Formula (Vb) wherein R and R are each independently -CH CH(OH)CH NH . In another embodiment
2 2 2
is a compound of Formula (Vb) wherein R is H, and R is -CH CH(OH)CH NH . In another embodiment
2 2 2
is a compound of Formula (Vb) wherein R is -CH CH(OH)CH NH , and R is H. In a further embodiment
2 2 2
is a compound of Formula (Vb) wherein R and R and the atoms to which they are attached form an
optionally substituted heterocycloalkyl ring.
[00468] In another embodiment is a compound of Formula (Vb) wherein X is optionally substituted
heteroaryl. In a further embodiment is a compound of Formula (Vb) wherein X is monosubstituted or
disubstituted heteroaryl. In a further embodiment is a compound of Formula (Vb) wherein X is heteroaryl
monosubstituted or disubstituted with a substituent independently selected from halogen, -CN, optionally
23 25 26
substituted -(C -C )alkyl, optionally substituted -O-(C -C )alkyl, OR , -NR R , and -NO . In a further
1 6 1 6 2
embodiment is a compound of Formula (Vb) wherein X is heteroaryl monosubstituted or disubstituted with
a substituent independently selected from -(C -C )alkyl.In a further embodiment is a compound of
Formula (Vb) wherein X is heteroaryl monosubstituted or disubstituted with methyl. In a further
embodiment is a compound of Formula (Vb) wherein X is pyridinyl monosubstituted or disubstituted with
a substituent independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally
23 25 26
substituted -O-(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound of Formula
1 6 2
(Vb) wherein X is pyridinyl monosubstituted or disubstituted with a substituent independently selected
from -(C -C )alkyl. In a further embodiment is a compound of Formula (Vb) wherein X is pyridinyl
monosubstituted or disubstituted with methyl. In a further embodiment is a compound of Formula (Vb) X
is pyrimidinyl monosubstituted or disubstituted with a substituent independently selected from halogen, -
23 25 26
CN, optionally substituted -(C -C )alkyl, optionally substituted -O-(C -C )alkyl, OR , -NR R , or -NO .
1 6 1 6 2
In a further embodiment is a compound of Formula (Vb) X is pyrimidinyl monosubstituted or disubstituted
18253141_1 (GHMatters) P111789.NZ
with a substituent independently selected from -(C -C )alkyl. In a further embodiment is a compound of
Formula (Vb) X is pyrimidinyl monosubstituted or disubstituted with methyl.
In another embodiment is a compound of Formula (Vb) wherein Y is optionally substituted aryl.
In a further embodiment is a compound of Formula (Vb) wherein Y is optionally substituted phenyl. In
another embodiment is a compound of Formula (Vb) wherein Y is optionally substituted heteroaryl. In
another embodiment is a compound of Formula (Vb) wherein Y is optionally substituted -(C -C )alkyl-. In
another embodiment is a compound of Formula (Vb) wherein Y is optionally substituted (C -
C )cycloalkyl-. In another embodiment is a compound of Formula (Vb) wherein Y is optionally substituted
heterocycloalkyl. In another embodiment is a compound of Formula (Vb) wherein Y is -O-. In another
embodiment is a compound of Formula (Vb) wherein Y is -(C -C )alkynyl. In another embodiment is a
compound of Formula (Vb) wherein Y is -O-(C -C )alkyl-. In another embodiment is a compound of
Formula (Vb) wherein Y is a bond.
In another embodiment is a compound of Formula (Vb) wherein Z is -(C -C )alkyl. In a further
1 12
embodiment is a compound of Formula (Vb) wherein Z is n-butyl, isobutyl, or tert-butyl. In another
embodiment is a compound of Formula (Vb) wherein Z is -O-(C -C )alkyl. In another embodiment is a
1 12
compound of Formula (Vb) wherein Z is -O-(C -C )cycloalkyl. In another embodiment is a compound of
Formula (Vb) wherein Z is -(C -C )alkenyl. In another embodiment is a compound of Formula (Vb)
2 12
wherein Z is optionally substituted aryl. In a further embodiment is a compound of Formula (Vb) wherein
Z is optionally substituted phenyl. In a further embodiment is a compound of Formula (Vb) wherein Z is
phenyl monsubstituted or disubstituted with a substituent independently selected from -(C -C )alkyl. In a
further embodiment is a compound of Formula (Vb) wherein Z is phenyl monosubstituted with n-butyl,
isobutyl, or tert-butyl. In a further embodiment is a compound of Formula (Vb) wherein Z is phenyl
monosubstituted with n-butyl. In a further embodiment is a compound of Formula (Vb) wherein Z is
phenyl monosubstituted with isobutyl. In a further embodiment is a compound of Formula (Vb) wherein Z
is phenyl monosubstituted with tert-butyl. In another embodiment is a compound of Formula (Vb) wherein
Z is optionally substituted heteroaryl. In another embodiment is a compound of Formula (Vb) wherein Z is
optionally substituted -(C -C )cycloalkyl. In another embodiment is a compound of Formula (Vb) wherein
Z is optionally substituted heterocycloalkyl. In another embodiment is a compound of Formula (Vb)
wherein Z is halogen.
[00471] In another embodiment is a compound of Formula (V) having the structure of Formula (Vc):
18253141_1 (GHMatters) P111789.NZ
Z X N
Formula (Vc);
wherein:
1 2 23
R and R are each independently H, -(C -C )alkyl, -(C -C )alkyl-OR , -CH CH(OH)CH NH , -
1 6 1 6 2 2 2
CH CH(heterocycloalkyl)CH NH , -CH C(O)NH , -CH C(O)N(H)CH CN, -(C -C )alkyl-C(O)OR , -
2 2 2 2 2 2 2 1 6
21 22 25 26 23 21 22
(C -C )alkyl-NR R , -(C -C )alkyl-C(O)NR R , -(C -C )alkyl-N(R )C(O)(C -C )alkylNR R , -
1 6 1 6 1 6 1 6
23 23
(C -C )alkyl-N(R )C(O)(C -C )alkyl, -(C -C )alkyl-C(O)N(R )(C -C )alkyl, -(C -C )alkyl-
1 6 1 6 1 6 1 6 1 6
23 23 21 22
C(O)N(R )(C -C )alkyl-heterocycloalkyl, -(C -C )alkyl-NR C(=NH)NR R , -(C -C )alkyl-
1 6 1 6 1 6
23 23 21 22
NR C(=NH)R , -(C -C )alkyl-[(C -C )alkyl-NR R ] , -(C -C )heteroalkyl, or optionally substituted
1 6 1 6 2 1 6
heterocycloalkyl;
or R and R and the atoms to which they are attached form an optionally substituted heterocycloalkyl ring;
11 23 23 23
R is H, -NH , -(C -C )alkyl, -(C -C )alkyl-OR , -(C -C )alkyl-SR , -(C -C )alkyl-C(O)OR , -(C -
2 1 6 1 6 1 6 1 6 1
21 22 23 23 23 23
)alkyl-NR R , -(C -C )alkyl-NR OR , -(C -C )alkyl-NHC(O)NR OR , -(C -C )alkyl-O-(C -
6 1 6 1 6 1 6 1
26 23 23 25 26
C )alkyl-NR R , -(C -C )alkyl-CN, -(C -C )alkyl-NR C(O)R , -(C -C )alkyl-C(O)NR R , -(C -
6 1 6 1 6 1 6 1
C )heteroalkyl-CO H, -(C -C )alkyl-S(O)(C -C )alkyl, -(C -C )alkyl-N(H)CH=NH, -(C -C )alkyl-
6 2 1 6 1 6 1 6 1 6
26
C(NH )=NH, -(C -C )alkyl-N(H)C(=NH)NH , -(C -C )alkyl-N(H)S(O) NR R , -(C -C )alkyl-
2 1 6 2 1 6 2 1 6
26
N(H)S(O) (C -C )alkyl, -(C -C )alkyl-N(H)-C(O)NR R , -(C -C )alkylC(O)N(H)[optionally
2 1 6 1 6 1 6
23 23
substituted(C -C )alkyl]-OR , -(C -C )alkylN(H)C(O)(C -C )alkyl-OR , -(C -
2 6 1 6 1 6 1
26
C )alkylC(O)N(H)heterocycloalkyl, -(C -C )alkylC(O)NR R , -(C -C )alkyl-N(H)-C(O)-(C -
6 1 6 1 6 1
26 25 26
C )alkyl-NR R , -(C -C )alkyl-N(H)-(C -C )alkylC(O)NR R , -(C -C )alkyl-heterocycloalkyl,
6 1 6 1 6 1 6
optionally substituted -(C -C )alkyl-N(H)heterocycloalkyl, or -(C -C )alkyl-heteroaryl;
1 6 1 6
X is optionally substituted heteroaryl;
Y is a bond, -O-, -S-, optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, -(C -
1 6 2 6 2 6 1
24 24 24
C )alkyl-N(R )(C -C )alkyl-, -O-(C -C )alkyl-, -O(C -C )aryl-, -N(R )(C -C )alkyl-, -N(R )SO (C -
6 1 6 1 6 6 10 1 6 2 1
C )alkyl-, -N(R )C(O)(C -C )alkyl-, -C(O)(C -C )alkyl-, -S(C -C )alkyl-, -SO (C -C )alkyl-, -
6 1 6 1 6 1 6 2 1 6
C(O)NH(C -C )alkyl-, optionally substituted -(C -C )cycloalkyl-, optionally substituted -
1 6 3 7
24 24 24
C(O)N(R )aryl-, optionally substituted -N(R )C(O)aryl-, optionally substituted -N(R )SO aryl-,
optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Z is H, halogen, -NH , -CN, -CF , -CO H, -(C -C )alkyl, -(C -C )alkenyl, -CH=((C -C )cycloalkyl), -
2 3 2 1 12 2 12 3 7
26
(C -C )alkynyl, -C(O)NR R , -O-(C -C )alkyl, -S-(C -C )alkyl, -O-(C -C )[optionally substituted
2 12 1 12 1 12 3 10
18253141_1 (GHMatters) P111789.NZ
23 23
(C -C )cycloalkyl], -O-(C -C )alkyl-OR , -(C -C )alkyl-OR , -(C -C )alkyl-CN, -S-(C -C )alkyl, -
3 7 1 6 1 12 1 12 1 12
24 24
N(R )(C -C )alkyl, -N(R )C(O)(C -C )alkyl, optionally substituted -(C -C )cycloalkyl, -(C -
1 12 1 12 3 7 1
C )alkyl-(C -C )cycloalkyl, -(C -C )alkyl-heterocycloalkyl, optionally substituted heterocycloalkyl,
6 3 7 1 6
optionally substituted aryl, or optionally substituted heteroaryl;
21 22
each R and R is independently H, -(C -C )alkyl, -(C -C )heteroalkyl, -(C -C )alkyl-CO H, -C(O)(C -
1 6 1 6 1 6 2 1
C )alkyl, -C(O)O(C -C )alkyl, -C(O)O(C -C )haloalkyl, -C(=NH)(C -C )alkyl, -C(=NH)N(R ) , -
6 1 6 1 6 1 6 2
31 31 21 22
C(O)N(R ) , or -SO N(R ) ; or R and R and the nitrogen atom to which they are attached form a
2 2 2
heterocycloalkyl ring;
31 31
each R is independently H or -(C -C )alkyl; or two R and the nitrogen atom to which they are attached
form a heterocycloalkyl ring;
each R is independently H or -(C -C )alkyl;
each R is independently H or -(C -C )alkyl;
26
each R and R is independently H or optionally substituted -(C -C )alkyl;
26
or R and R and the nitrogen atom to which they are attached form a heterocycloalkyl ring; and
[00472] or a pharmaceutically acceptable salt, solvate, or prodrug thereof.In another embodiment is a
compound of Formula (Vc) wherein R is -(C -C )alkyl. In another embodiment is a compound of
11 11
Formula (Vc) wherein R is -CH . In another embodiment is a compound of Formula (Vc) wherein R is
23 11
-(C -C )alkyl-OR . In another embodiment is a compound of Formula (Vc) wherein R is -CH OH. In
1 6 2
another embodiment is a compound of Formula (Vc) wherein R is -CH CH OH. In another embodiment
is a compound of Formula (Vc) wherein R is -(C -C )alkyl. In another embodiment is a compound of
11 21 22
Formula (Vc) wherein R is -(C -C )alkyl-NR R . In another embodiment is a compound of Formula
(Vc) wherein R is -(C -C )alkyl-NH . In another embodiment is a compound of Formula (Vc) wherein
1 6 2
11 11
R is -CH NH . In another embodiment is a compound of Formula (Vc) wherein R is -CH CH NH . In
2 2 2 2 2
another embodiment is a compound of Formula (Vc) wherein R is -CH CH CH NH . In another
2 2 2 2
embodiment is a compound of Formula (Vc) wherein R is -CH CH CH CH NH . In another embodiment
2 2 2 2 2
is a compound of Formula (Vc) wherein R is -(C -C )alkyl-CN. In another embodiment is a compound of
11 11
Formula (Vc) wherein R is -CH CN. In another embodiment is a compound of Formula (Vc) wherein R
26 11
is -(C -C )alkyl-C(O)NR R . In another embodiment is a compound of Formula (Vc) wherein R is -
CH C(O)NH . In another embodiment is a compound of Formula (Vc) wherein R is -CH CH C(O)NH .
2 2 2 2 2
In another embodiment is a compound of Formula (Vc) wherein R is -(C -C )alkyl-heteroaryl. In another
11 25 26
embodiment is a compound of Formula (Vc) wherein R is -(C -C )alkyl-N(H)S(O) NR R . In another
1 6 2
embodiment is a compound of Formula (Vc) wherein R is –CH N(H)S(O) NH . In another embodiment
2 2 2
is a compound of Formula (Vc) wherein R is H.
In another embodiment is a compound of Formula (Vc) wherein R and R are each
21 22
independently H or -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (Vc)
1 2 1 2
wherein R and R are each H. In another embodiment is a compound of Formula (Vc) wherein R and R
21 22
are each independently -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (Vc)
18253141_1 (GHMatters) P111789.NZ
1 2 21 22
wherein R is H, and R is -(C -C )alkyl-NR R . In another embodiment is a compound of Formula (Vc)
1 21 22 2
wherein R is -(C -C )alkyl-NR R , and R is H. In another embodiment is a compound of Formula (Vc)
wherein R is H, and R is -CH CH NH . In another embodiment is a compound of Formula (Vc) wherein
2 2 2
1 2 1
R is -CH CH NH , and R is H. In another embodiment is a compound of Formula (Vc) wherein R and
2 2 2
R are each -CH CH NH . In a further embodiment is a compound of Formula (Vc) wherein R is -(C -
2 2 2 1
21 22 2 1
C )alkyl-NR R and R is H. In a further embodiment is a compound of Formula (Vc) wherein R is -
2 1 2
CH CH NH and R is H. In a further embodiment is a compound of Formula (Vc) wherein R is H and R
2 2 2
21 22 1 2
is -(C -C )alkyl-NR R . In a further embodiment is a compound of Formula (Vc) wherein R is H and R
is -CH CH NH . In another embodiment is a compound of Formula (Vc) wherein R and R are each
2 2 2
21 22
independently H, -(C -C )alkyl-NR R , or -CH CH(OH)CH NH . In another embodiment is a compound
1 6 2 2 2
of Formula (Vc) wherein R and R are each independently -CH CH(OH)CH NH . In another embodiment
2 2 2
is a compound of Formula (Vc) wherein R is H, and R is -CH CH(OH)CH NH . In another embodiment
2 2 2
is a compound of Formula (Vc) wherein R is -CH CH(OH)CH NH , and R is H. In a further embodiment
2 2 2
is a compound of Formula (Vc) wherein R and R and the atoms to which they are attached form an
optionally substituted heterocycloalkyl ring.
In another embodiment is a compound of Formula (Vc) wherein X is optionally substituted
heteroaryl. In a further embodiment is a compound of Formula (Vc) wherein X is monosubstituted or
disubstituted heteroaryl. In a further embodiment is a compound of Formula (Vc) wherein X is heteroaryl
monosubstituted or disubstituted with a substituent independently selected from halogen, -CN, optionally
23 25 26
substituted -(C -C )alkyl, optionally substituted -O-(C -C )alkyl, OR , -NR R , and -NO . In a further
1 6 1 6 2
embodiment is a compound of Formula (Vc) wherein X is heteroaryl monosubstituted or disubstituted with
a substituent independently selected from -(C -C )alkyl.In a further embodiment is a compound of
Formula (Vc) wherein X is heteroaryl monosubstituted or disubstituted with methyl. In a further
embodiment is a compound of Formula (Vc) wherein X is pyridinyl monosubstituted or disubstituted with
a substituent independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally
23 25 26
substituted -O-(C -C )alkyl, OR , -NR R , or -NO . In a further embodiment is a compound of Formula
1 6 2
(Vc) wherein X is pyridinyl monosubstituted or disubstituted with a substituent independently selected
from -(C -C )alkyl. In a further embodiment is a compound of Formula (Vc) wherein X is pyridinyl
monosubstituted or disubstituted with methyl. In a further embodiment is a compound of Formula (Vc) X
is pyrimidinyl monosubstituted or disubstituted with a substituent independently selected from halogen, -
23 25 26
CN, optionally substituted -(C -C )alkyl, optionally substituted -O-(C -C )alkyl, OR , -NR R , or -NO .
1 6 1 6 2
In a further embodiment is a compound of Formula (Vc) X is pyrimidinyl monosubstituted or disubstituted
with a substituent independently selected from -(C -C )alkyl. In a further embodiment is a compound of
Formula (Vc) X is pyrimidinyl monosubstituted or disubstituted with methyl.
[00475] In another embodiment is a compound of Formula (Vc) wherein Y is optionally substituted aryl.
In a further embodiment is a compound of Formula (Vc) wherein Y is optionally substituted phenyl. In
another embodiment is a compound of Formula (Vc) wherein Y is optionally substituted heteroaryl. In
18253141_1 (GHMatters) P111789.NZ
another embodiment is a compound of Formula (Vc) wherein Y is optionally substituted -(C -C )alkyl-. In
another embodiment is a compound of Formula (Vc) wherein Y is optionally substituted (C -
C )cycloalkyl-. In another embodiment is a compound of Formula (Vc) wherein Y is optionally substituted
heterocycloalkyl. In another embodiment is a compound of Formula (Vc) wherein Y is -O-. In another
embodiment is a compound of Formula (Vc) wherein Y is -(C -C )alkynyl. In another embodiment is a
compound of Formula (Vc) wherein Y is -O-(C -C )alkyl-. In another embodiment is a compound of
Formula (Vc) wherein Y is a bond.
In another embodiment is a compound of Formula (Vc) wherein Z is -(C -C )alkyl. In a further
1 12
embodiment is a compound of Formula (Vc) wherein Z is n-butyl, isobutyl, or tert-butyl. In another
embodiment is a compound of Formula (Vc) wherein Z is -O-(C -C )alkyl. In another embodiment is a
1 12
compound of Formula (Vc) wherein Z is -O-(C -C )cycloalkyl. In another embodiment is a compound of
Formula (Vc) wherein Z is -(C -C )alkenyl. In another embodiment is a compound of Formula (Vc)
2 12
wherein Z is optionally substituted aryl. In a further embodiment is a compound of Formula (Vc) wherein
Z is optionally substituted phenyl. In a further embodiment is a compound of Formula (Vc) wherein Z is
phenyl monsubstituted or disubstituted with a substituent independently selected from -(C -C )alkyl. In a
further embodiment is a compound of Formula (Vc) wherein Z is phenyl monosubstituted with n-butyl,
isobutyl, or tert-butyl. In a further embodiment is a compound of Formula (Vc) wherein Z is phenyl
monosubstituted with n-butyl. In a further embodiment is a compound of Formula (Vc) wherein Z is
phenyl monosubstituted with isobutyl. In a further embodiment is a compound of Formula (Vc) wherein Z
is phenyl monosubstituted with tert-butyl. In another embodiment is a compound of Formula (Vc) wherein
Z is optionally substituted heteroaryl. In another embodiment is a compound of Formula (Vc) wherein Z is
optionally substituted -(C -C )cycloalkyl. In another embodiment is a compound of Formula (Vc) wherein
Z is optionally substituted heterocycloalkyl. In another embodiment is a compound of Formula (Vc)
wherein Z is halogen.
[00477] In some embodiments, the compound of Formula (V), (Va), (Vb) and (Vc) is selected from a
compound in table 2 or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
Table 2
Cp. # Name Structure
563 rac-(8S,11S,14S)-4,18-bis(2-
aminoethoxy)hydroxymethyl-
14-[methyl-[rac-(2S)amino[[2-
(4-tert-butylphenyl)-4,6-dimethyl-
pyrimidine
N OH
carbonyl]amino]butanoyl]amino]-
O HN
,13-dioxo-9,12-
N N N O
diazatricyclo[13.3.1.12,6]icosa-
1(18),2,4,6(20),15(19),16-hexaene-
8-carboxylic acid
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
638 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)methyl
H N O
[methyl-[rac-(2S)amino[[4,6- O
dimethyl(4-
N OH
pentoxyphenyl)pyrimidine
carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxylic acid
639 rac-(8S,11S,14S)-3,18-bis(2- 2
aminoethoxy)methyl
[methyl-[rac-(2S)amino[[2-[4- O
(1-ethylcyclopropoxy)phenyl]-4,6-
dimethyl-pyrimidine
O HN
carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxylic acid
640 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)methyl
[methyl-[rac-(2S)amino[[2-(4-
tert-butylphenyl)methyl-
pyrimidine
N OH
carbonyl]amino]butanoyl]amino]-
O HN
,13-dioxo-9,12-
N N N O
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxylic acid 2
641 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)methyl
[methyl-[rac-(2S)amino[[2-(4-
H N O
hexoxyphenyl)-4,6-dimethyl-
pyrimidine
O HN
carbonyl]amino]butanoyl]amino]-
N N N
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxylic acid
642 rac-(8S,11S,14S)(2-
aminoethoxy)hydroxy
methyl[methyl-[rac-(2S)
amino[[4,6-dimethyl(4-
pentoxyphenyl)pyrimidine
N OH
O HN
carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo-9,12- N O
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxylic acid
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
643 rac-(8S,11S,14S)(2-
aminoethoxy)hydroxymethyl-
14-[methyl-[rac-(2S)amino[[2-
(4-isopropoxyphenyl)-4,6-dimethyl-
pyrimidine N OH
O HN
carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene- NH
8-carboxylic acid
644 rac-(8S,11S,14S)(2-
aminoethoxy)hydroxymethyl-
14-[methyl-[rac-(2S)amino[[6-
(4-tert-butylphenyl)-2,4-dimethyl-
pyridine N OH
O HN
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxylic acid
645 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)methyl
[methyl-[rac-(2S)amino[[2-(4-
tert-butylphenyl)-4,6-dimethyl-
pyrimidine
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12-
N N N O
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxylic acid
646 rac-(8S,11S,14S)(2- H N
aminoethoxy)hydroxymethyl-
14-[methyl-[rac-(2S)amino[[2-
(4-tert-butylphenyl)-4,6-dimethyl-
pyrimidine N
carbonyl]amino]butanoyl]amino]-
,13-dioxo-9,12- O
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxylic acid
647 rac-(8S,11S,14S)-3,18-bis(2-
aminoethoxy)methyl
[methyl-[rac-(2S)amino[[2-
(1,1-dimethylindanyl)-4,6-
dimethyl-pyrimidine
N OH
carbonyl]amino]butanoyl]amino]- O HN
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxylic acid
18253141_1 (GHMatters) P111789.NZ
Cp. # Name Structure
648 rac-(8S,11S,14S)(2-
aminoethoxy)hydroxymethyl-
14-[methyl-[rac-(2S)amino
[[4,6-dimethyl(4-
pentoxyphenyl)pyrimidine N OH
O HN
carbonyl]amino]butanoyl]amino]-
N N N O
,13-dioxo-9,12-
diazatricyclo[13.3.1.12,6]icosa-
1(18),2(20),3,5,15(19),16-hexaene-
8-carboxylic acid
N OH
N N N O
In another aspect are hydrates or metabolites of any of the aforementioned compounds.
In another aspect are pharmaceutical compositions comprising any of the aforementioned
compounds together with a pharmaceutically acceptable excipient.
[00480] In another aspect described herein is the use of a compound described herein in the manufacture
of a medicament for treatment of a bacterial infection in a patient.
In another aspect are methods of treating a mammal in need of such treatment comprising
administering to the mammal an antibacterial effective amount of any of the aforementioned compounds at
a frequency and for a duration sufficient to provide a beneficial effect to the mammal. In one embodiment,
the mammal has a bacteria-related infection that is resistant to treatment with arylomycin A2. In a further
embodiment, the causative bacteria species of the bacteria infection is an infection involoving
Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes,
Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia,
Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi,
Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae,
Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Francisella
tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia
rettgeri, Providencia stuartii, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter
haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia,
Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae,
Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus
ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Helicobacter pylori,
Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae,
18253141_1 (GHMatters) P111789.NZ
Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae,
Neisseria meningitidis, Kingella, Moraxella, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides
distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides
thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Clostridium
difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare,
Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus
pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus
faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus,
Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus,
Staphylococcus hominis, or Staphylococcus saccharolyticus. In another embodiment the bacterial infection
is an infection involving a Gram-negative bacteria. In another embodiment the bacterial infection is a
lepB-mediated infection. In a further embodiment, the bacterial infection is an infection involving a Gram-
positive bacteria.
In a further embodiment are methods of treating a mammal in need of such treatment comprising
administering to the mammal a second therapeutic agent to any of the aforementioned methods of
treatment. In another embodiment, the second therapeutic agent is a not an SpsB inhibitor. In another
embodiment, the second therapeutic agent is an aminoglycoside antibiotic, fluoroquinolone antibiotic, β-
lactam antibiotic, macrolide antibiotic, glycopeptide antibiotic, rifampicin, chloramphenicol,
fluoramphenicol, colistin, mupirocin, bacitracin, daptomycin, or linezolid.
[00483] In some embodiments is a method for treating a bacterial infection in a patient, preferably a
human, where the treatment includes administering a therapeutically or pharmacologically effective
amount of a combination of 1) a β-lactam antibiotic; and 2) a compound of Formula (I), (Ia)-(If), (II), (IIa)-
(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc), or a pharmaceutically acceptable salt thereof;
and 3) a pharmaceutically acceptable carrier. In embodiments where a β-lactam antibiotic is used in
combination with a compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc),
(V), or (Va)-(Vc), the β-lactam antibiotic may be a carbapenem, cephalosporin, cephamycin, monobactam
or penicillin. Exemplary carbapenem antibiotics useful in the methods of the invention include ertapenem,
imipenem, biapenem, and meropenem. Exemplary cephalosporin antibiotics useful in the methods of the
invention include, ceftobiprole, ceftaroline, Cefiprome, Cefozopran, cefepime, Cefotaxime, and
ceftriazone. Exemplary penicillin antibiotics useful in the methods of the invention include ampicillin,
amoxacillin, piperacillin, oxacillin, cloxacillin, methicillin, and nafcillin. In some embodiments of the
invention, the β-lactam may be administered with a β-lactamase inhibitor. In some embodiments of the
invention, the carbapenem may be administered with a DHP inhibitor, e.g., cilastatin.
In various embodiments of the invention where a compound of Formula (I), (Ia)-(If), (II), (IIa)-
(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc) and a β-lactam antibiotic are used in
combination, the β-lactam antibiotic and compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-
(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc) can be administered sequentially or concurrently. Preferably,
18253141_1 (GHMatters) P111789.NZ
the β-lactam antibiotic and compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV),
(IVa)-(IVc), (V), or (Va)-(Vc)are administered together. When administered concurrently, the β-lactam
antibiotic and compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V),
or (Va)-(Vc) may be administered in the same formulation or in separate formulations. When administered
sequentially, either the β-lactam or compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc),
(IV), (IVa)-(IVc), (V), or (Va)-(Vc) may be administered first. After administration of the first compound,
the other compound is administered, for example, within from 1 to 60 minutes, e.g., within 1, 2, 3, 4, 5, 10,
, 30, or 60 minutes. In one aspect of the invention, when a β-lactamase inhibitor is used, it may be
administered separately, or in a formulation with the compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe),
(III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc) and/or β-lactam antibiotic. In one aspect of the
invention, when a DHP inhibitor is used to improve the stability of a carbapenem, it may be administered
separately, or in a formulation with the compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-
(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc) and/or carbapenem.
Further described herein are pharmaceutical compositions comprising a compound of Formula
(I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc), a pharmaceutically
acceptable carrier, and optionally a β-lactam antibiotic. In embodiments where a combination is used, the
β-lactam antibiotic and the compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV),
(IVa)-(IVc), (V), or (Va)-(Vc), are present in such amounts that their combination constitutes a
therapeutically effective amount. Due to the potentiating effects of the compound of Formula (I), (Ia)-(If),
(II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc), the amount of β-lactam antibiotic
present in a combination may be less that of a β-lactam antibiotic used alone. In certain embodiments, the
composition further comprises a β-lactamase antibiotic.
In further embodiments where the β-lactam antibiotic is a carbapenem, is provided a
pharmaceutical composition comprising a carbapenem antibiotic, a DHP inhibitor, a compound of Formula
(I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc), and a pharmaceutically
acceptable carrier. In some embodiments where the β-lactara antibiotic is a carbepenem, the carbapenem
antibiotic is preferably selected from the group consisting of ertapenem, imipenem, and meropenem.
In some embodiments is a compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc),
(IV), (IVa)-(IVc), (V), or (Va)-(Vc) for use in treating a bacterial infection. In some embodiments is a
compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc),
in combination with one or more additional therapeutical agents including a β-lactam antibiotic, for use in
treating a bacterial infection. In some embodiments is a compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe),
(III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc) for use as a medicament for treating a bacterial
infection. In some embodiments is a compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc),
(IV), (IVa)-(IVc), (V), or (Va)-(Vc), in combination with one or more additional therapeutical agents
including a β-lactam antibiotic, for use as a medicament for treating a bacterial infection. In some
embodiments is a compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc),
18253141_1 (GHMatters) P111789.NZ
(V), or (Va)-(Vc) for use in the preparation of a medicament for treating a bacterial infection. In some
embodiments is a compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc),
(V), or (Va)-(Vc), in combination with one or more additional therapeutical agents including a β-lactam
antibiotic, for use in the preparation of a medicament for treating a bacterial infection.
[00488] In some embodiments described herein, a compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe),
(III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc) can enhance the activity of a β-lactam antibacterial
agent by inducing susceptibility to the antibacterial agent in a drug- resistant strain such as MRSA. In
some embodiments, a compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-
(IVc), (V), or (Va)-(Vc) can enhance the activity of a β-lactam antibacterial agent by reducing the dosage
of the antibacterial agent need for a therapeutic effect in a drug-sensitive strain. For example, if a
compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc)
reduces the Minimum Inhibitory Concentration (MIC) of an antibacterial agent (where the MIC is the
minimum concentration of antibacterial agent which will completely inhibit growth) in a susceptible strain,
then such treatment may be advantageous to enable a reduction in the amount of antibacterial agent
administered (could reduce side effects of an antibiotic), or to decrease the frequency of administration. In
some embodiments, compounds of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-
(IVc), (V), or (Va)-(Vc) can enhance the activity of an antibacterial agent such as a carbapenem to prevent
the emergence of a resistant sub-population in a heterogeneous bacterial population with a resistant sub-
population.
[00489] Potentiators can be used to enhance the activity of antibacterial agents whose clinical efficacy
has been limited by the increasing prevalence of resistant strains. In some embodiments described herein, a
compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc)
is used as a potentiator wherein a compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc),
(IV), (IVa)-(IVc), (V), or (Va)-(Vc) can be administered together with a β-lactam antibiotic (either
concurrently or sequentially) to allow effective treatment of an infection involving a resistant bacterium, or
to reduce the amount of antibacterial agent necessary to treat an infection.
In one embodiment, is a compound described herein which displays antibiotic activity useful in
the treatment of bacterial infections, such as by way of example only, various strains of S. aureus, S.
pneumoniae, E. faecalis, E. faecium, B. subtilis and E. coli including species that are resistant to many
known antibiotics such as methicillin-resistant S. aureus (MRSA), vancomycin-resistant Enterococcus sp.
(VRE), multidrug-resistant E. faecium, macrolide-resistant S. aureus and S. epidermidis, and linezolide-
resistant S. aureus and E. faecium.
Methicillin-Resistant Staphylococcus aureus
Staphylococcus aureus (S. aureus), a spherical bacterium, is the most common cause of staph
infections. S. aureus has been known to cause a range of illnesses from minor skin infections, such as
pimples, impetigo, boils, cellulitis folliculitis, furuncles, carbuncles, scalded skin syndrome, abscesses, to
life-threatening diseases such as pneumonia, meningitis, osteomyelitis endocarditis, toxic shock syndrome,
18253141_1 (GHMatters) P111789.NZ
and septicemia. Further, S. aureus is one of the most common causes of nosocomial infections, often
causing postsurgical wound infections.
Methicillin was introduced in the late 1950s to treat infections caused by penicillin-resistant S.
aureus. It has been reported previously that S. aureus isolates had acquired resistance to methicillin
(methicillin-resistant S. aureus, MRSA). The methicillin resistance gene (mecA) encodes a methicillin-
resistant penicillin-binding protein that is not present in susceptible strains. mecA is carried on a mobile
genetic element, the staphylococcal cassette chromosome mec (SCCmec), of which four forms have been
described that differ in size and genetic composition. The methicillin-resistant penicillin-binding protein
allows for resistance to β-lactam antibiotics and obviates their clinical use during MRSA infections.
[00493] In one aspect is a method for treating a subject having a resistant bacterium comprising
administering to the subject a compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV),
(IVa)-(IVc), (V), or (Va)-(Vc) or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In one
embodiment, the bacterium is a Gram-positive bacteria. In another embodiment, the Gram-positive
bacterium is S. aureus. In further embodiment, the S. aureus is resistant or refractory to a beta-lactam
antibiotic. In yet a further embodiment, the beta-lactam antibiotic belongs to the class of penicillins. In a
further embodiment, the beta-lactam antibiotic is methicillin. In yet another embodiment, the subject has a
methicillin-resistant S. aureus bacteria. In one embodiment the beta-lactam antibiotic is flucloxacillin. In
another embodiment is a method for treating a subject having a dicloxacillin-resistant bacteria comprising
administering to the subject a compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV),
(IVa)-(IVc), (V), or (Va)-(Vc) or a pharmaceutically acceptable salt, solvate, or prodrug thereof wherein
the subject is refractory to dicloxacillin. Also disclosed herein is a method for treating a subject having a
methicillin-resistant bacteria comprising administering a compound of Formula (I), (Ia)-(If), (II), (IIa)-
(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc) or a pharmaceutically acceptable salt, solvate,
or prodrug thereof wherein the subject has been determined to have a methicillin-resistant bacteria. In one
embodiment the subject is screened for methicillin-resistant bacteria. In another embodiment, the subject
screening is performed through a nasal culture. In a further embodiment the methicillin-resistant bacteria is
detected by swabbing the nostril(s) of the subject and isolating the bacteria. In another embodiment, Real-
time PCR and/or Quantitative PCR is employed to determine whether the subject has a methicillin-
resistant bacteria.
[00494] In one embodiment is a method for treating a subject having a first-generation cephalosporin-
resistant bacteria comprising administering a compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III),
(IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc) or a pharmaceutically acceptable salt, solvate, or prodrug
thereof wherein the subject is refractory to a first-generation cephalosporin. In one embodiment, the
bacteria is resistant to a first-generation cephalosporin. In a further embodiment, the bacteria is resistant to
cefacetrile. In another embodiment, the bacteria is resistant to cefadroxil. In yet another embodiment, the
bacteria is resistant to cefalexin. In one embodiment, the bacteria is resistant to cefaloglycin. In another
embodiment, the bacteria is resistant to cefalonium. In another embodiment, the bacteria is resistant to
18253141_1 (GHMatters) P111789.NZ
cefaloridine. In yet another embodiment, the bacteria is resistant to cefalotin. In a further embodiment, the
bacteria is resistant to cefapirin. In yet a further embodiment, the bacteria is resistant to cefatrizine. In one
embodiment, the bacteria is resistant to cefazaflur. In another embodiment, the bacteria is resistant to
cefazedone. In yet another embodiment, the bacteria is resistant to cefazolin. In a further embodiment, the
bacteria is resistant to cefradine. In yet a further embodiment, the bacteria is resistant to cefroxadine. In
one embodiment, the bacteria is resistant to ceftezole.
In one embodiment is a method for treating a subject having a second-generation cephalosporin-
resistant bacteria comprising administering a compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III),
(IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc) or a pharmaceutically acceptable salt, solvate, or prodrug
thereof wherein the subject is refractory to a second-generation cephalosporin. In another embodiment, the
bacteria is resistant to a second-generation cephalosporin. In a further embodiment, the bacteria is resistant
to cefaclor. In another embodiment, the bacteria is resistant to cefonicid. In yet another embodiment, the
bacteria is resistant to cefprozil. In one embodiment, the bacteria is resistant to cefuroxime. In another
embodiment, the bacteria is resistant to cefuzonam. In another embodiment, the bacteria is resistant to
cefmetazole. In yet another embodiment, the bacteria is resistant to cefotetan. In a further embodiment, the
bacteria is resistant to cefoxitin.
In one embodiment is a method for treating a subject having a third-generation cephalosporin-
resistant bacteria comprising administering a compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III),
(IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc) or a pharmaceutically acceptable salt, solvate, or prodrug
thereof wherein the subject is refractory to a third-generation cephalosporin. In another embodiment, the
bacteria is resistant to a third-generation cephalosporin. In a further embodiment, the bacteria is resistant to
cefcapene. In another embodiment, the bacteria is resistant to cefdaloxime. In yet another embodiment, the
bacteria is resistant to cefdinir. In one embodiment, the bacteria is resistant to cefditoren. In another
embodiment, the bacteria is resistant to cefixime. In another embodiment, the bacteria is resistant to
cefmenoxime. In yet another embodiment, the bacteria is resistant to cefodizime. In a further embodiment,
the bacteria is resistant to cefotaxime. In yet a further embodiment, the bacteria is resistant to cefpimizole.
In one embodiment, the bacteria is resistant to cefpodoxime. In another embodiment, the bacteria is
resistant to cefteram. In yet another embodiment, the bacteria is resistant to ceftibuten. In a further
embodiment, the bacteria is resistant to ceftiofur. In yet a further embodiment, the bacteria is resistant to
ceftiolene. In one embodiment, the bacteria is resistant to ceftizoxime. In another embodiment, the bacteria
is resistant to ceftriaxone. In yet another embodiment, the bacteria is resistant to cefoperazone. In yet a
further embodiment, the bacteria is resistant to ceftazidime.
In one embodiment is a method for treating a subject having a fourth-generation cephalosporin-
resistant bacteria comprising administering a compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III),
(IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc) or a pharmaceutically acceptable salt, solvate, or prodrug
thereof wherein the subject is refractory to a fourth-generation cephalosporin. In another embodiment, the
bacteria is resistant to a fourth-generation cephalosporin. In a further embodiment, the bacteria is resistant
18253141_1 (GHMatters) P111789.NZ
to cefclidine. In another embodiment, the bacteria is resistant to cefepime. In yet another embodiment, the
bacteria is resistant to cefluprenam. In one embodiment, the bacteria is resistant to cefoselis. In another
embodiment, the bacteria is resistant to cefozopran. In another embodiment, the bacteria is resistant to
cefpirome. In yet another embodiment, the bacteria is refractory to cefquinome.
[00498] In one embodiment is a method for treating a subject having a carbapenem-resistant bacteria
comprising administering a compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV),
(IVa)-(IVc), (V), or (Va)-(Vc) or a pharmaceutically acceptable salt, solvate, or prodrug thereof wherein
the subject is refractory to a carbapenem. In another embodiment, the bacteria is resistant to a carbapenem.
In a further embodiment, the bacteria is resistant to imipenem. In another embodiment, the bacteria is
resistant to meropenem. In yet another embodiment, the bacteria is resistant to ertapenem. In one
embodiment, the bacteria is resistant to faropenem. In another embodiment, the bacteria is resistant to
doripenem. In another embodiment, the bacteria is resistant to panipenem. In yet another embodiment, the
bacteria is resistant to biapenem,
Vancomycin-Intermediate and Vancomycin-Resistant Staphylococcus aureus
[00499] Vancomycin-intermediate Staphylococcus aureus and vancomycin-resistant staphylococcus
aureus are specific types of antimicrobial-resistant Staph bacteria that are refractory to vancomycin
treatment. S. aureus isolates for which vancomycin MICs are 4-8 μg/mL are classified as vancomycin-
intermediate and isolates for which vancomycin MICs are ≥16 μg/mL are classified as vancomycin-
resistant (Clinical and Laboratory Standards Institute/NCCLS. Performance Standards for Antimicrobial
Susceptibility Testing. Sixteenth informational supplement. M100-S16. Wayne, PA: CLSI, 2006).
As used herein, the term “minimum inhibitory concentration” (MIC) refers to the lowest
concentration of an antibiotic that is needed to inhibit growth of a bacterial isolate in vitro. A common
method for determining the MIC of an antibiotic is to prepare several tubes containing serial dilutions of
the antibiotic, that are then inoculated with the bacterial isolate of interest. The MIC of an antibiotic is
determined from the tube with the lowest concentration that shows no turbidity (no growth).
In one aspect is a method of treating a subject having a bacterial infection comprising
administering to the subject a compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV),
(IVa)-(IVc), (V), or (Va)-(Vc) or a pharmaceutically acceptable salt, solvate, or prodrug thereof wherein
the bacterial infection comprises a vancomycin-intermediate Staphylococcus aureus bacterium. In one
embodiment, the vancomycin-intermediate Staphylococcus aureus bacterium has a MIC of between about
4 to about 8 µg/mL. In another embodiment, the vancomycin-intermediate Staphylococcus aureus
bacterium has a MIC of about 4 µg/mL. In yet another embodiment, the vancomycin-intermediate
Staphylococcus aureus bacterium has a MIC of about 5 µg/mL. In a further embodiment, the vancomycin-
intermediate Staphylococcus aureus bacterium has a MIC of about 6 µg/mL. In yet a further embodiment,
the vancomycin-intermediate Staphylococcus aureus bacterium has a MIC of about 7 µg/mL. In one
embodiment, the vancomycin-intermediate Staphylococcus aureus bacterium has a MIC of about 8 µg/mL.
18253141_1 (GHMatters) P111789.NZ
In another aspect is a method of treating a subject having a bacterial infection comprising
administering to the subject a compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV),
(IVa)-(IVc), (V), or (Va)-(Vc) or a pharmaceutically acceptable salt, solvate, or prodrug thereof wherein
the bacterial infection comprises a vancomycin-resistant Staphylococcus aureus bacterium. In one
embodiment, the vancomycin-resistant Staphylococcus aureus bacterium has a MIC of between about 16
µg/mL. In another embodiment, the vancomycin-resistant Staphylococcus aureus bacterium has a MIC of
about ≥ 16 µg/mL. In yet another embodiment, the vancomycin-resistant Staphylococcus aureus bacterium
has a MIC of about 20 µg/mL. In a further embodiment, the vancomycin-resistant Staphylococcus aureus
bacterium has a MIC of about 25 µg/mL.
[00503] In one embodiment, conditions treated by the compounds described herein include, but are not
limited to, endocarditis, osteomyelitis, neningitis, skin and skin structure infections, genitourinary tract
infections, abscesses, and necrotizing infections. In another embodiment, the compounds disclosed herein
are used to treat conditions, such as, but not limited to, diabetic foot infections, decubitus ulcers, burn
infections, animal or human bite wound infections, synergistic-necrotizing gangrene, necrotizing fascilitis,
intra-abdominal infection associated with breeching of the intestinal barrier, pelvic infection associated
with breeching of the intestinal barrier, aspiration pneumonia, and post-operative wound infections. In
another embodiment, the conditions listed herein are caused by, contain, or result in the presence of VISA
and/or VRSA.
Vancomycin-Resistant Enterococci
[00504] Enterococci are bacteria that are normally present in the human intestines and in the female
genital tract and are often found in the environment. These bacteria sometimes cause infections. In some
cases, enterococci have become resistant to vancomycin (also known as vancomycin-resistant enterococci
or VRE.) Common forms of resistance to vancomycin occur in enterococcal strains that involve the
acquisition of a set of genes endoding proteins that direct peptidoglycan precursors to incorporate D-Ala-
D-Lac instead of D-Ala-D-Ala. The six different types of vancomycin resistance shown by enterococcus
are: Van-A, Van-B, Van-C, Van-D, Van-E and Van-F. In some cases, Van-A VRE is resistant to both
vancomycin and teicoplanin, while in other cases, Van-B VRE is resistant to vancomycin but sensitive to
teicoplanin; in further cases Van-C is partly resistant to vancomycin, and sensitive to teicoplanin.
In one aspect, is a method of treating a subject having a vancomycin-resistant enterococci
comprising administering to the subject a compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-
(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc) or a pharmaceutically acceptable salt, solvate, or prodrug
thereof wherein the enterococci has developed resistance to vancomycin. In one embodiment, the subject
has been previously treated with vancomycin for a sustained period of time. In another embodiment, the
subject has been hospitalized. In yet another embodiment, the subject has a weakened immune system such
as patients in Intensive Care Units or in cancer or transplant wards. In a further embodiment, the subject
has undergone surgical procedures such as, for example, abdominal or chest surgery. In yet a further
embodiment, the subject has been colonized vith VRE. In one embodiment, the subject has a medical
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device such that an infection has developed. In another embodiment, the medical device is a urinary
catheter or central intravenous (IV) catheter.
In another embodiment, is a method of treating a subject having a vancomycin-resistant
enterococci comprising administering to the subject a compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe),
(III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc) or a pharmaceutically acceptable salt, solvate, or
prodrug thereof wherein the enterococcus has Van-A resistance.
In another embodiment, is a method of treating a subject having a vancomycin-resistant
enterococci comprising administering to the subject a compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe),
(III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc) or a pharmaceutically acceptable salt, solvate, or
prodrug thereof wherein the enterococcus has Van-B resistance.
In another embodiment, is a method of treating a subject having a vancomycin-resistant
enterococci comprising administering to the subject a compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe),
(III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc) or a pharmaceutically acceptable salt, solvate, or
prodrug thereof wherein the enterococcus has Van-C resistance.
Administration and Pharmaceutical Composition
Pharmaceutical compositions described herein comprise a therapeutically effective amount of a
compound described herein (i.e., a compound of any of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-
(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc)) formulated together with one or more pharmaceutically
acceptable carriers. As used herein, the term “pharmaceutically acceptable carrier” means a non-toxic,
inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as
lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives
such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt;
gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil;
safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such
as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum
hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol, and
phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate
and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring
and perfuming agents, preservatives and antioxidants can also be present in the composition, according to
the judgment of the formulator. The pharmaceutical compositions described herein can be administered to
humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally,
topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray, or a liquid aerosol or
dry powder formulation for inhalation.
[00510] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions,
microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid
dosage forms optionally contain inert diluents commonly used in the art such as, for example, water or
18253141_1 (GHMatters) P111789.NZ
other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),
glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures
thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents,
emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions are
optionally formulated according to the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation is optionally a sterile injectable solution, suspension
or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-
butanediol. Among the acceptable vehicles and solvents that are optionally employed are water, Ringer’s
solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally
employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed
including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the
preparation of injectables.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-
retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be
dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug
from subcutaneous or intramuscular injection. This is optionally accomplished by the use of a liquid
suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the
drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline
form. Alternatively, delayed absorption of a parenterally administered drug form is optionally
accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by
forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide.
Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of
drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are optionally prepared by entrapping the drug in
liposomes or microemulsions which are compatible with body tissues.
[00514] Compositions for rectal or vaginal administration are preferably suppositories which can be
prepared by mixing the compound described herein (i.e., a compound of any of Formula (I), (Ia)-(If), (II),
(IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc)) with suitable non-irritating excipients or
carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient
temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release
the active compound.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and
granules. In such solid dosage forms, the active compound is mixed with at least one inert,
18253141_1 (GHMatters) P111789.NZ
pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a)
fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such
as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c)
humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or
tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as
paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as,
for example, acetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay,
and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium
lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form optionally
comprise buffering agents.
Solid compositions of a similar type are optionally employed as fillers in soft and hard-filled
gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight
polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with
coatings and shells such as enteric coatings and other coatings known in the pharmaceutical formulating
art. They optionally contain opacifying agents and can also be of a composition that they release the active
ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
Examples of embedding compositions which can be used include polymeric substances and waxes.
Solid compositions of a similar type are optionally employed as fillers in soft and hard-filled
gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight
polyethylene glycols and the like.
The active compounds can also be in micro-encapsulated form with one or more excipients as
noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with
coatings and shells such as enteric coatings, release controlling coatings and other coatings known in the
pharmaceutical formulating art. In such solid dosage forms the active compound is optionally admixed
with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms optionally comprise, as
is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other
tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and
pills, the dosage forms optionally comprise buffering agents. They optionally contain opacifying agents
and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a
certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions
which can be used include polymeric substances and waxes.
Dosage forms for topical or transdermal administration of a compound described herein include
ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active
component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed
preservatives or buffers as are optionally required. Ophthalmic formulations, ear drops, and the like are
also contemplated.
18253141_1 (GHMatters) P111789.NZ
The ointments, pastes, creams and gels may contain, in addition to an active compound
described herein, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth,
cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or
mixtures thereof.
[00522] Compositions described herein are optionally formulated for delivery as a liquid aerosol or
inhalable dry powder. Liquid aerosol formulations are optionally nebulized predominantly into particle
sizes that can be delivered to the terminal and respiratory bronchioles where bacteria reside in patients with
bronchial infections, such as chronic bronchitis and pneumonia. Pathogenic bacteria are commonly present
throughout airways down to bronchi, bronchioli and lung parenchema, particularly in terminal and
respiratory bronchioles. During exacerbation of infection, bacteria can also be present in alveoli. Liquid
aerosol and inhalable dry powder formulations are preferably delivered throughout the endobronchial tree
to the terminal bronchioles and eventually to the parenchymal tissue.
Aerosolized formulations described herein are optionally delivered using an aerosol forming
device, such as a jet, vibrating porous plate or ultrasonic nebulizer, preferably selected to allow the
formation of a aerosol particles having with a mass medium average diameter predominantly between 1 to
. Further, the formulation preferably has balanced osmolarity ionic strength and chloride concentration,
and the smallest aerosolizable volume able to deliver effective dose of the compounds described herein
compound described herein (i.e., a compound of any of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-
(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc)) to the site of the infection. Additionally, the aerosolized
formulation preferably does not impair negatively the functionality of the airways and does not cause
undesirable side effects.
Aerosolization devices suitable for administration of aerosol formulations described herein
include, for example, jet, vibrating porous plate, ultrasonic nebulizers and energized dry powder inhalers,
that are able to nebulize the formulation into aerosol particle size predominantly in the size range from 1-
5µ. Predominantly in this application means that at least 70% but preferably more than 90% of all
generated aerosol particles are within 1-5µ range. A jet nebulizer works by air pressure to break a liquid
solution into aerosol droplets. Vibrating porous plate nebulizers work by using a sonic vacuum produced
by a rapidly vibrating porous plate to extrude a solvent droplet through a porous plate. An ultrasonic
nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets. A variety of
suitable devices are available, including, for example, AeroNebTM and AeroDoseTM vibrating porous
plate nebulizers (AeroGen, Inc., Sunnyvale, California), Sidestream® nebulizers (Medic-Aid Ltd., West
Sussex, England), Pari LC® and Pari LC Star® jet nebulizers (Pari Respiratory Equipment, Inc.,
Richmond, Virginia), and AerosonicTM (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden,
Germany) and UltraAire® (Omron Healthcare, Inc., Vernon Hills, Illinois) ultrasonic nebulizers.
[00525] In some embodiments, compounds described herein compound described herein (i.e., a
compound of any of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or
(Va)-(Vc)) are formulated for use as topical powders and sprays that contain, in addition to the compounds
18253141_1 (GHMatters) P111789.NZ
described herein, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and
polyamide powder, or mixtures of these substances. Sprays optionally contain customary propellants such
as chlorofluorohydrocarbons.
Transdermal patches have the added advantage of providing controlled delivery of a compound
to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper
medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The
rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a
polymer matrix or gel.
According to the methods of treatment described herein, bacterial infections are treated or
prevented in a patient such as a human or lower mammal by administering to the patient a therapeutically
effective amount of a compound described herein, in such amounts and for such time as is necessary to
achieve the desired result. By a “therapeutically effective amount” of a compound described herein is
meant a sufficient amount of the compound to treat bacterial infections, at a reasonable benefit/risk ratio
applicable to any medical treatment. It will be understood, however, that the total daily usage of the
compounds and compositions described herein will be decided by the attending physician within the scope
of sound medical judgment. The specific therapeutically effective dose level for any particular patient will
depend upon a variety of factors including the disorder being treated and the severity of the disorder; the
activity of the specific compound employed; the specific composition employed; the age, body weight,
general health, sex and diet of the patient; the time of administration, route of administration, and rate of
excretion of the specific compound employed; the duration of the treatment; drugs used in combination or
coincidental with the specific compound employed; and like factors known in the medical arts.
The total daily dose of the compounds described herein compound described herein (i.e., a
compound of any of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or
(Va)-(Vc)) administered to a human or other mammal in single or in divided doses can be in amounts, for
example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight. Single
dose compositions may contain such amounts or submultiples thereof to make up the daily dose. In
general, treatment regimens described herein comprise administration to a patient in need of such
treatment from about 10 mg to about 2000 mg of the compound(s) described herein per day in single or
multiple doses.
Examples
Compounds disclosed herein are made by the methods depicted in the reaction schemes shown
below. Procedures are provided herein that, in combination with the knowledge of the synthetic organic
chemist of ordinary skill in the art, are in some embodiments used to prepare the full range of compounds
as disclosed and claimed herein.
[00530] The starting materials and reagents used in preparing these compounds are either available from
commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or
Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures
18253141_1 (GHMatters) P111789.NZ
set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John
Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals
(Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991),
March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock’s Comprehensive
Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some
methods by which the compounds disclosed herein are in some embodiments synthesized, and various
modifications to these schemes can be made and will be suggested to one skilled in the art having referred
to this disclosure. The starting materials and the intermediates, and the final products of the reaction may
be isolated and purified if desired using conventional techniques, including but not limited to filtration,
distillation, crystallization, chromatography and the like. Such materials may be characterized using
conventional means, including physical constants and spectral data. Compounds are typically isolated as
formic acid salts by reverse phase HPLC using AcCN/H 0 with formic acid as an additive. In some
instances, purifications are conducted without formic acid, and the compounds are isolated as the free base.
The methods of LCMS analysis are as follows:
[00532] LCMS (Method 5-95 AB, ESI): ESI, 5% AcCN/H O, 0.7 min; to 95% AcCN/H O, 0.4 min; 1.5
mL/min, Merck RP-18e, 2 x 25 mm.
LCMS (Method 10-80AB, 2 min, ESI): ESI, 10% AcCN/H O (0.04% TFA), 0.9 min to 80%
AcCN/H O (0.04% TFA), then held for 0.6 min; 1.2 mL/min, Xtimate C18, 3 μm, 2.1 x 30 mm).
LCMS (Method 10-80AB, 7 min, ESI): ESI, 10% AcCN/H O (0.04% TFA), 6 min to 80%
AcCN/H O (0.04% TFA), then held for 0.9 min; 0.8 mL/min, Xtimate C18, 3 μm, 2.1 x 30 mm).
Example A: Synthesis of (S)-methyl 2-amino(4-methoxy(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)phenyl)propanoate
M O C NH
e e St p 2
M N e M N
O C St p 1 O C e
M O C N
oc oc
B B oc
Ag SO /I
M I/K CO
2 4 2
2 3 I
ace one
O O e
St p 3
St p 4 e
e M NH
M O C N
oc O
TFA DCM B
c OM
KOA /PdCl dppf
DMSO
[00535] Step 1: To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)(4-
hydroxyphenyl)propanoate (100 g, 0.323 mol) in acetone (2.0 L) was added K CO (37 g, 0.34 mol). After
the addition, MeI (32 mL, 0.97 mol) was added dropwise, and the reaction mixture was stirred at room
temperature for 72 h and monitored by TLC. The reaction had not yet gone to completion, so NaOH (0.1
18253141_1 (GHMatters) P111789.NZ
eq) was added to the reaction mixture. And after 2 h, the reaction was completed. The solid was filtered
and the solvent was removed. The residue was taken up in ethyl acetate and washed with H O, extracted
with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine, dried over Na SO
and concentrated to give (S)-methyl 2-((tert-butoxycarbonyl)amino)(4-methoxyphenyl)propanoate (100
g, 95.4%).
Step 2: To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)(4-
methoxyphenyl)propanoate (80 g, 40 g each x 2, run in two separate batches, 259 mmol overall) in
methanol (1.5 L in each of the two flasks) was added sequentially Ag SO (85 g, 272 mmol, ½-added to
each flask) and I (72 g, 283 mmol, ½-added to each flask). The reaction mixture was stirred at room
temperature for 2 h. The reaction was monitored by LCMS. When all (S)-methyl 2-((tert-
butoxycarbonyl)amino)(4-methoxyphenyl)propanoate had been consumed, then a solution of 10%
(w/w) sodium thiosulfate was added until the reaction turned pale yellow. The solid was filtered and most
of the methanol was evaporated by rotary evaporation. Water and ethyl acetate were added to each batch.
The aqueous layer was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were
washed with brine, dried over sodium sulfate and concentrated. The crude material was combined for the
two batches and they were purified together by flash column chromatography on silica gel (25% then 35%
then 40% ethyl acetate in hexanes) to give (S)-methyl 2-((tert-butoxycarbonyl)amino)(3-iodo
methoxyphenyl)propanoate (97 g, 89%).
Step 3: (S)-Methyl 2-((tert-butoxycarbonyl)amino)(3-iodomethoxyphenyl)propanoate (92
g, 46 g each run in two separate batches, 211 mmol) was dissolved in anhydrous DMSO (1.5 L, ½-added
for each batch) under argon and to the solution was added bis(pinacolato) diboron (80.5 g, 317 mmol, ½-
added for each batch) and KOAc (103 g, 1.05 mol, ½-added for each batch). This mixture was degassed
with argon for twenty minutes, then Pd(dppf)Cl (4.6 g, 6 mmol, ½-added for each batch) was added. The
mixture was degassed with argon five times, then kept under argon and heated to 80˚C for 3 h. TLC
showed that the reaction was complete, and the reaction mixture was cooled to room temperature and
filtered. The reaction mixture was dissolved in EA and washed with H O. The aqueous layer was extracted
ethyl acetate (3 x 200 mL). The combined organic layers were dried over sodium sulfate, filtered and
concentrated to give the crude product. The batches were then combined and purified together by flash
column chromatography on silica gel (3% ethyl acetate in hexanes, then 20% to 25% ethyl acetate in
hexanes to give (S)-methyl 2-((tert-butoxycarbonyl)amino)(4-methoxy(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)phenyl)propanoate (70 g, 76%).
Step 4: (S)-Methyl 2-((tert-butoxycarbonyl)amino)(4-methoxy(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)phenyl)propanoate (22 g, 50.6 mmol) was dissolved in dichloromethane (150 mL) and
treated with trifluoroacetic acid (50 mL). The reaction mixture was stirred at room temperature and the
reaction was monitored by HPLC. When all of the starting material had been consumed, the solvents were
evaporated, DCM was added and Na CO was added to neutralize the TFA. The mixture was filtered, and
the solution was concentrated. DCM was added to the concentrated oil, and the mixture was cooled at 0 C
18253141_1 (GHMatters) P111789.NZ
for 1hr, whereupon the solid precipitates that formed were filtered. The filtrate was concentrated to give
(S)-methyl 2-amino(4-methoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl)propanoate. The
material was used without further purification.
Example B: Synthesis of (S)((tert-butoxycarbonyl)amino)(4-hydroxyphenyl)acetic acid
B OH
OH OH
St p 1
St p 2
B O/
N HCO CH O /T OH
( 2 )
ace one
t /H2O
o uene
OH oc O
St p 3
oc a
B O/N HCO
N CO /THF
2 3 e
Et SiH
B OH
Step 1: To a stirred mixture of (S)amino(4-hydroxyphenyl)acetic acid (100 g, 0.6 mol, 1
eq) in a mixture of acetone (400 mL) and water (400 mL) was added di-tert-butyl dicarbonate (130.5 g, 0.6
mol, 1 eq) and NaHCO (75.4 g, 0.9 mol, 1.5 eq). The mixture was allowed to stir at 25 C overnight. After
HPLC showed the reaction was complete, the mixture was acidified with 5% citric acid (pH ~ 3). The
mixture was filtered and the filter cake was washed with water, then dried to give (S)((tert-
butoxycarbonyl)amino)(4-hydroxyphenyl)acetic acid (140 g, 87.5%). The crude product was used
directly without further purification.
Step 2: To a solution of (S)((tert-butoxycarbonyl)amino)(4-hydroxyphenyl)acetic acid (45
g, 0.17 mol) in dry benzene (500 mL) was added paraformaldehyde (75.6 g, 0.84 mol, 5 eq) and p-
toluenesulfonic acid (1.6 g, 8.5 mmol, 0.05 eq). A Dean-Stark apparatus with an attached condenser was
then fit to the top of the flask and the mixture was heated at approximately 120˚C until LC-MS showed the
reaction was complete. The reaction was then cooled and the benzene was evaporated. The residue was
taken up in ethyl acetate, washed with saturated NaHCO (2 x 150 mL), then dried over sodium sulfate,
and filtered. The solvent was removed to give (S)-tert-butyl 4-(4-hydroxyphenyl)oxooxazolidine
carboxylate (36 g, 76.5%).
Step 3: (S)-tert-Butyl 4-(4-hydroxyphenyl)oxooxazolidinecarboxylate (36 g, 0.13 mol, 1
eq) was dissolved in trifluoroacetic acid (75 mL) at 0 C then treated with triethylsilane (80 mL, 4 eq). The
mixture was stirred at room temperature overnight. After LC-MS showed the reaction was complete, TFA
was then evaporated to afford (S)(4-hydroxyphenyl)(methylamino)acetic acid, which was used
without further purification.
18253141_1 (GHMatters) P111789.NZ
Step 4: The resultant (S)(4-hydroxyphenyl)(methylamino)acetic acid was dissolved in
water (85 mL), and to this solution was added solid NaHCO until the pH reached 7. The solution was
cooled to 0 C, then Na CO was added until pH reached 9. A solution of di-tert-butyldicarbonate (28.3 g,
1.0 eq) in THF (75 mL) was added to the mixture. The mixture was allowed to warm to room temperature
then stirred overnight. After HPLC showed the reaction was complete, THF was then evaporated. The
aqueous solution was extracted 2x with hexanes and then acidified with citric acid to pH ~3-4. The
acidified solution was then extracted with ethyl acetate (200 mL x 3). The combined organic layers were
washed with brine, dried over sodium sulfate, filtered and concentrated to give (S)((tert-
butoxycarbonyl)(methyl)amino)(4-hydroxyphenyl)acetic acid (35 g, 97% via 2 steps).
Example C: Synthesis of Compound 101-B
CO M
101 B
H OM
OH O
St p 1
t 2 t
S p S p 3
EDCI/HOBt
I /Ag SO
Et N/DMF e
M I 2 2 4
ace one
e M OH
e M NH M NH
N N O
oc e
oc oc e B
H l B O M O M
B OH C
St p 5
St p 4 I
O BPi
LiOH
M NH H O/THF
M NH
N OH
HOBt/EDCI/DMF
oc e
oc H N
B O C C
O O M O
St p 6
CO M
PdCl dppf
N H DMF
CO /
B NH
M NH O
N NH
oc e e
O M O M O
CO M
101 A
St p 7
1 1 B
Step 1: To a solution of (S)((tert-butoxycarbonyl)(methyl)amino)(4-hydroxyphenyl)acetic
acid (35 g, 0.12 mol) in DMF (300 mL) was added triethylamine (18.4 mL, 0.14 mol, 1.1 eq), HOBt (16.2
g, 0.12 mol, 1 eq), Ala-OMe HCl (19.5 g, 0.14 mol, 1.1 eq) and EDC (26.7 g, 0.14 mol, 1.1 eq) and the
18253141_1 (GHMatters) P111789.NZ
reaction was stirred overnight. After LC-MS showed the reaction was complete, water and EtOAc were
added. The aqueous layer was extracted with EtOAc (3×150 mL), and the combined organic layers were
washed with 5% citric acid (pH – 3), saturated NaHCO (aq), water and brine. The combined organic
layers were then dried over sodium sulfate, filtered and concentrated to give (S)-methyl 2-((S)((tert-
butoxycarbonyl)(methyl)amino)(4-hydroxyphenyl)acetamido)propanoate (30 g, 65.8%) as a white
foam. The crude product was taken on to the next step directly without further purification.
Step 2: To a solution of (S)-methyl 2-((S)((tert-butoxycarbonyl)(methyl)amino)(4-
hydroxyphenyl)acetamido)propanoate (30 g, 82 mmol) in acetone (400 mL) was added K CO (56.6 g,
0.41 mol, 5 eq) and iodomethane (20.8 mL, 0.41 mol, 5 eq) and the reaction was stirred at reflux overnight.
After LC-MS showed the reaction was complete, the reaction was then cooled to room temperature and the
mixture was filtered. The filtrate was concentrated and the residue was taken up in water and ethyl acetate.
The aqueous phase was extracted with EtOAc (3 x 150 mL). The combined organic layers were dried over
sodium sulfate, filtered and concentrated to give (S)-methyl 2-((S)((tert-
butoxycarbonyl)(methyl)amino)(4-methoxyphenyl)acetamido)propanoate (28 g, 90%), as a white foam.
[00545] Step 3: To a solution of (S)-methyl 2-((S)((tert-butoxycarbonyl)(methyl)amino)(4-
methoxyphenyl)acetamido)propanoate (85 g, 0.22 mol, 1 eq) in methanol (1000 mL) was added
sequentially Ag SO (72.6 g, 0.23 mol, 1.05 eq) and I (59.6 g, 1.05 eq). After LC-MS showed the reaction
2 4 2
was complete, a solution of 10% (w/w) sodium thiosulfate was added until the reaction turned pale yellow.
Most of the methanol was evaporated by rotary evaporation and then water and ethyl acetate were added.
The aqueous layer was extracted with ethyl acetate (3 x 300 mL). The combined organic layers were
washed with brine, dried over sodium sulfate and concentrated to give (S)-methyl 2-((S)((tert-
butoxycarbonyl)(methyl)amino)(3-iodomethoxyphenyl)acetamido)propanoate (100 g, 88.5%).
Step 4: To (S)-methyl 2-((S)((tert-butoxycarbonyl)(methyl)amino)(3-iodo
methoxyphenyl)acetamido)propanoate (25 g, 49.4 mmol, 1 eq) in THF (300 mL) was added 0.2 M LiOH
(500 mL, 98.8 mmol, 2 eq). The solution was stirred until TLC showed all starting material had been
consumed. 5% citric acid (pH – 3) was added to pH – 3 and then the THF was evaporated by rotary
evaporation. The aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic layers
were washed with brine, dried over sodium sulfate, filtered and concentrated to give (S)((S)((tert-
butoxycarbonyl)(methyl)amino)(3-iodomethoxyphenyl)acetamido)propanoic acid (23 g, 94.6%),
which was used directly without further purification.
Step 5: To a solution of (S)-methyl 2-amino(4-methoxy(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)phenyl)propanoate (6.5 g, 19.4 mmol, 1 eq) and (S)((S)((tert-
butoxycarbonyl)(methyl)amino)(3-iodomethoxyphenyl)acetamido)propanoic acid (10 g, 20.3 mmol,
1.05 eq) in acetonitrile:DMF (2.2:1, 168 mL) was added HOBt (6.5 g, 48.5 mmol, 2.5 eq) and EDC (8.1 g,
42.7 mmol, 2.2 eq). The reaction was stirred at room temperature overnight. After LC-MS showed the
reaction was complete, diluted citric acid (pH- 3) was added and the aqueous was extracted with EtOAc (3
x 150 mL). The combined organic layers were then washed with saturated NaHCO solution, brine and
18253141_1 (GHMatters) P111789.NZ
dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated to give the crude
product (6S,9S,12S)-methyl 6-(3-iodomethoxyphenyl)(4-methoxy(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)benzyl)-2,2,5,9-tetramethyl-4,7,10-trioxooxa-5,8,11-triazatridecanoate, which
was used directly without further purification.
[00548] Step 6: (6S,9S,12S)-Methyl 6-(3-iodomethoxyphenyl)(4-methoxy(4,4,5,5-tetramethyl-
1,3,2-dioxaborolanyl)benzyl)-2,2,5,9-tetramethyl-4,7,10-trioxooxa-5,8,11-triazatridecanoate (16
g, 19.4 mmol, 1 eq) and NaHCO (16.3 g, 0.19 mol) were sealed in a flask with a condenser and put under
an atmosphere of argon. DMF (600 mL) in a round bottle flask was purged several times via cycling with
vacuum and Ar. PdCl (dppf) (3.3 g, 4.5 mmol) was then added to the DMF. The DMF solution was then
degassed with Ar for 15 minutes. The solution of PdCl (dppf) dissolved in DMF was then transferred via
syringe to the flask containing the substrate and NaHCO . The resulting mixture was submitted to several
more cycles of vacuum and Ar then heated to 120ºC overnight. After LCMS showed the reaction was
completed, DMF was evaporated under vacuum. The crude material was subjected to abbreviated column
chromatography (40% EA in PE) to remove most of the Pd species and then purified by prep HPLC to
give Compound 101-A (2.1 g, 19.5% over two steps).
Step 7: To a stirred solution of Compound 101-A (2.1 g, 3.78 mmol) in DCM (25 mL) was
added TFA (2 mL). The reaction was monitored via TLC and when starting material was consumed, the
solvent was evaporated under vacuum. The residue was then dissolved in EtOAc and the organic layer was
washed with saturated NaHCO (10 mL), dried over sodium sulfate and concentrated to give Compound
101-B (1.7 g, 98.8%). MS (ESI) m/z 456.2 (M + H) .
18253141_1 (GHMatters) P111789.NZ
Example D: Synthesis of Compound 101-G
O HO
O OH
AlBr /EtSH
O OH
HN HN
N O N O
HN O HN
101-B 101-C
i. CbzOSu, NaOH,
Dioxane/H O
1.25 M HCl
in MeOH
ii. 2M
NaOH, H
Cbz N O
Cbz N O
MeOH
101-D
101-E
NHBoc
NHBoc
BocHN
BocHN
NHBoc
Pd/C, H
OMe HN
MeOH
K CO , DMF HN H
H N O
Cbz N
O HN O
101-G
101-F
Step 1: To a solution of Compound 101-B (5.0 g, 11.0 mmol) in EtSH (116 mL, 1.61 mol),
AlBr (165 mL, 165 mmol) was added slowly at 0 C under N . The mixture was stirred for 18 h. The
volatiles were removed under reduced pressure and the residue was quenched by water (50 mL), which
was further washed by DCM (20 mL x 3). The aqueous layer was purified by prep-HPLC (acetonitrile 1–
% / 0.1% TFA in water) to give Compound 101-C (4.5g, 99.2% yield) as a white solid.
Step 2: To a solution of Compound 101-C (4.7 g, 8.9 mmol) in 1,4-dioxane/H O (9:1, 165 mL)
was added 1 N NaOH dropwise until pH~11. A solution of Cbz-OSu (6.66 g, 26.7 mmol) dissolved in 1,4-
dioxane (50 mL) was then added. After stirring for 1 h, NaOH (1.07 g, 26.7 mmol) was then added to the
reaction followed by MeOH (60 mL). This resulting mixture was allowed to stir for 20 mins. To the
reaction was then added dilute citric acid (10% v/v, 50 mL), the aqueous layer was extracted with EtOAc
(3 x 150 mL) and the combined organic layers were washed with brine (3 x 100 mL), dried over Na SO
and concentrated to give the crude product. The residue was diluted with DCM (50 mL) and the
suspension was filtered to give desired compound (3.2 g). The DCM phase was concentrated and the
residue was purified by silica gel column (eluting 10~20% methanol in EtOAc) to give the desired
compound (1.0 g). The combined batches gave Compound 101-D (4.2 g, 86.1% yield) as a white solid.
Step 3: To Compound 101-D (4.3 g, 7.85 mmol) was added a solution of 1.25M HCl in MeOH
(128 mL) and the reaction was stirred at 0 C. The volatiles were removed to afford Compound 101-E (4.15
g, 94.1% yield) as a white solid, which was used directly in the next step.
18253141_1 (GHMatters) P111789.NZ
Step 4: To a solution of Compound 101-E (3.9 g, 6.94 mmol) and K CO (14.4 g, 104 mmol) in
DMF (50 mL) was added tert-butyl 2-bromoethylcarbamate (15.6 g, 69.5 mmol) at 0 C. The mixture was
stirred at room temperature for 48 h. The mixture was filtered and the filtrate was diluted with EtOAc (500
mL). The EtOAc layer was washed with brine (2 x 400 mL), dried over Na SO , concentrated and purified
by chromatography on silica (solvent gradient: 0-60% EtOAc in petroleum ether) to afford Compound
101-F (4.8 g, 81.5% yield) as a white solid.
Step 5: To a solution of Compound 101-F (4.8 g, 5.7 mmol) in MeOH (100 mL), 10% Pd/C
(1.26 g, 1.18 mmol) on carbon was added at room temperature. The reaction mixture was stirred for 1 h at
the same temperature under hydrogen atmosphere (15 psi). The filtrate was then concentrated to afford
Compound 101-G (4.0 g, 99% yield) as a white solid.
Example E: Synthesis of Compounds 101-I, 101-J, 101-K, and 101-L
St p 1
NHB oc
b HN H oc
C COO B HN oc
oc B HN
B HN
NHB St p 2
HATU DIPEA
Pd/C H
, HN
O HN
DMF DCM
HN N
Cb O
H N N O
H N O
HN O
NHB oc
101 -
101 I
101 H
Step 1: To a solution of Compound 101-G (3.5 g, 4.9 mmol) and (S)
(((benzyloxy)carbonyl)amino)((tert-butoxycarbonyl)amino)hexanoic acid (2.4 g, 6.4 mmol) in DCM
(30 mL) at 0 C, HATU (3.7 g, 9.8 mmol) and DIPEA (1.9 g, 14.7 mmol) was added. The resulting
mixture was allowed to gradually warm up to room temperature and stirred for 2 h. The reaction mixture
was diluted with DCM (100 mL), which was washed with brine (100 mL x 3). The organic layer was dried
over Na SO , concentrated and the residue was purified by silica column chromatography to
afford Compound 101-H (5.3 g, 99% yield) as a white solid.
[00556] Step 2: The hydrogenation step was performed using Example D using Compound 101-H (1.5 g,
1.4 mmol) to afford Compound 101-I (1.2 g, 93% yield) as a white solid. LCMS (Method 5-95 AB, ESI):
t = 0.711, [M + H] = 942.6.
B HN
O HN
H N N O
101 J
18253141_1 (GHMatters) P111789.NZ
Compound 101-J was prepared from Compound 101-G and (S)
(((benzyloxy)carbonyl)amino)((tert-butoxycarbonyl)amino)pentanoic acid as described above. LCMS
(Method 5-95 AB, ESI): t = 0.841, [M + H] = 928.4.
B HN
O HN
H N N O
101 K
[00558] Compound 101-K was prepared from Compound 101G and (S)
(((benzyloxy)carbonyl)amino)((tert-butoxycarbonyl)amino)butanoic acid as described above. LCMS
(Method 5-95 AB, ESI): t = 0.838, [M + H] = 914.5.
B HN
O HN
H N N O
B HN
101 L
Compound 101-L was prepared from Compound 101G and (S)
(((benzyloxy)carbonyl)amino)((tert-butoxycarbonyl)amino)propanoic acid as described above. LCMS
(Method 5-95 AB, ESI): t = 0.833, [M + H] = 900.5.
Example F: Synthesis of 3-((tert-butoxycarbonyl)(decyl)amino)propanoic acid
St p 1
St p 2
21
Et N DCM
THF H
1 21 10 21
N OH
LiOH/EtOH
oc B
To a solution of methyl acrylate (2.2 g, 26 mmol) in THF (20 mL) was added a solution of
decanamine (6 g, 38 mmol) in THF (20 mL) at 0 C. The reaction mixture was stirred at 30°C for 48 h.
The resulting solution was concentrated to obtain methyl 3-(decylamino)propanoate (6.4 g).
Step 2: To a solution of crude methyl 3-(decylamino)propanoate (6.4 g, 15 mmol) and Et N (4 g,
40 mmol) in DCM (30 mL) was added dropwise a solution of Boc O (5.7 g, 26 mmol) in DCM (20 mL) at
0 C. The reaction mixture was then allowed to warm to 30°C gradually and stirred for 18 h. After the
reaction was completed, H O (50 mL) was added and the resulting aqueous layer was further extracted
with DCM (50 mL*2). The combined organic layers were concentrated and the residue was purified by
18253141_1 (GHMatters) P111789.NZ
silica gel column (PE/EtOAc=50/1~20/1) to give methyl 3-((tert-butoxycarbonyl)(decyl)amino)propanoate
(6.5 g, 73%) as a colorless oil.
Step 3: To a solution of methyl 3-((tert-butoxycarbonyl)(decyl)amino)propanoate (8.2 g, 23.9
mmol, crude) in EtOH (40 mL) was added a solution of LiOH (1.15 g, 48 mmol) in H O (20 mL) at 0 C.
The reaction mixture was then allowed to warm to 30°C gradually and stirred for 18 h. After the reaction
was complete, EtOH was removed under reduced pressure. The remaining aqueous solution was then
adjusted to pH=2~3 with 6 N HCl, followed by the extraction with EtOAc (50 mL *3). The combined
EtOAc layers were dried over Na SO , and concentrated to give 3-((tert-
butoxycarbonyl)(decyl)amino)propanoic acid (7 g, 88.6%) as a colorless oil. H NMR (400 MHz, CDCl )
δ 3.47-3.43 (t, J=6.8Hz, 2H), 3.19-3.15 (t, J=7.2Hz, 2H), 2.61 (brs, 2H), 1.51-1.39 (m, 11H), 1.24-1.22 (m,
14H), 0.88-0.84 (t, J=6.8Hz, 3H).
Example G: Synthesis of Compound 101
NHB oc
B HN oc
B HN
B HN
O Boc
- N OH
21
O Li H
O HN oc
, O B O
HATU DIPEA oc THF/H O H H
B HN
H N N O
2 N N N O
N O ,
N N N C H N O
DMF DCM 10 21
C H N O
21
- NHB
101 M
101 I
oc 101 N
NHB NH
B HN H N
H N CN
xx O O
, 5% TFA i HFIP
HATU DIPEA
DMF DCM
N CN N CN
B O HN
O HN
H H H
N N N O
N N N O
C H N O H N
21 C O
21
2 101
101 O
[00563] Step 1: Example E was applied to Compound 101-I (1.0 g, 1.27 mmol) and 3-((tert-
butoxycarbonyl)(decyl)amino)propanoic acid (504 mg, 1.53 mmol) to afford Compound 101-M (1.3 g,
82% yield) as a white solid.
Step 2: To a solution of Compound 101-M (1.3 g, 1.04 mmol) in THF/H O (40 mL, 1:1) was
added LiOH monohydrate (87 mg, 2.07 mmol) at 0 C. The mixture was allowed to gradually warm up to
room temperature and stirred for 1 h. Most THF was removed under reduced pressure and the resulting
mixture was adjusted pH=5 with saturated citric acid, which was further extracted by EtOAc (30 mL x 3).
The combined organic layers were washed with brine (100 mL), dried over Na SO and concentrated to
give Compound 101-N (1.1 g, 86% yield) as a white solid.
Steps 3 and 4: To a solution of Compound 101-N (180 mg, 0.15 mmol), aminoacetonitrile
hydrochloride (31 mg, 0.33 mmol) and DIPEA (38 mg, 0.29 mmol) in DCM/DMF (3 mL, 2:1) at 0 C,
HATU (56 mg, 0.15 mmol) was added while stirring. The resulting mixture was stirred at room
temperature for 1h. Most DCM was removed under reduced pressure and the residue was poured into
18253141_1 (GHMatters) P111789.NZ
water (10 mL), which was extracted with EtOAc (20 mL x 3). The combined organic layers were washed
with brine (50 mL), dried over Na SO , concentrated to the residue, which was purified by flash
chromatography column to afford Compound 101-O (140 mg, 76%) as a white solid.
Compound 101-O (130 mg, 0.10 mmol) was added to 5% TFA in HFIP (6.5 mL) and the
mixture was stirred at room temperature for 2 h. Volatiles were removed under reduced pressure and the
resulting crude was re-dissolved with DMF (5mL), which was neutralized with solid NaHCO . The filtrate
was then purified by HPLC to afford Compound 101 (54 mg, 60% yield) as a white solid. LCMS (Method
-95 AB, ESI): t = 0.710, M+H = 877.6; HNMR (400 MHz, MeOH-d4) δ 8.51 (brs, 2H, HCOOH),
7.28-7.25 (m, 2H), 7.20 (d, J=8 Hz, 1H), 7.18 (d, J=8 Hz, 1H), 6.90 (brs, 1H), 6.84 (brs, 1H), 6.37 (s, 1H),
4.82-4.79 (m, 3H), 4.28-4.20 (m, 4H), 4.21 (s, 2H), 3.33-3.26 (m, 2H), 3.26-3.16 (m, 5H), 3.16-3.12 (m,
1H), 3.11-2.95 (m, 2H), 2.95-2.91 (m, 2H), 2.90 (s, 3H), 2.73-2.66 (m, 2H), 1.75-1.65 (m, 6H), 1.64-1.51
(m, 1H), 1.50-1.16 (m, 18H), 0.92 (t, J=6.8 Hz, 3H).
Example H: Synthesis of 4’-(tert-butyl)methyl-[1,1’-biphenyl]carboxylic acid
Step 2
aq. NaOH
, K CO
Pd(dppf)Cl2 2 3
MeOH
dioxane, water. 100 C
Step 1
[00567] Step 1: To a solution of 4-t-butylbenzeneboronic acid (151.6 mg, 0.85 mmol) in 1,4-dioxane (5
mL) and water (1 mL) were added potassium carbonate (181.0 mg, 1.31 mmol), 1,1’-
bis(diphenylphosphino)ferrocene palladium dichloride (47.9 mg, 0.07 mmol), and methyl 4-bromo
methylbenzoate (150.0 mg, 0.65 mmol). The reaction mixture was stirred at 100 C for 2 h under N and
concentrated. The residue was taken up in EtOAc (20 mL) and washed with water (20 mL x 2) and brine
(20 mL). The organic layer was dried over MgSO and concentrated. The residue was purified by flash
column chromatography (5% EtOAc in petroleum ether, Rf = 0.7) to afford methyl 4-(4-tert-butylphenyl)-
2-methyl-benzoate (120 mg, 64.9% yield) as a colorless oil. LCMS (5-95AB_1.5min): t = 0.972 min, [M
+ H] = 281.9.
Step 2: Methyl 4-(4-tert-butylphenyl)methyl-benzoate (120.0 mg, 0.430 mmol) was
hydrolyzed to give 4’-(tert-butyl)methyl-[1,1’-biphenyl]carboxylic acid (100 mg, 0.3726 mmol,
87.7% yield) as a white solid.
Example I: Synthesis of methyl 4-(5-isobutylpyrazinyl)methylbenzoate
Step 1
Step
Br N
Br N
O O OH
N Br , K CO
Pd(PPh ) , K CO
3 4 2 3
Pd(PPh3)4 2 3
toluene/H 100 C
O, toluene/H 100 C O
O 2O,
18253141_1 (GHMatters) P111789.NZ
To a solution of 2,5-dibromopyrazine (200.0 mg, 0.84 mmol) in toluene (5 mL) and water (1
mL) were added potassium carbonate (348.6 mg, 2.52 mmol), methyl 2-methyl(4,4,5,5-tetramethyl-
1,3,2-dioxaborolanyl)benzoate (232.2 mg, 0.84 mmol) and tetrakis(triphenylphosphine)palladium(0)
(97.2 mg, 0.08 mmol). The reaction mixture was stirred at 80 C for 16 h and filtered. The filtrate was
diluted with H O (20 mL) and extracted with EtOAc (40 mL x 2). The combined organic layers were
washed with water (80 mL x 3) and brine (80 mL), dried over Na SO and concentrated. The residue was
purified by prep-TLC (7.5% EtOAc in petroleum ether) to obtain methyl 4-(5-bromopyrazinyl)
methylbenzoate (150 mg, 58.1% yield) as a white solid. H NMR (400 MHz, CDCl ): δ 8.81 (s, 1H), 8.75
(d, J = 1.2 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.88 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 3.93 (s, 3H), 2.70 (s,
3H).
To a solution of isobutylboronic acid (99.6 mg, 0.98 mmol) in toluene (3 mL) and water (0.3
mL) were added tetrakis(triphenylphosphine)palladium(0) (56.4 mg, 0.05 mmol), potassium carbonate
(202.5 mg, 1.47 mmol) and methyl 4-(5-bromopyrazinyl)methylbenzoate (150.0 mg, 0.49 mmol).
The reaction mixture was stirred at 100 C for 16 h and filtered. The filtrate was diluted with H O (20 mL)
and extracted with EtOAc (40 mL x 2). The combined organic layers were washed with water (80 mL x 3)
and brine (80 mL), dried over Na SO and concentrated. The residue was purified by prep-TLC (9.5%
EtOAc in petroleum ether, Rf = 0.4) to obtain methyl 4-(5-isobutylpyrazinyl)methylbenzoate (52 mg,
37.4% yield) as a yellow oil. LCMS (Method 5-95 AB, ESI): t = 0.956 min, [M+H] = 284.9.
Example J: Synthesis of ethyl 2-bromomethylpyrimidinecarboxylate
Br COOEt
COOEt
CHBr
To a solution of ethyl 2-aminomethylpyrimidinecarboxylate (4.0 g, 22 mmol) in CHBr
(66 mL) was added isopentyl nitrite (44 mL) and the mixture was stirred at 85 C for 4 h. The volatiles
were removed and the residue was taken up by EtOAc (100 mL), which was washed by brine (100 mL x
2). The organic layer was dried over Na SO , concentrated and the residue was purified by silica gel flash
column to give ethyl 2-bromomethylpyrimidinecarboxylate (3.0 g, 55.5% yield) as a white solid. H
NMR (400 MHz, CDCl ): δ 8.93 (s, 1H), 4.41 (q, J = 7.2 Hz, 2H), 2.82 (s, 3H), 1.41 (t, J = 7.0 Hz, 3H).
Example K: Synthesis of 2-fluorooctylbenzoic acid
Pd/C, H
Br F
Cl , CuI
Pd(PPh3)2 2
O MeOH
Et 100
NaOH
(aq)
MeOH, 100 C
18253141_1 (GHMatters) P111789.NZ
A mixture of methyl 4-bromofluorobenzoate (500.0 mg, 2.15 mmol), octyne (702.9 mg,
6.44 mmol), bis(triphenylphosphine)palladium(II)dichloride (75.3 mg, 0.11 mmol) and copper(I) iodide
(20.4 mg, 0.11 mmol) in triethylamine (9.83 mL, 70.9 mmol) was stirred at 100 C for 2 h under nitrogen
atmosphere. LCMS (5-95AB/1.5min): t = 1.006 min, [M + H] 262.9 showed 60% of DP. The reaction
was quenched with water (15 mL) and extracted with dichloromethane (3 × 25 mL). The combined organic
extracts were washed with brine (2 × 25 mL), dried over anhydrous Na SO and filtered. The filtrate was
concentrated and the residue was purified by column chromatography on silica gel (eluting with 5% ethyl
acetate in petroleum ether, Rf = 0.5) to afford methyl 2-fluoro(octynyl)benzoate (550 mg, 97.7%
yield) as a brown solid. LCMS (5-95AB_1.5 min): t = 1.006 min, [M + H] 262.9.
[00573] To a solution of methyl 2-fluoro(octynyl)benzoate (550.0 mg, 2.1 mmol) in methanol
(25 mL) was added 10% Palladium on carbon (111.56 mg, 0.10 mmol). The mixture was stirred at 30 C
under hydrogen (40 psi) for 16h. The reaction was filtered over a pad of Celite and concentrated. The
residue was purified by column chromatography on silica gel (eluting with petroleum ether / ethyl acetate
from 100:1 to 10:1) to afford methyl 2-fluorooctylbenzoate (500 mg, 89.5% yield) as a yellow
solid. LCMS (5-95AB_1.5min): t = 1.033 min, [M + H] 266.
To a solution of methyl 2-fluorooctylbenzoate (500.0 mg, 1.88 mmol) in methanol (5
mL) was added NaOH (1000.0 mg, 25 mmol) in water (5 mL). The mixture was stirred at 100 C for 2h,
cooled to RT and hydrochloric acid (1.0 M) was added until pH = 3-4. The mixture was extracted with
ethyl acetate (3 × 30 mL). The combined organic extracts were washed with brine (2 × 30 mL), dried over
sodium sulfate and filtered. The filtrate was concentrated to give 2-fluorooctylbenzoic acid (450 mg,
95% yield) as a yellow solid. H NMR (400 MHz, CDCl ): δ 7.94 (t, J = 8.0 Hz, 1H), 7.06 (d, J = 8.4 Hz,
1H), 6.99 (d, J = 12.0 Hz, 1H), 2.66 (t, J = 7.4 Hz, 2H), 1.65 - 1.62 (m, 2H), 1.31 – 1.28 (m, 10H), 0.89 (t,
J = 6.8 Hz, 3H).
Example L: Synthesis of 4-(tert-butyl)(difluoromethyl)benzoic acid
e ec uor a
S l tfl AgNO N S O
, , o ,
wa er
H N t 80 16 h
C C C
To a degassed mixture of 4-tert-butylmethyl-benzoic acid (192.0 mg, 1 mmol), sodium
persulfate (1.19 g, 4.99 mmol) and Selectfluor (1.77 g, 4.99 mmol) in acetonitrile (4 mL) and water (4 mL)
in dry-ice acetone bath was added silvernitrate (17.0 mg, 0.10 mmol). The mixture was degassed by three
freeze-pump-thaw cycles and heated at 80 C for 16 h. Water (10 mL) was added and the mixture was
extracted with EtOAc (15 mL x 2). The combined organic layers were concentrated and the residue was
purified by prep-TLC (petroleum ether/EtOAc/HOAc 2/1/0.01, Rf = 0.3) to give 4-(tert-butyl)
(difluoromethyl)benzoic acid (75 mg, 32.9% yield) as a white solid.
Example M: Synthesis of 3-butylmethylbenzoic acid
18253141_1 (GHMatters) P111789.NZ
St p 2
St p 3
S p ,
r B B OH
Pd PPh K N OH
e ( )
3 4 2 3
SOCl /M OH
THF H
o uene / O
COOH
e COOM
COOM
COOH
Step 1: To a mixture of 3-bromomethylbenzoic acid (5.0 g, 23 mmol) in MeOH (80 mL) was
added SOCl (11.0 g, 93 mmol) at 20 C. The mixture was stirred for 1.5h at 70 C. The volatiles were
removed and the residue was taken up by EtOAc (100 mL), which was washed sequentially with
saturated NaHCO and brine (each 100 mL). The EtOAc layer was dried over Na SO , concentrated and
3 2 4
the residue was purified by flash column chromatography to give methyl 3-bromomethylbenzoate (5.3g,
99% yield) as a red solid.
Step 2: A solution of methyl 3-bromomethylbenzoate (500 mg, 2.2 mmol), n-butyl boronic
acid (890 mg, 8.7 mmol), Pd(PPh ) (252 mg, 0.22 mmol) and K CO (905 mg, 6.6 mmol) in toluene (20
3 4 2 3
mL) was stirred at 100 C for 4 h. After filtration, the filtrate was washed with brine (20 mL x 3), dried
over Na SO and concentrated. The residue was purified by HPLC to give methyl 3-butyl
methylbenzoate (120 mg, 27% yield) as colorless oil. LCMS (Method 5-95 AB, ESI): t = 0.871, [M + H]
= 206.9.
Step 3: The ester hydrolysis method with NaOH as previously described (Example H) was
applied to methyl 3-butylmethylbenzoate (120 mg, 0.58 mmol) to afford 3-butylmethylbenzoic acid
(110 mg, 98% yield) as a white solid.
Example N: Synthesis of methyl 2-[(E)tert-butoxyoxo-propenyl]octyl-benzoate
St p 1
OtB OtB
OtB t
S p 2
8 17
M S OH
Pd Pt B
( )2
Pd db
O O OH
2( )3
Cy NM
Step 1: To a solution of methyl 2-chlorooctyl-benzoate (350.0 mg, 1.24 mmol) in 1,4-dioxane
(2 mL) were added t-butyl acrylate (174.5 mg, 1.36 mmol), bis(tri-t-butylphosphine)palladium(0) (9.5 mg,
0.02 mmol), tris(dibenzylideneacetone)dipalladium(0) (34.0 mg, 0.04 mmol) and N,N-
dicyclohexylmethylamine (265.9 mg, 1.36 mmol). The mixture was stirred at 25 C for 16 h under N and
filtered. The filtrate was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined
organic layers were dried over Na SO , filtered and concentrated. The residue was purified by prep-TLC
(10% EtOAc in petroleum ether, Rf = 0.7) to afford methyl 2-[(E)tert-butoxyoxo-propenyl]
octyl-benzoate (290 mg, 62.6% yield) as a yellow oil. H NMR (400 MHz, CDCl ): δ 8.35 (d, J = 16.0 Hz,
1H), 7.86 (d, J = 8.0 Hz, 1H), 7.39 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 6.23 (d, J = 15.9 Hz, 1H), 3.91 (s, 3H),
2.64 (t, J = 7.8 Hz, 2H), 1.65-1.55 (m, 2H), 1.54 (s, 9H), 1.33 - 1.22 (m, 10H), 0.88 (t, J = 6.6 Hz, 3H).
Step 2: To a solution of methyl 2-[(E)tert-butoxyoxo-propenyl]octyl-benzoate (290.0
mg, 0.77 mmol) in 1,2-dichloroethane (2 mL) was added trimethyltin hydroxide (1400.2 mg, 7.74 mmol)
and the mixture was stirred at 80 C for 16 h. LCMS (5-95AB/1.5min): t = 1.158 min, [M+Na]+383.1
18253141_1 (GHMatters) P111789.NZ
showed 36% of DP and 51% of SM. The mixture was diluted with 0.1N KHSO (5 mL) and extracted with
EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over Na SO , filtered and
concentrated. The residue was purified by prep-TLC (50% EtOAc in petroleum ether, Rf = 0.2) to afford
2-[(E)tert-butoxyoxo-propenyl]octyl-benzoic acid (80 mg, 28.7% yield) as a yellow solid.
Example O: Synthesis of Compound 102
Step 1
Cbz OH
Step
NHBoc Pd/C, H
O HN
O HN
H N N O
HN N N
O THF
EDCI, HOBT, N
Cbz N O
N DIEA, DMF
HN O O
NHBoc 102-B
102-A
NHBoc
101-E
Step 3
n -C H
H 4 9
Step 4
O HN
O H H AlCl
N N O
CH Cl
Cl N O
C H SH
12 25
102-C
NHBoc
Step 5
OH O HN
O HN H H
SOCl
H H 2
N N O
MeOH
NH 102-E
NH 102-D
-C H
Step
Boc NaHCO
O, O HN
N N O
dioxane, water
NHBoc
Step 1: To a solution of Compound 101-E (800 mg, 1.76 mmol) in DMF (15 mL) was added (S)-
2-(((benzyloxy)carbonyl)amino)((tert-butoxycarbonyl)amino)hexanoic acid (735 mg, 1.93 mmol), 3-
[(E)-ethylazo]-N,N-dimethyl-propanamine hydrochloride (946.77 mg, 5.27 mmol), 1-
hydroxybenzotriazole (711.94 mg, 5.27 mmol), and N,N-diisopropylethylamine (681 mg, 5.27 mmol). The
mixture was stirred at 30 C for 16 h. TLC showed the start material was consumed (50% ethyl acetate in
petroleum ether, R = 0.5). The mixture was poured into water (30 mL). The precipitate was filtered,
washed with water, re-dissolved in methanol, and concentrated to give Compound 102-A (1200 mg, 1.45
mmol, 83.5% yield) as a yellow solid.
[00582] Step 2: To a solution of Compound 102-A (1200 mg, 1.47 mmol) in methanol (15 mL) was
added Pd/C (200.0 mg, 1.47 mmol), and the mixture was stirred at 30 C under hydrogen (50 psi) for 16 h.
The catalyst was filtered off and the filtrate was concentrated to give Compound 102-B (900 mg, 1.12
mmol, 81.6% yield) as a white solid. LCMS (5-95AB_1.5min_1500): t = 0.782 min, [M + H] 684.4.
18253141_1 (GHMatters) P111789.NZ
Step 3: A mixture of 4-(4-butylphenyl)benzoic acid (200 mg, 0.79 mmol) in thionyl chloride
(5.0 mL) was stirred at 60 C for 16 h. The solution was concentrated and dissolved in dichloromethane (2
mL). To the solution of Compound 102-B (500 mg, 0.73 mmol) and triethylamine (74 mg, 0.73 mmol) in
dichloromethane (15 mL) was added the above solution of 4-(4-butylphenyl)benzoyl chloride in
dichloromethane. The reaction mixture was stirred at 25 C for 3 h. LCMS showed that all of start material
was consumed completely. TLC (10% dichloromethane in methanol, Rf = 0.4). The reaction was
concentrated to dryness and the residue was purified by flash column chromatography (eluted with 5%
dichloromethane in methanol). The desired fractions were concentrated to afford Compound 102-C (650
mg, 0.71 mmol, 96.6% yield) as a white solid. LCMS (5-95AB/1.5 min): t = 0.951 min, [M + H] 921.4.
Alternatively, this coupling reaction was performed using 4’-butyl-[1,1’-biphenyl]carboxylic acid using
conditions in Example 4.
Step 4: A mixture of aluminium chloride (2.8 g, 21.19 mmol) and 1-dodecanethiol (4.3 g, 21.19
mmol) in dichloromethane (12 mL) was stirred at 26 C for 5 min, and then cooled to 0 C. Then
Compound 102-C (650 mg, 0.71 mmol) was added slowly. The solution was stirred at 26 C for 2 h.
LCMS showed that all of start material was consumed completely. The solution was quenched by 1N
hydrochloride acid, and filtered. The filter cake was dried to afford crude Compound 102-D as a white
solid. LCMS (5-95AB/1.5 min): t = 0.828 min, [M + H] =778.4.
Step 5: A solution of Compound 331-D (500 mg, 0.64 mmol) and thionyl chloride (229 mg, 1.93
mmol) in methanol (10 mL) was stirred at 60 C for 1 h. LCMS showed that all of start material was
consumed completely. The solution was concentrated to afford Compound 102-E (500 mg, 0.63 mmol,
98.2% yield) as a yellow solid. LCMS (5-95AB/1.5 min): t = 0.856 min, [M + H] = 792.8.
Step 6: To the solution of Compound 102-E (500 mg, 0.63 mmol) and sodium bicarbonate (10.6
mg, 0.13 mmol) in 1,4-dioxane (6 mL) and water (2 mL) was added di-tert-butyl dicarbonate (138 mg,
0.63 mmol). LCMS showed that all of start material was consumed completely. TLC (5% dichloromethane
in methanol, Rf = 0.2). The reaction was concentrated to dryness and the residue was taken up in ethyl
acetate (50 mL). It was washed with water (20 mL x 2) and brine (10 mL), dried (sodium sulfate) and
concentrated. The crude was purified by flash column chromatography (eluted with 5% dichloromethane
in methanol). The desired fractions were concentrated in vacuo afford Compound 102-F (500 mg, 0.56
mmol, 88.8% yield) as a white solid. LCMS (5-95AB/1.5 min): t = 1.048 min, [M + H] = 892.4.
Example P: Synthesis of Compound 103
NHBoc
NHBoc
BocHN O
BocHN O
TMSNCO
TEA, DCM HN
OMe H
O HN CbzHN N O
CbzHN N O
HN O
103-A
18253141_1 (GHMatters) P111789.NZ
To a solution of Compound 103-A (120 mg, 0.13 mmol) and Et N (53 μL, 0.38 mmol) in DCM
(5 mL) was added trimethylsilyl isocyanate (44 mg, 0.38 mmol) at 0°C. The resulting mixture was warmed
up to room temperature while stirring and stirred at the same temperature for 2 h. The volatiles were
removed and the residue was purified by prep-TLC to afford Compound 103 (90 mg, 72% yield) as a
white solid. LCMS (Method 5-95 AB, ESI): RT = 0.759, [M + H] = 991.7.
Example Q: Synthesis of (S)(((benzyloxy)carbonyl)amino)(N-methyl
nitrophenylsulfonamido)butanoic acid
t 2 t
S p S p 3
z Cb HN
Cb HN K CO CH I N
Cb HN
2 3 3 a
O O z
OH Cb OH
M OH/H O
D M TEA
C DMF 2
Step 1: To a solution of (S)amino(((benzyloxy)carbonyl)amino)butanoic acid (2000.0 mg,
7.93 mmol) in N,N-dimethylformamide (50 mL) were added 2-nitrobenzenesulfonylchloride (0.46 mL,
23.78 mmol) and triethylamine (4.42 mL, 31.71 mmol) dropwise. The reaction mixture was stirred at 25
C for 12 h and filtered. To the filtrate was added water (50 mL) and the resulting precipitate was collected
to obtain (S)(((benzyloxy)carbonyl)amino)(2-nitrophenylsulfonamido)butanoic acid (2000 mg,
4.5723 mmol, 57.7% yield) as a white solid. LCMS (Method 5-95 AB, ESI): RT = 0.790 min, [M + H] =
437.0.
Step 2: To a solution of (S)(((benzyloxy)carbonyl)amino)(2-
nitrophenylsulfonamido)butanoic acid (800.0 mg, 1.83 mmol) in N,N-dimethylformamide (5 mL) were
added iodomethane (4.59 mL, 73.43 mmol) and potassium carbonate (758.3 mg, 5.49 mmol). The mixture
was stirred at 25 C for 14 h, diluted with H O (20 mL) and extracted with EtOAc (35 mL x 3). The
combined organic layers were washed with water (30 mL x4) and brine (40 mL), dried over Na SO and
concentrated. The residue was purified by flash column chromatography (30% EtOAc in petroleum ether,
Rf = 0.3) to obtain (S)-methyl 2-(((benzyloxy)carbonyl)amino)(N-methyl
nitrophenylsulfonamido)butanoate (610 mg, 71.7% yield) as a yellow oil. LCMS (Method 5-95 AB, ESI):
RT = 0.813 min, [M + H] = 466.1.
[00590] Step 3: NaOH hydrolysis of the ester afforded (S)(((benzyloxy)carbonyl)amino)(N-
methylnitrophenylsulfonamido)butanoic acid.
Example R: Synthesis of (S)(((benzyloxy)carbonyl)amino)((tert-
butyldimethylsilyl)oxy)butanoic acid
O O O
H N CbzHN CbzHN
CbzCl, NaHCO
OH OH OH
TBSCl, TEA
OH OH OTBS
18253141_1 (GHMatters) P111789.NZ
To a mixture of benzyl chloroformate (930.84 mg, 5.46 mmol) and sodium bicarbonate (705.25
mg, 8.39 mmol) in water (10 mL) was added (2S)aminohydroxy-butanoic acid (500.0 mg, 4.2
mmol), and stirred at 15 C for 3 hours under nitrogen. The reaction mixture was washed with ethyl acetate
(20 mL x 3), acidified to pH 4 using 2N HCl (about 20 mL) at 0 C, and extracted with ethyl acetate (30
mL x 3). The combined organic layers were dried over sodium sulfate and concentrated to afford (2S)
(benzyloxycarbonylamino)hydroxy-butanoic acid (450 mg, 1.7769 mmol, 42.3% yield) as a colorless
oil. It was used in the next step without further purification.
To a mixture of (2S)(benzyloxycarbonylamino)hydroxy-butanoic acid (450.0 mg, 1.78
mmol) and triethylamine (395.57 mg, 3.91 mmol) in N,N-dimethylformamide (8 mL) was added tert-
butyldimethylchlorosilane (401.72 mg, 2.67 mmol) at 0 C and stirred at 15 C for 1 hour. The reaction
mixture was diluted with water (30 mL) and sodium carbonate (5 g) was added. The resulting mixture was
washed with ethyl acetate (15 mL x 3). The aqueous phase was acidified to pH 4 using 2 N HCl (about 20
mL) at 0 C and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over
sodium sulfate and concentrated to afford the (S)(((benzyloxy)carbonyl)amino)((tert-
butyldimethylsilyl)oxy)butanoic acid (450 mg, 1.2245 mmol, 68.9% yield) as a colorless oil. It was used in
the next step without further purification. LCMS (Method 5-95 AB, ESI): t = 0.833 min, [M+Na] =
389.9.
Example S: Synthesis of (S)decanamidopentanoic acid
C H Cl
9 19 OH
H N C H N
9 19
NaOH, H O, THF H
[00593] To a stirred solution of decanoyl chloride (500 mg, 2.6 mmol) in THF (5 mL) was added (S)
aminopentanoic acid (461 mg, 3.9 mmol) and 2N NaOH (5.0 mL) at 0 C and the resulting mixture was
stirred at 0 C for 1 h. The pH of the mixture was adjusted to pH=2 using 1N HCl, which was extracted
with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over
Na SO and concentrated to afford (S)decanamidopentanoic acid (630 mg, 88.5% yield) as a white solid,
which was used directly in the next step. LCMS (5-95 AB, ESI): t = 0.904, [M + H] = 272.0.
Example T: Synthesis of Compound 104
H N O
Compound 104 was synthesized following procedures analogous to those described for Example
C (Compound 101-B), in which (S)((tert-butoxycarbonyl)amino)(4-hydroxyphenyl)acetic acid and
18253141_1 (GHMatters) P111789.NZ
methyl (S)aminocyclopropylacetate were used in Step 1, to afford the title compound as brown solid.
LCMS (ESI): [M+H] = 354.
Example U: Synthesis of Compound 105
HN O HN
H NO Step 1 H
N O S N O
H N O N O
acid/DBU
MeI/K CO O Mercaptoacetic
O HN
S N O
Step 2
Step 3 HN
HN O
[00596] Step 1: To a solution of Compound 104 (1.16 g, 2.48 mmol) and triethylamine (0.86 mL, 6.20
mmol) in acetonitrile (25 mL) was added 4-nitrobenzenesulfonyl chloride (660 mg, 2.98 mmol) in portions,
and the resulting reaction mixture was stirred at room temperature for 4 h. The precipitate was collected by
filtration, washed with small amount of acetonitrile, and dried under vacuum overnight to give 1.14 g
(70%) of methyl (4S,7S,10S)cyclopropyl-1 ,2 -dimethoxy((4-nitrophenyl)sulfonamido)-6,9-dioxo-
5,8-diaza-1,2(1,3)-dibenzenacyclodecaphanecarboxylate as an off white solid, which was carried
forward without further purification. LCMS (ESI): [M+H] = 653.
Step 2: To a mixture of (4S,7S,10S)cyclopropyl-1 ,2 -dimethoxy((4-
nitrophenyl)sulfonamido)-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphanecarboxylate (1.14 g,
1.75 mmol) and K CO (1.93 g, 14.0 mmol,) in acetone (20 mL) was added iodomethane (0.870 mL, 14.0
mmol). The resulting reaction mixture was stirred at room temperature overnight. The mixture was filtered
and evaporated in vacuo. The residue was diluted with water, extracted with isopropyl acetate (2 x 100 ml),
dried over Mg SO , filtered, evaporated in vacuo, and dried under vacuum to give 1.21 g (100%) of methyl
(4S,7S,10S)cyclopropyl-1 ,2 -dimethoxy((N-methylnitrophenyl)sulfonamido)-6,9-dioxo-5,8-
diaza-1,2(1,3)-dibenzenacyclodecaphanecarboxylate as off white solid, which was carried forward
without purification. LCMS (ESI): [M+H] = 667.
Step 3: To a solution methyl (4S,7S,10S)cyclopropyl-1 ,2 -dimethoxy((N-methyl
nitrophenyl)sulfonamido)-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphanecarboxylate (1.11 g,
1.66 mmol) in acetonitrile (22 mL) was added mercaptoacetic acid (6.6 equiv., 1.01 g, 11.0 mmol) and
DBU (2.50 mL, 16.6 mmol), and the resulting mixture stirred at room temperature for 3 h. The reaction
mixture was evaporated in vacuo, diluted with isopropyl acetate (50 mL) and washed with saturated
aqueous NaHCO (50 mL). The aqueous layer was again extracted with iPrOAc (50 mL). The combined
organics were washed with water and brine, dried over Mg SO , filtered, evaporated in vacuo, and dried
18253141_1 (GHMatters) P111789.NZ
under vacuum to give 776 mg (96.8%) of Compound 105 as an off white solid. LCMS (ESI) [M + H] =
482.
Example V: Synthesis of Compounds 106-B1 and 106-B2
Boc HO
Steps 1 2 O OH
HCl/MeOH
+ Not
OMe OMe
Boc Et N
2) 2 3
H HN
HN separated
Cbz N O H
N O Cbz N O
Cbz N O
N O N
101-D
106-A1 106-A2
Minor
Major
NHBoc
BocHN
BocO
Step 3 O
OBoc
NHBoc
106-A1 and OMe
K CO , DMF
2 3 HN
106-A2
HN H
H Cbz N O
Cbz N O O
106-B2
106-B1
Peak 2
Peak 1
Major
Minor
[00599] Step 1: Compound 101-D (2.0 g, 3.65 mmol) was added to a solution of 1.25N HCl/MeOH (150
mL) and the mixture was stirred at 0 C for 4 h. The volatiles were removed to give the crude as a white
solid.
Step 2: The above crude was dissolved in DCM (5 mL) and the mixture was added Boc O (0.93
g, 4.27 mmol) and TEA (1.08 g, 10.7 mmol). The resulting mixture was stirred for at room temperature for
16 h. The volatiles were removed and the residue was purified by silica gel flash column to obtain
Compound 106-A1 and 106-A2 as a mixture of regioisomers (1.8 g, 76.4% yield) as a white solid. LCMS
(5-95 AB, ESI): t = 0.880, [M + H] = 684.6.
To a mixture of Compound 106-A1 and 106-A2 (1.8 g, 2.72 mmol) and t-butyl (2-bromoethyl)carbamate
(3.0 g, 13.6 mmol) in DMF (5 mL) was added K CO (3.8 g, 27.2 mmol) and the reaction mixture was
stirred at room temperature for 3 h. The reaction mixture was added with DCM (50 mL), which was
washed with 2N HCl, saturated NaHCO and brine (20 mL each). The organic layer was then dried over
Na SO , concentrated and the residue was purified on silica gel flash column to afford the mixture of
regioisomers, which was further purified by SFC (OD, 250mm x 30mm, 5um) to afford Compound 106-
B1(80 mg, 3.6% yield) and Compound 106-B2 (1.6 g, 73.2% yield) as a white solid.
Example 1: Synthesis of Compound 201
18253141_1 (GHMatters) P111789.NZ
H N O
O HN
N N O
DMF-DMA Pd , t-BuXPhos
N H H O (dba)
2 4 2 2 3 N
N toluene
EtOH NaOtBu, N
1 Step
Step O
Step 2 NH OH
Step 1: A solution of 1-(4-butylphenyl)ethanone (500 mg, 2.8 mmol), DMF-DMA (406 mg,
3.4 mmol) and proline (32.66mg, 0.2800mmol) was stirred at 80 C for 3 h. The reaction was quenched
with water (15 mL), which was extracted with EtOAc (3 x 20 mL). The combined organic layers were
washed with brine (50 mL), dried over Na SO , concentrated and the crude was purified by silica gel
chromatography, eluting with 0-20% EtOAc in petroleum ether, to give 1-(4-butylphenyl)
(dimethylamino)propenone (550 mg, 84% yield) as a yellow solid.
Step 2: A solution of 1-(4-butylphenyl)(dimethylamino)propenone (400 mg, 1.73 mmol)
and hydrazine monohydrate (90 μL, 8.65 mmol) in EtOH (5 mL) was stirred at 90 C for 2 h. The reaction
was partitioned between water and EtOAc (50 mL each). The organic layer was dried over Na SO ,
concentrated to give 3-(4-butylphenyl)-1H-pyrazole (300 mg, 87% yield) as yellow oil, which was used
directly in the next step.
Step 3: A solution of 3-(4-butylphenyl)-1H-pyrazole (240 mg, 1.2 mmol), methyl 4-bromo
methylbenzoate (412 mg, 1.8 mmol), Pd (dba) (27 mg, 0.03 mmol), t-BuXPhos (51 mg, 0.12 mmol) and
NaOt-Bu (173 mg, 1.8 mmol) in toluene (3 mL) was stirred at 80 C under N for 7 hr. The reaction was
portioned with water and EtOAc (50 mL each). The organic layer was dried over Na SO , concentrated
and the residue was purified by HPLC to give 4-(3-(4-butylphenyl)-1H-pyrazolyl)methylbenzoic
acid (90 mg, 22.5% yield) as a white solid. H NMR (400 MHz, DMSO-d6): δ 8.65 (d, J=5.6 Hz, 1H),
7.98 (d, J=8.0 Hz, 1H), 7.89-7.80 (m, 4H), 7.28 (d, J=8.0 Hz, 2H), 7.05 (d, J=5.6 Hz, 1H), 2.63 (s, 3H),
2.60 (t, J=7.2 Hz, 2H), 1.62-1.55 (m, 2H), 1.37-1.28 (m, 2H), 0.91 (t, J=7.2 Hz, 3H).
Compound 201 (formic acid salt) was prepared as a white solid from Compound 101-K and 4-
(3-(4-butylphenyl)-1H-pyrazolyl)methylbenzoic acid by utilizing methods analogous to those
described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.656 min, [M + H] = 954.5; H NMR (400
MHz, MeOH-d ) δ 8.50 (br s, 2H), 8.28 (br s, 1H), 7.82-7.74 (m, 4H), 7.54 (d, J=8.0 Hz, 1H), 7.34 (d,
J=8.0 Hz, 1H), 7.27 (d, J=8 Hz, 2H), 7.24-7.16 (m, 2H), 7.10-7.05 (m, 1H), 6.93-6.85 (m, 2H), 6.77 (s,
1H), 6.42 (s, 1H), 5.21-5.14 (m, 1H), 4.82-4.77 (m, 2H), 4.28-4.10 (m, 4H), 4.20 (s, 2H), 3.30-3.07 (m,
18253141_1 (GHMatters) P111789.NZ
8H), 2.95 (s, 3H), 2.67 (t, J=8 Hz, 2H), 2.51(s, 3H), 2.36-2.24 (m, 1H), 2.23-2.10 (m, 1H), 1.70-1.60 (m,
2H), 1.46-1.33(m, 5H), 0.97 (t, J=7.2 Hz, 3H).
Example 2: Synthesis of Compound 202
H N O
O HN
N N O
[00605] Compound 202 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example H. LCMS (Method 5-95 AB, ESI): t = 0.608
min, [M + H] = 958.5; H NMR (400 MHz, MeOH-d ) δ 8.48 (br s, 2H), 7.94 (d, J=8.4 Hz, 2H), 7.86 (d,
J=8.0 Hz, 2H), 7.66-7.57 (m, 3H), 7.36 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H),
6.93 (s, 1H), 6.85 (s, 1H), 6.38 (s, 1H), 5.21-5.18 (m, 1H), 4.95-4.78 (m, 2H), 4.30-4.10 (m, 4H), 4.20 (s,
2H), 3.50-3.18 (m, 8H), 2.98 (s, 3H), 2.55 (s, 3H), 2.33-2.25 (m, 1H), 2.25-2.16 (m, 1H), 1.38 (d, J=6.8,
3H).
Example 3: Synthesis of Compound 203
H N O
O HN
N N O
Compound 203 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example H. LCMS (Method 5-95 AB, ESI): t = 0.735
min, [M + H] = 888.4; H NMR (400 MHz, MeOH-d ) δ 8.51 (br s, 2H), 7.58-7.35 (m, 7H), 7.35-7.33 (m,
1H), 7.23-7.18 (m, 2H), 7.11-7.08 (m, 2H), 6.88 (br s, 1H), 6.38 (s, 1H), 5.17-5.10 (m, 1H), 4.85-4.80 (m,
2H), 4.25-4.20 (m, 4H), 4.22 (s, 2H), 3.27-3.00 (m, 8H), 2.95 (s, 3H), 2.52 (s, 3H), 2.29-2.16 (m, 2H), 1.42
(t, J=7.2 Hz, 3H), 1.39 (s, 9H).
Example 4: Synthesis of Compound 204
H N O
N N O
Compound 204 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example I. LCMS (Method 5-95 AB, ESI): t = 0.710
min, [M + H] = 918.6; H NMR (400 MHz, MeOH-d ) δ 8.95 (s, 2H), 8.50 (br s, 1H), 7.65-7.58 (m, 2H),
18253141_1 (GHMatters) P111789.NZ
7.50 (d, J=8.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.24-7.16 (m, 2H), 7.07 (d, J=8.0 Hz, 1H), 6.90 (d, J=2.4
Hz, 1H), 6.69 (s, 1H), 6.45 (s, 1H), 5.22-5.16 (m, 1H), 4.80-4.76 (m, 2H), 4.30-4.18 (m, 4H), 4.20 (s, 2H),
3.27-3.06 (m, 8H), 3.00 (t, J=7.6 Hz, 2H), 2.98 (s, 3H), 2.48 (s, 3H), 2.35-2.24 (m, 1H), 2.22-2.11 (m, 1H),
1.91-1.81 (m, 2H), 1.42-1.33 (m, 9H), 0.93 (t, J=6.8 Hz, 3H).
Example 5: Synthesis of Compound 205
H N O
N N O
Step 1: A solution of 6-bromomethylnicotinic acid (140 mg, 0.65 mmol), 4-n-pentyl-benzene
boronic acid (187 mg, 0.97 mmol), Pd(dppf)Cl (95 mg, 0.13 mmol) and Cs CO (634 mg, 1.94 mmol) in
2 2 3
toluene/H O (11 mL, v/v=10/1) was stirred at 110 C for 16 h under N . After filtration, the filtrate was
partitioned with EtOAc and H O (each 50 mL). The organic layer was washed with brine (2 x 30 mL),
dried over Na SO , concentrated and the residue was purified by preparatory-TLC to obtain 2-methyl(4-
pentylphenyl)nicotinic acid (120 mg, 65% yield) as a colorless oil. H NMR (400 MHz, CD Cl) δ 8.36 (d,
J=8.4 Hz, 1H), 8.01 (d, J=8.4 Hz, 2H), 7.66 (d, J=8.4 Hz, 1H), 7.31 (d, J=8.4 Hz, 2H), 2.96 (s, 3H), 2.68 (t,
J=8.0 Hz, 2H), 1.66-1.34 (m, 6H), 0.91 (t, J=6.0 Hz, 3H).
[00609] Compound 205 (formic acid salt) was prepared as a white solid from Compound 101-K and 2-
methyl(4-pentylphenyl)nicotinic acid by utilizing methods analogous to those described in Example G.
LCMS (Method 5-95 AB, ESI): t = 0.643 min, [M + H] = 903.5; H NMR (400 MHz, MeOH-d ) δ 8.50
(s, 1H), 7.80-7.65 (m, 3H), 7.31 (d, J=8.4 Hz, 1H), 7.31-7.21 (m, 2H), 7.19-7.12 (m, 2H), 6.92 (s, 1H),
6.82 (s, 1H), 6.39 (s, 1H), 5.19-5.16 (m, 1H), 4.90-4.79 (m, 2H), 4.30-4.15 (m, 4H), 4.20 (s, 2H), 3.30-3.15
(m, 8H), 2.96 (s, 3H), 2.68 (t, J=7.6 Hz, 2H), 2.65 (s, 3H), 2.32-2.27 (m, 1H), 2.20-2.13 (m, 1H), 1.38-1.25
(m, 6H), 0.93 (t, J=6.4 Hz, 3H).
Example 6: Synthesis of Compound 206
H N O
O HN
Compound 206 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous those described in Example 5. LCMS (Method 5-95 AB, ESI): t = 0.706 min,
[M + H] = 889.6; H NMR (400 MHz, MeOH-d ) δ 8.50 (s, 2H), 7.92 (d, J=8.4 Hz, 2H), 7.84 (d, J=8.0
Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.36-7.28 (m, 1H), 7.25- 7.16 (m, 2H), 7.10 (d,
J=8.4 Hz, 1H), 6.90 (d, J=2.0 Hz, 1H), 6.77 (s, 1H), 6.41 (s, 1H), 5.19-5.16 (m, 1H), 4.85-4.79 (m, 2H),
4.24-4.15 (m, 4H), 4.20 (s, 2H), 3.17-3.08 (m, 8H), 2.96 (s, 3H), 2.68 (s, 3H), 2.30-2.26 (m, 1H), 2.18-2.12
(m, 1H), 1.37 (s, 9H), 1.36 (t, J=6.4 Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 7: Synthesis of Compound 207
H N O
O HN
N N O
Compound 207 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 5. LCMS (Method 5-95 AB, ESI): t = 0.707
min, [M + H] = 889.6; H NMR (400 MHz, MeOH-d ) δ 8.49 (br s, 3H), 7.88-7.82 (m, 3H), 7.72 (d,
J=8.4 Hz, 1H), 7.31-7.29 (m, 3H), 7.20-7.18 (m, 2H), 7.11 (d, J=8.4 Hz, 1H), 6.89 (d, J=2.0 Hz, 1H), 6.74
(s, 1H), 6.43 (s, 1H), 5.17-5.15 (m, 1H), 4.79-4.75 (m, 2H), 4.30-4.15 (m, 4H), 4.20 (s, 2H), 3.34-3.10 (m,
8H), 2.96 (s, 3H), 2.69 (t, J=8.0 Hz, 2H), 2.66 (s, 3H), 2.40-2.25 (m, 1H), 2.20-2.05 (m, 1H), 1.55-1.50 (m,
2H), 1.42-1.34 (m, 4H), 0.96 (t, J=7.2 Hz, 3H).
Example 8: Synthesis of Compound 208
O HN
N N O
Compound 208 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 5. LCMS (Method 5-95 AB, ESI): t = 0.690
min, [M + H] = 875.5; H NMR (400 MHz, MeOH-d ) δ 8.42 (s, 1H), 7.93 (d, J=8.0 Hz, 2H), 7.86 (d,
J=8.0 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.33 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.4 Hz, 1H), 7.18 (d, J=8.4 Hz,
1H), 7.09 (d, J=8.4 Hz, 1H), 6.91 (s, 1H), 6.82 (s, 1H), 6.37 (s, 1H), 5.19-5.17 (m, 1H), 4.98-4.78 (m, 2H),
4.23-4.15 (m, 4H), 4.19 (s, 2H), 3.55-3.13 (m, 8H), 2.95 (s, 3H), 2.69 (s, 3H), 2.67 (t, J=8.0 Hz, 2H), 2.33-
2.24 (m, 1H), 2.24- 2.08 (m, 1H), 1.72-1.67 (m, 2H), 1.39-1.33 (m, 2H), 0.97 (t, J=7.6 Hz, 3H).
Example 9: Synthesis of Compound 209
H N O
N N N
O HN
N N O
Compound 209 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 5 and Example I. LCMS (Method 5-95 AB,
ESI): t = 0.679 min, [M + H] = 905.5; H NMR (400 MHz, MeOH-d ) δ 9.29 (s, 2H), 7.89 (s, 2H), 7.32
(d, J=7.6 Hz, 1H), 7.25-7.11 (m, 2H), 7.10-7.00 (m, 1H), 6.88 (s, 1H), 6.67 (br s, 1H), 6.44 (s, 1H), 5.20-
5.16 (m, 1H), 4.76-4.64 (m, 2H), 4.40-4.11 (m, 6H), 3.29-2.89 (m, 13H), 2.64 (s, 3H), 2.36-2.09 (m, 2H),
1.90-1.84 (m, 2H), 1.43-1.32 (m, 6H), 0.93 (t, J=6.4 Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
DCM, 0 C
Example 10: Synthesis of Compound 210
N N CN
N N O
, KOAc
(BPin)2
O, pyr
Pd(dppf)Cl2
Step 2
Step 1
Step 1: A mixture of 4-(tert-butyl)methylphenol (1.0 g, 6.1 mmol), pyridine (0.96 g, 12.2
mmol) and trifluoromethanesulfonic anhydride (2.1 g, 12.2 mmol) in DCM (10 mL) was stirred at 20 C
for 2 h. The reaction mixture was diluted with water (30 mL), which was extracted by EtOAc (3 x 30 mL).
The combined organic layers were washed with brine (2 x 50 mL), dried over MgSO and concentrated to
give 4-(tert-butyl)methylphenyl trifluoromethanesulfonate (1.5 g, 83% yield) as a colorless oil.
Step 2: A mixture of 4-(tert-butyl)methylphenyl trifluoromethanesulfonate (1.0 g, 3.4 mmol),
bis(pinacolato)diboron (2.6 g, 10.2 mmol), Pd(dppf)Cl (247 mg, 0.34 mmol), and potassium acetate (1.7 g,
17.0 mmol) in 1,4-dioxane (10 mL) was stirred at 80 C under nitrogen for 12 h. The reaction mixture was
diluted with water (30 mL), which was extracted by EtOAc (3 x 30 mL). The combined organic layers
were washed with brine (2 x 50 mL), dried over MgSO and concentrated and the residue was purified by
prep-TLC (5% EtOAc in petroleum ether) to give 2-(4-(tert-butyl)methylphenyl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (700 mg, 76% yield) as a colorless oil. H NMR (400 MHz, CDCl ) δ 7.72 (d, J = 8.4
Hz, 1H), 7.23-7.18 (m, 2H), 2.50 (s, 3H), 1.32 (s, 12H), 1.30 (s, 9H).
Compound 210 (formic acid salt) was prepared as a white solid from Compound 101-K and 2-
(4-(tert-butyl)methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane by utilizing methods analogous to
those described in Example 5. LCMS (Method 5-95 AB, ESI): t = 0.706 min, [M + H] = 904.2; H NMR
(400 MHz, MeOH-d ) δ 8.49 (br s, 4H), 7.91 (d, J=8.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.36–7.10 (m, 7H),
6.90 (s, 1H), 6.82 (s, 1H), 6.37 (s, 1H), 5.19-5.15 (m, 1H), 4.90-4.78 (m, 2H), 4.24-4.17 (m, 4H), 4.19 (s,
2H), 3.34-3.05 (m, 8H), 2.96 (s, 3H), 2.40-2.20 (m, 1H), 2.32 (s, 3H), 2.20-2.05 (m, 1H), 1.36 (s, 9H), 1.35
(d, J=7.2 Hz, 3H).
Example 11: Synthesis of Compound 211
N N CN
N N O
18253141_1 (GHMatters) P111789.NZ
Compound 211 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous those described in Example 5. LCMS (Method 5-95 AB, ESI): t = 0.705 min,
[M + H] = 941.4; H NMR (400 MHz, MeOH-d ) δ 8.04 (d, J=8.0 Hz, 2H), 7.89 (d, J=8.0 Hz, 1H), 7.79
(d, J=8.4 Hz, 1H), 7.61 (d, J=8.0 Hz, 2H), 7.37-7.28 (m, 1H), 7.26-7.17 (m, 2H), 7.10 (d, J=8.4 Hz, 1H),
6.91 (s, 1H), 6.81 (s, 1H), 6.39 (s, 1H), 5.20-5.15 (m, 1H), 4.83-4.78 (m, 2H), 4.28-4.17 (m, 4H), 4.20 (s,
2H), 3.37-3.08 (m, 8H), 2.96 (s, 3H), 2.70 (s, 3H), 2.34-2.25 (m, 1H), 2.20-2.12 (m, 1H), 1.43 (br s, 2H),
1.36 (d, J=6.8 Hz, 3H), 1.17-1.11 (br s, 2H).
Example 12: Synthesis of Compound 212
Ph P MeBr N
CH I N CN
3 2 2,TFA,
O HN
t-BuOK ZnEt
N N O
Br Br
Step
Step 2 NH
[00618] Step 1: A mixture of 1-(4-bromophenyl)ethanone (1.0 g, 5.0 mmol),
methyl(triphenyl)phosphonium chloride (4.1 g, 13 mmol), and t-BuOK (1.5 g, 13 mmol) in THF (50 mL)
was stirred at 20 C for 3 h. The volatiles were removed and the residue was re-dissolved in EtOAc (50
mL), which was washed with brine (2 x 50 mL). The organic layer was dried over MgSO , concentrated
and the residue was purified by flash column chromatography, eluting with 5% EtOAc in petroleum ether,
to give 1-bromo(propenyl)benzene (800 mg, 81% yield) as a colorless oil.
Step 2: To a solution of Et Zn (1N in toluene, 3.5 mL) in DCM (10 mL) was added a solution of
trifluoroacetic acid (1.54 mL, 20.0 mmol) in DCM (10 mL) dropwise via syringe at 0 C under N and the
mixture was stirred for 20 min at the same temperature, followed by the addition of a solution of 1-bromo-
4-(propenyl)benzene (346 mg, 1.76 mmol) in DCM (10 mL). After an additional 20 min of stirring,
CH I (0.28 mL, 3.5 mmol) was added and the resulting mixture was stirred at 25 C for 16 h. The reaction
was diluted with petroleum ether (30 mL), which was washed with 1N aq HCl, saturated NaHCO and
brine (each 20 mL). The organic layer was dried over MgSO , concentrated and the residue was purified
by HPLC to give 1-bromo(1-methylcyclopropyl)benzene (150 mg, 40% yield) as a colorless oil.
Compound 212 (formic acid salt) was prepared as a white solid from 101-K and 1-bromo(1-
methylcyclopropyl)benzene by utilizing methods analogous those described in Example 10. LCMS
(Method 5-95 AB, ESI): t = 0.689 min, [M + H] = 887.4; H NMR (400 MHz, MeOH-d ) δ 8.46 (br s,
3H), 7.92 (d, J=8.4 Hz, 2H), 7.85 (d, J =8.4 Hz, 1H), 7.73 (d, J =8.0 Hz, 1H), 7.37 (d, J =8.0 Hz, 2H), 7.31
(d, J =8.0 Hz, 1H), 7.23 (d, J =8.0 Hz, 1H), 7.18 (d, J =8.4 Hz, 1H), 7.09 (d, J =8.4 Hz, 1H), 6.90 (s, 1H),
6.80 (s, 1H), 6.38 (s, 1H), 5.20-5.13 (m, 1H), 4.85-4.79 (m, 2H), 4.26-4.16 (m, 4H), 4.19 (s, 2H), 3.28-3.07
(m, 8H), 2.95 (s, 3H), 2.68 (s, 3H), 2.33-2.23 (m, 1H), 2.21-2.09 (m, 1H), 1.45 (s, 3H), 1.35 (d, J =7.2 Hz,
3H), 0.92 (s, 2H), 0.83 (s, 2H).
Example 13: Synthesis of Compound 213
18253141_1 (GHMatters) P111789.NZ
Br N
N N CN
Cl , CuI
Pd(PPh3)2 2 O HN
N N O
Et 80 C
Step 1
Step 1: A mixture of compound 6-bromomethylnicotinic acid (100 mg, 0.46 mmol), 3,3-
dimethylbutyne (380 mg, 4.6 mmol), CuI (17.6 mg, 0.09 mmol), Pd(dppf)Cl (32.5 mg, 0.05 mmol) in
Et N (10 mL) was stirred at 60 C under N for 16 h. The mixture was diluted with water (20 mL), which
was extracted by EtOAc (2 x 20 mL). The combined organic layers were washed with brine (2 x 40 mL).
The organic layer was dried over Na SO , concentrated and the residue was purified by preparatory-
TLC (eluting with 10% MeOH in DCM, R = 0.4) to give 6-(3,3-dimethylbutynyl)methylnicotinic
acid (60 mg, 60% yield) as a yellow solid. LCMS (Method 5-95 AB, ESI): t = 0.642 min, [M + H] =
217.8.
[00622] Compound 213 (formic acid salt) was prepared as a white solid from Compound 101-K and 6-
(3,3-dimethylbutynyl)methylnicotinic acid by utilizing methods analogous to those described in
= 0.616 min, [M + H] = 837.4; H NMR (400 MHz,
Example G. LCMS (Method 5-95 AB, ESI): t
MeOH-d ) δ 8.50 (br s, 2H), 7.78 (d, J=8.0 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.23
(d, J=8.0 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.10 (d, J=8.0 Hz, 1H), 6.89 (s, 1H), 6.78 (s, 1H), 6.40 (s, 1H),
5.15-5.13 (m, 1H), 4.85-4.78 (m, 2H), 4.28-4.18 (m, 4H), 4.20 (s, 2H), 3.24-3.10 (m, 8H), 2.94 (s, 3H),
2.57 (s, 3H), 1.36 (s, 9H), 1.35 (d, J=6.8 Hz, 3H).
Example 14: Synthesis of Compound 214
N N CN
O HN
N N O
Compound 214 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 13. LCMS (Method 5-95 AB, ESI): t = 0.689
min, [M + H] = 863.9; H NMR (400 MHz, MeOH-d ) δ 8.46 (br s, 2H), 7.78 (d, J=7.6 Hz, 1H), 7.37 (d,
J=7.6 Hz, 1H), 7.33-7.27 (m, 1H), 7.24 (d, J=4.8 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H),
6.89 (d, J =2.2 Hz, 1H), 6.81 (s, 1H), 6.36 (s, 1H), 5.16-5.09 (m, 1H), 4.80-4.71 (m, 2H), 4.25-4.16 (m,
4H), 4.19 (s, 2H), 3.34-3.08 (m, 8H), 2.93 (s, 3H), 2.74-2.66 (m, 1H), 2.57 (s, 3H), 2.33-2.20 (m, 1H),
2.18-2.06 (m, 1H), 1.95-1.89 (m, 2H), 1.79-1.76 (m, 2H), 1.59-1.55 (m, 3H), 1.45 - 1.37 (m, 3H), 1.34 (d,
J =7.2 Hz, 3H).
Example 15: Synthesis of Compound 215
18253141_1 (GHMatters) P111789.NZ
DCM, 0 C
NHBoc
NHBoc
BocHN
BocHN
Br N
LiOH, THF/H O
1) 2
ClH H N
HATU, DIEA
1) 2) HATU,DIEA
O N O
% TFA in HFIP
O HN
O HN
H N N O B N N O
O , Na CO
2) Pd(dppf)Cl O O
2 2 3
NHBoc
NHBoc
101K
215-1
H N O
N N CN
O HN
N N O
Starting from Compound 101-K, typical amide coupling (HATU/DIEA), Suzuki coupling ester
hydrolysis (LiOH, THF/H O), amide coupling (HATU/DIEA) and Boc removal (TFA/HFIP) conditions,
analogous to those described in Examples G and H, were applied to afford Compound 215 (formic acid
salt) as a white solid. LCMS (Method 5-95 AB, ESI): t = 0.702 min, [M + H] = 889.5; H NMR (400
MHz, MeOH-d ) δ 8.58 (s, 1H), 8.49 (br s, 3H), 7.92-7.87 (m, 2H), 7.78 (s, 1H), 7.57-7.51 (m, 3H), 7.32
(d, J=8.0Hz, 1H), 7.20 (d, J=8.0Hz, 2H), 7.08 (d, J=8.0Hz, 1H), 6.89 (s, 1H), 6.43 (s, 1H), 5.20-5.17 (m,
1H), 4.82-4.79 (m, 2H), 4.24-4.18 (m, 4H), 4.20 (s, 2H), 3.16-3.12 (m, 8H), 2.95 (s, 3H), 2.52 (s,
3H), 2.29-2.17 (m, 2H), 1.38 (s, 9H), 1.36 (d, J=7.2 Hz, 3H).
Example 16: Synthesis of Compound 216
H N O
, KOAc
(BPin) N N
2 CN
Tf O HN
2O, pyr
Pd(dppf)Cl2
N N N O
Compound 216 (formic acid salt) was prepared as a white solid starting from 5,6,7,8-
tetrahydronaphthalenol and Compound 101-K by utilizing methods analogous to those described in
Example 10 and Example J. LCMS (Method 5-95 AB, ESI): t = 0.709 min, [M + H] = 888.5; H NMR
(400 MHz, MeOH-d ) δ 8.77 (s, 1H), 8.48 (br s, 2H), 8.20-8.05 (m, 2H), 7.40-7.30 (m, 1H), 7.30-7.15 (m,
3H), 7.15-7.05 (m, 1H), 6.91 (s, 1H), 6.80 (s, 1H), 6.40 (s, 1H), 5.25-5.15 (m, 1H), 4.75-4.70 (m, 2H),
4.25-4.15 (m, 4H), 4.19 (s, 2H), 3.25-3.05 (m, 8H), 2.96 (s, 3H), 2.87 (br s, 4H), 2.75 (s, 3H), 2.35-2.25 (m,
1H), 2.25-2.10 (m, 1H), 1.86 (br s, 4H), 1.36 (d, J=6.8 Hz, 3H).
Example 17: Synthesis of Compound 217
18253141_1 (GHMatters) P111789.NZ
(HO)
2 N N CN
NHTs O HN
CHO H H
TsNHNH
2 Br N N N O
K CO Br
Step 1: A mixture of cyclobutane carbaldehyde (202 mg, 2.4 mmol) and 4-
methylbenzenesulfonohydrazide (448 mg, 2.4 mmol) in 1,4-dioxane (1 mL) was stirred at 50 C for 1 h.
The volatiles were removed under reduced pressure to give N’-(cyclobutylmethylene)
methylbenzenesulfonohydrazide (607 mg), which was used directly in the next step.
Step 2: A mixture of N’-(cyclobutylmethylene)methylbenzenesulfonohydrazide (600 mg, 2.4
mmol), 4-bromophenyl boronic acid (716 mg, 3.6 mmol), and K CO (657 mg, 4.8 mmol) in 1,4-dioxane
(20 mL) was stirred at 110 C for 16 h. The reaction was diluted with water (10 mL), which was extracted
with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (50 mL), dried over
MgSO , concentrated and the residue was purified by silica-gel column chromatography, eluting with
petroleum ether, to give 1-bromo(cyclobutylmethyl)benzene (378 mg, 71% yield) as colorless oil.
Compound 217 (formic acid salt) was prepared as a white solid from 1-bromo
(cyclobutylmethyl)benzene and Compound 101-K by utilizing methods analogous to those described in
Example 10 and Example J. LCMS (Method 5-95 AB, ESI): t = 0.640 min, [M + H] = 902.5; H NMR
(400 MHz, MeOH-d ) δ 8.77 (s, 2H), 8.55 (br s, 2H), 8.31 (d, J=8.4 Hz, 1H), 7.32-7.28 (m, 3H), 7.20-7.17
(m, 2H), 7.07 (d, J=8.4 Hz, 1H), 6.88 (s, 1H), 6.76 (s, 1H), 6.74 (s, 1H), 5.18 (t, J=5.2 Hz, 1H), 4.85-4.78
(m, 2H), 4.21-4.15 (m, 4H), 4.19 (s, 2H), 3.14-3.00 (m, 8H), 2.95 (s, 3H), 2.78 (d, J=7.6 Hz, 2H), 2.66 (s,
3H), 2.20-2.10 (m, 1H), 2.07-2.00 (m, 3H), 1.95-1.78 (m, 4H), 1.35 (d, J=6.8 Hz, 3H).
Example 18: Synthesis of Compound 218
N N CN
O HN
N N (S) N O
Compound 218 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 17. LCMS (Method 5-95 AB, ESI): t = 0.757
min, [M + H] = 916.5; H NMR (400 MHz, MeOH-d ) δ 8.79 (s, 1H), 8.48 (br s, 2H), 8.36 (d, J=8.4 Hz,
2H), 7.34-7.30 (m, 3H), 7.25-7.17 (m, 2H), 7.10 (d, J=8.4 Hz, 1H), 6.91 (d, J=2.0 Hz, 1H), 6.82 (s, 1H),
6.39 (s, 1H), 5.21-5.16 (m, 1H), 4.72-4.68 (m, 2H), 4.26-4.16 (m, 4H), 4.20 (s, 2H), 3.40-3.04 (m, 8H),
2.96 (s, 3H), 2.70-2.50 (m, 2H), 2.40 (s, 6H), 2.33-2.27 (m, 1H), 2.20-2.12 (m, 2H), 1.80-1.65 (m, 4H),
1.61-1.53 (m, 2H), 1.36 (d, J=6.8 Hz, 3H), 1.30-1.22 (m, 2H).
Example 19: Synthesis of Compound 219
18253141_1 (GHMatters) P111789.NZ
H N O
N N CN
O HN
N N (S) N O
Compound 219 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 10 and Example J. LCMS (Method 5-95 AB,
ESI): t = 0.714 min, [M + H] = 942.6; H NMR (400 MHz, MeOH-d ) δ 8.82 (s, 1H), 8.46 (d, J=8.0 Hz,
2H), 7.63 (d, J=8.0 Hz, 2H), 7.33 (d, J=8.4 Hz, 1H), 7.22 (m, 2H), 7.10 (d, J=8.4 Hz, 1H), 6.91 (d, J=1.6
Hz, 1H), 6.81 (s, 1H), 6.40 (s, 1H), 5.22-5.17 (m, 1H), 4.75-4.71 (m, 2H), 4.28-4.15 (m, 4H), 4.20 (s, 2H),
3.35-3.07 (m, 8H), 2.96 (s, 3H), 2.72 (s, 3H), 2.33-2.27 (m, 1H), 2.21-2.14 (m, 1H), 1.43 (br s, 2H), 1.36
(d, J=6.8 Hz, 3H), 1.16 (br s, 2H).
Example 20: Synthesis of Compound 220
H N O
O HN
N N N O
Compound 220 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 17. LCMS (Method 5-95 AB, ESI): t = 0.632
min, [M + H] = 904.6; H NMR (400 MHz, MeOH-d ) δ 8.77 (s, 1H), 8.48 (br s, 2H), 8.32 (d, J=8.0 Hz,
2H), 7.40-7.30 (m, 3H), 7.21 (d, J=8.0 Hz, 2H), 7.09 (d, J=8.0 Hz, 1H), 6.89 (s, 1H), 6.75 (s, 1H), 6.44 (s,
1H), 5.20-5.15 (m, 1H), 4.85-4.75 (m, 2H), 4.35-4.15 (m, 4H), 4.20 (s, 2H), 3.40-3.05 (m, 8H), 2.96 (s,
3H), 2.72 (t, J=7.6 Hz, 2H), 2.69 (s, 3H), 2.35-2.25 (m, 1H), 2.20-2.10 (m, 1H), 1.70-1.50 (m, 3H), 1.36 (d,
J=6.4 Hz, 3H), 0.98 (d, J=6.0 Hz, 6H).
Example 21: Synthesis of Compound 221
H N O
OH OBn
Bpin2
N N CN
BnBr, K CO Na
, CO
2 3 1) Pd(PPh3)4 2 3 HN
H N N O
Pd/C, (S)
2) 2
Step 1 N O
Step
[00632] Step 1: A mixture of 4-bromonaphthalenol (2.0 g, 9.0 mmol), benzyl bromide (2.3 g, 13.5
mmol), and K CO (3.7 g, 27 mmol) in DMF (1 mL) was stirred at 20 C for 16 h. The reaction was
poured into water (50 mL), which was extracted with EtOAc (3 x 50 mL). The combined organic layers
were washed with brine (2 x 100 mL), dried over Na SO , concentrated and the residue was purified by
silica-gel chromatography to give 1-(benzyloxy)bromonaphthalene (2.0 g, 71.2% yield) as a yellow oil.
18253141_1 (GHMatters) P111789.NZ
Step 2: Typical Suzuki (Example H) and hydrogenation conditions (Example D) were applied to 1-
(benzyloxy)bromonaphthalene to give 4-ethylnaphthalenol as a white solid.
Compound 221 (formic acid salt) was prepared as a white solid from Compound 101-K and 4-
ethylnaphthalenol by utilizing methods analogous to those described in Example 10 and Example J.
LCMS (Method 5-95 AB, ESI): t = 0.701 min, [M + H] = 912.5; H NMR (400 MHz, MeOH-d ) δ 8.93
(s, 1H), 8.50 (d, J=8.4 Hz, 1H), 8.23 (d, J=8.4 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.63-7.53 (m, 3H), 7.37-
7.32 (m, 1H), 7.25-7.16 (m, 2H), 7.11 (d, J=8.0 Hz, 1H), 6.92 (s, 1H), 6.84 (s, 1H), 6.42 (s, 1H), 5.24-5.20
(m, 1H), 4.83-4.80 (m, 2H), 4.27-4.13 (m, 4H), 4.19 (s, 2H), 3.50-3.46 (m, 1H), 3.29-3.07 (m, 9H), 2.98 (s,
3H), 2.77 (s, 3H), 2.35-2.29 (m, 1H), 2.21-2.16 (m, 1H), 1.43 (t, J=7.2 Hz, 3H), 1.36 (d, J=6.8 Hz, 3H).
Example 22: Synthesis of Compound 222
H N O
Br OH
BnBr,K CO Na CO N
, N CN
2 3 1) Pd(dppf)Cl2 2 3
O HN
Pd/C, H
2) 2 N N N O
OH (S)
OH N O
Alkylation (example 21), Suzuki (Example H) and hydrogenation (Pd/C, H , Example D)
conditions were applied to 4-bromomethylphenol to give 2-methylpropylphenol as a colorless oil.
Compound 222 (formic acid salt) was prepared as a white solid from Compound 101-K by utilizing
methods analogous to those described in Example 21 and Example J. LCMS (Method 5-95 AB, ESI): t =
0.680 min, [M + H] = 890.5; H NMR (400 MHz, MeOH-d ) δ 8.82 (s, 1H), 8.45 (br s, 3H), 7.64 (d,
J=7.2 Hz, 1H), 7.32-7.25 (m, 1H), 7.20-7.09 (m, 5H), 6.89 (s, 1H), 6.77 (s, 1H), 6.42 (s, 1H), 5.20-5.15 (m,
1H), 4.85-4.78 (m, 2H), 4.27-4.15 (m, 4H), 4.20 (s, 2H), 3.30-3.13 (m, 8H), 2.96 (s, 3H), 2.63 (s, 3H), 2.62
(t, J=7.2 Hz, 2H), 2.49 (s, 3H), 2.40-2.25 (m, 1H), 2.20-2.05 (m, 1H), 1.71-1.66 (m, 2H), 1.36 (d, J=6.8 Hz,
3H), 0.97 (t, J=6.8 Hz, 3H).
Example 23: Synthesis of Compound 223
H N O
N N CN
O HN
N N N O
Compound 223 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 22. LCMS (Method 5-95 AB, ESI): t = 0.714
min, [M + H] = 904.4; H NMR (400 MHz, MeOH-d ) δ 8.82 (s, 1H), 8.46 (br s, 2H), 7.68 (d, J=7.6 Hz,
1H), 7.32-7.25 (m, 1H), 7.22-7.10 (m, 5H), 6.90 (s, 1H), 6.80 (s, 1H), 6.39 (s, 1H), 5.20-5.15 (m, 1H),
4.85-4.78 (m, 2H), 4.27-4.15 (m, 4H), 4.20 (s, 2H), 3.30-3.13 (m, 8H), 2.95 (s, 3H), 2.75-2.61 (m, 2H),
2.69 (s, 3H), 2.50 (s, 3H), 2.40-2.25 (m, 1H), 2.20-2.05 (m, 1H), 1.66-1.62 (m, 2H), 1.39-1.34 (m, 5H),
0.96 (t, J=7.6 Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 24: Synthesis of Compound 224
H N O
N N CN
O HN
N N (S) N O
Compound 224 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 12 and Example J. LCMS (Method 5-95 AB,
ESI): t = 0.599 min, [M + H] = 888.5; H NMR (400 MHz, MeOH-d ) δ 8.75 (s, 1H), 8.50 (br s, 2H),
8.28 (d, J=8.0 Hz, 2H), 7.37-7.30 (m, 3H), 7.21-7.19 (m, 2H), 7.07 (d, J=8.0 Hz, 1H), 6.88 (s, 1H), 6.70
(s,1H), 6.48 (s, 1H), 5.20-5.16 (m, 1H), 4.85-4.78 (m, 2H), 4.28-4.21 (m, 6H), 3.31-3.13 (m, 8H), 2.96 (s,
3H), 2.67 (s, 3H), 2.31-2.27 (m, 1H), 2.19-2.16 (m, 1H), 1.47 (s, 3H), 1.35 (d, J=7.2 Hz, 1H), 0.97-0.94 (m,
2H), 0.86-0.83 (m, 2H).
Example 25: Synthesis of Compound 225
H N O
N CN
O HN
N N N O
Compound 225 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 2 and Example J. LCMS (Method 5-95 AB,
ESI): t = 0.607 min, [M + H] = 960.5; H NMR (400 MHz, MeOH-d ) δ 8.87 (s, 1H), 8.65 (d, J=8.4 Hz,
2H), 8.50 (br s, 2H), 7.98 (d, J=8.4 Hz, 2H), 7.33-7.31 (m, 1H), 7.24-7.18 (m, 2H), 7.10 (d, J=8.4 Hz, 1H),
6.91 (s, 1H), 6.79 (s, 1H), 6.41 (s, 1H), 5.20-5.18 (m, 1H), 4.80-4.78 (m,2H), 4.25-4.20 (m, 6H), 3.48-3.44
(m, 1H), 3.17-3.07 (m, 7H), 2.97 (s, 3H), 2.73 (s, 3H), 2.30-2.28 (m, 1H), 2.18-2.17 (m, 1H), 1.36 (d,
J=6.4 Hz, 3H).
Example 26: Synthesis of Compound 226
H N O
N N CN
O HN
N N N O
Br NH
Br +
BF K
O NH HCl
N , K CO N
1) Pd(PPh3)4 2 3
DMF-DMA NaOEt/EtOH
NaOH, MeOH/H O
2) 2
N O N OH
Step 1 Step 2
O Step 3
18253141_1 (GHMatters) P111789.NZ
Step 1: A mixture of DMF-DMA (2.5 g, 21 mmol) and methyl acetoacetate (2.0 g, 17 mmol)
was stirred at 100 C for 2 h. The reaction was concentrated to give methyl 2-((dimethylamino)methylene)-
3-oxobutanoate (2.8 g), which was used directly in the next step.
Step 2: A mixture of methyl 2-((dimethylamino)methylene)oxobutanoate (800 mg, 4.7 mmol),
4-bromobenzamidine hydrochloride (1.0 g, 4.3 mmol) and sodium ethoxide (293 mg, 4.3 mmol) in ethanol
(15 mL) was stirred at 70 C for 2 h. The volatiles were removed and the residue was extracted with
EtOAc (50 mL), which was washed with brine (2 x 50 mL). The organic layer was dried over Na SO ,
concentrated and the residue was purified on silica-gel column, eluting with 0-2% EtOAc in petroleum
ether, to afford methyl 2-(4-bromophenyl)methylpyrimidinecarboxylate (700 mg, 47% yield) as a
white solid.
Step 3: Starting from methyl 2-(4-bromophenyl)methylpyrimidinecarboxylate, typical
Suzuki and ester hydrolysis (NaOH, MeOH) conditions were applied to give 4-methyl(4-
neopentylphenyl)pyrimidinecarboxylic acid as a white solid.
Compound 226 (formic acid salt) was prepared as a white solid from Compound 101-K and 4-
methyl(4-neopentylphenyl)pyrimidinecarboxylic acid by utilizing methods analogous to those
described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.617 min, [M + H] = 904.5; H NMR (400
MHz, MeOH-d ) δ 8.77 (s, 1H), 8.47 (br s, 1H), 8.30 (d, J=8.0 Hz, 2H), 7.35-7.27 (m, 3H), 7.24-7.17 (m,
2H), 7.09 (d, J=8.4 Hz, 1H), 6.89 (d, J=1.6 Hz, 1H), 6.72 (s, 1H), 6.47 (s, 1H), 5.22-5.16 (m, 1H), 4.82-
4.75 (m, 2H), 4.32-4.17 (m, 4H), 4.19 (s, 2H), 3.29-3.06 (m, 8H), 2.97 (s, 3H), 2.69 (s, 3H), 2.61 (s, 2H),
2.36-2.27 (m, 1H), 2.23-2.14 (m, 1H), 1.37 (d, J=6.8 Hz, 3H), 0.97 (s, 9H).
Example 27: Synthesis of Compound 227
H N O
Cl CuI
Pd(PPh3)2 2
Et N H
1-pentyne,
N CN
O O HN
N N N O
Step 1
Step 1: Typical Sonogashira condition (Example K) was applied to 2-(4-iodophenyl)-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane to give 4,4,5,5-tetramethyl(4-(pentynyl)phenyl)-1,3,2-
dioxaborolane as a yellow oil.
Compound 227 (formic acid salt) was prepared as a white solid from Compound 101-K and
4,4,5,5-tetramethyl(4-(pentynyl)phenyl)-1,3,2-dioxaborolane by utilizing methods analogous to
those described in Example J. LCMS (Method 5-95 AB, ESI): t = 0.613 min, [M + H] = 900.6; H NMR
(400 MHz, MeOH-d ) δ 8.78 (s, 1H), 8.48 (br s, 2H), 8.36 (d, J=8.0 Hz, 2H), 7.48 (d, J=8.0 Hz, 2H), 7.32
(d, J=8.4 Hz, 1H), 7.20 (d, J=8.4 Hz, 2H), 7.09 (d, J=8.4 Hz, 1H), 6.89 (s, 1H), 6.74 (s, 1H), 6.45 (s, 1H),
.25-5.15 (m, 1H), 4.80-4.75 (m, 2H), 4.30-4.15 (m, 6H), 3.40-3.35 (m, 1H), 3.30-3.10 (m, 7H), 2.96 (s,
3H), 2.69 (s, 3H), 2.44 (t, J=7.2 Hz, 2H), 2.35-2.25 (m, 1H), 2.25-2.15 (m, 1H), 1.66 (q, J=6.8 Hz, 2H),
1.36 (d, J=6.4 Hz, 3H), 1.09 (t, J=7.6 Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 28: Synthesis of Compound 228
H N O
Cl , CuI
1) Pd(PPh3)2 2
Br N
Et 80 C N N CN
O HN
N OEt
N OH H H
NaOH, MeOH/H O
2) 2
N N N O
Step 1
Step 1: Starting from ethyl 2-bromomethylpyrimidinecarboxylate (described in Example
26), typical Sonogashira (Example K) and ester hydrolysis (NaOH, MeOH/H O, described in Example H)
conditions were applied to give 2-(3,3-dimethylbutynyl)methylpyrimidinecarboxylic acid as a
yellow solid.
Compound 228 (formic acid salt) was prepared as a white solid from Compound 101-K and 2-
(3,3-dimethylbutynyl)methylpyrimidinecarboxylic acid by utilizing methods analogous to
those described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.542 min, [M + H] = 838.3; H NMR
(400 MHz, MeOH-d ) δ 8.68 (s, 1H), 8.47 (br s, 3H), 7.30 (d, J=8.4 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.18
(d, J=8.4 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.90 (s, 1H), 6.81 (s, 1H), 6.37 (s, 1H), 5.16-5.12 (m, 1H), 4.81-
4.77 (m, 2H), 4.26-4.16 (m, 4H), 4.19 (s, 2H), 3.48 (br s, 1H), 3.21-3.09 (m, 7H), 2.93 (s, 3H), 2.61 (s, 3H),
2.29-2.24 (m, 1H), 2.16-2.11 (m, 1H), 1.38 (s, 9H), 1.36 (t, J=6.4 Hz, 3H).
Example 29: Synthesis of Compound 229
H N O
N N CN
O HN
N N (S) N O
Compound 229 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 28. LCMS (Method 0-30 AB, ESI): t = 0.999
min, [M + H] = 824.3; H NMR (400 MHz, MeOH-d ) δ 8.68 (s, 1H), 8.49 (br. s., 1H), 7.29 (d, J=8.4 Hz,
1H), 7.24 (d, J=8.4 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.89 (s, 1H), 6.80 (s, 1H),
6.37 (s, 1H), 5.14 (t, J=6.8 Hz, 1H), 4.87-4.76 (m, 2H), 4.25-4.16 (m, 4H), 4.19 (s, 2H), 3.40-3.30 (m, 1H),
3.20-3.08 (m, 7H), 2.93 (s, 3H), 2.90-2.83 (m, 1H), 2.60 (s, 3H), 2.32-2.21 (m, 1H), 2.18-2.08 (m, 1H),
1.34 (d, J=6.8 Hz, 3H), 1.31 (d, J=7.2 Hz, 6H).
Example 30: Synthesis of Compound 230
H N O
N N CN
O HN
N N N O
18253141_1 (GHMatters) P111789.NZ
Compound 230 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example J. LCMS (Method 5-95 AB, ESI): t = 0.727
min, [M + H] = 902.4; H NMR (400 MHz, MeOH-d ) δ 8.78 (s, 1H), 8.40-8.33 (m, 2H), 7.40 (d, J=8.0
Hz, 1H), 7.37-7.31 (m, 1H), 7.23-7.17 (m, 2H), 7.14-7.08 (m, 2H), 6.93 (s, 1H), 6.84 (s, 1H), 6.38 (s, 1H),
5.20-5.16 (m, 1H), 4.83-4.78 (m, 2H), 4.38-4.16 (m, 6H), 3.48-3.18 (m, 8H), 2.96 (s, 3H), 2.71 (s, 3H),
2.40-2.30 (m, 1H), 2.25-2.07 (m, 4H), 1.94-1.61 (m, 8H), 1.37 (d, J=6.8 Hz, 3H).
Example 31: Synthesis of Compound 231
H N O
N N CN
O HN
N N N O
Compound 231 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 17. LCMS (Method 5-95 AB, ESI): t = 0.649
min, [M + H] = 918.4; H NMR (400 MHz, MeOH-d ) δ 8.81 (s, 1H), 8.45 (br s, 1H), 8.42 (d, J=8.0 Hz,
2H), 7.43 (d, J=8.0 Hz, 2H), 7.38-7.32 (m, 1H), 7.28-7.19 (m, 2H), 7.11 (d, J=8.4 Hz, 1H), 6.93 (s, 1H),
6.83 (s, 1H), 6.41 (s, 1H), 5.22-5.20 (m, 1H), 4.84-4.80 (m, 2H), 4.30-4.21 (m, 6H), 4.11-4.08 (m, 2H),
3.65-3.58 (m, 2H), 3.25-3.11 (m, 8H), 2.97 (s, 3H), 2.73 (s, 3H), 2.34-2.28 (m, 1H), 2.23-2.14 (m, 1H),
1.88-1.81(m, 5H), 1.39 (t, J=6.4 Hz, 3H).
Example 32: Synthesis of Compound 232
N OH
H N B
Br N
N OH
LiOH
, K CO
1) Pd(PPh3)4 2 3
THF/H O OH
iAmONO, CHBr
OEt 2) 3 N
O Step 2
Step 1
101-K, HATU, DIEA
, Na CO
2) Pd(dppf)Cl
2 2 3
N B(OH)2
LiOH, THF/H2O
3) H
OH N N N
HATU, DIEA
O HN
NH HCl
N 2.
N N N O
% TFA in HFIP N O
Step 1: Starting from ethyl 2-bromomethylpyrimidinecarboxylate (described in Example
26), typical Suzuki (Example H) and Sandmeyer conditions (Example J) were followed to give ethyl 2’-
bromomethyl-[2,5’-bipyrimidine]carboxylate as a white solid.
Step 2: Typical ester hydrolysis condition (LiOH, THF/H O, Example G) was applied to ethyl
2’-bromomethyl-[2,5’-bipyrimidine]carboxylate to give 2’-bromomethyl-[2,5’-bipyrimidine]
carboxylic acid as a white solid. LCMS (Method 5-95 AB, ESI): t = 0.671, [M + H] = 295.0.
Step 3: Starting from Compound 101-K and 2’-bromomethyl-[2,5’-bipyrimidine]
carboxylic acid, typical amide coupling (HATU/DIEA), Suzuki, ester hydrolysis (LiOH, THF/H O), amide
18253141_1 (GHMatters) P111789.NZ
coupling (HATU/DIEA), and Boc removal (TFA/HFIP) conditions, analogous to those described in
Examples G and H, were followed to give Compound 232 (formic acid salt) as a white solid. LCMS
(Method 5-95 AB, ESI): t = 0.753 min, [M + H] = 968.6; H NMR (400 MHz, MeOH-d ) δ 9.66 (s, 2H),
8.80 (s, 1H), 8.54-8.36 (m, 5H), 7.60 (d, J=7.6 Hz, 2H), 7.33-7.22 (m, 2H), 7.09-6.97 (m, 2H), 6.85 (s, 1H),
6.61 (s, 1H), 6.48 (s, 1H), 5.22-5.18 (m, 1H), 4.85-4.74 (m, 2H), 4.39-4.16 (m, 6H), 3.28-3.05 (m, 8H),
2.97 (s, 3H), 2.68 (s, 3H), 2.33-2.15 (m, 2H), 1.39 (s, 9H), 1.36 (d, J=6.8 Hz, 3H).
Example 33: Synthesis of Compound 233
Br O
K N N
, CO
1) Pd(PPh3)4 2 3
Pd/C, H
2) 2 N N N O
NaOH, MeOH/H O
3) 2
OH O O
Step 1
Step 1: Starting from ethyl 2-(4-bromophenyl)methylpyrimidinecarboxylate (described in
Example 26), typical Suzuki, hydrogenation (Pd/C, H ) and ester hydrolysis (NaOH, MeOH/H O)
conditions, analogous to those described in Examples G and H, were applied to give 2-(4-
cyclohexylphenyl)methylpyrimidinecarboxylic acid as a white solid. LCMS (Method 5-95 AB, ESI):
t = 0.901 min, [M + H] = 296.9.
Compound 233 (formic acid salt) was prepared as a white solid from Compound 101-K and 2-
(4-cyclohexylphenyl)methylpyrimidinecarboxylic acid by utilizing methods analogous to those
described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.746 min, [M + H] = 916.4; H NMR (400
MHz, MeOH-d ) δ 8.78 (s, 1H), 8.37-8.30 (m, 3H), 7.40-7.31 (m, 2H), 7.25-7.20 (m, 2H), 7.10 (d, J=8.4
Hz, 1H), 6.92 (s, 1H), 6.83 (s, 1H), 6.38 (s, 1H), 5.21-5.16 (m, 1H), 4.84-4.80 (m, 2H), 4.33-4.17 (m, 4H),
4.20 (s, 2H), 3.50-3.46 (m, 1H), 3.27-3.10 (m, 7H), 2.95 (s, 3H), 2.71 (s, 3H), 2.60-2.50 (m, 1H), 2.34-2.29
(m, 1H), 2.19-2.15 (m, 1H), 1.92-1.87 (m, 4H), 1.82-1.77 (m, 2H), 1.55-1.45 (m, 4H), 1.36 (d, J=7.2 Hz,
3H).
Example 34: Synthesis of Compound 234
Me Zn, TiCl H
O HN
N N N O
Step 1
Step 1: To a solution of TiCl (3.2 mL, 28.4 mmol) in DCM (10 mL) was added Me Zn (1N in
toluene, 28.4 mL) at -78 C and the resulting orange-brown solution was stirred vigorously at the same
temperature for 1 h, followed by the dropwise addition of a solution of 5-bromo-2,3-dihydro-1 -inden-
1-one (1.0g, 4.74 mmol) in DCM (20 mL). The mixture was stirred at -78 C for 2 h; then allowed to reach
-10 C before quenching with ice-cold saturated aqueous NH Cl solution. The organic layer was separated
18253141_1 (GHMatters) P111789.NZ
and the aqueous layer was extracted with DCM (2 x 40 mL). The combined organic layers were dried over
Na SO , concentrated and the residue was purified by silica-gel column, eluting with petroleum ether, to
give 5-bromo-1,1-dimethyl-2,3-dihydro-1H-indene (450 mg, 42% yield) as a yellow oil. 1H NMR (400
MHz, CDCl ) δ 7.35 (s, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 2.90 (t, J=7.2 Hz, 2H), 1.95 (t,
J=7.2 Hz, 2H), 1.27 (s, 6H).
Compound 234 (formic acid salt) was prepared as a white solid from Compound 101-K and 5-
bromo-1,1-dimethyl-2,3-dihydro-1H-indene by utilizing methods analogous to those described in Example
and Example J. LCMS (Method 5-95 AB, ESI): t = 0.725 min, [M + H] = 902.6; H NMR (400 MHz,
MeOH-d ) δ 8.74 (s, 1H), 8.52 (br s, 1H), 8.18 (d, J=8.0 Hz, 1H), 8.13 (s, 1H), 7.31-7.21(m, 3H), 7.12-
7.05 (m, 2H), 6.85 (s, 1H), 6.60 (s, 1H), 6.54 (s, 1H), 5.20-5.15 (m, 1H),4.82-4.69 (m, 2H), 4.34-4.18 (m,
6H), 3.23-3.12 (m, 8H), 2.95 (br s, 5H), 2.65 (s, 3H), 2.20-2.17 (m, 2H), 2.01 (t, J=6.8 Hz, 2H), 1.36 (d,
J=6.8 Hz, 3H), 1.32 (s, 6H).
Example 35: Synthesis of Compound 235
Br Cl
EtONa/EtOH
HMDSLi N N
N O HN
, K CO H H
2) Pd(PPh3)4 2 3
N N N O
NH N
CN 2
B(OH)2 N O
NaOH, MeOH/H O OH O O
3) 2
Step 1
Step 2 NH
[00656] Step 1: To a solution of 4-bromochlorobenzonitrile (2.0 g, 9.2 mmol) in THF (20 mL) at 0 C
was added HMDSLi (1N solution in THF, 13.9 mL) dropwise and the reaction was stirred at 0 C for 16 h,
followed by the addition of aqueous HCl (1N, 10 mL). The resulting precipitate was collected,
washed with EtOAc and dried under vacuum to give 4-bromochlorobenzimidamide (4.0 g, 93% yield).
Step 2: 2-(4-Butylchlorophenyl)methylpyrimidinecarboxylic acid was prepared as a
white solid from 4-bromochlorobenzimidamide by utilizing methods analogous to those described in
Example 26.
Compound 235 (formic acid salt) was prepared as a white solid from Compound 101-K and 2-
(4-butylchlorophenyl)methylpyrimidinecarboxylic acid by utilizing methods analogous to those
described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.713 min, [M + H] = 924.4; H NMR (400
MHz, MeOH-d ) δ 8.86 (s, 1H), 8.50 (br s, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.40 (s, 1H), 7.35-7.28 (m, 2H),
7.25 (d, J=8.4 Hz, 1H), 7.20 (d, J=8.8 Hz, 1H), 7.10 (d, J=8.8 Hz, 1H), 6.92 (s, 1H), 6.82 (s, 1H), 6.40 (s,
1H), 5.23-5.16 (m, 1H), 4.81-4.78 (m, 2H), 4.27-4.17 (m, 4H), 4.20 (s, 2H), 3.36-3.13 (m, 8H), 2.96 (s,
3H), 2.74-2.69 (m, 2H), 2.71 (s, 3H), 2.34-2.27 (m, 1H), 2.21-2.15 (m, 1H), 1.71-1.62 (m, 2H), 1.46-1.35
(m, 5H), 0.98 (t, J=7.2 Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 36: Synthesis of Compound 236
O HN
N N N O
Compound 236 (formic acid salt) was prepared as a white solid from (4-
bromophenyl)(phenyl)methanone and Compound 101-K by utilizing methods analogous to those described
in Example 34. LCMS (Method 5-95 AB, ESI): t = 0.632 min, [M + H] = 952.4; H NMR (400 MHz,
MeOH-d ) δ 8.74 (s, 1H), 8.49 (br s, 2H), 8.27 (d, J=7.6 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 7.32-7.10 (m,
8H), 7.03 (d, J=8.4 Hz, 1H), 6.86 (s, 1H), 6.67 (s, 1H), 6.47 (s, 1H), 5.21-5.14 (m, 1H), 4.79-4.75 (m, 2H),
4.32-4.13 (m, 6H), 3.25-3.07 (m, 8H), 2.95 (s, 3H), 2.66 (s, 3H), 2.37-2.23 (m, 1H), 2.21-2.08 (m, 1H),
1.73 (s, 6H), 1.35 (d, J=6.8 Hz, 3H).
Example 37: Synthesis of Compound 237
O HN
N N N O
Compound 237 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example J. LCMS (Method 5-95 AB, ESI): t = 0.706
min, [M + H] = 890.7; H NMR (400 MHz, MeOH-d ) δ 8.81 (s, 1H), 8.50 (s, 1H), 8.45 (br s, 1H), 8.26
(d, J=8.0 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.37-7.30 (m, 1H), 7.26-7.17 (m, 2H),
7.09 (d, J=8.0 Hz, 1H), 6.91 (d, J=2.0 Hz, 1H), 6.82 (s, 1H), 6.39 (s, 1H), 5.23-5.16 (m, 1H), 4.80-4.76 (m,
2H), 4.29-4.15 (m, 6H), 3.27-3.09 (m, 8H), 2.96 (s, 3H), 2.72 (s, 3H), 2.35-2.26 (m, 1H), 2.22-2.13 (m,
1H), 1.40 (s, 9H), 1.36 (d, J=6.5 Hz,3H).
Example 38: Synthesis of Compound 238
N N N O
O O OEt O OEt
O PPh
NC OEt NaH, MeI ,
O O LiAlH 3
DEAD
OEt OEt
Br Br
Step 3
Step
Step 2
Step 1
18253141_1 (GHMatters) P111789.NZ
Step 1: A mixture of ethyl 2-(4-bromophenyl)acetate (10.0 g, 41 mmol) and lithium
diisopropylamide (2N in THF, 41 mL) in dry THF (60 mL) was stirred at -78 C for 0.5 h, followed by the
addition of ethyl cyano-formate (4.14 mL, 45 mmol). The resulting mixture was gradually warmed up to
°C while stirring and was stirred at the same temperature for 18 h. The reaction was quenched with
water (30 mL), which was partitioned between 1N aqueous HCl (150 mL) and DCM (150 mL). The
organic layer was dried over Na SO and concentrated and the residue was purified by silica-gel
chromatography, eluting with 0-20% EtOAc in petroleum ether, to give diethyl 2-(4-
bromophenyl)malonate (8.5 g, 66% yield) as colorless oil.
Step 2: A mixture of diethyl 2-(4-bromophenyl)malonate (10.0 g, 32 mmol) and NaH (60%
dispersion in oil, 2.5 g, 64 mmol) in dry THF (80 mL) was stirred at 0 °C for 0.5 h, followed by the
addition of iodomethane (6.0 mL, 96 mmol). The resulting mixture was gradually warmed up to 20 °C
while stirring and was stirred at the same temperature for 16 h. The reaction was partitioned between 1N
aqueous HCl (150 mL) and DCM (150 mL). The organic layer was dried over Na SO and concentrated
and the residue was purified by silica-gel chromatography, eluting with 0-20% EtOAc in petroleum ether,
to give diethyl 2-(4-bromophenyl)methylmalonate (5.2 g, 50% yield) as colorless oil.
Step 3: A mixture of diethyl 2-(4-bromophenyl)methylmalonate (5.2 g, 15.8 mmol) and
LiAlH (3.0 g, 79 mmol) was stirred at 0 °C for 5 h. The mixture was quenched by water (20 mL), which
was partitioned between 1N aqueous HCl (100 mL) and DCM (150 mL). The organic layer was dried over
Na SO and concentrated and the residue was purified by silica-gel chromatography, eluting with
EtOAc/petroleum ether (1:1) to give 2-(4-bromophenyl)methylpropane-1,3-diol (2.3 g, 59% yield) as a
white solid.
Step 4: A mixture of 2-(4-bromophenyl)methylpropane-1,3-diol (2.0 g, 8.2 mmol),
triphenylphosphine (4.3 g, 16.4 mmol) and diisopropyl azodicarboxylate (3.2 mL, 16.4 mmol) in toluene
(20 mL) was heated under microwave irradiation at 140 C for 1 h. The volatiles were removed and the
residue was purified by silica-gel column, eluting with 10% EtOAc/petroleum ether to give 3-(4-
bromophenyl)methyloxetane (0.58 g, 31% yield) as colorless oil. H NMR (400MHz, CD Cl) δ 7.48 (d,
J=8.4 Hz, 2H), 7.09 (d, J=8.4 Hz, 2H), 4.92 (d, J=5.2 Hz, 2H), 4.63 (d, J=5.2 Hz, 2H), 1.71 (s, 3H).
Compound 238 (formic acid salt) was prepared as a white solid from Compound 101-K and 3-
(4-bromophenyl)methyloxetane by utilizing methods analogous to those described in Example 10 and
Example J. LCMS (Method 5-95 AB, ESI): t = 0.618 min, [M + H] = 904.7; H NMR (400 MHz,
MeOH-d ) δ 8.80 (s, 1H), 8.46 (br s, 3H), 8.43 (s, 1H), 7.38 (d, J=8.0 Hz, 2H), 7.33 (d, J=8.4 Hz,1H),
7.23-7.19 (m, 2H), 7.09 (d, J=8.4 Hz), 6.91 (s, 1H), 6.77 (s, 1H),6.42 (s,1H), 5.20-5.16 (m, 1H), 5.03-5.00
(m, 2H), 4.83-4.80 (m, 2H), 4.73-4.70 (m, 2H), 4.30-4.20 (m, 6H), 3.25-3.12 (m, 8H), 2.96 (s, 3H), 2.71 (s,
3H), 2.30-2.16 (m, 2H), 1.76 (s, 3H), 1.36 (d, J=6.8 Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 39: Synthesis of Compound 239
O HN
N N N O
Compound 239 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 17. LCMS (Method 5-95 AB, ESI): t = 0.790
min, [M + H] = 968.6; H NMR (400 MHz, MeOH-d ) δ 8.78 (s, 1H), 8.51 (br s, 3H), 8.36 (d, J=8.0 Hz,
2H), 7.52 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.0 Hz, 1H), 7.23-7.17 (m, 2H), 7.08 (d, J=8.4 Hz, 1H), 6.89 (s,
1H), 6.73 (s, 1H), 6.46 (s, 1H), 5.17-5.21 (m, 1H), 4.81-4.79 (m, 2H), 4.31-4.19 (m, 6H), 3.10-3.22 (m,
8H), 2.97 (s, 3H), 2.69 (s, 3H), 2.56 (br s, 2H), 2.27-2.32 (m, 1H), 2.19-2.16 (m, 1H), 2.00-2.10 (m, 6H),
1.78-1.94 (m, 6H), 1.70-1.62 (m, 2H), 1.36 (d, J=7.2 Hz, 3H).
Example 40: Synthesis of Compound 240
O HN
N N N
Compound 240 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 26. LCMS (Method 5-95 AB, ESI): t = 0.774
min, [M + H] = 932.7; H NMR (400 MHz, MeOH-d ) δ 8.75 (s, 1H), 8.48 (br s, 2H), 8.29 (d, J=8.0 Hz,
2H), 8.31 (d, J=8.0 Hz, 2H), 7.24-7.13 (m, 2H), 7.08 (d, J=8.0 Hz, 2H), 6.88 (s, 1H), 6.71 (s, 1H), 6.47 (s,
1H), 5.21-5.16 (m, 1H), 4.82-4.75 (m, 2H), 4.35-4.16 (m, 4H), 4.21 (s, 2H), 3.27-3.05 (m, 8H), 2.96 (s,
3H), 2.76-2.64 (m, 2H), 2.67 (s, 3H), 2.32-2.27 (m, 1H), 2.21-2.14 (m, 1H), 1.71-1.64 (m, 2H), 1.45-1.25
(m, 11H), 0.90 (t, J=6.8 Hz 3H).
Example 41: Synthesis of Compound 241
O HN
N N N
Compound 241 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example J. LCMS (Method 5-95 AB, ESI): t = 0.731
min, [M + H] = 920.4; H NMR (400 MHz, MeOH-d ) δ 8.72 (s, 1H), 8.51 (br s, 2H), 8.33 (d, J=8.4 Hz,
2H), 7.31 (d, J=8.0 Hz, 1H), 7.23-7.16 (m, 2H), 7.08 (d, J=8.0 Hz, 1H), 7.01 (d, J=8.4 Hz, 2H), 6.88 (s,
1H), 6.71 (s, 1H), 6.48 (s, 1H), 5.22-5.15 (m, 1H), 4.85-4.79 (m, 2H), 4.35-4.13 (m, 6H), 4.07 (t, J=6.4 Hz,
18253141_1 (GHMatters) P111789.NZ
2H), 3.29-3.01 (m, 8H), 2.96 (s, 3H), 2.66 (s, 3H), 2.35-2.24 (m, 1H), 2.22-2.15 (m, 1H), 1.88 - 1.78 (m,
2H), 1.50-1.38 (m, 6H), 1.35 (d, J=6.8 Hz, 3H), 0.98 (t, J=7.2 Hz, 3H).
Example 42: Synthesis of Compound 242
O HN
N N N O
[00669] Compound 242 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example J. LCMS (Method 5-95 AB, ESI): t = 0.713
min, [M + H] = 920.5; H NMR (400 MHz, MeOH-d ) δ 8.80 (s, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.36 (d,
J=8.4 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.20 (d, J=8.8 Hz, 1H), 7.11 (d, J=8.8 Hz, 1H), 6.92 (s, 1H), 6.89-
6.85 (m, 2H), 6.83 (s, 1H), 6.39 (s, 1H), 5.21-5.16 (m, 1H), 4.84-4.79 (m, 2H), 4.34-4.18 (m, 6H), 4.05 (t,
J=6.4 Hz, 2H), 3.37-3.11 (m, 8H), 2.96 (s, 3H), 2.70 (s, 3H), 2.56 (s, 3H), 2.32-2.27 (m, 1H), 2.21-2.15 (m,
1H), 1.82-1.75 (m, 2H), 1.61 - 1.48 (m, 4H), 1.36 (d, J=7.2 Hz, 3H), 1.01 (t, J=7.6 Hz, 3H).
Example 43: Synthesis of Compound 243
O HN
N N N
Compound 243 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example J. LCMS (Method 5-95 AB, ESI): t = 0.731
min, [M + H] = 934.5; H NMR (400 MHz, MeOH-d ) δ 8.75 (s, 1H), 8.08 (s, 2H), 7.33-7.28 (m, 1H),
7.23-7.17 (m, 2H), 7.11-7.05 (m, 1H), 6.88 (s, 1H), 6.73 (s, 1H), 6.45 (s, 1H), 5.20-5.14 (m, 1H), 4.82-4.75
(m, 2H), 4.29-4.17 (m, 6H), 3.89-3.83 (m, 2H), 3.25-3.10 (m, 8H), 2.96 (s, 3H), 2.67 (s, 3H), 2.43 (s, 6H),
2.33-2.10 (m, 2H), 1.89- 1.77 (m, 2H), 1.66-1.54 (m, 2H), 1.36 (d, J=6.8 Hz, 3H), 1.04 (t, J=7.2 Hz, 3H).
Example 44: Synthesis of Compound 244
Cs CO H
HO 2 3
N N CN
O HN
DMF H H
N N N O
F Br
Step 1
Step 1: A mixture of 4-bromofluorophenol (1.0 g, 5.2 mmol), 1-bromobutane (1.1 g, 7.8
mmol), and Cs CO (5.1 g, 15.7 mmol) in DMF (20 mL) was stirred at 20 C for 16 h under N . The
2 3 2
volatiles were removed and the residue was re-dissolved with EtOAc (100 mL), which was washed by
brine (2 x 100 mL). The organic layer was dried over Na SO , concentrated and the residue was purified
18253141_1 (GHMatters) P111789.NZ
by silica-gel column, eluting with petroleum ether, to give 4-bromobutoxyfluorobenzene (1.1 g, 85%
yield) as a yellow oil.
Compound 244 (formic acis salt) was prepared as a white solid from Compound 101-K and 4-
bromobutoxyfluorobenzene by utilizing methods analogous to those described in Example 10 and
Example J. LCMS (Method 5-95 AB, ESI): t = 0.720 min, [M + H] = 924.4; H NMR (400 MHz,
MeOH-d ) δ 8.72 (s, 1H), 8.50 (br s, 1H), 8.22 (d, J=8.4 Hz, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.32 (d, J=8.4
Hz, 1H), 7.25-7.15 (m, 3H), 7.08 (d, J=8.4 Hz, 1H), 6.88 (s, 1H), 6.69 (s, 1H), 6.47 (s, 1H), 5.22-5.15 (m,
1H), 4.82-4.77 (m, 2H), 4.39-4.19 (m, 6H), 4.16 (t, J=6.0 Hz, 2H), 3.29-3.03 (m, 8H), 2.96 (s, 3H), 2.66 (s,
3H), 2.31-2.28 (m, 1H), 2.19-2.16 (m, 1H), 1.90-1.79 (m, 2H), 1.60-1.52 (m, 2H), 1.36 (d, J=7.2 Hz, 3H),
1.03 (t, J=7.2 Hz, 3H).
Example 45: Synthesis of Compound 245
HO N N CN
Cs CO
O HN
N N N O
Compound 245 (formic acid salt) was prepared as a white solid from Compound 101-K and 1-
bromo(isopentyloxy)benzene by utilizing methods analogous to those described in Example 244. LCMS
(Method 5-95 AB, ESI): t = 0.623 min, [M + H] = 920.6; H NMR (400 MHz, MeOH-d ) δ 8.71 (s, 1H),
8.51 (br s, 1H), 8.28 (br s, 2H), 7.32-7.30 (m, 1H), 7.22-7.15 (m, 2H), 7.09-7.07 (m, 1H), 7.05-7.01 (m,
2H), 6.87 (s, 1H), 6.66 (br s, 1H), 6.48 (br s, 1H), 5.19-5.18 (m, 1H), 4.85-4.78 (m, 2H), 4.29-4.18 (m, 6H),
4.11 (t, J=6.4 Hz, 2H), 3.31-3.13 (m, 8H), 2.96 (s, 3H), 2.65 (s, 3H), 2.28-2.17 (m, 1H), 2.17-2.15 (m, 1H),
1.90-1.86 (m, 1H), 1.74-1.69 (m, 2H), 1.36 (d, J=6.4 Hz, 3H), 1.01 (t, J=6.4 Hz, 6H).
Example 46: Synthesis of Compound 246
N N CN
O HN
N N N O
Compound 246 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example J. LCMS (Method 5-95 AB, ESI): t = 0.556
min, [M + H] = 892.4; H NMR (400 MHz, MeOH-d ) δ 8.70 (s, 1H), 8.49 (br s, 1H), 8.29 (d, J=8.8 Hz,
2H), 7.35-7.28 (m, 1H), 7.24-7.13 (m, 2H), 7.08 (d, J=8.4 Hz, 1H), 6.98 (d, J=8.8 Hz, 2H), 6.87 (d, J=2.2
Hz, 1H), 6.68 (s, 1H), 6.48 (s, 1H), 5.22-5.13 (m, 1H), 4.80-4.71 (m, 2H), 4.36-4.12 (m, 7H), 3.26-3.07 (m,
8H), 2.96 (s, 3H), 2.65 (s, 3H), 2.32-2.24 (m, 1H), 2.22-2.13 (m, 1H), 1.38-1.3 (m, 9H).
18253141_1 (GHMatters) P111789.NZ
Example 47: Synthesis of Compound 247
Cl O
N N CN
N N N O
Compound 247 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example J. LCMS (Method 5-95 AB, ESI): t = 0.632
min, [M + H] = 940.8; H NMR (400 MHz, MeOH-d ) δ 8.72 (s, 1H), 8.50 (br s, 2H), 8.40-8.30 (m, 2H),
7.31 (d, J=8.8 Hz, 1H), 7.25-7.10 (m, 3H), 7.07 (d, J=8.8 Hz, 1H), 6.86 (s, 1H), 6.63 (s, 1H), 6.51 (s, 1H),
.25-5.15 (m, 1H), 4.80-4.75 (m, 2H), 4.40-4.20 (m, 6H), 4.17 (t, J=6.4 Hz, 2Hz), 3.40-3.05 (m, 8H), 2.96
(s, 3H), 2.66 (s, 3H), 2.35-2.25 (m, 1H), 2.20-2.15 (m, 1H), 1.90-1.80 (m, 2H), 1.62-1.55 (m, 2H), 1.36 (d,
J=6.8 Hz, 3H), 1.04 (t, J=7.6 Hz, 3H).
Example 48: Synthesis of Compound 248
N N CN
O HN
N N N O
Compound 248 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example J. LCMS (Method 5-95 AB, ESI): t = 0.634
min, [M + H] = 934.7; H NMR (400 MHz, MeOH-d ) δ 8.74 (s, 1H), 8.49 (br s, 2H), 8.38 (br s, 2H),
7.32 (d, J=8.4 Hz, 1H), 7.23-7.17 (m, 2H), 7.09 (d, J=8.4 Hz, 1H), 7.05-6.99 (m, 2H), 6.91 (s, 1H), 6.78
(br s, 1H), 6.42 (br s, 1H), 5.20-5.14 (m, 1H), 4.81-4.75 (m, 2H), 4.25-4.16(m, 6H), 4.07 (t, J=6.4 Hz, 2H),
3.48 (br s, 1H), 3.27-3.07 (m, 7H), 2.95 (s, 3H), 2.68 (s, 3H), 2.37-2.20 (m, 1H), 2.20-2.07 (m, 1H), 1.88-
1.75 (m, 3H), 1.51- 1.49 (m, 2H), 1.44-1.29 (m, 6H), 0.94 (t, J=7.2 Hz, 3H).
Example 49: Synthesis of Compound 249
HO O
N N CN
O HN
TFA, Et SiH
N N N O
Br Br
Br N O
Step 2
Step
Step 1: A mixture of 1-(5-bromohydroxyphenyl)ethanone (1.0 g, 4.65 mmol) and
pyrrolidine (0.78 mL, 9.3 mmol) in toluene (8 mL) was stirred at 25 C for 10 min, followed by the
addition of acetone (3 mL). The resulting mixture was stirred at the same temperature for 16 h. The
volatiles were removed and the residue was taken up by EtOAc (50 mL), which was washed with brine (2
x 50 mL). The organic layer was dried over Na SO , concentrated and the residue was purified by silica-
18253141_1 (GHMatters) P111789.NZ
gel column, eluting with 0-5% EtOAc in petroleum ether, to give 6-bromo-2,2-dimethylchromanone
(850 mg, 72% yield) as yellow oil.
Step 2: A mixture of 6-bromo-2,2-dimethylchromanone (650 mg, 2.55 mmol) and
triethylsilane (1.45 g, 12.8 mmol) in TFA (6 mL) was stirred at 0 C for 12 h. The volatiles were removed
and the residue was taken up by EtOAc (50 mL), which was washed with saturated aqueous NaHCO and
brine (each 50 mL). The organic layer was dried over Na SO , concentrated and the residue was purified
by silica-gel column, eluting with 1-5% EtOAc in petroleum ether, to give 6-bromo-2,2-dimethylchromane
(490 mg, 80% yield) as a colorless oil. H NMR (400 MHz, CDCl ) δ 7.19-7.16 (m, 2H), 6.66 (d, J=8.4 Hz,
1H), 2.76 (t, J=6.8 Hz, 1H), 1.79 (t, J=6.8 Hz, 1H), 1.33 (s, 6H).
[00679] Compound 249 (formic acid salt) was prepared as a white solid from Compound 101-K and 6-
bromo-2,2-dimethylchromane by utilizing methods analogous to those described in Example 10 and
Example J. LCMS (Method 5-95 AB, ESI): t = 0.709 min, [M + H] = 918.5; H NMR (400 MHz,
MeOH-d ) δ 8.68 (s, 1H), 8.46 (br s, 1H), 8.12-8.06 (m, 2H), 7.31 (d, J=8.0 Hz, 1H), 7.22 (d, J=8.4 Hz,
1H), 7.16 (d, J=8.0 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.86 (s, 1H), 6.79 (d, J=8.4 Hz, 1H), 6.63 (s, 1H),
6.52 (s, 1H), 5.21-5.15 (m, 1H), 4.81-4.70 (m, 2H), 4.36-4.21 (m, 6H), 3.29-3.15 (m, 8H), 2.97 (s, 3H),
2.88 (d, J=6.4 Hz, 2H), 2.64 (s, 3H), 2.35-2.25 (m, 1H), 2.22-2.12 (m, 1H), 1.89 (t, J=6.4 Hz, 2H), 1.38 (s,
6H), 1.36 (d, J=7.2 Hz, 3H).
Example 50: Synthesis of Compound 250
NH Teoc
NHBoc 2
Teoc HN
BocHN 2
Cl O
NaHCO
TFA/DCM 3
Step 4
Step O HN Step 3 O
O HN
H H O HN
N N O
Cbz N O O
Cbz N O
Cbz N O
NHBoc
250-1
250-2
Teoc
250-3
Teoc
Teoc N
TEAF
N N CN
N N CN
O HN Step 5 O
H H H H
N N N O
N N N O
N O O
Teoc
250-4
, Et N
(COCl)3 3
HO Cl O
Step
[00680] Step 1: Typical Boc removal (TFA/DCM) condition was applied to compound 250-1 (prepared
following procedures analogous to those described for Compound 101-H) to give compound 250-2.
18253141_1 (GHMatters) P111789.NZ
Step 2: To a solution of (COCl) (916 mg, 2.85 mmol) in dry diethyl ether (6 mL) was added 2-
(triethylsilyl)-ethanol (1.0 g, 8.46 mmol) and pyridine (535 mg, 6.77 mmol) and the mixture was stirred at
-30 C for 4 h. After filtration, the filtrate was evaporated under reduced pressure and the residue was
distilled to give 2-(trimethylsilyl)ethyl carbonochloridate (1.0 g, 65% yield).
[00682] Step 3: A solution of 2-(trimethylsilyl)ethyl carbonochloridate (580 mg, 3.21 mmol) in 1,4-
dioxane (10 mL) was treated with saturated aqueous NaHCO solution until pH~7-8, followed by the
addition of compound 250-2 (400 mg, 0.53 mmol). The resulting mixture was stirred at 20 C for 2 h. The
volatiles were removed and the residue was taken up by EtOAc (30 mL), which was washed with saturated
brine (30 mL). The organic layer was dried over Na SO , concentrated and the residue was purified by
Prep-TLC (DCM/MeOH=10:1, Rf=0.4) to give compound 250-3 (500 mg, 79% yield) as a yellow solid.
LCMS (Method 5-95 AB, ESI): t = 1.007 min, [M + H] = 1180.7.
Step 4: Compound 250-4 was prepared as a white solid from compound 250-3 by utilizing
methods analogous to those described in Example 10 and Example J. LCMS (Method 5-95 AB, ESI): t =
1.048 min, [M + H] = 1339.7.
[00684] Step 5: A mixture of compound 250-4 (70 mg, 0.05 mmol) and tetraethylammonium fluoride
(1N in THF, 0.26 mL) in THF (3 mL) was stirred at 60 C for 16 h. The volatiles were removed and the
residue was purified by HPLC, eluting with 14-45% acetonitrile (0.225% formic acid) in water, to give
Compound 250 (formic acid salt) (31.7 mg, 67% yield) as a white solid. LCMS (Method 5-95 AB, ESI): t
= 0.694 min, [M + Na] = 928.5; H NMR (400 MHz, MeOH-d ) δ 8.76 (s, 1H), 8.43 (br s, 3H), 8.35 (d,
J=8.4 Hz, 2H), 7.32 (d, J=8.4 Hz, 1H), 7.23-7.17 (m, 2H), 7.13-7.07 (m, 3H), 6.89 (s, 1H), 6.76 (s, 1H),
6.42 (s, 1H), 5.20-5.15 (m, 1H), 4.85-4.75 (m, 2H), 4.30-4.18 (m, 6H), 3.28-3.11 (m, 8H), 2.95 (s, 3H),
2.68 (s, 3H), 2.40-2.30 (m, 1H), 2.20-2.14 (m, 1H), 1.43 (s, 9H), 1.36 (d, J=7.2 Hz, 3H).
Example 51: Synthesis of Compound 251
O HN
N N N O
[00685] Compound 251 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example J. LCMS (Method 5-95 AB, ESI): t = 0.663
min, [M + H] = 892.5; H NMR (400 MHz, MeOH-d ) δ 8.78 (s, 1H), 8.48 (br s, 1H), 7.97-7.93 (m, 2H),
7.38 (d, J=8.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.4 Hz, 2H), 6.89 (s,
1H), 6.72 (s, 1H), 6.46 (s, 1H), 5.21-5.17 (m, 1H), 4.83-4.80 (m, 2H), 4.72-4.68 (m, 1H), 4.31-4.20 (m,
6H), 3.25-3.13 (m, 8H), 2.96 (s, 3H), 2.69 (s, 3H), 2.21-2.18 (m, 1H), 2.17-2.13 (m, 1H), 1.38-1.35 (m,
9H).
18253141_1 (GHMatters) P111789.NZ
Example 52: Synthesis of Compound 252
N N CN
N N N O
Compound 252 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 10 and Example J. LCMS (Method 5-95 AB,
ESI): t = 0.619 min, [M + H] = 920.3; H NMR (400 MHz, MeOH-d ) δ 8.75 (s, 1H), 8.52 (br s, 2H),
8.37 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.0 Hz, 1H), 7.22 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.0 Hz, 1H), 7.05
(d, J=8.0 Hz, 2H), 6.91 (d, J=1.8 Hz, 1H), 6.76 (s, 1H), 6.46 (s, 1H), 5.23-5.16 (m, 1H), 4.85-4.78 (m, 2H),
4.32-4.19 (m, 6H), 3.75 (s, 2H), 3.28-3.12 (m, 8H), 2.97 (s, 3H), 2.69 (s, 3H), 2.36-2.27 (m, 1H), 2.23-2.11
(m, 1H), 1.38 (d, J=6.8 Hz, 3H), 1.10 (s, 9H).
Example 53: Synthesis of Compound 253
N N N
Me O
Me O
Me O
H N NH
O O 2 2
POCl , DIEA
HNO 3
acetaldehyde N O
HN O
Me O
MeOH
Cl N Me
O N Me
Step 2
HO N Me
Step 1
Step 3
B(OH)2
Na CO NaOH N
2 3 Pd(dppf)Cl2
MeOH/H O
N N OH
step 4
step 5
Step 1: A mixture of urea (0.52 g, 8.6 mmol), acetaldehyde (0.49 mL, 8.6 mmol), methyl 3-
oxobutanoate (1.0 g, 8.6 mmol) and glacial acetic acid (1 drop) in methanol (2 mL) was stirred at 90 C for
16 h. To the reaction mixture was added water (10 mL), followed by the filtration; the cake was then
washed with water and dried in air to obtain methyl 4,6-dimethyloxo-1,2,3,4-tetrahydropyrimidine
carboxylate (900 mg, 56.7% yield) as a pale yellow solid.
Step 2: Methyl 4,6-dimethyloxo-1,2,3,4-tetrahydropyrimidinecarboxylate (900 mg, 4.9
mmol) was added in portions to an ice-cooled solution of 50% HNO (4.0 mL) over 3 min. The reaction
mixture was stirred at 0 C for 10 min. The mixture was poured into ice water (20 mL), neutralized with
solid K CO and the resulting mixture was extracted with ethyl acetate (10 mL). The aqueous layer was
18253141_1 (GHMatters) P111789.NZ
extracted again with CHCl (40 mL x 2). The organic layers were combined, dried over Na SO and
3 2 4
concentrated to obtain methyl 2-hydroxy-4,6-dimethylpyrimidinecarboxylate (500 mg, 2.7 mmol,
56.1% yield) as a pale yellow solid.
Step 3: A mixture of methyl 2-hydroxy-4,6-dimethylpyrimidinecarboxylate, POCl (6.2 mL,
66.5 mmol), and DIPEA (1.28 g, 9.9 mmol) was stirred at 110 C for 3 h. The mixture was evaporated in
vacuo, diluted with ethyl acetate (40 mL), washed with saturated aqueous NaHCO solution (25 mL), brine
(30 mL), dried over Na SO and evaporated in vacuo. The residue was purified via silica gel
chromatography (0-30% ethyl acetate in petroleum ether) to give methyl 2-chloro-4,6-dimethylpyrimidine-
-carboxylate (350 mg, 1.7 mmol, 63.6% yield) as a white solid. H NMR (400 MHz, CDCl3) δ 3.98 (s,
3H), 2.55 (s, 6H).
Step 4: A mixture of methyl 2-chloro-4,6-dimethylpyrimidinecarboxylate (4.5 g, 22.4 mmol),
4-tert-butylbenzene boronic acid (4.8 g, 26.9 mmol), Pd(dppf)Cl (1.6 g, 2.24 mmol) and Na CO (4.8 g,
2 2 3
44.9 mmol) in dioxane/water (110 mL, v/v=10/1) was stirred at 100 C under N for 16 h. The mixture was
diluted with water (150 mL), and extracted with EtOAc (200 mL x 3). The combined organic layers were
washed with brine (300 mL x 2), dried over Na SO , concentrated and purified by silica-gel
chromatography, eluting with 0-5% EtOAc in petroleum ether, to give methyl 2-(4-(tert-butyl)phenyl)-4,6-
dimethylpyrimidinecarboxylate (6.2 g, 93% yield) as a white solid. LCMS (Method 5-95 AB, ESI): t =
= 299.1.
1.075 min, [M + H]
Step 5: A mixture of methyl 2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidinecarboxylate (6.2
g, 20.8 mmol) and NaOH (1.7 g, 41.6 mmol) in MeOH/water (80 mL, v/v=1:1) was stirred at 90 C for 4 h.
The volatiles were removed under reduced pressure and the residue was acidified with 1N HCl to pH=4~5,
followed by the extration with EtOAc (100 mL x 2). The combined organic layers were washed with brine
(100 mL x 2), dried over Na SO and concentrated to give 2-(4-(tert-butyl)phenyl)-4,6-
dimethylpyrimidinecarboxylic acid (5.8 g, 98% yield) as a white solid. LCMS (Method 5-95 AB, ESI):
t = 0.936 min, [M + H] = 285.0; H NMR (400 MHz, MeOH-d ) δ 8.39 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.4
Hz, 2H), 2.75 (s, 6H), 1.37 (s, 9H).
Compound 253 (formic acid salt) was prepared as a white solid from Compound 101-K and 2-
(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidinecarboxylic acidby utilizing methods analogous to those
described in Example J. LCMS (Method 5-95 AB, ESI): t = 0.715 min, [M + H] = 904.6; H NMR (400
MHz, MeOH-d ) δ 8.48 (br s, 1H), 8.34 (d, J=8.0 Hz, 2H), 7.55 (d, J=8.0 Hz, 2H), 7.24-7.15 (m, 2H), 7.04
(d, J=8.0 Hz, 1H), 6.95-6.90 (m, 1H), 6.83 (s, 1H), 6.73 (s, 1H), 6.47 (s, 1H), 5.28-5.23 (m, 1H), 4.83-4.80
(m, 2H), 4.54-4.45 (m, 2H), 4.32-4.23 (m, 4H), 3.42-3.38 (m, 1H), 3.27-3.12 (m, 7H), 3.05 (s, 3H), 2.57 (s,
6H), 2.38-2.26 (m, 1H), 2.25-2.13 (m, 1H), 1.39 (s, 3H), 1.35 (t, J=7.2 Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 54: Synthesis of Compound 254
O HN
N N N O
Compound 254 (formic acid salt) was prepared as a white solid from Compound 106-B2 by
utilizing methods analogous to those described in Example 53 and V. LCMS (Method 5-95 AB, ESI): t =
0.776 min, [M + H] = 861.5; H NMR (500 MHz, DMSO-d6) δ 9.17 (d, J = 7.3 Hz, 1H), 8.98 (d, J = 7.7
Hz, 1H), 8.71 (t, J = 5.5 Hz, 1H), 8.44 (d, J = 9.0 Hz, 1H), 8.36 – 8.29 (m, 2H), 7.59 – 7.52 (m, 2H), 7.19 –
7.04 (m, 3H), 6.90 – 6.80 (m, 2H), 6.71 (s, 1H), 6.42 (s, 1H), 5.09 – 5.01 (m, 1H), 4.80 – 4.66 (m, 2H),
4.29 – 4.15 (m, 4H), 3.19 – 3.09 (m, 3H), 3.02 – 2.88 (m, 6H), 2.50 (s, 6H), 2.14 – 2.03 (m, 1H), 2.02 –
1.91 (m, 1H), 1.35 (s, 9H), 1.21 (d, J = 6.6 Hz, 3H).
Example 55: Synthesis of Compound 255
N N CN
O HN
N N N O
Compound 255 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 53. LCMS (Method 5-95 AB, ESI): t = 0.715
min, [M + H] = 904.5; H NMR (400 MHz, MeOH-d ) δ 8.44 (br s, 2H), 8.33 (d, J=7.6 Hz, 2H), 7.35-
7.27 (m, 3H), 7.26-7.18 (m, 2H), 7.10 (d, J=8.4 Hz, 1H), 6.92 (s, 1H), 6.83 (s, 1H), 6.42 (s, 1H), 5.24-5.20
(m, 1H), 4.85-4.75(m, 2H), 4.30-4.16 (m, 6H), 3.49-3.47 (m, 1H), 3.26-3.10 (m, 6H), 3.01 (s, 3H), 2.69 (t,
J=7.6 Hz, 2H), 2.57 (s, 6H), 2.32-2.24 (m, 1H), 2.20-2.12 (m, 1H), 1.69-1.63 (m, 2H), 1.43-1.38 (m, 2H),
1.36 (d, J=6.8 Hz, 3H), 0.97 (t, J=7.6 Hz, 3H).
Example 56: Synthesis of Compound 256
7 15
Cl N
Cl , Na CO N
1) Pd(PPh3)2 2 2 3 N N
O HN
N OH
N N N
Et N
O Cl , CuI,
2) Pd(PPh3)2 2 3
Pd/C,H2
NaOH
Step 1
Step 1: Starting from methyl 2-chloro-4,6-dimethylpyrimidinecarboxylate (described in
Example 53), typical Suzuki, Sonogashira, hydrogenation (Pd/C, H ) and ester hydrolysis (NaOH,
MeOH/H O) conditions, analogous to those described in Examples D, H, and K, were applied to give 2-(4-
heptylphenyl)-4,6-dimethylpyrimidinecarboxylic acid as a white solid.
18253141_1 (GHMatters) P111789.NZ
Compound 256 (formic acid salt) was prepared as a white solid from Compound 101-K and 2-
(4-heptylphenyl)-4,6-dimethylpyrimidinecarboxylic acid by utilizing methods analogous to those
described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.652 min, [M + H] = 946.4; H NMR (400
MHz, MeOH-d ) δ 8.48 (br s, 2H), 8.24-8.18 (m, 2H), 7.31-7.22 (m, 4H), 7.12-7.06 (m, 2H), 6.88 (s, 1H),
6.66 (s, 1H), 6.53 (s, 1H), 5.25-5.21 (m, 1H), 4.85-4.77 (m, 2H), 4.34 (s, 2H), 4.30-4.22 (m, 4H), 3.27-3.16
(m, 4H), 3.18-3.05 (m, 4H), 3.02 (s, 3H), 2.69 (t, J=7.6 Hz, 2H), 2.50 (s, 6H), 2.32-2.26 (m, 1H), 2.20-2.14
(m, 1H), 1.70-1.61 (m, 2H), 1.42-1.28 (m, 11H), 0.91 (t, J=6.8 Hz, 3H).
Example 57: Synthesis of Compound 257
N N CN
N N N O
[00697] Compound 257 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 53. LCMS (Method 5-95 AB, ESI): t = 0.737
min, [M + Na] = 942.6; H NMR (400 MHz, MeOH-d ) δ 8.50 (br s, 1H), 8.40 (d, J=8.0 Hz, 2H), 7.68 (d,
J=8.0 Hz, 2H), 7.31 (d, J=8.0 Hz, 1H), 7.30-7.15 (m, 2H), 7.11 (d, J=8.0 Hz, 1H), 6.94 (d, J=2.0 Hz, 1H),
6.83 (s, 1H), 6.45 (s, 1H), 5.30-5.20 (m, 1H), 4.80-4.70 (m, 2H), 4.30-4.10 (m, 6H), 3.25-3.10 (m, 8H),
3.03 (s, 3H), 2.59 (s, 6H), 2.35-2.25 (m, 1H), 2.25-2.10 (m, 1H), 1.38 (d, J=7.2 Hz, 3H), 0.33 (s, 9H).
Example 58: Synthesis of Compound 258
N N CN
O HN
N N N O
Compound 258 (formic acid salt) was prepared as a white solid from Compound 101-K by
= 0.733
utilizing methods analogous to those described in Example 53. LCMS (Method 5-95 AB, ESI): t
min, [M + H] = 905.0; H NMR (400 MHz, MeOH-d ) δ 8.50 (br s, 1H), 8.28 (d, J=8.0 Hz, 2H), 7.35-
7.25 (m, 3H), 7.25-7.15 (m, 2H), 7.09 (d, J=8.4 Hz, 1H), 6.90 (s, 1H), 6.75 (brs, 1H), 6.48 (s, 1H), 5.35-
.20 (m, 1H), 4.80-4.70 (m, 2H), 4.40-4.10 (m, 6H), 3.30-3.05 (m, 8H), 3.01 (s, 3H), 2.60-2.45 (m, 8H),
2.35-2.25 (m, 1H), 2.25-2.10 (m, 1H), 2.00-1.90 (m, 1H), 1.36 (d, J=7.2 Hz, 3H), 0.96 (t, J=6.8 Hz, 6H).
Example 59: Synthesis of Compound 259
O HN
N N N
18253141_1 (GHMatters) P111789.NZ
Compound 259 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 53. LCMS (Method 5-95 AB, ESI): t = 0.621
min, [M + H] = 902.4; H NMR (400 MHz, MeOH-d ) δ 8.51 (brs, 2H), 8.04 (brs, 2H), 7.45-7.35 (m, 1H),
7.30-7.05 (m, 5H), 6.89 (s, 1H), 6.72 (s, 1H), 6.49 (s, 1H), 5.30-5.20 (m, 1H), 4.85-4.75 (m, 2H), 4.35-4.10
(m, 6H), 3.35-3.05 (m, 8H), 3.01 (s, 3H), 2.84 (brs, 4H), 2.52 (s, 6H), 2.30-2.20 (m, 1H), 2.20-2.10 (m,
1H), 1.86 (brs, 4H), 1.35 (d, J=7.2 Hz, 3H).
Example 60: Synthesis of Compound 260
N N CN
O HN
N N N O
Compound 260 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 53. LCMS (Method 5-95 AB, ESI): t = 0.682
min, [M + H] = 876.7; H NMR (400 MHz, MeOH-d ) δ 8.49 (br s, 2H), 8.35-8.15 (m, 2H), 7.40-7.30 (m,
3H), 7.30-7.15 (m, 2H), 7.09 (d, J=8.4 Hz, 1H), 6.89 (s, 1H), 6.73 (s, 1H), 6.48 (s, 1H), 5.35-5.20 (m, 1H),
4.85-4.75 (m, 2H), 4.35-4.10 (m, 6H), 3.30-3.05 (m, 8H), 3.01 (s, 3H), 2.74 (q, J=7.2 Hz, 2H), 2.53 (s, 6H),
2.35-2.25 (m, 1H), 2.25-2.05 (m, 1H), 1.36 (d, J=6.4 Hz, 3H), 1.30 (t, J=7.2 Hz, 3H).
Example 61: Synthesis of Compound 261
N N CN
O HN
N N N O
Compound 261 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Examples 53 and 10. LCMS (Method 5-95 AB, ESI): t
= 0.735 min, [M + H] = 918.6; H NMR (400 MHz, MeOH-d ) δ 8.42 (br s, 2H), 8.33 (d, J=8.4 Hz, 2H),
7.48 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.0 Hz, 2H), 7.10 (d, J=8.0 Hz, 1H), 6.92 (s,
1H), 6.79 (s, 1H), 6.44 (s, 1H), 5.30-5.20 (m, 1H), 4.85-4.75 (m, 2H), 4.35-4.15 (m, 6H), 3.30-3.05 (m,
8H), 3.01 (s, 3H), 2.56 (s, 6H), 2.35-2.25 (m, 1H), 2.25-2.10 (m, 1H), 1.78 (q, J=7.2 Hz, 2H), 1.40-1.35 (m,
9H), 0.72 (t, J=6.8 Hz, 3H).
Example 62: Synthesis of Compound 262
N N CN
N N N O
18253141_1 (GHMatters) P111789.NZ
Compound 262 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Examples 53 and 17. LCMS (Method 5-95 AB, ESI): t
= 0.775 min, [M + H] = 918.4; H NMR (400 MHz, MeOH-d ) δ 8.45 (br s, 1H), 8.22 (d, J=8.0 Hz, 2H),
7.35-7.15 (m, 4H), 7.15-7.05 (m, 2H), 6.88 (s, 1H), 6.66 (s, 1H), 6.52 (s, 1H), 5.30-5.20 (m, 1H), 4.85-4.70
(m, 2H), 4.40-4.15 (m, 6H), 3.40-3.35 (m, 1H), 3.30-3.20 (m, 3H), 3.15 - 2.95 (m, 7H), 2.71 (t, J=8.0 Hz,
2H), 2.50 (s, 6H), 2.35-2.25 (m, 1H), 2.25-2.15 (m, 1H), 1.65-1.50 (m, 3H), 1.36 (d, J=6.8 Hz, 3H), 0.98 (t,
J=5.6 Hz, 6H).
Example 63: Synthesis of Compound 263
O HN
N N N O
[00703] Compound 263 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Examples 10 and 53. LCMS (Method 5-95 AB, ESI): t
= 0.711 min, [M + H] = 904.4; H NMR (400 MHz, MeOH-d ) δ 8.48 (br s, 1H), 8.14 (d, J=7.6 Hz, 1H),
7.58 (d, J=8.0 Hz, 1H), 7.42-7.28 (m, 3H), 7.25-7.16 (m, 2H), 7.10 (d, J=8.4 Hz, 1H), 6.90 (s, 1H), 6.73 (s,
1H), 6.48 (s, 1H), 5.27-5.23 (m, 1H), 4.82-4.76 (m, 2H), 4.36-4.17 (m, 6H), 3.29-3.09 (m, 8H), 3.02 (s,
3H), 2.55 (s, 6H), 2.34-2.26 (m, 1H), 2.22-2.14 (m, 1H), 1.40 (s, 9H), 1.36 (d, J=6.4 Hz, 3H).
Example 64: Synthesis of Compound 264
N N N
O HN
NaH, MeI
N N N
CN N
Step 1
Step 1: A mixture of 2-(4-bromophenyl)acetonitrile (3.0 g, 15.3 mmol) and NaH (60% in oil,
1.84 g, 45.9 mmol) in THF (100 mL) was stirred at 0 C for 1 h, followed by the dropwise addition of
iodomethane (9.5 g, 67.2 mmol). The resulting mixture was stirred at 20 C for 16 h. The reaction mixture
was quenched with saturated aqueous NH Cl solution (50 mL), which was extracted with EtOAc (3 x
50ml). The combined organic layers were washed with brine (2 x 100 mL), dried over Na SO ,
concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 0-5% EtOAc
in petroleum ether, to give 2-(4-bromophenyl)methylpropanenitrile (3.3 g, 96% yield) as pale yellow oil.
H NMR (400 MHz, CDCl ) δ 7.23 (d, J=8.0 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 1.72 (s, 6H).
Compound 264 (formic acid salt) was prepared as a white solid from Compound 101-K and 2-
(4-bromophenyl)methylpropanenitrile by utilizing methods analogous to those described in Examples
and 53. LCMS (Method 0-30 AB, ESI): t = 1.153 min, [M + H] = 915.5; H NMR (400 MHz, MeOH-
d ) δ 8.50 (br s, 2H), 8.32 (d, J=8.0 Hz, 2H), 7.58 (d, J=8.0 Hz, 2H), 7.27 (brs, 2H), 7.10-7.01 (m, 2H),
18253141_1 (GHMatters) P111789.NZ
6.84 (s, 1H), 6.60 (brs, 1H), 6.49 (brs, 1H), 5.35-5.29 (m, 1H), 4.82-4.72 (m, 2H), 4.40 (s, 2H), 4.30-4.22
(m, 4H), 3.29-3.21 (m, 4H), 3.14 (t, J=7.7 Hz, 2H), 3.02 (s, 3H), 3.01-2.90 (m, 2H), 2.46 (s, 6H), 2.32-2.26
(m, 1H), 2.20-2.13 (m, 1H), 1.79 (s, 6H), 1.35 (d, J=6.6 Hz, 3H).
Example 65: Synthesis of Compound 265
O HN
N N N O
Compound 265 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Examples 10 and 53. LCMS (Method 5-95 AB, ESI): t
= 0.671 min, [M + Na] = 896.8; H NMR (400 MHz, MeOH-d ) δ 8.58 (br s, 2H), 8.31 (d, J=8.0 Hz, 2H),
7.53 (d, J=8.0 Hz, 2H), 7.31-7.21 (m, 2H), 7.16-7.08 (m, 2H), 6.90-6.78 (m, 2H), 6.67 (s, 1H), 6.51 (s, 1H),
5.92 (d, J=17.6 Hz, 1H), 5.36 (d, J=10.6 Hz, 1H), 5.00-4.70 (m, 3H), 4.34-4.26 (m, 4H), 4.22 (s, 2H),
3.27-3.23 (m, 4H), 3.18-3.05 (m, 4H), 3.02 (s, 3H), 2.52 (s, 6H), 2.30-2.28 (m, 1H), 2.20-2.13 (m, 1H),
1.36 (d, J=6.0 Hz, 3H).
Example 66: Synthesis of Compound 266
O HN
Ph P MeI
N N N O
KOt-Bu, THF
Br Br
Step 1
[00707] Step 1: Conditions analogous to those described in Example 12 were applied to 1-(4-
bromophenyl)ethanone to afford 1-bromo(propenyl)benzene as a colorless oil. H NMR (400
MHz, CDCl ) δ= 7.45 (d, J=8.4 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 5.38 (s, 1H), 5.12 (s, 1H), 2.14 (s, 3H).
Compound 266 (formic acid salt) was prepared as a white solid from Compound 101-K and 1-
bromo(propenyl)benzene by utilizing methods analogous to those described in Examples 10 and
53. LCMS (Method 5-95 AB, ESI): t = 0.704 min, [M + H] = 888.8; H NMR (400 MHz, MeOH-d ) δ
8.47 (br s, 1H), 8.37 (d, J=8.0 Hz, 2H), 7.61 (d, J=8.0 Hz, 2H), 7.32-7.27 (m, 1H), 7.23-7.16 (m, 2H), 7.09
(d, J=8.0 Hz, 1H), 6.90 (brs, 1H), 6.76 (brs, 1H), 6.44 (s, 1H), 5.51 (s, 1H), 5.25-5.20 (m, 1H), 4.95-4.76
(m, 3H), 4.30-4.16 (m, 6H), 3.27-3.05 (m, 8H), 3.00 (s, 3H), 2.55 (s, 6H), 2.29-2.24 (m, 1H), 2.20 (s, 3H),
2.18-2.12 (m, 1H), 1.35 (d, J=7.2 Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 67: Synthesis of Compound 267
O HN
NaH, MeI
N N N O
Step 1
Step 1: A mixture of 2-(4-bromophenyl)propanol (300 mg, 1.39 mmol) and NaH (60% in oil,
62 mg, 1.53 mmol) in THF (5 mL) was stirred at 0 C for 1 h, followed by the addition of iodomethane
(3.8 g, 27 mmol). The resulting mixture was stirred at 15 C for 5 h. The reaction was diluted with water
(30 mL), which was extracted by EtOAc (3 x 30 mL). The combined organic layers were washed with
brine (50 mL), dried over Na SO and concentrated to afford 1-bromo(2-methoxypropanyl)benzene
(300 mg) as a colorless oil, which was used directly in the next step without further purification. H NMR
(400 MHz, CDCl ) δ 7.47 (d, J = 8.4 Hz, 2H), 7.28 (d, J =8.4 Hz, 2H), 3.05 (s, 3H), 1.50 (s, 6H).
[00710] Compound 267 (formic acid salt) was prepared as a white solid from Compound 101-K and 1-
bromo(2-methoxypropanyl)benzene by utilizing methods analogous to those described in Examples
and 53. LCMS (Method 5-95 AB, ESI): t = 0.664 min, [M + H] = 920.5; H NMR (400 MHz, MeOH-
d ) δ 8.46 (br s, 2H), 8.37 (d, J=8.0 Hz, 2H), 7.53 (d, J=8.0 Hz, 2H), 7.30 (d, J=8.4 Hz, 1H), 7.22-7.17 (m,
2H), 7.10 (d, J=8.4 Hz, 1H), 6.90 (s, 1H), 6.74 (s, 1H), 6.46 (s, 1H), 5.25-5.23 (m, 1H), 4.80-4.76 (m, 1H),
4.45-4.15 (m, 7H), 3.26-3.05 (m, 11H), 3.01 (s, 3H), 2.54 (s, 6H), 2.40-2.20 (m, 1H), 2.15-2.05 (m, 1H),
1.56 (s, 6H), 1.35 (d, J=6.4 Hz, 3H).
Example 68: Synthesis of Compound 268
Cl N
Cl Cl , Na CO
1) Pd(PPh3)2 2 2 3 H N
OH O HN
B H H
N OH N N N
Cl , Na CO
2) Pd(PPh3)2 2 2 3
NaOH, MeOH/H O
3) 2
Step 1
Step 1: Starting from (3,4-dichlorophenyl)boronic acid, sequential Suzuki coupling and ester
hydrolysis (NaOH, MeOH/H O) conditions, analogous to those described in Example H, were followed to
give 2-(3,4-dibutylphenyl)-4,6-dimethylpyrimidinecarboxylic acid as a white solid.
Compound 268 (formic acid salt) was prepared as a white solid from Compound 101-K and 2-
(3,4-dibutylphenyl)-4,6-dimethylpyrimidinecarboxylic acid by utilizing methods analogous to those
described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.687 min, [M + H] = 960.5; H NMR (400
MHz, MeOH-d ) δ 8.47 (br s, 3H), 8.19 (s, 1H), 8.09 (d, J=8.4 Hz, 1H), 7.32-7.16 (m, 4H), 7.09 (d, J=8.4
Hz, 1H), 6.90 (s, 1H), 6.77 (s, 1H), 6.45 (s, 1H), 5.26-5.20 (m, 1H), 4.83-4.77 (m, 2H), 4.33-4.15 (m, 6H),
3.27-3.06 (m, 8H), 3.00 (s, 3H), 2.78-2.66 (m, 4H), 2.54 (s, 6H), 2.31-2.25 (m, 1H), 2.19-2.13 (m, 1H),
1.68-1.56 (m, 4H), 1.52-1.41 (m, 4H), 1.35 (d, J=7.2 Hz, 3H), 0.99 (t, J=7.6 Hz, 6H).
18253141_1 (GHMatters) P111789.NZ
Example 69: Synthesis of Compound 269
O HN
N N N O
Compound 269 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Examples 53 and 34. LCMS (Method 5-95 AB, ESI): t
= 0.723 min, [M + H] = 916.4; H NMR (400 MHz, MeOH-d ) δ 8.44 (br s, 3H), 8.13-8.02 (m, 2H),7.27-
7.18 (m, 4H),7.08 (b rs, 2H),6.85 (s, 1H),6.60 (br s, 1H), 5.32-5.28 (m, 1H), 4.80-4.76 (m, 2H), 4.40 (s,
2H), 4.35-4.24 (m, 4H), 3.40-3.33 (m, 1H),3.28-3.23 (m, 2H),3.14 (t, J=7.6 Hz, 3H), 3.06-2.89 (m, 8H),
2.46 (s, 6H), 2.34-2.24 (m, 1H), 2.21-2.11 (m,1H), 2.00 (t, J=7.6 Hz, 3H),1.35 (d, J=6.4 Hz, 3H), 1.31 (s,
6H).
Example 70: Synthesis of Compound 270
O HN
Me Zn, TiCl
1) 2 4
N N N O
, DCM
2) 3
Step
Step 1: Starting from 6-methoxy-3,4-dihydronaphthalen-1(2H)-one, di-methylation and de-
methylation conditions (as described in Examples 34 and 98) were followed to give 5,5-dimethyl-5,6,7,8-
tetrahydronaphthalenol as a yellow oil.
[00715] Compound 270 (formic acid salt) was prepared as a white solid from Compound 101-K and 5,5-
dimethyl-5,6,7,8-tetrahydronaphthalenol by utilizing methods analogous to those described in Examples
and 53. LCMS (Method 5-95 AB, ESI): t = 0.741 min, [M + H] = 930.5; H NMR (400 MHz, MeOH-
d ) δ 8.51 (br s, 3H), 8.03-7.95 (m, 2H), 7.42 (d, J=8.0 Hz, 1H), 7.28 (br s, 2H), 7.10-7.02 (m, 2H), 6.86 (s,
1H), 6.63 (br s, 1H), 5.31 (br s, 1H), 4.80-4.78 (m, 2H), 4.39 (br s, 2H), 4.27 (br s, 4H), 3.25-3.14 (m, 6H),
3.10-2.95 (m, 2H), 3.04 (s, 3H), 2.87-2.79 (m, 2H), 2.47 (s, 6H), 2.32-2.17 (m, 2H), 2.31-2.17 (m, 2H),
1.89-1.88 (m, 2H), 1.77-1.76 (m, 2H), 1.40-1.35 (m, 9H).
Example 71: Synthesis of Compound 271
Me Zn, TiCl
2 4 N N N O
O Br
O Br
18253141_1 (GHMatters) P111789.NZ
Step 1: Following di-methylation conditions analogous to those described in Example 34, 7-
bromochromanone was converted to 7-bromo-4,4-dimethylchromane. H NMR (400 MHz, CDCl ) δ
7.11 (d, J=8.0 Hz, 1H), 7.00-6.95 (m, 2H), 4.18 (t, J=5.2 Hz, 2H), 1.82 (t, J=5.2 Hz, 2H), 1.31 (s, 6H).
Compound 271 (formic acid salt) was prepared as a white solid from Compound 101-K and 7-
bromo-4,4-dimethylchromane by utilizing methods analogous to those described in Examples 10 and 53.
LCMS (Method 5-95 AB, ESI): t = 0.690 min, [M + H] = 932.4; H NMR (400 MHz, MeOH-d ) δ 8.50
(br s, 2H), 7.84 (d, J=8.0 Hz, 1H), 7.40-7.22 (m, 4H), 7.02 (d, J=8.0 Hz, 1H), 6.86-6.70 (m, 3H), 5.37-5.33
(m, 1H), 4.85-4.72 (m, 2H), 4.54-4.45 (m, 2H), 4.25-4.15 (m, 6H), 3.45-3.41 (m, 3H), 3.28-3.24 (m, 3H),
3.16-3.12 (m, 2H), 3.02 (s, 3H), 2.85-2.77 (m, 1H), 2.37-2.31 (m, 5H), 2.17-2.12 (m, 2H), 1.93-1.89 (m,
2H), 1.43-1.34 (m, 9H).
Example 72: Synthesis of Compound 272
O HN
N N N O
Compound 272 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 66. LCMS (Method 5-95 AB, ESI): t = 0.739
min, [M + H] = 916.5; H NMR (400 MHz, MeOH-d ) δ 8.45 (br s, 2H), 8.28 (d, J=8.0 Hz, 2H), 7.29 (d,
J=8.0 Hz, 1H), 7.24-7.15 (m, 4H), 7.09 (d, J=8.4 Hz, 1H), 6.89 (s, 1H), 6.69 (s, 1H), 6.50 (s, 1H), 5.26-
.23 (m, 1H), 4.81-4.76 (m, 2H), 4.32-4.17 (m, 6H), 3.31-3.12 (m, 8H), 3.01 (s, 3H), 2.52 (s, 6H), 2.32-
2.13 (m, 2H), 2.00 (s, 3H), 1.86 (s, 3H), 1.63 (s, 3H), 1.36 (d, J=6.4 Hz, 3H).
Example 73: Synthesis of Compound 273
O HN
N N N O
Compound 273 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 66. LCMS (Method 5-95 AB, ESI): t = 0.724
min, [M + H] = 902.4; H NMR (400 MHz, MeOH-d ) δ 8.49 (br s, 3H), 8.19 (d, J=7.2 Hz, 2H), 7.30-
7.20 (m, 4H), 7.08 (brs, 2H), 6.86 (s, 1H), 6.61 (s, 1H), 6.55 (s, 1H), 6.35 (s, 1H), 5.35-5.25 (m, 1H), 4.85-
4.75 (m, 2H), 4.40-4.20 (m, 8H), 3.28-3.24 (m, 2H), 3.17-3.13 (m, 2H), 3.05-2.95 (m, 2H), 3.01 (s, 3H),
2.46 (s, 6H), 2.35-2.25 (m, 1H), 2.20-2.10 (m, 1H), 1.96 (s, 3H), 1.94 (s, 3H), 1.35 (d, J=6.8 Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 74: Synthesis of Compound 274
O HN
N N N O
Compound 274 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 66. LCMS (Method 5-95 AB, ESI): t = 0.682
min, [M + H] = 928.6; H NMR (400 MHz, MeOH-d ) δ 8.49 (br s, 3H), 8.26 (d, J=8.0 Hz, 2H), 7.39 (d,
J=8.0 Hz, 2H), 7.29 (d, J=8.0 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.14-7.09 (m, 2H), 6.89 (s, 1H), 6.66 (s,
1H), 6.54 (s, 1H), 6.45 (s, 1H), 5.29-5.26 (m, 1H), 4.79-4.60 (m, 2H), 4.34-4.23 (m, 6H), 3.27-3.00 (m,
8H), 3.02 (s, 3H), 2.67-2.61 (m, 2H), 2.56-2.49 (m, 6H), 2.52 (s, 2H), 2.33-2.28 (m, 1H), 2.20-2.16 (m,
1H), 1.90-1.83 (m, 2H), 1.75-1.71 (m, 2H), 1.36 (d, J=7.2 Hz, 3H).
Example 75: Synthesis of Compound 275
Pd/C, H H H
1) 2
N N N O
N OH
N OMe NaOH
Step 1
Step 1: Starting from methyl 2-(4-(cyclopentylidenemethyl)phenyl)-4,6-dimethylpyrimidine
carboxylate (as described in Example 74), typical hydrogenation (Pd/C, H , Example D) and ester
hydrolysis (NaOH, MeOH/H O, Example H) conditions were applied to give 2-(4-
(cyclopentylmethyl)phenyl)-4,6-dimethylpyrimidinecarboxylic acid as a white solid. LCMS (Method 5-
95 AB, ESI): t = 1.015 min, [M + H] = 311.0.
Compound 275 (formic acid salt) was prepared as a white solid from Compound 101-K and 2-
(4-(cyclopentylmethyl)phenyl)-4,6-dimethylpyrimidinecarboxylic acid by utilizing methods analogous
to those described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.747 min, [M + H] = 930.5; H
NMR (400 MHz, MeOH-d ) δ 8.53 (br s, 3H), 8.17 (d, J=8.0 Hz, 2H), 7.30-7.22 (m, 4H), 7.13-7.07 (m,
2H), 6.87 (s, 1H), 6.64 (s, 1H), 6.55 (br s, 1H), 5.34-5.30 (m, 1H), 4.82-4.77 (m, 2H), 4.38-4.26 (m, 6H),
3.29-3.14 (m, 8H), 3.04 (s, 3H), 2.71 (d, J=7.6 Hz, 2H), 2.47 (s, 6H), 2.34-2.29 (m, 1H), 2.19-2.18 (m, 1H),
1.76-1.60 (m, 7H), 1.37 (d, J=7.2 Hz, 3H), 1.33-1.26 (m, 2H).
Example 76: Synthesis of Compound 276
18253141_1 (GHMatters) P111789.NZ
O Pd ,
2(dba)3,PCy3 O HN
Pin B
HN S 2 2 O
N N N O
N Pd
O (dba) Cl
Step 2
Step 1
Step 1: A mixture of 4-methyl-N’-(pentanylidene)benzenesulfonohydrazide (1.0 g, 3.9 mmol),
1-(bromomethyl)chlorobenzene (88 mg, 4.3 mmol), Pd (dba) (90 mg, 0.10 mmol), tri(2-
furyl)phosphine (183 mg, 0.79 mmol) and t-BuOLi (944 mg, 11.8 mmol) in toluene (40 mL) was stirred at
80 C for 16 h under nitrogen. The volatiles were removed under reduced pressure and the residue was
taken up by EtOAc (100 mL), which was washed by brine (100 mL). The organic layer was dried over
MgSO , concentrated and the residue was purified by silica gel chromatography, eluting with 5% EtOAc
in petroleum ether, to give 1-chloro(2-ethylbutenyl)benzene (200 mg, 26% yield) as a colorless oil.
H NMR (CDCl , 400MHz): 7.28 (d, J=8.4 Hz, 2H), 7.14 (d, J=8.4 Hz, 2H), 6.18 (s, 1H), 2.24-2.14 (m,
4H), 1.14-1.05 (m, 6H).
Step 2: A mixture of 1-chloro(2-ethylbutenyl)benzene (500 mg, 2.6
mmol), bis(pinacolato)diboron (783 mg, 3.1 mmol), Pd (dba) (118 mg, 0.13 mmol),
tricyclohexylphosphine (86 mg, 0.31 mmol) and potassium acetate (755 mg, 7.7 mmol) in 1,4-dioxane (20
mL) was stirred at 100 C for 16 h under nitrogen. The volatiles were removed under reduced pressure and
the residue was purified by silica gel chromatography, eluting with 0-1% EtOAc in petroleum ether, to
give 2-(4-(2-ethylbutenyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (400 mg, 54% yield) as a
greenish oil.
Compound 276 (formic acid salt) was prepared as a white solid from Compound 101-K and 2-
(4-(2-ethylbutenyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane by utilizing methods analogous
to those described in Example 53. LCMS (Method 5-95 AB, ESI): t = 0.641 min, [M + H] = 930.5; H
NMR (400 MHz, MeOH-d ) δ 8.51 (s, 2H), 8.20 (d, J=8.0 Hz, 2H), 7.31-7.22 (m, 4H), 7.08 (br s, 2H),
6.86 (s, 1H), 6.66-6.51 (m, 2H), 6.32 (s, 1H), 5.33-5.26 (m, 1H), 4.87-4.72 (m, 2H), 4.32 (s, 2H), 4.29-4.20
(m, 4H), 3.29-3.20 (m, 4H), 3.18-3.12 (s, 2H), 3.08-2.98 (m, 5H), 2.47 (s, 6H), 2.40-2.24 (m, 5H), 2.22-
2.12 (m, 1H), 1.35 (d, J=6.4 Hz, 3H), 1.20-1.10 (m, 6H).
Example 77: Synthesis of Compound 277
Pd/C, H N
N 1) 2
O HN
NaOH
2) N N N O
N N OH
Step 1
Step 1: Starting from methyl 2-(4-(2-ethylbutenyl)phenyl)-4,6-dimethylpyrimidine
carboxylate (prepared as described in Example 76), typical hydrogenation (Pd/C, H , Example D) and ester
18253141_1 (GHMatters) P111789.NZ
hydrolysis (NaOH, MeOH/H O, Example H) conditions were applied to give 2-(4-(2-ethylbutyl)phenyl)-
4,6-dimethylpyrimidinecarboxylic acid as a white solid.
Compound 277 (formic acid salt) was prepared as a white solid from Compound 101-K and 2-
(4-(2-ethylbutyl)phenyl)-4,6-dimethylpyrimidinecarboxylic acid by utilizing methods analogous to
those described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.767 min, [M + H] = 932.4; H NMR
(400 MHz, MeOH-d ) δ 8.49 (br s, 2H), 8.20 (d, J=8.0 Hz, 2H), 7.32-7.18 (m, 4H), 7.15-7.04 (m, 2H),
6.86 (s, 1H), 6.62 (s, 1H), 6.53 (s, 1H), 5.30-5.23 (m, 1H), 4.78-4.55 (m, 2H), 4.34 (s, 2H), 4.27-4.16 (m,
4H), 3.28-3.19 (m, 4H), 3.13-3.05 (m, 4H), 3.01 (s, 3H), 2.62 (d, J=7.2 Hz, 2H), 2.49 (s, 6H), 2.35-2.23 (m,
1H), 2.20-2.12 (m, 1H), 1.64-1.53 (m, 1H), 1.39-1.31 (m, 7H), 0.93 (t, J=7.2 Hz, 6H).
Example 78: Synthesis of Compound 278
N N N
Compound 278 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 56. LCMS (Method 5-95 AB, ESI): t = 0.631
min, [M + H] = 916.4; H NMR (400 MHz, MeOH-d ) δ 8.14-8.10 (m, 2H), 7.48-7.40 (m, 2H), 7.26 (br s,
2H),7.07-7.00 (m, 2H), 6.83 (s, 1H), 6.66 (s, 1H), 6.50-6.38 (m, 3H), 5.34-5.30 (m, 1H), 4.79-4.74 (m, 2H),
4.30-4.20 (m, 6H), 3.31 - 3.14 (m, 6H), 2.91(s, 3H), 2.90-2.80 (m, 2H), 2.45 (s, 6H), 2.28-2.21(m, 4H),
1.60-1.51 (m, 2H), 1.36 (d, J=6.8 Hz, 3H), 1.01 (t, J=7.6 Hz, 3H).
Example 79: Synthesis of Compound 279
Br N N
O HN
PPh Br
N N N O
KOt-Bu, THF O
H O O
Step 1
[00729] Step 1: Typical Wittig reaction condition (as described in Example 12) was applied to 4-
bromobenzaldehyde to give (E)bromo(butenyl)benzene as a colorless oil.
Compound 279 (formic acid salt) was prepared as a white solid from Compound 101-K and (E)-
1-bromo(butenyl)benzene by utilizing methods analogous to those described in Example 53.
LCMS (Method 5-95 AB, ESI): t = 0.714 min, [M + H] = 902.5; H NMR (400 MHz, MeOH-d ) δ 8.46
(br s, 1H), 8.25-8.21 (m, 2H), 7.45-7.05 (m, 7H), 6.88 (brs, 1H), 6.50-6.40 (m, 3H), 5.79-5.73 (m, 1H),
.27-5.22 (m, 1H), 4.81-4.75 (m, 2H), 4.32-4.20 (m, 6H), 3.24-3.11 (m, 6H), 3.05-2.96 (m, 5H), 2.52 (s,
6H), 2.41-2.27 (m, 3H), 2.20-2.13 (m, 1H), 1.36 (d, J=6.8 Hz, 3H), 1.10 (t, J=7.6 Hz, 3H)
Example 80: Synthesis of Compound 280
18253141_1 (GHMatters) P111789.NZ
O HN
N N N O
Compound 280 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Examples 12 and 53. LCMS (Method 5-95 AB, ESI): t
= 0.586 min, [M + H] = 902.3; H NMR (400 MHz, MeOH-d ) δ 8.50 (br s, 1H), 8.35-8.20 (m, 2H), 7.36-
7.28 (m, 3H), 7.21 (d, J=8.4 Hz, 2H), 7.09 (d, J=8.4 Hz, 1H), 6.90 (br s, 1H), 6.76 (br s, 1H), 6.46 (s, 1H),
.26-5.20 (m, 1H), 4.79-4.70 (m, 2H), 4.35-4.19 (m, 4H), 4.21 (s, 2H), 3.26-3.18 (m, 4H), 3.16-3.09 (m,
4H), 3.01 (s, 3H), 2.54 (s, 6H), 2.32-2.25 (m, 1H), 2.20-2.13 (m, 1H), 1.47 (s, 3H), 1.36 (d, J=6.6 Hz, 3H),
0.94 (br s, 2H), 0.84 (br s, 2H).
Example 81: Synthesis of Compound 281
O HN
N N N O
Compound 281 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Examples 12 and 53. LCMS (Method 5-95 AB, ESI): t
= 0.721 min, [M + H] = 916.5; H NMR (400 MHz, MeOH-d ) δ 8.50 (br s, 2H), 8.20 (d, J=8.0 Hz, 2H),
7.35 (d, J=8.0 Hz, 2H), 7.30-7.20 (m, 2H), 7.08 (br s, 2H), 6.86 (s, 1H), 6.57 (br s, 1H), 5.35-5.25 (m, 1H),
4.85-4.75 (m, 2H), 4.40-4.20 (m, 6H), 3.30-3.20 (m, 4H), 3.16-3.12 (m, 2H), 3.05-2.95 (m, 5H), 2.48 (s,
6H), 2.35-2.25 (m, 1H), 2.20-2.10 (m, 1H), 1.68 (q, J=7.2 Hz, 2H), 1.35 (d, J=6.8 Hz, 3H), 0.92 (t, J=6.8
Hz, 3H), 0.84 (br s, 2H), 0.78 (br s, 2H).
Example 82: Synthesis of Compound 282
O HN
N N N O
[00733] Compound 282 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Examples 12 and 53. LCMS (Method 5-95 AB, ESI): t
= 0.753 min, [M + H] = 930.4; H NMR (400 MHz, MeOH-d ) δ 8.51 (br s, 2H), 8.22 (d, J=8.0 Hz, 2H),
7.38 (d, J=8.0 Hz, 2H), 7.31-7.25 (m, 2H), 7.10 (br s, 2H), 6.88 (s, 1H), 6.62 (s, 1H), 6.58 (s, 1H), 5.32-
.28 (m, 1H), 4.82-4.77 (m, 3H), 4.36 (s, 2H), 4.30-4.21 (m, 4H), 3.32-3.10 (m, 8H), 3.04 (s, 3H), 2.50 (s,
18253141_1 (GHMatters) P111789.NZ
6H), 2.35-2.15 (m, 2H), 1.67-1.63 (m, 2H), 1.41-1.31 (m, 5H), 0.92 (t, J = 6.8 Hz, 3H), 0.88-0.84 (m, 2H),
0.80-0.76 (m, 2H).
Example 83: Synthesis of Compound 283
O HN
N N N O
[00734] Compound 283 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Examples 12 and 53. LCMS (Method 5-95 AB, ESI): t
= 0.775 min, [M + H] = 944.6; H NMR (400 MHz, MeOH-d ) δ8.46 (brs, 3H), 8.31 (d, J=8.0 Hz, 2H),
7.40 (d, J=8.0 Hz, 2H), 7.30 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.0 Hz, 2H), 7.10 (d, J=8.4 Hz, 1H), 6.91 (s,
1H), 6.80 (brs, 1H), 6.44 (s, 1H), 5.25-5.21 (m, 1H), 4.89-4.80 (m, 2H), 4.30-4.18 (m, 6H), 3.25-3.09 (m,
8H), 3.01 (s, 3H), 2.56 (s, 6H), 2.31-2.26 (m, 1H), 2.19-2.14 (m, 1H), 1.65 (brs, 3H), 1.39-1.26 (m, 7H),
0.91-0.80 (m, 5H), 0.79-0.72 (m., 2H).
Example 84: Synthesis of Compound 284
O Ph P Me Br
1) 3
O HN
KOt-Bu, THF
N N N O
CH I , ZnEt
2 2 2
step 1
Step 1: Starting from 5-bromo-2,3-dihydro-1H-indenone, Wittig and cyclo-proponation
conditions (as described in Example 12) were followed to give 5’-bromo-2’,3’-dihydrospiro[cyclopropane-
1,1’-indene] as a yellow oil. H NMR (400 MHz, CDCl ) δ 7.32 (d, J=1.6 Hz, 1H), 7.23 (dd, J=8.0, 1.6 Hz,
1H), 6.53(d, J=8.0 Hz, 1H), 3.03 (t, J=7.2 Hz, 2H), 2.13 (t, J=7.2 Hz, 2H), 0.97-0.93 (m, 2H), 0.89-0.87
(m, 2H).
Compound 284 (formic acid salt) was prepared as a white solid from Compound 101-K and 5’-
bromo-2’,3’-dihydrospiro[cyclopropane-1,1’-indene] by utilizing methods analogous to those described in
Example 53. LCMS (Method 5-95 AB, ESI): t = 0.711 min, [M + Na] = 936.5; H NMR (400 MHz,
MeOH-d ) δ 8.49 (brs, 2H), 8.15-8.02 (m, 2H), 7.31-7.21 (m, 2H), 7.16-7.07 (m, 2H), 6.90-6.81 (m, 1H),
6.77 (d, J=8.0 Hz, 1H), 6.70-6.47 (m, 2H), 5.28-5.25 (m, 1H), 4.84-4.75 (m, 2H), 4.35 (s, 2H), 4.29-4.19
(m, 4H), 3.29-3.19 (m, 4H), 3.18-2.97 (m, 9H), 2.48 (s, 6H), 2.34-2.25 (m, 1H), 2.28-2.11 (m, 3H), 1.36 (d,
J=6.8 Hz, 3 H), 1.04-0.95 (m, 4H).
Example 85: Synthesis of Compound 285
18253141_1 (GHMatters) P111789.NZ
+ N N
Ph P Me Br
1) 3 O O HN
KOt-Bu, THF
N N N O
CH I , ZnEt
2) 2 2 2
O Br
O Br
step 1
Step 1: Starting from 7-bromochromanone, Wittig and cyclo-propanation conditions (as
described in Example 12) were followed to give 7-bromospiro[chromane-4,1’-cyclopropane] as a yellow
oil. H NMR (400 MHz, CDCl ) δ 6.96 (d, J=8.0 Hz, 1H), 6.95 (s, 1H), 6.51(d, J=8.0 Hz, 2H), 4.28 (t,
J=5.2 Hz, 2H), 1.85(t, J=5.2 Hz, 2H), 1.03(t, J=4.4 Hz, 2H), 0.86(t, J=4.4 Hz, 2H).
Compound 285 (formic acid salt) was prepared as a white solid from Compound 101-K and 7-
bromospiro[chromane-4,1’-cyclopropane] by utilizing methods analogous to those described in Example
53. LCMS (Method 5-95 AB, ESI): t = 0.683 min, [M + H] = 930.4; H NMR (400 MHz, MeOH-d )
δ8.51 (br s, 2H), 7.80 (br s, 1H), 7.53-7.41 (m, 1H), 7.31-7.20 (m, 2H), 7.15-6.89 (m, 3H), 6.85-6.72 (m,
2H), 6.67 (s, 1H), 5.32-5.21 (m, 1H), 4.80-4.70 (m, 2H), 4.37-4.25 (m, 8H), 3.46-3.35 (m, 2H), 3.27-3.20
(m, 4H), 3.18-3.10 (m, 2H), 3.02 (s, 3H), 2.96-2.85 (m, 2H), 2.38 (s, 6H), 2.30-2.25 (m, 1H), 2.19-2.10 (m,
1H), 1.96-1.87 (m, 2H), 1.35 (d, J=6.2 Hz, 3H), 1.20-1.12 (m, 2H), 1.00-0.91 (m, 2H).
Example 86: Synthesis of Compound 286
O HN
PPh Me Br-, t-BuOK
AlCl 1)
N N N O
I ZnEt
CH ,
2) 2 2 2
Step 1 Br
Step 2
[00739] Step 1: To a mixture of cyclopentane carbonyl chloride (2.0 g, 15 mmol) and bromo- benzene
(7.1 g, 45 mmol) was added AlCl (3.0 g, 22.5 mmol) slowly at 0 C and the mixture was stirred for at 20
C for 3 h. The mixture was quenched with a saturated aqueous NH Cl solution (20 mL),
which was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (100
mL), dried over Na SO , concentrated and the residue was purified by silica gel chromatography, eluting
with 0-5% EtOAc in petroleum ether, to give (4-bromophenyl)(cyclopentyl)methanone (1.56 g, 41% yield)
as a yellow oil.
Step 2: Starting from (4-bromophenyl)(cyclopentyl)methanone, Wittig and cyclo-proponation
conditions (as described in Example 12) were followed to give 1-bromo(1-
cyclopentylcyclopropyl)benzene as a yellow oil. H NMR (400 MHz, CDCl ) δ 7.39 (d, J=8.0 Hz, 2H),
7.19 (d, J=8.0 Hz, 2H), 1.80-1.75 (m, 1H), 1.63-1.60 (m, 2H), 1.50-1.45 (m, 4H), 1.12-1.07 (m, 2H), 0.71
(br s, 2H), 0.67 (br s, 2H).
Compound 286 (formic acid salt) was prepared as a white solid from Compound 101-K and 1-
bromo(1-cyclopentylcyclopropyl)benzene by utilizing methods analogous to those described in
Example 53. LCMS (Method 5-95 AB, ESI): t = 0.769 min, [M + H] = 956.5; H NMR (400 MHz,
18253141_1 (GHMatters) P111789.NZ
MeOH-d ) δ 8.47 (br s, 2H), 8.20 (br s, 2H), 7.39 (d, J=7.6 Hz, 2H), 7.26 (brs, 2H), 7.09 (brs, 2H), 6.87 (s,
1H), 6.64 (s, 1H), 6.50 (s, 1H), 5.32-5.24 (m, 1H), 4.80-4.72 (m, 2H), 4.36 (s, 2H), 4.29-4.17 (m, 4H),
3.29-3.08 (m, 8H), 3.02 (s, 3H), 2.49 (s, 6H), 2.33-2.22 (m, 1H), 2.21-2.12 (m, 1H),1.97-1.88 (m,
1H),1.74-1.62 (m, 2H), 1.51 (brs, 4H), 1.36 (d, J=6 Hz, 3 H), 1.22 (br s, 2H), 0.81 (br s, 2H), 0.75 (br s,
2H).
Example 87: Synthesis of Compound 287
O HN
N N N O
N OMe
Br NaOH, MeOH/H O
Zn, Pd 2
2(dba)3,S-phos N OH
Step 2
Step 1
Step 1: A mixture of Zn (684 mg, 10.5 mmol), 1-(bromomethyl)(tert-butyl)benzene (792 mg,
3.5 mmol) and iodine (100 mg) in DMF (3 mL) was stirred at 25 C for 1 h under nitrogen, followed by the
addition of methyl 2-chloro-4,6-dimethylpyrimidinecarboxylate (described in Example 53) (350 mg,
1.75 mmol), 2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl (36 mg, 0.09 mmol) and Pd (dba) (40 mg,
0.04 mmol). The resulting mixture was stirred for another 3 h at 60 C under nitrogen. The reaction
mixture was diluted with EtOAc (50 mL), which was washed with brine (50 mL). The organic layer was
dried over Na SO , concentrated and the residue was purified by silica gel chromatography, eluting with
20% EtOAc in petroleum ether, to give methyl 2-(4-(tert-butyl)benzyl)-4,6-dimethylpyrimidine
carboxylate (350 mg, 51% yield) as colorless oil. H NMR (400 MHz, CDCl ) δ 7.32 (br s, 4H), 4.18 (s,
2H), 3.94 (s, 3H), 2.51(s, 6H), 1.30 (s, 9H).
Step 2: Typical ester hydrolysis condition (NaOH, MeOH/H O) as described in Example H were
applied to methyl 2-(4-(tert-butyl)benzyl)-4,6-dimethylpyrimidinecarboxylate to give 2-(4-(tert-
butyl)benzyl)-4,6-dimethylpyrimidinecarboxylic acid as a white solid.
Compound 287 (formic acid salt) was prepared as a white solid from Compound 101-K and 2-
(4-(tert-butyl)benzyl)-4,6-dimethylpyrimidinecarboxylic acid by utilizing methods analogous to those
described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.694 min, [M + H] = 918.5; H NMR (400
MHz, MeOH-d ) δ 8.46 (brs, 3H), 7.31-7.18 (m, 7H), 7.11 (d, J=8.8 Hz, 1H), 6.90 (d, J=2.0 Hz, 1H), 6.80
(s, 1H), 6.38 (s, 1H), 5.17-5.15 (m, 1H), 4.83-4.77 (m, 2H), 4.26-4.13 (m, 8H), 3.34-3.05 (m, 8H), 2.97 (s,
3H), 2.49 (s, 6H), 2.25-2.15 (m, 1H), 2.15-2.01 (m, 1H), 1.34 (d, J=6.4 Hz, 3H), 1.29 (s, 9H).
18253141_1 (GHMatters) P111789.NZ
Example 88: Synthesis of Compound 288
O HN
N N N
NaOH, MeOH/H O
NaH, MeI
N OH
N N OMe
Step 2
Step
Step 1: A mixture of methyl 2-[(4-tert-butylphenyl)methyl]-4,6-dimethyl-pyrimidine
carboxylate (described in Example 87) (150.0 mg, 0.4800 mmol) and NaH (28.8 mg, 1.2 mmol) in DMF (5
mL) was stirred at 0 C for 2 h, followed by the addition of iodomethane (2.6 g, 18.3 mmol). The resulting
mixture was stirred at 20 C for 5 h. The reaction was diluted with water (30 mL), which was extracted by
EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over MgSO ,
concentrated and the residue was purified by preparatory-TLC (eluent: 10% EtOAc in petroleum, Rf =0.5)
to give methyl 2-[1-(4-tert-butylphenyl)methyl-ethyl]-4,6-dimethyl-pyrimidinecarboxylate (40 mg,
24.5% yield) as a colorless oil. LCMS (Method 5-95 AB, ESI): t = 1.050 min, [M + H] = 341.3.
Step 2: Starting from methyl 2-[1-(4-tert-butylphenyl)methyl-ethyl]-4,6-dimethyl-pyrimidine-
-carboxylate (40 mg, 0.12 mmol),
ester hydrolysis conditions (NaOH, MeOH/H O, described in Example H) were followed to give 2-(2-(4-(tert-
butyl)phenyl)propanyl)-4,6-dimethylpyrimidinecarboxylic acid (38 mg, 99% yield) as a white solid.
[00747] Compound 288 (formic acid salt) was prepared as a white solid from Compound 101-K and 2-
(2-(4-(tert-butyl)phenyl)propanyl)-4,6-dimethylpyrimidinecarboxylic acid by utilizing methods
analogous to those described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.755 min, [M + H] =
946.5; H NMR (400 MHz, MeOH-d ) δ 8.47 (brs, 4H), 7.40-7.20 (m, 6H), 7.17 (d, J=8.4 Hz, 1H), 7.10 (d,
J=8.4 Hz, 1H), 6.90 (d, J=2.0 Hz, 1H), 6.82 (s, 1H), 6.37 (s, 1H), 5.17-5.15 (m, 1H), 4.80-4.77 (m, 1H),
4.40-4.10 (m, 7H), 3.34-3.00 (m, 8H), 2.97 (s, 3H), 2.80-2.70 (m, 3H), 2.48 (s, 3H), 2.25-2.15 (m, 1H),
2.15-2.00 (m, 1H), 1.70 (d, J=7.2Hz, 3H), 1.34-1.25 (m, 15H).
Example 89: Synthesis of Compound 289
N N N
O F F
DAST NaOH, MeOH
CrO , AcOH
N OMe
N OMe N OMe
N OH
step 1
step 2 O step 3
18253141_1 (GHMatters) P111789.NZ
Step 1: A mixture of methyl 2-(4-(tert-butyl)benzyl)-4,6-dimethylpyrimidinecarboxylate
(prepared as described in Example 88) (250 mg, 0.80 mmol) and CrO (240 mg, 2.4 mmol) in acetic acid
(5 mL) was stirred at 30 C for 6 h. The reaction mixture was diluted with water (30 mL), which was
extracted by EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 50 mL), dried
over MgSO , concentrated and the residue was purified by prep-TLC (eluting with 20% EtOAc in
petroleum ether) to give methyl 2-(4-(tert-butyl)benzoyl)-4,6-dimethylpyrimidinecarboxylate (150 mg,
57% yield) as a white solid. LCMS (Method 5-95 AB, ESI): t = 0.932 min, [M + H] = 326.9.
Step 2: A mixture of methyl 2-(4-(tert-butyl)benzoyl)-4,6-dimethylpyrimidinecarboxylate
(120 mg, 0.37 mmol) and diethylaminosulfur trifluoride (2 mL) was stirred at 50 C for 2 h. The reaction
was diluted with water (30 mL), which was extracted by EtOAc (3 x 30 mL). The combined organic layers
were washed with brine (2 x 50 mL), dried over MgSO , concentrated and the residue was purified by
prep-TLC (eluting with 20% EtOAc in petroleum ether) to give methyl 2-((4-(tert-
butyl)phenyl)difluoromethyl)-4,6-dimethylpyrimidinecarboxylate (80 mg, 62% yield) as a white solid.
Step 3: Typical ester hydrolysis conditions (NaOH, MeOH/H O, as described in Example H) were applied
to methyl 2-((4-(tert-butyl)phenyl)difluoromethyl)-4,6-dimethylpyrimidinecarboxylate to give 2-((4-
(tert-butyl)phenyl)difluoromethyl)-4,6-dimethylpyrimidinecarboxylic acid as a white solid. LCMS
(Method 5-95 AB, ESI): t = 0.899 min, [M + H] = 334.9.
Compound 289 (formic acid salt) was prepared as a white solid from Compound 101-K and 2-
((4-(tert-butyl)phenyl)difluoromethyl)-4,6-dimethylpyrimidinecarboxylic acid by utilizing methods
analogous to those described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.748 min, [M + H] =
954.6; H NMR (400 MHz, MeOH-d ) δ 8.51 (brs, 2H), 7.54 (d, J=8.0 Hz, 2H), 7.48 (d, J=8.0 Hz, 2H),
7.30-7.20 (m, 2H), 7.17 (d, J=8.0 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 6.90 (s, 1H), 6.83 (s,1H), 6.38 (s, 1H),
.20-5.15 (m, 1H), 4.79-4.75 (m, 1H), 4.25-4.15 (m, 7H), 3.35-3.32 (m, 1H), 3.20-3.05 (m, 7H), 2.97 (s,
3H), 2.56 (s, 6H), 2.30-2.20 (m, 1H), 2.15-2.05 (m, 1H), 1.36 (d, J=7.2 Hz, 3H), 1.32 (s, 9H).
Example 90: Synthesis of Compound 290
LDA, HCHO MeLi
O O HN
N N N O
Br Br
Step 2
Step 1
Step 1: To a solution of LDA (2N in THF, 35 mL) was added 4-bromomethylbenzoic acid
(5.0 g, 23.2 mmol) over 15 min and the reaction was stirred at -40 °C for 30 min. After warming to 15 °C,
HCHO (2.7 g, 93 mmol) was added while keeping the internal temperature (ice water bath) below 18 °C.
The resulting mixture was stirred at 15 °C for 2 h, and then cooled to 0 °C followed by the addition of
aqueous 3N HCl until pH<3. The above mixture was then extracted with EtOAc (2 x 100 mL) and the
combined organic layers were then concentrated to roughly 50 mL, to which Amberlyst® 15 ion exchange
resin (1.5 g) was added and the mixture was stirred at 48 °C for 14 h. The volatiles were removed and the
18253141_1 (GHMatters) P111789.NZ
residue was purified by silica-gel column, eluting with 20-30% EtOAc in petroleum ether, to give 6-
bromoisochromanone (1.5 g, 28% yield) as a light yellow solid. H NMR (400MHz, CDCl ) δ 7.97 (d,
J=8.5 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.46 (s, 1H), 4.55 (t, J=6.0 Hz, 2H), 3.06 (t, J=6.0 Hz, 2H).
Step 2: To a solution of 6-bromoisochromanone (800 mg, 3.5 mmol) in THF (10 mL) was
added MeMgBr (3N solution in Et O, 8.2 mL) at -78 C. The mixture was stirred at the same temperature
for 0.5 h; then warmed up to 20 C while stirring and was stirred for additional 1 h. The reaction was
poured into cold saturated aqueous NH Cl (50 mL), which was extracted with EtOAc (2 x 50 mL). The
combined organic layers were dried over Na SO , evaporated in vacuo and the residue was purified by
silica gel chromatography, eluting with 50-60% EtOAc in petroleum ether, to give 6-bromo-1,1-
dimethylisochromane (600 mg, 71% yield) as a white solid.
Compound 290 (formic acid salt) was prepared as a white solid from Compound 101-K and 6-
bromo-1,1-dimethylisochromane by utilizing methods analogous to those described in Example 53. LCMS
(Method 5-95 AB, ESI): t = 0.532 min, [M + H] = 932.3; H NMR (400 MHz, MeOH-d ) δ 8.50 (br s,
1H), 8.10-7.95 (m, 2H), 7.33-7.18 (m, 3H), 7.13-6.95 (m, 2H), 6.83 (s, 1H), 6.63 (s, 1H), 6.48 (s, 1H),
5.35-5.25 (m, 1H), 4.82-4.70 (m, 2H), 4.48-4.30 (m, 4H), 4.25 (s, 2H), 3.98 (t, J=5.6 Hz, 2H), 3.30-3.28
(m, 2H), 3.24 (brs, 2H), 3.14 (t, J=8.0 Hz, 2H), 3.02 (s, 3H), 2.97-2.62 (m, 4H), 2.44 (s, 6H), 2.33-2.16 (m,
2H), 1.57 (s, 6H), 1.35 (d, J=6.8 Hz, 3H).
Example 91: Synthesis of Compound 291
O HN
N N N O
[00754] Compound 291 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 53. LCMS (Method 5-95 AB, ESI): t = 0.674
min, [M + H] = 918.5; H NMR (400 MHz, MeOH-d ) δ 8.53 (brs, 2H), 8.10-8.04 (m, 3H), 7.25-7.21 (m,
2H), 7.06 (d, J=7.6 Hz, 2H), 6.82 (s, 1H), 6.68 (brs, 2H), 5.31-5.27 (m, 2H), 4.80-4.75 (m, 3H), 4.26-4.17
(m, 6H), 3.31-3.25 (m, 1H), 3.17-3.13 (m, 7H), 3.09 (s, 3H), 2.39 (s, 6H), 2.23-2.15 (m, 1H), 2.12-2.05 (m,
1H), 1.51 (s, 6H),1.34 (d, J=6.8 Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 92: Synthesis of Compound 292
O N N
O HN
N N N O
Pd(OAc) PhI(OAc)
NaH, MeI KOAc LiAlH
NC NaOH Ac-Gly-OH,
Br Br
Step 3
Step
Step 1
Step
Step 1: Typical alkylation (NaH, MeI) conditions (as described in Example 88) were applied to
1-bromo(isocyanomethyl)benzene to give 1-bromo(2-isocyanopropanyl)benzene as a yellow oil.
[00756] Step 2: A mixture of 1-bromo(2-isocyanopropanyl)benzene (1.77 g, 7.9 mmol) and NaOH
(948 mg, 23.7 mmol) in EtOH/H O (40 mL, v/v=1/1) was stirred at 100 C for 16 h. The volatiles were
removed and the residue was treated with aq 1N HCl until pH=4, which was then extracted with EtOAc
(3x 30 mL). The combined organic layers were washed with brine (2 x 80 mL), dried over Na SO and
evaporated in vacuo to give 2-(4-bromophenyl)methylpropanoic acid (1.9 g, 99% yield) as a yellow
solid.
Step 3: A mixture of 2-(4-bromophenyl)methylpropanoic acid (1.0 g, 4.1 mmol), PhI(OAc)
(2.0 g, 6.2 mmol), Pd(OAc) (46 mg, 0.21 mmol), 2-acetamidoacetic acid (144 mg, 1.2 mmol) and K CO
2 2 3
(807 mg, 8.2 mmol) in tert-butanol (10 mL) was stirred at 100 C for 20 h under nitrogen. The volatiles
were removed and the residue was purified by silica gel chromatography, eluting with 0-10% EtOAc in
petroleum ether, to give 6-bromo-3,3-dimethylbenzofuran-2(3H)-one (260 mg, 26% yield) as a off-white
solid. H NMR (400 MHz, MeOH-d4) δ 7.37 (s, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.28 (d, J=7.6 Hz, 1H), 1.47
(s, 6H).
Step 4: To a solution of lithium aluminum hydride (49 mg, 1.29 mmol) in THF (10 mL) was
added 6-bromo-3,3-dimethylbenzofuran-2(3H)-one (260 mg, 1.1 mmol) at 0 C and the mixture was stirred
for at 25 C for 2 h. The reaction was quenched with saturated aqueous NH Cl (20 mL), which was
extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with brine (50 mL),
concentrated and the residue was purified by preparatory TLC (eluting with 30% ethyl acetate in
petroleum ether, R =0.5) to give 6-bromo-3,3-dimethyl-2,3-dihydrobenzofuran (180 mg, 74% yield) as a
off-white solid.
[00759] Compound 292 (formic acid salt) was prepared as a white solid from Compound 101-K and 6-
bromo-3,3-dimethyl-2,3-dihydrobenzofuran by utilizing methods analogous to those described in Example
53. LCMS (Method 5-95 AB, ESI): t = 0.688 min, [M + H] = 918.5; H NMR (400 MHz, MeOH-d ) δ
8.53 (br s, 2H), 7.92 (d, J=8.0 Hz, 1H), 7.49-7.38 (m, 1H), 7.32-7.26 (m, 1H), 7.24-7.19 (m, 1H), 7.17 (d,
J=8.0 Hz, 1H), 7.00-6.93 (m, 1H), 6.89-6.66 (m, 3H), 6.13 (brs, 1H), 5.39-5.31 (m, 1H), 4.80-4.70 (m, 2H),
18253141_1 (GHMatters) P111789.NZ
4.51-4.33 (m, 2H), 4.33-4.16 (m, 6H), 3.40-3.33 (m, 2H), 3.20-3.05 (m, 4H), 3.02 (s, 3H), 2.88-2.67 (m,
2H), 2.31 (s, 6H), 2.23-1.98 (m, 2H), 1.43-1.30 (m, 9H).
Example 93: Synthesis of Compound 293
N O HN
N N N
Cl OH
Cl N
N SnBu
, Na CO N
N 1) Pd(dppf)Cl2 2 3
Pd(PPh3)4
N OMe
NaOH
N OH
Step 1
Step 2
[00760] Step 1: A mixture of methyl 2-chloro-4,6-dimethylpyrimidinecarboxylate (described in
Example 53) (200 mg, 1.00 mmol), 5-chloro(tributylstannyl)pyridine (400 mg, 0.99 mmol), and
Pd(PPh ) (115 mg, 0.10 mmol) in toluene (6 mL) was stirred at 110 C for 16 h under nitrogen. The
volatiles were removed and the residue was purified by silica gel chromatography, eluting with 0-50%
EtOAc in petroleum ether, to give methyl 2-(5-chloropyridinyl)-4,6-dimethylpyrimidinecarboxylate
(140 mg, 51% yield) as a white solid.
Step 2: Starting from methyl 2-(5-chloropyridinyl)-4,6-dimethylpyrimidinecarboxylate,
typical Suzuki coupling and ester hydrolysis conditions, as described in Example H, were followed to give
2-(5-butylpyridinyl)-4,6-dimethylpyrimidinecarboxylic acid as a white solid.
Compound 293 (formic acid salt) was prepared as a white solid from Compound 101-K and 2-
(5-butylpyridinyl)-4,6-dimethylpyrimidinecarboxylic acid by utilizing methods analogous to those
described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.636 min, [M + H] = 905.8; H NMR (400
MHz, MeOH-d ) δ 8.85 (br s, 1H), 8.42 (d, J=8.0 Hz, 2H), 7.76-7.72 (m, 1H), 7.29 (d, J=8.0 Hz, 1H),
7.24-7.20 (m, 1H), 6.86-6.59 (m, 4H), 5.45-5.36 (m, 1H), 4.79-4.70 (m, 2H), 4.67-4.41 (m, 2H), 4.31-4.15
(m, 4H), 3.59-3.34 (m, 4H), 3.30-3.03 (m, 4H), 3.01 (s, 3H), 2.76 (t, J=7.6 Hz, 2H), 2.37 (s, 6H), 2.27-2.00
(m, 2H), 1.79-1.67 (m, 2H), 1.55-1.44 (m, 2H), 1.36 (d, J=6.8 Hz, 3H), 1.04 (t, J=7.2 Hz, 3H).
Example 94: Synthesis of Compound 294
, B Pin O
1) Pd(dppf)Cl2 2 2
F F F F
, Na CO
2) Pd(dppf)Cl2 2 3
Cl N
N OMe
O HN
N OH N N N O
DAST
NaOH
O O O
Step 1
Step 1: Starting with 1-(4-bromophenyl)butanone, typical Suzuki borylation, Suzuki, di-
fluoronation (described in Example 89) and ester hydrolysis (NaOH, MeOH/H O) conditions were applied
to give 2-(4-(1,1-difluorobutyl)phenyl)-4,6-dimethylpyrimidinecarboxylic acid as a white solid. LCMS
(Method 5-95 AB, ESI): t = 0.844 min, [M + H] = 320.9
18253141_1 (GHMatters) P111789.NZ
Compound 294 (formic acid salt) was prepared as a white solid from Compound 101-K and 2-
(4-(1,1-difluorobutyl)phenyl)-4,6-dimethylpyrimidinecarboxylic acid by utilizing methods analogous to
those described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.725 min, [M + H] = 940.5; H NMR
(400 MHz, MeOH-d ) δ 8.37 (d, J=8.0 Hz, 2H), 7.55 (d, J=8.0 Hz, 2H), 7.32-7.22 (m, 2H), 7.08 (brs, 2H),
6.86 (s, 1H), 6.56 (brs, 2H), 5.31-5.25 (m, 1H), 4.82-4.75 (m, 2H), 4.44-4.20 (m, 6H), 3.38 - 3.32 (m, 3H),
3.18-3.13 (m, 3H), 3.07-2.96 (m, 5H), 2.49 (s, 6H), 2.35-2.09 (m, 4H), 1.52-1.42 (m, 2H), 1.35 (d, J=6.8
Hz, 3H), 0.98 (t, J=7.2 Hz, 3H).
Example 95: Synthesis of Compound 295
O HN
PhNTf , LDA H H
N N N O
O OTf
step 1
[00765] Step 1: To a solution of 4-(tert-butyl)cyclohexanone (1.54 g, 10 mmol) in THF (20 mL) was
added LDA (2N in THF, 5.5 mL) dropwise at -78 C and the mixture was stirred at the same temperature
for 2 h, followed by the addition of PhNTf (3.9 g, 11 mmol). The resulting mixture was stirred at 20 C
for 12 h. The reaction was diluted with EtOAc (60 mL), which was washed with brine (2 x 50 mL). The
organic layer was dried over Na SO , concentrated and the residue was purified by silica gel
chromatography, eluting with 5% EtOAc in petroleum ether, to give 4-(tert-butyl)cyclohexenyl
trifluoromethanesulfonate (800 mg, 28% yield) as a colorless oil. H NMR (400 MHz, MeOH-d4): δ 5.74
(t, J=2.8 Hz, 1H), 2.40-2.10 (m, 3H), 2.00-1.85 (m, 2H), 1.40-1.20 (m, 2H), 0.87 (s, 9H).
Compound 295 (formic acid salt) was prepared as a white solid from Compound 101-K and 4-
(tert-butyl)cyclohexenyl trifluoromethanesulfonate by utilizing methods analogous to those
described in Examples 53 and 10. LCMS (Method 5-95 AB, ESI): t = 0.740 min, [M + H] = 908.5; H
NMR (400 MHz, MeOH-d ) δ 8.56 (br s, 3H), 7.30-7.15 (m, 4H), 7.12-7.05 (m, 1H), 6.85 (brs, 1H), 6.68
(brs, 1H), 6.45 (brs, 1H), 5.20-5.10 (m, 1H), 4.79-4.75 (m, 2H), 4.40-4.10 (m, 6H), 3.33-3.05 (m, 8H),
2.98 (s, 3H), 2.90-2.60 (m, 1H), 2.44 (s, 6H), 2.40-1.90 (m, 7H), 1.36 (d, J=6.8 Hz, 3H), 1.23-1.05 (m, 1H),
0.98 (s, 9H).
Example 96: Synthesis of Compound 296
O HN
N N N O
N NaOH
Pd/C, H , MeOH +
N OH
N O N MeOH, H O
Step 1
Step 2 O
18253141_1 (GHMatters) P111789.NZ
Step 1: A mixture of 2-(4-tert-butylcyclohexenyl)-4,6-dimethyl-pyrimidine carboxylate (as
described in Example 95) (250 mg, 0.83 mmol) and 10% Pd/C (88 mg, 0.08 mmol) in MeOH (100 mL)
was stirred at 15 C for 5 h under H . The volatiles were removed and the residue was purified and the cis
and trans stereoisomers separated by preparatory-TLC (10% EtOAc in petroleum ether, Rf=0.7) to give
(cis)-methyl 2-(4-tert-butylcyclohexyl)-4,6-dimethyl-pyrimidinecarboxylate (70 mg, 28%
yield) and (trans)-methyl 2-(4-tert-butylcyclohexyl)-4,6-dimethyl-pyrimidinecarboxylate (100 mg, 40%
yield) as a white solid.
Step 2: Starting from (trans)-methyl 2-(4-tert-butylcyclohexyl)-4,6-dimethyl-pyrimidine
carboxylate (70 mg, 0.23 mmol), typical ester hydrolysis conditions (NaOH, MeOH/H O) were followed
to give (trans)tert-butylcyclohexyl)-4,6-dimethylpyrimidinecarboxylic acid (65 mg, 97% yield) as a
white solid.
Compound 296 (formic acid salt) was prepared as a white solid from Compound 101-K and
(trans)tert-butylcyclohexyl)-4,6-dimethylpyrimidinecarboxylic acid by utilizing methods analogous
to those described in Example 53. LCMS (Method 5-95 AB, ESI): t = 0.740 min, [M + H] = 910.6; H
NMR (400 MHz, MeOH-d ) δ 8.56 (br s, 3H), 7.29-7.26 (m, 2H), 7.19 (d, J= 8.4 Hz, 1H), 7.10 (d, J=8.4
Hz, 1H), 6.90 (d, J=2.0 Hz, 1H), 6.82 (s, 1H), 6.38 (s, 1H), 5.20-5.15 (m, 1H), 4.79-4.75 (m, 2H), 4.40-
4.10 (m, 6H), 3.33-3.05 (m, 8H), 2.97 (s, 3H), 2.75-2.65 (m, 1H), 2.49 (s, 6H), 2.30-2.05 (m, 2H), 2.00-
1.85 (m, 4H), 1.70-1.55 (m, 2H), 1.35 (d, J=6.8 Hz, 3H), 1.25-1.05 (m, 3H), 0.91 (s, 9H).
Example 97: Synthesis of Compound 297
O HN
N N N O
Compound 297 (formic acid salt) was prepared as a white solid from Compound 101-K and
(cis)-methyl 2-(4-tert-butylcyclohexyl)-4,6-dimethyl-pyrimidinecarboxylate by utilizing methods
analogous to those described in Example 96. LCMS (Method 5-95 AB, ESI): t = 0.740 min, [M + H] =
910.6; H NMR (400 MHz, MeOH-d ) δ 8.50 (br s, 2H), 7.28-7.26 (m, 2H), 7.18 (d, J=8.4 Hz, 1H), 7.09
(d, J=8.8 Hz, 1H),, 6.90 (d, J=2.0 Hz, 1H), 6.82 (d, J=2.0 Hz, 1H), 6.39 (s, 1H), 5.20-5.15 (m, 1H), 4.79-
4.75 (m, 2H), 4.40-4.10 (m, 6H), 3.25-3.05 (m, 8H), 2.98 (s, 3H), 2.55 (s, 6H), 2.55-2.40 (m, 2H), 2.30-
2.00 (m, 2H), 1.75-1.60 (m, 2H), 1.60-1.50 (m, 2H), 1.40-1.20 (m, 3H), 1.38 (d, J=6.8 Hz, 3H), 1.20-1.05
(m, 1H), 0.81 (s, 9H).
18253141_1 (GHMatters) P111789.NZ
Example 98: Synthesis of Compound 298
O HN
OH N N N O
MeI, K CO
1) 2 3
B Pin , KOAc,
BBr DCM
Br DCM , N
2 Pd(dppf)Cl2
, Na CO N
3) Pd(dppf)Cl2 2 3 OH OH
OMe N OMe
Cl N
Step 3
N OMe
Step 1
Step 2
Step1: To a solution of 3-(tert-butyl)phenol (1.5 g, 10 mmol) in DCM (20 mL) was added a
solution of bromine (0.51 mL, 10 mmol) in DCM (5 mL) over 15 min while keeping the temperature of the
reaction below 35 °C. After that, the reaction was quenched with 5% aqueous Na S SO (15 mL) while
2 2 3
stirring. The organic layer was separated, washed with brine (50 mL), dried over Na SO , concentrated and
the residue was purified by flash chromatography on silica, eluting with 0-5% EtOAc in petroleum ether,
to give 2-bromo(tert-butyl)phenol (1.6 g, 70% yield) as a colorless oil. H NMR (400 MHz, CDCl ) δ
7.37 (d, J=8.0 Hz, 1H), 7.07 (s, 1H), 6.85 (d, J= 8.0 Hz, 1H), 5.44 (s, 1H), 1.30 (s, 9H).
[00772] Step 2: Starting from 2-bromo(tert-butyl)phenol, typical alkylation (as described in Example
21), Suzuki borylation and Suzuki coupling conditions (as described in Example 10) were applied to give
methyl 2-(4-(tert-butyl)methoxyphenyl)-4,6-dimethylpyrimidinecarboxylate as a yellow oil. LCMS
(ESI): [M + H] = 329.0.
Step 3: To a solution of 2-(4-(tert-butyl)methoxyphenyl)-4,6-dimethylpyrimidine
(87 μL, 0.91 mmol) and the mixture
carboxylate (150 mg, 0.46 mmol) in DCM (10 mL) was added BBr
was stirred at 0 C for 12 h. The reaction was quenched with 5% aqueous Na S SO (10 mL), the organic
2 2 3
layer was separated, washed with brine (50 mL), dried over Na SO , concentrated and the residue was
purified by HPLC to give 2-(4-(tert-butyl)hydroxyphenyl)-4,6-dimethylpyrimidinecarboxylic acid
(50 mg, 36.4% yield) as a yellow solid. LCMS (ESI): [M + H] = 300.9.
[00774] Compound 298 (formic acid salt) was prepared as a white solid from Compound 101-K and 2-
(4-(tert-butyl)hydroxyphenyl)-4,6-dimethylpyrimidinecarboxylic acid by utilizing methods
analogous to those described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.730 min, [M + H] =
920.5; H NMR (400 MHz, MeOH-d ) δ 8.50 (br s, 3H), 8.34 (d, J=8.4 Hz, 2H), 7.30-7.25 (m, 2H), 7.02-
6.98 (m, 2H), 6.82 (s, 1H), 6.69 (brs, 1H), 5.35-5.31 (m, 1H), 4.85-4.78 (m, 2H), 4.32-4.12 (m, 6H), 3.38-
3.34 (m, 2H), 3.16-3.12 (m, 4H), 3.02 (s, 3H), 3.00-2.90 (m, 2H), 2.43 (s, 6H), 2.31-2.10 (m, 2H), 1.40-
1.35 (m, 12H).
18253141_1 (GHMatters) P111789.NZ
Example 99: Synthesis of Compound 299
O HN
Selectfluor
F N N N O
F O O
Step 1
Step 1: A mixture of 4-(tert-butyl)phenol (2.0 g, 13 mmol) and Selectfluor (5.2 g, 14.6 mmol) in
MeOH (25 mL) was stirred at 85 C for 4 h. The volatiles were removed and the residue was taken up by
EtOAc (50 mL), which was washed with brine (2 x 50 mL). The organic layer was dried over Na SO ,
concentrated and the residue was purified by silica gel chromatography, eluting with 0-10% EtOAc in
petroleum ether, to give 4-(tert-butyl)fluorophenol (900 mg, 40% yield). H NMR (400 MHz, CDCl ) δ
7.12-7.00 (m, 2H), 6.96-6.89 (m, 1H), 5.04(s, 1H), 1.29 (s, 9H).
Compound 299 (formic acid salt) was prepared as a white solid from Compound 101-K and 4-
(tert-butyl)fluorophenol by utilizing methods analogous to those described in Examples 10 and 53.
LCMS (Method 5-95 AB, ESI): t = 0.711 min, [M + H] = 922.5; H NMR (400 MHz, MeOH-d ) δ
8.51(br s, 3H), 7.85-7.82 (m, 1H), 7.36-7.05 (m, 6H), 6.88 (s, 1H), 6.68(s, 1H), 6.51 (s, 1H), 5.30-5.24 (m,
1H), 4.80-4.70 (m, 2H), 4.30-4.20 (m, 6H), 3.32-3.00 (m, 8H), 2.95 (s, 3H), 2.56 (s, 6H), 2.35-2.25 (m,
1H), 2.25-2.15 (m, 1H), 1.38 (s, 9H), 1.36 (d, J=6.4 Hz, 3H).
Example 100: Synthesis of Compound 300
O HN
N N N
Compound 300 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 56. LCMS (Method 5-95 AB, ESI): t = 0.683
min, [M + H] = 888.4; H NMR (400 MHz, MeOH-d ) δ 8.52 (br s, 1H), 8.10 (d, J=7.6Hz, 2H), 7.26 (brs,
2H), 7.15-7.01 (m, 4H), 6.84 (s, 1H), 6.62 (s, 1H), 6.51 (s, 1H), 5.33-5.27 (m, 1H), 4.80-4.72 (m, 1H), 4.36
(brs, 3H), 4.27-4.23 (m, 4H), 3.29-3.26 (m, 2H), 3.22-3.06 (m, 6H), 3.02 (s, 3H), 2.99-2.90 (m, 2H), 2.43
(s, 6H), 2.33-2.23 (m, 1H), 2.21-2.10 (m, 1H), 2.03-1.93 (m, 1H), 1.35 (d, J=6.8 Hz, 3H), 1.10-1.03 (m,
2H), 0.81-0.75 (m, 2H).
Example 101: Synthesis of Compound 301
O HN
N N N
18253141_1 (GHMatters) P111789.NZ
Compound 301 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 56. LCMS (Method 5-95 AB, ESI): t = 0.709
min, [M + H] = 902.4; H NMR (400 MHz, MeOH-d ) δ 8.53 (br s, 1H), 8.15 (d, J=7.8 Hz, 2H), 7.28-
7.23 (m, 4H), 7.07-6.95 (m, 2H), 6.83 (s, 1H), 6.67 (s, 1H), 6.46 (s, 1H), 5.33-5.29 (m, 1H), 4.79-4.74 (m,
2H), 4.32-4.19 (m, 6H), 3.68-3.58 (m, 1H), 3.22-3.06 (m, 7H), 3.02 (s, 3H), 2.47-2.38 (m, 2H), 2.42 (s,
6H), 2.32-2.04 (m, 6H), 1.97-1.88 (m, 1H), 1.34 (d, J=6.8 Hz, 3H).
Example 102: Synthesis of Compound 302
O HN
N N N O
BPin
Pd Pd/C,
s-phos, 2(dba)3 1) 2
N OMe NaOH N OH
N OMe 2)
Step 1
O 2 O
O Step
Step 1: A solution of methyl 2-(4-chlorophenyl)-4,6-dimethylpyrimidinecarboxylate (100mg,
0.36 mmol, described in Example 56), 2-(cyclopentenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(91 mg, 0.47 mmol), Pd (dba) (8.3 mg, 0.01 mmol), S-phos(7.4 mg, 0.02 mmol) and K PO (230 mg, 1.1
2 3 3 4
mmol) in 1,4-dioxane/H O (6 mL, v/v=5/1) was stirred at 110 C for 16 h under N . After filtration, the
volatiles were removed under reduced pressure and the residue was purified by preparatory-TLC (eluent:
EtOAc: petroleum ether=1:10) to obtain methyl 2-(4-(cyclopentenyl)phenyl)-4,6-
dimethylpyrimidinecarboxylate (110 mg, 99% yield) as a white solid. LCMS (Method 5-95 AB, ESI):
t = 0.969 min, [M + H] = 309.3.
Step 2: Starting from methyl 2-(4-(cyclopentenyl)phenyl)-4,6-dimethylpyrimidine
carboxylate, hydrogenation (as described in Example D) and ester hydrolysis (as described in Example H)
conditions were followed to give 2-(4-cyclopentylphenyl)-4,6-dimethylpyrimidinecarboxylic acid as a
white solid. LCMS (Method 5-95 AB, ESI): t = 0.986 min, [M + H] = 297.0
Compound 302 (formic acid salt) was prepared as a white solid from Compound 101-K and 2-
(4-cyclopentylphenyl)-4,6-dimethylpyrimidinecarboxylic acid by utilizing methods analogous to those
described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.727 min, [M + H] = 916.4; H NMR (400
MHz, MeOH-d ) δ 8.50 (br s, 2H), 8.34-8.30 (m, 2H), 7.40 (d, J=8.8 Hz, 2H), 7.37-7.29 (m, 2H), 7.22 (d,
J=8.8 Hz, 2H), 7.13-7.08 (m, 2H), 6.51 (brs, 1H), 5.28-5.22 (m, 1H), 4.85-4.75 (m, 2H), 4.35-4.23 (m, 6H),
3.26-3.00 (m, 8H), 3.01 (s, 3H), 2.57 (s, 6H), 2.33-2.13 (m, 4H), 1.95-1.62 (m, 7H), 1.36 (d, J=6.8 Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 103: Synthesis of Compound 303
O HN
N N N O
Compound 303 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 302. LCMS (Method 5-95 AB, ESI): t = 0.610
min, [M + H] = 928.5; H NMR (400 MHz, MeOH-d ) δ 8.47 (b rs, 2H), 8.37-8.31 (m, 2H), 7.52 (d,
J=8.0 Hz, 2H), 7.33-7.17 (m, 3H), 7.16-7.01 (m, 2H), 6.79 (s, 1H), 6.50 (s, 1H), 6.29 (s, 1H), 5.29-5.18 (m,
1H), 4.83-4.75 (m, 2H), 4.25-4.10 (m, 4H), 4.20 (s, 2H), 3.56-3.36 (m, 1H), 3.29-2.99 (m, 10H), 2.55 (s,
6H), 2.51-2.45 (m, 2H), 2.36-2.24 (m, 3H), 2.22-2.11(m, 1H), 1.90-1.80 (m, 2H), 1.75-1.65 (m, 2H), 1.44-
1.35 (m, 3H).
Example 104 : Synthesis of Compound 304
N N N O
Compound 304 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 302. LCMS (Method 5-95 AB, ESI): t = 0.610
min, [M + H] = 928.5; H NMR (400 MHz, MeOH-d ) δ 8.54 (br s, 1H), 8.34-8.30 (m, 2H), 7.38-7.15 (m,
5H), 7.14-7.03 (m, 2H), 6.92 (s, 0.5H), 6.79(s, 0.5H), 6.50 (s, 0.5 H), 6.41(s, 0.5H), 5.26-5.19 (m, 1H),
4.85-4.78 (m, 2H), 4.25-4.17 (m, 4H), 4.20 (s, 2H), 3.30-2.97(m, 11H), 2.66-2.60 (m, 1H), 2.57(s, 6H),
2.36-2.24 (m, 1H), 2.21-2.09 (m, 1H), 1.96-1.77 (m, 5H), 1.55-1.42 (m, 5H), 1.36 (d, J=6.8 Hz, 3H).
Example 105: Synthesis of Compound 305
Pd/C,
P(Tolyl)3 Pd(OAc)2 O HN
N N N O
Step 1
Step 2
[00784] Step 1: A mixture of cycloheptene (155 mg, 1.6 mmol), 1-(benzyloxy)iodobenzene (200 mg,
0.64 mmol), Pd(OAc) (3.6 mg, 0.02 mmol), P(tolyl) (9.8 mg, 0.03 mmol), (t-Bu) NBr (208 mg, 0.64
2 3 4
mmol) and K CO (224 mg, 1.6 mmol) in DMF (10 mL) was stirred at 110 C for 16 h. The volatiles were
removed and the residue was taken up in EtOAc (50 mL), which was washed with brine (2 x 50 mL). The
organic layer was dried over MgSO , concentrated and the residue was purified by preparatory-TLC
18253141_1 (GHMatters) P111789.NZ
(eluting with 1% EtOAc in petroleum ether) to give 1-(4-(benzyloxy)phenyl)cycloheptene (100 mg,
56% yield) as a colorless oil.
Step 2: Typical hydrogenation conditions (Pd/C, H , as described in Example D) were applied to
1-(4-(benzyloxy)phenyl)cycloheptene to give 4-cycloheptylphenol as a white solid.
[00786] Compound 305 (formic acid salt) was prepared as a white solid from Compound 101-K and 4-
cycloheptylphenol by utilizing methods analogous to those described in Examples 53 and 10. LCMS
(Method 5-95 AB, ESI): t = 0.765 min, [M + H] = 944.5; H NMR (400 MHz, MeOH-d ) δ 8.54 (brs,
2H), 8.21-8.17 (m, 2H), 7.30-7.18 (m, 4H), 7.05 (brs, 2H), 6.84 (s, 1H), 6.65-6.55 (m, 2H), 5.30-5.22 (m,
1H), 4.83-4.79 (m, 2H), 4.33-4.11 (m, 6H), 3.17-3.04 (m, 6H), 3.04-2.85 (m, 5H), 2.80-2.70 (m, 1H), 2.46
(s, 6H), 2.30-2.20 (m, 1H), 2.16-2.03 (m, 1H), 1.98-1.82 (m, 4H), 1.80-1.60 (m, 8H), 1.35 (d, J=6.8 Hz,
3H).
Example 106: Synthesis of Compound 306
O HN
N N N O
Compound 306 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Examples 53 and 27. LCMS (Method 5-95 AB, ESI): t
= 0.535 min, [M + H] = 852.5; H NMR (400 MHz, MeOH-d ) δ 8.50 (brs, 1H), 7.30-7.22 (m, 2H), 7.20
(d, J=8.0 Hz, 2H), 7.11 (d, J=8.0 Hz, 1H), 6.89 (d, J=1.6 Hz, 1H), 6.76 (s, 1H), 6.44 (s, 1H), 5.25-5.15 (m,
1H), 4.85-4.70 (m, 2H), 4.35-4.15 (m, 6H), 3.40-3.12 (m, 8H), 2.99 (s, 3H), 2.47 (s, 6H), 2.35-2.15 (m,
2H), 1.41 (s, 9H), 1.36 (d, J=7.2 Hz, 3H).
Example 107: Synthesis of Compound 307
N N N O
Compound 307 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Examples 53 and 27. LCMS (Method 5-95 AB, ESI): t
= 900.5; H NMR (400 MHz, MeOH-d ) δ 8.45 (brs, 2H), 7.56 (d, J=8.0 Hz, 2H),
= 0.701 min, [M + H]
7.32-7.19 (m, 5H), 7.08 (d, J=8.0 Hz, 1H), 6.89 (d, J=2.4 Hz, 1H), 6.75(s, 1H), 6.45 (s, 1H), 5.23-5.20 (m,
1H), 4.80-4.78 (m, 2H), 4.29 (s, 2H), 4.24-4.20 (brs, 4H), 3.36-3.34 (m, 1H), 3.25-3.09 (m, 7H), 2.99 (s,
3H), 2.70 (q, J=7.6 Hz, 2H), 2.50 (s, 6H), 2.29-2.14 (m, 2H), 1.35 (d, J=6.8 Hz, 3H), 1.26 (t, J=7.6 Hz,
3H).
18253141_1 (GHMatters) P111789.NZ
Example 108: Synthesis of Compound 308
O HN
N N N O
Compound 308 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Examples 53 and 27. LCMS (Method 5-95 AB, ESI): t
= 0.747 min, [M + H] = 928.5; H NMR (400 MHz, MeOH-d ) δ 8.47 (brs, 3H),7.56 (d, J=8.0 Hz, 2H),
7.31-7.27 (m, 3H), 7.24-7.19 (m, 2H), 7.08 (d, J=8.0 Hz, 1H), 6.89 (s, 1H), 6.75 (s, 1H), 6.46 (s, 1H),
.24-5.20 (m, 1H), 4.81-4.77 (m, 2H), 4.30 (s, 2H), 4.21 (brs, 4H), 3.36-3.21 (m, 8H), 3.13 (s, 3H), 2.69 (t,
J=7.2 Hz, 2H), 2.50 (s, 6H), 2.31-2.11 (m, 2H),1.68-1.60 (m, 2H), 1.43-1.35 (m, 5H), 0.97 (t, J=7.2 Hz,
3H).
Example 109: Synthesis of Compound 309
O HN
N N N O
Compound 309 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Examples 53 and 27. LCMS (Method 5-95 AB, ESI): t
= 0.638 min, [M + H] = 872.7; H NMR (400 MHz, MeOH-d ) δ 8.48 (brs, 2H), 7.63 (d, J=8.0 Hz, 2H),
7.53-7.45 (m, 3H), 7.28-7.18 (m, 3H), 7.05 (d, J=8.0 Hz, 1H), 6.86 (s, 1H), 6.64 (s, 1H), 6.51(s, 1H), 5.26-
.23(m, 1H), 4.81-4.76 (m, 2H), 4.35 (s, 2H), 4.22 (brs, 4H), 3.38-3.22(m, 5H), 3.14-3.07 (m,3H), 2.99 (s,
3H), 2.47 (s, 6H), 2.31-2.12 (m, 2H), 1.35 (d, J=6.8 Hz, 3H).
Example 110: Synthesis of Compound 310
TMS H
K CO
CuI, Cl 2 3 O HN
Pd(PPh )
3 2 2
N N N O
step 1
step 2
[00791] Step 1: Typical Sonogoshira condition (as described in Example 13) was applied to 1-bromo
vinylbenzene to give trimethyl((4-vinylphenyl)ethynyl)silane as a yellow oil.
Step 2: A mixture of trimethyl((4-vinylphenyl)ethynyl)silane (200 mg, 1.0 mmol) and K CO (345 mg, 2.5
mmol) in MeOH (10 mL) was stirred at 25 C for 3 h. The volatiles were removed and the residue was
purified by silica gel chromatography, eluting with 0-1% EtOAc in petroleum ether, to give 1-ethynyl
vinylbenzene (60 mg, 47% yield) as a yellow oil.
18253141_1 (GHMatters) P111789.NZ
Compound 310 (formic acid salt) was prepared as a white solid from Compound 101-K and 1-
ethynylvinylbenzene by utilizing methods analogous to those described in Examples 53 and 27. LCMS
(Method 5-95 AB, ESI): t = 0.692 min, [M + H] = 898.6; H NMR (400 MHz, MeOH-d ) δ 8.14 (brs,
3H), 7.63 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.30-7.09 (m, 4H), 6.93 (s, 1H), 6.84-6.75 (m, 2H),
6.42 (s, 1H), 5.93 (d, J=17.6 Hz, 1H), 5.38 (d, J=11.2 Hz, 1H), 5.23-5.19 (m, 1H), 4.81-4.77 (m, 2H), 4.34-
4.22 (m, 4H), 4.20 (s, 2H), 3.49-3.46 (m, 1H), 3.20-3.09 (m, 7H), 3.01 (s, 3H), 2.54 (s, 6H), 2.30-2.24 (m,
1H), 2.22-2.13 (m, 1H), 1.36 (d, J=7.2 Hz, 3H).
Example 111: Synthesis of Compound 311
O HN
N N N O
[00793] Compound 311 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 110. LCMS (Method 5-95 AB, ESI): t = 0.741
min, [M + H] = 928.5; H NMR (400 MHz, MeOH-d ) δ 8.49 (brs, 2H), 7.59 (d, J=8.0 Hz, 2H), 7.50 (d,
J=8.0 Hz, 2H), 7.32-7.17 (m, 3H), 7.10 (d, J=8.4 Hz, 1H), 6.92 (brs, 1H), 6.84-6.80 (m, 1H), 6.24 (s, 1H),
.38-5.34 (m, 1H), 4.83-4.76 (m, 2H), 4.28-4.18 (m, 4H), 4.20 (s, 2H), 3.38-3.08 (m, 8H), 3.01 (s, 3H),
2.52 (s, 6H), 2.28-2.23 (s, 1H), 2.20-2.16 (m, 2H), 1.35 (s, 9H), 1.33 (d, J=6.8 Hz, 3H).
Example 112: Synthesis of Compound 312
+ N N
Ph PiPr I
O HN
tBuOK, THF N N N
Step 1
Step 1: Typical Wittig condition (as described in Example 12) was applied to 1-(4-
bromophenyl)ethanone to give 1-bromo(3-methylbutenyl)benzene as a colorless oil.
[00795] Compound 312 (formic acid salt) was prepared as a white solid from Compound 101-K and 1-
bromo(3-methylbutenyl)benzene by utilizing methods analogous to those described in Example
110. LCMS (Method 5-95 AB, ESI): t = 0.752 min, [M + H] = 940.6; H NMR (400 MHz, MeOH-d ) δ
8.49 (brs, 2H), 7.61 (d, J=8.0 Hz, 2H), 7.31-7.18 (m, 5H), 7.09 (d, J=8.4 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H),
6.83 (s, 1H), 6.42 (s, 1H), 5.23-5.19 (m, 1H), 4.83-4.78 (m, 2H), 4.25-4.19 (m, 4H), 4.20 (s, 2H), 3.48-3.45
(m, 1H), 3.20-3.08 (m, 7H), 3.00 (s, 3H), 2.54 (s, 6H), 2.29-2.24 (m, 1H), 2.20-2.12 (m, 1H), 1.98 (s, 3H),
1.85 (s, 3H), 1.61 (s, 3H), 1.36 (d, J=6.4 Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 113: Synthesis of Compound 313
Ph3PiPr I
O HN
THF H H
tBuOK,
N N N O
Step
Step 1: Typical Wittig condition (as described in Example 12) was applied to 4-
bromobenzaldehyde to give 1-bromo(3-methylbutenyl)benzene as a colorless oil. H NMR (400
MHz, CDCl ) δ 7.44 (d, J=8.0 Hz, 2H), 7.10 (d, J=8.0 Hz, 2H), 1.90 (s, 3H), 1.85 (s, 3H).
Compound 313 (formic acid salt) was prepared as a white solid from Compound 101-K and 1-
bromo(3-methylbutenyl)benzene by utilizing methods analogous to those described in Example
110. LCMS (Method 5-95 AB, ESI): t = 0.728 min, [M + H] = 926.6; H NMR (400 MHz, MeOH-d ) δ
8.45 (brs, 1H), 7.60 (d, J=8.0 Hz, 2H), 7.36-7.17 (m, 5H), 7.09 (d, J=8.4 Hz, 1H), 6.91 (brs, 1H), 6.79 (brs,
1H), 6.43 (s, 1H), 6.32 (s, 1H), 5.24-5.18 (m, 1H), 4.83-4.78 (m, 2H), 4.34-4.17 (m, 6H), 3.49-3.46 (m,
1H), 3.26-3.07 (m, 7H), 3.00 (s, 3H), 2.52 (s, 6H), 2.32-2.24 (m, 1H), 2.19-2.14 (m, 1H), 1.95 (s, 3H), 1.91
(s, 3H), 1.36 (d, J=6.8 Hz, 3H).
Example 114: Synthesis of Compound 314
Ph PMe I
O HN
tBuOK, THF
N N N
Step 1
[00798] Step 1: Typical Wittig condition (as described in Example 12) was applied to 1-(4-
bromophenyl)ethanone to give 1-bromo(propenyl)benzene as a colorless oil. H NMR (400
MHz, CDCl ) δ 7.45 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 5.36 (s, 1H), 5.11 (s, 1H), 2.13 (s, 3H).
Compound 314 (formic acid salt) was prepared as a white solid from Compound 101-K and 1-
bromo(propenyl)benzene by utilizing methods analogous to those described in Example 110.
LCMS (Method 5-95 AB, ESI): t = 0.730 min, [M + H] = 912.4; H NMR (400 MHz, MeOH-d ) δ 7.65-
7.57 (m, 3H), 7.39-7.05 (m, 5H), 6.93 (brs, 1H), 6.84 (brs, 1H), 6.42 (brs, 1H), 5.51 (s, 1H), 5.23-5.19 (m,
1H), 4.82-4.77 (m, 2H), 4.35-4.18 (s, 6H), 3.48-3.35 (m, 3H), 3.28-3.07 (m, 5H), 3.00 (s, 3H), 2.54 (s, 3H),
2.23-2.12 (m, 9H), 1.36 (d, J=6.4 Hz, 3H).
Example 115: Synthesis of Compound 315
Cl N NH
N N N
° O HN
N N NaOH
EtOH, 80 C H H
N N N O
N OH
Step 2
1 O O
Step
18253141_1 (GHMatters) P111789.NZ
Step 1: A mixture of methyl 2-chloro-4,6-dimethylpyrimidinecarboxylate (described in
Example 53) (150 mg, 0.75 mmol) and 4-(tert-butyl)piperidine (158 mg, 1.1 mmol) in EtOH (10 mL) was
stirred at 80 C for 2 h. The volatiles were removed and the residue was purified by preparatory-TLC (20%
EtOAc in petroleum ether, R = 0.6) to give methyl 2-(4-(tert-butyl)piperidinyl)-4,6-dimethylpyrimidine-
5-carboxylate (140 mg, 61% yield) as a yellow oil. LCMS (Method 5-95 AB, ESI): t = 0.987 min, [M +
H] = 306.0.
Step 2: Typical ester hydrolysis conditions (NaOH, MeOH/H O, described in Example H) were
applied to methyl 2-(4-(tert-butyl)piperidinyl)-4,6-dimethylpyrimidinecarboxylate to give 2-(4-(tert-
butyl)piperidinyl)-4,6-dimethylpyrimidinecarboxylic acid as a white solid.
[00802] Compound 315 (formic acid salt) was prepared as a white solid from Compound 101-K and 2-
(4-(tert-butyl)piperidinyl)-4,6-dimethylpyrimidinecarboxylic acid by utilizing methods analogous to
those described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.713 min, [M + H] = 911.8; H NMR
(400 MHz, MeOH-d ) δ 8.49 (brs, 4H), 7.25 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.4 Hz, 1H), 7.11 (d, J=8.4 Hz,
1H), 6.88 (s, 1H), 6.72 (s, 1H), 6.49 (s, 1H), 5.20-5.15 (m, 1H), 4.85-4.75 (m, 2H), 4.35-4.20 (m, 6H),
3.30-3.26 (m, 1H), 3.26-3.20 (m, 4H), 3.18-3.08 (m, 3H), 2.98 (s, 3H), 2.80-2.60 (m, 4H), 2.27 (s, 6H),
2.26-2.20 (m, 1H), 2.18-2.10 (m, 1H), 1.64-1.56 (m, 2H),1.36 (d, J=6.8 Hz, 3H), 1.32-1.05 (m, 3H), 0.89
(s, 9H).
Example 116: Synthesis of Compound 316
N N N
O HN
N N N O
[00803] Compound 316 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 315. LCMS (Method 5-95 AB, ESI): t = 0.532
min, [M + H] = 883.4; H NMR (400 MHz, MeOH-d ) δ 8.45 (brs, 2H), 7.26 (d, J=8.4 Hz, 2H), 7.19 (d,
J=8.4 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 6.89 (s, 1H), 6.77 (s, 1H), 6.43 (s, 1H), 5.17-5.10 (m, 1H), 4.80-
.75 (m, 2H), 4.30-4.19 (m, 4H), 4.21 (s, 2H), 4.07-4.04 (m, 2H), 3.90-3.88 (m, 2H), 3.25-3.20 (m, 4H),
3.19-3.07 (m, 4H), 2.97 (s, 3H), 2.62-2.60 (m, 1H), 2.31 (s, 6H), 2.27-2.22 (m, 1H), 2.16-2.10 (m, 1H),
1.35 (d, J=7.2 Hz, 3H), 0.94 (s, 9H).
Example 117: Synthesis of Compound 317
HO O
NH O
Cl N
N N N
O HN
EtOH, DIPEA H H
N OMe
N N N O
NaH, H Br
2) 5 11 N O
NaOH N
O OH
Step 1
18253141_1 (GHMatters) P111789.NZ
Step 1: Starting from methyl 2-chloro-4,6-dimethylpyrimidinecarboxylate, described in
Example 53, typical S Ar (as described in Example 315), alkylation (as described in Example 38) and
ester hydrolysis (as described in Example H) conditions were followed to give 4,6-dimethyl(4-
(pentyloxy)piperidinyl)pyrimidinecarboxylic acid as a white solid.
[00805] Compound 317 (formic acid salt) was prepared as a white solid from Compound 101-K and 4,6-
dimethyl(4-(pentyloxy)piperidinyl)pyrimidinecarboxylic acid by utilizing methods analogous to
those described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.592 min, [M + H] = 941.4; H NMR
(400 MHz, MeOH-d ) δ 8.36 (brs, 4H), 7.26-7.20 (m, 3H), 7.11 (d, J=8.0, 1H), 6.88 (brs, 1H), 6.73 (s, 1H),
6.47 (s, 1H), 5.19-5.16 (m, 1H), 4.85-4.78 (m, 2H), 4.31-4.21 (m, 8H), 3.55-3.50 (m, 3H), 3.25-3.09 (m,
8H), 2.97 (s, 3H), 2.26 (s, 6H), 2.24-2.11 (m, 3H), 1.88-1.85 (m, 2H), 1.58-1.56 (m, 2H), 1.43-1.34
(m,11H), 0.93 (s, 3H).
Example 118: Synthesis of Compound 318
BocN
TFA/DCM N N N
BINAP,Pd(OAc)2
O HN
KOAc, toluene
N N N O
NBoc
step 1
step 2
Step 1: A mixture of 1-bromo(tert-butyl)benzene (550 mg, 2.6 mmol), tert-butyl piperazine-
1-carboxylate (577 mg, 3.1 mmol), Pd(OAc) (23 mg, 0.10 mmol), BINAP (1.6 g, 2.6 mmol) and Cs CO
2 2 3
(1.23 g, 3.9 mmol) in toluene (10 mL) was stirred at 90 C for 16 h. The volatiles were removed and the
residue was re-dissolved with EtOAc (50 mL), which was washed with brine (50 mL). The organic layer
was dried over Na SO , concentrated and the residue was purified by silica gel chromatography, eluting
with 5% EtOAc in petroleum ether, to give tert-butyl 4-(4-(tert-butyl)phenyl)piperazinecarboxylate
(300 mg, 37% yield) as a yellow solid. LCMS (Method 5-95 AB, ESI): t = 0.872 min, [M + H] = 318.9.
Step 2: A solution of tert-butyl 4-(4-tert-butylphenyl)piperazinecarboxylate (300 mg, 0.94
mmol) in 20% TFA in DCM (15 mL) was stirred at 20 C for 16 h. The volatiles were removed under
reduced pressure and the residue was treated with saturated aqueous NaHCO until pH>7, which was then
extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried
over Na SO and concentrated to give 1-(4-tert-butylphenyl)piperazine (200 mg, 97% yield) as a yellow
solid.
Compound 318 (formic acid salt) was prepared as a white solid from Compound 101-K and 1-
(4-(tert-butyl)phenyl)piperazine by utilizing methods analogous to those described in Example 315. LCMS
(Method 5-95 AB, ESI): t = 0.724 min, [M + H] = 988.6; H NMR (400 MHz, MeOH-d ) δ 8.49 (br s,
2H), 7.31 (d, J=8.4 Hz, 2H), 7.28-7.18 (m, 3H), 7.10 (d, J=8.4 Hz, 1H), 6.96 (d, J=8.4 Hz, 2H), 6.88 (s,
1H), 6.71 (s, 1H), 6.48 (s, 1H), 5.20-5.16 (m, 1H), 4.81-4.77 (m, 2H), 4.30 (s, 2H), 4.22 (brs, 4H), 3.93
(brs, 4H), 3.28-3.05 (m, 8H), 2.98 (s, 3H), 2.29 (s, 6H), 2.20-2.12 (m, 1H), 2.09-2.02 (m, 1H), 1.36 (d,
J=6.8 Hz, 3H), 1.30 (s, 9H).
18253141_1 (GHMatters) P111789.NZ
Example 119: Synthesis of Compound 319
Cl N O
O N N N
O HN
NaH, DMF
O 1) H H
N N N
NaOH N
2) O
NH N OH
Step
Step 1: Starting from 4-(tert-butyl)pyridin-2(1H)-one and methyl 2-chloro-4,6-
dimethylpyrimidinecarboxylate (described in Example 53), typical alkylation (as described in Example
315) and ester hydrolysis (described in Example H) conditions were applied to give 2-(4-(tert-butyl)
oxopyridin-1(2H)-yl)-4,6-dimethylpyrimidinecarboxylic acid as a white solid. LCMS (Method 5-95 AB,
ESI): t = 0.378 min, [M + H] = 302.1.
Compound 319 (formic acid salt) was prepared as a white solid from Compound 101-K and 2-
(4-(tert-butyl)oxopyridin-1(2H)-yl)-4,6-dimethylpyrimidinecarboxylic acid by utilizing methods
analogous to those described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.644 min, [M + H] =
921.6; H NMR (400 MHz, MeOH-d ) δ 8.48 (brs, 3H), 7.68 (d, J=8.0 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H),
7.26-7.17 (m, 2H), 7.10 (d, J=8.0 Hz, 1H), 6.92 (s, 1H), 6.78 (s, 1H), 6.63 (d, J=8.0 Hz, 1H), 6.57 (s, 1H),
6.45 (s, 1H), 5.26-5.23 (m, 1H), 4.81-4.74 (m, 2H), 4.30-4.19 (m, 6H), 3.22-3.10 (m, 8H), 3.01 (s, 3H),
2.55 (s, 6H), 2.35-2.25 (m, 1H), 2.22-2.12 (m, 1H), 1.36 (d, J=6.8 Hz, 3H), 1.33 (s, 9H).
Example 120: Synthesis of Compound 320
NH N N
Pd N N
s-phos, 2(dba)3 NaOH
O HN
N OMe
N N N O
N OMe N OH
step 1
step 2
Step 1: A mixture of methyl 2-(4-chlorophenyl)-4,6-dimethylpyrimidinecarboxylate (120 mg,
0.43 mmol) and 4-(tert-butyl)piperidine (780 mg, 0.56 mmol), Pd (dba) (20 mg, 0.02 mmol), 2-
dicyclohexylphosphino-2’,6’-dimethoxybiphenyl (18 mg, 0.04 mmol) and t-BuONa (62.5 mg, 0.65
mmol) in toluene (8 mL) was stirred for at 100 C for 24 h under N . The volatiles were removed under
reduced pressure and the residue was purified by preparatory-TLC (eluting with 20% EtOAc in petroleum
ether) to give methyl 2-(4-(4-(tert-butyl)piperidinyl)phenyl)-4,6-dimethylpyrimidinecarboxylate (80
mg, 48% yield) as a yellow solid.
Step 2: Typical ester hydrolysis conditions (NaOH, MeOH/H O) as described in Example H
were applied to methyl 2-(4-(4-(tert-butyl)piperidinyl)phenyl)-4,6-dimethylpyrimidinecarboxylate to
give 2-(4-(4-(tert-butyl)piperidinyl)phenyl)-4,6-dimethylpyrimidinecarboxylic acid as a white solid.
Compound 320 (formic acid salt) was prepared as a white solid from Compound 101-K and 2-
(4-(4-(tert-butyl)piperidinyl)phenyl)-4,6-dimethylpyrimidinecarboxylic acid by utilizing methods
analogous to those described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.924 min, [M + H] =
987.6; H NMR (400 MHz, MeOH-d ) δ 8.50 (brs, 2H), 8.18-8.14 (m, 2H), 7.31-7.26 (m, 1H), 7.25-7.20
18253141_1 (GHMatters) P111789.NZ
(m, 1H), 7.18-7.07 (m, 2H), 6.98 (d, J=8.4 Hz, 2H), 6.88 (brs, 1H), 6.66 (brs, 1H), 6.54 (s, 1H), 5.28-5.21
(m, 1H), 4.83-4.75 (m, 2H), 4.35-4.19 (m, 4H), 4.23(s, 2H), 4.03-3.93 (m, 2H), 3.29-3.07 (m, 8H), 3.01 (s,
3H), 2.80-2.69 (m, 2H), 2.47 (s, 6H), 2.32-2.21 (m, 1H), 2.19-2.10 (m, 1H), 1.89-1.81 (m,, 2H), 1.50-1.40
(m, 2H), 1.35 (d, J=6.8 Hz, 3H), 1.30-1.25 (m, 1H), 0.93 (s, 9H).
Example 121: Synthesis of Compound 321
O HN
N N N O
Compound 321 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 120. LCMS (Method 5-95 AB, ESI): t = 0.690
min, [M + H] = 917.5; H NMR (400 MHz, MeOH-d ) δ 8.51 (brs, 3H), 8.20-8.10 (m, 2H), 7.30-7.15 (m,
3H), 7.09 (d, J=8.4 Hz, 1H), 6.88 (s, 1H), 6.69 (s, 1H), 6.60 (d, J=8.4 Hz, 2H), 6.52 (s, 1H), 5.30-5.20 (m,
1H), 4.85-4.75 (m, 2H), 4.30-4.15 (m, 6H), 3.45-3.35 (m, 5H), 3.26-3.05 (m, 7H), 3.01 (s, 3H), 2.46 (s,
6H), 2.30-2.25 (m, 1H), 2.20-2.05 (m, 5H), 1.35 (d, J=6.4 Hz, 3H).
Example 122: Synthesis of Compound 322
O HN
N N N O
[00815] Compound 322 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 120. LCMS (Method 5-95 AB, ESI): t = 0.693
min, [M + H] = 967.6; H NMR (400 MHz, MeOH-d ) δ 8.49 (brs, 1H), 8.24 (d, J=8.4 Hz, 2H), 7.31-7.25
(m, 1H), 7.24-7.13 (m, 2H), 7.11-7.02 (m, 3H), 6.88 (s, 1H), 6.70 (brs, 1H), 6.49 (s, 1H), 5.26-5.21 (m,
1H), 4.80-4.77 (m, 2H), 4.32-4.16 (m, 4H), 4.22 (s, 2H), 3.56-3.51 (m, 4H), 3.30-3.04 (m, 8H), 3.00 (s,
3H), 2.48 (s, 6H), 2.35-2.02 (m, 6H), 1.35 (d, J=6.4 Hz, 3H).
Example 123: Synthesis of Compound 323
O HN
N N N O
Compound 323 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 120. LCMS (Method 5-95 AB, ESI): t = 0.651
min, [M + H] = 903.3; H NMR (400 MHz, MeOH-d ) δ 8.09 (brs, 2H), 7.34-7.06 (m, 5H), 6.87 (s, 1H),
6.65-6.38 (m, 5H), 5.30-5.24 (m, 1H), 4.84-4.81 (m, 2H), 4.43-4.23 (m, 6H), 4.04-3.94 (m, 4H), 3.33-3.10
(m, 5H), 3.02 (brs, 6H), 2.43 (s, 6H), 2.40-2.35 (m, 2H), 2.32-2.11 (m, 2H), 1.35 (d, J=6.8 Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 124: Synthesis of Compound 324
O HN
N N N O
Compound 324 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 120. LCMS (Method 5-95 AB, ESI): t = 0.950
min, [M + H] = 931.5; H NMR (400 MHz, MeOH-d ) δ 8.51 (brs, 2H), 8.10 (d, J=8.4 Hz, 2H), 7.26 (brs,
2H), 7.09 (brs, 2H), 6.94 (d, J=8.4 Hz, 2H), 6.86 (s, 1H), 6.61 (brs, 1H), 6.57 (brs, 1H), 5.31-5.27 (m, 1H)
4.85-4.78 (m, 2H), 4.35 (s, 2H), 4.25 (brs, 4H), 3.37-3.34 (m,4H), 3.28-3.10 (m, 6H), 3.05-2.93 (m, 2H),
3.02 (s, 3H), 2.42 (s, 6H), 2.34-2.23 (m, 1H), 2.20-2.10 (m, 1H), 1.76-1.66 (m, 6H), 1.35 (d, J=6.8 Hz, 3H).
Example 125: Synthesis of Compound 325
O HN
N N N O
Compound 325 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 120. LCMS (Method 5-95 AB, ESI): t = 0.719
min, [M + H] = 945.5; H NMR (400 MHz, MeOH-d ) δ 8.50 (brs, 1H), 8.02-7.98 (m, 2H), 7.28-7.24 (m,
2H), 7.13- 6.99 (m, 2H), 6.83 (brs, 1H), 6.75-6.60 (m, 3H), 6.50 (brs, 1H), 5.35-5.25 (m, 1H), 4.78-4.75
(m, 2H), 4.27 (s, 2H), 4.25- 4.18 (m, 4H), 3.62-3.58 (m, 4H), 3.31-3.26 (m, 4H), 3.25-3.21 (m, 2H), 3.15-
3.11 (m, 2H), 3.02 (s, 3H), 2.37 (s, 6H), 2.30-2.25 (m, 1H), 2.21-2.09 (m, 1H), 1.86 (brs, 4H), 1.61 (brs,
4H), 1.34 (d, J=6.8 Hz, 3H).
Example 126: Synthesis of Compound 326
O HN
N N N
[00819] Compound 326 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 120. LCMS (Method 5-95 AB, ESI): t = 0.615
min, [M + H] = 959.6; H NMR (400 MHz, MeOH-d ) δ 8.23 (brs, 2H), 8.22-8.18 (m, 2H), 7.39-6.86 (m,
6H), 6.79-6.59 (m, 2H), 6.49 (s, 1H), 5.29-5.11 (m, 1H), 4.75-4.67 (m, 2H), 4.39-4.04 (m, 6H), 3.64-3.55
(m, 4H), 3.30-2.83 (m,11H), 2.50 (s, 6H), 2.35-2.06 (m, 2H), 1.81 (brs, 4H), 1.55 (brs, 4H), 1.45-1.39 (m,
2H), 1.36 (t, J=7.2 Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 127: Synthesis of Compound 327
O HN
N N N O
Compound 327 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 120. LCMS (Method 5-95 AB, ESI): t = 0.681
min, [M + H] = 959.7; H NMR (400 MHz, MeOH-d ) δ 8.41 (brs, 2H), 8.25 (d, J=8.0 Hz, 2H), 7.30-7.10
(m, 4H), 7.00 (d, J=8.4 Hz, 2H), 6.91 (s, 1H), 6.79 (s, 1H), 6.44 (s, 1H), 5.24-5.20 (m, 1H), 4.85-4.75 (m,
2H), 4.36-4.18 (m, 8H), 3.90-3.82 (m, 2H), 3.29-3.22 (m, 6H), 3.16-3.11 (m, 2H), 3.01 (s, 3H), 2.52 (s,
6H), 2.40-2.25 (m, 3H), 2.20-2.10 (m, 1H), 1.90-1.83 (m, 1H), 1.80-1.72 (m, 2H), 1.36 (d, J=6.4 Hz, 3H),
0.98 (d, J=6.4 Hz, 6H), 0.87-0.74 (m, 1H).
Example 128: Synthesis of Compound 328
O HN
N N N O
Compound 328 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 53. LCMS (Method 5-95 AB, ESI): t = 0.667
min, [M + H] = 934.6; H NMR (400 MHz, MeOH-d ) δ 8.15 (d, J=8.0 Hz, 2H), 7.26 (brs, 2H), 7.15-7.05
(m, 2H), 6.94 (d, J=8.4 Hz, 2H), 6.85 (s, 1H), 6.62 (s, 1H), 6.51 (s, 1H), 5.35-5.25 (m, 1H), 4.80-4.70 (m,
2H), 4.27 (s, 2H), 4.25-4.15 (m, 4H), 4.06 (t, J=6.8 Hz, 2H), 3.40-3.35 (m, 1H), 3.30-2.85 (m, 10H), 2.42
(s, 6H), 2.35-2.25 (m, 1H), 2.25-2.15 (m, 1H), 1.85-1.75 (m, 2H), 1.55-1.40 (m, 4H), 1.35 (d, J=6.4 Hz,
3H), 0.98 (t, J=7.2 Hz, 3H).
Example 129: Synthesis of Compound 329
O HN
N N N
Compound 329 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 53. LCMS (Method 5-95 AB, ESI): t = 0.740
min, [M + H] = 934.5; H NMR (400 MHz, MeOH-d ) δ 8.47 (brs, 1H), 8.25-8.18 (m, 2H), 7.28-7.22 (m,
2H), 7.10 (brs, 2H), 6.95 (d, J=8.4 Hz, 2H), 6.86 (brs, 1H), 6.57 (brs, 1H), 5.29-5.25 (m, 1H), 4.85-4.75 (m,
2H), 4.38-4.22 (m, 6H), 4.10 (t, J=6.8 Hz, 2H), 3.27-3.05 (m, 8H), 3.01 (s, 3H), 2.48 (s, 6H), 2.34-2.24 (m,
1H), 2.21-2.10 (m, 1H), 1.95-1.82 (m, 1H), 1.75-1.63 (m, 2H), 1.35 (d, J=6.8 Hz, 3H), 1.00 (d, J=6.4 Hz,
6H).
18253141_1 (GHMatters) P111789.NZ
Example 130: Synthesis of Compound 330
O HN
N N N O
Compound 330 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 53. LCMS (Method 5-95 AB, ESI): t = 0.698
min, [M + H] = 906.4; H NMR (400 MHz, MeOH-d ) δ 8.49 (brs, 2H), 8.18 (d, J=8.0 Hz, 2H), 7.30-7.22
(m, 2H), 7.09 (brs, 2H), 6.95 (d, J=8.4 Hz, 2H), 6.86 (s, 1H), 6.60 (brs, 1H), 6.56 (brs, 1H), 5.35-5.25 (m,
1H), 4.85-4.70 (m, 2H), 4.37 (s, 2H), 4.30-4.15 (m, 4H), 4.03 (t, J=6.4 Hz, 2H), 3.25-2.90 (m, 8H), 3.02 (s,
3H), 2.44 (s, 6H), 2.35-2.20 (m, 1H), 2.20-2.10 (m, 1H), 1.90-1.80 (m, 2H), 1.35 (d, J=6.8 Hz, 3H), 1.09 (t,
J=7.6 Hz, 3H).
Example 131: Synthesis of Compound 331
O HN
N N N O
Compound 331 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 53. LCMS (Method 5-95 AB, ESI): t = 0.724
min, [M + H] = 920.4; H NMR (400 MHz, MeOH-d ) δ 8.50 (brs, 3H), 8.13 (d, J=7.6 Hz, 2H), 7.26 (brs,
2H), 7.15-7.00 (m, 2H), 6.93 (d, J=8.4 Hz, 2H), 6.84 (s, 1H), 6.65 (s, 1H), 6.48 (s, 1H), 5.35-5.25 (m, 1H),
4.85-4.70 (m, 2H), 4.28 (s, 3H), 4.30-4.15 (m, 4H), 4.07 (t, J=6.4 Hz, 2H), 3.40-2.90 (m, 8H), 3.02 (s, 3H),
2.41 (s, 6H), 2.35-2.25 (m, 1H), 2.20-2.10 (m, 1H), 1.85-1.75 (m, 2H), 1.60-1.50 (m, 2H), 1.35 (d, J=6.8
Hz, 3H), 1.03 (t, J=6.8 Hz, 3H).
Example 132: Synthesis of Compound 332
O HN
N N N O
Compound 332 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 53. LCMS (Method 5-95 AB, ESI): t = 0.780
min, [M + H] = 948.7; H NMR (400 MHz, MeOH-d ) δ 8.50 (brs, 3H), 8.19 (d, J=8.0 Hz, 2H), 7.26 (brs,
2H), 7.09 (brs, 2H), 6.95 (d, J=8.8 Hz, 2H), 6.86 (s, 1H), 6.60 (brs, 1H), 6.56 (brs, 1H), 5.32-5.25 (m, 1H),
4.81-4.71 (m, 2H), 4.37 (s, 2H), 4.30-4.21 (m, 4H), 4.06 (t, J=6.4 Hz, 2H), 3.25-2.95 (m, 8H), 3.02 (s, 3H),
2.44 (s, 6H), 2.30-2.15 (m, 2H), 1.87-1.79 (m, 2H), 1.57-1.48 (m, 2H), 1.47-1.24 (m, 7H), 0.95 (t, J=6.4
Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 133: Synthesis of Compound 333
O HN
N N N O
Compound 333 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 53. LCMS (Method 5-95 AB, ESI): t = 0.502
min, [M + H] = 922.4; H NMR (400 MHz, MeOH-d ) δ 8.24 (d, J=8.0 Hz, 2H), 7.29-7.20 (m, 2H), 7.16-
7.05 (m, 2H), 6.99 (d, J=8.0 Hz, 2H), 6.87 (s, 1H), 6.62 (s, 1H), 6.55 (s, 1H), 5.31-5.24 (m, 1H), 4.85-4.76
(m, 2H), 4.40-4.17 (m, 8H), 3.79 (t, J=4.0 Hz, 2H), 3.46 (s, 3H), 3.28-2.95 (m, 8H), 3.01 (s, 3H), 2.47 (s,
6H), 2.34-2.25 (m, 1H), 2.19-2.10 (m, 1H), 1.35 (t, J=6.8 Hz, 2H).
Example 134: Synthesis of Compound 334
O O HN
N N N O
Compound 334 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 53. LCMS (Method 5-95 AB, ESI): t = 0.640
min, [M + H] = 906.6; H NMR (400 MHz, MeOH-d ) δ 8.49 (brs, 2H), 7.90-7.75 (m, 2H), 7.40-7.02 (m,
4H), 6.95-6.80 (m, 2H), 6.67 (brs, 1H), 6.49 (brs, 1H), 5.30-5.20 (m, 1H), 4.79-4.75 (m, 1H), 4.40-4.10 (m,
11H), 3.25-3.10 (m, 8H), 3.00 (s, 3H), 2.47 (s, 6H), 2.35-2.15 (m, 1H), 2.15-2.05 (m, 1H), 1.35 (d, J=6.8
Hz, 3H).
Example 135: Synthesis of Compound 335
HO O
O HN
K CO , DMF
N N N
Step 1
Step 1: A mixture of 4-bromophenol (500 mg, 2.9 mmol), bromocyclobutane (585 mg, 4.4
mmol) and K CO (800 mg, 5.8 mmol) in DMF (2 mL) was stirred at 80 C for
16 h. The volatiles were removed under reduced pressure and the residue was taken up in EtOAc (50 mL),
which was washed with brine (50 mL). The organic layer was dried over MgSO , concentrated and the
residue was purified by preparatory-TLC (eluting with 5% EtOAc in petroleum ether, R =0.3) to afford 1-
bromocyclobutoxybenzene (400 mg, 61% yield) as a colorless oil. H NMR (400 MHz, MeOH-d ) δ
7.35 (d, J=8.0 Hz, 2H), 6.70 (d, J=8.0 Hz, 2H), 4.65-4.55 (m, 1H), 2.47-2.43 (m, 2H), 2.19-2.13 (m, 2H),
1.85-1.75 (m, 1H), 1.70-1.60 (m, 1H).
18253141_1 (GHMatters) P111789.NZ
Compound 335 (formic acid salt) was prepared as a white solid from Compound 101-K and 1-
bromocyclobutoxybenzene by utilizing methods analogous to those described in Example 53. LCMS
(Method 5-95 AB, ESI): t = 0.687 min, [M + H] = 918.7; H NMR (400 MHz, MeOH-d ) δ 8.49 (brs,
2H), 8.25 (brs, 2H), 7.30-7.20 (m, 2H), 7.17-7.06 (m., 2H), 6.88 (brs, 3H), 6.67 (brs, 1H), 6.52 (s, 1H),
5.27-5.23 (m, 1H), 4.84-4.73 (m, 3H), 4.35-4.19 (m, 6H), 3.25-3.00 (m, 11H), 2.58- 2.45 (m, 2H), 2.49 (s,
6H), 2.36-2.09 (m, 5H), 1.96-1.86 (m, 1H), 1.82-1.73 (m, 1H), 1.35 (d, J=6.8 Hz, 3H).
Example 136: Synthesis of Compound 336
O HN
N N N O
Compound 336 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 135. LCMS (Method 5-95 AB, ESI): t = 0.714
min, [M + H] = 932.3; H NMR (400 MHz, MeOH-d ) δ 8.50 (brs, 3H), 8.14 (d, J=8.0 Hz, 2H), 7.26 (brs,
2H), 7.15-7.00 (m, 2H), 6.90 (d, J=8.4 Hz, 2H), 6.84 (s, 1H), 6.63 (s, 1H), 6.51 (s, 1H), 5.35-5.25 (m, 1H),
4.85-4.70 (m, 3H), 4.39 (s, 2H), 4.25-4.15 (m, 4H), 3.40-3.10 (m, 5H), 3.02 (s, 3H), 3.00-2.85 (m, 2H),
2.42 (s, 6H), 2.35-2.20 (m, 1H), 2.20-2.10 (m, 1H), 2.10-1.95 (m, 2H), 1.95-1.80 (m, 4H), 1.80-1.65 (m,
2H), 1.35 (d, J=6.8 Hz, 3H).
Example 137: Synthesis of Compound 337
O HN
N N N
Compound 337 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 135. LCMS (Method 5-95 AB, ESI): t = 0.730
min, [M + H] = 946.6; H NMR (400 MHz, MeOH-d ) δ 8.50 (brs, 3H), 8.15 (d, J=8.0 Hz, 2H), 7.26 (brs,
2H), 7.10-7.00 (m, 2H), 6.93 (d, J=8.4 Hz, 2H), 6.84 (s, 1H), 6.62 (s, 1H), 6.52 (s, 1H), 5.35-5.25 (m, 1H),
4.85-4.70 (m, 2H), 4.50-4.30 (m, 3H), 4.25 (brs, 4H), 3.40-3.10 (m, 5H), 3.02 (s, 3H), 3.00-2.85 (m, 2H),
2.42 (s, 6H), 2.35-2.20 (m, 1H), 2.20-2.10 (m, 1H), 2.10-2.00 (m, 2H), 1.90-1.80 (m, 2H), 1.70-1.40 (m,
6H), 1.35 (d, J=6.8 Hz, 3H).
Example 138: Synthesis of Compound 338
O HN
N N N O
18253141_1 (GHMatters) P111789.NZ
Compound 338 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 135. LCMS (Method 5-95 AB, ESI): t = 0.767
min, [M + H] = 948.5; H NMR (400 MHz, MeOH-d ) δ 8.49 (brs, 2H), 8.29 (d, J=8.0 Hz, 2H), 7.29 (d,
J=8.0 Hz, 1H), 7.24-7.13 (m, 2H), 7.09 (d,J=8.0 Hz, 1H), 6.99 (d, J=8.0 Hz, 2H), 6.89 (s, 1H), 6.70 (s, 1H),
6.50 (s, 1H), 5.27-5.23 (m, 1H), 4.81-4.75 (m, 2H), 4.29 (s, 2H), 4.25-4.20 (m, 4H), 4.14 (t, J=7.2 Hz, 2H),
3.24-3.11 (m, 8H), 3.01 (s, 3H), 2.50 (s, 6H), 2.34-2.22 (m,1H), 2.21-2.09 (m,1H), 1.77 (t, J=7.2 Hz, 2H),
1.35(d, J=6.4 Hz, 3H), 1.04 (s, 9H).
Example 139: Synthesis of Compound 339
O HN
N N N O
[00833] Compound 339 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 135. LCMS (Method 5-95 AB, ESI): t = 0.612
min, [M + H] = 934.4; H NMR (400 MHz, MeOH-d ) δ 8.51 (brs, 3H), 8.24 (d, J=8.0 Hz, 1H), 8.14 (d,
J=8.0 Hz, 1H), 7.28-7.24 (m, 2H), 7.11-6.88 (m, 6H), 6.67 (s, 0.5H), 6.61 (0.5H), 5.34-5.29 (m, 1H), 4.80-
4.77 (m, 2H), 4.37-4.22 (m, 7H), 3.36-3.00 (m, 11H), 2.50 (s, 3H), 2.43 (s, 3H), 2.34-2.18 (m, 2H), 1.77-
1.72 (m, 4H) 1.45-1.35 (m, 3H), 1.04-1.00 (m, 6H).
Example 140: Synthesis of Compound 340
O HN
N N N O
Compound 340 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 135. LCMS (Method 5-95 AB, ESI): t = 0.618
min, [M + H] = 960.3; H NMR (400 MHz, MeOH-d ) δ 8.52 (brs, 2H), 8.11 (d, J=8.0 Hz, 2H), 7.26 (brs,
2H), 7.07 (d, J=8.0 Hz, 1H), 7.02-6.96 (m, 1H), 6.86 (d, J=8.4 Hz, 2H), 6.82 (s,1H), 6.67 (s, 1H), 6.44 (s,
1H), 5.33-5.30 (m, 1H), 4.79-4.74 (m, 2H), 4.63-4.56 (m, 1H), 4.37 (s, 2H), 4.26-4.23 (m, 4H), 3.27-3.00
(m, 8H), 3.02 (s, 3H), 2.38 (s, 6H), 2.32-2.26 (m, 1H), 2.11-2.03 (m, 3H), 1.88-1.77 (m, 5H), 1.68-1.65 (m,
5H), 1.57-1.53 (m, 2H), 1.34 (d, J=6.4 Hz, 3H).
Example 141: Synthesis of Compound 341
O HN
N N N O
18253141_1 (GHMatters) P111789.NZ
Compound 341 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 135. LCMS (Method 5-95 AB, ESI): t = 0.789
min, [M + H] = 962.6; H NMR (400 MHz, MeOH-d ) δ 8.51 (brs, 2H), 8.22 (d, J=8.0 Hz, 1H), 7.30-7.20
(m, 2H), 7.13-7.04 (m, 2H), 6.94 (d, J=8.4 Hz, 2H), 6.87 (s, 1H), 6.61 (brs, 1H), 6.56 (brs, 1H), 5.30-5.24
(m, 1H), 4.85-4.73 (m, 2H), 4.49-4.44 (m, 1H), 4.31 (s, 2H), 4.26-4.21 (m, 4H), 3.31-2.95 (m, 8H), 3.01 (s,
3H), 2.46 (s, 6H), 2.31-2.26 (m, 1H), 2.15 -2.05 (m, 1H), 1.77-1.64 (m, 4H), 1.56-1.40 (m, 4H), 1.35 (d,
J=6.4 Hz, 3H), 0.96 (t, J=7.6 Hz, 6H).
Example 142: Synthesis of Compound 342
O HN
N N N O
[00836] Compound 342 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 50. LCMS (Method 5-95 AB, ESI): t = 0.707
min, [M + H] = 920.5; H NMR (400 MHz, MeOH-d ) δ 8.17 (d, J=8.0 Hz, 2H), 7.25 (brs, 2H), 7.11-
6.99 (m, 4H), 6.84 (s, 1H), 6.64 (s, 1H), 6.52 (s, 1H), 5.36-5.23 (m, 1H), 4.84-4.74 (m, 2H), 4.36 (s, 2H),
4.28-4.15 (m, 4H), 3.26-3.10 (m, 6H), 3.10-2.89 (m, 2H), 3.02 (s, 3H), 2.44 (s, 6H), 2.34-2.22 (m, 1H),
2.18-2.09 (m, 1H), 1.43 (s, 9H), 1.35 (d, J=7.2Hz, 3H).
Example 143: Synthesis of Compound 343
O HN
N N N O
Compound 343 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 50. LCMS (Method 5-95 AB, ESI): t = 0.706
min, [M + H] = 934.4; H NMR (400 MHz, MeOH-d ) δ 8.52 (brs, 3H), 8.35-8.29 (m, 3H), 7.49-7.43 (m,
4H), 7.30-7.27 (m, 1H), 7.11 (brs, 1H), 6.91 (s, 1H), 6.54 (s, 1H), 4.82-4.80 (m, 2H), 4.58 (brs, 4H), 4.24
(brs, 5H), 3.21-3.13 (m, 8H), 3.04 (s, 3H), 2.54 (s, 6H), 2.30-2.10 (m, 2H), 1.37 (d, J=6.8 Hz, 3H), 1.35 (s,
9H).
Example 144: Synthesis of Compound 344
HO N N
O HN
NaH H H
N N N O
Pd/C, H O
NO Br
t-BuONO, CHBr
3) 3 O O
Step 1 2
18253141_1 (GHMatters) P111789.NZ
Step 1: Starting from 1-fluoronitrobenzene, typical alkylation (using NaH as described in
Example 38), hydrogenation (using Pd/C and H as described in Example E) and Sandmyer (as described
in Example J) conditions were followed to give 1-bromo(1-methylcyclopropoxy)benzene as a yellow
solid.
[00839] Compound 344 (formic acid salt) was prepared as a white solid from Compound 101-K and 1-
bromo(1-methylcyclopropoxy)benzene by utilizing methods analogous to those described in Example
53. LCMS (Method 5-95 AB, ESI): t = 0.709 min, [M + H] = 918.5; H NMR (400 MHz, MeOH-d ) δ
8.46 (brs, 2H), 8.27 (d, J=7.6 Hz, 2H), 7.31-7.21 (m, 2H), 7.20-7.12 (m, 1H), 7.11-7.04 (m, 3H), 6.88 (s,
1H), 6.68 (s, 1H), 6.52 (s, 1H), 5.30-6.22 (m, 1H), 4.81-4.74 (m, 2H), 4.37-4.17 (m, 6H), 3.29-3.20 (m,
5H), 3.17-3.08 (m, 3H), 3.02 (s, 3H), 2.49(s, 6H), 2.34-2.24 (m, 1H), 2.21-2.11 (m, 1H), 1.59 (s, 3H), 1.36
(d, J=6.8 Hz, 3 H), 1.02-0.95 (m, 2H), 0.84-0.76 (m, 2H).
Example 145: Synthesis of Compound 345
O HN
O H H
EtMgBr, Ti(iPrO)4
N N N O
Step 1
Step 1: To a stirred solution of methyl propionate (5.0 g, 56.8 mmol) and Ti(i-PrO) (1.6 g, 5.7
mmol) in Et O (80 mL) was added EtMgBr (3N in Et O, 41.6 mL) over a period of 1 h, and the mixture
was stirred for another 10 min. The mixture was then poured into cold 10% aqueous H SO (100 mL)
while maintaining the temperature below 5 C. The resulting mixture was extracted with Et O (3 x 100
mL). The combined organic layers were washed with brine (50 mL), dried over Na SO , and concentrated
to give 1-ethylcyclopropanol (4.5 g, 92% yield) as a yellow oil. H NMR (400 MHz, CDCl ) δ 1.56 (q,
J=7.2 Hz, 2H), 1.00 (t, J=7.2 Hz, 3H), 0.70 (t, J=5.6 Hz, 2H), 0.42 (t, J=5.6 Hz 2H).
Compound 345 (formic acid salt) was prepared as a white solid from Compound 101-K and 1-
ethylcyclopropanol by utilizing methods analogous to those described in Example 144. LCMS (Method
-95 AB, ESI): t = 0.602 min, [M + H] = 932.4; H NMR (400 MHz, MeOH-d ) δ 8.45 (brs, 2H), 8.23 (d,
J= 8.0 Hz, 2H), 7.28 (brs, 2H), 7.16-7.03 (m, 4H), 6.89 (s, 1H), 6.62 (brs, 1H), 6.58 (brs, 1H), 5.30-5.28
(m, 1H), 4.84-4.79 (m, 2H), 4.40 (s, 2H), 4.35-4.23 (m, 4H), 3.32-3.28 (m, 4H), 3.04 (brs, 7H), 2.49 (s,
6H), 2.34-2.25 (m, 1H), 2.24-2.13 (m, 1H), 1.87 (q, J=6.8 Hz, 2H), 1.37 (d, J=6.4 Hz, 3H), 1.07 (t, J=6.8
Hz, 3H), 1.01-0.95 (m, 2H), 0.86-0.81 (m, 2H).
Example 146: Synthesis of Compound 346
O HN
N N N O
18253141_1 (GHMatters) P111789.NZ
Compound 346 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 145. LCMS (Method 5-95 AB, ESI): t = 0.731
min, [M + H] = 946.5; H NMR (400 MHz, MeOH-d ) δ 8.52 (brs, 2H), 8.17 (d, J=7.6 Hz, 2H), 7.25 (brs,
2H), 7.12-6.97 (m, 4H), 6.83 (s, 1H), 6.64 (s, 1H), 6.50 (s, 1H), 5.29-5.26 (m, 1H), 4.84-4.75 (m, 2H),
4.37-4.17 (m, 6H), 3.25-2.95 (m, 8H), 3.02 (s, 3H), 2.42 (s, 6H), 2.30-2.23 (m, 1H), 2.14-2.11 (m, 1H),
1.86-1.74 (m, 2H), 1.60-1.50 (m, 2H), 1.35 (d, J=6.8 Hz, 3H), 1.03-0.88 (m, 5H), 0.84-0.80 (m, 2H).
Example 147: Synthesis of Compound 347
O HN
N N N O
Compound 347 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 145. LCMS (Method 5-95 AB, ESI): t = 0.745
min, [M + H] = 960.5; H NMR (400 MHz, MeOH-d ) δ 8.51 (brs, 1H), 8.19 (d, J=7.6 Hz, 2H), 7.23 (d,
J=8.0 Hz, 2H), 7.11-6.97 (m, 4H), 6.85 (s, 1H), 6.58 (brs, 2H), 5.30-5.26 (m, 1H), 4.83-4.72 (m, 2H), 4.24
(s, 2H), 4.20-4.10 (m, 4H), 3.30-3.08 (m, 8H), 3.01 (s, 3H), 2.43 (s, 6H), 2.32-2.22 (m, 1H), 2.20-2.10 (m,
1H), 1.89-1.76 (m, 2H), 1.51-1.45 (m, 2H), 1.43-1.30 (m, 5H), 1.00-0.85 (m, 5H), 0.85-0.78 (m, 2H).
Example 148: Synthesis of Compound 348
O HN
N N N
Cl N
HO OH
N OMe
NaOH
, Na CO
Pd(dppf)Cl2 2 3
N OMe N OH
PPh , DIAD
B N OMe
OH Step 3
Step O
Step 2
Step 1: Typical Suzuki conditions, as described in Example H, were applied to (4-
hydroxyphenyl)boronic acid and methyl 2-chloro-4,6-dimethylpyrimidinecarboxylate (described in
Example 53) to give methyl 2-(4-hydroxyphenyl)-4,6-dimethylpyrimidinecarboxylate as a white solid.
H NMR (400 MHz, CDCl ) δ8.39 (d, J = 8.8 Hz, 2H), 6.91 (d, J =8.8 Hz, 2H), 5.11 (s, 1H), 3.95 (s, 3H),
2.58 (s, 6H).
Step 2: To a solution of methyl 2-(4-hydroxyphenyl)-4,6-dimethylpyrimidinecarboxylate (50
mg, 0.19 mmol), 4,4-dimethylcyclohexanol (62 mg, 0.48 mmol) and PPh (127 mg, 0.48 mmol) in
toluene (5 mL) was added diisopropyl azodicarboxylate (98 mg, 0.48 mmol) dropwise at 0 C and the
resulting mixture was stirred at 80 C for 2 h. The volatiles were removed under reduced pressure and the
residue was purified by preparatory-TLC (eluting with 30% EtOAc in petroleum ether) to give methyl 2-
18253141_1 (GHMatters) P111789.NZ
(4-((4,4-dimethylcyclohexyl)oxy)phenyl)-4,6-dimethylpyrimidinecarboxylate (50 mg, 70% yield) as a
white solid.
Step 3: Typical ester hydrolysis condition (NaOH, MeOH/H O, as described in Example H) was
applied to methyl 2-(4-((4,4-dimethylcyclohexyl)oxy)phenyl)-4,6-dimethylpyrimidinecarboxylate to
give 2-(4-((4,4-dimethylcyclohexyl)oxy)phenyl)-4,6-dimethylpyrimidinecarboxylic acid as a white
solid. LCMS (Method 5-95 AB, ESI): t = 1.022 min, [M + H] = 355.0.
Compound 348 (formic acid salt) was prepared as a white solid from Compound 101-K and 2-
(4-((4,4-dimethylcyclohexyl)oxy)phenyl)-4,6-dimethylpyrimidinecarboxylic acid by utilizing methods
analogous to those described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.740 min, [M + H] =
974.6; H NMR (400 MHz, MeOH-d ) δ 8.51 (brs, 1H), 8.25 (d, J= 8.0 Hz, 2H), 7.30-7.15 (m, 2H), 7.14-
7.05 (m, 2H), 6.96 (d, J=8.4 Hz, 2H), 6.87 (s, 1H), 6.64 (s, 1H), 6.52 (s, 1H), 5.26-5.23 (m, 1H), 4.85-4.75
(m, 2H), 4.45-4.40 (m, 1H), 4.30-4.10 (m, 6H), 3.30-2.95 (m, 8H), 3.00 (s, 3H), 2.47 (s, 6H), 2.25-2.15 (m,
1H), 2.15-2.00 (m, 1H), 1.95-1.85 (m, 2H), 1.75-1.60 (m, 2H), 1.59-1.45 (m, 2H), 1.40-1.25 (m, 5H), 1.01
(s, 3H), 0.99 (s, 3H).
Example 149: Synthesis of Compound 349
PtO , H
OH H H H
N N N O
Step 1
Step 1: A mixture of 2,3-dihydro-1H-indenol (100 mg, 0.75 mmol) and PtO (30.0 mg, 0.75
mmol) was stirred in MeOH/AcOH (11 mL, v/v=10/1) under H (15 psi) for 16 h. After filtration, the
volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography,
eluting with 15% EtOAc in petroleum ether, to give (cis)-octahydro-1H-indenol (20 mg, 19% yield) as
a colorless oil. H NMR (400 MHz, CDCl ) δ 4.41-4.35 (m, 1H), 2.10-1.98 (m, 2H), 1.95-1.80 (m, 2H),
1.55-1.45 (m, 6H), 1.38-1.22 (m, 3H), 0.90-0.80 (m, 1H).
Compound 349 (formic acid salt, mixture of diastereomers) was prepared as a white solid using
101-K and (cis)-octahydro-1H-indenol by utilizing methods analogous to those described in Example
148. LCMS (Method 5-95 AB, ESI): t = 0.750 min, [M + H] = 986.6; H NMR (400 MHz, MeOH-d ) δ
8.51 (brs, 3H), 8.30 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz, 1H), 7.19 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.4 Hz,
1H), 7.00-6.80 (m, 3H), 6.74 (s, 1H), 6.46 (s, 1H), 5.26-5.20 (m, 1H), 5.00-4.75 (m, 3H), 4.21 (s, 2H),
4.20-4.16 (m, 4H), 3.34-3.05 (m, 8H), 3.00 (s, 3H), 2.51 (s, 6H), 2.40-2.05 (m, 7H), 1.85-1.75 (m, 2H),
1.70-1.45 (m, 4H), 1.40-1.30 (m, 6H).
18253141_1 (GHMatters) P111789.NZ
Example 150: Synthesis of Compound 350
O HN
N N N O
Compound 350 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 148. LCMS (Method 5-95 AB, ESI): t = 0.750
min, [M + H] = 958.5; H NMR (400 MHz, MeOH-d ) δ 8.49 (brs, 3H), 8.20 (d, J=8.0 Hz, 2H), 7.28-7.22
(m, 2H), 7.09-7.07 (m, 2H), 6.90-6.86 (m, 3H), 6.60 (brs, 1H), 6.55 (brs, 1H), 5.28-5.25 (m, 1H), 4.85-
4.77 (m, 2H), 4.32-4.30 (m, 3H), 4.25-4.19 (m, 4H), 3.25-3.05 (m, 8H), 3.01 (s, 1H), 2.45 (s, 6H), 2.31-
2.12 (m, 2H), 1.89-1.84 (m, 1H), 1.70-1.57 (m, 5H), 1.35 (d, J=6.4 Hz, 3H), 1.26-1.22 (m, 4H).
Example 151: Synthesis of Compound 351
F O HN
F N N N O
Cl N
F N O F
Pd , N
2(dba)3 P(t-Bu)3 F
NaOH
F B 1.2 eq Ag 2 eq CsF F N
F N COOH
COOMe
F OH
Step 1
Step 2
Step 1: A mixture of (4-butoxy-2,3,5,6-tetrafluorophenyl)boronic acid (146 mg, 0.55 mmol),
ethyl 2-chloro-4,6-dimethylpyrimidinecarboxylate (100 mg, 0.50 mmol), Pd (dba) (23 mg, 0.02 mmol),
P(t-Bu) (15 mg, 0.07 mmol), Ag O (139 mg, 0.6 mmol) and CsF (189 mg, 1.25 mmol) in toluene (5
mL) was stirred at 100 C for 20 h under N . The volatiles were removed under reduced pressure and the
residue was purified by preparatory-TLC (eluting with 10% EtOAc in petroleum ether, R = 0.4) to give
methyl 2-(4-butoxy-2,3,5,6-tetrafluorophenyl)-4,6-dimethylpyrimidinecarboxylate (50 mg, 26%
yield) as a colorless oil. LCMS (ESI): [M + H] = 387.1.
Step 2: Typical ester hydrolysis conditions (NaOH, MeOH/H O, Example H) were applied to
methyl 2-(4-butoxy-2,3,5,6-tetrafluorophenyl)-4,6-dimethylpyrimidinecarboxylate to give 2-(4-butoxy-
2,3,5,6-tetrafluorophenyl)-4,6-dimethylpyrimidinecarboxylic acid as a white solid.
Compound 351 (formic acid salt) was prepared as a white solid from Compound 101-K and 2-
(4-butoxy-2,3,5,6-tetrafluorophenyl)-4,6-dimethylpyrimidinecarboxylic acid by utilizing methods
analogous to those described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.619 min, [M + H] =
18253141_1 (GHMatters) P111789.NZ
992.5; H NMR (400 MHz, MeOH-d ) δ 8.50 (brs, 1H), 7.34-7.28 (m, 1H), 7.27-7.22 (m, 1H), 7.19 (d,
J=8.4 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.92 (d, J=2.4 Hz, 1H), 6.84 (d, J=2.4 Hz, 1H), 6.41 (s, 1H), 5.24-
.18 (m, 1H), 4.82-4.80 (m, 2H), 4.36 (t, J=6.4 Hz, 2H), 4.26-4.17 (m, 6H), 3.36-3.37 (m, 1H), 3.21-3.10
(m, 7H), 3.01 (s, 3H), 2.61 (s, 6H), 2.34-2.24 (m, 1H), 2.21-2.11 (m, 1H), 1.85-1.76 (m, 2H), 1.61-1.51 (m,
2H), 1.36 (d, J=7.0 Hz, 3H),1.02 (t, J=7.4 Hz, 3H).
Example 152: Synthesis of Compound 352
C H Br H
11
K CO , DMF O HN
N N N O
Step 1
Step 1: A mixture of 4-bromobenzenethiol (300 mg, 1.6 mmol), 1-bromopentane (1.2 g, 8.0
mmol) and K CO (658 mg, 4.8 mmol) in DMF (7 mL) was stirred at 80 C for 16 h. The reaction was
poured into water (20 mL), which was extracted with EtOAc (3 x 30 mL). The combined organic layers
were washed with brine (2 x 50 mL), dried over Na SO , concentrated and the residue was purified via
silica gel chromatography, eluting with 5% EtOAc in petroleum ether, to give (4-
bromophenyl)(pentyl)sulfane (300 mg, 73% yield) as a colorless oil.
Compound 352 (formic acid salt) was prepared as a white solid from Compound 101-K and (4-
bromophenyl)(pentyl)sulfane by utilizing methods analogous to those described in Example 53. LCMS
(Method 5-95 AB, ESI): t = 0.760 min, [M + H] = 950.4; H NMR (400 MHz, MeOH-d ) δ 8.50 (brs,
3H), 8.31 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 7.27 (d, J=2.0 Hz, 1H), 7.20 (d, J=8.4 Hz, 2H), 7.09
(d, J=8.4 Hz, 1H), 6.90 (s, 1H), 6.89 (s, 1H), 6.45 (s, 1H), 5.24-5.20 (m, 1H), 4.86-4.75 (m, 1H), 4.24-4.15
(m, 7H), 3.20-2.95 (m, 13H), 2.53 (s, 6H), 2.25-2.15 (m, 1H), 2.15-2.05 (m, 1H), 1.75-1.60 (m, 2H), 1.50-
1.25 (m, 7H), 0.93 (t, J=7.2 Hz, 3H).
Example 153: Synthesis of Compound 353
O N O N N
Cl N
O HN
K CO , DMF NaOH
2 3 H H
N OH
N OMe N N N O
N OMe
O O O
Step 1 Step
Step 1: A mixture of methyl 2-chloro-4,6-dimethylpyrimidinecarboxylate (described in
Example 53) (100 mg, 0.50 mmol), 4-tert-butyl phenol (97 mg, 0.65 mmol) and K CO (207 mg, 1.5 mmol)
in DMF (3 mL) was stirred at 100 C for 4 h. The volatiles were removed under reduced pressure and the
residue was taken up by EtOAc (30 mL), which was washed with brine (2 x 30 mL). The organic layer was
dried over Na SO , concentrated and the residue was purified by reverse-phase HPLC to give methyl 2-(4-
(tert-butyl)phenoxy)-4,6-dimethylpyrimidinecarboxylate (73 mg, 47% yield) as white solid. LCMS
(Method 5-95 AB, ESI): t = 0.953 min, [M + H] = 314.9.
18253141_1 (GHMatters) P111789.NZ
Step 2: Typical ester hydrolysis conditions (NaOH, MeOH/H O, described in Example H) were
applied to methyl 2-(4-(tert-butyl)phenoxy)-4,6-dimethylpyrimidinecarboxylate to give 2-(4-(tert-
butyl)phenoxy)-4,6-dimethylpyrimidinecarboxylic acid as a white solid.
Compound 353 (formic acid salt) was prepared as a white solid from Compound 101-K and 2-
(4-(tert-butyl)phenoxy)-4,6-dimethylpyrimidinecarboxylic acid by utilizing methods analogous to those
described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.721 min, [M + H] = 920.5; H NMR (400
MHz, MeOH-d ) δ 8.48 (brs, 2H),7.46 (d, J=8.8 Hz, 2H), 7.26-7.14 (m, 3H), 7.11-7.03 (m, 3H), 6.89 (s,
1H), 6.79 (s, 1H), 6.40 (s, 1H), 5.20-5.14 (m, 1H), 4.79-4.62 (m, 2H), 4.29-4.18 (m, 6H), 3.40-3.35 (m,
1H), 3.21-3.08 (m, 7H), 2.97 (s, 3H), 2.41 (s, 6H), 2.30-2.10 (m, 2H), 1.36 (s, 9H), 1.35 (d, J=6.8 Hz, 3H).
Example 154: Synthesis of Compound 354
O N N
O HN
N N N O
Compound 354 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 153. LCMS (Method 5-95 AB, ESI): t = 0.738
min, [M + H] = 920.4; H NMR (400 MHz, MeOH-d ) δ 8.51 (brs, 2H), 7.26-7.21 (m, 4H), 7.18 (d, J=8.4
Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 7.01 (d, J=8.4 Hz, 2H), 6.88 (d, J=2.4 Hz, 1H), 6.75 (s, 1H), 6.44 (s, 1H),
.20-5.17 (m, 1H), 4.82-4.77 (m, 2H), 4.25-4.18 (m, 6H), 3.40-3.35 (m, 1H), 3.18-3.00 (m, 7H), 2.98 (s,
3H), 2.66 (t, J=8.4 Hz, 2H), 2.40 (s, 6H), 2.30-2.21 (m, 1H), 2.18-2.08 (m, 1H), 1.67-1.61 (m, 2H), 1.49-
1.30 (m, 5H), 0.97 (t, J=7.5 Hz, 3H).
Example 155: Synthesis of Compound 355
B H N
O N N
OH HN
Br O
Pd H H
s-phos, 2(dba) BBr3
N N N O
K PO , Toluene
step 2
step 1
Step 1: Typical Suzuki conditions, as described in Example H, were applied to 1,2-dibromo
methoxybenzene to give 1,2-dibutylmethoxybenzene as a colorless oil.
Step 2: To a solution of 1,2-dibutylmethoxybenzene (410 mg, 1.9 mmol) in DCM (20
mL) added BBr (0.54 mL, 5.6 mmol) at 0 C and the mixture was stirred at 15 C for 16 h. The reaction
was quenched with MeOH (20 mL), the volatiles were removed under reduced pressure, and the residue
was purified by silica gel chromatography, eluting with 0-20% EtOAc in petroleum ether, to give 3,4-
dibutylphenol (370 mg, 96% yield) as a brown oil. H NMR (400 MHz, MeOH-d4): δ 6.91 (d, J=8.4 Hz,
1H), 6.56 (d, J=2.8 Hz, 1H), 6.55-6.50 (m, 1H), 2.60-2.45 (m, 4H), 1.60-1.45 (m, 4H), 1.45-1.30 (m, 4H),
1.00-0.92 (m, 6H).
18253141_1 (GHMatters) P111789.NZ
Compound 355 (formic acid salt) was prepared as a white solid from Compound 101-K and 3,4-
dibutylphenol by utilizing methods analogous to those described in Example 153. LCMS (Method 5-95
AB, ESI): t = 0.791 min, [M + H] = 976.4; H NMR (400 MHz, MeOH-d ) δ 8.50 (brs, 1H), 7.32-7.26
(m, 2H), 7.21-7.15 (m, 2H), 7.11-7.04 (m, 3H), 6.93-6.88 (m, 2H), 6.46 (s, 1H), 5.20-5.15 (m, 1H), 4.85-
4.75 (m, 2H), 4.23-4.12 (m, 6H), 3.18-2.99 (m, 11H), 2.66 (t, J=7.6 Hz, 4H), 2.44 (s, 6H), 2.30-2.23 (m,
1H), 2.16-2.10 (m, 1H), 1.65-1.55 (m, 4H), 1.49-1.38 (m, 7H), 0.97 (t, J=7.6 Hz, 6H).
Example 156: Synthesis of Compound 356
O HN
N N N O
HO Br Br
K CO CuCl Pd/C, H
tBuMgCl, 2
DMF THF
MeOH
Step 1
OBn Step 3
Step 2
Step 1: Typical alkylation conditions (as described in Example 21) was applied to 4-
(benzyloxy)phenol to give 1-(benzyloxy)(3-bromopropoxy)benzene as a colorless oil.
Step 2: To a solution of 1-(benzyloxy)(3-bromopropoxy)benzene (1.5 g, 4.67 mmol) and CuI
(231 mg, 2.33 mmol) in THF (50 mL) was added t-BuMgCl (2N in Et O, 23.4 mL) and the mixture was
stirred at 25 C for 4h. The reaction was quenched with a saturated aqueous NH Cl solution (30 mL), and
the resulting mixture was extracted by EtOAc (3 x 30 mL). The combined organic layers were washed
with brine (2 x 100 mL), dried over Na SO , concentrated and the residue was purified by reverse-phase
HPLC (acetonitrile 60-98%/0.225% formic acid in water) to give 1-(benzyloxy)((4,4-
dimethylpentyl)oxy)benzene as a white solid. H NMR (400 MHz, CDCl ) δ 7.35-7.21 (m, 5H), 6.90 (d,
J=8.8 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 5.01 (s, 2H), 3.88 (t, J=6.4 Hz, 2H), 1.76-1.70 (m, 2H), 1.30-1.20
(m, 2H), 0.91 (s, 9H).
[00865] Step 3: Typical hydrogenation conditions, as described in Example D, were applied to 1-
(benzyloxy)((4,4-dimethylpentyl)oxy)benzene to give 4-((4,4-dimethylpentyl)oxy)phenol as a colorless
oil.
Compound 356 (formic acid salt) was prepared as a white solid from Compound 101-K and 4-
((4,4-dimethylpentyl)oxy)phenol by utilizing methods analogous to those described in Examples 10 and 53.
LCMS (Method 5-95 AB, ESI): t = 0.766 min, [M + H] = 962.6; H NMR (400 MHz, MeOH-d ) δ 8.52
(brs, 1H), 8.23 (d, J=7.6 Hz, 2H), 7.26-7.21 (m, 2H), 7.12-7.08 (m, 2H), 6.96 (d, J=8.4 Hz, 2H), 6.86 (d,
J= 2.4 Hz, 1H), 6.62 (brs, 1H), 6.54 (brs, 1H), 5.28-5.25 (m, 1H), 4.80-4.75 (m, 1H), 4.60-4.45 (m, 1H),
4.40-4.10 (m, 6H), 4.03 (t, J=6.4 Hz, 2H), 3.33-3.15 (m, 4H), 3.15-2.90 (m, 7H), 2.46 (s, 6H), 2.40-2.20
(m, 1H), 2.20-2.05 (m, 1H), 1.84-1.76 (m, 2H), 1.42-1.33 (m, 5H), 0.96 (s, 9H).
18253141_1 (GHMatters) P111789.NZ
Example 157: Synthesis of Compound 357
O HN
N N N O
Compound 357 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 156. LCMS (Method 5-95 AB, ESI): t = 0.780
min, [M + H] = 976.6; H NMR (400 MHz, MeOH-d ) δ 8.52 (brs, 1H), 8.27-8.22 (m, 2H), 7.25-7.18 (m,
2H), 7.14-7.05 (m, 2H), 7.04-6.95 (m, 2H), 6.86 (s, 1H), 6.65 (brs, 1H), 6.53 (brs, 1H), 5.27-5.24 (m, 1H),
4.85-4.75 (m, 2H), 4.35-4.20 (m, 6H), 4.07 (t, J=7.2 Hz, 2H), 3.20-2.90 (m, 11H), 2.47 (s, 6H), 2.25-2.15
(m, 1H), 2.14-2.05 (m, 1H), 1.81-1.70 (m, 2H), 1.50-1.40 (m, 2H), 1.36 (d, J=7.2 Hz, 3H), 1.30-1.20 (m,
2H), 0.94 (s, 9H).
Example 158: Synthesis of Compound 358
Cl N
O N N
HCl SOCl
O HN
O H H
O DMF
H N O
2 N N O
Step 1 Step 2
Step 1: To a solution of ethyl (E)aminobutenoate (17.0 g, 132 mmol) in toluene (100 mL)
was added HCl (4N in dioxane, 66 mL) and the mixture was stirred at reflux for 16 h. After filtration, the
filtrate was concentrated and the residue was purified by silica gel chromatography, eluting with 5%
MeOH/EtOAc, to give ethyl 2,4-dimethyloxo-1,6-dihydropyridinecarboxylate (5.0 g, 20% yield) as a
white solid. H NMR (400 MHz, CDCl ) δ 6.25 (s, 1H), 4.33 (q, J=7.2 Hz, 2H), 2.52 (s, 3H), 2.29 (s, 3H),
1.36 (t, J=7.2 Hz, 3H).
Step 2: To a solution of ethyl 2,4-dimethyloxo-1,6-dihydropyridinecarboxylate (2.0 g, 10.2
(3.66 g, 30.7 mmol) and DMF (1.12 g, 15.4 mmol) and the
mmol) in toluene (100 mL) was added SOCl
mixture was stirred at 80 C for 12 h. The reaction mixture was diluted with water (50 mL), which was
extracted by EtOAc (3 x 50 mL). The combined organic portions were washed with brine (2 x 100 mL),
dried over MgSO , concentrated and the residue was purified by silica gel chromatography, eluting with
% EtOAc in petroleum ether, to give ethyl 6-chloro-2,4-dimethylnicotinate (2.0 g, 91% yield) as a
brown oil. LCMS (Method 5-95 AB, ESI): t = 0.816 min, [M + H] = 213.8.
[00870] Compound 358 (formic acid salt) was prepared as a white solid from Compound 101-K and
ethyl 6-chloro-2,4-dimethylnicotinate by utilizing methods analogous to those described in Example 53.
LCMS (Method 5-95 AB, ESI): t = 0.670 min, [M + H] = 903.8; H NMR (400 MHz, MeOH-d ) δ 8.46
(brs, 3H), 7.80-7.74 (m, 2H), 7.51-7.47 (m, 3H), 7.29-7.22 (m, 2H), 7.20-7.05 (m, 2H), 6.87 (s, 1H), 6.56
18253141_1 (GHMatters) P111789.NZ
(brs, 2H), 5.30-5.26 (m, 1H), 4.86-4.77 (m, 1H), 4.45-4.15 (m, 7H), 3.34-3.10 (m, 8H), 3.03 (s, 3H), 2.50
(s, 3H), 2.40-2.10 (m, 5H), 1.37 (s, 9H), 1.35 (d, J=6.8 Hz, 3H).
Example 159: Synthesis of Compound 359
O HN
N N O
[00871] Compound 359 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 158. LCMS (Method 5-95 AB, ESI): t = 0.705
min, [M + H] = 933.7; H NMR (400 MHz, MeOH-d ) δ 8.46 (brs, 2H), 7.60 (brs, 2H), 7.41 (brs, 1H),
7.29-7.20 (m, 2H), 7.15-7.01 (m, 2H), 6.94 (d, J=8.4 Hz, 2H), 6.81 (s, 1H), 6.75 (s, 1H), 6.37 (s, 1H), 5.34
(brs, 1H), 4.79-4.74 (m, 1H), 4.55-4.30 (m, 2H), 4.30-4.10 (m, 5H), 3.68 (s, 2H), 3.44-3.34 (m, 1H), 3.31-
3.05 (m, 5H), 3.04 (s, 3H), 3.00-2.85 (m, 2H), 2.50-2.00 (m, 8H),1.37 (d, J=6.8 Hz, 3H), 1.07 (s, 9H).
Example 160: Synthesis of Compound 360
N N O
Compound 360 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 158. LCMS (Method 5-95 AB, ESI): t = 0.515
min, [M + H] = 905.4; H NMR (400 MHz, MeOH-d ) δ 8.47 (brs, 3H), 7.61 (brs, 2H), 7.38 (brs, 1H),
7.27-7.23 (m, 2H), 7.11-7.05 (m, 2H), 6.91 (d, J=8.4 Hz, 2H), 6.82 (s, 1H), 6.69 (s, 1H), 6.37 (s, 1H),
.40-5.30 (m, 1H), 4.76-4.65 (m, 2H), 4.55-4.31 (m, 2H), 4.30-4.10 (m, 5H), 3.34-3.11 (m, 6H), 3.03 (s,
3H), 3.01-2.85 (m, 2H), 2.50-2.00 (m, 8H), 1.35 (d, J= 6.0 Hz, 6H), 1.34 (d, J=6.4 Hz, 3H).
Example 161: Synthesis of Compound 361
O HN
N N O
Compound 361 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 158. LCMS (Method 5-95 AB, ESI): t = 0.688
min, [M + H] = 915.5; H NMR (400 MHz, MeOH-d ) δ 8.43 (brs, 2H), 7.63-7.15 (m, 6H), 7.12 (brs, 2H),
6.86 (s, 1H), 6.59 (brs, 1H), 5.33-5.27 (m, 1H), 4.79-4.76 (m, 2H), 4.44-4.20 (m, 6H), 3.31-3.12 (m, 8H),
18253141_1 (GHMatters) P111789.NZ
3.04 (s, 3H), 2.95 (t, J=6.8 Hz, 2H), 2.48 (s, 3H), 2.30 (s, 3H), 2.28-2.14 (m, 2H), 1.99 (t, J=6.8 Hz, 2H),
1.37 (d, J=6.4 Hz, 3H), 1.36 (s, 6H).
Example 162: Synthesis of Comopund 362
O HN
N N O
[00874] Compound 362 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 158. LCMS (Method 5-95 AB, ESI): t = 0.700
min, [M + H] = 933.4; H NMR (400 MHz, MeOH-d ) δ 8.50 (brs, 2H), 7.94-7.86 (m, 2H), 7.50 (brs, 1H),
7.32-7.15 (m, 3H), 7.10 (d, J=8.4 Hz, 1H), 7.04-6.98 (m, 2H), 6.92 (d, J=2.0 Hz, 1H), 6.86-6.81 (m, 1H),
6.57 (s, 1H), 5.37-5.30 (m, 1H), 4.82-4.73 (m, 2H), 4.26-4.17 (m, 6H), 4.03 (t, J=6.4 Hz, 2H), 3.22-3.09
(m, 8H), 3.02 (s, 3H), 2.56 (s, 3H), 2.43 (s, 3H), 2.31-2.25 (m, 1H), 2.17-2.11 (m, 1H), 1.84-1.78 (m, 2H),
1.54-1.38 (m, 4H), 1.32 (d, J=6.8 Hz, 3H), 0.97 (t, J=6.8 Hz, 3H).
Example 163: Synthesis of Compound 363
F N N O
Compound 363 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 158. LCMS (Method 5-95 AB, ESI): t = 0.700
min, [M + H] = 921.5; H NMR (400 MHz, MeOH-d ) δ 8.50 (s, 1H), 7.75-7.64 (m, 1H), 7.50 (s, 1H),
7.36-7.05 (m, 5H), 6.88 (s, 1H), 6.64 (brs, 1H), 6.54 (brs, 1H), 5.30-5.25 (m, 1H), 4.80-4.72 (m, 2H), 4.39-
4.16 (m, 6H), 3.28-3.06 (m, 8H), 3.03 (s, 3H), 2.52 (s, 3H), 2.34 (s, 3H), 2.31-2.12 (m, 2H), 1.38 (s, 9H),
1.36 (d, J=6.8 Hz, 3H).
Example 164: Synthesis of Compound 364
O HN
N N O
Compound 364 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 158. LCMS (Method 5-95 AB, ESI): t = 0.690
min, [M + H] = 945.4; H NMR (400 MHz, MeOH-d ) δ 8.47 (brs, 3H), 7.78 (brs, 2H), 7.45 (brs, 1H),
7.27-7.08 (m, 4H), 6.98 (d, J=8.4 Hz, 2H), 6.87 (s, 1H), 6.65 (brs, 1H), 6.52 (brs, 1H), 5.30-5.20 (m, 1H),
18253141_1 (GHMatters) P111789.NZ
4.85-4.75 (m, 2H), 4.50-4.15 (m, 7H), 3.25-3.10 (m, 8H), 3.02 (s, 3H), 2.51 (s, 3H), 2.40-2.05 (m, 7H),
2.05-1.95 (m, 2H), 1.90-1.75 (m, 2H), 1.70-1.40 (m, 6H), 1.36 (d, J=7.2 Hz, 3H).
Example 165: Synthesis of Compound 365
O HN
l OH
N OEt
Cl OH
1 Pd dppf Cl N CO
) ( ) 2 2 3
Pd PPh N OH
( 3)4
N OEt
n u a e
N S B o uene
T l 2 N OH M OH/H O
3 ) 2
St p 1 St p 2
[00877] Step 1: A solution of 5-chloro(tributylstannyl)pyridine (400 mg, 0.99 mmol), ethyl 6-chloro-
2,4-dimethyl-pyridinecarboxylate (234 mg, 1.09 mmol) and Pd(PPh ) (115 mg, 0.10 mmol) in toluene
(10 mL) was stirred at 110 C for 8 h. After filtration, the volatiles were removed under reduced pressure
and the residue was purified via silica gel chromatography, eluting with 0-5% EtOAc in petroleum ether,
to give ethyl 6-(5-chloropyridyl)-2,4-dimethyl-pyridinecarboxylate (120 mg, 42% yield) as a white
solid. H NMR (400MHz, CDCl ) δ 8.62 (s, 1H), 8.42 (d, J=8.6 Hz, 1H), 8.08 (s, 1H), 7.81-7.75 (m, 1H),
4.42 (q, J=7.2 Hz, 2H), 2.63 (s, 3H), 2.43 (s, 3H), 1.43 (t, J=7.2 Hz, 3H).
Step 2: Starting from ethyl 6-(5-chloropyridyl)-2,4-dimethyl-pyridinecarboxylate, typical
Suzuki and ester hydrolysis conditions (as described in Example 10) were followed to give 5’-butyl-4,6-
dimethyl-[2,2’-bipyridine]carboxylic acid as a colorless oil.
[00879] Compound 365 (formic acid salt) was prepared as a white solid from Compound 101-K and 5’-
butyl-4,6-dimethyl-[2,2’-bipyridine]carboxylic acid by utilizing methods analogous to those described
in Example G. LCMS (Method 5-95 AB, ESI): t = 0.536 min, [M + H] = 904.3; H NMR (400 MHz,
MeOH-d ) δ 8.60 (brs, 1H), 8.38 (brs, 1H), 8.12 (brs, 1H), 7.85-7.61 (m, 2H), 7.32-7.21 (m, 2H), 6.92 (brs,
1H), 6.80 (brs, 1H), 6.66 (brs, 1H), 6.25 (brs, 1H), 5.40-5.29 (m, 1H), 4.90-4.83 (m, 1H), 4.79-4.71 (m,
1H), 4.46 (brs, 2H), 4.29-4.20 (m, 4H), 3.48-3.39 (m, 1H), 3.33--3.10 (m, 7H), 3.03 (s, 3H), 2.74 (t, J=7.6
Hz, 2H), 2.51-2.38 (m, 2H), 2.34-2.09 (m, 4H), 1.75-1.67 (m, 2H), 1.49-1.42 (m, 2H), 1.36 (d, J=6.8 Hz,
3H), 1.02 (t, J=7.6 Hz, 3H).
Example 166: Synthesis of Compound 366
O HN
N N O
18253141_1 (GHMatters) P111789.NZ
Compound 366 (trifluoroacetic acid salt) was prepared as a white solid from Compound 101-K
by utilizing methods analogous to those described in Example 158. LCMS (Method 5-95 AB, ESI): t =
0.704 min, [M + H] = 903.3; H NMR (400 MHz, MeOH-d ) δ 7.70-7.64 (m, 2H), 7.46-7.42 (m, 1H),
7.30-7.22 (m, 4H), 7.20-7.01 (m, 2H), 6.86 (s, 1H), 6.70 (brs, 1H), 6.48 (brs, 1H), 5.38-5.32 (m, 1H), 4.80-
4.74 (m, 1H), 4.49-4.15 (m, 7H), 3.26-2.87 (m, 8H), 3.05 (s, 3H), 2.70 (t, J=7.6 Hz, 2H), 2.51 (s, 3H),
2.36-2.12 (m, 5H), 1.71-1.63 (m, 2H), 1.45-1.36 (m, 2H), 1.38 (d, J=6.8 Hz, 3H), 1.00 (t, J=7.2 Hz, 3H).
Example 167: Synthesis of Compound 367
F O HN
F N N O
Compound 367 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 151. LCMS (Method 5-95 AB, ESI): t = 0.740
min, [M + H] = 991.5; H NMR (400 MHz, MeOH-d ) δ 8.50 (brs, 1H), 7.41 (s, 1H), 7.34-7.22 (m, 2H),
7.19 (d, J=8.4 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.92 (d, J=2.0 Hz, 1H), 6.83 (d, J=2.0 Hz, 1H), 6.41 (s,
1H), 5.23-5.20 (m, 1H), 4.85-4.77 (m, 2H), 4.34 (t, J=6.4 Hz, 2H), 4.28-4.16 (m, 6H), 3.23-3.09 (m, 8H),
3.01 (s, 3H), 2.60 (s, 3H), 2.45 (s, 3H), 2.33-2.23 (m, 1H), 2.21-2.11 (m, 1H), 1.84-1.76 (m, 2H), 1.61-1.51
(m, 2H), 1.36 (d, J=6.6 Hz, 3H), 1.02 (t, J=7.4 Hz, 3H).
Example 168: Synthesis of Compound 368
H HNO NO
SO , 2 O HN
2 4 3
- N N N
O O N O
Step 1
Step 1: To a stirred solution of 1-bromo(tert-butyl)benzene (3.0 g, 14 mmol) in concentrated
sulfuric acid (12 mL) was added HNO (0.69 mL, 15.5 mmol) dropwise at 0 C. The mixture was stirred at
0 C for 1 h. The volatiles were removed under reduced pressure and the residue was taken up by EtOAc
(50 mL), which was washed with a saturated aqueous Na CO and brine (50 mL each). The organic layer
was dried over MgSO , concentrated and the residue was purified by silica gel chromatography,
eluting with petroleum ether, to give 1-bromo(tert-butyl)nitrobenzene (1.7 g, 47% yield) as a
colorless oil.
[00883] Compound 368 (formic acid salt) was prepared as a white solid from Compound 101-K and 1-
bromo(tert-butyl)nitrobenzene by utilizing methods analogous to those described in Example 158.
LCMS (Method 5-95 AB, ESI): t = 0.712 min, [M + H] = 948.4; H NMR (400 MHz, MeOH-d ) δ 8.48
(brs, 1H), 7.97 (d, J=2.0 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.34 (s, 1H), 7.31-7.15
(m, 3H), 7.10 (d, J=8.4 Hz, 1H), 6.90 (d, J=2.4 Hz, 1H), 6.79 (s, 1H), 6.42 (s, 1H), 5.24-5.20 (m, 1H),
18253141_1 (GHMatters) P111789.NZ
4.79-4.73 (m, 2H), 4.29-4.15 (m, 6H), 3.29-3.03 (m, 8H), 3.00 (s, 3H), 2.49 (s, 3H), 2.41 (s, 3H), 2.33-2.22
(m, 1H), 2.21-2.10 (m, 1H), 1.41 (s, 9H), 1.35 (d, J=6.8 Hz, 3H).
Example 169: Synthesis of Compound 369
O HN
NH N N O
[00884] Compound 369 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 168. LCMS (Method 5-95 AB, ESI): t = 0.664
min, [M + H] = 918.3; H NMR (400 MHz, MeOH-d ) δ 8.49 (brs, 1H), 7.41-7.15 (m, 5H), 7.09 (d, J=8.4
Hz, 1H), 6.89 (brs, 2H), 6.80 (brs, 1H), 6.78 (brs, 1H), 6.49(s, 1H), 5.29-5.24 (m, 1H), 4.84-4.75 (m, 2H),
4.37-4.17 (m, 6H), 3.31-3.11 (m, 8H), 3.01 (s, 3H), 2.54 (s, 3H), 2.31-2.23 (m, 4H), 2.18-2.13 (m, 1H),
1.36 (d, J=6.8 Hz, 3H), 1.33 (s, 9H).
Example 170: Synthesis of Compound 370
H N O
N CN
O HN
N N O
Compound 370 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example H. LCMS (Method 5-95 AB, ESI): t = 0.747
min, [M + H] = 902.6; H NMR (400 MHz, MeOH-d ) δ 8.53 (brs, 2H), 7.50-7.40 (m, 4H), 7.31-7.15 (m,
5H), 7.06 (d, J=8.4 Hz, 1H), 6.89 (d, J=2.0 Hz, 1H), 6.67 (s, 1H), 6.51 (s, 1H), 5.28-5.25 (m, 1H),4.80-
4.78 (m, 2H), 4.26-4.17 (m, 6H), 3.22-3.07 (m, 8H), 3.02 (s, 3H), 2.35-2.25 (m, 1H), 2.31 (s, 6H), 2.20-
2.11 (m, 1H), 1.37 (d, J=6.8 Hz, 3H), 1.36 (s, 9H).
Example 171: Synthesis of Compound 371
H N O
Cl N CN
O HN
N N O
Compound 371 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example H. LCMS (Method 5-95 AB, ESI): t = 0.747
min, [M + H] = 908.3; H NMR (400 MHz, MeOH-d ) δ 8.50 (brs, 2H), 7.75 (s, 1H), 7.66-7.52 (m, 6H),
7.34-7.22 (m, 2H), 7.18 (d, J=8.4 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.91 (s, 1H), 6.82 (s, 1H), 6.34 (s, 1H),
18253141_1 (GHMatters) P111789.NZ
.23-5.19 (m, 1H), 4.79-4.73 (m, 2H), 4.29-4.16 (m, 6H), 3.23-3.07 (m, 8H), 2.95 (s, 3H), 2.34-2.29 (m,
1H), 2.19-2.14 (m, 1H), 1.37 (d, J=6.8 Hz, 3H), 1.36 (s, 9H).
Example 172: Synthesis of Compound 372
H N O
NH N CN
O HN
N (S) N O
[00887] Compound 372 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example H. LCMS (Method 5-95 AB, ESI): t = 0.726
min, [M + H] = 889.4; H NMR (400 MHz, MeOH-d ) δ 8.50 (brs, 3H), 7.59-7.54 (m, 3H), 7.50-7.47 (m,
2H), 7.36-7.33 (m, 1H), 7.26-7.22 (m, 1H), 7.16 (d, J=8.6 Hz, 1H), 7.09 (d, J=8.6 Hz, 1H), 7.04 (d, J=2.0
Hz, 1H), 6.94-6.89 (m, 2H), 6.82 (d, J=2.0 Hz, 1H), 6.34 (s, 1H), 5.16-5.12 (m, 1H), 4.83-4.80 (m, 2H),
4.22-4.17 (m, 6H), 3.18-3.09 (m, 8H), 2.87 (s, 3H), 2.35-2.26 (m, 1H), 2.20-2.12 (m, 1H), 1.36 (s, 9H),
1.35 (d, J=6.8 Hz, 3H).
Example 173: Synthesis of Compound 373
H N O
NH N CN
O HN
N N O
t-Bu
t-Bu t-Bu
B(OH)2
Br NO
H O , NaClO , KH PO
2 NO OsO4 NO 2 2 2 2 4
, K CO
HNO /HOAc 1) Pd(dppf)Cl2 2 3 2 2
3 NO
NaIO4 MeCN/H
2O,rt
Tf Et N
2) O,
, tributylvinyltin
3) Pd(PPh3)4 Step 4 COOH
Step 3
Step
Step 2
Step 1: To a stirred mixture of 4-bromomethylphenol (4.0 g, 21.4 mmol) in acetic acid (22
mL) at 0 C was added fuming HNO (1.25 mL, 27.8 mmol) over 30 min and the mixture was stirred at 0
C for another 15 min. The reaction was poured into ice water (80 mL) and the resulting precipitate was
collected via filtration, redissolved by DCM (100 mL), which was dried over Na SO , concentrated and the
residue was purified by silica gel chromatography, eluting with 0-1% EtOAc in petroleum ether, to give 4-
bromomethylnitrophenol (2.9 g, 58% yield) as a yellow solid.
Step 2: Starting from 4-bromomethylnitrophenol, typical Suzuki and triflation (as described in
Example 10) and Stille (as described in Example 165) conditions were followed to give 4’-(tert-butyl)
methylnitrovinyl-1,1’-biphenyl as a yellow oil.
Step 3: A mixture of 4’-(tert-butyl)methylnitrovinyl-1,1’-biphenyl (100 mg, 0.34 mmol),
OsO (2.5 wt% in t-BuOH, 500 mg), NaIO (362 mg, 1.7 mmol) and 0.2 M phosphate buffer (pH 7.2, 0.2
mL) in acetonitrile/H O (7.5 mL, v/v=2/1) was stirred at 25 C for 24 h. The reaction was diluted with
water (20 mL), which was extracted with EtOAc (2 x 20 mL). The combined organic layers were dried
18253141_1 (GHMatters) P111789.NZ
over Na SO , concentrated and the residue was purified by preparatory-TLC to give 4’-(tert-butyl)
methylnitro-[1,1’-biphenyl]carbaldehyde (40 mg, 40% yield) as a white solid. H NMR (400MHz,
CDCl ) δ 10.36 (s, 1H), 8.14 (s, 1H), 7.77 (s, 1H), 7.60-7.50 (m, 4H), 2.60 (s, 3H), 1.38 (s, 9H).
Step 4: A mixture of 4’-(tert-butyl)methylnitro-[1,1’-biphenyl]carbaldehyde (40 mg,
0.14 mmol), H O (35% aqueous solution, 75 μL), NaClO (25 mg, 0.27 mmol) and KH PO (3 mg, 0.02
2 2 2 2 4
mmol) in acetonitrile/H O (6 mL, v/v=5/1) was stirred at 25 C for 24 h. Na S O (50 mg) was then added
2 2 2 3
to quench the excess of H O . The mixture was partitioned between brine and EtOAc (each 20 mL) and the
organic layer was dried over Na SO , and concentrated to give 4’-(tert-butyl)methylnitro-[1,1’-
biphenyl]carboxylic acid (35 mg, 83% yield) as a white solid.
[00891] Compound 373 (formic acid salt) was prepared as a white solid from Compound 101-K and 4’-
(tert-butyl)methylnitro-[1,1’-biphenyl]carboxylic acid by utilizing methods analogous to those
described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.742 min, [M + H] = 903.4; H NMR (400
MHz, MeOH-d ) δ 8.51 (brs, 1H), 7.41 (brs, 4H), 7.31 (d, J=7.6 Hz, 1H), 7.24-7.12 (m, 2H), 7.08 (d, J=8.0
Hz, 1H), 6.89 (d, J=7.6 Hz, 2H), 6.73 (brs, 1H), 6.70 (brs, 1H), 6.53 (s, 1H), 5.20-5.17 (m, 1H), 4.80-4.78
(m, 1H), 4.67-4.61 (m, 1H), 4.30-4.15 (m, 6H), 3.23-3.11 (m, 8H), 3.00 (s, 3H), 2.33-2.05 (m, 2H), 2.21 (s,
3H), 1.36 (brs, 12H).
Example 174: Synthesis of Compound 374
H N O
O HN
N N O
t (S)
NaOH
Pd(OAc)2 BuXphos N O
OMe OH
K PO , toluene
O Step 2
Step 1 2
Step 1: A mixture of methyl 4-bromo-2,3-dimethylbenzoate (150 mg, 0.62 mmol), 4-(tert-
butyl)phenol (139 mg, 0.93 mmol), Pd(OAc) (7.0 mg, 0.03 mmol), 2-di-tert-butylphosphino-2’,4’,6’-
triisopropylbiphenyl (26 mg, 0.06 mmol) and K PO (330 mg, 1.85 mmol) in toluene (8 mL) was stirred at
100 C for 16 h under N . The volatiles were removed under reduced pressure and the residue was purified
by silica gel chromatography, eluting with 0-30% EtOAc in petroleum ether, to give methyl 4-(4-(tert-
butyl)phenoxy)-2,3-dimethylbenzoate (180 mg, 93% yield) as a light yellow oil.
Step 2: Typical ester hydrolysis conditions (NaOH, MeOH/H O, as described in Example H) were applied
to methyl 4-(4-(tert-butyl)phenoxy)-2,3-dimethylbenzoate to give 4-(4-(tert-butyl)phenoxy)-2,3-
dimethylbenzoic acid as a white solid. LCMS (Method 5-95 AB, ESI): t = 0.990 min, [M + H] = 299.0.
Compound 374 (formic acid salt) was prepared as a white solid from Compound 101-K and 4-
(4-(tert-butyl)phenoxy)-2,3-dimethylbenzoic acid by utilizing methods analogous to those described in
Example G. LCMS (Method 5-95 AB, ESI): t = 0.765 min, [M + H] = 918.5; H NMR (400 MHz,
MeOH-d ) δ 8.50 (brs, 2H), 7.38 (d, J=8.0 Hz, 2H), 7.35-7.16 (m, 4H), 7.10 (d, J=8.0 Hz, 1H), 6.90 (d,
J=8.0 Hz, 1H), 6.85-6.81 (m, 3H), 6.75 (d, J=8.0 Hz, 1H), 6.35 (s, 1H), 5.15-5.12 (m, 1H), 4.83-4.78 (m,
2H), 4.26-4.18 (m, 6H), 3.27-3.03 (m, 8H), 2.94 (s, 3H), 2.38 (s, 3H), 2.30-2.20 (m, 1H), 2.24 (s, 3H),
2.18-2.09 (m, 1H), 1.35 (d, J=7.2 Hz, 3H), 1.32 (s, 9H).
18253141_1 (GHMatters) P111789.NZ
Example 175: Synthesis of Compound 375
H N O
O HN
N N O
Compound 375 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 174. LCMS (Method 5-95 AB, ESI): t = 0.621
min, [M + H] = 918.5; H NMR (400 MHz, MeOH-d ) δ 8.51 (brs, 1H), 7.43 (d, J=8.8 Hz, 2H), 7.31-7.25
(m, 2H), 7.19 (d, J=8.4 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 6.96 - 6.91 (m, 3H), 6.84 (s, 1H), 6.70 (brs, 2H),
6.39 (s, 1H), 5.20-5.18 (m, 1H), 4.83-4.75 (m, 2H), 4.29-4.18 (m, 6H), 3.39-3.35 (m, 1H), 3.26-3.10 (m,
7H), 3.01 (s, 3H), 2.35-2.25 (m, 1H), 2.31 (s, 6H), 2.19-2.10 (m, 1H), 1.37 (d, J=6.8 Hz, 3H), 1.36 (s, 9H).
Example 176: Synthesis of Compound 376
H N O
O Cl N
O HN
N N O
Compound 376 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 174. LCMS (Method 5-95 AB, ESI): t = 0.621
min, [M + H] = 924.4; H NMR (400 MHz, MeOH-d ) δ 8.49 (brs, 2H), 7.50-7.46 (m, 3H), 7.29 (d, J=8.4
Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.16 (d, J=8.4 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 7.02-6.95 (m, 4H), 6.89 (s,
1H), 6.81 (s, 1H), 6.31 (s, 1H), 5.19-5.13 (m, 1H), 4.80-4.73 (m, 2H), 4.25-4.15 (m, 6H), 3.36-3.32 (m,
1H), 3.21-3.07 (m, 7H), 2.91 (s, 3H), 2.34-2.23 (m, 1H), 2.17-2.08 (m, 1H), 1.35 (brs, 12H).
Example 177: Synthesis of Compound 377
H N O
O Cl
O HN
N N O
Compound 377 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 174. LCMS (Method 5-95 AB, ESI): t = 0.760
min, [M + H] = 924.4; H NMR (400 MHz, MeOH-d ) δ 8.51 (brs, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.30-7.22
(m, 3H), 7.15 (d, J=8.4 Hz, 1H), 7.10-6.94 (m, 6H), 6.81 (s, 1H), 6.38 (s, 1H), 6.31 (s, 1H), 5.18-5.13 (m,
1H), 4.79-4.73 (m, 2H), 4.24-4.16 (m, 6H), 3.45-3.40 (m, 1H), 3.18-3.06 (m, 7H), 2.93-2.88 (m, 3H), 2.62
(t, J=6.8 Hz, 2H), 2.33-2.22 (m, 1H), 2.17-2.07 (m, 1H), 1.61-1.58 (m, 2H), 1.43-1.33 (m, 5H), 0.96 (t,
J=7.6 Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 178: Synthesis of Compound 378
H N O
O Cl N
O HN
Compound 378 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 174. LCMS (Method 5-95 AB, ESI): t = 0.825
min, [M + H] = 979.5; H NMR (400 MHz, MeOH-d ) δ 8.50 (brs, 3H), 7.49 (d, J=8.4 Hz, 1H), 7.30-6.80
(m, 11H), 6.32 (s, 1H), 5.20-5.15 (m, 1H), 4.85-4.75 (m, 2H), 4.25-4.15 (m, 4H), 4.20 (s, 2H), 3.26-3.00
(m, 8H), 2.92 (s, 3H), 2.65-2.55 (m, 4H), 2.32-2.20 (m, 1H), 2.20-2.09 (m, 1H), 1.60-1.50 (m, 4H), 1.50-
1.25 (m, 7H), 1.00-0.90 (m, 6H).
Example 179: Synthesis of Compound 379
H N O
O HN
N N O
Compound 379 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 53. LCMS (Method 5-95 AB, ESI): t = 0.730
min, [M + H] = 914.5; H NMR (400 MHz, MeOH-d ) δ 8.50 (brs, 2H), 7.78 (d, J=8.0 Hz, 1H), 7.39 (d,
J=8.8 Hz, 1H), 7.23 (d, J=8.8 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.90-6.80 (m, 4H),
6.38 (s, 1H), 5.11-5.09 (m, 2H), 4.51-4.47 (m, 2H), 4.38-4.34 (m, 1H), 4.28-4.24 (m, 4H), 4.20 (s, 2H),
3.40-3.35 (m, 1H), 3.22-3.09 (m, 7H), 2.87 (s, 3H), 2.67 (t, J=6.4 Hz, 2H), 2.32-2.26 (m, 2H), 1.68-1.58
(m, 3H), 1.39-1.26 (m, 10H), 0.90 (t, J=6.6 Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 180: Synthesis of Compound 380
step 1
Cl , CuI,
1) Pd(PPh3)2 2
K CO MeOH
2) 2 3
HO O
HCl.NH OH,
O HO CuSO KHCO
AcONa NCS N
Sodium ascorbate
step 2
step 3
step 4
NaOH
step 5
H N O
O N N
N N O
Step 1: Starting from 1-bromo(hexyloxy)benzene, typical Sonogoshira and trimethylsilyl
removal conditions (as described in Example 110) were followed to give 1-ethynyl(hexyloxy)benzene
as yellow oil.
Step 2: A mixture of methyl 4-formylbenzoate (4.0 g, 24.4 mmol), hydroxylamino hydrochloride
(3.4 g, 48.8 mmol) and sodium acetate (4.0 g, 48.8 mmol) in MeOH/H O (21 mL, v/v=20/1) was stirred at
C for 3 h. The volatiles were removed under reduced pressure and the residue was partitioned between
H O (100 mL) and EtOAc (100 mL). The organic layer was dried over Na SO , concentrated and the
2 2 4
residue was purified by silica gel chromatography, eluting with 0-30% EtOAc in petroleum ether, to give
methyl (E)((hydroxyimino)methyl)benzoate (2 g, 46% yield) as white solid.
Step 3: A mixture of methyl (E)((hydroxyimino)methyl)benzoate (1.0 g, 5.6 mmol) and N-
chlorosuccinimide (1.1 g, 8.4 mmol) in DMF (10 mL) was stirred at 25 C for 4 h. The volatiles were
removed and the residue was purified by silica gel chromatography, eluting with 0-20% EtOAc in
petroleum ether, to give methyl (Z)(chloro(hydroxyimino)methyl)benzoate (966 mg, 81% yield) as a
white solid.
Step 4: A mixture of 1-ethynyl(hexyloxy)benzene (from Step 1) (320 mg, 1.6 mmol), methyl
(Z)(chloro(hydroxyimino)methyl)benzoate (405 mg, 1.9 mmol), KHCO (681 mg, 6.8 mmol), CuSO (8
mg, 0.03 mmol) and sodium ascorbate (3.1 mg, 0.02 mmol) in 2-methylpropanol (8 mL) was stirred at
45 C for 1 h. The reaction mixture was diluted with H O (20 mL), which was extracted with EtOAc (2 x
mL). The combined organic layers were dried over Na SO , concentrated and the residue was purified
by silica gel chromatography, eluting with 0-60% DCM in petroleum ether, to give methyl 4-(5-(4-
(hexyloxy)phenyl)isoxazolyl)benzoate (120 mg, 20% yield) as a white solid. H NMR (400MHz, CDCl )
δ 8.16 (d, J=8.4 Hz, 2H), 7.95 (d, J=8.4 Hz, 2H), 7.78 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 6.75 (s,
1H), 4.03 (t, J=6.4 Hz, 2H), 3.97 (s, 3H), 1.86-1.79 (m, 2H), 1.49-1.26 (m, 6H), 0.93 (t, J=6.4 Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Step 5: Typical ester hydrolysis conditions (NaOH, MeOH/H O, described in Example H) were
applied to methyl 4-(5-(4-(hexyloxy)phenyl)isoxazolyl)benzoate to give 4-(5-(4-
(hexyloxy)phenyl)isoxazolyl)benzoic acid as a white solid.
Compound 380 (formic acid salt) was prepared as a white solid from Compound 101-K and 4-
(5-(4-(hexyloxy)phenyl)isoxazolyl)benzoic acid by utilizing methods analogous to those described in
Example G. LCMS (Method 5-95 AB, ESI): t = 0.793 min, [M + H] = 985.6; H NMR (400 MHz,
MeOH-d ) δ 8.49 (brs, 2H), 8.10-7.98 (m, 4H), 7.85 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 1H), 7.23 (d,
J=8.4 Hz, 1H), 7.16 (d, J=8.4 Hz, 2H), 7.10-7.07 (m, 3H), 6.89 (brs, 1H), 6.80 (s, 1H), 6.37 (s, 1H), 5.21-
.15 (m, 1H), 4.85-4.75 (m, 2H), 4.33-4.15 (m, 6H), 4.07 (t, J=6.0 Hz, 2H), 3.29-2.97 (m, 8H), 2.89 (s,
3H), 2.38-2.29 (m, 1H), 2.24-2.17 (m, 1H), 1.86-1.78 (m, 2H), 1.56-1.32 (m, 9H), 0.94 (t, J=6.4 Hz, 3H).
Examples 181 and 182: Synthesis of Compounds 381 and 382
H N O
H N O
N CN
O O HN
N O O HN
N N O
N H H
N N O
381 NH
B(OH)
PdCl PPh
2(dppf), 3 1) Pd(dppf)Cl
N O OH
NaOH
Ag CO , H O 2)
2 3 2
Step 2
Step 1
Step 1: A mixture of ethyl 4-methyloxazolecarboxylate (600 mg, 4.25 mmol), 1-bromo
iodobenzene (1.44 g, 5.10 mmol), Pd(dppf)Cl (158 mg, 0.21 mmol), PPh (112 mg, 0.43 mmol) and
Ag CO (2.34 g, 8.50 mmol) in H O (20 mL) was stirred at 70 C for 16 h under N . The reaction mixture
2 3 2 2
was extracted with DCM (3 x 20 mL). The combined organic layers were dried over Na SO , concentrated
and the residue was purified by silica gel chromatography, eluting with 0-10% EtOAc in petroleum ether,
to give ethyl 2-(4-bromophenyl)methyloxazolecarboxylate (1.0 g, 80% yield) as a white solid. 1H
NMR (400 MHz, CDCl ) δ 7.99 (d, J=8.4 Hz, 2H), 7.62 (d, J=8.4 Hz, 2H), 4.42 (q, J=7.2 Hz, 2H), 2.54 (s,
3H), 1.42 (t, J=7.2 Hz, 3H).
Step 2: Starting from ethyl 2-(4-bromophenyl)methyloxazolecarboxylate, typical Suzuki
and ester hydrolysis conditions, as described in Example H, were followed to give 4-methyl(4-
pentylphenyl)oxazolecarboxylic acid as a white solid.
The title compounds (formic acid salts) were prepared as white solids using 101-K and 4-
methyl(4-pentylphenyl)oxazolecarboxylic acid by utilizing methods analogous to those described in
Example G, with the two epimers separated under achiral HPLC conditions.
Compound 381: LCMS (Method 5-95 AB, ESI): t = 0.738 min, [M + H] = 893.5; H NMR (400 MHz,
MeOH-d ) δ 8.47 (brs, 3H), 8.09 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.4 Hz, 1H), 7.24 (d,
J=8.4 Hz, 1H), 7.13-7.07 (m, 2H), 6.89 (s, 1H), 6.81 (s, 1H), 6.31 (s, 1H), 5.17-5.11 (m, 2H), 4.54-4.50 (m,
18253141_1 (GHMatters) P111789.NZ
1H), 4.28-4.14 (m, 4H), 4.19 (s, 2H), 3.26-3.04 (m, 8H), 2.88 (s, 3H), 2.71 (t, J=8.0 Hz, 2H), 2.54 (s, 3H),
2.37-2.31 (m, 1H), 2.21-2.16 (m, 1H), 1.73-1.63 (m, 3H), 1.40-1.29 (m, 6H), 0.92 (t, J=6.8 Hz, 3H).
Compound 382: LCMS (Method 5-95 AB, ESI): t = 0.747 min, [M + H] = 893.8; H NMR
(400 MHz, MeOH-d ) δ 8.49 (brs, 2H), 8.08 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz,
1H), 7.23 (d, J=8.4 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.89 (s, 1H), 6.80 (s, 1H),
6.30 (s, 1H), 5.28-5.22 (m, 2H), 4.59-4.57 (m, 1H), 4.28-4.15 (m, 4H), 4.18 (s, 2H), 3.27-3.05 (m, 8H),
2.88 (s, 3H), 2.74-2.69 (m, 2H), 2.51 (s, 3H), 2.30-2.28 (m, 1H), 2.18-2.17 (m, 1H), 1.71-1.63 (m, 3H),
1.43-1.34 (m, 6H), 0.91 (t, J=6.6 Hz, 3H).
Example 183: Synthesis of Compound 383
H N O
N O HN
N N O
SOCl , MeOH
2 NaOH
B(OH)2
Cu(OAc) MeOH/H O
COOH
COOMe
COOH
COOMe
Step 1 Step 2
Step 3
Step 1: A mixture of 2-oxo-1,2-dihydropyridinecarboxylic acid (1.5 g, 10.8 mmol) and SOCl
(3.1 mL, 43.2 mmol) in MeOH (30 mL) was stirred at 80 C for 3 h. The volatiles were removed under
reduced pressure and the residue was taken up by EtOAc (50 mL), which was washed with saturated
aqueous Na CO solution (2 x 30 mL). The organic layer was dried over Na SO and concentrated to give
2 3 2 4
methyl 2-oxo-1,2-dihydropyridinecarboxylate (540 mg, 33% yield) as a white solid.
Step 2: A mixture of methyl 2-oxo-1,2-dihydropyridinecarboxylate (540 mg, 3.5 mmol),
Cu(OAc)2 (128 mg, 0.71 mmol) and (4-(tert-butyl)phenyl)boronic acid (816 mg, 4.6 mmol) in DCM (20
mL) and pyridine (2 mL) was stirred at 25 C for 24 h. The volatiles were removed under reduced pressure
and the residue was taken up by EtOAc (50 mL), which was washed with brine (2 x 50 mL). The organic
layer was dried over Na SO , concentrated and the residue was purified by silica gel chromatography,
eluting with 0-5% MeOH in DCM, to give methyl 1-(4-(tert-butyl)phenyl)oxo-1,2-dihydropyridine
carboxylate (440 mg, 44% yield) as a brown solid. LCMS (Method 5-95 AB, ESI): t = 0.863 min, [M +
H] = 285.9.
[00911] Step 3: Typical ester hydrolysis conditions (NaOH, MeOH/H O, as described in Example H)
were applied to methyl 1-(4-(tert-butyl)phenyl)oxo-1,2-dihydropyridinecarboxylate to give 1-(4-
(tert-butyl)phenyl)oxo-1,2-dihydropyridinecarboxylic acid as a yellow solid.
Compound 383 (formic acid salt) was prepared as a white solid from Compound 101-K and 1-
(4-(tert-butyl)phenyl)oxo-1,2-dihydropyridinecarboxylic acid by utilizing methods analogous to
18253141_1 (GHMatters) P111789.NZ
those described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.676 min, [M + H] = 891.8; H NMR
(400 MHz, MeOH-d ) δ 8.49 (brs, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.30-7.19 (m, 3H),
7.18-7.10 (m, 3H), 6.99 (brs, 1H), 6.85 (brs, 2H), 6.68 (brs, 1H), 5.11-5.02 (m, 1H), 4.85-4.78 (m, 2H),
4.37-4.18 (m, 6H), 3.29-3.08 (m, 8H), 2.92 (s, 3H), 2.34-2.19 (m, 2H), 1.38 (brs, 12H).
Example 184: Synthesis of Compound 384
H N O
N O HN
N N N O
Compound 384 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 183. LCMS (Method 5-95 AB, ESI): t = 0.698
min, [M + H] = 892.5; H NMR (400 MHz, MeOH-d ) δ 8.51 (brs, 2H), 8.27 (s, 1H), 7.55-7.48 (m, 3H),
7.35-7.19 (m, 5H), 7.16 (d, J=8.4 Hz, 1H), 6.86 (d, J=2.0 Hz, 1H), 6.72 (s, 1H), 6.62 (brs, 1H), 5.17-5.07
(m, 1H), 4.85-4.75 (m, 2H), 4.40-4.20 (m, 4H), 4.23 (s, 2H), 3.25-3.09 (m, 8H), 2.95 (s, 3H), 2.37-2.18 (m,
2H), 1.40 (brs, 12H).
Example 185: Synthesis of Compound 385
H N O
N HN
N N N O
AcHN
Step 1
MeCN
N Cu(OAc)
H NaOH
NH OAc
N OMe N OH
Step 2
Step 3
Step 1: To a solution of methyl 3-oxobutanoate (5.0 g, 43 mmol) and DBU (9.8 g, 65 mmol) in
acetonitrile (40 mL) was added 4-acetamido benzenesulfonylazide (15.5 g, 65 mmol) at 0 C and the
mixture was stirred at 20 C for 1 h. After filtration, the filtrate was concentrated and the residue was
partitioned with saturated aqueous NaHCO solution and EtOAc (50 mL each). The organic layer was
18253141_1 (GHMatters) P111789.NZ
dried over Na SO , concentrated and the residue was purified via silica gel chromatography, eluting with
4% EtOAc in petroleum ether, to give methyl 2-diazooxobutanoate (2.4 g, 39% yield) as a colorless oil.
Step 2: A sealed tube containing 4-(tert-butyl)benzohydrazide (425 mg, 2.2 mmol), Cu(OAc)
(128 mg, 0.70 mmol) and NH OAc (542 mg, 7.0 mmol) in 1,2-dichloroethane (2 mL) was heated under
microwave irradiation at 80 C for 10 min. The mixture was filtered through silica gel, washed with 50%
EtOAc in petroleum ether, and concentrated. Methyl 2-diazooxobutanoate (200 mg, 1.4 mmol) and
AcOH (2 mL) were added to the residue and the resulting mixture was heated under microwave irradiation
at 110 C for 5 min. The volatiles were removed under reduced pressure and the residue was re-dissolved
with EtOAc (50 mL), which was washed with saturated aqueous NaHCO and brine (50 mL each). The
organic layer was dried over Na SO , concentrated and the residue was purified via silica gel
chromatography, eluting with 5-20% EtOAc in petroleum ether, to give methyl 3-(4-(tert-butyl)phenyl)
methyl-1,2,4-triazinecarboxylate (20 mg, 5% yield) as a yellow solid. H NMR (400 MHz, CDCl )
δ 8.53 (d, J =8.4 Hz, 2H), 7.57 (d, J =8.4 Hz, 2H), 4.08 (s, 3H), 2.88 (s, 3H), 1.38 (s, 9H).
Step 3: Typical ester hydrolysisconditions (NaOH, MeOH/H O, described in Example H) was applied to
methyl 3-(4-(tert-butyl)phenyl)methyl-1,2,4-triazinecarboxylate to give 3-(4-(tert-butyl)phenyl)
methyl-1,2,4-triazinecarboxylic acid as a yellow solid. LCMS (Method 5-95 AB, ESI): t = 0.875 min,
[M + H] = 271.9.
Compound 385 (formic acid salt) was prepared as a white solid from Compound 101-K and 3-
(4-(tert-butyl)phenyl)methyl-1,2,4-triazinecarboxylic acid by utilizing methods analogous to those
described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.720 min, [M + H] = 891.5; H NMR (400
MHz, MeOH-d ) δ 8.52-8.44 (m, 4H), 7.63 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.4 Hz, 1H), 7.23 (d, J=8.0 Hz,
1H), 7.15 (d, J=8.0 Hz, 1H), 7.08 (d, J=8.0 Hz, 1H), 6.89 (s, 1H), 6.79 (s, 1H), 6.37 (s, 1H), 5.25-5.21 (m,
1H), 4.82-4.75 (m, 2H), 4.22-4.15 (m, 6H), 3.20-3.09 (m, 7H), 2.95 (s, 3H), 2.89 (s, 3H), 2.37-2.17 (m,
2H), 1.39 (s, 9H), 1.36 (d, J=6.4 Hz, 3H).
Example 186: Synthesis of Compound 386
N CN
N O HN
N N N
MeI, Cs CO
O 1)
I , THF O NH
Mg, 2
NaOH
O NaOMe
Br (COOMe) N OH
O Step 3
Step 2
Step
Step 1: To a solution of 1-bromo(tert-butyl)benzene (3.0 g, 14.1 mmol) in THF (20 mL) at 0
C was added Mg (741 mg, 28.2 mmol) and I (357 mg, 1.41 mmol). The mixture was gradually warmed
up to 75 C while stirring and then stirred at that temperature for 3 h. The above mixture was then added
18253141_1 (GHMatters) P111789.NZ
dropwise to a solution of di-methyl oxalate in THF (20 mL) at -78 C and the resulting mixture was stirred
at the same temperature for 1 h, then gradually warmed up to 20 C while stirring and stirred for another
12 h. The reaction was quenched with saturated aqueous NH Cl solution (20 mL), which was extracted
with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over
Na SO , concentrated and the residue was purified by silica gel chromatography, eluting with 0-5% EtOAc
in petroleum ether, to methyl 2-(4-(tert-butyl)phenyl)oxoacetate (900 mg, 48% yield). H NMR (400
MHz, CDCl ) δ 7.96 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 3.98 (s, 3H), 1.36 (s, 9H).
Step 2: A mixture of methyl 2-(4-(tert-butyl)phenyl)oxoacetate (900 mg, 4.1 mmol), methyl
2,3-diaminopropanoate (1.45 g, 12.3 mmol) and NaOMe (1.1 g, 20.5 mmol) in MeOH (30 mL) was stirred
at 70 C for 12 h. The volatiles were removed and the residue was purified by reverse-phase HPLC to give
methyl 5-(4-(tert-butyl)phenyl)oxo-1,6-dihydropyrazinecarboxylate (80 mg, 6.8% yield) as a yellow
solid. H NMR (400 MHz, CDCl ) δ 8.28 (d, J=8.4 Hz, 2H), 8.13 (s, 1H), 7.50 (d, J=8.4 Hz, 2H), 3.97 (s,
3H), 1.36 (s, 9H).
Step 3: Starting from methyl 5-(4-(tert-butyl)phenyl)oxo-1,6-dihydropyrazinecarboxylate,
typical alkylation (as described in Example 21) and ester hydrolysis conditions (as described in Example H)
were followed to give 5-(4-(tert-butyl)phenyl)methyloxo-1,6-dihydropyrazinecarboxylic acid as a
yellow solid.
Compound 386 (formic acid salt) was prepared as a white solid from Compound 101-K and 5-
(4-(tert-butyl)phenyl)methyloxo-1,6-dihydropyrazinecarboxylic acid by utilizing methods
analogous to those described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.716 min, [M + H] =
906.6; H NMR (400 MHz, MeOH-d ) δ 8.49 (brs, 2H), 8.38-8.34 (m, 3H), 7.56-7.52 (m, 2H), 7.30-7.22
(m, 2H), 7.09-7.04 (m, 2H), 6.88 (s, 1H), 6.81 (s, 1H), 6.33 (s, 1H), 5.20-5.16 (m, 1H), 4.81-4.77 (m, 2H),
4.22-4.16 (m, 6H), 3.69 (s, 3H), 3.40-3.35 (m, 1H), 3.18-3.06 (m, 7H), 2.88 (s, 3H), 2.36-2.33 (m, 1H),
2.14-2.10 (m, 1H), 1.39 (s, 9H), 1.36 (d, J=6.8 Hz, 3H).
Example 187: Synthesis of Compound 387
H N O
N HN
N N N O
Br ,
O tributylvinyltin
Cl 1) Pd(PPh3)4
MeMgBr
Cu(OAc)2
NaIO
N OsO ,
2) 4 4
Cl H O NaClO KH PO N
N , ,
3) 2 2 2 2 4
COOH
Step 1
Step 2
Step 3
18253141_1 (GHMatters) P111789.NZ
Step 1: Typical Chan-Lam conditions (as described in Example 183) were applied to 4,5-
dichloropyridazin-3(2H)-one to give 2-(4-(tert-butyl)phenyl)-4,5-dichloropyridazin-3(2H)-one as a white
solid.
Step 2: To a solution of 2-(4-(tert-butyl)phenyl)-4,5-dichloropyridazin-3(2H)-one (1.0 g, 3.4
mmol) in THF (30 mL) was added MeMgBr (3N in Et O, 9.0 mL) dropwise at 0 C and the reaction was
stirred at the same temperature for 2 h. The reaction was quenched with saturated aqueous NH Cl solution
(40 mL), which was extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with
brine (100 mL), dried over Na SO concentrated and the residue was purified by silica gel
2 4,
chromatography, eluting with 25% EtOAc in petroleum ether, to give 2-(4-(tert-butyl)phenyl)chloro
methylpyridazin-3(2H)-one (350 mg, 38% yield) as a off-white solid. H NMR (400 MHz, CDCl ) δ 8.01
(s, 1H), 7.56 (d, J=7.6 Hz, 2H), 7.25 (d, J=7.6 Hz, 2H), 2.39 (s, 3H), 1.38 (s, 9H).
Step 3: 1-(4-(tert-Butyl)phenyl)methyloxo-1,6-dihydropyridazinecarboxylic acid was prepared as
a white solid from 2-(4-(tert-butyl)phenyl)chloromethylpyridazin-3(2H)-one by utilizing methods
analogous to those described in Example 173. LCMS (Method 5-95 AB, ESI): t = 0.886, [M + H] =
286.9
Compound 387 (formic acid salt) was prepared as a white solid from Compound 101-K and 1-
(4-(tert-butyl)phenyl)methyloxo-1,6-dihydropyridazinecarboxylic acid by utilizing methods
analogous to those described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.695 min, [M + H] =
906.6; H NMR (400 MHz, MeOH-d ) δ 8.46 (brs, 2H), 8.08 (s, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.36 (d,
J=8.4 Hz, 2H), 7.30-7.21 (m, 2H), 7.15-7.04 (m, 2H), 6.88 (s, 1H), 6.80 (s, 1H), 6.30 (s, 1H), 5.20-5.15 (m,
1H), 4.78-4.74 (m, 2H), 4.24-4.18 (m, 4H), 4.20 (s, 2H), 3.40-3.35 (m, 1H), 3.20-3.11 (m, 7H), 2.90 (s,
3H), 2.44 (s, 3H), 2.31-2.26 (m, 1H), 2.15-2.08 (m, 1H), 1.40 (s, 9H), 1.36 (d, J=6.4 Hz, 3H).
Example 188: Synthesis of Compound 388
O HN
N N O
[00924] Compound 388 (formic acid salt) was prepared as a white solid from 101-K by utilizing
methods analogous to those described in Example L and Example 4. LCMS (Method 5-95 AB, ESI): t =
0.788 min, [M + H] = 955.7; H NMR (400 MHz, MeOH-d ) δ 9.04 (s, 2H), 8.50 (brs, 3H), 8.07 (s, 1H),
7.98 (d, J=8.0 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.33-7.07 (m, 5H), 6.90 (s, 1H), 6.80 (s, 1H), 6.36 (s, 1H),
.22-5.18 (m, 1H), 4.85-4.78 (m, 2H), 4.23-4.19 (m, 7H), 3.47-3.40 (m, 1H), 3.25-3.05 (m, 7H), 3.01 (t,
J=7.6 Hz, 2H), 2.93 (s, 3H), 2.40-2.25 (m, 1H), 2.20-2.05 (m, 1H), 1.88-1.84 (m, 2H), 1.50-1.25 (m, 9H),
0.92 (t, J=6.4 Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 189: Synthesis of Compound 389
H N O
N O HN
BuOK
(i-pent)Peppsi, H H
dioxane OH
Step 1 O
2 G03087546
Step 1: A mixture of ethyl piperidinecarboxylate (200 mg, 1.27 mmol), 1-bromo(tert-
butyl)benzene (407 mg, 1.91 mmol), dichloro[1,3-bis(2,6-dipentylphenyl)imidazolylidene](3-
chloropyridyl)palladium(II) (50 mg, 0.06mmol) and t-BuOK (357 mg, 3.18 mmol) in 1,4-dioxane (5 mL)
was stirred at 110 C for 16 h under N . The volatiles were removed under reduced pressureand the residue
was purified by reverse-phase HPLC, eluting with acetonitrile 17-47% / 0.225% formic acid in water, to
afford 1-(4-(tert-butyl)phenyl)piperidinecarboxylic acid (15 mg, 4.5% yield) as a white solid. LCMS
(Method 5-95 AB, ESI): t = 0.723 min, [M + H] = 262.2.
[00926] Compound 389 (formic acid salt) was prepared as a white solid from Compound 101-K and 1-
(4-(tert-butyl)phenyl)piperidinecarboxylic acid by utilizing methods analogous to those described in
= 0.643 min, [M + H] = 881.5; H NMR (400 MHz,
Example G. LCMS (Method 5-95 AB, ESI): t
MeOH-d ) δ 8.37 (brs, 3H), 7.29-7.22 (m, 4H), 7.15-6.99 (m, 3H), 6.95-6.92 (m, 2H), 6.86-6.77 (m, 1H),
6.36-6.29 (m, 1H), 4.96-4.95 (m, 1H), 4.80-4.76 (m, 2H), 4.26-4.08 (m, 6H), 3.70-3.64 (m, 2H), 3.33-3.32
(m, 1H), 3.21-3.04 (m, 7H), 2.86-2.83 (m, 3H), 2.73-2.69 (m, 2H), 2.47-2.43 (m, 1H), 2.21-2.17 (m, 1H),
2.05-2.02 (m, 1H), 2.00-1.82 (m, 4H), 1.44-1.35 (m, 3H), 1.28 (s, 9H).
Example 190: Synthesis of Compound 390
H N O
O HN
N N N O
NHBoc
BocHN O
TsNHNH
1) 2
K CO , dioxane
2) 2 3
N O HN
CDI, 101-K
B(OH)2 H
N N N O
O N O
TFA/DCM NH
Step 2
Step 1
NHBoc
390-1
[00927] Step 1: 4-(4-(tert-Butyl)phenyl)piperidine was prepared as a white solid from tert-butyl 4-
oxopiperidinecarboxylate by utilizing methods analogous to those described in Example 17. LCMS
(Method 5-95 AB, ESI): t = 0.731, [M + H] = 218.2
Step 2: A mixture of Compound 101-K (100 mg, 0.11 mmol) and CDI (19 mg, 0.11 mmol) in
DCM (2 mL) was stirred at 20 C for 16 h, followed by the addition of 4-(4-(tert-butyl)phenyl)piperidine
18253141_1 (GHMatters) P111789.NZ
(47 mg, 0.22 mmol). The resulting mixture was stirred for another 24 h. The reaction mixture was diluted
with DCM (30 mL), which was washed with brine (2 x 30 mL). The organic layer was dried over Na SO ,
concentrated and the residue was purified by preparatory-TLC to give compound 390-1 (50 mg, 40%
yield) as a white solid. LCMS (Method 5-95 AB, ESI): t = 1.061, [M + H] = 1157.9
[00929] Compound 390 (formic acid salt) was prepared as a white solid from compound 390-1 by
utilizing methods analogous to those described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.725
min, [M + H] = 881.6; H NMR (400 MHz, MeOH-d ) δ 7.37-7.33 (m, 3H), 7.19-7.15 (m, 3H), 7.11-7.06
(m, 2H), 6.89 (s, 1H), 6.82 (s, 1H), 6.31 (s, 1H), 4.82-4.75 (m, 1H), 4.23-4.19 (m, 8H), 3.26-3.17 (m, 4H),
3.14-3.05 (m, 4H), 2.98-2.91 (m, 4H), 2.88 (s, 3H), 2.77-2.71 (m, 2H), 2.18-2.16 (m, 1H), 1.89-1.86 (m,
2H), 1.66-1.60 (m, 2H), 1.43-1.34 (m, 3H), 1.30 (s, 9H).
Examples 191 and 192: Synthesis of Compounds 391 and 392
H N O
H N O O
N CN
N CN O HN
O HN
N N O
H (S)
N N O N O
2 392
2 391
TsNHNH
1) 2
O K CO dioxane
2) 2 3
B(OH)2
Step 1
Step 1: Starting from methyl 4-oxocyclohexanecarboxylate, the methods analogous to those
described in Example 17 were followed to give methyl (trans)(4-(tert-butyl)phenyl)cyclohexane
carboxylate and methyl (cis)(4-(tert-butyl)phenyl)cyclohexanecarboxylate after preparatory-TLC
separation.
Methyl (trans)(4-(tert-butyl)phenyl)cyclohexanecarboxylate: H NMR (400 MHz, CDCl )
δ 7.33 (d, J=8.2 Hz, 2H), 7.15 (d, J=8.2 Hz, 2H), 3.70 (s, 3H), 2.54-2.48 (m, 1H), 2.40-2.34 (m, 1H), 2.14-
2.08 (m, 2H), 2.03-1.96 (m, 2H), 1.66-1.57 (m, 2H), 1.54-1.43 (m, 2H), 1.32 (s, 9H).
Methyl (cis)(4-(tert-butyl)phenyl)cyclohexanecarboxylate: H NMR (400 MHz, CDCl ) δ 7.31 (d,
J=8.4 Hz, 2H), 7.14 (d, J=8.4 Hz, 2H), 3.73 (s, 3H), 2.72 (brs, 1H), 2.58-2.49 (m, 1H), 2.29-2.22 (m, 2H),
1.84-1.76 (m, 2H), 1.70 - 1.62 (m, 4H), 1.32 (s, 9H).
Compound 391 (formic acid salt) and Compound 392 (formic acid salt) were each prepared as a
white solid from 101-K and methyl (trans)(4-(tert-butyl)phenyl)cyclohexanecarboxylate or methyl
(cis)(4-(tert-butyl)phenyl)cyclohexanecarboxylate, respectively, by utilizing methods analogous to
those described in Example G.
Compound 391: LCMS (Method 5-95 AB, ESI): t = 0.730 min, [M + H] = 880.5; H NMR
(400 MHz, MeOH-d ) δ 7.32-7.28 (m, 3H), 7.27-7.22 (m, 1H), 7.21-7.16 (m, 1H), 7.16-7.10 (m, 3H), 6.90
18253141_1 (GHMatters) P111789.NZ
(brs, 1H), 6.82 (brs, 1H), 6.32 (s, 1H), 4.85-4.75 (m, 3H), 4.33-4.12 (m, 6H), 3.26-2.96 (m, 8H), 2.83 (s,
3H), 2.54-2.35 (m, 3H), 2.22-2.16 (m, 1H), 2.08-2.01 (m, 1H), 1.98-1.90 (m, 4H), 1.73-1.49 (m, 5H), 1.36
(t, J=6.8 Hz, 2H), 1.30 (s, 9H).
Compound 392: LCMS (Method 5-95 AB, ESI): t = 0.738 min, [M + H] = 880.5; H NMR
(400 MHz, MeOH-d ) δ 8.49 (brs, 2H), 7.34-7.28 (m, 3H), 7.27-7.21 (m, 1H), 7.19-7.13 (m, 3H), 7.09 (d,
J=8.4 Hz, 1H), 6.89 (d, J=2.0 Hz, 1H), 6.82 (d, J=2.0 Hz, 1H), 6.29 (s, 1H), 4.98-4.95 (m, 1H), 4.81-4.76
(m, 2H), 4.28-4.16 (m, 6H), 3.30-3.09 (m, 6H), 3.07-2.98 (m, 2H), 2.85 (s, 3H), 2.67-2.61 (m, 2H), 2.29-
2.13 (m, 1H), 2.10-1.88 (m, 5H), 1.76-1.73 (m, 4H), 1.35 (d, J=6.8 Hz, 3H), 1.29 (s, 9H).
Example 193: Synthesis of Compound 393
H N O
N N O
B(OH)2
,x-Phos
1) Pd(OAc)2
, BF -Et O
PhI(OAc)
2 3 2 O
NaOH
N NH
Step 1
Step 2
Step 1: A mixture of 4-chloropyridinamine (500 mg, 3.9 mmol), methyl 3-oxobutanoate (542
mg, 4.7 mmol), PhI(OAc) (1.5 g, 4.7 mmol) and BF ·Et O (0.1 mL, 0.78mmol) in toluene (20 mL) was
2 3 2
stirred at 110 C for 24 h. The volatiles were removed under reduced pressure and the residue was
partitioned between EtOAc and H O (50 mL each). The organic layer was dried over Na SO , concentrated
2 2 4
and the residue was purified via silica gel chromatography, eluting with 20% EtOAc in petroleum ether, to
give methyl 7-chloromethylimidazo[1,2-a]pyridinecarboxylate (280 mg, 32% yield) as a white solid.
H NMR (400 MHz, CDCl ) δ 9.22 (d, J=8.8 Hz, 1H), 7.59 (d, J=2.4 Hz, 1H), 6.95 (dd, J=8.8, 2.4
Hz, 1H), 3.95 (s, 1H), 2.69 (s, 1H).
[00936] Step 2: Starting from methyl 7-chloromethylimidazo[1,2-a]pyridinecarboxylate, typical
Suzuki and ester hydrolysis conditions, analogous to those described in Example H, were followed to give
7-(4-(tert-butyl)phenyl)methylimidazo[1,2-a]pyridinecarboxylic acid as a white solid. LCMS
(Method 5-95 AB, ESI): t = 0.786, [M + H] = 308.9
Compound 393 (formic acid salt) was prepared as a white solid from Compound 101-K and 7-
(4-(tert-butyl)phenyl)methylimidazo[1,2-a]pyridinecarboxylic acid by utilizing methods analogous
to those described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.704 min, [M + H] = 928.7; H
NMR (400 MHz, MeOH-d ) δ 9.19 (d, J=8.0 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.72 (d, J=8.0 Hz, 2H), 7.56
(d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.16 (d, J=8.4
Hz, 1H), 7.08 (d, J=8.0 Hz, 1H), 6.90 (d, J=2.0 Hz, 1H), 6.81 (brs, 1H), 6.37 (s, 1H), 5.28-5.25 (m, 1H),
18253141_1 (GHMatters) P111789.NZ
4.81-4.75 (m, 2H), 4.22-4.15 (m, 6H), 3.34-3.10 (m, 8H), 2.93 (s, 3H), 2.70 (s, 3H), 2.38-2.30 (m,
1H), 2.19-2.13 (m, 1H), 1.36 (brs, 12H).
Example 194: Synthesis of Compound 394
H N O
O HN
N N O
[00938] Compound 394 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example H. LCMS (Method 5-95 AB, ESI): t = 0.692
min, [M + H] = 891.5; H NMR (400 MHz, MeOH-d ) δ 8.48 (brs, 2H), 8.39 (s, 1H), 7.91 (d, J=8.4 Hz,
1H), 7.79 (s, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.19 (d, J=8.4
Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.92 (d, J=2.2 Hz, 1H), 6.81 (s, 1H), 6.40 (s, 1H), 5.24-5.17 (m, 1H),
4.84-4.77 (m, 2H), 4.31-4.14 (m, 6H), 3.40-3.35 (m, 1H), 3.27-3.08 (m, 7H), 2.99 (s, 3H), 2.87 (t, J=7.5
Hz, 3H), 2.78 (s, 3H), 2.34-2.29 (m, 1H), 2.23-2.14 (m, 1H), 1.81-1.71 (m, 2H), 1.51-1.26 (m, 9H), 0.91 (t,
J=6.8 Hz, 3H).
Example 195: Synthesis of Compound 395
H N O
O HN
N N O
[00939] Compound 395 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example H. LCMS (Method 5-95 AB, ESI): t = 0.693
min, [M + H] = 891.8; H NMR (400 MHz, MeOH-d ) δ 8.49 (brs, 2H), 8.38 (s, 1H), 7.92 (d, J=8.4 Hz,
1H), 7.77 (s, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.19 (d, J=8.4
Hz, 1H), 7.10 (d, J=8.8 Hz, 1H), 6.92 (d, J=2.0 Hz, 1H), 6.81 (s, 1H), 6.41 (s, 1H), 5.23-5.17 (m, 1H),
4.84-4.77 (m, 2H), 4.35-4.21 (m, 4H), 4.20 (s, 2H), 3.40-3.35 (m, 1H), 3.27-3.12 (m, 7H), 2.99 (s, 3H),
2.85 (t, J=7.5 Hz, 3H), 2.77 (s, 3H), 2.35-2.27 (m, 1H), 2.24-2.16 (m, 1H), 1.79-1.71 (m, 2H), 1.45-1.30
(m, 9H), 0.91 (t, J=6.8 Hz, 3H).
Example 196: Synthesis of Compound 396
18253141_1 (GHMatters) P111789.NZ
H N O
O HN
N N O
O N O
O O N
C H Br, K CO
1) 6 13 2 3
SnCl , ZnCl
H OEt
NaOH
HO 2)
Step 1
Step 2
Step 1: A mixture of 5-hydroxynitrobenzaldehyde (1.5 g, 9.0 mmol), ethyl acetoacetate (1.17
g, 9.0 mmol), ZnCl (6.1 g, 45 mmol) and SnCl (8.5 g, 45 mmol) in EtOH (30 mL) was stirred at 70 C
for 3 h under N . The volatiles were removed under reduced pressure and the residue was taken up by
EtOAc (50 mL), which was washed with brine (2 x 50 mL). The organic layer was dried over Na SO ,
concentrated and the residue was purified by silica gel chromatography, eluting with 0-10% MeOH in
DCM, to give ethyl 6-hydroxymethylquinolinecarboxylate (500 mg, 24% yield) as a brown solid. H
NMR (400 MHz, MeOH-d4) 9.44 (s, 1H), 8.12 (d, J=9.2 Hz, 1H), 7.80 (dd, J=9.2, 2.4 Hz, 1H), 7.60 (d,
J=2.4 Hz, 1H), 4.53 (q, J=7.2 Hz, 2H), 3.19 (s, 3H), 1.50 (t, J=7.2 Hz, 3H).
Step 2: Starting from ethyl 6-hydroxymethylquinolinecarboxylate, typical akylation (as described in
Example 21) and ester hydrolysis (NaOH, MeOH/H O, described in Example H) conditions were followed
to give 6-(hexyloxy)methylquinolinecarboxylic acid as a white solid. LCMS (Method 5-95 AB, ESI):
t = 0.798 min, [M + H] = 287.9.
[00941] Compound 396 (formic acid salt) was prepared as a white solid from Compound 101-K and 6-
(hexyloxy)methylquinolinecarboxylic acid by utilizing methods analogous to those described in
Example G. LCMS (Method 5-95 AB, ESI): t = 0.706 min, [M + H] = 907.4; H NMR (400 MHz,
MeOH-d ) δ 8.45 (brs, 1H), 8.32 (s, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.34-7.30 (m,
2H), 7.23 (d, J=8.0 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 6.91 (s, 1H), 6.81 (s, 1H),
6.39 (s, 1H), 5.21-5.18 (m, 1H), 4.81-4.77 (m, 2H), 4.24-4.16 (m, 6H), 4.12 (t, J=6.4 Hz, 2H), 3.40-3.35
(m, 1H), 3.20-3.10 (m, 7H), 2.98 (s, 3H), 2.73 (s, 3H), 2.22-2.19 (m, 1H), 2.18-2.10 (m, 1H), 1.88-1.84 (m,
2H), 1.55-1.53 (m, 2H), 1.42-1.35 (m, 7H), 0.94 (t, J=6.8 Hz, 3H).
Example 197: Synthesis of Compound 397
O HN
O N O
18253141_1 (GHMatters) P111789.NZ
1) Pd(OAc) BuXphos
NaOH
Compound 397 (formic acid salt) was prepared as a white solid from Compound 101-K and
ethyl 6-hydroxymethylquinolinecarboxylate (described in Example 396) by utilizing methods
= 0.733 min, [M + H] =
analogous to those described in Example 174. LCMS (Method 5-95 AB, ESI): t
955.6; H NMR (400 MHz, MeOH-d ) δ 8.54 (brs, 2H), 8.29 (s, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.61-7.55 (m,
1H), 7.49 (d, J=8.4 Hz, 2H), 7.32 (d, J=2.4 Hz, 2H), 7.24 (d, J=8.0 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.12-
7.04 (m, 3H), 6.90 (d, J=2.0 Hz, 1H), 6.80 (s, 1H), 6.38 (s, 1H), 5.21-5.15 (m, 1H), 4.80-4.78 (m, 2H),
4.28-4.16 (m, 6H), 3.29-3.10 (m, 8H), 2.97 (s, 3H), 2.76 (s, 3H), 2.34-2.10 (m, 2H), 1.36 (s, 9H), 1.34 (d,
J=6.8 Hz, 3H).
Example 198: Synthesis of Compound 398
H N O
O HN
N N O
N N O
Br N
N Br
Br NO
2 Br N O TBAI
FeCl 4H O Pd(OAc)2
SnCl , NaOAc 2 2
Br N OEt
N Br
N Br
Step 3
Step 1 Step 2
Step 1: A mixture of 2,5-dibromonitropyridine (3.0 g, 10.6 mmol), SnCl (10.1 g, 53.2 mmol)
and sodium acetate (8.7 g, 106 mmol) in MeOH/THF (130 mL, v/v=2/1) was stirred at 0 C for 5 h. After
filtration, the filtrate was concentrated and the residue was partitioned between EtOAc and saturated
aqueous NaHCO (100 mL each). The organic layer was washed with brine (2 x 100 mL), dried over
Na SO , concnetrated to give N-(2,5-dibromopyridinyl)hydroxylamine (2.7 g) as a yellow solid, which
was used directly in the next step.
Step 2: A mixture of N-(2,5-dibromopyridinyl)hydroxylamine (3.6 g, 13.4 mmol), ethyl (E)-
2-methylbutenoate (5.2 g, 40.2 mmol), and FeCl ·4H O (0.27 g, 1.34 mmol) in 1,4-dioxane (20
mL) was stirred at 70 C for 6 h. After filtration, the filtrate was concentrated to dryness and the residue
was purified via silica gel chromatography, eluting with 0-10% EtOAc in petroleum ether, to give ethyl 3-
((2,5-dibromopyridinyl)amino)methylenebutanoate (800 mg, 16% yield) as a pale yellow oil.
Step 3: A mixture of ethyl 3-((2,5-dibromopyridinyl)amino)methylenebutanoate (800 mg,
2.1 mmol), tetra-butyl ammonium iodide (782 mg, 2.1 mmol) and Pd(OAc) (48 mg, 0.21 mmol) in DMF
(10 mL), was stirred at 90 C for 72 h under N . After filtration, the filtrate was concentrated and the
residue was purified via silica gel chromatography, eluting with 0-5% EtOAc in petroleum ether, to give
ethyl 7-bromomethyl-1,5-naphthyridinecarboxylate (100 mg, 16% yield) as a white solid.
18253141_1 (GHMatters) P111789.NZ
Compound 398 (formic acid salt) was prepared as a white solid from Compound 101-K and
ethyl 7-bromomethyl-1,5-naphthyridinecarboxylate by utilizing methods analogous to those
described in Example 194. LCMS (Method 5-95 AB, ESI): t = 0.710 min, [M + H] = 892.5; H NMR
(400 MHz, MeOH-d ) δ 8.85 (s, 1H), 8.50 (brs, 3H), 8.39 (s, 1H), 8.11 (s, 1H), 7.32-7.01 (m, 4H), 6.81
(brs, 1H), 6.53 (brs, 2H), 5.25-5.19 (m, 1H), 4.81-4.75 (m, 2H), 4.39-4.20 (m, 6H), 3.30-3.06 (m, 8H),
3.00 (s, 3H), 2.90-2.87 (m, 2H), 2.78 (s, 3H), 2.34-2.22 (m, 2H), 1.77-1.75 (m, 2H), 1.50-1.31 (m, 9H),
0.93 (t, J=6.8 Hz, 3H).
Example 199: Synthesis of Compound 399
H N O
N N O
C H OH
6 13
O O B
TMS NH
OH N
I OEt
1) 2(dba)3 S-phos,
Cl CuI
, PTSA
Pd(PPh3)2 2
OEt K PO
NaOH
Et NH 2)
Step 2
Cl Step 3
Step 1 Cl
Step 1: Typical Sonogoshira conditions, as described in Example K, were applied to 4-chloro
iodoaniline to give 4-chloro((trimethylsilyl)ethynyl)aniline as a brown oil.
Step 2: A mixture of 4-chloro((trimethylsilyl)ethynyl)aniline (420 mg, 1.9 mmol), ethyl
acetoacetate (0.36 mL, 2.8 mmol) and p-toluene sulfonic acid (357 mg, 1.9 mmol) in EtOH (16 mL) was
stirred at 85 C for 16 h. The volatiles were removed under reduced pressure and the residue was re-
dissolved with EtOAc (20 mL), which was washed with saturated aqueous NaHCO and brine (20 mL
each). The organic layer was dried over Na SO , concentrated and the residue was purified via silica gel
chromatography, eluting with 5% EtOAc in petroleum ether, to give ethyl 6-chloro-2,4-dimethylquinoline-
3-carboxylate (90 mg, 18% yield) as a white solid. H NMR (400 MHz, CDCl ) δ 7.98 (d, J=2.0 Hz, 1H),
7.96 (d, J=9.2 Hz, 1H), 7.67 (dd, J=9.2, 2.0 Hz, 1H), 4.50 (q, J=7.2 Hz, 2H), 2.70 (s, 3H), 2.63 (s,
3H), 1.46 (t, J=7.2 Hz, 3H).
Step 3: Starting from ethyl 6-chloro-2,4-dimethylquinolinecarboxylate, typical Suzuki
(Pd (dba) /S-phos coupling and ester hydrolysis (NaOH, MeOH/H O, as described in Example H)
2 3 2
conditions were followed to give 6-hexyl-2,4-dimethylquinolinecarboxylic acid as a yellow solid.
LCMS (Method 5-95 AB, ESI): t = 0.659 min, [M + H] = 285.9
Compound 399 (formic acid salt) was prepared as a white solid from Compound 101-K and 6-
hexyl-2,4-dimethylquinolinecarboxylic acid by utilizing methods analogous to those described in
Example G. LCMS (Method 5-95 AB, ESI): t = 0.707 min, [M + H] = 905.6; H NMR (400 MHz,
MeOH-d ) δ 8.50 (brs, 2H), 7.88-7.85 (m, 2H), 7.64 (d, J=8.4 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.22-7.18
(m, 2H), 7.08 (d, J=8.4 Hz, 1H), 6.89 (brs, 1H), 6.74 (brs, 1H), 6.44 (s, 1H), 5.27-5.23 (m, 1H), 4.78-4.77
18253141_1 (GHMatters) P111789.NZ
(m, 2H), 4.25-4.18 (m, 6H), 3.19-3.11 (m, 8H), 3.02 (s, 3H), 2.83 (t, J=7.6 Hz, 2H), 2.69 (s, 3H), 2.64 (s,
3H), 2.27-2.17 (m, 2H), 1.72-1.70 (m, 2H), 1.40-1.20 (m, 9H), 0.89 (t, J=6.8 Hz, 3H).
Example 200: Synthesis of Compound 400
H N O
N N O
1) 3
SOCl , MeOH
2) 2
SOCl , MeOH
OH 2
3) 2O, Pyr
Tf OMe
2) 2O, Pyr
OH K
, CO
4) Pd(dppf)Cl2 2 3
, K CO
3) Pd(dppf)Cl2 2 3
O C H
6 13B(OH)2
MeB(OH)
2 NaOH
Step 1
Step 2
Step 1: Starting from 3-hydroxymethoxynaphthoic acid, typical methyl ester formation
(described in Example M), triflation, Suzuki conditions (described in Example 10) were followed to give
methyl 7-methoxymethylnaphthoate as a white solid. LCMS (Method 5-95 AB, ESI): t = 0.813 min,
[M + H] = 230.9.
[00952] Step 2: Starting from methyl 7-methoxymethylnaphthoate, de-methylation, methyl ester
formation (as described in Example M), triflation and Suzuki coupling (as described in Example10 ) and
ester hydrolysis conditions (as described in Example H) were followed to give 7-hexylmethyl
naphthoic acid as a white solid. LCMS (Method 5-95 AB, ESI): t = 0.944 min, [M + H] = 270.9.
Compound 400 (trifluoroacetic acid salt) was prepared as a white solid from Compound 101-K
and 7-hexylmethylnaphthoic acid by utilizing methods analogous to those described in Example G.
LCMS (Method 5-95 AB, ESI): t = 0.693 min, [M + H] = 890.4; H NMR (400 MHz, MeOH-d ) δ 7.94
(s, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.75-7.65 (m, 2H), 7.44 (d, J=8.4 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.27
(d, J=8.4 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 6.94 (d, J=2.0 Hz, 1H), 6.85 (s, 1H),
6.39 (s, 1H), 5.25-5.18 (m, 1H), 4.83-4.75 (m, 2H), 4.28-4.21 (m, 6H), 3.40-3.35 (m, 1H), 3.26-3.12 (m,
7H), 3.00 (s, 3H), 2.81 (t, J=8.0 Hz, 2H), 2.57 (s, 3H), 2.37-2.27 (m, 1H), 2.25-2.14 (m, 1H), 1.75-1.71
(m, 2H), 1.45-1.20 (m, 11H), 0.92 (t, J=7.2 Hz, 3H).
Example 201: Synthesis of Compound 401
H N O
H N O
N N N
O O HN
N N O
N N O
Br N O
Br N O
18253141_1 (GHMatters) P111789.NZ
OH O
MeO NH
IBX N NaOH
H BrMg
NBS OH
Step 4
Step 1
Step Step
Step 1: To a solution of 4-(tert-butyl)benzaldehyde (5.0 g, 30.8 mmol) in THF (50 mL) was
added ethynyl magnesium bromide (0.5 N in THF, 92.5 mL) dropwise at 0 C and the mixture was stirred
at 20 C for 4 h. The reaction was quenched with saturated aqueous NH Cl (30 mL), which was extracted
with EtOAc (3 x 30 mL). The combined organic layers were dried by Na SO , concentrated and the
residue was purified by silica gel chromatography, eluting with 0-5% EtOAc in petroleum ether, to give 1-
(4-(tert-butyl)phenyl)propynol (4.5 g, 78% yield) as a colorless oil.
Step 2: A mixture of 1-(4-(tert-butyl)phenyl)propynol (4.5 g, 24 mmol), 2-iodoxybenzoic
acid (20 g, 72 mmol) in EtOAc (50 mL) was stirred at 80 C for 4 h. After filtration, the filtrate was
evaporated in vacuo to give 1-(4-(tert-butyl)phenyl)propynone (4.2 g) as a yellow oil, which was
used directly in the next step.
Step 3: A mixture of 1-(4-(tert-butyl)phenyl)propynone (3.9 g, 20.8 mmol) and methyl
(E)aminobutenoate (2.0 g, 17.4 mmol) in EtOH (30 mL) was stirred at 50 C for 0.5 h. After cooling
to 0 C, N-bromosuccinimide (3.7 g, 20.8 mmol) was added to the above solution and the resulting mixture
was stirred at 0 C for 0.5 h. The volatiles were removed and the residue was re-dissolved by EtOAc (50
mL), which was washed with brine (2 x 50 mL). The organic layer was dried by Na SO , concentrated and
the residue was purified by reverse-phase HPLC (solvent gradient: acetonitrile 45-95%/(0.225%formic
acid)-water) to give methyl 5-bromo(4-(tert-butyl)phenyl)methylnicotinate (3.2 g, 51% yield) as a
yellow oil. LCMS (Method 5-95 AB, ESI): t = 0.945 min, [M + H] = 361.9.
[00957] Step 4: Typical ester hydrolysis conditions, as described in Example H, were applied to methyl
-bromo(4-(tert-butyl)phenyl)methylnicotinate to give 5-bromo(4-(tert-butyl)phenyl)
methylnicotinic acid as a yellow solid.
Compound 401 (formic acid salt) was prepared as a white solid from Compound 101-K and 5-
bromo(4-(tert-butyl)phenyl)methylnicotinic acid by utilizing methods analogous to those described
in Example G. LCMS (Method 5-95 AB, ESI): t = 0.743 min, [M + H] = 967.4; H NMR (400 MHz,
MeOH-d ) δ 8.49 (brs, 3H), 8.16 (s, 1H), 7.65-7.50 (m, 4H), 7.32 (d, J=8.4 Hz, 1H), 7.25 (d, J=8.4 Hz,
1H), 7.19 (d, J=8.4 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.91 (s, 1H), 6.83 (s, 1H), 6.39 (s, 1H), 5.20-5.10 (m,
1H), 4.85-4.75 (m, 2H), 4.25-4.15 (m, 6H), 3.40-3.35 (m, 1H), 3.20-3.10 (m, 7H), 2.95 (s, 3H), 2.62 (s,
3H), 2.33-2.25 (m, 1H), 2.20-2.10 (m, 1H), 1.39 (s, 9H), 1.36 (d, J=6.8 Hz, 3H).
Example 202: Synthesis of Compound 402
18253141_1 (GHMatters) P111789.NZ
H N O
O HN
N N O
Step 1: Starting from methyl 5-bromo(4-(tert-butyl)phenyl)methylnicotinate (described in
Example 201), typical Suzuki and ester hydrolysis conditions (as described in Example H) were followed
to give 6-(4-(tert-butyl)phenyl)-2,5-dimethylnicotinic acid as a yellow solid.
[00960] Compound 402 (formic acid salt) was prepared as a white solid from Compound 101-K and 6-
(4-(tert-butyl)phenyl)-2,5-dimethylnicotinic acid by utilizing methods analogous to those described in
Example G. LCMS (Method 5-95 AB, ESI): t = 0.688 min, [M + H] = 903.5; H NMR (400 MHz,
MeOH-d ) δ 8.47 (brs, 2H), 7.77 (s, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.0 Hz,
1H), 7.24 (d, J=8.0 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.10 (d, J=8.8 Hz, 1H), 6.92 (brs, 1H), 6.83 (s, 1H),
6.38 (s, 1H), 5.20-5.15 (m, 1H), 4.85-4.75 (m, 2H), 4.25-4.15 (m, 6H), 3.40-3.35 (m, 1H), 3.25-3.10 (m,
7H), 2.96 (s, 3H), 2.60 (s, 3H), 2.35 (s, 3H), 2.33-2.25 (m, 1H), 2.20-2.10 (m, 1H), 1.40 (s, 9H), 1.36 (d,
J=7.2 Hz, 3H).
Example 203: Synthesis of Compound 403
H N O
MeO O
N MeONa, CuBr
Step 1
Step 1: A mixture of methyl 5-bromo(4-(tert-butyl)phenyl)methylnicotinate (described in
Example 402) (400 mg, 1.1mmol), NaOMe (90 mg, 1.7 mmol) and CuBr (16 mg, 0.11 mmol) in
NMP/MeOH (9 mL, v/v=8/1) was stirred at 110 C for 20 h under N . The volatiles were removed under
reduced pressure and the residue was purified by reverse-phase HPLC (acetonitrile 50-75% / 0.2% formic
acid in water) to give 6-(4-(tert-butyl)phenyl)methoxymethylnicotinic acid (22 mg, 6% yield) as a
white solid. LCMS (Method 5-95 AB, ESI): t = 0.833 min, [M + H] = 300.2.
Compound 403 (formic acid salt) was prepared as a white solid from Compound 101-K and 6-
(4-(tert-butyl)phenyl)methoxymethylnicotinic acid by utilizing methods analogous to those described
in Example G. LCMS (Method 5-95 AB, ESI): t = 0.710 min, [M + H] = 919.6; H NMR (400 MHz,
MeOH-d ) δ 8.48 (brs, 2H), 7.75 (d, J=8.4 Hz, 2H), 7.54 (s, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.0 Hz,
18253141_1 (GHMatters) P111789.NZ
1H), 7.24 (d, J=8.0 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.10 (d, J=8.0 Hz, 1H), 6.91 (d, J=2.4 Hz, 1H), 6.82
(s, 1H), 6.38 (s, 1H), 5.19-5.16 (m, 1H), 4.81-4.78 (m, 2H), 4.24-4.19 (m, 6H), 3.92 (s, 3H), 3.40-3.35 (m,
1H), 3.20-3.10 (m, 7H), 2.96 (s, 3H), 2.58 (s, 3H), 2.35-2.14 (m, 2H), 1.37 (s, 9H), 1.36 (d, J=6.0 Hz, 3H).
Example 204: Synthesis of Compound 404
H N O
N N O
HO N O
KOH,Pd , t-BuXphos N
2(dba)
Step 1
Step 1: A mixture of of methyl 5-bromo(4-(tert-butyl)phenyl)methylnicotinate (described
in Example 402) (120 mg, 0.33 mmol), Pd (dba) (6.1 mg, 0.99 mmol), t-BuXphos (11 mg, 0.03 mmol)
and KOH (56 mg, 0.99 mmol) in 1,4-dioxane/H O (8 mL, v/v=4/1) was stirred at 100 C for 12 h under N .
The volatiles were removed under reduced pressure and the residue was purified by reverse-phase HPLC
(acetonitrile 25-55% / 0.2% formic acid in water) to give 6-(4-(tert-butyl)phenyl)hydroxy
methylnicotinic acid (10 mg, 11% yield) as a white solid. LCMS (Method 5-95 AB, ESI): t = 0.634 min,
[M + H] = 286.4.
Compound 404 (formic acid salt) was prepared as a white solid from Compound 101-K and 6-
(4-(tert-butyl)phenyl)hydroxymethylnicotinic acid by utilizing methods analogous to those described
in Example G. LCMS (Method 5-95 AB, ESI): t = 0.692 min, [M + H] = 905.9; H NMR (400 MHz,
MeOH-d ) δ 8.49 (brs, 3H), 7.84 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 7.35-7.29 (m, 2H), 7.25 (d,
J=8.0 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.91 (d, J=2.8 Hz, 1H), 6.83 (s, 1H), 6.38 (s,
1H), 5.16-5.14 (m, 1H), 4.62-4.54 (m, 2H), 4.25-4.14 (m, 6H), 3.50-3.47 (m, 1H), 3.20-3.07 (m, 5H), 2.96
(s, 3H), 2.82-2.65 (m, 2H), 2.56 (s, 3H), 2.34-2.10 (m, 2H), 1.38 (s, 9H), 1.37 (d, J=7.2 Hz, 3H).
Example 205: Synthesis of Compound 405
H N O
O HN
N N O
H N N
18253141_1 (GHMatters) P111789.NZ
Ph Ph 2(dba)3
NaOH N
N Cs CO
1) Xantphos, 2 3
HCl in water
2) OH
2 H N
Br 2
O Step 2
Step 1 O
Step 1: A mixture of methyl 5-bromo(4-(tert-butyl)phenyl)methylnicotinate (described in
Example 402) (200 mg, 0.53 mmol), benzophenone imine (145 mg, 0.80 mmol), Pd (dba) (49 mg, 0.05
mmol), Xantphos (62 mg, 0.11 mmol) and Cs CO (346 mg, 1.06 mmol) in toluene (2 mL) was stirred at
90 C for 16 h under N . The reaction mixture was diluted with water (20 mL), which was extracted by
EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over MgSO ,
concentrated and the residue was purified by preparatory-TLC (20% EtOAc in petroleum ether, R = 0.5).
To the above isolated material was added HCl solution (2N, 3 mL) and the mixture was stirred at 20 C for
3 h. The volatiles were removed and the residue was purified by prep-TLC to give methyl 5-amino(4-
(tert-butyl)phenyl)methylnicotinate (100 mg, 78% yield) as a white solid. LCMS (Method 5-95 AB,
ESI): t = 0.757 min, [M + H] = 298.9.
Step 2: Typical ester hydrolysis conditions (NaOH, MeOH/H O, described in Example H) were
applied to methyl 5-amino(4-(tert-butyl)phenyl)methylnicotinate to give 5-amino(4-(tert-
butyl)phenyl)methylnicotinic acid as a white solid.
[00967] Compound 405 (formic acid salt) was prepared as a white solid from Compound 101-K and 5-
amino(4-(tert-butyl)phenyl)methylnicotinic acid by utilizing methods analogous to those described
in Example G. LCMS (Method 5-95 AB, ESI): t = 0.650 min, [M + H] = 904.5; H NMR (400 MHz,
MeOH-d ) δ 8.45 (brs, 2H), 7.60-7.40 (m, 4H), 7.35-7.15 (m, 4H), 7.12 (d, J=8.4 Hz, 1H), 6.87 (s, 1H),
6.72 (s, 1H), 6.45 (s, 1H), 5.16-5.13 (m, 1H), 4.85-4.75 (m, 2H), 4.40-4.05 (m, 6H), 3.40-3.35 (m, 1H),
3.25-3.05 (m, 7H), 2.97 (s, 3H), 2.43 (s, 3H), 2.35-2.10 (m, 2H), 1.37 (s, 9H), 1.36 (d, J=6.4 Hz, 3H).
Example 206: Synthesis of Compound 406
H N O
O HN
N N O
O N N O
H SO , H O
NaOH
2 4 2 2
0 3h
OMe C,
O N 2
O Step 2
Step 1
Step 1: A mixture of methyl 5-amino(4-(tert-butyl)phenyl)methylnicotinate (described in
Example 205, 200 mg, 0.67 mmol) in 98% aqueous H SO and 50% aqueous H O (4 mL, v/v=1/1) was
2 4 2 2
stirred at 0 C for 16 h. The mixture was quenched with saturated Na CO solution until pH=7, and then
extracted by EtOAc (3 x 20 mL). The combined organic layers were washed with brine (50 mL), dried
over MgSO , concentrated and the residue was purified by preparatory-TLC (10% EtOAc in petroleum
18253141_1 (GHMatters) P111789.NZ
ether, R =0.5) to give methyl 6-(4-(tert-butyl)phenyl)methylnitronicotinate (60 mg, 27% yield) as a
white solid. LCMS (Method 5-95 AB, ESI): t = 1.010 min, [M + H] = 329.1.
Step 2: Typical ester hydrolysis conditions (NaOH, MeOH/H O, as described in Example H)
were applied to methyl 6-(4-(tert-butyl)phenyl)methylnitronicotinate to give 6-(4-(tert-
butyl)phenyl)methylnitronicotinic acid as a white solid.
Compound 406 (formic acid salt) was prepared as a white solid from Compound 101-K and 6-
(4-(tert-butyl)phenyl)methylnitronicotinic acid by utilizing methods analogous to those described in
Example G. LCMS (Method 5-95 AB, ESI): t = 0.730 min, [M + H] = 934.5; H NMR (400 MHz,
MeOH-d ) δ 8.32 (s, 1H), 7.60-7.40 (m, 4H), 7.24 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.17 (d,
J=8.0 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 6.92 (d, J=2.0 Hz, 1H), 6.83 (s, 1H), 6.38 (s, 1H), 5.19-5.17 (m,
1H), 4.79-4.75 (m, 2H), 4.40-4.05 (m, 6H), 3.30-3.05 (m, 8H), 2.95 (s, 3H), 2.75 (s, 3H), 2.40-2.10 (m,
2H), 1.38 (s, 9H), 1.37 (d, J=7.2 Hz, 3H).
Example 207: Synthesis of Compound 407
H N O
O HN
N N O
Cl N O
CuI, NaNO , HCl NaOH
OMe Cl
Step 2 O
Step
Step 1: To a solution of methyl 5-amino(4-(tert-butyl)phenyl)methylnicotinate (described
in Example 205, 200 mg, 0.67 mmol) in 6M aqueous HCl (6 mL) was added a solution of NaNO (139 mg,
2.0 mmol) in H O (2 mL) dropwsie at 0 C and the mixture was stirred at 15 C for 3 h, followed by the
addition of CuCl (398 mg, 4.0 mmol). The resulting mixture was stirred at 15 C for 16 h. The reaction
was diluted with H O (20 mL), which was extracted by EtOAc (3 x 20 mL). The combined organic layers
were washed with brine (2 x 50 mL), dried over MgSO , concentrated and the residue was purified by
preparatory-TLC (30% EtOAc in petroleum ether) to give methyl 6-(4-(tert-butyl)phenyl)chloro
methylnicotinate (50 mg, 24% yield) as a colorless oil. LCMS (Method 5-95 AB, ESI): t = 1.060 min, [M
+ H] = 317.9.
[00972] Step 2: Typical ester hydrolysis conditions (NaOH, MeOH/H O, as described in Example H)
were applied to methyl 6-(4-(tert-butyl)phenyl)chloromethylnicotinate to give 6-(4-(tert-
butyl)phenyl)chloromethylnicotinic acid as a white solid.
Compound 407 (formic acid salt) was prepared as a white solid from Compound 101-K and 6-
(4-(tert-butyl)phenyl)chloromethylnicotinic acid by utilizing methods analogous to those described
18253141_1 (GHMatters) P111789.NZ
in Example G. LCMS (Method 5-95 AB, ESI): t = 0.740 min, [M + H] = 923.5; H NMR (400 MHz,
MeOH-d ) δ 8.44 (brs, 1H), 7.98 (s, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.56 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.0 Hz,
1H), 7.28-7.10 (m, 2H), 7.11 (d, J=8.4 Hz, 1H), 6.91 (d, J=2.4 Hz, 1H), 6.83 (s, 1H), 6.38 (s, 1H), 5.17-
.15 (m, 1H), 4.79-4.75 (m, 1H), 4.40-4.10 (m, 7H), 3.30-3.05 (m, 8H), 2.95 (s, 3H), 2.63 (s, 3H), 2.35-
2.05 (m, 2H), 1.38 (s, 9H), 1.35 (d, J=6.4 Hz, 3H).
Example 208: Synthesis of Compound 408
H N O
N N O
N N O
HCHO, NaBH CN NaOH
OMe OH
Step 2
Step 1
Step 1: A mixture of methyl 5-amino(4-(tert-butyl)phenyl)methylnicotinate (described in
Example 205, 50 mg, 0.17 mmol), NaBH CN (53 mg, 0.84 mmol) and paraformaldehyde (50 mg, 1.7
mmol) in acetic acid (3 mL) was stirred at 20 C for 10 h. The reaction was quenched with saturated
aqueous Na CO to adjust pH to 8, and then extracted with EtOAc (2 x 20 mL). The combined organic
layers were dried over Na SO , concentrated and the residue was purified by preparatory-TLC (20%
EtOAc in petroleum ether, R =0.5) to give methyl 6-(4-(tert-butyl)phenyl)(dimethylamino)
methylnicotinate (50 mg, 91% yield) as a yellow solid.
Step 2: Typical ester hydrolysis conditions (NaOH, MeOH/H O, as described in Example H)
were applied to methyl 6-(4-(tert-butyl)phenyl)(dimethylamino)methylnicotinate to give 6-(4-(tert-
butyl)phenyl)(dimethylamino)methylnicotinic acid as a white solid. LCMS (Method 5-95 AB, ESI):
t = 0.787 min, [M + H] = 313.4.
[00976] Compound 408 (formic acid salt) was prepared as a white solid from Compound 101-K and 6-
(4-(tert-butyl)phenyl)(dimethylamino)methylnicotinic acid by utilizing methods analogous to those
described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.711 min, [M + H] = 932.5; H NMR (400
MHz, MeOH-d ) δ 8.46 (brs, 3H), 7.71 (d, J=8.4 Hz, 2H), 7.54-7.48 (m,3H), 7.32 (d, J=8.0 Hz, 1H), 7.26-
7.15 (m, 2H), 7.10 (d, J=8.4 Hz, 1H), 6.92 (d, J=2.4 Hz, 1H), 6.83 (s,1H), 6.34 (s,1H), 5.20-5.14 (m, 1H),
4.82-4.78 (m, 2H), 4.30-4.15 (m, 6H), 3.36-3.10 (m, 8H), 2.96 (s, 3H), 2.60 (s, 6H), 2.55 (s, 3H), 2.32-2.27
(m, 1H), 2.20-2.15 (m, 1H), 1.38 (s, 9H), 1.36 (d, J=6.0 Hz, 3H).
Example 209: Synthesis of Compound 409
18253141_1 (GHMatters) P111789.NZ
H N O
N N O
N N O
N Cs CO MeI N K CO , PhSH N NaOH N
NsCl, Py , 2 3
N 2 3
Ns O OH
Ns O
N Step 4 N
H N N Step 3
Step 2
Step 1
Step 1: To a solution of methyl 5-amino(4-(tert-butyl)phenyl)methylnicotinate (described
in Example 205, 50 mg, 0.17 mmol) in DCM (2 mL) and pyridine (0.5 mL) was added 2-nitro
benzenesulfonyl chloride (111 mg, 0.50 mmol) and the mixture was stirred at 15 C for 16 h. The reaction
mixture was diluted with water (20 mL), which was extracted by EtOAc (2 x 20 mL). The combined
organic layers were washed with brine (30 mL), dried over MgSO , concentrated and the residue was
purified by preparatory-TLC (20% EtOAc in petroleum ether, R =0.5) to give methyl 6-(4-(tert-
butyl)phenyl)methyl((4-nitrophenyl)sulfonamido)nicotinate (50 mg, 62% yield) as a yellow solid.
LCMS (Method 5-95 AB, ESI): t = 0.963 min, [M + H] = 484.1.
Step 2: Typical alkylation conditions (as described in Example 21) were applied to methyl 6-(4-
(tert-butyl)phenyl)methyl((4-nitrophenyl)sulfonamido)nicotinate to give methyl 6-(4-(tert-
butyl)phenyl)methyl((N-methylnitrophenyl)sulfonamido)nicotinate as a yellow solid.
Step 3: A mixture of methyl 6-(4-(tert-butyl)phenyl)methyl((N-methyl
nitrophenyl)sulfonamido)nicotinate (50 mg, 0.10 mmol) and K CO (70 mg, 0.50 mmol) in DMF (3 mL)
and thiophenol (4.2 mL) was stirred at 20 C for 2 h. The reaction was partitioned between EtOAc and
brine (30 mL each); the organic layer was dried over Na SO , concentrated and the residue was purified by
silica gel chromatography, eluting with 30% EtOAc in petroleum ether, to give methyl 6-(4-(tert-
butyl)phenyl)methyl(methylamino)nicotinate (25 mg, 80% yield) as a colorless oil. LCMS (Method
5-95 AB, ESI): t = 0.688 min, [M + H] = 313.4.
Step 4: Typical ester hydrolysis conditions (NaOH, MeOH/H O, as described in Example H)
were applied to methyl 6-(4-(tert-butyl)phenyl)methyl(methylamino)nicotinate to give 6-(4-(tert-
butyl)phenyl)methyl(methylamino)nicotinic acid as a white solid.
Compound 409 (formic acid salt) was prepared as a white solid from Compound 101-K and 6-
(4-(tert-butyl)phenyl)methyl(methylamino)nicotinic acid by utilizing methods analogous to those
described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.650 min, [M + H] = 918.5; H NMR (400
MHz, MeOH-d ) δ 8.52 (brs, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.0 Hz, 2H), 7.35-7.16 (m, 3H), 7.13-
7.05 (m, 2H), 6.91 (s, 1H), 6.82 (s, 1H), 6.36 (s, 1H), 5.20-5.10 (m, 1H), 4.79-4.75 (m, 1H), 4.40-4.10 (m,
7H), 3.40-3.35 (m, 1H), 3.25-3.05 (m, 7H), 2.95 (s, 3H), 2.80 (s, 3H), 2.47 (s, 3H), 2.35-2.10 (m, 2H), 1.42
(s, 9H), 1.36 (d, J=7.2 Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 210: Synthesis of Compound 410
H N O
O N O
CN H
NaOEt/EtOH EtO
O O HN
N N O
O H N O
Step
Step 1: A mixture of methyl (Z)((dimethylamino)methylene)oxobutanoate (6.7 g, 36
mmol), 2-cyanoacetamide (2.98 g, 35 mmol), acetic acid (5.3 g, 88 mmol), and sodium ethoxide (1.24 g,
3.8 mmol) in EtOH (60 mL) was stirred at 15 C for 1 h. The volatiles were removed and 1N aqueous HCl
(50 mL) was added. The precipitate was filtered, washed with H O and saturated NaHCO solution and
dried in an oven to yield ethyl 5-cyanomethyloxo-1,6-dihydropyridinecarboxylate (4.5 g, 62%
yield) as a yellow solid. LCMS (Method 5-95 AB, ESI): t = 0.614 min, [M + H] = 206.8.
Compound 410 (formic acid salt) was prepared as a white solid from Compound 101-K and ethyl 5-cyano-
2-methyloxo-1,6-dihydropyridinecarboxylate by utilizing methods analogous to those described in
Example 158. LCMS (Method 5-95 AB, ESI): t = 0.605 min, [M + H] = 914.6; H NMR (400 MHz,
MeOH-d ) δ 8.48 (brs, 3H), 8.23 (s, 1H), 7.90 (d, J=8.4 Hz, 2H), 7.62 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz,
1H), 7.24-7.20 (m, 2H), 7.10 (d, J=8.4 Hz, 1H), 6.92 (d, J=2.4 Hz, 1H), 6.82 (s, 1H), 6.41 (s, 1H), 5.20-
.16 (m, 1H), 4.80-4.78 (m, 2H), 4.25-4.18 (m, 6H), 3.40-3.35 (m, 1H), 3.18-3.12 (m, 7H), 2.96 (s, 3H),
2.75 (s, 3H), 2.31-2.28 (m, 1H), 2.18-2.15 (m, 1H), 1.40 (s, 9H), 1.36 (t, J=6.8 Hz, 3H).
Example 211: Synthesis of Compound 411
H N O
NH N
N N N O
Cl Cl B
Pd , Cs CO 2
1) 2(dba)3 s-phos, 2 3
N OMe
HCl/H O OH
, K CO 2) N
Pd(PPh ) 2
3 4 2 3 N OMe
NaOH
4-Amino(4-(tert-butyl)phenyl)nicotinic acid was prepared as a white solid from methyl 4,6-
dichloronicotinate by utilizing typical Suzuki procedure (as described in Example H) and the methods
described in Example 205. LCMS (Method 5-95 AB, ESI): t = 0.744 min, [M + H] = 270.9.
Compound 411 (formic acid salt) was prepared as a white solid from Compound 101-K and 4-amino(4-
(tert-butyl)phenyl)nicotinic acid by utilizing methods analogous to those described in Example 158.
LCMS (Method 5-95 AB, ESI): t = 0.570 min, [M + H] = 890.5; H NMR (400 MHz, MeOH-d ) δ 8.58
(brs, 1H), 7.79 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.0 Hz, 1H), 7.30-7.05 (m, 5H), 6.89
18253141_1 (GHMatters) P111789.NZ
(s, 1H), 6.81 (s, 1H), 6.34 (s, 1H), 5.20-5.10 (m, 1H), 4.79-4.75 (m, 1H), 4.40-4.10 (m, 7H), 3.25-3.05 (m,
8H), 2.87 (s, 3H), 2.35-2.20 (m, 1H), 2.15-2.05 (m, 1H), 1.37 (s, 9H), 1.36 (d, J=7.2 Hz, 3H).
Example 212: Synthesis of Compound 412
H N O
Cl N NH Cl N NH
2 2 H N
TMSCHN
N NH N
O HN
OH O
N N O
Step 1
[00984] Step 1: A mixture of 2-aminochloronicotinic acid (150 mg, 0.87 mmol) and TMSCHN (2N
solution in hexane, 0.87 mL) in toluene (10 mL) and methanol (2.5 mL) was stirred at 25 C for 16 h. The
volatiles were removed under reduced pressure and the residue was partitioned between EtOAc and brine
(50 mL each). The organic layer was dried over Na SO and concentrated to give methyl 2-amino
chloronicotinate (156 mg) as a white solid, which was used directly in the next step.
Compound 412 (formic acid salt) was prepared as a white solid from Compound 101-K and methyl 2-
aminochloronicotinate by utilizing methods analogous to those described in Example 158. LCMS
(Method 5-95 AB, ESI): t = 0.689 min, [M + H] = 890.5; H NMR (400 MHz, MeOH-d ) δ 8.46 (brs,
3H), 8.03-7.98 (m, 1H), 7.92-7.80 (m, 2H), 7.49 (d, J = 7.6 Hz, 2H), 7.33-7.21 (m, 2H), 7.16-7.05 (m, 3H),
6.86 (d, J = 1.6 Hz, 2H), 6.78 (s, 1H), 6.44 (s, 1H), 5.12-5.09 (m, 1H), 4.81-4.75 (m, 2H), 4.24-4.14 (m,
6H), 3.37-3.36 (m, 1H), 3.20-3.11 (m, 7H), 2.89 (s, 3H), 2.34-2.16 (m, 2H), 1.37 (s, 9H), 1.36 (d, J=7.2 Hz,
3H).
Example 213: Synthesis of Compound 413
H N O
O HN
N N N
Cl Cl 2
B Cl
Pd , Cs Co
1) 2(dba)3 s-phos, 2 3
N OH
N OMe
N OMe HCl/H O
, K CO 2) 2
Pd(PPh3)4 2 3
NaOH
[00985] Compound 413 (formic acid salt) was prepared as a white solid from 101-K by utilizing
methods analogous to those described in Example 211. LCMS (Method 5-95 AB, ESI): t = 0.658 min, [M
+ H] = 904.4; H NMR (400 MHz, MeOH-d ) δ 8.42 (brs, 1H), 7.71 (d, J=8.0 Hz, 2H), 7.63 (d, J=8.0 Hz,
2H), 7.35 (d, J=8.4 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 7.01
(s, 1H), 6.92 (d, J=2.0 Hz, 1H), 6.83 (s, 1H), 6.43 (s, 1H), 5.11-5.05 (m, 1H), 4.83-4.75 (m, 2H), 4.32-4.23
18253141_1 (GHMatters) P111789.NZ
(m, 4H), 4.20 (s, 2H), 3.28-3.08 (m, 8H), 2.98 (s, 3H), 2.59 (s, 3H), 2.30-2.10 (m, 2H), 1.38 (s, 9H), 1.36
(d, J=7.2 Hz, 3H).
Example 214: Synthesis of Compound 414
H N O
N NH N
N N O
Cl N Cl OH
N NH
Pd , Cs Co 2
Na 1) 2(dba)3 s-phos, 2 3
, CO
1) Pd(PPh3)4 2 3
N Cl
TMSCHN HCl/H O OH
COOH 2) 2
2) 2
NaOH
Step 1
O Step
Steps 1-1: 2-Amino(4-(tert-butyl)phenyl)methylnicotinic acid was prepared as a white
solid from 2,6-dichloromethylnicotinic acid by utilizing typical Suzuki procedures (as described in
Example H) and the methods described in Examples 212 and 205. LCMS (Method 5-95 AB, ESI): t =
0.665 min, [M + H] = 284.9.
Compound 414 (formic acid salt) was prepared as a white solid from Compound 101-K and 2-amino(4-
(tert-butyl)phenyl)methylnicotinic acid by utilizing methods analogous to those described in Example G.
LCMS (Method 5-95 AB, ESI): t = 0.669 min, [M + H] = 904.5; H NMR (400 MHz, MeOH-d ) δ 8.31
(brs, 2H), 7.75 (d, J=8.4 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.45-7.38 (m, 2H), 7.30-7.14 (m, 3H), 7.06-6.95
(m, 3H), 6.85 (s, 0.5H), 6.82 (s, 0.5H), 6.55 (s, 0.5H), 6.48 (s, 0.5H), 5.10-5.06 (m, 1H), 4.85-4.75 (m, 2H),
4.33-4.16 (m, 6H), 3.30-2.95 (m, 8H) 2.97 (s, 3H), 2.29-2.16 (m, 5H), 1.39 (s, 9H), 1.37 (d, J=7.2 Hz, 3H).
Example 215: Synthesis of Compound 415
N NH N
O HN
N N O
O N N O
N NH Cl N NH
Cl 2
N NH 2
Cl TMSCHN
2 2 HNO , H SO
3 2 4
O N COOMe
COOMe 2
COOH
Step 2
Step 1
Step 1: Following a procedure analogous to that described in Example 212, Step 1, 2-amino
chloronicotinic acid was converted to methyl 2-aminochloronicotinate as a white solid.
Step 2: A mixture of methyl 2-aminochloronicotinate (300 mg, 1.6 mmol) and HNO (80 μL,
1.9 mmol) in sulfuric acid (10 mL) was stirred at 0 C for 1 h. The volatiles were removed and the residue
18253141_1 (GHMatters) P111789.NZ
was taken up in EtOAc (50 mL), which was washed with brine (2 x 50 mL). The organic layer was dried
over MgSO , concentrated and the residue was purified by silica gel chromatography, eluting with
% EtOAc in petroleum ether, to give methyl 2-aminochloronitronicotinate (150 mg, 40% yield) as
a colorless oil LCMS (ESI): [M + H] = 232.0.
[00989] Compound 415 (formic acid salt) was prepared as a white solid from Compound 101-K and
methyl 2-aminochloronitronicotinate by utilizing methods analogous to those described in Example
158. LCMS (Method 5-95 AB, ESI): t = 0.728 min, [M + H] = 935.4; H NMR (400 MHz, MeOH-d ) δ
8.47 (brs, 2H), 7.54-7.47 (m, 3H), 7.43-7.36 (m, 2H), 7.31-7.17 (m, 3H), 7.12 (d, J=8.4 Hz, 1H), 6.94 (s,
1H), 6.80 (s, 1H), 6.39 (brs, 1H), 5.17-5.13 (m, 1H), 4.62-4.55 (m, 2H), 4.28-4.18 (m, 6H), 3.28-3.10 (m,
8H), 2.91 (s, 3H), 2.35-2.31 (m, 1H), 2.26-2.18 (m, 1H), 1.39 (s, 9H), 1.38 (t, J=7.2 Hz, 3H).
Example 216: Synthesis of Compound 416
H N O
N NH N
O HN
N N O
H N N O
Compound 416 (formic acid salt) was prepared as a white solid by utilizing methods analogous
to those described in Example 215. LCMS (Method 5-95 AB, ESI): t = 0.653 min, [M + H] = 905.4; H
NMR (400 MHz, MeOH-d ) δ 8.40 (brs, 2H), 7.55-7.47 (m, 5H), 7.32-7.15 (m, 3H), 7.11 (d, J=8.8 Hz,
1H), 6.86 (s, 1H), 6.75 (s, 1H), 6.47 (brs, 1H), 5.08-5.03 (m, 1H), 4.79-4.73 (m, 2H), 4.35-4.14 (m, 6H),
3.40-3.35 (m, 1H), 3.23-3.00 (m, 7H), 2.91 (s, 3H), 2.36-2.13 (m, 2H), 1.38 (d, J=7.2 Hz, 3H), 1.37 (s, 9H).
Example 217: Synthesis of Compound 417
H N O
N N N O
[00991] Compound 417 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 26. LCMS (Method 5-95 AB, ESI): t = 0.749
min, [M + H] = 904.7; H NMR (400 MHz, MeOH-d ) δ 8.74 (s, 1H), 8.49 (brs, 1H), 8.34 (d, J = 8.0 Hz,
2H), 7.33-7.28 (m, 3H), 7.22-7.18 (m, 2H), 7.08 (d, J = 8.0 Hz, 1H), 6.89 (d, J=1.6 Hz, 1H), 6.77 (s, 1H),
6.42 (s, 1H), 5.19-5.16 (m,1H), 4.80-4.78 (m,2H), 4.26-4.19 (m, 6H), 3.26-2.95 (m, 13H), 2.57 (d, J=6.4
Hz, 2H), 2.34-2.25 (m, 1H), 2.20-2.13 (m, 1H), 1.97-1.90 (m, 1H), 1.39-1.34 (m, 6H), 0.94 (d, J=6.4 Hz,
6H).
18253141_1 (GHMatters) P111789.NZ
Example 218: Synthesis of Compound 418
H N O
N CHF N
N N N O
B(OH)2
1) Pd(dppf)Cl2
HMDSLi, O
2) 2
N NH
Step 1
MeO Me N
N CHF
MeO N CHF
NH NaOH
DMF F
N OH
Et N
N OEt
Step 2 Ste
Step 3 O
Step 1: Starting from 4-bromobenzonitrile, typical Suzuki and amidine formation conditions,
analogous to those described in Example 35, were followed to give 4-isobutylbenzimidamide as a colorless
oil. LCMS (Method 5-95 AB, ESI): t = 0.563 min, [M + H] = 177.0.
Step 2: Ethyl (E)((dimethylamino)methylene)-4,4-difluorooxobutanoate was prepared as a
yellow oil by utilizing methods analogous to those described in Example 26.
Step 3: A mixture of ethyl (E)((dimethylamino)methylene)-4,4-difluorooxobutanoate (400
mg, 1.8 mmol), 4-isobutylbenzimidamide (478 mg, 2.7 mmol) and triethylamine (505 μL, 3.6 mmol) in
toluene (15 mL) was stirred at 110 C for
1 h. The volatiles were removed and the residue was purified via silica gel chromatography, eluting with 0-
2% EtOAc in petroleum ether, to give ethyl 4-(difluoromethyl)(4-isobutylphenyl)pyrimidine
carboxylate (500 mg, 83% yield) as a white solid. H NMR (400 MHz, CDCl ): δ 9.36 (s, 1H), 8.49 (d,
J=8.4 Hz, 2H), 7.42 (t, J=54 Hz, 1H), 7.29 (d, J=8.4 Hz, 2H), 4.47 (q, J=6.8 Hz, 2H), 2.57 (d, J=7.2 Hz,
2H), 1.99-1.88 (m, 1H), 1.45 (t, J=6.8 Hz, 3H), 1.29 (d, J=6.4 Hz, 6H).
Step 4: Typical ester hydrolysis conditions (NaOH, MeOH/H O, as described in Example H)
were applied to ethyl 4-(difluoromethyl)(4-isobutylphenyl)pyrimidinecarboxylate to give 4-
(difluoromethyl)(4-isobutylphenyl)pyrimidinecarboxylic acid as a white solid.
[00996] Compound 418 (formic acid salt) was prepared as a white solid from Compound 101-K and 4-
(difluoromethyl)(4-isobutylphenyl)pyrimidinecarboxylic acid by utilizing methods analogous to
those described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.762 min, [M + H] = 926.6; H NMR
(400 MHz, MeOH-d ) δ 9.09 (s, 1H), 8.48-8.44 (m, 3H), 7.37-7.34 (m, 3H), 7.29-7.25 (m, 1H), 7.21 (d,
J=8.0 Hz, 1H), 7.15-7.11 (m, 1H), 6.93 (d, J=2.4 Hz, 1H), 6.84 (s, 1H), 6.40 (s, 1H), 5.24-5.21 (m, 1H),
4.83-4.80 (m, 1H), 4.30-4.17 (m, 7H), 3.38-3.35 (m, 1H), 3.26-3.12 (m, 8H), 2.97 (s, 3H), 2.61 (d, J=8.0
Hz, 3H), 2.34-2.18 (m, 1H), 1.99-1.96 (m, 1H), 1.38 (d, J=6.8 Hz, 3H), 0.97 (d, J=6.8 Hz, 6H).
18253141_1 (GHMatters) P111789.NZ
Example 219: Synthesis of Compound 419
H N O
EtOOC COOEt
N O N OH N
NaOH
O HN
NH H
N OH
EtONa, EtOH N OEt N N N O
Step 2
Step 1 O
Step 1: A mixture of 4-(tert-butyl)benzimidamide (4.0 g, 22.7 mmol), diethyl 2-
(ethoxymethylene)malonate (4.9 g, 22.7 mmol) and sodium ethoxide (1.7 g, 25.0 mmol) in EtOH (10 mL)
was stirred at 60 C for 1 h. The volatiles were removed and the residue was taken up in EtOAc (100 mL),
which was washed with brine (100 mL). The organic layer was dried over MgSO , concentrated and the
residue was purified by silica gel chromatography, eluting with 40% EtOAc in petroleum ether, to give
ethyl 2-(4-(tert-butyl)phenyl)oxo-1,6-dihydropyrimidinecarboxylate (800 mg, 12% yield) as a white
solid. LCMS (Method 5-95 AB, ESI): t = 0.749 min, [M + H] = 300.9.
[00997] Step 2: Typical ester hydrolysis conditions (NaOH, MeOH/H O, as described in Example H)
were applied to ethyl 2-(4-(tert-butyl)phenyl)oxo-1,6-dihydropyrimidinecarboxylate to give 2-(4-
(tert-butyl)phenyl)oxo-1,6-dihydropyrimidinecarboxylic acid as a white solid.
Compound 419 (formic acid salt) was prepared as a white solid from Compound 101-K and 2-
(4-(tert-butyl)phenyl)oxo-1,6-dihydropyrimidinecarboxylic acid by utilizing methods analogous to
those described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.693 min, [M + H] = 892.9; H NMR
(400 MHz, MeOH-d ) δ 8.76 (s, 1H), 8.50 (brs, 1H), 8.07 (d, J=8.0 Hz, 2H), 7.53 (d, J=8.0 Hz,
2H), 7.30 (d, J=8.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H), 6.86
(brs, 1H), 6.78 (s, 1H), 6.39 (s, 1H), 5.21-5.17 (m, 1H), 4.80-4.76 (m, 2H), 4.21-4.16 (m, 6H), 3.40-3.35
(m, 1H), 3.15-3.10 (m, 7H), 2.86 (s, 3H), 2.33-2.28 (m, 1H), 2.19-2.14 (m, 1H), 1.37 (s, 9H), 1.36 (d,
J=7.2 Hz, 3H).
Example 220: Synthesis of Compound 420
H N O
HOOC
N O CN
O HN
N N N O
NHBoc
NHBoc
BocHN O
BocHN O
Br COOt-Bu .
t ClH H N
BuOOC
K CO
1) 2 3 1) HATU,DIEA
N O OH
N OH OMe Me SnOH
2) 3 LiOH
O HN 2)
O HN
H TFA/HFIP
N N N O
N N N O (S)
Step 1
Step 2
NHBoc
NHBoc
420-1
420-2
18253141_1 (GHMatters) P111789.NZ
Step 1: Starting from compound 420-1 (prepared as described in Example 219), typical
alkylation (as described in Example 21) and Me SnOH methyl ester hydrolysis (as described in Example N)
conditions were followed to give compound 420-2 as a white solid.
Step 2: Starting from compound 420-2, typical amide coupling (HATU/DIEA), ester hydrolysis
(LiOH, THF/H O) and Boc removal (TFA/HFIP) conditions, as described in Example G, were followed to
give Compound 420 (formic acid salt) as a white solid. LCMS (Method 5-95 AB, ESI): t = 0.722, [M +
H] = 950.5; H NMR (400 MHz, MeOH-d ) δ 8.97 (s, 1H), 8.43 (brs, 2H), 8.35 (d, J=8.0 Hz, 2H), 7.53
(d, J=8.0 Hz, 2H), 7.41 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.07 (d, J=8.4
Hz, 1H), 6.87 (s, 1H), 6.83 (s, 1H), 6.47(s, 1H), 5.17-5.13 (m, 1H), 4.82-4.71 (m, 4H), 4.35-4.16 (m, 6H),
3.29-3.08 (m, 8H), 2.88 (s, 3H), 2.45-2.30 (m, 1H), 2.26-2.10 (m, 1H), 1.36 (s, 9H), 1.35 (d, J=7.2 Hz, 3H).
Example 221: Synthesis of Compound 421
H N O
N Cl N
N N N O
EtO OEt
NaOH N
EtONa
N OEt N OH
POCl
2) 3
Cl O Cl O
Step 2
Step 1
Step 1: Ethyl 2-(4-(tert-butyl)phenyl)chloromethylpyrimidinecarboxylate was prepared
as a yellow solid by utilizing typical chlorination (POCl ) conditions (as described in Example 53) and the
methods described in Example 219. LCMS (Method 5-95 AB, ESI): t = 1.110 min, [M + H] = 332.9.
Step 2: A mixture of ethyl 2-(4-(tert-butyl)phenyl)chloromethylpyrimidinecarboxylate
(100 mg, 0.30 mmol) and NaOH (60 mg, 1.5 mmol) in THF/H O (15 mL, v/v=2/1) was stirred at 20 C for
1h. The reaction was adjusted to pH=4 using saturated aqueous KHSO , and then extracted with EtOAc (3
x 20 mL). The combined organic layers were washed with brine (50 mL), dried over
Na SO , concentrated and the residue was purified by reverse-phase HPLC (acetonitrile 50-80% /
0.05% HCl in water) to give 2-(4-(tert-butyl)phenyl)chloromethylpyrimidinecarboxylic acid (60
mg, 66% yield) as a white solid. LCMS (Method 5-95 AB, ESI): t = 0.965 min, [M + H] = 304.9.
Compound 421 (trifluoroacetic acid salt) was prepared as a white solid from Compound 101-K
and 2-(4-(tert-butyl)phenyl)chloromethylpyrimidinecarboxylic acid by utilizing methods
analogous to those described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.727 min, [M + H] =
924.4; H NMR (400 MHz, MeOH-d ) δ 8.35 (d, J=8.4 Hz, 2H), 7.56 (d, J=8.4 Hz, 2H), 7.35-7.15 (m, 3H),
7.10 (d, J=8.0 Hz, 1H), 6.91 (s, 1H), 6.79 (s, 1H), 6.39 (s, 1H), 5.30-5.20 (m, 1H), 4.80-4.75 (m, 2H),
18253141_1 (GHMatters) P111789.NZ
4.30-4.05 (m, 6H), 3.25-3.10 (m, 8H), 2.99 (s, 3H), 2.59 (s, 3H), 2.35-2.05 (m, 2H), 1.38 (s, 9H), 1.37 (d,
J=6.8 Hz, 3H).
Example 222: Synthesis of Compound 422
H N O
N OMe N
MeI, CO
N 1) 2 3
O HN
N N N O
NaOH
2) N OH
N OEt N O
OMe O
OH O
Step 1
[001004] Step 1: Starting from ethyl 2-(4-(tert-butyl)phenyl)chloromethylpyrimidinecarboxylate
(described in Example 221), typical alkylation (as described in Example 21) and ester hydrolysis
conditions (NaOH, MeOH/H O, described in Example H) were followed to give 2-(4-(tert-butyl)phenyl)-
4-methoxymethylpyrimidinecarboxylic acid as a white solid. LCMS (Method 5-95 AB, ESI): t =
0.815 min, [M + H] = 300.9.
[001005] Compound 422 (formic acid salt) was prepared as a white solid from Compound 101-K and 2-
(4-(tert-butyl)phenyl)methoxymethylpyrimidinecarboxylic acid by utilizing methods analogous to
those described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.727 min, [M + H] = 920.6; H NMR
(400 MHz, MeOH-d ) δ 8.50 (brs, 2H), 8.36 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.32-7.28 (m, 1H),
7.16-7.26 (m, 2H), 7.10 (d, J=8.4 Hz, 1H), 6.92 (d, J=2.4 Hz, 1H), 6.81 (s, 1H), 6.36 (s, 1H), 5.23-5.20 (m,
1H), 4.84-4.78 (m, 2H), 4.30-4.10 (m, 6H), 4.11 (s, 3H), 3.25-3.09 (m, 8H), 2.96 (s, 3H), 2.51 (s, 3H),
2.30-2.20 (m, 1H), 2.20-2.09 (m, 1H), 1.38 (s, 9H), 1.37 (d, J=6.8 Hz, 3H).
Example 223: Synthesis of Compound 423
H N O
NaOH
N N N
N OH
N OEt N N N
Step 1
OH O
OH O O O
Step 1: Typical ester hydrolysis conditions (NaOH, MeOH/H O, as described in Example H)
were applied to ethyl 2-(4-(tert-butyl)phenyl)chloromethylpyrimidinecarboxylate (described in
Example 221) to give 2-(4-(tert-butyl)phenyl)hydroxymethylpyrimidinecarboxylic acid as a white
solid. LCMS (Method 5-95 AB, ESI): t = 0.788 min, [M + H] = 286.9.
Compound 423 (formic acid salt) was prepared as a white solid from Compound 101-K and 2-
(4-(tert-butyl)phenyl)hydroxymethylpyrimidinecarboxylic acid by utilizing methods analogous to
those described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.690 min, [M + H] = 906.4; H NMR
(400 MHz, MeOH-d ) δ 8.44 (brs, 1H), 7.98 (d, J=8.0 Hz, 2H), 7.59 (d, J=8.0 Hz, 2H), 7.31 (d, J=8.4 Hz,
1H), 7.18 (d, J=8.8 Hz, 2H), 7.08 (d, J=8.0 Hz, 1H), 6.86 (s, 1H), 6.75 (s, 1H), 6.38 (s, 1H), 5.20-5.10 (m,
1H), 4.79-4.75 (m, 1H), 4.40-4.10 (m, 7H), 3.25-3.05 (m, 8H), 2.91 (s, 3H), 2.57 (s, 3H), 2.35-2.20 (m,
1H), 2.15-2.05 (m, 1H), 1.38 (s, 9H), 1.37 (d, J=6.8 Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 224: Synthesis of Compound 424
H N O
N NMe N
N NMe 2
Me NH N NMe NaOH HN
N Cl
N N N O
N OH
N OEt N O
N OEt
Step 2
Step 1
Step 1: A mixture of ethyl 2-(4-(tert-butyl)phenyl)chloromethylpyrimidinecarboxylate
(described in Example 221, 40 mg, 0.12 mmol), Me NH (33 mg, 33% w/w in H O, 0.24 mmol) and DIEA
(31 mg, 0.24 mmol) in DMF (5 mL) was stirred at 70 C for 3 h. The volatiles were removed and the
residue was taken up by EtOAc (20 mL), which was washed with brine (2 x 20 mL). The organic layer was
dried over MgSO , concentrated and the residue was purified by preparatory-TLC (30% EtOAc in
petroleum ether, R =0.5) to give ethyl 2-(4-(tert-butyl)phenyl)(dimethylamino)methylpyrimidine
carboxylate (30 mg, 73% yield) as a white solid. LCMS (Method 5-95 AB, ESI): t = 0.811 min, [M + H]
= 342.0.
Step 2: Typical ester hydrolysis conditions (NaOH, MeOH/H O, as described in Example H)
were applied to ethyl 2-(4-(tert-butyl)phenyl)(dimethylamino)methylpyrimidinecarboxylate to
give 2-(4-(tert-butyl)phenyl)(dimethylamino)methylpyrimidinecarboxylic acid as a white solid.
LCMS (Method 5-95 AB, ESI): t = 0.769 min, [M + H] = 313.9.
[001010] Compound 424 (formic acid salt) was prepared as a white solid from Compound 101-K and 2-
(4-(tert-butyl)phenyl)(dimethylamino)methylpyrimidinecarboxylic acid by utilizing methods
analogous to those described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.690 min, [M + H] =
933.6; H NMR (400 MHz, MeOH-d ) δ 8.50 (brs, 2H), 8.23 (d, J=8.4 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H),
7.25-7.07 (m, 3H), 7.09 (d, J=8.4 Hz, 1H), 6.90 (d, J=2.4 Hz, 1H), 6.79 (s, 1H), 6.43 (s, 1H), 5.19-5.16 (m,
1H), 4.86-4.77 (m, 2H), 4.30-4.10 (m, 6H), 3.40-3.32 (m, 1H), 3.24 (s, 6H), 3.23-3.13 (m, 7H), 3.00 (s,
3H), 2.44 (s, 3H), 2.25-2.15 (m, 1H), 2.15-2.05 (m, 1H), 1.41 (s, 9H), 1.37 (d, J=7.2 Hz, 3H).
Example 225: Synthesis of Compound 425
H N O
N NHMe
N N N O
Compound 425 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 224. LCMS (Method 5-95 AB, ESI): t = 0.690
min, [M + H] = 919.5; H NMR (400 MHz, MeOH-d ) δ 8.48 (brs, 2H), 8.27 (d, J=8.4 Hz, 2H), 7.52 (d,
J=8.4 Hz, 2H), 7.33 (d, J=8.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.91 (d, J=2.4 Hz,
1H), 6.83 (s, 1H), 6.45 (s, 1H), 5.09-5.07 (m, 1H), 4.85-4.75 (m, 2H), 4.30-4.05 (m, 6H), 3.30-3.05 (m,
11H), 2.97 (s, 3H), 2.43 (s, 3H), 2.30-2.05 (m, 2H), 1.37 (brs, 12H).
18253141_1 (GHMatters) P111789.NZ
Example 226: Synthesis of Compound 426
H N O
N NH N
O HN
N N N O
Compound 226 (trifluoroacetic acid salt) was prepared as a white solid from Compound 101-K
by utilizing the methods analogous to those described in Example 224. LCMS (Method 5-95 AB, ESI): t
= 0.660 min, [M + H] = 905.5; H NMR (400 MHz, MeOH-d ) δ 8.20 (d, J=8.4 Hz, 2H), 7.50 (d, J=8.4
Hz, 2H), 7.33 (d, J=8.8 Hz, 1H), 7.25-7.15 (m, 2H), 7.09 (d, J=8.8 Hz, 1H), 6.90 (d, J=2.4 Hz, 1H), 6.81 (s,
1H), 6.44 (s, 1H), 5.15-5.10 (m, 1H), 4.85-4.75 (m, 2H), 4.30-4.10 (m, 6H), 3.40-3.35 (m, 1H), 3.25-3.05
(m, 7H), 2.97 (s, 3H), 2.45 (s, 3H), 2.25-2.05 (m, 2H), 1.41 (s, 9H), 1.36 (d, J=7.2 Hz, 3H).
Example 227: Synthesis of Compound 427
H N O
N NH N
O HN
N N N O
K CO , DMF N O
CN CN
Step 1
Step 1: Typical alkylation condition (as described in Example 21) was applied to 4-
hydroxybenzonitrile to give 4-(3,3-dimethylbutoxy)benzonitrile as a colorless oil. H NMR (400 MHz,
CDCl ) δ 7.55 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 4.06 (t, J=7.2 Hz, 2H), 1.74 (t, J=7.2 Hz, 2H),
0.99 (s, 3H).
[001014] Compound 427 (formic acid salt) was prepared as a white solid from Compound 101-K and 4-
(3,3-dimethylbutoxy)benzonitrile by utilizing methods analogous to those described in Examples 35, 221,
and 226. LCMS (Method 5-95 AB, ESI): t = 0.711 min, [M + H] = 949.5; H NMR (400 MHz, MeOH-
d ) δ 8.45 (brs, 1H), 8.24-8.13 (m, 2H), 7.35-7.29 (m, 1H), 7.24-7.17 (m, 2H), 7.10 (d, J=8.4 Hz, 1H),
7.00-6.93 (m, 2H), 6.89 (s, 1H), 6.76 (brs, 1H), 6.51 (br s, 1H), 5.10-5.05 (m, 1H), 4.86-4.78 (m, 2H),
4.30-4.16 (m, 6H), 4.12 (t, J=7.2 Hz, 2H), 3.28-3.24 (m, 4H), 3.17-3.00 (m, 4H), 2.95 (s, 3H), 2.45-2.37
(m, 3H), 2.29-2.10 (m, 2H), 1.75 (t, J=7.2 Hz, 2H), 1.47-1.32 (m, 3H), 1.03 (s, 9H).
Example 228: Synthesis of Compound 428
H N O
N CF N
N N N O
18253141_1 (GHMatters) P111789.NZ
MeOOC SO F
NaI, TFA N CF
N N CF NaOH 3
Cl N I
2-butanone
CuI, DMF
COOH
COOEt COOEt
COOEt
Step
Step 2
Step 1
Step 1: A mixture of ethyl 2-(4-(tert-butyl)phenyl)chloromethylpyrimidinecarboxylate
(described in Example 221, 500 mg, 1.5 mmol), NaI (4.5 g, 30 mmol), and TFA (856 mg, 7.5 mmol) in 2-
butanone (3 mL) was stirred at 60 C for 2h. The volatiles were removed and the residue was taken up in
EtOAc (50 mL), which was washed with brine (2 x 50 mL). The organic layer was dried over MgSO ,
concentrated and the residue was purified by silica gel chromatography, eluting 20% EtOAc in petroleum
ether, to give ethyl 2-(4-(tert-butyl)phenyl)iodomethylpyrimidinecarboxylate (400 mg, 63% yield)
as a colorless oil. LCMS (Method 5-95 AB, ESI): t = 1.160 min, [M + H] = 424.9.
Step 2: A mixture of ethyl 2-(4-(tert-butyl)phenyl)iodomethylpyrimidinecarboxylate
(50 mg, 0.12 mmol), methyl 2,2-difluoro(fluorosulfonyl)acetate (57 mg, 0.30 mmol), and CuI (34 mg,
0.18 mmol) in DMF (2 mL) was stirred at 80 C for 15 h. The volatiles were removed and the residue was
taken up in EtOAc (20 mL), which was washed with brine (2 x 20 mL). The organic layer was dried over
MgSO , concentrated and the residue was purified by preparatory-TLC (20% EtOAc in petroleum ether, R
= 0.6) to give ethyl 2-(4-(tert-butyl)phenyl)methyl(trifluoromethyl)pyrimidinecarboxylate (25 mg,
58% yield) as a colorless oil. LCMS (Method 5-95 AB, ESI): t = 1.150 min, [M + H] = 367.0.
Step 3: Typical ester hydrolysis conditions (NaOH, MeOH/H O, described in Example H) were
applied to ethyl 2-(4-(tert-butyl)phenyl)methyl(trifluoromethyl)pyrimidinecarboxylate to give 2-
(4-(tert-butyl)phenyl)methyl(trifluoromethyl)pyrimidinecarboxylic acid as a white solid. LCMS
(Method 5-95 AB, ESI): t = 1.020 min, [M + H] = 339.0.
[001018] Compound 428 (formic acid salt) was prepared as a white solid from Compound 101-K and 2-
(4-(tert-butyl)phenyl)methyl(trifluoromethyl)pyrimidinecarboxylic acid by utilizing methods
analogous to those described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.750 min, [M + H] =
958.5; H NMR (400 MHz, MeOH-d ) δ 8.42 (d, J=8.4 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H), 7.30-7.19 (m, 3H),
7.10 (d, J=8.0 Hz, 1H), 6.90 (s, 1H), 6.79 (s, 1H), 6.40 (s, 1H), 5.26-5.23 (m, 1H), 4.80-4.75 (m, 1H),
4.35-4.10 (m, 7H), 3.33-3.09 (m, 8H), 3.00 (s, 3H), 2.40-2.20 (m, 1H), 2.20-2.05 (m, 1H), 1.39 (s, 9H),
1.35 (d, J=6.8 Hz, 3H).
Example 229: Synthesis of Compound 429
N NH N CN
O HN
N N N O
NH O O
18253141_1 (GHMatters) P111789.NZ
O MeO
EtO NH
EtOH 2
1) MeOH/H O
CN N NHPMB 2
N NH
PTSA CAN 2 N NH
PMBHN N toluene NaOH
MeCN,H O
MeS SMe NH COOEt
2 COOEt
COOH
Step 2 Step 4
NH NH Step 3
2 NH
2 NH
TEA, EtOH
Step 1
Step 1: A solution of ethyl 2-cyano-3,3-bis(methylthio)acrylate (900 mg, 4.1 mmol) and (4-
methoxyphenyl)methanamine (682 mg, 5.0 mmol) in EtOH (16 mL) was stirred at 60 C for 2 h. After
cooling the mixture to 0 C, 4-(tert-butyl)benzimidamide (725 mg, 4.1 mmol) and triethylamine (1.71 mL,
12.3 mmol) were added. The resulting mixture was stirred at 60 C for 22 h. The volatiles were removed
under reduced pressure and the residue was taken up by EtOAc (40 mL), which was washed with brine (40
mL). The organic layer was dried over Na SO and the residue was purified by preparatory reverse-phase
HPLC to give (E)-ethyl 3-((Z)-(amino(4-(tert-butyl)phenyl)methylene)amino)cyano((4-
methoxybenzyl)amino)acrylate (220 mg, 17.5% yield) as a white solid.
[001020] Step 2: A solution of (E)-ethyl 3-((Z)-(amino(4-(tert-butyl)phenyl)methylene)amino)cyano
((4-methoxybenzyl)amino)acrylate (250 mg, 0.58 mmol) and p-TsOH (5.0 mg, 0.03 mmol) in toluene (8
mL) was stirred at 110 C for 3 days under N . The volatiles were removed under reduced pressure and the
residue was taken up by EtOAc (40 mL), which was washed with brine (40 mL). The organic layer was
dried over Na SO and the residue was purified by preparatory-TLC (eluent: EtOAc: petroleum ether = 1:3,
Rf =0.5) to give ethyl 4-amino(4-(tert-butyl)phenyl)((4-methoxybenzyl)amino)pyrimidine
carboxylate (130 mg, 52% yield) as a white solid. LCMS (Method 5-95 AB, ESI): t = 0.809 min, [M +
H] = 435.1.
Step 3: A solution of ethyl 4-amino(4-(tert-butyl)phenyl)((4-
methoxybenzyl)amino)pyrimidinecarboxylate (120 mg, 0.28 mmol) and (NH ) Ce(NO ) (454 mg, 0.83
4 2 3 6
mmol) in MeCN/H O (0.4 mL, v/v=1/1) was stirred at 0 C for 30 min. The reaction was washed with
saturated Na CO (15 mL), which was extracted with EtOAc (3 x 15 mL). The combined organic layers
were concentrated and the residue was purified by preparatory-TLC (EtOAc: petroleum ether= 1:3) to
afford ethyl 4,6-diamino(4-(tert-butyl)phenyl)pyrimidinecarboxylate (15 mg, 17% yield).
Step 4: Typical ester hydrolysis conditions (NaOH, MeOH/H O, described in Example H) were applied to
ethyl 4,6-diamino(4-(tert-butyl)phenyl)pyrimidinecarboxylate to give 4,6-diamino(4-(tert-
butyl)phenyl)pyrimidinecarboxylic acid as a white solid. LCMS (Method 5-95 AB, ESI): t = 0.902 min,
[M + H] = 286.9.
Compound 429 (formic acid salt) was prepared as a white solid from Compound 101-K and 2-
(4-(tert-butyl)phenyl)methyl(trifluoromethyl)pyrimidinecarboxylic acid by utilizing methods
analogous to those described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.676 min, [M + H] =
906.6; H NMR (400 MHz, MeOH-d ) δ 8.34 (brs, 1H), 8.14 (d, J=8.8 Hz, 1H), 8.07 (d, J=8.0 Hz, 1H),
7.47 (t, J=8.8 Hz, 2H), 7.34-7.28 (m, 2H), 7.21-7.18 (m, 2H), 7.11-7.06 (m, 2H), 6.89-6.77 (m, 1H), 6.51-
6.48 (m, 1H), 5.17-5.10 (m, 1H), 4.80-4.72 (m, 2H), 4.30-4.05 (m, 4H), 4.17 (s, 2H), 3.28-2.90 (m, 11H),
2.26-2.18 (m, 1H), 2.16-2.10 (m, 1H), 1.42 (s, 9H), 1.41 (d, J=6.8 Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 230: Synthesis of Compound 430
O HN
N N O
Compound 430 (trifluoroacetic acid salt) was prepared as a white solid by utilizing methods
analogous to those described in Example 5 and Example O. LCMS (Method 5-95 AB, ESI): t = 0.791 min,
[M + H] = 803.5; H NMR (400 MHz, MeOH-d ) δ 7.86 (d, J=8.0 Hz, 2H), 7.74 (d, J=8.0 Hz, 1H), 7.67
(d, J=8.0 Hz, 1H), 7.27 (d, J=8.0 Hz, 2H), 7.16 (d, J=8.0 Hz, 1H), 7.08-6.91 (m, 4H), 6.91 (s, 1H), 6.86 (s,
1H), 6.47 (s, 1H), 5.20-5.15 (m, 1H), 4.68-4.57 (m, 2H), 4.20 (s, 2H), 3.17-3.05 (m, 4H), 2.93 (s, 3H), 2.68
(s, 3H), 2.55 (d, J=6.8 Hz, 2H), 2.33-2.24 (m, 1H), 2.20-2.11 (m, 1H), 1.96-1.87 (m, 1H), 1.36 (d, J=6.4
Hz, 3H), 0.94 (d, J=6.4 Hz, 6H).
Example 231: Synthesis of Compound 431
O HN
N N N O
Compound 431 (formic acid salt) was prepared as a white solid by utilizing methods analogous
to those described in Example J and Example O. LCMS (Method 5-95 AB, ESI): t = 0.814 min, [M + H]
= 804.4; H NMR (400 MHz, MeOH-d ) δ 8.80 (s, 1H), 8.50 (br s, 1H), 8.23 (d, J=8.0 Hz, 2H), 8.51 (d,
J=8.0 Hz, 2H), 7.20-7.02 (m, 3H), 6.99 (d, J=8.0 Hz, 1H), 6.93 (s, 1H), 6.86 (s, 1H), 6.75 (s, 1H), 5.21-
.15 (m, 1H), 4.83-4.77 (m, 1H), 4.60-4.54 (m, 1H), 4.27 (s, 2H), 3.20-2.85 (m, 4H), 2.96 (s, 3H), 2.55 (s,
3H), 2.32-2.19 (m, 2H), 1.45 (s, 9H), 1.39 (d, J=6.8 Hz, 3H).
Example 232: Synthesis of Compound 432
N N N O
[001025] Compound 432 (trifluoroacetic acid salt) was prepared as a white solid by utilizing methods
analogous to those described in Example O. LCMS (Method 5-95 AB, ESI): t = 0.833 min, [M + H] =
818.5; H NMR (400 MHz, MeOH-d ) δ 8.80 (s, 1H), 8.28 (d, J=7.6 Hz, 2H), 7.31 (d, J=7.6 Hz, 2H), 7.13
(d, J=7.6 Hz, 1H), 7.05-6.90 (m, 3H), 6.87-6.78 (m, 2H), 6.53 (s, 1H), 5.19-5.11 (m, 1H), 4.70-4.50 (m,
2H), 4.23 (s, 2H), 3.20-3.09 (m, 2H), 3.07-2.99 (m, 2H), 2.95 (s, 3H), 2.73-2.65 (m, 2H), 2.62 (s, 3H),
2.29-2.20 (m, 1H), 2.18-2.12 (m, 1H), 1.72-1.59 (m, 2H), 1.39-1.29 (m, 7H), 0.94 (br s, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 233: Synthesis of Compound 433
H N O
O HN
N N N O
Compound 433 (formic acid salt) was prepared as a white solid by utilizing methods analogous
to those described in Example J and Example O. LCMS (Method 5-95 AB, ESI): t = 0.731 min, [M + H]
= 918.8; H NMR (400 MHz, MeOH-d ) δ 8.79 (s, 1H), 8.52 (br s, 2H), 8.37 (d, J=8.8 Hz, 2H), 7.55 (d,
J=8.0 Hz, 2H), 7.31-7.28 (m, 1H), 7.20-7.17 (m, 2H), 7.13 (d, J=8.8 Hz, 1H), 7.02 (d, J=8.0 Hz,
1H), 6.84 (d, J=3.2 Hz, 1H), 6.73 (s, 1H), 6.38 (s, 1H), 5.19-5.16 (m, 1H), 4.82-4.75 (m, 2H), 4.26-4.02 (m,
4H), 4.20 (s, 2H), 3.40-3.30 (m, 1H), 3.14-3.06 (m, 3H), 2.99-2.93 (m, 4H), 2.97 (s, 3H), 2.69 (s, 3H),
2.31-2.00 (m, 4H), 1.38 (s, 9H), 1.35 (d, J=7.2 Hz, 3H).
Example 234: Synthesis of Compound 434
H N O
O HN
N N N O
Compound 434 (formic acid salt) was prepared as a white solid by utilizing methods analogous
to those described in Example 53 and Example O. LCMS (Method 5-95 AB, ESI): t = 0.602 min, [M +
H] = 932.4; H NMR (400 MHz, MeOH-d ) δ 8.51 (br s, 2H), 8.27 (d, J=8.8 Hz, 2H), 7.50 (d, J=8.8 Hz,
2H), 7.26 (d, J=8.4 Hz, 1H), 7.15 (d, J=8.8 Hz, 2H), 7.02 (d, J=8.4 Hz, 1H), 6.82 (s, 1H), 6.63 (s, 1H),
6.48 (s, 1H), 5.27-5.23 (m, 1H), 4.77-4.74 (m, 2H), 4.28-4.04 (m, 4H), 4.22 (s, 2H), 3.12 (t, J=7.9 Hz, 2H),
3.08-2.97 (m, 6H), 3.03 (s, 3H), 2.52 (s, 6H), 2.32-2.24 (m, 1H), 2.19-2.03 (m, 4H), 1.38 (s, 9H), 1.34 (d,
J=6.8 Hz, 3H).
Example 235: Synthesis of Compound 435
H N O
O HN
N N N O
Compound 435 (formic acid salt) was prepared as a white solid by utilizing methods analogous
to those described in Example 128 and Example O. LCMS (Method 5-95 AB, ESI): t = 0.626 min, [M +
H] = 962.4; H NMR (400 MHz, MeOH-d ) δ 8.51 (br s, 2H), 8.25 (d, J=8.4 Hz, 2H), 7.28-7.24 (m, 1H),
7.16 (d, J=8.4 Hz, 1H), 7.10 (br s, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.96 (d, J=8.4 Hz, 2H), 6.82 (s, 1H), 6.58
(s, 1H), 6.53 (s, 1H), 5.30-5.23 (m, 1H), 4.81-4.75 (m, 2H), 4.32-4.19 (m, 4H), 4.08-4.04 (m, 4H), 3.13 (t,
J=7.6 Hz, 2H), 3.11-2.92 (m, 6H), 3.03 (s, 3H), 2.47 (s, 6H), 2.31-2.23 (m, 1H), 2.19-2.16 (m, 1H), 2.14-
1.99 (m, 4H), 1.87-1.78 (m, 2H), 1.53-1.41 (m, 4H), 1.34 (d, J=6.8 Hz, 3H), 0.98 (t, J=7.2Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 236: Synthesis of Compound 436
H N O
N NH N
O HN
N N N O
Compound 436 (formic acid salt) was prepared as a white solid by utilizing methods analogous
to those described in Example 226 and Example O. LCMS (Method 5-95 AB, ESI): t = 0.722 min, [M +
H] = 977.4; H NMR (400 MHz, MeOH-d ) δ 8.46 (br s, 1H), 8.24 (d, J=8.8 Hz, 2H), 7.32-7.29 (m, 1H),
7.21 (d, J=8.4 Hz, 1H), 7.12 (d, J=8.8 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.98 (d, J=8.8 Hz, 2H), 6.85 (s,
1H), 6.76 (s, 1H), 6.42 (s, 1H), 5.12-5.05 (m, 1H), 4.79-4.75 (m, 2H), 4.29-4.03 (m, 8H), 3.40-3.30 (m,
2H), 3.15-2.85 (m, 6H), 2.94 (s, 3H), 2.44 (s, 3H), 2.30-1.98 (m, 2H), 1.75 (t, J=7.2 Hz, 2H), 1.40-1.30 (m,
4H), 1.02 (s, 9H).
Example 237: Synthesis of Compound 437
H N O
O HN
N N N
Compound 437 (formic acid salt) was prepared as a white solid by utilizing methods analogous
to those described in Example 53 and Example O. LCMS (Method 5-95 AB, ESI): t = 0.724 min, [M +
H] = 960.5; H NMR (400 MHz, MeOH-d ) δ 8.53 (br s, 2H), 8.23 (d, J=8.0 Hz, 2H), 7.47 (d, J=8.0 Hz,
2H), 7.23 (d, J=8.0 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 7.00-6.97 (m, 2H), 6.79 (d, J=2.4 Hz, 1H), 6.56 (s,
1H), 6.51 (s, 1H), 5.30-5.27 (m, 1H), 4.79-4.74 (m, 2H), 4.21 (s, 2H), 4.19-4.00 (m, 4H), 3.11 (t, J=8.0 Hz,
2H), 3.02 (s, 3H), 2.97-2.84 (m, 6H), 2.47 (s, 6H), 2.32-2.23 (m, 1H), 2.18-2.09 (m, 1H), 1.88-1.72 (m,
8H), 1.39 (s, 9H), 1.34 (d, J=7.2 Hz, 3H).
Example 238: Synthesis of Compound 438
H N (S)
O HN
N N N O
NHBoc
NHBoc NHBoc
MsCl, TEA
LiBr
HO MsO
DCM acetone
Step 1 Step 2
Step 1: To a solution of tert-butyl-(S)hydroxymethylethylcarbamate (3.9 g, 22.3 mmol)
and triethylamine (5.6 g, 55.6 mmol) in DCM (30 mL) was dropwise added methanesulfonyl chloride
18253141_1 (GHMatters) P111789.NZ
(3.77 g, 32.9 mmol) at 0 °C. The resulting mixture was gradually warmed up while stirring and stirred at
°C for 6 h. The reaction was diluted with DCM (40 mL), which was washed with saturated aqueous
NaHCO and brine (each 40 mL). The organic layer was dried over Na SO , concentrated and the residue
3 2 4
was purified on silica gel column, eluting with 0-20% EtOAc in petroleum ether, to give (S)(tert-
butoxycarbonylamino)propyl methanesulfonate (3.0 g, 53% yield) as a white solid.
Step 2: A solution of (S)(tert-butoxycarbonylamino)propyl methanesulfonate (3.0 g, 11.8
mmol) and LiBr (4.1 g, 47.4 mmol) in acetone (10 mL) was stirred at 25 °C for 16 h. The reaction was
diluted with EtOAc (40 mL) and washed with saturated aqueous NaHCO and brine (each 40 mL). The
organic layer was dried over Na SO , concentrated and the residue was purified on silica gel column,
eluting with 0-20% EtOAc in petroleum ether, to give tert-butyl N-(S)bromomethyl-ethyl carbamate
(1.8 g, 64% yield) as a white solid.
Compound 438 (formic acid salt) was prepared as a white solid from tert-butyl N-(S)bromo-
1-methyl-ethyl carbamate utilizing methods analogous to those described in Example J and Example O.
LCMS (Method 5-95 AB, ESI): t = 0.733 min, [M + H] = 918.5; H NMR (400 MHz, MeOH-d ) δ 8.72
(s, 1H), 8.49 (br s, 3H), 8.24 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.4 Hz, 1H), 7.24 (d,
J=8.4 Hz, 1H), 7.15-7.05 (m, 2H), 6.84 (s, 1H), 6.58 (br s, 2H), 5.25-5.15 (m, 1H), 4.80-4.65 (m, 2H),
4.25-4.00 (m, 4H), 4.20 (s, 2H), 3.65-3.45 (m, 2H), 3.20-3.00 (m, 4H), 2.97 (s, 3H), 2.65 (s, 3H), 2.35-2.15
(m, 2H), 1.39 (s, 9H), 1.36 (d, J=7.2 Hz, 3H), 1.34 (d, J=7.2 Hz, 3H), 1.23 (d, J=6.4 Hz, 3H).
Example 239: Synthesis of Compound 439
H N O
N N CN
O HN
N N N O
O Br O
NaN , CeCl
K CO 3 3 OH
H OMe
Cbz N O HN
Cbz N O
Cbz N O
Step 1 N O
Step 2
101-E O
439-1
439-2
OH OH
NH NHBoc
NHBoc
PPh , H O
Boc Et N
OH O, OH
OMe OMe
HN HN
Step 4 H
Cbz N O Cbz N O
N O N O
Step 3
439-3
439-4
18253141_1 (GHMatters) P111789.NZ
Step 1: A mixture of compound 101-E (300 mg, 0.53 mmol), 2-(bromomethyl)oxirane (732 mg,
.3 mmol) and K CO (738 mg, 5.3 mmol) in DMF (10 mL) was stirred at 50 °C for 4 h. The reaction was
taken up by EtOAc (100 mL), which was washed with brine (3 x 100 mL). The organic layer was dried
over Na SO , concentrated, and the residue was purified by preparatory reverse-phase HPLC (water
(0.225% formic acid)-acetonitrile) to give compound 439-1 (200 mg, 56% yield) as a white solid. LCMS
(Method 5-95 AB, ESI): t = 0.868 min, [M + H] = 674.3.
Step 2: A solution of compound 439-1 (300 mg, 0.45 mmol), sodium azide (675 mg, 10.3 mmol)
and CeCl (56 mg, 0.22 mmol) in acetonitrile (9 mL) was stirred at 75 °C for 12 h. The reaction mixture
was taken up by EtOAc (50 ml), which was washed with saturated aqueous Na CO solution (30 mL). The
organic layer was dried over Na SO , concentrated and the residue was purified by preparatory-TLC
(eluting with 10% MeOH in DCM, Rf=0.4) to give compound 439-2 (175 mg, 48% yield) as a white solid.
LCMS (Method 5-95 AB, ESI): t = 0.883 min, [M + H] = 760.2.
Step 3: A solution of compound 439-2 (175 mg, 0.23 mmol) and PPh (104 mg, 0.39 mmol) in
THF/H O (11 mL, v/v=10/1) was stirred at 50 °C for 12 h. The reaction mixture was taken up by EtOAc
(50 mL), which was washed with saturated aqueous Na CO solution (30 mL). The organic layer was dried
over Na SO , concentrated and the residue was purified by preparatory-TLC (eluting with 10% MeOH in
DCM, Rf=0.5) to give compound 439-3 (165 mg, 99% yield) as a white solid. LCMS (Method 5-95 AB,
ESI): t = 0.694 min, [M + H] = 708.3.
Step 4: A solution of compound 439-3 (165 mg, 0.23 mmol), Boc O (109 mg, 0.50 mmol) and
triethylamine (60 mg, 0.59 mmol) in DCM (5 mL) was stirred at 20 °C for 12 h. The volatiles were
removed under reduced pressure and the residue was taken up in EtOAc (30 mL), which was washed with
brine (2 x 30 mL). The organic layer was dried over Na SO , concentrated and the residue was then
purified by preparatory-TLC (eluting with 10% MeOH in DCM, Rf=0.3) to give compound 439-4 (150 mg,
70% yield) as a white solid. LCMS (Method 5-95 AB, ESI): t = 0.908 min, [M + Na] = 930.5.
[001038] Compound 439 (formic acid salt) was prepared as a white solid from compound 439-4 and
utilizing methods analogous to those described in Example 53. LCMS (Method 5-95 AB, ESI): t = 0.720
min, [M + H] = 964.5; H NMR (400 MHz, MeOH-d ) δ 8.53 (br s, 2H), 8.20 (d, J=8.0 Hz, 2H), 7.47 (d,
J=8.0 Hz, 2H), 7.28-7.20 (m, 2H), 7.02 (d, J=8.0 Hz, 2H), 6.80 (s, 1H), 6.61 (s, 1H), 6.49 (s, 1H), 5.36-
.20 (m, 1H), 4.82-4.60 (m, 2H), 4.30-3.90 (m, 6H), 4.20 (s, 2H), 3.20-2.60 (m, 11H), 2.46 (s, 6H), 2.35-
2.23 (m, 1H), 2.18-2.10 (m, 1H), 1.39 (s, 9H), 1.34 (d, J=6.8 Hz, 3H).
Example 240: Synthesis of Compound 440
18253141_1 (GHMatters) P111789.NZ
N CN
O HN
N N N O
OH O
m-CPBA
HN OMe
K CO , DMF DCM OMe
H HN
Cbz N O H
Cbz N O
Cbz N O
Step 1
Step 2 O
101-E 440-1
440-2
Step 1: A mixture of compound 101-E (300 mg, 0.53 mmol), 3-bromo(bromoethyl)- 1-
propene (0.31 mL, 2.7 mmol) and K CO (369 mg, 2.7 mmol) in DMF (5 mL) was stirred at 25 °C for 3 h.
The reaction was taken up by EtOAc (30 mL), which was washed with brine (2 x 30 mL). The organic
layer was dried over Na SO , concentrated and the residue was purified by preparatory-TLC (eluting with
2% MeOH in DCM, Rf=0.3) to give compound 440-1 (300 mg, 92% yield) as a white solid. LCMS
(Method 5-95 AB, ESI): t = 0.906 min, [M + H] = 614.1.
Step 2: A solution of compound 440-1 (150 mg, 0.24 mmol) and m-CPBA (422 mg, 2.4
mmol) in DCM (20 mL) was stirred at 0 °C for 30 min, then warmed up to 20 °C while stirring and stirred
for 12 h at the same temperature. The mixture was washed with saturated aqueous NaHCO and brine
(each 30 mL). The organic layer was dried over Na SO , concentrated and the residue was purified by
preparatory-TLC (eluting with 3% MeOH in DCM, Rf=0.3) to give compound 440-2 (120 mg, 78%
yield) as a yellow solid. LCMS (Method 5-95 AB, ESI): t = 0.759 min, [M + Na] = 652.1.
[001041] Compound 440 (trifluoroacetic acid salt) was prepared as a white solid from compound 440-2
and utilizing methods analogous to those described in Example 239. LCMS (Method 5-95 AB, ESI): t =
0.751 min, [M + H] = 903.4; H NMR (400 MHz, MeOH-d ) δ 8.32-8.20 (m, 2H), 7.53-7.48 (m, 2H),
7.45-7.10 (m, 4H), 7.08 (br s, 1H), 6.66 (br s, 1H), 6.61 (br s, 1H), 5.31-5.28 (m, 1H), 4.85-4.75 (m, 2H),
4.65-4.55 (m, 2H), 4.49-4.45 (m, 3H), 4.31-4.24 (m, 3H), 3.15 (t, J=6.8 Hz, 2H), 3.06-2.89 (m, 2H), 2.99
(s, 3H), 2.51 (br s, 6H), 2.30-2.15 (m, 2H), 1.40 (s, 9H), 1.37 (d, J=6.8 Hz, 3H).
Example 241: Synthesis of Compound 441
18253141_1 (GHMatters) P111789.NZ
HN NH
HN N O
N N CN
O HN
N N N O
NHTeoc
NHBoc NHTeoc
BocHN TeocHN
TeocHN O
TFA/HFIP
TEAF
Teoc N N CN
OMe OMe
NH HN O HN
H H H
2 N N N O
Cbz NH O Cbz N O (S)
Step 3
N O N O
Et N
2) 3
101-F 441-1 Step 2
1 NHBoc
Step
441-2
HN NH
H N O N
HCl HN N O
NH N
Et HN
N/DCM
N NH CN
O NH
N N CN
N NH NH O
(S) H
N N N O
Step 4
NHBoc
441-3
NHBoc
441-4
Step 1: A solution of compound 101-F (200 mg, 0.24 mmol) in 5% TFA in HFIP (5 mL) was
stirred at 20 °C for 1 h. The volatiles were removed under reduced pressure and the residue was added to a
solution of 4-nitrophenyl (2-(trimethylsilyl)ethyl) carbonate (230 mg, 0.81 mmol) and Et N (352 mg, 3.5
mmol) in DCM (20 mL). The resulting mixture was stirred at 20 °C for 16 h. The reaction was quenched
with water (30 mL) and the organic layer was washed with brine (30 mL), dried over Na SO , concentrated
and the residue was purified by preparatory TLC (eluting with 10% MeOH in DCM, Rf=0.3) to give
compound 441-1 (200 mg, 92% yield) as a yellow solid. LCMS (Method 5-95 AB, ESI): t = 1.097 min,
[M + Na] = 958.5.
Step 2: Compound 441-2 was prepared as a white solid from compound 441-1 and utilizing
methods analogous to those described in Example 53. LCMS (Method 5-95 AB, ESI): t = 1.204 min, [M
+ H] = 1294.0.
Step 3: A solution of compound 441-2 (50 mg, 0.04 mmol) and tetrabutylammonium fluoride
(69 mg, 0.31 mmol) in DMF (3 mL) was stirred at 50 °C for 1.5 h. The reaction was diluted with EtOAc
(50 mL), which was washed with brine (2 x 50 mL). The organic layer was dried over Na SO and
evaporated in vacuo to give compound 441-3 (38 mg, 0.038 mmol, 98% yield) as a white solid, which was
used directly in the next step. LCMS (Method 5-95 AB, ESI): t = 0.814 min, [M + H] = 1004.7.
Step 4: A solution of compound 441-3 (38 mg, 0.040 mmol), N-methylpyrazole
carboxamidine (19 mg, 0.15 mmol) and Et N (57 mg, 0.57 mmol) in DCM (2 mL) was stirred at 20 °C for
2 days. The reaction was quenched with water (10 mL), which was extracted with EtOAc (3 x 15 mL). The
combined organic layers were washed with brine (50 mL), dried over Na SO , concentrated and the
18253141_1 (GHMatters) P111789.NZ
residue was purified by preparatory-TLC (eluting with 10% MeOH in DCM, Rf=0.1) to give compound
441-4 (20 mg, 45% yield) as a white solid. LCMS (Method 5-95 AB, ESI): t = 0.699 min, [M + H] =
1116.6.
Step 5: Typical Boc removal condition (TFA/HFIP, described in Example G) was applied to
compound 441-4 to give compound 440 (formic acid salt) as a white solid. LCMS (Method 5-95 AB, ESI):
t = 0.723 min, [M + H] = 1016.6; H NMR (400 MHz, MeOH-d ) δ 8.50 (br s, 1H), 8.34 (d, J=8.4 Hz,
2H), 7.55 (d, J=8.4 Hz, 2H), 7.37-7.00 (m, 4H), 6.89 (s, 1H), 6.77 (s, 1H), 6.43 (s, 1H), 5.23-5.19 (m, 1H),
4.85-4.76 (m, 2H), 4.25-4.00 (m, 4H), 4.21 (s, 2H), 3.73-3.42 (m, 4H), 3.27-2.95 (m, 7H), 2.67 (s, 3H),
2.62 (s, 6H), 2.60 (s, 3H), 2.34-2.10 (m, 2H), 1.38 (s, 9H), 1.31 (d, J=7.2 Hz, 3H).
Example 242: Synthesis of Compound 442
N N CN
O HN
N N N O
NHBoc
BocHN
N N CN
O HN
N N N O
NH O
Step 1
NHFmoc
101-G
442-1
HCHO,
NaBH(OAc)
DCM N N CN
O HN
N N N O
Step 2
NHFmoc
442-2
Step 1: Compound 442-1 was prepared as a white solid using by using compound 101-G and
utilizing methods analogous to those described in Example J. LCMS (Method 5-95 AB, ESI): t = 0.865
min, [M + H] = 1113.9.
Step 2: A mixture of compound 442-1 (200 mg, 0.17 mmol) and (HCHO) (104 mg, 3.45 mmol),
triethylamine (72 μL, 0.52 mmol), acetic acid (60 μL, 1.04 mmol) and NaBH CN (217 mg, 3.45mmol) in
MeOH/H O (5.5 mL, v/v=10/1) was stirred at 15 °C for 32 h. The volatiles were removed under reduced
pressure and the residue was purified by preparatory reverse-phase HPLC (acetonitrile 20-50%/0.225%
formic acid in water) to afford compound 442-2 (60 mg, 30% yield) as a white solid. LCMS (Method 5-95
AB, ESI): t = 0.863 min, [M + H] = 1168.8.
18253141_1 (GHMatters) P111789.NZ
Step 3: A solution of compound 442-2 (50 mg, 0.04 mmol) and quinuclidine (24 mg, 0.21
mmol) in DCM (5 mL) was stirred at 20 °C for 48 h. The volatiles were removed under reduced pressure
and the residue was purified by reverse-phase HPLC (acetonitrile 0-40%/0.225% formic acid in water) to
afford to give compound 442 (formic acid salt) (9.5 mg, 0.01 mmol, 23% yield) as a white solid. LCMS
(Method 5-95 AB, ESI): t = 0.725 min, [M + H] = 946.6; H NMR (400 MHz, MeOH-d ) δ 8.76 (s, 1H),
8.52 (br s., 1H), 8.33 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H), 7.30-7.24 (m, 1H), 7.18-7.08 (m, 2H),
6.99 (d, J=8.4 Hz, 1H), 6.80 (d, J=2.4 Hz, 1H), 6.69 (s, 1H), 6.41 (s, 1H), 5.21-5.14 (m, 1H), 4.82-4.72 (m,
2H), 4.30-4.08 (m, 4H), 4.22 (s, 2H), 3.21-3.02 (m, 4H), 2.91 (s, 3H), 2.89-2.81 (m, 4H), 2.66 (s, 3H), 2.37
(s, 6H), 2.27 (s, 6H), 1.38 (s, 9H), 1.34 (d, J=6.4 Hz, 3H).
Example 243: Synthesis of Compound 443
N N O
MeNH HCl,
1) H
HATU/DIEA
Cbz O
LiOH, THF/H O
2) 2
COOH
Step 1 O
Step 1: Typical amide coupling (HATU/DIEA) and ester hydrolysis (LiOH, THF/H O)
conditions, as described in Examples E and G, were applied to Cbz-Asp-OMe to give N -
((benzyloxy)carbonyl)-N -methyl-L-asparagine as a white solid. LCMS (Method 5-95 AB, ESI): t = 0.567,
[M + H] = 281.1
Compound 443 (trifluoroacetic acid salt) was prepared as a white solid from Compound 101-G
and N -((benzyloxy)carbonyl)-N -methyl-L-asparagine by utilizing methods analogous to those described
in Example G. LCMS (Method 5-95 AB, ESI): t = 0.815 min, [M + H] = 896.6; H NMR (400 MHz,
MeOH-d ) δ 7.25-7.01 (m, 7H), 6.87 (s, 1H), 6.80 (s, 1H), 6.28 (s, 1H), 4.95-4.75 (m, 3H), 4.35-4.20 (m,
4H), 4.18 (s, 2H), 3.30-3.00 (m, 8H), 2.79 (d, J=8.0 Hz, 3H), 2.69 (s, 3H), 2.62-2.59 (m, 2H), 2.41 (s, 3H),
1.60 (br s, 2H), 1.45-1.29 (m, 13H), 0.87 (t, J=6.8 Hz, 3H).
Example 244: Synthesis of Compound 444
18253141_1 (GHMatters) P111789.NZ
Compound 444 (formic acid salt) was prepared as a white solid from compound 101-G by
utilizing methods analogous to those described in Example 243. LCMS (Method 5-95 AB, ESI): t = 0.815
min, [M + H] = 896.6; H NMR (400 MHz, MeOH-d ) δ 8.54 (br s, 1H), 7.31-7.29 (m, 2H), 7.22 (d,
J=8.0 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H), 7.08-7.04 (m, 3H), 6.87 (d, J=2.4 Hz, 1H), 6.72 (s, 1H), 6.48 (s,
1H), 5.08-5.04 (m, 1H), 4.79-4.76 (m, 2H), 4.19-4.12 (m, 6H), 3.31-3.30 (m, 1H), 3.15-3.06 (m, 4H),
3.05(s, 3H), 3.01 (s, 3H), 2.92 (s, 3H), 2.65-2.51 (m, 3H), 2.37 (s, 3H), 2.24-2.17 (m, 1H), 2.03-1.98 (m,
1H), 1.60-1.58 (m, 2H), 1.35-1.29 (m, 15H), 0.89 (t, J=6.8 Hz, 3H).
Example 245: Synthesis of Compound 445
[001053] Compound 445 (formic acid salt) was prepared as a white solid from compound 101-G by
utilizing methods analogous to those described in Example 243. LCMS (Method 5-95 AB, ESI): t = 0.814
min, [M + H] = 924.7; H NMR (400 MHz, MeOH-d ) δ 8.51 (br s, 1H),7.37 (d, J=8.0 Hz, 1H), 7.31 (d,
J=8.4 Hz, 1H),7.24 (d, J=8.0 Hz, 1H),7.16 (d, J=8.4 Hz, 1H),7.11-7.05 (m, 3H), 6.89 (s, 1H), 6.81 (s, 1H),
6.44 (s, 1H), 5.00-4.75 (m, 3H), 4.25-4.15 (m, 4H), 4.20 (s, 2H), 3.21-3.18 (m, 6H), 2.99 (s, 3H), 2.61 (t,
J=7.6 Hz, 2H), 2.41-2.35 (m, 1H), 2.04-1.92 (m, 1H), 1.61 (br s, 2H), 1.39-1.25 (m, 14H), 1.09 (t, J=7.2
Hz, 3H), 0.90 (t, J=6.8 Hz, 3H).
Example 246: Synthesis of Compound 446
Compound 446 (formic acid salt) was prepared as a white solid from compound 101-G by
utilizing methods analogous to those described in Example 243. LCMS (Method 5-95 AB, ESI): t = 0.696
min, [M + H] = 940.6; H NMR (400 MHz, MeOH-d ) δ 8.48 (br s, 2H), 7.38 (d, J=7.5 Hz, 1H), 7.31 (d,
J=8.0 Hz, 1H), 7.24 (d, J=7.5 Hz, 1H), 7.15 (d, J=8.0 Hz, 1H), 7.05-7.11 (m, 3H), 6.89 (br s, 1H), 6.81 (br
s, 1H), 6.40 (s, 1H), 5.01-4.97 (m, 1H), 4.80-4.75 (m, 2H), 4.26-4.16 (m, 6H), 3.57 (t, J=6.4 Hz, 2H), 3.21-
3.14 (m, 4H), 2.98 (s, 3H), 2.60 (t, J=6.4 Hz, 2H), 2.45-2.37 (s, 5H), 2.29-2.19 (m, 2H), 2.05-1.93 (m, 2H),
1.63-1.57 (m, 2H), 1.44-1.22 (m, 15H), 0.92-0.85 (m, 3H).
Example 247: Synthesis of Compound 447
18253141_1 (GHMatters) P111789.NZ
Compound 447 (trifluoroacetic acid salt) was prepared as a white solid from compound 101-G
by utilizing methods analogous to those described in Example 243. LCMS (Method 5-95 AB, ESI): t =
0.782 min, [M + Na] = 974.7; H NMR (400 MHz, MeOH-d ) δ 7.30-7.24 (m, 2H), 7.19 (d, J=8.0 Hz,
1H), 7.10 (d, J=8.0 Hz, 1H), 7.03-7.01 (m, 3H), 6.82 (s, 1H), 6.67 (br s, 1H), 6.50 (br s, 1H), 5.07-5.03 (m,
1H), 4.78-4.73 (m, 2H), 4.34-4.29 (m, 1H), 4.23-4.19 (m, 3H), 4.12-4.07 (m, 4H), 4.00-3.95 (m, 1H), 3.62-
3.53 (m, 2H), 3.13-3.06 (m, 1H), 2.98-2.82 (m, 7H), 2.53-2.51 (m, 3H), 2.35 (br s, 3H), 2.28-2.24 (m, 1H),
2.15-2.00 (m, 1H), 1.63-1.48 (m, 2H), 1.34-1.23 (m, 15H), 0.90 (t, J=6.4 Hz, 3H).
Example 248: Synthesis of Compound 448
Compound 448 (trifluoroacetic acid salt) was prepared as a white solid from compound 101-G
by utilizing methods analogous to those described in Example 243. LCMS (Method 5-95 AB, ESI): t =
0.794 min, [M + H] = 971.2; H NMR (400 MHz, MeOH-d ) δ 7.33 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.0 Hz,
1H), 7.20 (d, J=8.0 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 7.04-7.02 (m, 3H), 6.84-6.83 (m, 1H), 6.69 (s, 1H),
6.48 (s, 1H), 5.04-5.01(m, 1H), 4.77-4.75 (m, 2H),4.19 (s, 2H), 4.12-3.90 (m, 5H), 3.63-3.59 (m, 3H),
3.25-3.27 (m, 1H) 3.14-3.07 (m, 1H), 2.98-2.89 (m, 6H), 2.55-2.41 (m, 4H), 2.36 (br s, 3H), 2.26-2.17 (m,
1H), 2.03-2.02 (m, 1H), 1.64-1.53 (m, 2H), 1.36-1.29 (m, 15H), 0.90 (t, J=6.8 Hz, 3H).
Example 249: Synthesis of Compound 449
H N O
C H N C
8 17
N N O
18253141_1 (GHMatters) P111789.NZ
NHBoc
NHBoc
Cbz OH
NHBoc
BocHN O
BocHN O
HN O
BocHN O
Fmoc
HATU, DIEA
O HN
CbzHN (S) N O
CbzHN N O
HN O
1 Step
Step
101-G Fmoc 449-2
449-1
NHBoc
Cl S NCO
BocHN O
Step 3 t-BuOH
O HN
CbzHN (S) N O
Cl S NHBoc
Et DCM
HN O
NHBoc
449-3
Step 4
Step 1: Typical amide coupling condition (HATU/DIEA, described in Example E) was applied
to compound 101-G (500 mg, 0.70 mmol) and (S)((((9H-fluorenyl)methoxy)carbonyl)amino)
(((benzyloxy)carbonyl)amino)butanoic acid (332 mg, 0.70 mmol) to give compound 449-1 (400 mg, 49%
yield) as a white solid. LCMS (Method 5-95 AB, ESI): t = 1.039 min, [M + H] = 1170.4.
Step 2: A solution of compound 449-1 (150 mg, 0.13 mmol) and quinuclidine (43 mg, 0.38
mmol) in DCM (8 mL) was stirred at 25 °C for 24 h. The volatiles were concentrated and the residue was
purified by preparatory-TLC (eluting with 10% methanol in DCM, Rf = 0.2) to give compound 449-2 (90
mg, 74.1% yield) as a white solid.
[001059] Step 3: To a stirred solution of t-BuOH (1.86 mL, 19.5 mmol) in DCM (12 mL) at 0 °C was
added sulfurisocyanatidic chloride (1.41 mL, 15.0 mmol) dropwise over 10 min. The reaction mixture was
gradually warmed up to 25 °C while stirring and was stirred at the same temperature for 0.5 h. The solvent
was concentrated in vacuo to one-third volume and the flask was placed back into the 0 °C bath, where the
product started to precipitate out from the solution. After filtration, the product was washed with hexane
and dried in an oven to give tert-butyl (chlorosulfonyl)carbamate (1.8 g, 55.6% yield) as a colorless solid.
H NMR (400MHz, CDCl ) δ 8.45 (br s, 1H), 1.56 (s, 9H).
Step 4: A solution of compound 449-2 (90 mg, 0.09 mmol), tert-butyl (chlorosulfonyl)carbamate
(82 mg, 0.38 mmol) and Et N (53 μL, 0.38 mmol) in DCM (5 mL) was stirred at 25 °C for 16 hr. The
volatiles were removed under reduced pressure and the residue was purified by preparatory-TLC (eluting
with 5% methanol in DCM, Rf=0.5) to afford compound 449-3 (70 mg, 65.4% yield) as a white solid.
LCMS (Method 5-95 AB, ESI): t = 0.947 min, [M-Boc+ H] = 1027.1.
Compound 449 (formic acid salt) was prepared as a white solid from compound 449-3 by
utilizing methods analogous to those described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.710
min, [M + H] = 948.1; H NMR (400 MHz, MeOH-d ) δ 8.49 (br s, 3H), 7.36 (d, J=7.2 Hz, 1H), 7.36-
7.28 (m, 1H), 7.28-7.20 (m, 1H), 7.16 (d, J=8.8 Hz, 1H), 7.12-7.02 (m, 3H), 6.89 (d, J=2.4 Hz, 1H), 6.80
(d, J=2.4 Hz, 1H), 6.43 (s, 1H), 5.14-5.07 (m, 1H), 4.79-4.73 (m, 2H), 4.29-4.11 (m, 6H), 3.38-3.32 (m,
2H), 3.26-3.08 (m, 6H), 2.99 (s, 3H), 2.64-2.55 (m, 2H), 2.41 (s, 3H), 2.22-2.10 (m, 2H), 2.04-1.90 (m,
2H), 1.65-1.56 (m, 2H), 1.45-1.22 (m, 11H), 0.90 (t, J=6.8 Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 250: Synthesis of Compound 450
H N O
N CN
O O HN
N N N O
Cbz OH Cbz OH N O
FmocOSu, Et N
Step 1
N NH
NH NHFmoc
Step 1: A solution of (S)amino(((benzyloxy)carbonyl)amino)pentanoic acid (500 mg, 1.88
mmol), FmocOSu (950 mg, 2.82 mmol) and Et N (0.52 mL, 3.76 mmol) in DCM/MeOH (20 mL, v/v=1/1)
was stirred at 25 °C for 18 h. After that, the reaction mixture was washed with a solution of 1N KHSO and
brine (each 20 mL) and the organic layer was dried over Na SO , concentrated in vacuo and the residue
was purified via silica gel chromatography, eluting with 5% MeOH in DCM, to give (S)((((9H-fluoren-
9-yl)methoxy)carbonyl)amino)(((benzyloxy)carbonyl)amino)pentanoic acid (700 mg, 76.3% yield) as
a white solid. LCMS (Method 5-95 AB, ESI): t = 0.891 min, [M + H] = 489.3.
[001063] Compound 450 (formic acid salt) was prepared as a white solid from compound 101-G and (S)-
-((((9H-fluorenyl)methoxy)carbonyl)amino)(((benzyloxy)carbonyl)amino)pentanoic acid by
utilizing methods analogous to those described in Example P. LCMS (Method 5-95 AB, ESI): t = 0.705
min, [M + H] = 925.6; H NMR (400 MHz, MeOH-d ) δ 8.51 (br s, 2H), 7.35-7.29 (m, 2H), 7.28-7.20 (m,
2H), 7.16 (d, J=8.4 Hz, 1H), 7.11-7.04 (m, 3H), 6.88 (d, J=2.2 Hz, 1H), 6.80 (d, J=2.2 Hz, 1H), 6.44 (s,
1H), 4.79-4.73 (m, 3H), 4.25-4.13 (m, 6H), 3.26-3.08 (m, 8H), 2.97 (s, 3H), 2.60 (t, J=7.5 Hz, 2H), 2.40 (s,
3H), 1.98-1.88 (m, 2H), 1.83-1.67 (m, 4H), 1.63-1.58 (m, 2H), 1.37-1.24 (m, 11H), 0.90 (t, J=6.8 Hz, 3H).
Example 251: Synthesis of Compound 451
H N O
N N CN
N N (S) N O
HN NH
Compound 451 (formic acid salt) was prepared as a white solid from compound 101-G by
utilizing methods analogous to those described in Example P. LCMS (Method 5-95 AB, ESI): t = 0.776
min, [M + H] = 947.8; H NMR (400 MHz, MeOH-d ) δ 8.78 (s, 1H), 8.50 (br s, 2H), 8.22 (d, J=8.0 Hz,
2H), 7.37-7.26 (m, 3H), 7.20 (d, J=8.0 Hz, 1H), 7.15-7.02 (m, 2H), 6.85 (s, 1H), 6.62 (br s, 2H), 5.05-5.03
(m, 1H), 4.77-4.73 (m, 2H), 4.36-4.15 (m, 4H), 4.29 (s, 2H), 3.37-3.35 (m, 1H), 3.30-3.05 (m, 7H), 2.99 (s,
3H), 2.70 (t, J=7.2 Hz, 2H), 2.67 (s, 3H), 2.16-2.10 (m, 1H), 1.97-1.92 (m, 1H), 1.75-1.60 (m, 3H), 1.47-
1.32 (m, 7H), 0.93 (t, J=6.8 Hz, 3H).
Example 252: Synthesis of Compound 452
18253141_1 (GHMatters) P111789.NZ
H N O
N N CN
O HN
N N (S) N O
HN NH
Compound 452 (formic acid salt) was prepared as a white solid from compound 101-G by
utilizing methods analogous to those described in Example P. LCMS (Method 5-95 AB, ESI): t = 0.750
min, [M + H] = 933.6; H NMR (400 MHz, MeOH-d ) δ 8.78 (s, 1H), 8.50 (br s, 2H), 8.26 (d, J=8.0 Hz,
2H), 7.52 (d, J=8.0 Hz, 2H), 7.31 (d, J=8.0 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.13-7.00 (m, 2H), 6.85 (s,
1H), 6.60 (br s, 2H), 5.04-5.01 (m, 1H), 4.77-4.73 (m, 2H), 4.34-4.18 (m, 4H), 4.22 (s, 2H), 3.37-3.35 (m,
1H), 3.27-3.05 (m, 7H), 2.99 (s, 3H), 2.67 (s, 3H), 2.16-2.10 (m, 1H), 1.97-1.94 (m, 1H), 1.39 (s, 9H), 1.35
(d, J=6.8 Hz, 3H).
Example 253: Synthesis of Compound 453
O NH
N NH O
Compound 453 (formic acid salt) was prepared as a white solid from compound 101-G by
utilizing methods analogous to those described in Example 53 and Example Q. LCMS (Method 5-95 AB,
ESI): t = 0.627 min, [M + H] = 854.6; H NMR (400 MHz, MeOH-d ) δ 8.45 (br s, 5H), 7.39 (d, J=8.0
Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.11 - 7.09 (m, 3H), 6.89
(s, 1H), 6.81 (s, 1H), 6.26 (s, 1H), 5.31-5.29 (m, 1H), 4.80-4.76 (m, 2H), 4.25- 4.20 (m, 4H), 4.19 (s, 2H),
3.61-3.47 (m, 2H), 3.25-3.17 (m, 6H), 2.88 (s, 3H), 2.75 (s, 3H), 2.64-2.60 (m, 2H), 2.42 (s, 3H), 1.64-1.60
(m, 2H), 1.34-1.29 (m, 11H), 0.90 (t, J=7.0 Hz, 3H).
Example 254: Synthesis of Compound 454
H N CN
N N O
18253141_1 (GHMatters) P111789.NZ
NHBoc NHBoc
HATU, DIEA
Fmoc OH
BocHN O BocHN O
2) piperidine
OMe OMe
HN O HN
N O H N N O
2 (R)
HN O N O
Step 1
O Trt O
454-1
101G
Step 1: Typical amide coupling (HATU/DIEA, described in Example E) with compound 101G
and N-(((9H-fluorenyl)methoxy)carbonyl)-S-trityl-L-cysteine, followed by Fmoc removal (with
piperidine), were followed to give compound 454-1 as a white solid. LCMS (Method 5-95 AB, ESI): t =
0.793 min, [M + H] = 1059.6
Compound 454 (formic acid salt) was prepared as a white solid from compound 454-1 by
utilizing methods analogous to those described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.805
min, [M + H] = 857.6; H NMR (400 MHz, MeOH-d ) δ 8.49 (br s, 1H), 7.45-7.00 (m, 7H), 6.89 (s, 2H),
6.81 (s, 1H), 6.37 (s, 1H), 5.15-5.05 (m, 1H), 4.75-4.70 (m, 2H), 4.30-4.05 (m, 6H), 3.25-2.90 (m, 9H),
2.82-2.70 (m, 2H), 2.61 (t, J=6.4 Hz, 2H), 2.41 (s, 3H), 1.70-1.55 (m, 2H), 1.40-1.20 (m, 11H), 0.89 (t,
J=6.8 Hz, 3H).
Example 255: Synthesis of Compound 455
N CN
N N O
N CN
OM z e
Cb OM
[001069] To a solution of (S)-methyl 2-(((benzyloxy)carbonyl)amino)hydroxybutanoate (400 mg, 1.16
mmol) in DMF (5 mL) was added NaCN (62 mg, 1.27 mmol) at room temperature and the reaction
mixture was warmed to 75 C while stirring and stirred at the same temperature for 2 h. The volatiles were
removed and the residue was taken by EtOAc (40 mL), which was washed by brine (40 mL). The organic
layer was dried over Na SO , concentrated and the residue was purified by Prep-TLC to give (S)-methyl 2-
(((benzyloxy)carbonyl)amino)cyanobutanoate (210 mg, 65.6% yield) as colorless oil. LCMS (Method
-95 AB, ESI): t = 0.779, M+Na = 298.9.
Compound 455-diastereomeric mixture) (formic acid salt) was prepared as a diautilizing the
methods previously described. LCMS (Method 5-95 AB, ESI): t = 0.814, [M + H] = 830.4.
Compound 455 (formic acid salt) was separated as a single unknown stereoisomer. LCMS (Method 5-95
AB, ESI): t = 0.696 min, [M + H] = 830.3; H NMR (400 MHz, MeOH-d ) δ 8.45 (br s, 1H), 7.32-
18253141_1 (GHMatters) P111789.NZ
7.11(m, 4H), 6.91 (s, 1H), 6.83 (s, 1H), 6.27 (s, 1H), 5.13-4.78 (m, 3H), 4.27-4.20 (m, 4H), 4.21 (s, 2H),
3.23-3.19 (m, 4H), 2.92 (s, 3H), 2.70-2.53 (m, 3H), 2.34-1.99 (m, 4H), 1.70- 1.64 (m, 2H), 1.40-1.31 (m,
23H), 0.90 (t, J=6.8 Hz, 3H).
Example 256: Synthesis of Compound 456
N O HN
Boc TEA
2O, Cbz OH
Cbz OH
N N O
NHBoc O O
Compound 456 (trifluoroacetic acid salt) was prepared as a white solid from compound 101-G
by utilizing methods analogous to those described in Example G. LCMS (Method 5-95 AB, ESI): t =
0.760 min, [M + H] = 854.6; H NMR (400 MHz, MeOH-d ) δ 7.40 (d, J=7.2 Hz, 1H), 7.29-7.08 (m, 5H),
6.90-6.80 (m, 3H), 6.29 (s, 1H), 4.85-4.76 (m, 3H), 4.30-4.20 (m, 4H), 4.18 (s, 2H), 3.31-3.05 (m, 8H),
2.92 (s, 3H), 2.60 (d, J=7.6 Hz, 2H), 2.42 (s, 3H), 2.20-2.00 (m, 2H), 1.60 (t, J=6.4 Hz, 2H), 1.34-1.29 (m,
11H), 0.89 (t, J=7.6 Hz, 3H).
Example 257: Synthesis of Compound 457
N CN
O HN
N N N O
Compound 457 (formic acid salt) was prepared as a white solid from compound 101-L by
utilizing methods analogous to those described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.601
min, [M + H] = 876.5; H NMR (400 MHz, MeOH-d ) δ 8.86 (s, 1H), 8.45 (br s, 2H), 8.37 (d, J=8.0 Hz,
2H), 7.56 (d, J=8.0 Hz, 2H), 7.33 (d, J=7.6 Hz, 1H), 7.24-7.18 (m, 2H), 7.09 (d, J=7.6 Hz, 1H), 6.91
(s,1H), 6.79 (s, 1H), 6.33 (s, 1H), 5.35-5.34 (m, 1H), 4.90-4.81 (m, 2H), 4.28-4.20 (m, 6H), 3.52-3.48 (m,
2H), 3.48-3.31 (m, 7H), 3.30-3.24 (m, 2H), 2.91 (s, 3H), 2.75 (s, 3H), 1.39 (s, 9H), 1.37 (d, J=6.8 Hz, 3H).
Example 258: Synthesis of Compound 458
H N O
N N CN
O HN
N N N O
Compound 458 (formic acid salt) was prepared as a white solid from compound 101-G by
utilizing methods analogous to those described in Example R. LCMS (Method 5-95 AB, ESI): t = 0.765
min, [M + H] = 891.3; H NMR (400 MHz, MeOH-d ) δ 8.72 (s, 1H), 8.53 (br s, 1H), 8.18 (d, J=7.6 Hz,
2H), 7.33-7.18 (m, 4H), 7.05 (d, J=7.6 Hz, 2H), 6.83 (s, 1H), 6.74 (s, 1H), 6.51 (s, 1H), 5.23-5.18 (m, 1H),
18253141_1 (GHMatters) P111789.NZ
4.82-4.73 (m, 2H), 4.35-4.18 (m, 6H), 3.76 (t, J=5.2 Hz, 2H), 3.25-3.00 (m, 6H), 3.03 (s, 3H), 2.63 (s, 3H),
2.57 (d, J=6.8 Hz, 2H), 2.22-2.10 (m, 1H), 2.02-1.89 (m, 2H), 1.35 (d, J=7.2 Hz, 3H), 0.96 (d, J=5.6 Hz,
6H).
Example 259: Synthesis of Compound 459
H N O
N N CN
O HN
N N N O
Compound 459 (formic acid salt) was prepared as a white solid from Compound 101-G by
utilizing methods analogous to those described in Example R. LCMS (Method 5-95 AB, ESI): t = 0.747
min, [M + H] = 891.4; H NMR (400 MHz, MeOH-d ) δ 8.71 (s, 1H), 8.53 (br s, 2H), 8.21 (d, J=8.0 Hz,
2H), 7.49 (d, J=8.0 Hz, 2H), 7.31 (d, J=8.0 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.05 (d, J=8.0 Hz, 2H), 6.83
(s, 1H), 6.73 (s, 1H), 6.54 (s, 1H), 5.21-5.15 (m, 1H), 4.83-4.80 (m, 1H), 4.74-4.69 (m, 1H), 4.39-4.15 (m,
4H), 4.22 (s, 2H), 3.76 (t, J=5.6 Hz, 2H), 3.35-2.90 (m, 6H), 3.03 (s, 3H), 2.64 (s, 3H), 2.16-2.10 (m, 1H),
2.06-1.90 (m, 1H), 1.39 (s, 9H), 1.37 (d, J=6.4 Hz, 3H).
Example 260: Synthesis of Compound 460
H N O
N N CN
N N N O
NHBoc
NHBoc
BocHN O
BocHN O
TBAF/THF
O HN N O
NH OMe, NaBH CN
3) 2 3
H H O HN
N N N O
N N N O
OTBS Step 1
460-1 OMe
460-2
Step 1: Starting from compound 460-1 (described in Example 259), TBS deprotection, DMP
oxidation and reductive amination were applied to give compound 460-2 as a white solid. LCMS (Method
-95 AB, ESI): t = 0.872 min, [M + H] = 1096.6.
Compound 460 (formic acid salt) was prepared as a white solid from compound 460-2 by
utilizing methods analogous to those described in Example G. LCMS (Method 5-95 AB, ESI): t = 0.633
min, [M + H] = 920.4; H NMR (400 MHz, MeOH-d ) δ 8.69 (s, 1H), 8.50 (brs, 3H), 8.18 (d, J=7.6 Hz,
2H), 7.50 (d, J=8.4 Hz, 2H), 7.31-7.23 (m, 2H), 7.04 (brs, 2H), 6.81 (s, 1H), 6.75 (s, 1H), 6.46 (s, 1H),
18253141_1 (GHMatters) P111789.NZ
.18-5.15 (m, 1H), 4.85-4.75 (m, 2H), 4.73-4.67 (m, 1H), 4.40-4.15 (m, 3H), 4.25 (s, 3H), 3.54-3.48 (m,
1H), 3.32-3.23 (m, 3H), 3.13-2.90 (m, 4H), 3.05 (s, 3H), 2.63 (s, 3H), 2.22-2.18 (m, 1H), 2.01-1.97 (m,
1H), 1.39 (s, 9H), 1.36 (d, J=6.0 Hz, 3H).
Example 261: Synthesis of Compound 461
H N O
N CN
O HN
NHBoc
NHBoc
BocHN
BocHN
Boc Boc 5%TFA/HFIP
Raney
CbzCl, NaHCO
N N 2)
NaCN 3
O HN
LiOH
3) O HN H
101G HATU, DIEA N O
N N O
TsO NC
Step 1
Step 2 O
Step
461-1 462-2
Step 1: A solution of 1-(tert-butyl) 2-methyl (2S,4R)(tosyloxy)pyrrolidine-1,2-dicarboxylate
(1.0 g, 2.5 mmol) and sodium cyanide (320 mg, 6.53 mmol) in DMSO (10 mL) was stirred at 80 °C for 5 h.
The reaction was diluted with EtOAc (120 mL) and washed with brine (60 mL x 3). The organic layer was
dried over Na SO , concentrated and the residue was purified by silica gel chromatography, eluting with
% EtOAc in petroleum ether, to give 1-(tert-butyl) 2-methyl (2S,4S)cyanopyrrolidine-1,2-
dicarboxylate (300 mg, 47% yield) as a white solid.
Step 2: Starting from 1-(tert-butyl) 2-methyl (2S,4S)cyanopyrrolidine-1,2-dicarboxylate,
typical Boc removal, Cbz protection, ester hydrolysis and amide coupling with 101G (using procedures
analogous to those described in Examples 4 and 7) were applied to give compound 461-1 as a white solid.
LCMS (Method 5-95 AB, ESI): t = 0.925 min, [M + H-Boc] = 870.5.
Step 3: To a solution of compound 461-1 (155 mg, 0.16 mmol) and nickel (66.6 mg, 1.13 mmol)
in THF (20 mL) was added one drop ammonia and the mixture was stirred at 20 °C for 12 h under H (15
psi). The reaction mixture was filtered and the filtrate was concentrated. The resulting residue was purified
by preparatory-TLC (eluting with 10% MeOH in DCM, Rf = 0.15) to give compound 461-2 (120 mg, 77%
yield) as a white solid. LCMS (Method 5-95 AB, ESI): t = 0.719 min, [M + H] = 974.8.
Compound 461 (formic acid salt) was prepared as a white solid from compound 461-2 by
utilizing previously described methods. LCMS (Method 5-95 AB, ESI): t = 0.717 min, [M + H] = 866.7;
H NMR (400 MHz, MeOH-d ) δ 8.45 (s, 2H), 7.38 (d, J=8.0 Hz, 1H), 7.27-7.08 (m, 6H), 6.89 (s, 1H),
6.84 (s, 1H), 6.40 (s, 1H), 5.11-5.08 (m, 1H), 4.80-4.70 (m, 2H), 4.23-4.15 (m, 4H), 4.19 (s, 2H), 3.62-3.58
(m, 1H), 3.47 (brs,1H), 3.19-3.14 (m, 3H), 3.05-2.98 (m, 4H), 2.95 (s, 3H), 2.74-2.68 (m, 2H), 2.63-2.59
(m, 2H), 2.37-2.32 (m, 1H), 2.35 (s, 3H), 1.81-1.78 (m, 1H), 1.67-1.54 (m, 2H), 1.36-1.33 (m, 9H), 0.90 (t,
J=5.2 Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 262: Synthesis of Compound 462
H N O
N N CN
O HN
N N N O
HN NH
O CbzHN (S)
SOCl /MeOH
1) 2
CbzHN
DIEA NH
BocN NHBoc
BocN NHBoc
LiOH H O
3) 2
Step 1
Step 1: Starting from (S)amino(((benzyloxy)carbonyl)amino)propanoic acid, methyl ester
formation (as described in Example M), guanidine formation (as described in Example 241) and ester
hydrolysis (as described in Example G), (S)(((benzyloxy)carbonyl)amino)(2,3-bis(tert-
butoxycarbonyl) guanidino)propanoic acid was obtained as a white solid. LCMS (Method 5-95 AB, ESI):
t = 0.907 min, [M + H] = 481.2.
Compound 462 (formic acid salt) was prepared as a white solid from compound 101G and (S)
(((benzyloxy) carbonyl)amino)(2,3-bis(tert-butoxycarbonyl)guanidino)propanoic acid by utilizing
previously disclosed methods. LCMS (Method 5-95 AB, ESI): t = 0.602 min, [M + H] = 918.5; H NMR
(400 MHz, MeOH-d ) δ 8.77 (s, 1H), 8.51 (br s, 1H), 8.35 (d, J=8.0 Hz, 1H), 7.55 (d, J=8.8 Hz, 1H),
7.30 (d, J=8.0 Hz, 1H), 7.22-7.16 (m, 2H), 7.08 (d, J=8.8 Hz, 1H), 6.89 (d, J=2.4 Hz, 1H), 6.76 (s, 1H),
6.40 (s, 1H), 5.28 (t, J=6.4 Hz, 1H), 4.82-4.75 (m, 2H), 4.25-4.18 (m, 4H), 4.20 (s, 2H), 3.79-3.74 (m, 1H),
3.66-3.61 (m, 1H), 3.16-3.08 (m, 5H), 2.93 (s, 3H), 2.76-2.65 (m, 1H), 2.68 (s, 3H), 1.38 (s, 9H), 1.37 (d,
J=7.6 Hz, 3H).
Example 263: Synthesis of Compound 463
OH N
O O HN
N N O
Compound 463 (formic acid salt) was prepared as a white solid utilizing methods analogous to
those described in Example S and Example 7. LCMS (Method 5-95 AB, ESI): t = 0.576 min, [M + Na] =
902.4; H NMR (400 MHz, MeOH-d ) δ 8.52 (brs, 2H), 7.30-7.22 (m, 2H), 7.15 (d, J=8.4 Hz, 1H), 7.08 (d,
J=8.4 Hz, 1H), 6.87 (s, 1H), 6.81 (s, 1H), 6.26 (s, 1H), 5.05-4.70 (m, 2H), 4.40-4.30 (m, 1H), 4.25-4.10 (m,
6H), 3.85-3.70 (m, 2H), 3.20–3.00 (m, 8H), 2.81 (s, 3H), 2.40-2.25 (m, 2H), 2.25-2.13 (m, 1H), 2.10-1.95
(m, 1H), 1.70-1.55 (m, 2H), 1.40-1.20 (m, 15H), 0.90 (t, J=6.4 Hz, 3H).
Example 264: Synthesis of Compound 464
18253141_1 (GHMatters) P111789.NZ
N N O
N N O
Compound 464 was prepared as a white solid utilizing methods analogous to those described in
Example S and Example 7. LCMS (Method 5-95 AB, ESI): t = 0.724 min, [M + H] = 975.5; H NMR
(400 MHz, MeOH-d ) δ 8.33 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.30 (d, J=7.2 Hz, 1H), 7.24 (d,
J=7.2 Hz, 1H), 7.16 (d, J=8.4 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.91 (s, 1H), 6.89 (s, 1H), 6.32 (s, 1H),
.10-4.81 (m, 3H), 4.56 (m, 1H), 4.24-4.18 (brs, 4H), 4.20 (s, 2H), 3.35-3.30 (m, 1H), 3.21-3.07 (m, 7H),
2.86 (s, 3H), 2.58 (s, 6H), 2.29-2.17 (m, 1H), 2.13-2.01 (m, 1H), 1.43 (d, J=7.0 Hz, 3H), 1.44 (s, 9H), 1.37
(t, J=7.2 Hz, 3H).
Example 265: Synthesis of Compound 465
O O HN
N N N O
Compound 465 was prepared utilizing methods analogous to those described in Example S and
Example 7. LCMS (Method 5-95 AB, ESI): t = 0.625 min, [M + H] = 991.8; H NMR (400 MHz,
MeOH-d ) δ 8.34 (d, J=8.4Hz, 2H), 7.54 (d, J=8.8Hz, 2H), 7.34-7.22 (m, 2H), 7.15 (d, J=8.4Hz, 1H),
7.12-7.07 (m, 1H), 6.92 (s, 1H), 6.84 (s, 1H), 6.30 (s, 1H), 5.15-4.59 (m, 4H), 4.27-4.17 (m, 4H), 4.19 (s,
2H), 3.89 (d, J=6.0Hz, 2H), 3.26-3.01 (m, 8H), 2.87 (s, 3H), 2.60 (s, 6H), 2.28-2.19 (m, 1H), 2.14-2.05 (m,
1H), 1.37 (s, 9H), 1.36 (t, J=7.2 Hz, 3H).
Example 266: Synthesis of Compound 466
Ot-Bu
O O HN
N N O
N N N O
Compound 466 was prepared utilizing methods analogous to those described in Example S and
= 0.663 min, [M + H] = 1047.8; H NMR (400 MHz,
Example 7. LCMS (Method 5-95 AB, ESI): t
MeOH-d ) δ 8.50 (brs, 2H), 8.33 (d, J=8.4Hz, 2H), 7.54 (d, J=8.4Hz, 2H), 7.32-7.19 (m, 2H), 7.19-7.03 (m,
2H), 6.90 (s, 1H), 6.81 (s, 1H), 6.32 (s, 1H), 5.28-4.70 (m, 4H), 4.25-4.08 (m, 4H), 4.19 (s, 2H), 3.75 (d,
18253141_1 (GHMatters) P111789.NZ
J=6.0Hz, 2H), 3.42-3.33 (m, 1H), 3.29-3.09 (m, 10H), 2.88 (s, 3H), 2.59 (s, 6H), 2.32-2.15 (m, 1H), 2.14-
2.00 (m, 1H), 1.40 (s, 9H), 1.37 (t, J=7.2 Hz, 3H), 1.23(s, 9H).
Example 267: Synthesis of Compound 467
OH N
O O HN
N N O
N N N O
[001087] Compound 467 was prepared utilizing methods analogous to those described in Example S and
Example 7. LCMS (Method 5-95 AB, ESI): t = 0.716 min, [M + H] = 991.8; H NMR (400 MHz,
MeOH-d ) 8.54 (br s, 1H), 8.33 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.36-7.22 (m, 2H), 7.13-7.04 (m,
2H), 6.89 (s, 1H), 6.81 (s, 1H), 6.30 (s, 1H), 5.14-4.66 (m, 4H), 4.21-4.09 (m, 4H), 4.19 (s, 2H), 3.92 (d,
J=6.0 Hz, 2H), 3.24-3.07 (m, 8H), 2.87 (s, 3H), 2.53 (s, 6H), 2.26-2.21 (m, 1H), 2.10-2.01 (m, 1H), 1.37-
1.29 (m, 12H).
Example 268: Synthesis of Compound 468
Ot-Bu N
O O HN
N N O
N N N O
Compound 468 was prepared utilizing methods analogous to those described in Example S and
Example 7. LCMS (Method 5-95 AB, ESI): t = 0.766 min, [M + H] = 1047.6; H NMR (400 MHz,
MeOH-d ) δ 8.53 (br s, 1H), 8.33 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H), 7.31-7.01 (m, 5H), 6.85 (s,
1H), 6.37 (s, 1H), 5.10-4.71 (m, 4H), 4.31-4.12 (m, 6H), 3.80-3.74 (m, 2H), 3.10-2.90 (m, 8H), 2.86 (s,
3H), 2.53 (s, 6H), 2.23-2.18 (m, 1H), 2.04-2.02 (m, 1H), 1.42 (t, J=7.2 Hz, 3H), 1.38 (s, 9H), 1.24 (s, 9H).
Example 269: Synthesis of Compound 469
O O HN
N N O
N N N O
[001089] Compound 469 (formic acid salt) was prepared as a white solid utilizing methods analogous to
those described in Example S and Example 7. LCMS (Method 5-95 AB, ESI): t = 0.744 min, [M + Na] =
1025.7; H NMR (400 MHz, MeOH-d ) δ 8.48 (br s, 1H), 8.33 (d, J=8.4Hz, 2H), 7.53 (d, J=8.4Hz, 2H),
18253141_1 (GHMatters) P111789.NZ
7.32-6.82 (m, 6H), 6.30 (s, 1H), 5.10-4.79 (m, 4H), 4.25-4.18 (m, 6H), 3.17-3.16 (m, 9H), 2.93-2.87 (m,
2H), 2.58 (s, 6H), 2.24-2.00 (m, 2H), 1.78-1.76 (m, 2H), 1.52-1.37 (m, 14H), 1.03 (t, J=5.2 Hz, 3H).
Example 270: Synthesis of Compound 470
N N O
N N N
[001090] Compound 470 (formic acid salt) was prepared as a white solid utilizing methods analogous to
those described in Example S and Example 7. LCMS (Method 5-95 AB, ESI): t = 0.625 min, [M + H] =
961.5; H NMR (400 MHz, MeOH-d ) δ 8.50 (br s, 2H), 8.34 (d, J=8.4Hz, 2H), 7.55 (d, J=8.4Hz, 2H),
7.35-7.21 (m, 2H), 7.17-7.06 (m, 2H), 6.94 (s, 1H), 6.75 (s, 1H), 6.32 (s, 1H), 5.11-4.80 (m, 4H), 4.22-4.10
(m, 7H), 3.51-3.32 (m, 1H), 3.21-3.00 (m, 7H), 2.88 (s, 3H), 2.61 (s, 6H), 2.32-2.18 (m, 1H), 2.12-2.00 (m,
1H), 1.42 (s, 9H), 1.36 (t, J=6.4 Hz, 3H).
Example 271: Synthesis of Compound 471
C CH
6 13 3
O HN
N N O
O O CH
C H CH O
6 13 3
O HN
N N O
BocHN O
O O CH
O CH
471-1
471-2
Compound 471-1 was prepared as a white solid utilizing methods analogous to those described
in Example C, starting with (S)((tert-butoxycarbonyl)amino)(4-hydroxyphenyl)acetic acid instead of
(S)((tert-butoxycarbonyl)(methyl)amino)(4-hydroxyphenyl)acetic acid. LCMS (Method 5-95 AB,
ESI): t = 0.828 min, [M + Na] = 564.2.
Compound 471-2 was prepared as a white solid from compound 471-1 utilizing methods analogous to
those described in Example O. LCMS (Method 5-95 AB, ESI): t = 0.699 min, [M + H] = 716.3.
Starting from compound 471-2, typical Boc O protection (Boc O, Et N, as described in Example 6), ester
2 2 3
hydrolysis (LiOH, THF/H O, as described in Example G), amide coupling (HATU/DIEA, as described in
Example G) and Boc removal (TFA/HFIP, as described in Example G) conditions were applied to give
compound 471 (formic acid salt) as a white solid. LCMS (Method 5-95 AB, ESI): t = 0.691 min, [M +
H] = 741.1; H NMR (400 MHz, DMSO-d ) δ 9.09 (d, J=8.4 Hz, 1H), 8.85-8.70 (m, 2H), 8.55(d, J=7.2
18253141_1 (GHMatters) P111789.NZ
Hz, 1H), 8.31 (s, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.15-6.90 (m, 6H), 6.63 (t, J=8.4 Hz,
2H), 5.66 (d, J=8.0 Hz, 1H), 4.90-4.80 (m, 1H), 4.65-4.60 (m, 1H), 4.60-4.50 (m, 1H), 4.17 (d, J=5.2 Hz,
1H), 3.00-2.85 (m, 4H), 2.60-2.50 (m, 2H), 2.32 (s, 3H), 2.15-2.00 (m, 1H), 2.00-1.90 (m, 1H), 1.60-1.50
(m, 2H), 1.30-1.15 (m, 9H), 0.85 (t, J=6.8 Hz, 3H).
Example 272: Synthesis of Compound 472
O HN
N N N
O O CH
Compound 472 (formic acid salt) was prepared as a white solid from compound 471-1, by
utilizing methods analogous to those described in Example D and Example G. LCMS (Method 5-95 AB,
ESI): t = 0.719 min, [M + H] = 876.5; H NMR (400 MHz, MeOH-d ) δ 8.84 (s, 1H), 8.78 (s, 1H), 8.45
(br s, 1H), 8.38-8.36 (m, 2H), 7.57-7.49 (m, 3H), 7.31-7.06 (m, 2H), 7.04-7.02 (m, 2H), 6.83 (br s, 1H),
.86 (s, 1H), 5.76 (s, 1H), 4.75-4.70 (m, 2H), 4.52-4.48 (m, 1H), 4.24-4.15 (m, 6H), 3.19-3.09 (m, 7H),
2.72 (s, 2H), 2.66 (s, 2H), 2.25-2.00 (m, 2H), 1.38 (br s, 12H).
Example 273: Synthesis of Compound 473
CH N
O HN
N N O
O O CH
EtI, Cs CO
NsCl, Et N 2 3
O HN
Acetone HN
H H N O
Ns N O
N Ns N O 3
O Step HN O
Step 1 N O
H N O N O 2
Step
O CH
O CH 3
O CH O CH
473-4
473-3
471-1
473-2
Step 1: To a solution of compound 471-1 (390 mg, 0.88 mmol) and 4-nitro-benzene sulfonyl
chloride (255 mg, 1.15 mmol) in acetonitrile (5 mL) was added Et N (0.31 mL, 2.21 mmol) dropwise at 0
°C. The mixture was stirred at the same temperature for 3 h. The precipitate was collected, which was
dried over oven to give compound 473-2 (520 mg, 94% yield) as a yellow solid.
[001094] Step 2: To a solution of compound 473-2 (520 mg, 0.83 mmol) and ethyl iodide (650 mg, 4.15
mmol) in acetone (10 mL) at 0 °C was added K CO (573 mg, 4.15 mmol) and the mixture was gradually
warmed up to 25 °C while stirring and stirred at the same temperature for 14 h. The volatiles were
removed and the residue was re-dissolved with ethyl acetate (120 mL), which was washed with brine (3 x
50 mL). The organic layer was dried over Na SO , concentrated and the residue was purified by silica gel
18253141_1 (GHMatters) P111789.NZ
chromatography, eluting with 50% ethyl acetate in petroleum ether, to give compound 473-3 (400 mg,
73.6% yield) as a white solid.
Step 3: A solution of compound 473-3 (400 mg, 0.61 mmol), thioglycolic acid (0.28 mL, 4.03
mmol) and DBU (0.92 mL, 6.17 mmol) in acetonitrile (5 mL) was stirred at 25 °C for 4 h. The volatiles
were removed under reduced pressure and the residue was re-dissolved with ethyl acetate (100 mL), which
washed with brine (3 x 50 mL). The organic layer was dried over Na SO , concentrated and the residue
was purified by silica gel chromatography, eluting with 67% ethyl acetate in petroleum ether, to give
compound 473-4 (260 mg, 91% yield) as a white solid. LCMS (Method 5-95 AB, ESI): t = 0.698 min, [M
+ H] = 470.5.
[001096] Starting from compound 473-4, compound 473 (formic acid salt) was prepared as a white solid
utilizing methods analogous to those described in Example 271. LCMS (Method 5-95 AB, ESI): t = 0.811
min, [M + H] = 768.5; H NMR (400 MHz, MeOH-d ) δ 8.50 (br s, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.19 (d,
J=8.0 Hz, 1H), 7.08-7.00 (m, 4H), 6.99 (br s, 1H), 6.91 (d, J=8.0 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.28 (s,
1H), 5.14 (m, 1H), 4.85-4.77 (m, 1H), 4.60 (br s, 1H), 4.18 (s, 2H), 3.40-3.25 (m, 2H), 3.16-3.08 (m, 4H),
2.60 (t, J=7.6 Hz, 2H), 2.40 (s, 3H), 2.25-2.00 (m, 2H), 1.60-1.50 (m, 3H), 1.35-1.32 (m, 8H), 0.97 (t,
J=7.2 Hz, 3H), 0.89 (t, J=6.8 Hz, 3H).
Example 274: Synthesis of Compound 474
CH N
O HN
N N O
O O CH
NH NH
Cbz OH
OHC NHBoc
BocHN
IBCF, NMM
NaBH CN
3 O O
HN O HN
H H H
N O N N O
HN O N
Cbz O
2 O CH O CH
Step 2
O CH Step 1
NHBoc BocHN NHBoc
471-1
474-2
474-3
[001097] Step 1: To a solution of compound 471-1 (480 mg, 1.09 mmol), tert-butyl (2-
oxoethyl)carbamate (173 mg, 1.2 mmol) and acetic acid (0.3 mL) in MeOH (10 mL) was added NaBH CN
(75 mg, 1.2 mmol) and the resulting solution was stirred at 20 °C for 6 h. The volatiles were removed
under reduced pressure and the residue was re-dissolved by EtOAc (40 mL), which was washed with brine
(2 x 40 mL). The organic layer was dried over MgSO , concentrated and the residue was purified by
preparatory-TLC (eluting with 50% EtOAc in petroleum ether, Rf=0.4) to afford compound 474-2 (440
mg, 69% yield) as a white solid. LCMS (Method 5-95 AB, ESI): t = 0.619 min, [M + H] = 585.1.
Step 2: A solution of (S)(((benzyloxy)carbonyl)amino)((tert-
butoxycarbonyl)amino)butanoic acid (200 mg, 0.57 mmol), N-methyl morpholine (115 mg, 1.14mmol) and
isobutyl chloroformate (62 mg, 0.45 mmol) in THF (10 mL) was stirred at -10 °C for 1 h, followed by the
18253141_1 (GHMatters) P111789.NZ
addition of compound 474-2 (232 mg, 0.40 mmol). The resulting mixture was stirred at the same
temperature for another 1 h. The volatiles were removed under reduced pressure and the residue was re-
dissolved by EtOAc (30 mL), which was washed with brine (2 x 30 mL). The organic layer was dried over
MgSO , concentrated and the residue was purified by preparatory-TLC (eluting with 50% EtOAc in
petroleum ether, Rf=0.3) to give compound 474-3 (130 mg, 25% yield) as a white solid. LCMS (Method
-95 AB, ESI): t = 0.835 min, [M + H] = 919.6.
Starting from compound 474-3, compound 474 (formic acid salt) was prepared as a white solid
utilizing methods analogous to those described in Example 271. LCMS (Method 5-95 AB, ESI): t = 0.661
min, [M + H] = 783.5; H NMR (400 MHz, MeOH-d ) δ 8.55 (br s, 2H), 7.44 (d, J=7.2 Hz, 1H), 7.33 (d,
J=7.2 Hz, 1H), 7.17 (br s, 1H), 7.18-7.06 (m, 4H), 6.96-6.81 (m, 1H), 6.29 (s, 1H), 5.99 (s, 1H), 5.09 (br
s,1H), 4.78-4.76 (m, 2H), 4.17 (d, J=8.0 Hz, 2H), 3.78-3.40 (m, 4H), 3.35-3.02 (m, 4H), 2.61 (t, J=7.2 Hz,
2H), 2.47 (s, 3H), 2.41-2.05 (m, 2H), 1.64-1.60 (m, 2H), 1.37-1.30 (m, 9H), 0.91 (t, J=6.8 Hz, 3H).
Example 275: Synthesis of Compound 475
O HN
N N O
CH N O
O O CH
NH OH
[001100] Compound 475 (formic acid salt) was prepared as a white solid utilizing methods analogous to
those described in Example 274. LCMS (Method 5-95 AB, ESI): t = 0.814 min, [M + H] = 784.6; H
NMR (400 MHz, MeOH-d ) δ 8.54 (br s, 3H), 7.33 (d, J=8.0 Hz, 1H), 7.18-7.01 (m, 6H), 6.87 (d, J=8.0
Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 6.15 (s, 1H), 5.00-4.75 (m, 3H), 4.18 (s, 2H), 3.80-3.70 (m, 2H), 3.30-
3.10 (m, 3H), 3.07-3.01 (m, 3H), 2.63-2.59 (m, 2H), 2.40 (s, 3H), 2.30-2.15 (m, 1H), 2.13-2.02 (m, 1H),
1.70-1.50 (m, 3H), 1.37-1.27 (m, 8H), 0.90 (t, J=6.8 Hz, 3H).
Example 276: Synthesis of Compound 476
O HN
N N N O
Compound 476 (formic acid salt) was prepared as a white solid utilizing methods analogous to
those described in Example 7. LCMS (Method 5-95 AB, ESI): t = 0.718 min, [M + H] = 876.4; H NMR
(400 MHz, MeOH-d ) δ 8.72 (s, 1H), 8.46 (br s, 2H), 8.28 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.35-
7.30 (m, 1H), 7.25-7.20 (m, 1H), 7.12 (d, J=8.4 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.86 (s, 1H), 6.64 (s, 1H),
6.56 (s, 1H), 5.22-5.18 (m, 1H), 4.80-4.70 (m, 2H), 4.67 (d, J=14.4 Hz, 1H), 4.34-4.22 (m, 4H), 4.20 (s,
2H), 3.59-3.52 (m, 1H), 3.31-3.25 (m, 4H), 3.18-3.12 (m, 2H), 3.00-2.95 (m, 1H), 2.92 (s, 3H), 2.66 (s,
3H), 2.28-2.17 (m, 1H), 2.15-2.01 (m, 1H), 1.39 (s, 9H).
18253141_1 (GHMatters) P111789.NZ
Example 277: Synthesis of Compound 477
N N N O
Compound 477 (formic acid salt) was prepared as a white solid utilizing methods analogous to
those described in Example 7. LCMS (Method 5-95 AB, ESI): t = 0.722 min, [M + H] = 906.4; H NMR
(400 MHz, MeOH-d ) δ 8.72 (s, 1H), 8.50 (br s, 3H), 8.30 (d, J=7.6 Hz, 2H), 7.53 (d, J=8.0 Hz, 2H), 7.31
(d, J=7.6 Hz, 1H), 7.22-7.14 (m, 2H), 7.06 (d, J=8.0 Hz, 1H), 6.79 (s, 1H), 6.66 (s, 1H), 6.50 (s, 1H), 5.20-
.15 (m, 1H), 4.81-4.75 (m, 2H), 4.28-4.14 (m, 4H), 4.19 (s, 2H), 3.72 (d, J=7.2 Hz, 2H), 3.43-3.38 (m,
2H), 3.22-3.13 (m, 5H), 3.05-3.01 (m, 1H), 2.95 (s, 3H), 2.67 (s, 3H), 2.27-2.66 (m, 1H), 2.18-2.16 (m,
1H), 1.38 (s, 9H).
Example 278: Synthesis of Compound 478
H N O
O HN
N N O
Compound 478 (formic acid salt) was prepared from Compound 105 (Example U) utilizing
methods analogous to those described in Example G (Compound 101) to give a white solid. LCMS (ESI):
[M+H] = 880; H NMR (400 MHz, Methanol-d ) δ 7.34-7.32 (m, 2H), 7.26 (dd, J = 8.6, 2.3 Hz, 1H), 7.19
(d, J = 8.6 Hz, 1H), 7.16 – 7.08 (m, 3H), 6.82 (dd, J = 9.8, 2.4 Hz, 2H), 6.39 (s, 1H), 5.15 (dd, J = 7.9, 5.5
Hz, 1H), 4.98 (dd, J = 11.5, 3.2 Hz, 1H), 4.29 – 4.19 (m, 7H), 3.30 (d, J = 3.3 Hz, 1H), 3.24-3.17 (m, 5H),
3.16 – 3.09 (m, 2H), 2.93 (s, 2H), 2.64 (t, J = 7.6 Hz, 2H), 2.44 (s, 3H), 2.34 – 2.25 (m, 1H), 2.19-2.10 (m,
1H), 1.63 (q, J = 7.3 Hz, 2H), 1.39 – 1.28 (m, 9H), 1.26-1.19 (m, 1H), 0.96 – 0.88 (m, 3H), 0.57 – 0.49 (m,
4H).
Example 279: Synthesis of Compound 479
H N O
O HN
N N O
Compound 479 (formic acid salt) was prepared utilizing methods analogous to those described
in Example G (Compound 101) to give a white solid. LCMS (ESI): [M+H] = 868; H NMR (400 MHz,
18253141_1 (GHMatters) P111789.NZ
Methanol-d ) δ 7.37 – 7.32 (m, 2H), 7.27 (dd, J = 8.6, 2.4 Hz, 1H), 7.20 (d, J = 8.6 Hz, 1H), 7.15 – 7.08 (m,
3H), 6.88 (dd, J = 17.2, 2.4 Hz, 2H), 6.34 (s, 1H), 5.15 (dd, J = 7.8, 5.5 Hz, 1H), 4.94 (dd, J = 11.5, 3.1 Hz,
1H), 4.62 (t, J = 7.4 Hz, 1H), 4.31 – 4.19 (m, 6H), 3.25 (q, J = 4.9 Hz, 4H), 3.16 – 3.09 (m, 2H), 2.94 (s,
3H), 2.64 (t, J = 7.6 Hz, 2H), 2.43 (s, 3H), 2.34-2.23 (m, 1H), 2.19 – 2.09 (m, 1H), 1.88-1.78 (m, 1H),
1.73-1.59 (m, 2H), 1.38 – 1.29 (m, 10H), 0.98 (t, J = 7.4 Hz, 3H), 0.95 – 0.89 (m, 2H).
Example 280: Synthesis of Compound 480
H N O
O HN
N N O
Compound 480 (formic acid salt) was prepared utilizing methods analogous to those described
in Example 279 and Example G (Compound 101) to give a white solid. LCMS (ESI): [M+H] = 854; H
NMR (400 MHz, Methanol-d ) δ 7.46 (dd, J = 18.2, 7.7 Hz, 1H), 7.36 (dd, J = 22.5, 7.7 Hz, 1H), 7.29 –
7.20 (m, 1H), 7.15 – 7.03 (m, 3H), 6.99 (d, J = 8.3 Hz, 1H), 6.84 – 6.79 (m, 1H), 5.87 (s, 1H), 4.99 – 4.91
(m, 2H), 4.69 – 4.61 (m, 1H), 4.52 (d, J = 11.0 Hz, 1H), 4.21 – 3.99 (m, 6H), 3.12 – 2.92 (m, 4H), 2.61 (td,
J = 7.6, 3.9 Hz, 3H), 2.40 (d, J = 22.7 Hz, 3H), 1.80 (dt, J = 12.5, 6.5 Hz, 1H), 1.64 (d, J = 21.1 Hz, 3H),
1.30 (d, J = 13.8 Hz, 12H), 0.97 (t, J = 7.4 Hz, 3H), 0.92 – 0.87 (m, 3H).
Example 281: Synthesis of Compound 481
NHBoc
BocHN
O HN
O HN
BocHN
481-1
Compound 481-1 was prepared as an off-white solid following the method for compound 101-I
using (2S,4R)benzyloxycarbonyl(tert-butoxycarbonylamino)pyrrolidinecarboxylic acid. LCMS
(ESI): [M+H] = 926.
[001107] Compound 481 (formic acid salt) was prepared utilizing methods analogous to those described
in Example G (Compound 101) to give a off white solid. LCMS (ESI): [M+H] = 852; H NMR (400 MHz,
Methanol-d ) δ 7.42 – 7.36 (m, 1H), 7.29 – 7.04 (m, 8H), 6.87 (dd, J = 21.4, 2.5 Hz, 1H), 6.39 (d, J = 6.2
Hz, 1H), 5.21 (t, J = 7.2 Hz, 1H), 4.80 – 4.72 (m, 1H), 4.24 – 4.15 (m, 5H), 3.84 – 3.78 (m, 1H), 3.75 –
3.68 (m, 1H), 3.25 – 3.19 (m, 1H), 3.19 – 3.11 (m, 4H), 2.95 (d, J = 3.2 Hz, 3H), 2.62 (t, J = 7.6 Hz, 2H),
2.39 (s, 2H), 2.34 (q, J = 5.4, 4.6 Hz, 4H), 1.62 (dt, J = 14.9, 8.1 Hz, 3H), 1.38 – 1.28 (m, 10H), 0.93 –
0.88 (m, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 282: Synthesis of Compound 482
H N O
O HN
N N O
Compound 482 (formic acid salt) was prepared as an off-white solid utilizing methods
analogous to those described in Example G (Compound 101). LCMS (Method A, ESI): t = 3.519 min, [M
+ H] = 860; H NMR (400 MHz, Methanol-d ) δ 7.40 – 7.34 (m, 1H), 7.23 (dd, J = 8.6, 2.4 Hz, 1H), 7.18
(d, J = 8.4 Hz, 1H), 7.09 (d, J = 8.6 Hz, 1H), 6.85 (dd, J = 18.5, 2.5 Hz, 2H), 6.30 (s, 1H), 5.02 (dd, J = 7.9,
.8 Hz, 1H), 4.88 (d, J = 3.1 Hz, 1H), 4.80 – 4.74 (m, 1H), 4.26 – 4.18 (m, 6H), 4.00 – 3.88 (m, 2H), 3.58
(dd, J = 10.1, 4.1 Hz, 1H), 3.22 – 3.16 (m, 4H), 2.88 (s, 3H), 2.44 – 2.37 (m, 2H), 2.31 – 2.26 (m, 1H),
1.65 (q, J = 7.4 Hz, 2H), 1.42 – 1.27 (m, 26H), 0.93 – 0.87 (m, 3H).
Example 283: Synthesis of Compound 483
H N O
N N O
Compound 483 (formic acid salt) was prepared as an off-white solid utilizing methods
analogous to those described in Example G (Compound 101). LC-MS: (Method A, ESI): t = 3.522 min,
[M + H] = 860; H NMR (400 MHz, Methanol-d ) δ 7.31 (dd, J = 8.6, 2.5 Hz, 1H), 7.17 (dd, J = 8.5, 2.4
Hz, 1H), 7.11 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.78 (dd, J = 19.8, 2.4 Hz, 2H), 6.22 (s, 1H),
4.99 (dd, J = 8.3, 5.2 Hz, 1H), 4.81 (s, 1H), 4.69 (q, J = 6.7 Hz, 1H), 4.24 – 4.10 (m, 6H), 4.01 – 3.96 (m,
2H), 3.63 (q, J = 7.4 Hz, 1H), 3.22 – 3.15 (m, 4H), 3.11 – 3.01 (m, 1H), 2.81 (s, 3H), 2.38 – 2.26 (m, 4H),
1.58 (q, J = 7.3 Hz, 2H), 1.36 – 1.19 (m, 24H), 0.87 – 0.80 (m, 3H).
Example 284: Synthesis of Compound 484
H N O
O HN
N N O
18253141_1 (GHMatters) P111789.NZ
Compound 484 (formic acid salt) was prepared as an off-white solid utilizing methods
analogous to those described in Example G (Compound 101). LC-MS: (Method A, ESI): t = 2.073 min,
[M + H] = 796; H NMR (400 MHz, DMSO-d ) δ 9.04 (d, J = 7.8 Hz, 1H), 8.78 (t, J = 5.7 Hz, 1H), 8.73
(d, J = 7.7 Hz, 1H), 8.37 (d, J = 9.0 Hz, 1H), 7.66 – 7.58 (m, 2H), 7.22 – 7.13 (m, 2H), 7.06 (dd, J = 27.1,
8.6 Hz, 2H), 6.71 (d, J = 2.5 Hz, 2H), 6.28 (s, 1H), 4.97 – 4.90 (m, 1H), 4.80 – 4.67 (m, 2H), 4.17 (d, J =
.8 Hz, 2H), 4.03 – 3.93 (m, 3H), 3.18 (d, J = 16.8 Hz, 2H), 3.04 – 2.97 (m, 1H), 2.88 – 2.72 (m, 10H),
2.05 – 1.91 (m, 2H), 1.80 – 1.71 (m, 4H), 1.19 (d, J = 6.7 Hz, 3H).
Example 285: Synthesis of compound 485
N N N O
CCH AcOH
(OEt)3 3
O O toluene
Pyridine,
Step 1
LiOH
NaOEt, EtOH
THF/water
Step 3 Step 4
LiHMDS
Step 2
Step 1: A solution of ethyl 3-oxopentanoate (1.00 mL, 7.02 mmol), triethyl orthoacetate (2.0 mL,
11 mmol), pyridine (57 μL, 0.698 mmol), acetic acid (40 μL, 0.697 mmol) and toluene (6.0 mL, 56 mmol)
was heated in a sealed vial at 120 °C for 23 h. The reaction mixture was evaporated under reduced pressure
to yield the crude product as an orange oil. The crude product was purified via flash chromatography on
silica gel (40 g silica, solvent gradient: 0-50% ethyl acetate in heptanes) to yield 254.2 mg (17%) of ethyl
(Z)(1-ethoxyethylidene)oxopentanoate as an orange oil. LCMS (ESI): [M+H] = 215.0.
Step 2: To a solution of 4-tert-butylbenzonitrile (9.00 mL, 53 mmol) in diethyl ether (100 mL,
960 mmol) at 0 °C was added lithium bis(trimethylsilyl)amide (1 mol/L) in THF (110.0 mL, 110.0 mmol),
dropwise over 30 minutes. The reaction was stirred at 0 °C for 2 h and then warmed to room temperature.
After an additional 6 h, the reaction was cooled in an ice bath and quenched by careful addition of
hydrogen chloride (12 mol/L in water) (20 mL, 240 mmol), diluted with water (50 mL) and then stirred for
minutes. The resulting mixture was extracted with water (4 x 50 mL). The combined aqueous extracts
were adjusted to pH ~13 with aqueous sodium hydroxide (10 mol/L) in water (15 mL, 150 mmol), and
then extracted with 10% isopropanol in dichloromethane (4 x 50 mL). The combined dichlormethane
extracts were dried over magnesium sulfate, and filtered. The filtered solids were stirred with 1:1
DCM:EtOAc and re-filtered, the combined filtrates were evaporated in vacuo to yield 3.494 g (37%) of 4-
(tert-butyl)benzimidamide. LCMS (ESI): [M+H] = 177.15; H NMR (400 MHz, DMSO-d ) δ 7.68 (d, J =
8.4 Hz, 2H), 7.43 (d, J = 8.2 Hz, 2H), 6.98 (br s, 3H), 1.29 (s, 9H).
18253141_1 (GHMatters) P111789.NZ
Step 3: A mixture of ethyl (2Z)(1-ethoxyethylidene)oxo-pentanoate (254.2 mg, 1.186
mmol), 4-tert-butyl-benzamidine (197.0 mg, 1.118 mmol), sodium ethoxide (21 wt% solution in ethanol)
(0.80 mL, 2.1 mmol), and ethanol (1.5 mL, 26 mmol) was heated in a sealed vial at 70 °C overnight. The
reaction mixture was evaporated onto celite. The crude product was purified via flash chromatography on
silica gel (12 g silica, solvent gradient: 0-50% ethyl acetate in heptanes) to yield 80.2 mg (22%) of ethyl 2-
(4-(tert-butyl)phenyl)ethylmethylpyrimidinecarboxylate as a clear, colorless oil. LCMS (ESI):
[M+H] = 327.
Step 4: To a solution of ethyl 2-(4-tert-butylphenyl)ethylmethyl-pyrimidinecarboxylate
(97 mg, 0.2972 mmol) in tetrahydrofuran (2.0 mL, 25 mmol) was added lithium hydroxide (1.0 M in water)
(0.30 mL, 0.30 mmol). The reaction mixture was stirred at room temperature for 3.5 h. Following the
addition of additional lithium hydroxide (1.0 M in water) (0.90 mL, 0.90 mmol) and methanol (1 mL), the
reaction mixture was heated 50 °C overnight. The reaction mixture was diluted with dichloromethane,
neutralized with hydrochloric acid (1 mol/L) in water (1.2 mL), and washed with brine. The aqueous layer
was extracted with an additional portion of dichloromethane, and the combined organic layers were dried
over magnesium sulfate, filtered, and evaporated in vacuo to yield 88.4 mg (99.7%) of 2-(4-(tert-
butyl)phenyl)ethylmethylpyrimidinecarboxylic acid, which was carried forward without
purification. LCMS (ESI): [M+H] = 299.15.
Compound 485 (TFA salt) was prepared from 2-(4-(tert-butyl)phenyl)ethyl
methylpyrimidinecarboxylic acid and Compound 101-K utilizing methods analogous to those described
in Example G (Compound 101). LCMS (Method A, ESI): t = 2.971 min, [M+H] = 918.5; H NMR (400
MHz, DMSO-d ) δ 9.18 (d, J = 7.3 Hz, 1H), 8.96 (d, J = 7.9 Hz, 1H), 8.71 (t, J = 5.7 Hz, 1H), 8.37 – 8.29
(m, 3H), 7.99 – 7.72 (m, 6H), 7.56 (d, J = 8.5 Hz, 2H), 7.28 – 7.22 (m, 1H), 7.21 – 7.07 (m, 3H), 6.74 (s,
1H), 6.45 (s, 1H), 5.09 – 4.99 (m, 1H), 4.82 – 4.66 (m, 2H), 4.28 – 4.05 (m, 7H), 3.21 – 2.98 (m, 11H),
2.91 (s, 3H), 2.77 (q, J = 7.4 Hz, 2H), 2.02 (d, J = 39.8 Hz, 2H), 1.34 (s, 9H), 1.29 (t, J = 7.5 Hz, 3H), 1.21
(d, J = 6.7 Hz, 3H).
Example 286: Synthesis of compound 486
O HN
N N N O
Compound 486 (TFA salt) was prepared from ethyl 3-oxohexanoate utilizing methods analogous
to those described in Example 285. LCMS (Method A, ESI): t = 3.162 min, [M+H] = 932.5; H NMR
(400 MHz, DMSO-d ) δ 9.18 (d, J = 7.3 Hz, 1H), 8.95 (d, J = 7.9 Hz, 1H), 8.71 (t, J = 5.7 Hz, 1H), 8.38 –
8.30 (m, 3H), 7.93 – 7.76 (m, 10H), 7.56 (d, J = 8.5 Hz, 2H), 7.26 – 7.08 (m, 3H), 6.74 (d, J = 2.4 Hz, 1H),
18253141_1 (GHMatters) P111789.NZ
6.47 (s, 1H), 5.09 – 4.98 (m, 1H), 4.81 – 4.67 (m, 2H), 4.29 – 4.05 (m, 6H), 3.28 – 2.93 (m, 6H), 2.91 (s,
2H), 2.79 – 2.63 (m, 2H), 2.12 – 1.92 (m, 2H), 1.78 (q, J = 7.5 Hz, 2H), 1.34 (s, 9H), 1.21 (d, J = 6.7 Hz,
2H), 0.95 (t, J = 7.3 Hz, 2H).
Example 287: Synthesis of compound 487
N N N O
Compound 487 (TFA salt) was prepared from ethyl 4-methyloxopentanoate utilizing methods
analogous to those described in Example 285. LCMS (Method A, ESI): t = 3.260 min, [M+H] = 932.5;
H NMR (400 MHz, DMSO-d ) δ 9.20 (d, J = 7.3 Hz, 1H), 8.95 (d, J = 8.1 Hz, 1H), 8.69 (d, J = 5.8 Hz,
1H), 8.38 – 8.29 (m, 3H), 7.83 (s, 9H), 7.57 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.6 Hz, 1H), 7.20 – 7.06 (m,
3H), 6.73 (s, 2H), 6.46 (s, 1H), 5.08 – 4.97 (m, 1H), 4.80 – 4.65 (m, 2H), 4.28 – 4.06 (m, 6H), 3.25 – 2.97
(m, 8H), 2.91 (s, 3H), 2.13 – 1.92 (m, 2H), 1.34 (s, 9H), 1.29 (d, J = 6.6 Hz, 6H), 1.21 (d, J = 6.7 Hz, 3H).
Example 288: Synthesis of Compound 488
O HN
N N O
N NH O
S OH
Step
Step 1
[001118] Step 1: To a solution of ethyl 3-oxobicyclo[3.1.0]hexanecarboxylate (519.9 mg, 3.091 mmol)
in ethanol (8.0 mL, 140 mmol) was added 4-methylbenzenesulfonohydrazide (596.9 mg, 3.109 mmol).
The reaction mixture was stirred at room temperature for 90 min, and then evaporated in vacuo to yield
ethyl 3-(2-tosylhydrazono)bicyclo[3.1.0]hexanecarboxylate which was carried forward without
purification. LCMS (ESI): [M+H] = 337.05.
[001119] Step 2: The product obtained in Step 1 was combined with (4-tert-butylphenyl)boronic acid
(840.2 mg, 4.720 mmol), potassium carbonate (669 mg, 4.8405 mmol) and 1,4-dioxane (12 mL, 140 mmol)
and the mixture was heated at 100 °C for 2 h. Additional (4-tert-butylphenyl)boronic acid (514.5 mg,
2.890 mmol) and 1,4-dioxane (10 mL) were added and the reaction mixture was heated at 110 °C
18253141_1 (GHMatters) P111789.NZ
overnight. The reaction mixture was evaporated in vacuo onto celite. The crude product was purified via
flash chromatography on silica gel (40 g silica, solvent gradient: 0-20% ethyl acetate in heptanes) to
provide 249.5 mg of ethyl 3-(4-(tert-butyl)phenyl)bicyclo[3.1.0]hexanecarboxylate as a yellow oil (28%
yield over 2 steps).
[001120] Compound 488 (TFA salt) was prepared from of ethyl 3-(4-(tert-
butyl)phenyl)bicyclo[3.1.0]hexanecarboxylate utilizing methods analogous to those described in
Example 285. LCMS (Method A, ESI): t = 2.997 min, [M+H] = 879.5.
Example 289: Synthesis of Compound 489
O HN
N N N O
NH O O
Step
Step 2
1eq NaOEt
EtOH
(0.2M)
NH POCl
rt, 1h 3
N O N Cl
N O N O
Step 3
Step 4
methylamine
2M in THF N NH
LiOH/THF/MeOH N NH
N OH
Step 1: To a solution of 4-tert-butylbenzamidine (1.02 g, 5.78 mmol) in ethanol (29 mL) was
added diethyl 2-(ethoxymethylene)propanedioate (1.25 g, 5.78 mmol), followed by sodium ethoxide (2.6
M solution in ethanol, 2.4 mL, 5.78 mmol). The reaction was left to stir under nitrogen at room
temperature. After 1.5 h the reaction was concentrated to give 2.29 g of the crude product, which was
carried over without purification.
Step 2: To a vial containing ethyl 2-(4-tert-butylphenyl)oxo-1H-pyrimidinecarboxylate
(1.20 g, 4.0 mmol) was added phosphoryl chloride (1.9 mL, 20 mmol). The reaction was heated to 60 °C.
After 1.5 h additional 3 equiv of phosphoryl chloride was added (1.2 mL, 12 mmol). After 3 h the reaction
was evaporated in vacuo and used directly in the next step.
[001123] Step 3: To a solution of ethyl 2-(4-tert-butylphenyl)chloro-pyrimidinecarboxylate (1.28 g,
4 mmol) in THF (8 mL) was added a solution of methylamine (2 M) in THF (8 mL, 16 mmol). After
stirring for 2 h at room temperature the reaction was concentrated, treated with water, and extracted with
DCM (3 times). Combined organic layers were washed with brine, dried over magnesium sulfate, filtered,
and concentrated. Purification by flash chromatography on silica gel (solvent gradient: 0-40 % isopropyl
acetate/heptane, then 100% isopropyl acetate) gave the desired product (0.754 g, 60%) as a white solid.
LCMS (ESI): [M+1] = 314.2; H NMR (400 MHz, DMSO-d ) δ 8.83 (s, 1H), 8.38 – 8.31 (m, 2H), 8.22 (d,
18253141_1 (GHMatters) P111789.NZ
J = 5.2 Hz, 1H), 7.54 (d, J = 8.5 Hz, 2H), 4.33 (q, J = 7.1 Hz, 2H), 3.11 (d, J = 4.8 Hz, 3H), 1.37 – 1.30 (m,
12H).
Step 4: To a solution of ethyl 2-(4-tert-butylphenyl)(methylamino)pyrimidinecarboxylate
(0.15 g, 0.50 mmol) in THF (2.7 mL) and methanol (0.8 mL) was added a solution of lithium hydroxide
(1M) in water (1.5 mL, 1.5 mmol). The reaction was heated to 60 °C. After stirring overnight the reaction
was evaporated in vacuo, treated with dilute HCl to reach a pH of ~ 5-6, and extracted with ethyl acetate (3
times). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and
evaporated in vacuo. The crude solid was dissolved in DCM and filtered through a pad of celite, washing
with 5 % methanol/DCM. The filtrate was evaporated in vacuo to give the title compound (142 mg) as a
white solid. LCMS (ESI): [M+1] = 286; H NMR (400 MHz, DMSO-d ) δ 13.24 (s, 1H), 8.77 (s, 1H),
8.33 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.3 Hz, 2H), 7.14 (s, 1H), 3.09 (d, J = 4.7 Hz, 3H), 1.32 (s, 9H).
Step 5: Compound 489 (TFA salt) was prepared from 2-(4-(tert-butyl)phenyl)
(methylamino)pyrimidinecarboxylic acid utilizing the methods described in Example G (Compound
101-K). LCMS (Method A, ESI): t = 2.82 min, [M + H] = 906.4; H NMR (400 MHz, DMSO-d ) δ 9.04
(d, J = 7.8 Hz, 1H), 8.95 (d, J = 7.8 Hz, 1H), 8.83 (s, 1H), 8.71 (t, J = 5.7 Hz, 1H), 8.56 (d, J = 5.5 Hz, 1H),
8.39 (d, J = 9.1 Hz, 1H), 8.36 – 8.24 (m, 2H), 7.94 – 7.68 (m, 10H), 7.59 – 7.48 (m, 2H), 7.30 – 7.20 (m,
2H), 7.15 (d, J = 8.7 Hz, 1H), 7.08 (t, J = 7.0 Hz, 1H), 6.76 – 6.68 (m, 2H), 6.32 (s, 1H), 5.04 – 4.90 (m,
1H), 4.83 – 4.64 (m, 2H), 4.23 – 4.07 (m, 6H), 3.17 – 2.99 (m, 10H), 2.73 (s, 3H), 2.11 (s, 2H), 1.40 – 1.27
(m, 11H), 1.22 (d, J = 6.8 Hz, 3H).
Example 290: Synthesis of Compound 490
O HN
N N N O
N O O
Compound 490 (TFA salt) was prepared as a white solid utilizing methods analogous to those
described in Example 289. LCMS (Method A, ESI): t = 2.66 min, [M + H] = 920.5; H NMR (400 MHz,
DMSO-d ) δ 9.12 (d, J = 7.3 Hz, 1H), 8.95 (d, J = 8.0 Hz, 1H), 8.71 (t, J = 5.6 Hz, 1H), 8.39 – 8.23 (m,
4H), 7.95 – 7.72 (m, 10H), 7.56 – 7.49 (m, 2H), 7.28 – 7.02 (m, 4H), 6.73 (d, J = 2.4 Hz, 2H), 6.40 (s, 1H),
4.91 (q, J = 7.4 Hz, 1H), 4.81 – 4.65 (m, 2H), 4.26 – 4.06 (m, 6H), 3.22 – 2.91 (m, 15H), 2.85 (s, 2H), 2.08
– 1.95 (m, 2H), 1.33 (s, 9H), 1.21 (d, J = 6.7 Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 291: Synthesis of Compound 491
O HN
N N N
N HATU, DIPEA
4M HCl in dioxane O CbzCl, DIPEA O
N N N N
N OH DCM, 0°C OMe
OMe OMe
Step 2
Step 1
O Step 3
NH NHCbz
NHBoc 2
NHBoc
BocHN
N 101-G
Compound
1M THF
LiOH, O
DEPBT, NaHCO
OH 3
Step 4
THF, 60°C
O HN
NHCbz
Step 5 N N N O
491-1
Step 1: To a mixture of 2-(4-tert-butylphenyl)methyl-pyrimidinecarboxylic acid (prepared
as described in Example 69) (811 mg, 3.0 mmol) and DCM (9 mL) was added DIPEA (1.57 mL, 9 mmol)
then HATU (1.25 g, 3.3 mmol). The reaction mixture was stirred at 20 °C for 5 min then [(1S)[(tert-
butoxycarbonylamino)methyl]methoxyoxo-ethyl]ammonium chloride (917 mg, 3.6 mmol) was
added. The mixture was stirred at 20 °C for 18 h and then diluted with DCM, washed with saturated
aqueous ammonium chloride, brine and then dried over Na SO and the solvent removed. The residue was
purified by silica gel chromatography (eluting with 40% ethyl acetate/cyclohexane) to give methyl (2S)
(tert-butoxycarbonylamino)[[2-(4-tert-butylphenyl)methyl-pyrimidinecarbonyl]amino]propanoate
(1.37 g, 97%) as a white foam solid. LCMS (ESI): [M + H] = 471.
Step 2: Methyl (2S)(tert-butoxycarbonylamino)[[2-(4-tert-butylphenyl)methyl-
pyrimidinecarbonyl]amino]propanoate (1.37 g, 2.91 mmol) was dissolved in HCl in dioxane (4.0 M, 5
mL, 20 mmol) and stirred at 20 °C for 5 h. The solvent was removed to give [(2S)[[2-(4-tert-
butylphenyl)methyl-pyrimidinecarbonyl]amino]methoxyoxo-propyl]ammonium chloride 1.3 g
(109%) as an off white solid. LCMS (ESI): [M + H] = 371.
Step 3: To a solution of [(2S)[[2-(4-tert-butylphenyl)methyl-pyrimidine
carbonyl]amino]methoxyoxo-propyl]ammonium chloride (407 mg, 1 mmol) in DCM (4 mL) under
nitrogen at 0 °C was added DIPEA (0.52 mL, 3 mmol) followed by benzyl chloroformate (0.17 mL, 1.1
mmol) dropwise. The mixture was stirred at 0 °C for 2 h. The reaction was quenched with water, diluted
with DCM and allowed to warm to 20 °C. The phases were separated, and the organic layer was washed
with brine, dried over Na SO and the solvent removed. The residue was purified by silica gel
chromatography (eluting with 50% ethyl acetate/cyclohexane) to give methyl (2S)
(benzyloxycarbonylamino)[[2-(4-tert-butylphenyl)methyl-pyrimidinecarbonyl]amino]propanoate
(426 mg, 84%) as a white foam. LCMS (ESI): [M + H] = 505.
18253141_1 (GHMatters) P111789.NZ
Step 4: To methyl (2S)(benzyloxycarbonylamino)[[2-(4-tert-butylphenyl)methyl-
pyrimidinecarbonyl]amino]propanoate (423 mg, 0.84 mmol) in THF (4 mL) was added lithium
hydroxide (1.0 M aqueous solution, 1.0 mL, 1.0 mmol). The mixture was stirred at 20 °C for 2 h. The
solvent was removed, the residue dissolved in water and acidified to ca. pH 2 with 1M aqueous HCl. The
mixture was extracted with ethyl acetate twice and the combined organic layers were washed with brine,
dried over Na SO and the solvent removed to give (2S)(benzyloxycarbonylamino)[[2-(4-tert-
butylphenyl)methyl-pyrimidinecarbonyl]amino]propanoic acid (416 mg, 101%) as a white foam.
LCMS (ESI): [M + H] = 491.
Step 5: To a mixture of Compound 101-G (592 mg, 0.83 mmol) and (2S)
(benzyloxycarbonylamino)[[2-(4-tert-butylphenyl)methyl-pyrimidinecarbonyl]amino]propanoic
acid (407 mg, 0.83 mmol) in THF (5.0 mL) under nitrogen was added sodium hydrogencarbonate (279 mg,
3.32 mmol) followed by DEPBT (745 mg, 2.49 mmol). The mixture was stirred at 60 °C for 18 h. The
mixture was cooled to ambient temperature, diluted with ethyl acetate and the organic layer was washed
successively with saturated aqueous sodium hydrogen carbonate and brine then dried over Na SO and the
solvent was removed. The residue was purified by silica gel chromatography (solvent gradient: 50%-100%
ethyl acetate in cyclohexane) to give compound 491-1 (422 mg, 43%) as a white glassy solid. LCMS (ESI):
[M + H] = 1186.
Starting from compound 494-1 and (N-tert-butoxycarbonyl)glycine, the typical amide coupling
(HATU/DIEA), hydrolysis and global Boc removal (TFA/HFIP) procedures (as described in Examples 5
and 7) were followed to afford Compound 491 (trifluoroacetic acid salt) as a white solid. LCMS (ESI): t
= 2.50 min, [M + H] = 933.7. H NMR (400 MHz, DMSO-d ) δ 9.18 (d, J = 8.2 Hz, 1H), 8.99 (d, J = 8.2
Hz, 1H), 8.85 (s, 1H), 8.76-8.70 (m, 1H), 8.66-8.60 (m, 1H), 8.40-8.31 (m, 3H), 8.10-7.84 (m, 9H), 7.58 (d,
J = 8.9 Hz, 2H), 7.28-7.03 (m, 4H), 6.73 (s, 2H), 6.36 (s, 1H), 5.10-5.02 (m, 1H), 4.79-4.67 (m, 2H), 4.27-
4.07 (m, 6H), 3.77-2.97 (m, 11H), 2.86 (s, 2H), 2.63 (s, 3H), 1.33 (s, 9H), 1.22 (d, J = 7.4 Hz, 3H).
Example 292: Synthesis of Compound 492
O HN
N N N O
LiOH
CbzHN CbzHN
CbzHN CbzHN
BocHN
Asymmetric
O OH
Hydrogenation
DBU, DCM
NHBoc NHBoc
Step 3
OMe NHBoc
Step
Step 1
Step 1: To a mixture of methyl 2-(benzyloxycarbonylamino)dimethoxyphosphoryl-acetate
(994 mg, 3.0 mmol) and tert-butyl N-(1,1-dimethyloxo-ethyl)carbamate (562 mg, 3.0 mmol) in DCM
(5.0 mL) was added 1,8-diazabicyclo[5.4.0]undecane (0.45 mL, 3 mmol). The mixture was stirred at 20 °C
18253141_1 (GHMatters) P111789.NZ
for 18 h. The reaction mixture was diluted with DCM, washed successively with 1M aqueous HCl, and
brine, then dried over Na SO and the solvent was removed. The residue was purified by silica gel
chromatography (eluting with 30% ethyl acetate/cyclohexane) to give methyl (E)
(benzyloxycarbonylamino)(tert-butoxycarbonylamino)methyl-pentenoate (746 mg, 63%) as a
colorless oil. LCMS (ESI): [M + Na] = 415.
Step 2: A solution of methyl (E)(benzyloxycarbonylamino)(tert-butoxycarbonylamino)
methyl-pentenoate (740 mg, 1.89 mmol) in methanol (10 mL) was added to 1,2-bis[(2S,5S)-2,5-
diethylphosphoplano]benzene(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (136 mg, 0.19
mmol) in a glass lined steel bomb. The bomb was flushed with nitrogen four times and then flushed
with hydrogen, the pressure increased to 4.5 atm and the mixture was stirred for 18 h. The pressure was
released, the mixture was removed from the bomb and the solvent removed. The residue was purified by
silica gel chromatography (eluting with 20% ethyl acetate/cyclohexane) to give methyl (2S)
(benzyloxycarbonylamino)(tert-butoxycarbonylamino)methyl-pentanoate (425 mg, 57%) as a white
solid. LCMS (ESI): [M + H] = 395.
[001135] Step 3: To a solution of methyl (2S)(benzyloxycarbonylamino)(tert-
butoxycarbonylamino)methyl-pentanoate (412 mg, 1.04 mmol) in THF (5 mL) was added a solution of
LiOH (1.0M, 1.1 mL, 1.1 mmol). The mixture was stirred at 20 °C for 5 h. The solvent was removed and
the residue dissolved in water, acidified with 1.0 M aqueous HCl, and extracted twice with ethyl acetate.
The combined organic extracts were washed with brine, dried over Na SO and the solvent removed to
give (2S)(benzyloxycarbonylamino)(tert-butoxycarbonylamino)methyl-pentanoic acid (390 mg,
98%) as a white solid. LCMS (ESI): [M - H] = 379.
Compound 101-G was coupled to (2S)(benzyloxycarbonylamino)(tert-
butoxycarbonylamino)methyl-pentanoic acid and hydrogenated as described in Example E. The
resulting compound was coupled with 2-(4-tert-butylphenyl)-4,6-dimethyl-pyrimidinecarboxylic acid
[001137] , followed by ester hydrolysis, coupling with aminoacetonitrile hydrochloride and global
deprotection using the procedures described in Example G to afford Compound 492 (formic acid salt) as a
white solid. LCMS (ESI): t = 2.78 min, [M + H] = 932.5. H NMR (400 MHz, DMSO-d ) δ 9.25 (d, J =
7.6 Hz, 1H), 8.96 (d, J = 7.9 Hz, 1H), 8.74-8.69 (m, 1H), 8.39-8.29 (m, 3H), 7.56 (d, J = 8.3 Hz, 2H), 7.30-
7.06 (m, 5H), 6.78-6.71 (m, 2H), 6.46 (s, 1H), 5.11-5.03 (m, 1H), 4.79-4.64 (m, 2H), 4.22-4.05 (m, 7H),
3.25-3.01 (m, 6H), 2.95 (s, 3H), 2.25-2.17 (m, 1H), 2.00-1.91 (m, 1H), 1.33 (s, 15H), 1.19 (d, J = 6.9 Hz,
3H).
Example 293: Synthesis of Compound 493
18253141_1 (GHMatters) P111789.NZ
O HN
N N N O
O NH
NHBoc
BocHN
NHBoc
BocHN
N OMe
K CO , MeCN
O HN
N OMe
N N N O
O HN then Boc O
2 N O
N N N O
493-2
NH 493-1
O NH
Compound 493-1 was prepared as a white solid (373 mg) following procedures analogous to
those described in Example 291, using [(1S)(tert-butoxycarbonylamino)methoxycarbonyl-
propyl]ammonium chloride in place of [(1S)[(tert-butoxycarbonylamino)methyl]methoxyoxo-
ethyl]ammonium chloride. LCMS (ESI): [M + H] = 1066.
To Compound 493-1 (373 mg, 0.35 mmol) in acetonitrile (3.0 mL) was added potassium
carbonate (58 mg, 0.42 mmol) and 2-bromoacetamide (46 mg, 0.33 mmol). DMF (0.5 mL) added to aid
solubility. The mixture was stirred at 20 °C for 18 h then potassium carbonate (58 mg, 0.42 mmol) and di-
tert-butyl dicarbonate (92 mg, 0.42 mmol) were added. The reaction was stirred at 20 °C for 3 h and the
resulting mixture was then partitioned between ethyl acetate and water and the phases separated. The
organic layer was washed with brine, dried over Na SO and the solvent removed. The residue was
purified by silica gel chromatography (eluting with 7% MeOH/DCM) to give Compound 493-2 (295 mg,
69%) as a glass. LCMS (ESI): [M + H] = 1247.
[001140] Starting from Compound 493-2, typical hydrolysis, amide coupling (HATU/DIEA) and global
Boc removal (TFA/HFIP) procedures (as described in Example G) were followed to afford Compound 493
(formic acid salt) as a white solid. LCMS (ESI): t = 2.51 min, [M + H] = 947.5. H NMR (400 MHz,
DMSO-d ) δ 9.15 (d, J = 7.2 Hz, 1H), 8.97 (d, J = 7.8 Hz, 2H), 8.82 (s, 2H), 8.73-8.67 (m, 2H), 8.44-8.32
(m, 3H), 8.02-7.66 (m, 4H), 7.63-7.55 (m, 3H), 7.30-7.00 (m, 5H), 6.73 (s, 2H), 6.38 (s, 1H), 5.05-4.93 (m,
1H), 4.80-4.67 (m, 2H), 4.30-4.02 (m, 6H), 3.21-2.94 (m, 8H), 2.84 (s, 3H), 2.65 (s, 3H), 2.54 (s, 2H), 1.34
(s, 9H), 1.22 (d, J = 7.0 Hz, 3H).
Example 294: Synthesis of Compound 494
18253141_1 (GHMatters) P111789.NZ
O HN
N N N O
NHBoc
NHBoc
BocHN
BocHN
HCO Na
N OMe
ClCO Et
2 HN
N OMe O
O HN
H H N N N O
N N N N O
HN O
494-1
493-1
Step 1: A mixture of Compound 493-1 (340 mg, 0.32 mmol) and sodium formate (26 mg, 0.38
mmol) in ethyl formate (5 mL) was stirred at 50 °C for 5 h. The mixture was partitioned between ethyl
acetate and water and the phases separated. The organic layer was washed with brine, dried over Na SO
and the solvent removed. The residue was purified via silica gel chromatography (solvent gradient: 0-10%
MeOH/DCM) to give Compound 494-1 (273 mg, 78%) as a white solid. LCMS (ESI): [M + H] = 1095.
Starting from Compound 494-1, typical hydrolysis, amide coupling (HATU/DIEA) and global
Boc removal (TFA/HFIP) procedures (as described in Examples E and G) were followed to afford
Compound 494 (formic acid salt) as a white solid. LCMS (ESI): t = 2.94 min, [M + H] = 918.7. H NMR
(400 MHz, DMSO-d ) δ 9.11-9.00 (m, 2H), 8.84-8.77 (m, 2H), 8.39-7.98 (m, 8H), 7.60-7.55 (m, 2H),
7.23-7.02 (m, 4H), 6.76-6.66 (m, 2H), 6.37 (s, 1H), 4.89-4.67 (m, 4H), 4.17 (d, J = 6.9 Hz, 2H), 4.10-4.01
(m, 4H), 3.30-3.19 (m, 2H), 3.17 (s, 1H), 3.05-2.87 (m, 6H), 2.83 (s, 2H), 2.65 (s, 3H), 2.03-1.74 (m, 2H),
1.37 (s, 9H), 1.19 (d, J = 8.4 Hz, 3H).
Example 295: Synthesis of Compound 495
O HN
N N N O
O LiOH O
BF O
CbzHN CbzHN
HO OH
N O THF
Chloroform
O O Step 2
Step 1
NHBoc
NHBoc
Step 1: To a solution of methyl (S)-N-Z-aziridinecarboxylate (1.26 mL, 6.38 mmol) and tert-
butyl N-(2-hydroxyoxyethyl)carbamate (3.45 mL, 22.32 mmol) in chloroform (45 mL) at 0 °C, under
18253141_1 (GHMatters) P111789.NZ
argon, was added, dropwise, boron trifluoride diethyl etherate (0.81 mL, 6.38 mmol). The reaction mixture
was allowed to reach ambient temperature over 30 min. The reaction was quenched with saturated aqueous
NaHCO (70 mL) and extracted with DCM. The organic extracts were dried over MgSO and the solvent
removed. The crude residue was purified by silica gel chromatography (eluting with 50% ethyl
acetate/cyclohexane) to give methyl (2S)(benzyloxycarbonylamino)[2-(tert-
butoxycarbonylamino)ethoxy]propanoate (1.30 g, 3.28 mmol) as a colorless oil. LCMS (ESI): [M + Na] =
419.
Step 2: To a solution of methyl (2S)(benzyloxycarbonylamino)[2-(tert-
butoxycarbonylamino)ethoxy]propanoate (1.3 g, 3.28 mmol) in THF (30 mL) was added lithium
hydroxide (1.0 M, 6.56 mL, 6.56 mmol) and the reaction mixture was stirred at 50 °C for 30 min. The
reaction was quenched with 1N aqueous HCl (8.0 mL) followed by water (50 mL) and the resulting
mixture was extracted with DCM. The combined organic extracts were dried over MgSO and the solvent
removed to give (2S)(benzyloxycarbonylamino)[2-(tert-butoxycarbonylamino)ethoxy]propanoic acid
(1.20 g, 3.14 mmol) as a colorless oil. LCMS (ESI): [M + Na] = 405.
[001145] Compound 101-G was coupled to (2S)(benzyloxycarbonylamino)[2-(tert-
butoxycarbonylamino)ethoxy]propanoic and hydrogenated as described in Example E. The resulting
compound was coupled with 2-(4-tert-butylphenyl)-4,6-dimethyl-pyrimidinecarboxylic acid, followed
by ester hydrolysis, coupling with aminoacetonitrile hydrochloride and global deprotection using
the procedures described in Example G to afford Compound 495 (formic acid salt) as a white solid. LCMS
(ESI): t = 2.48 min, [M + H] = 934.4. H NMR (400 MHz, DMSO-d ) δ 9.21-9.11 (m, 1H), 8.96 (d, J =
8.0 Hz, 1H), 8.72 (t, J = 5.4 Hz, 1H), 8.41-8.29 (m, 3H), 7.90-7.74 (m, 6H), 7.55 (d, J = 8.4 Hz, 2H), 7.28-
7.06 (m, 4H), 6.73-6.69 (m, 1H), 6.43 (s, 1H), 5.20-5.12 (m, 1H), 4.78-4.56 (m, 1H), 4.28-4.07 (m, 6H),
3.86-3.78 (m, 2H), 3.74-3.61 (m, 6H), 3.25-2.96 (m, 9H), 2.91 (s, 3H), 2.65 (m, 2H), 2.46 (d, J = 5.2 Hz,
1H), 1.34 (s, 9H), 1.24-1.18 (m, 3H).
Example 296: Synthesis of Compound 496
N N CN
O HN
N N N O
HN O
18253141_1 (GHMatters) P111789.NZ
N OMe
OH O N
K CO , DMF , KOAc
2 3 Pd(dppf)Cl2
Na CO
O Pd(dppf)Cl2 2 3
B OH
80 C
, DMF
Br Br (PinB)2
Dioxane/H O
Step 1
Step 2
496-2
496-1
496-3
2. NaOH, MeOH/H O
Steps 3-4
NHBoc
BocHN
NHBoc
BocHN
O N OH
O 496-3
TBAF
O HN
HATU, DIPEA THF
N N N O
O HN rt
DCM,
Step 6
H N O
2 O O
N Step 5
NHTeoc
NHTeoc
496-4
496-5
NHBoc
NHBoc
BocHN
BocHN
Ac O
DIPEA
O HN
N OMe
O HN
H H N N N O
N N N Step 7 N O
HN O
496-7
496-6
NHBoc
BocHN
1. LiOH, THF
N N CN
2. HCl.H N CN O HN
N N N O
HATU, DIPEA
Step 8
HN O
496-8
Step 1: To a solution of 4-bromophenol (1.0 g, 5.78 mmol) in DMF (10 mL) was added
bromocyclohexane (1.8 g, 11.0 mmol) and K CO (2.4 g, 17.4 mmol) and the reaction was stirred at 80 °C
for 16 h. The reaction mixture was poured into water (20 mL), which was extracted with EtOAc (50 mL x
3). The combined organic layers were washed with brine (100 mL x 2), dried over Na SO and
concentrated. The residue was purified by silica gel chromatography, eluting with petroleum ether, to give
compound 496-1 (170.0 mg, 11%) as a colorless oil.
Step 2: To a solution of compound 496-1 (170.0 mg, 0.67 mmol) in DMF (5 mL) was added
bis(pinacolato)diboron (254 mg, 1.00 mmol), Pd(dppf)Cl (24.4 mg, 0.03 mmol) and potassium acetate
(196 mg, 2.00 mmol) and the resulting mixture was stirred at 80 °C under nitrogen for 3 h. The reaction
was poured into water (20 mL), which was extracted with EtOAc (20 mL x 3). The combined organic
layers were washed with brine (50 mL x 2), dried over Na SO and concentrated. The residue was purified
by silica gel chromatography (eluent: 8% EtOAc in petroleum ether) to give compound 496-2 (140 mg,
70% yield) as a yellow oil.
18253141_1 (GHMatters) P111789.NZ
Step 3: A mixture of compound 496-2 (200 mg, 0.66 mmol) in 1,4-dioxane (5 mL) and H O (1
mL) was added methyl 2-chloro-4,6-dimethylpyrimidinecarboxylate (described in Example 53) (199
mg, 0.99 mmol) and K CO (274 mg, 2.0 mmol) and Pd(dppf)Cl (48.4 mg, 0.07 mmol) and the resulting
2 3 2
mixture was stirred at 110 °C under nitrogen for 16 h. After filtration, the filtrate was diluted with H O (20
mL), which was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with water
and brine (30 mL each), dried over Na SO and concentrated. The residue was purified by prep-TLC
(eluent: 10% EtOAC in petroleum ether) to give methyl 2-(4-(cyclohexyloxy)phenyl)-4,6-
dimethylpyrimidinecarboxylate (110 mg, 59% yield) as a white solid. LCMS (ESI): [M+H] = 341.0.
Step 4: To a solution of methyl 2-(4-(cyclohexyloxy)phenyl)-4,6-dimethylpyrimidine
carboxylate (110 mg, 0.32 mmol) in methanol (10 mL) was added 1.0 M aqueous NaOH (1.62 mL, 1.62
mmol) and the mixture was stirred at 80 °C for 4 h. The reaction mixture was adjusted to pH=4 using
saturated aqueous KHSO , which was added with EtOAc (40 mL). The organic layer was washed with
brine (30 mL x 2), dried over Na SO and concentrated to afford compound 496-3 (100 mg, 95% yield) as
a white solid, which was used directly in the next step.
[001150] Compound 496-4 was prepared from Compound 101-G and (S)
(((benzyloxy)carbonyl)amino)(((2-(trimethylsilyl)ethoxy)carbonyl)amino)butanoic acid using
conditions analogous to those described in Example E. LCMS (ESI): [M + H] = 958.
Step 5: Example E was applied to Compound 496-4 (3.37 g, 3.52 mmol) and Compound 496-3
(1.26 g, 3.87 mmol) to give Compound 496-5 (3.78 g, 85%) as a white solid. LCMS (ESI): [M + H] =
1266.
Step 6: To a solution of Compound 496-5 (3.05 g, 2.41 mmol) in THF (15 mL) was added a
solution of tetrabutylammonium fluoride (1.0 M in THF, 3.6 mL, 3.6 mmol). The mixture was stirred at
50 °C for 18 h. The mixture was cooled to room temperature and the solvent removed. The residue was
dissolved in ethyl acetate, washed with brine, dried over Na SO and the solvent removed to give
Compound 496-6 (3.20 g, 118%) as an off white solid. The residue used directly without further
purification. LCMS (ESI): [M + H] = 1122.
Step 7: To Compound 496-6 (280 mg, 0.25 mmol) in DCM (3 mL) at 0 °C was added DIPEA
(0.07 mL, 0.38 mmol) followed by acetic anhydride (28 mg, 0.28 mmol). The mixture was stirred at
0 °C for 2 h. The mixture was partitioned between DCM and water and the phases separated. The organic
layer was washed with brine, dried over Na SO and the solvent was removed. The residue was purified on
silica gel column (8% MeOH/DCM) to give Compound 496-7 (195 mg, 67%) as a white solid. LCMS
(ESI): [M + H] = 1164.
Steps 8-9: Starting from Compound 496-7, typical hydrolysis, amide coupling (HATU/DIEA)
and global Boc removal (TFA/HFIP) procedures (Example G) were followed to afford Compound 496
(trifluoroacetic acid salt) as a white solid. LCMS (ESI): t = 3.18 min, [M + H] = 988.4. H NMR (400
MHz, DMSO-d ) δ 9.05-8.96 (m, 2H), 8.76 (t, J = 5.8 Hz, 1H), 8.37-8.28 (m, 5H), 7.94 (t, J = 5.8 Hz, 1H),
7.28-6.93 (m, 7H), 6.76-6.68 (m, 2H), 6.39 (s, 1H), 4.88-4.81 (m, 1H), 4.78-4.67 (m, 2H), 4.49-4.42 (m,
18253141_1 (GHMatters) P111789.NZ
1H), 4.19-4.15 (m, 2H), 4.07-3.94 (m, 4H), 3.23-3.14 (m, 3H), 3.03-2.82 (m, 4H), 2.84 (s, 3H), 2.44 (s,
1H), 1.99-1.92 (m, 2H), 1.79 (s, 3H), 1.77-1.69 (m, 3H), 1.58-1.37 (m, 4H), 1.33-1.23 (m, 1H), 1.19 (d, J =
7.2 Hz, 3H).
Example 297: Synthesis of Compound 497
O HN
N N N
Compound 497 (trifluoroacetic acid salt) was prepared as a white solid utilizing methods
analogous to those described in Example 296 using methanesulfonyl chloride in place of acetic anhydride
in Step 7. LCMS (ESI): t = 3.30 min, [M + H] = 1024.4. H NMR (400 MHz, DMSO-d ) δ 9.01-8.86 (m,
2H), 8.67 (t, J = 7.4 Hz, 1H), 8.33-8.28 (m, 3H), 7.30-7.02 (m, 9H), 6.78-6.72 (m, 2H), 6.42 (s, 1H), 4.97-
4.91 (m, 1H), 4.77-4.69 (m, 2H), 4.48-4.40 (m, 1H), 4.28-4.03 (m, 7H), 3.26-2.98 (m, 8H), 2.90 (s, 3H),
2.88 (s, 3H), 2.00-1.91 (m, 3H), 1.86-1.70 (m, 3H), 1.59-1.51 (m, 1H), 1.50-1.35 (m, 4H), 1.33-1.24 (m,
1H), 1.24 (d, J = 6.6 Hz, 3H).
Example 298: Synthesis of Compound 498
O HN
N N N O
HN O
[001156] Compound 498 (formic acid salt) was prepared as a white solid utilizing the methods in
Example 296 using trimethyl isocyanate in place of acetic anhydride in Step 7. LCMS (ESI): t = 3.06 min,
[M + H] = 989.4. H NMR (400 MHz, DMSO-d ) δ 9.06-8.96 (m, 2H), 8.78 (t, J = 5.5 Hz, 1H), 8.33-8.29
(m, 5H), 7.21-7.18 (m, 1H), 7.16-7.10 (m, 2H), 7.07-7.02 (m, 4H), 6.76-6.68 (m, 2H), 6.39 (s, 1H), 6.16-
6.09 (m, 1H), 5.51-5.39 (m, 2H), 4.89-4.81 (m, 1H), 4.78-4.67 (m, 2H), 4.48-4.41 (m, 1H), 4.22-4.14 (m,
2H), 4.08-3.95 (m, 4H), 3.21-2.85 (m, 7H), 2.84 (s, 3H), 2.45 (s, 1H), 2.00-1.92 (m, 2H), 1.92-1.84 (m,
1H), 1.76-1.69 (m, 2H), 1.58-1.51 (m, 1H), 1.48-1.37 (m, 3H), 1.33-1.24 (m, 1H), 1.24 (d, J = 6.4 Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 299: Synthesis of Compound 499
N N N
O NH
Compound 499 (trifluoroacetic acid salt) was prepared as a white solid utilizing the methods in
Example 296 using trimethylsilyl isocyanate in place of acetic anhydride in Step 7. LCMS (ESI): t = 3.05
min, [M + H] = 975.3. H NMR (400 MHz, DMSO-d ) δ 9.01-8.95 (m, 2H), 8.70 (t, J = 5.3 Hz, 1H),
8.34-8.26 (m, 3H), 7.88 (br s, 6H), 7.28-7.03 (m, 6H), 6.77-6.70 (m, 2H), 6.41 (s, 1H), 6.14-6.07 (m, 1H),
.78-5.64 (m, 2H), 5.01-4.94 (m, 1H), 4.79-4.66 (m, 2H), 4.49-4.41 (m, 1H), 4.28-4.08 (m, 7H), 3.51-3.43
(m, 2H), 3.24-3.00 (m, 8H), 2.94 (s, 2H), 2.47-2.44 (m, 1H), 2.00-1.92 (m, 2H), 1.77-1.69 (m, 2H), 1.59-
1.24 (m, 7H), 1.21 (d, J = 7.0 Hz, 3H).
Example 300: Synthesis of Compound 500
O HN
N N N O
Compound 500 (trifluoroacetic acid salt) was prepared as a white solid utilizing the methods in
Example 296 using tert-butyl (chlorosulfonyl)carbamate (formed by mixing equimolar amounts of
chlorosulfonyl isocyanate and tert-butanol in DCM) in place of acetic anhydride in Step 7. LCMS (ESI): t
= 3.22 min, [M + H] = 1025.4. ¹H NMR (400 MHz, DMSO-d ) δ 9.01-8.95 (m, 2H), 8.72-8.67 (m, 1H),
8.34-8.25 (m, 3H), 7.92-7.81 (br s, 6H), 7.26-7.03 (m, 7H), 6.75-6.68 (m, 3H), 6.53 (s, 2H), 6.45 (s, 1H),
4.97-4.90 (m, 1H), 4.79-4.69 (m, 2H), 4.48-4.42 (m, 1H), 4.25-4.10 (m, 6H), 3.25-2.97 (m, 9H), 2.89 (s,
3H), 2.01-1.95 (m, 3H), 1.83-1.69 (m, 3H), 1.57-1.25 (m, 6H), 1.21 (d, J = 6.8 Hz, 3H).
Example 301: Synthesis of Compound 501
O HN
N N N
O NH
Compound 501 (formic acid salt) was prepared as a white solid utilizing the methods in
Example 296 using trimethylsilyl isocyanate in place of acetic anhydride in Step 7. LCMS (ESI): t = 3.06
18253141_1 (GHMatters) P111789.NZ
min, [M + H] = 1003.5. ¹H NMR (400 MHz, DMSO-d ) δ 9.11-8.99 (m, 2H), 8.80 (t, J = 5.6 Hz, 1H),
8.35-8.28 (m, 4H), 7.19-7.02 (m, 7H), 6.76-6.70 (m, 2H), 6.41 (s, 1H), 6.05-5.96 (m, 1H), 5.38 (s, 2H),
4.86-4.68 (m, 4H), 4.48-4.42 (m, 2H), 4.21-4.13 (m, 2H), 4.08-4.00 (m, 6H), 3.22-3.07 (m, 2H), 3.05-2.95
(m, 3H), 2.86 (s, 6H), 2.68-2.63 (m, 1H), 2.48 (s, 4H), 2.01-1.93 (m, 3H), 1.80-1.70 (m, 3H), 1.63-1.24 (m,
9H), 1.20 (d, J = 6.8 Hz, 3H).
Example 302: Synthesis of Compound 502
O HN
N N N O
O S O
Compound 502 (trifluoroacetic acid salt) was prepared as a white solid utilizing methods
analogous to those described in Example 296 using tert-butyl (chlorosulfonyl)carbamate (formed by
mixing equimolar amounts of chlorosulfonyl isocyanate and tert-butanol in DCM) in place of acetic
anhydride in Step 7. LCMS (ESI): t = 3.09 min, [M + H] = 1001.5. ¹H NMR (400 MHz, DMSO-d ) δ
9.10-8.99 (m, 2H), 8.80-8.74 (m, 1H), 8.40 (d, J = 8.8 Hz, 1H), 8.35-8.29 (m, 4H), 7.24-7.03 (m, 7H), 6.74
(dd, J = 1.6, 13.2 Hz, 2H), 6.65 (s, 3H), 6.38 (s, 1H), 5.13 (dd, J = 7.6, 13.6 Hz, 1H), 4.77-4.70 (m, 2H),
4.48-4.42 (m, 1H), 4.21-4.15 (m, 2H), 4.14-4.01 (m, 6H), 3.18 (d, J = 16.0 Hz, 2H), 3.06-2.97 (m, 2H)
2.95-2.91 (m, 6H), 2.48 (s, 4H), 2.46-2.43 (m, 1H), 1.97 (d, J = 6.4 Hz, 3H), 1.78-1.73 (m, 3H), 1.57-1.23
(m, 7H), 1.20 (d, J = 6.8 Hz, 3H).
Example 303: Synthesis of Compound 503
N N N O
O S O
Compound 503 (trifluoroacetic acid salt) was prepared as a white solid utilizing the methods in Example
296 using tert-butyl (chlorosulfonyl)carbamate (formed by mixing equimolar amounts of chlorosulfonyl
isocyanate and tert-butanol in DCM) in place of acetic anhydride in Step 7. LCMS (ESI): t = 3.15 min,
[M + H] = 1039.6. ¹H NMR (400 MHz, DMSO-d ) δ 8.97 (d, J = 6.8 Hz, 2H), 8.70 (t, J = 5.6 Hz, 1H),
8.34-8.25 (m, 3H), 7.94-7.88 (m, 6H), 7.25-7.03 (m, 7H), 6.73 (t, J = 2.4 Hz, 2H), 6.53-6.44 (m, 3H), 4.82-
4.69 (m, 3H), 4.48-4.42 (m, 1H), 4.25-4.11 (m, 6H), 3.25-2.88 (m, 12H), 2.49-2.43 (m, 4H), 1.97-1.26 (m,
15H), 1.22 (d, J = 6.8 Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 304: Synthesis of Compound 504
O HN
N N N O
NHBoc
NHBoc
BocHN
BocHN
Na O
N OMe
ClCO Et
N OMe 2 O HN
O HN
H H N N N O
Step 1
N N N O
504-1
496-6
Step 1: A mixture of Compound 496-6 (described in Example 296) (280 mg, 0.25 mmol) and
sodium formate (20.4 mg, 0.38 mmol) in ethyl formate (4 mL) was stirred at 50 °C for 18 h. The mixture
was partitioned between ethyl acetate and water and the phases separated. The organic layer was washed
with brine, dried over Na SO and the solvent removed. The residue was purified by silica gel
chromatography (eluting with 7% MeOH/DCM) to give Compound 504-1 (168 mg, 58%) as a white solid.
LCMS (ESI): [M + H] = 1150.
[001162] Starting from Compound 504-1, typical hydrolysis, amide coupling (HATU/DIEA) and global
Boc removal (TFA/HFIP) procedures (as described in Examples 5 and 7) were followed to afford
Compound 504 (formic acid salt) as a white solid. LCMS (ESI): t = 3.70 min, [M + H] = 974.3. ¹H NMR
(400 MHz, DMSO-d ) δ 9.05-8.97 (m, 2H), 8.72-8.67 (m, 1H), 8.38-8.00 (m, 6H), 7.25-6.99 (m, 6H),
6.80-6.67 (m, 2H), 6.42 (s, 1H), 4.89-4.82 (m, 1H), 4.80-4.66 (m, 3H), 4.49-4.40 (m, 2H), 4.17 (d, J = 5.7
Hz, 3H), 4.13-4.00 (m, 6H), 3.30-3.19 (m, 4H), 3.05-2.90 (m, 6H), 2.85 (s, 3H), 2.68-2.63 (m, 1H), 2.00-
1.87 (m, 3H), 1.82 -1.68 (m, 3H), 1.59-1.20 (m, 7H), 1.19 (d, J = 5.7 Hz, 3H).
Example 305: Synthesis of Compound 505
O HN
N N N O
H N O
Compound 505 (formic acid salt) was prepared as a white solid from Compound 101-G and
Compound 496-3 (described in Example 296), utilizing methods analogous to those described in Example
7. LCMS (ESI): t = 3.15 min, [M + H] = 974.4. ¹H NMR (400 MHz, DMSO-d ) δ 9.06-8.87 (m, 2H),
8.74-8.63 (m, 1H), 8.37-8.28 (m, 2H), 8.25 (s, 1H), 7.45-6.91 (m, 6H), 6.88-6.66 (m, 2H), 6.42 (s, 1H),
18253141_1 (GHMatters) P111789.NZ
4.96-4.58 (m, 3H), 4.51-4.40 (m, 1H), 4.17 (d, J = 5.8 Hz, 2H), 4.12-3.99 (m, 4H), 3.25-3.09 (m, 1H),
3.05-2.85 (m, 6H), 2.34-2.22 (m, 2H), 2.09-1.89 (m, 2H), 1.84-1.67 (m, 2H), 1.60-1.36 (m, 4H), 1.35-1.17
(m, 4H).
Example 306: Synthesis of Compound 506
O HN
N N N O
NHBoc NHBoc
NHBoc
O BocHN BocHN
BocHN
FmocHN
TrtHN O
piperidine,
HATU, DIPEA
HN O HN
H Step 2 H
DCM, DMF
H N N O
FmocHN N O
N O N O
Step 1
TrtHN O TrtHN O
O 506-1 506-2
101-G
Step 1: Following a HATU Coupling with Compound 101-G (357 mg, 0.50 mmol) and Fmoc-L-
Asn(Trt)-OH (448 mg, 0.75 mmol) afforded Compound 506-1 (561 mg, 87%). LCMS (ESI): [M + H] =
1292.
[001165] Step 2: To a solution of Compound 506-1 (503 mg, 0.389 mmol) in DMF (3.0 mL) was
added piperidine (0.385 mL, 3.89 mmol). The mixture was stirred at ambient temperature for 18 h. The
mixture was partitioned between ethyl acetate and water and the organic layer was washed with brine,
dried over Na SO and the solvent removed. The crude residue was purified via silica gel chromatography
(solvent gradient: 0-10% MeOH/DCM) to give Compound 506-2 (300 mg, 72%) as an off-white solid.
LCMS (ESI): [M + H] = 1070.
Compound 506 (trifluoroacetic acid salt) was obtained as a white solid from Compound 506-2,
following typical amide coupling (HATU/DIEA), hydrolysis, amide coupling (HATU/DIEA) and global
Boc/Trityl removal (TFA/HFIP) procedures (as described in Example G). LCMS (ESI): t = 3.10 min, [M
+ H] = 933.5. ¹H NMR (400 MHz, DMSO-d ) δ 9.03 (d, J = 7.7 Hz, 1H), 8.50 (d, J = 8.8 Hz, 1H), 8.34-
8.27 (m, 2H), 7.84-7.76 (m, 1H), 7.40 (s, 1H), 7.10 (s, 1H), 7.08-7.01 (m, 3H), 6.99-6.90 (m, 2H), 6.80-
6.73 (m, 2H), 6.31 (s, 1H), 5.31-5.23 (m, 1H), 4.68-4.58 (m, 2H), 4.50-4.41 (m, 1H), 4.08-3.96 (m, 4H),
3.10-3.00 (m, 1H), 2.95-2.83 (m, 5H), 2.68-2.59 (m, 2H), 2.42-2.38 (m, 1H), 2.45 (s, 1H), 2.01-1.90 (m,
2H), 1.78-1.69 (m, 2H), 1.59-1.22 (m, 6H), 1.17 (d, J = 6.5 Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 307: Synthesis of Compound 507
O HN
N N N O
Compound 507 was prepared as a white solid utilizing methods analogous to those described in Example R
using (S)(((benzyloxy)carbonyl)amino)((tert-butyldimethylsilyl)oxy)propanoic acid, 2-[4-
(cyclohexoxy)phenyl]-4,6-dimethyl-pyrimidinecarboxylic acid and Compound 101-G and purified by
chiral SFC. LCMS (ESI): t = 3.06 min, [M + H] = 960.3. ¹H NMR (400 MHz, DMSO-d ) δ 9.08-8.93 (m,
2H), 8.76-8.66 (d, J = 7.1 Hz, 1H), 8.36-8.25 (m, 2H), 7.89 (br s, 6H), 7.39-7.01 (m, 7H), 6.78-6.68 (m,
2H), 6.45 (s, 1H), 5.03-4.93 (m, 1H), 4.80-4.67 (m, 2H), 4.50-4.40 (m, 1H), 4.33-4.07 (m, 6H), 3.82-3.74
(m, 1H), 3.64-3.54 (m, 1H), 3.24-2.97 (m, 6H), 2.92 (s, 3H), 2.69-2.62 (m, 1H), 2.47 (s, 1H), 2.43 (s, 1H),
2.02-1.91 (m, 2H), 1.79-1.68 (m, 2H), 1.61-1.15 (m, 9H).
Example 308: Synthesis of Compound 508
O HN
N N N O
Compound 508 was isolated as a minor epimer from the synthesis of Compound 507, via chrial
SFC. LCMS (ESI): t = 3.13 min, [M + H] = 933.5. ¹H NMR (400 MHz, DMSO-d ) δ 9.06 (d, J = 7.1 Hz,
1H), 8.66 (t, J = 5.4 Hz, 1H), 8.53 (d, J = 9.0 Hz, 1H), 8.74-8.49 (m, 2H), 8.36-8.18 (m, 2H), 7.86 (br s,
6H), 7.32-7.22 (m, 1H), 7.20-7.01 (m, 5H), 6.94 (s, 1H), 6.42 (s, 1H), 5.04-4.93 (m, 1H), 4.65-4.54 (m,
1H), 4.50-4.40 (m, 1H), 4.28-4.11 (m, 6H), 3.97-3.86 (m, 1H), 3.84-3.75 (m, 1H), 3.65-3.56 (m, 1H), 3.23-
3.05 (m, 6H), 3.01 (s, 3H), 2.74-2.64 (m, 1H), 2.41 (s, 1H), 2.02-1.90 (m, 2H), 1.80-1.68 (m, 2H), 1.61-
1.14 (m, 9H).
Example 309: Synthesis of Compound 509
O HN
N N N O
Compound 509 (trifluoroacetic acid salt) was prepared as a white solid utilizing methods
analogous to those described in Example R from (S)(((benzyloxy)carbonyl)amino)((tert-
butyldimethylsilyl)oxy)butanoic acid, 2-[4-(cyclohexoxy)phenyl]-4,6-dimethyl-pyrimidinecarboxylic
18253141_1 (GHMatters) P111789.NZ
acid and Compound 101-G. LCMS (ESI): t = 3.14 min, [M + H] = 947.5. H NMR (400 MHz, DMSO-d )
δ H NMR (400 MHz, DMSO-d ) δ 8.98-8.95 (m, 2H), 8.69 (t, J = 4.5 Hz, 1H), 8.33-8.23 (m, 3H), 7.94-
7.84 (br s, 6H), 7.26-7.04 (m, 7H), 6.76-6.70 (m, 2H), 6.45 (s, 1H), 5.18-4.97 (m, 2H), 4.79-4.67 (m, 2H),
4.49-4.42 (m, 2H), 4.29-4.07 (m, 6H), 3.56-3.50 (m, 2H), 3.22-2.97 (m, 7H), 2.89 (s, 3H), 2.00-1.83 (m,
3H), 1.79-1.69 (m, 3H), 1.99-1.51 (m, 1H), 1.50-1.35 (m, 4H), 1.33-1.25 (m, 2H), 1.21 (d, J = 7.0 Hz, 3H).
Example 310: Synthesis of Compound 510
N CN
O HN
N N O
N N O
NHBoc NHBoc
NHBoc
BocHN BocHN
BocHN
O O O
FmocHN
Piperidine
OMe OMe
O HN HN O HN
H HATU, DIPEA H H
H H DMF
H N N
O N N O N N O
FmocHN N O H N N O
Step 2
O O O O
Step 1
496-4
TeocHN 510-1 TeocHN 510-2
TeocHN
NHBoc
BocHN
1. Tail, HATU
DIPEA, DCM N CN
O O HN
N N O
2. LiOH, THF
3. HCl.H N CN
2 O O
HATU, DIPEA
NHTeoc
O 510-3
Step 3
Step 1: To a mixture of Compound 496-4 (described in Example 296)(479 mg, 0.50
mmol) and (2S)(9H-fluorenylmethoxycarbonylamino)butanoic acid (195 mg, 0.60 mmol) in DCM (7
mL) was added DIPEA (0.17 mL, 1 mmol) followed by HATU (247 mg, 0.65 mmol) portion wise. The
mixture was stirred at 20 °C for 16 h. The mixture was diluted with DCM, washed with water, brine, then
dried over Na SO and the solvent removed. The crude product was purified via silica gel chromatography
(solvent gradient: 70-80% ethyl acetate/cyclohexane) to give Compound 510-1 (435 mg, 69%) as a
colorless oil. LCMS (ESI): [M + H] = 1265.
Step 2: To Compound 510-1 (432 mg, 0.34 mmol) in DMF (4 mL) was added piperidine (0.34
mL, 3.41 mmol) and the mixture stirred at 20 °C for 16 h. The mixture was diluted with water and
extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over
Na SO and the solvent removed. The residue was purified by silica gel chromatography (solvent gradient:
7-10% MeOH/DCM) to give Compound 510-2 (313 mg, 88%) as a white solid. LCMS (ESI): [M + H]
=1044.
18253141_1 (GHMatters) P111789.NZ
Step 3: The methods of Example G were applied to Compound 510-2 to afford Compound 510-3
(133 mg, 33% over 3 steps) as a colorless glass. LCMS (ESI): [M + H] = 1376.
Step 4: To a solution of Compound 510-3 (130 mg, 0.09 mmol) in THF (2 mL) was added a
solution of tetrabutylammonium fluoride (1.0 M in THF, 0.14 mL, 0.14 mmol) and the mixture stirred
at 60 °C for 24 hours. The mixture was allowed to cool to ambient temperature and the solvent was
removed under reduced pressure. The residue was partitioned between ethyl acetate and brine, the phases
separated. The organic layer was dried over Na SO and the solvent removed. The general global Boc
removal (TFA/HFIP) procedure of Example G was followed to give Compound 510 (trifluoroacetic acid
salt) as a white solid. LCMS (ESI): t = 2.86 min, [M + H] = 1032.2. H NMR (400 MHz, DMSO-d ) δ
8.97 (d, J = 8.0 Hz, 1H), 8.79 (d, J = 6.4 Hz, 1H), 8.73 (t, J = 5.6 Hz, 1H), 8.59 (d, J = 8.4 Hz, 1H), 8.38 (d,
J = 8.8 Hz, 1H), 8.31 (d, J = 8.8 Hz, 2H), 7.99-7.89 (m, 6H), 7.79 (s, 3H), 7.33-7.02 (m, 7H), 6.71 (s, 2H),
6.30 (s, 1H), 4.96-4.89 (m, 1H), 4.78-4.67 (m, 2H), 4.47-4.33 (m, 2H), 4.24-4.10 (m, 5H), 3.27-2.81 (m,
9H), 2.74 (s, 3H), 2.47 (s, 4H), 2.06-1.84 (m, 4H), 1.78-1.23 (m, 11H), 1.21 (d, J = 6.8 Hz, 3H), 0.97 (t, J
= 7.2 Hz, 3H).
Example 311: Synthesis of Compound 511
N N N O
HN O
NHBoc NHBoc
BocHN
BocHN
O 1. LiOH, THF O
2. HCl.H N CN H N
N OMe N N
O HN HATU, DIPEA O HN
H H H H
N N N O N N N O
N O N O
O O O O
Steps 1-2
511-1
TeocHN TeocHN
496-4
NHBoc
BocHN
HO O
TBAF O
1. OTBS
HATU
O HN
H H DIPEA
Step 3
N N N O
N O CH Cl
2. TFA/HFIP
511-2 Steps 4-5
Steps 1 and 2: The methods of Example G were applied to Compound 496-4 (described in
Example 296)(1.20 g, 0.95 mmol) to afford Compound 511-1 (898 mg, 73% over 2 steps) as a white foam.
LCMS (ESI): [M + H] = 1266.
Step 3: To a solution of Compound 511-1 (895 mg, 0.69 mmol) in THF (5 mL) was added a
solution of tetrabutylammonium fluoride (1.0 M in THF, 1 mL, 1 mmol). The mixture was stirred at 20 °C
18253141_1 (GHMatters) P111789.NZ
for 16 h, then the temperature raised to 50 °C and stirred for a further 6 h. The mixture was cooled to
ambient temperature and the solvent removed under reduced pressure. The residue was partitioned
between ethyl acetate and brine and the phases separated. The organic layer was collected and dried over
Na SO and solvent removed to yield Compound 511-2 (888 mg, 112%) as a white solid. This material
was used directly in the next steps without further purification. LCMS (ESI): [M + H] = 1146.
Steps 4 and 5: Starting from Compound 511-2 and 2-[tert-butyl(dimethyl)silyl]oxyacetic acid,
the amide coupling (HATU/DIEA) and global Boc removal (TFA/HFIP) procedures of Example G were
followed to afford Compound 511 (trifluoroacetic acid salt) as a white solid. LCMS (ESI): t = 3.05 min,
[M + H] = 1004.8. H NMR (400 MHz, DMSO-d ) δ 9.01 (d, J =7 Hz, 1H), 8.96 (d, J = 7.0 Hz, 1H), 8.69
(t, J = 5.5 Hz, 1H), 8.32 (d, J = 8.7 Hz, 2H), 8.27 (d, J = 8.7 Hz, 1H), 7.94-7.80 (br s, 6H), 7.28-7.02 (m,
7H), 6.73 (dd, J = 2.0, 10.7 Hz, 2H), 6.43 (s, 1H), 4.89-4.66 (m, 4H), 4.49-4.41 (m, 2H), 4.28-4.08 (m, 6H),
3.78 (s, 2H), 3.32-2.97 (m, 9H), 2.85 (s, 3H), 2.03-1.92 (m, 3H), 1.82-1.69 (m, 3H), 1.60-1.35 (m, 5H),
1.35-1.24 (m, 2H), 1.21 (d, J = 7.0 Hz, 3H).
Example 312: Synthesis of Compound 512
O HN
N N N
Step 1: To a solution of 1,1`-carbonylimidazole (55 mg, 0.34 mmol) in THF (2.0 mL) under
nitrogen at 20 °C was added a solution of Compound 511-2 (195 mg, 0.17 mmol) in THF (2.0
mL) dropwise. The mixture was stirred at 20 °C for 1 hour, then O-(tert-butyldimethylsilyl)hydroxylamine
(75 mg, 0.51 mmol) was added. The mixture was stirred at 20 °C for 18 h. The temperature was raised to
50 °C and stirred for a further 4 h. The mixture was cooled to ambient temperature, partitioned between
ethyl acetate and water and the phases separated. The organic layer was washed with 0.1M aqueous HCl,
brine, dried over Na SO and the solvent removed under reduced pressure. The resulting residue was used
directly in next step without further purification LCMS (ESI): [M + H] = 1206.
Step 2: The global Boc removal (TFA/HFIP) procedure of Example G was followed to give
Compound 512 (trifluoroacetic acid salt) as a white solid. LCMS (ESI): t = 3.20 min, [M + H] = 1005.7.
H NMR (400 MHz, DMSO-d ) δ 9.01-8.95 (m, 2H), 8.70 (t, J = 5.5 Hz, 1H), 8.60-8.51 (br s, 2H), 8.35-
8.25 (m, 4H), 7.97-7.83 (br s, 6H), 7.28-7.01 (m, 7H), 6.87 (t, J = 5.5 Hz, 1H), 6.75-6.71 (br s, 2H), 6.44 (s,
1H), 4.87-4.79 (m, 2H), 4.79-4.67 (m, 2H), 4.50-4.41 (m, 2H), 4.29-4.08 (m, 6H), 3.26-2.96 (m, 9H), 2.86
(s, 3H), 2.01-1.93 (m, 3H), 1.80-1.69 (m, 3H), 1.60-1.50 (m, 1H), 1.50-1.35 (m, 4H), 1.35-1.25 (m, 2H),
1.21 (d, J = 7.0 Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 313: Synthesis of Compound 513
N N CN
N N N O
Compound 513 (formic acid salt) was prepared as a white solid from Compound 101-K by
utilizing methods analogous to those described in Example 53. LCMS (Method 5-95 AB, ESI): t = 0.754
min, [M + H] = 918.8; H NMR (400 MHz, MeOH-d ) δ 8.46 (br s, 3H), 8.28 (d, J=8.4 Hz, 2H), 7.32-
7.26 (m, 3H), 7.20 (d, J=8.4 Hz, 2H), 7.09 (d, J=8.4 Hz, 1H), 6.90 (s, 1H), 6.75 (brs, 1H), 6.45 (s, 1H),
.25-5.21 (m, 1H), 4.85-4.78 (m, 2H), 4.29-4.19 (m, 6H), 3.23-3.05 (m, 8H), 3.00 (s, 3H), 2.69 (t, J=7.6
Hz, 2H), 2.53 (s, 6H), 2.33-2.22 (m, 1H), 2.20-2.10 (m, 1H), 1.70-1.64 (m, 2H), 1.38-1.33 (m, 7H), 0.92 (t,
J=6.8 Hz, 3H).
Examples 314-358: Synthesis of compounds 514-558
The following compounds in table 3 were prepared by utilizing methods analogous to those
previously described.
Table 3
Comp. # Structure
N N N O
O HN
N N N O
O HN
N N N O
18253141_1 (GHMatters) P111789.NZ
Comp. # Structure
N N N O
O HN
N N N O
N NH N
O HN
N N O
NH O O
O HN
N N N O
O HN
N N N O
H N HO
O HN
N N N O
18253141_1 (GHMatters) P111789.NZ
Comp. # Structure
N N N O
H N HO
O HN
N N N O
H N HO
N N O
H N O
N N N
O HN
N N N O
O HN
N N N
H N O
O HN
N N O
NH O O
O HN N
N N O
18253141_1 (GHMatters) P111789.NZ
Comp. # Structure
N N N O
N NH N
O HN
N N N O
H N O
O HN
N N O
HN N
H N O
N NH N
N O HN
N N N O
H N HO
O HN
N N N O
O HN
N N N O
18253141_1 (GHMatters) P111789.NZ
Comp. # Structure
H N O
O HN
F N N O
F O O
H OH
H N O
NH N
O HN
N N N O
H N HO
539 O
N N N O
H N O
N N N
N N N O
H N HO
O HN
N N O
N N N O
O HN
N N N O
18253141_1 (GHMatters) P111789.NZ
Comp. # Structure
H N O
NH N
O HN
N N N
H N O
NH N
N N N O
H N O
O HN
N N O
NH O O
N NH N
N N N O
H OH
H N HO
N NH N
O HN
N N N O
549 2
O HN
N N N O
H N O
N N N
O HN
N N N O
18253141_1 (GHMatters) P111789.NZ
Comp. # Structure
H N O
N N N O
O HN
N N N O
O HN
N N N O
H N O
N Cl N
O HN
N N O
NH O O
H N O
O HN
N N N
H N HO
N N O
NH O O
18253141_1 (GHMatters) P111789.NZ
Comp. # Structure
NH N
O HN
N N N O
O HN
N N N O
Example 359. Synthesis of compound 559
H N HO
O HN
N N N O
Step 1. Methyl (4S,7S,10S)((S)((tert-butoxycarbonyl)amino)(2-(4-(tert-butyl)phenyl)-4,6-
dimethylpyrimidinecarboxamido)-N-methylbutanamido)-1 -(2-((tert-butoxycarbonyl)amino)ethoxy)-2 -
hydroxymethyl-2 -nitro-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphanecarboxylate
O O O O
HN HO
HN HO
O HN
N N N O
N N N O
559-1
HN O
To a mixture of compound 559-1 (77.4 mg, 0.0746 mmol) and acetic acid (1.0 mL, 17 mmol)
was added nitric acid (11 μL, 0.22 mmol). The reaction mixture was stirred at room temperature for 2 h.
The reaction mixture was evaporated under reduced pressure, and the resulting residue was diluted with
dichloromethane, washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate,
filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (4
18253141_1 (GHMatters) P111789.NZ
g silica, solvent gradient: 0-5% methanol in dichloromethane) to yield 63.1 mg (78%) of the title
compound. LCMS (ESI): [M+H] = 1082.45.
Step 2. methyl (4S,7S,10S)-2 -amino((S)((tert-butoxycarbonyl)amino)(2-(4-(tert-butyl)phenyl)-
4,6-dimethylpyrimidinecarboxamido)-N-methylbutanamido)-1 -(2-((tert-
butoxycarbonyl)amino)ethoxy)-2 -hydroxymethyl-6,9-dioxo-5,8-diaza-1,2(1,3)-
dibenzenacyclodecaphanecarboxylate
HN HO
N N N
HN O
To a solution of methyl (4S,7S,10S)((S)((tert-butoxycarbonyl)amino)(2-(4-(tert-
butyl)phenyl)-4,6-dimethylpyrimidinecarboxamido)-N-methylbutanamido)-1 -(2-((tert-
butoxycarbonyl)amino)ethoxy)-2 -hydroxymethyl-2 -nitro-6,9-dioxo-5,8-diaza-1,2(1,3)-
dibenzenacyclodecaphanecarboxylate (63.1 mg, 0.0583 mmol) in ethanol (2.0 mL) was added
palladium (10 wt. % on carbon) (6.5 mg, 0.0061 mmol). The reaction mixture was purged with nitrogen
and then with hydrogen, and stirred at room temperature under a balloon of hydrogen for 24 h. The
reaction mixture was filtered through celite, rinsing with methanol, and the filtrate was evaporated in
vacuo to yield the title compound (57.7 mg, 94%). LCMS (ESI): [M+H] = 1052.4.
Step 3. methyl (4S,7S,10S)-2 -acetamido((S)((tert-butoxycarbonyl)amino)(2-(4-(tert-
butyl)phenyl)-4,6-dimethylpyrimidinecarboxamido)-N-methylbutanamido)-1 -(2-((tert-
butoxycarbonyl)amino)ethoxy)-2 -hydroxymethyl-6,9-dioxo-5,8-diaza-1,2(1,3)-
dibenzenacyclodecaphanecarboxylate
HN HO
O HN
N N N O
To a solution of methyl (4S,7S,10S)-2 -amino((S)((tert-butoxycarbonyl)amino)(2-(4-
(tert-butyl)phenyl)-4,6-dimethylpyrimidinecarboxamido)-N-methylbutanamido)-1 -(2-((tert-
18253141_1 (GHMatters) P111789.NZ
butoxycarbonyl)amino)ethoxy)-2 -hydroxymethyl-6,9-dioxo-5,8-diaza-1,2(1,3)-
dibenzenacyclodecaphanecarboxylate (57.7 mg, 0.0548 mmol) in dichloromethane (1.5 mL) was added
acetic anhydride (16 μL, 0.169 mmol) and pyridine (27 μL, 0.330 mmol). The reaction mixture was stirred
at room temperature for 2 h. The reaction mixture was evaporated onto celite, and the crude product was
purified via flash chromatography on silica gel (4 g silica, solvent gradient: 0-5% methanol in DCM) to
yield 60.0 mg (69%) of the title compound. LCMS (ESI): [M+H] = 1094.5.
Step 4. (4S,7S,10S)-2 -acetamido((S)((tert-butoxycarbonyl)amino)(2-(4-(tert-butyl)phenyl)-4,6-
dimethylpyrimidinecarboxamido)-N-methylbutanamido)-1 -(2-((tert-butoxycarbonyl)amino)ethoxy)-2 -
hydroxymethyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphanecarboxylic acid
HN HO
N OH
O HN
N N N O
HN O
To a solution of methyl (4S,7S,10S)-2 -acetamido((S)((tert-butoxycarbonyl)amino)(2-
(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidinecarboxamido)-N-methylbutanamido)-1 -(2-((tert-
butoxycarbonyl)amino)ethoxy)-2 -hydroxymethyl-6,9-dioxo-5,8-diaza-1,2(1,3)-
dibenzenacyclodecaphanecarboxylate (41.3 mg, 0.0377 mmol) in tetrahydrofuran (1.0 mL) was added
water (0.20 mL) and lithium hydroxide (1.0 M in water) (0.10 mL, 0.10 mmol). The reaction mixture was
stirred at room temperature for 1 h. The reaction mixture was evaporated in vacuo, and carried forward
without purification assuming quantitative yield. LCMS (ESI): [M+H] = 1081.25.
Step 5. tert-butyl ((S)(((3S,6S,9S)-1 -acetamido-2 -(2-((tert-butoxycarbonyl)amino)ethoxy)
((cyanomethyl)carbamoyl)-1 -hydroxymethyl-4,7-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-
3-yl)(methyl)amino)(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidinecarboxamido)
oxobutyl)carbamate
HN HO
O HN
N N N O
HN O
18253141_1 (GHMatters) P111789.NZ
To a mixture of (4S,7S,10S)-2 -acetamido((S)((tert-butoxycarbonyl)amino)(2-(4-(tert-
butyl)phenyl)-4,6-dimethylpyrimidinecarboxamido)-N-methylbutanamido)-1 -(2-((tert-
butoxycarbonyl)amino)ethoxy)-2 -hydroxymethyl-6,9-dioxo-5,8-diaza-1,2(1,3)-
dibenzenacyclodecaphanecarboxylic acid (0.0377 mmol, 0.0377 mmol), aminoacetonitrile
hydrochloride (7.5 mg, 0.081 mmol), HATU (32.0 mg, 0.0825 mmol) and DMF (1.0 mL) was added N,N-
diisopropylethylamine (33 μL, 0.189 mmol). The reaction mixture was stirred at room temperature for 3 h.
To the reaction mixture was added 8.6 mg aminoacetonitrile hydrochloride, 50 uL N,N-
diisopropylethylamine, and 31.6 mg HATU. The reaction mixture was stirred overnight at room
temperature. The reaction mixture was diluted with ethyl acetate and washed with 2:1:1
water:brine:sodium bicarbonate, 10% aqueous citric acid, and brine, dried over magnesium sulfate, filtered,
and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (4 g silica,
solvent gradient: 0-10% methanol in dichloromethane) to yield 33.1 mg (42%) of the title compound.
LCMS (ESI): [M+H] = 1118.
Step 6. (4S,7S,10S)-2 -acetamido((S)amino(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine
carboxamido)-N-methylbutanamido)-1 -(2-aminoethoxy)-N-(cyanomethyl)-2 -hydroxymethyl-6,9-
dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphanecarboxamide
To a solution of tert-butyl ((S)(((3S,6S,9S)-1 -acetamido-2 -(2-((tert-
-hydroxymethyl-4,7-dioxo-5,8-diaza-
butoxycarbonyl)amino)ethoxy)((cyanomethyl)carbamoyl)-1
1,2(1,3)-dibenzenacyclodecaphaneyl)(methyl)amino)(2-(4-(tert-butyl)phenyl)-4,6-
dimethylpyrimidinecarboxamido)oxobutyl)carbamate (33.1 mg, 0.0296 mmol) in 1,1,1,3,3,3-
hexafluoropropanol (1.0 mL) was added trifluoroacetic acid (0.1 mL, 1 mmol). The reaction mixture
was stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo, azeotroping with
diethyl ether (2 x 2 mL). The resulting residue was purified via reverse phase preparatory HPLC and
lyophilized to yield 3.4 mg (12%) of the title compound. LCMS (Method A, ESI): t = 4.443 min, [M+H]
= 918.4; H NMR (400 MHz, DMSO-d ) δ 9.92 (s, 1H), 9.20 – 9.07 (m, 2H), 9.00 (d, J = 7.9 Hz, 1H), 8.73
– 8.65 (m, 1H), 8.58 – 8.41 (m, 1H), 8.36 – 8.28 (m, 3H), 7.56 (d, J = 8.5 Hz, 3H), 7.22 – 7.12 (m, 3H),
6.86 – 6.47 (m, 3H), 6.43 (s, 1H), 5.04 (s, 1H), 4.84 – 4.63 (m, 2H), 4.37 – 4.12 (m, 5H), 3.20 (d, J = 4.9
Hz, 3H), 3.12 (d, J = 3.5 Hz, 3H), 2.95 (d, J = 15.8 Hz, 6H), 2.18 – 2.01 (m, 5H), 1.33 (d, J = 2.2 Hz, 12H),
1.21 (d, J = 6.9 Hz, 3H).
Example 360. Synthesis of Compound 560
H N HO
O HN
N N N
Step 1. methyl (S)((tert-butoxycarbonyl)amino)(3-fluorohydroxyiodophenyl)propanoate
18253141_1 (GHMatters) P111789.NZ
HN (S)
To a solution of methyl (2S)(tert-butoxycarbonylamino)(3-fluorohydroxy-
phenyl)propanoate (1.4814 g, 4.256 mmol) in methanol (10.0 mL) was sequentially added silver sulfate
(1.418 g, 4.548 mmol) and iodine (1.123 g, 4.40 mmol). The reaction mixture was stirred at room
temperature for 2 h. The reaction was quenched with aqueous sodium thiosulfate and extracted with ethyl
acetate. The organic portion was dried over brine and magnesium sulfate, filtered, and evaporated in vacuo.
The crude product was purified via flash chromatography on silica gel (40 g silica, solvent gradient: 0-
100% ethyl acetate in dichloromethane) to yield 1.5246 g (81%) of the title compound. LCMS (ESI):
[M+Na] = 461.95.
Step 2. methyl (S)(4-(benzyloxy)fluoroiodophenyl)((tert-butoxycarbonyl)amino)propanoate
HN (S)
To a mixture of methyl (S)((tert-butoxycarbonyl)amino)(3-fluorohydroxy
iodophenyl)propanoate (1.5246 g, 3.471 mmol), potassium carbonate (962 mg, 6.9604 mmol) and N,N-
dimethylformamide (12 mL) was added benzyl bromide (0.50 mL, 4.2 mmol). The reaction mixture was
stirred at room temperature for 19 h. The reaction mixture was diluted with ethyl acetate, washed with
water and brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was
purified via flash chromatography on silica gel (40 g silica, solvent gradient: 0-50% ethyl acetate in
heptanes) to yield 1.6527 g (95%) of the title compound as a clear colorless gum. LCMS (ESI): [M+Na] =
552.0.
Step 3. methyl (S)(4-(benzyloxy)fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl)
((tert-butoxycarbonyl)amino)propanoate
HN (S)
18253141_1 (GHMatters) P111789.NZ
A mixture of methyl (S)(4-(benzyloxy)fluoroiodophenyl)((tert-
butoxycarbonyl)amino)propanoate (1.6527 g, 3.122 mmol), bis(pinacolato)diboron (1.3990 g, 5.455
mmol), potassium acetate (0.985 g, 9.94 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)
chloride, complex with dichloromethane (1:1) (0.289 g, 0.354 mmol), and dimethylsulfoxide (10.0 mL)
was heated at 70 °C under nitrogen for 16 h. The reaction mixture was diluted with ethyl acetate, washed
with water (2x) and brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude
product was purified via flash chromatography on silica gel (40 g silica, solvent gradient: 0-100% ethyl
acetate in dichloromethane) to yield 0.9468 g (57%) of the title compound. LCMS (ESI): [M+H-Boc] =
430.15, [M+NH ] = 547.25. H NMR (400 MHz, DMSO-d ) δ 7.54 – 7.49 (m, 2H), 7.41 – 7.22 (m, 6H),
4.96 (s, 2H), 4.15 (td, J = 9.4, 4.7 Hz, 1H), 3.62 (s, 3H), 2.99 (dd, J = 13.7, 4.7 Hz, 1H), 2.82 (dd, J = 13.8,
.4 Hz, 1H), 1.32 (s, 9H), 1.29 (s, 12H).
Step 4. methyl (S)amino(4-(benzyloxy)fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)phenyl)propanoate
H N (S)
[001189] To a solution of methyl (S)(4-(benzyloxy)fluoro(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)phenyl)((tert-butoxycarbonyl)amino)propanoate (945 mg, 1.785 mmol) in
dichloromethane (8 mL) was added trifluoroacetic acid (1.0 mL, 13 mmol). The reaction mixture was
stirred at room temperature. After 7 h, the reaction mixture was evaporated in vacuo to afford the title
compound as a TFA salt, which was carried forward without purification. LCMS (ESI): [M+H] = 430.
Step 5. methyl (5S,8S,11S)(4-(benzyloxy)fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)benzyl)(4-(2-((tert-butoxycarbonyl)amino)ethoxy)iodophenyl)-4,8-dimethyl-3,6,9-trioxo
phenyloxa-4,7,10-triazadodecanoate
O N O O
O OH
N O O
O N O H N (S)
O N O
To a solution of (2S)[[(2S)[benzyloxycarbonyl(methyl)amino][4-[2-(tert-
butoxycarbonylamino)ethoxy]iodo-phenyl]acetyl]amino]propanoic acid (1.011 g, 1.542 mmol) in THF
(5 mL) was added 2-chloro-4,6-dimethoxy-1,3,5-triazine (365.9 mg, 2.084 mmol) and 4-methylmorpholine
(0.90 mL, 8.2 mmol). After 20 minutes a solution of methyl (S)amino(4-(benzyloxy)fluoro
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl)propanoate (1.785 mmol, 1.785 mmol) in THF (5 mL)
was added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was
18253141_1 (GHMatters) P111789.NZ
diluted with ethyl acetate, washed with water (2x) and brine, dried over magnesium sulfate, filtered, and
evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (40 g silica,
solvent gradient: 0-5% methanol in dichloromethane) to yield 1.412 g (86%) of the title compound. LCMS
(ESI): [M+H-tBu] = 1011.20, [M+NH ] = 1084.30.
Step 6. methyl (4S,7S,10S)-2 -(benzyloxy)(((benzyloxy)carbonyl)(methyl)amino)-1 -(2-((tert-
butoxycarbonyl)amino)ethoxy)-2 -fluoromethyl-6,9-dioxo-5,8-diaza-1,2(1,3)-
dibenzenacyclodecaphanecarboxylate
O HN
O N O
To a mixture of methyl (5S,8S,11S)(4-(benzyloxy)fluoro(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)benzyl)(4-(2-((tert-butoxycarbonyl)amino)ethoxy)iodophenyl)-4,8-dimethyl-
3,6,9-trioxophenyloxa-4,7,10-triazadodecanoate (1.412 g, 1.324 mmol) and potassium phosphate
tribasic (883 mg, 4.0766 mmol) in acetonitrile (60 mL) was added water (6.0 mL), followed by [1,1'-
bis(diphenylphosphino)ferrocene]palladium(II) chloride, complex with dichloromethane (1:1) (169.0 mg,
0.2070 mmol). The reaction mixture was heated under a nitrogen balloon at 70 °C for 90 min. The reaction
mixture was evaporated under reduced pressure to remove the majority of acetonitrile. The residual
material was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate,
filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel
(40 g silica, solvent gradient: 0-5% methanol in dichloromethane) to yield 335.0 mg (31%) of the title
compound. LCMS (ESI): [M+H] = 813.3.
6 5 6
Step 7. methyl (4S,7S,10S)-1 -(2-((tert-butoxycarbonyl)amino)ethoxy)-2 -fluoro-2 -hydroxymethyl
(methylamino)-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphanecarboxylate
HN HO
HN O
A suspension of methyl (4S,7S,10S)-2 -(benzyloxy)(((benzyloxy)carbonyl)(methyl)amino)(2-((tert-butoxycarbonyl)amino)ethoxy)-2 -fluoromethyl-6,9-dioxo-5,8-diaza-1,2(1,3)-
dibenzenacyclodecaphanecarboxylate (335 mg, 335 mg, 0.4121 mmol) in ethanol (3 mL) was purged
with nitrogen. Ammonium formate (411.1 mg, 6.520 mmol) and palladium hydroxide (20 wt. % on carbon)
18253141_1 (GHMatters) P111789.NZ
(139.7 mg, 0.1990 mmol) were added and the reaction mixture heated under microwave irradiation at 100
°C for 20 minutes. 72.7 mg palladium hydroxide (20 wt. % on carbon) and 220.3 mg ammonium formate
were added and the mixture heated under microwave irradiation at 100 °C for 45 minutes. The reaction
mixture was filtered through celite, rinsing with dichloromethane. The filtrate was diluted further with
dichloromethane and washed with aqueous sodium bicarbonate to remove formate salt. The aqueous layer
was extracted with an additional portion of DCM, and the combined DCM portions were dried over brine
and magnesium sulfate, filtered, and evaporated in vacuo to yield 261.8 mg (quantitative) of the title
compound, which was carried forward without purification. LCMS (ESI): [M+H] = 589.25.
Step 8. methyl (4S,7S,10S)((S)((((9H-fluorenyl)methoxy)carbonyl)amino)((tert-
6 5 6
butoxycarbonyl)amino)-N-methylbutanamido)-1 -(2-((tert-butoxycarbonyl)amino)ethoxy)-2 -fluoro-2 -
hydroxymethyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphanecarboxylate
HN HO
O HN
O N N O
HN O
To a solution of (2S)(tert-butoxycarbonylamino)(9H-fluoren
ylmethoxycarbonylamino)butanoic acid (196.0 mg, 0.4449 mmol) in THF (1.0 mL) was added 2-chloro-
4,6-dimethoxy-1,3,5-triazine (117.1 mg, 0.6670 mmol) and 4-methylmorpholine (0.20 mL, 1.8 mmol)
6 5 6
After 20 minutes a solution of methyl (4S,7S,10S)-1 -(2-((tert-butoxycarbonyl)amino)ethoxy)-2 -fluoro-2 -
hydroxymethyl(methylamino)-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane
carboxylate (261.8 mg, 0.4003 mmol) in THF (2 mL) was added. The reaction mixture was stirred at room
temperature for 2 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine,
dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified via flash
chromatography on silica gel (12 g silica, solvent gradient: 0-100% ethyl acetate in dichloromethane) to
yield 273.4 mg (68%) of the title compound. LCMS (ESI): [M+H] = 1011.40.
Step 9. methyl (4S,7S,10S)((S)amino((tert-butoxycarbonyl)amino)-N-methylbutanamido)-1 -(2-
((tert-butoxycarbonyl)amino)ethoxy)-2 -fluoro-2 -hydroxymethyl-6,9-dioxo-5,8-diaza-1,2(1,3)-
dibenzenacyclodecaphanecarboxylate
18253141_1 (GHMatters) P111789.NZ
HN HO
O HN
H N N O
HN O
To a solution of methyl (4S,7S,10S)((S)((((9H-fluorenyl)methoxy)carbonyl)amino)
((tert-butoxycarbonyl)amino)-N-methylbutanamido)-1 -(2-((tert-butoxycarbonyl)amino)ethoxy)-2 -fluorohydroxymethyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphanecarboxylate (273.4 mg,
0.2704 mmol) in THF (3.0 mL) was added tetrabutylammonium fluoride (1 mol/L in THF, 0.55 mL, 0.55
mmol). The reaction mixture was stirred at room temperature. After 4 h, the reaction mixture was
partitioned between heptanes (50 mL) and water (50 mL) with 5 mL of 10% aqueous citric acid added.
The organic layer was extracted again with 10% aqueous citric acid. The combined aqueous portions were
adjusted to pH ~8 with solid sodium bicarbonate and extracted with DCM (3 x 50 mL). The combined
dichloromethane portions were dried over magnesium sulfate, filtered, and evaporated in vacuo to yield the
title compound in quantitative yield, which was carried forward without purification. LCMS (ESI):
[M+H] = 789.40.
Step 10. methyl (4S,7S,10S)((S)((tert-butoxycarbonyl)amino)(2-(4-(tert-butyl)phenyl)-4,6-
dimethylpyrimidinecarboxamido)-N-methylbutanamido)-1 -(2-((tert-butoxycarbonyl)amino)ethoxy)-2 -
fluoro-2 -hydroxymethyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphanecarboxylate
HN HO
O HN
N N N O
HN O
To a solution of 2-(4-tert-butylphenyl)-4,6-dimethyl-pyrimidinecarboxylic acid (91.5 mg,
0.322 mmol) in tetrahydrofuran (2 mL) was added triethylamine (0.20 mL, 1.4 mmol) followed by thionyl
chloride (42 μL, 0.577 mmol). The reaction mixture was stirred at room temperature for 10 minutes, and
then evaporated in vacuo. The resulting residue was suspended in 2 mL THF. Half of this THF solution
(approximately 0.161 mmol) was added to a 0 °C cooled solution of methyl (4S,7S,10S)((S)amino-
4-((tert-butoxycarbonyl)amino)-N-methylbutanamido)-1 -(2-((tert-butoxycarbonyl)amino)ethoxy)-2 -
fluoro-2 -hydroxymethyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphanecarboxylate (0.135
18253141_1 (GHMatters) P111789.NZ
mmol, 0.135 mmol) and triethylamine (60.0 μL, 0.426 mmol) in tetrahydrofuran (2 mL). The reaction
mixture was stirred at 0 °C, allowing the ice bath to slowly warm to room temperature. After 3 h, the
reaction mixture was evaporated onto celite, and the crude product was purified via flash chromatography
on silica gel (12 g silica, solvent gradient: 0-5% methanol in dichloromethane) to yield 99.6 mg (70%) of
the title compound. LCMS (ESI): [M+H] = 1055.50
Step 11. (4S,7S,10S)((S)amino(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine
6 5 6
carboxamido)-N-methylbutanamido)-1 -(2-aminoethoxy)-N-(cyanomethyl)-2 -fluoro-2 -hydroxy
methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphanecarboxamide
The title compound was prepared as a TFA salt from methyl (4S,7S,10S)((S)((tert-
butoxycarbonyl)amino)(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidinecarboxamido)-N-
6 5 6
methylbutanamido)-1 -(2-((tert-butoxycarbonyl)amino)ethoxy)-2 -fluoro-2 -hydroxymethyl-6,9-dioxo-
,8-diaza-1,2(1,3)-dibenzenacyclodecaphanecarboxylate following procedures analogous to those
described for example 559, steps 4-6. LCMS (Method A, ESI): t = 4.499 min, [M+H] = 879.4; H NMR
(400 MHz, DMSO-d ) δ 9.17 (d, J = 7.3 Hz, 1H), 8.99 (d, J = 7.9 Hz, 1H), 8.70 (t, J = 5.6 Hz, 1H), 8.45 (d,
J = 9.0 Hz, 1H), 8.37 – 8.30 (m, 2H), 7.56 (d, J = 8.6 Hz, 2H), 7.22 – 7.07 (m, 3H), 6.81 (s, 1H), 6.52 (s,
1H), 6.43 (s, 1H), 5.04 (q, J = 7.7 Hz, 1H), 4.80-4.64 (m, 2H), 4.33-4.21 (m, 2H), 4.19 – 4.15 (m, 2H),
3.46-3.38 (m, 2H), 3.24-3.18 (m, 3H), 3.17 – 3.07 (m, 1H), 3.03 – 2.93 (m, 3H), 2.91 (s, 3H), 2.54 (s, 1H),
2.47-2.44 (m, 1H), 2.14 – 1.89 (m, 2H), 1.34 (s, 11H), 1.21 (d, J = 6.7 Hz, 3H).
Example 361: Synthesis of Compound 561
Step 1: methyl ((S)((tert-butoxycarbonyl)(methyl)amino)(4-methoxyphenyl)acetyl)-L-alaninate
O N O
To a solution of methyl ((S)((tert-butoxycarbonyl)(methyl)amino)(4-
hydroxyphenyl)acetyl)-L-alaninate (13.8 mmol, 5.54 g) in acetone (10 mL) was added potassium
carbonate (14.25 mmol, 1.97 g) and iodomethane (14.25 mmol, 2.02 g) and the reaction was stirred at
room temperature overnight. The solvent was evaporated. EtOAc was added and the mixture was filtered.
The filtrate was washed with water and brine, dried over Na SO and concentrated to give compound 561-
1 (1.355 g, 100%) as an oil, which was used as is. (MS+1) m/z 381.1
18253141_1 (GHMatters) P111789.NZ
Step 2: methyl ((S)((tert-butoxycarbonyl)(methyl)amino)(3-iodomethoxyphenyl)acetyl)-L-
alaninate
O N O
To a solution of compound 561-1 (3.562 mmol, 1.355 g) in methanol (50 mL) at 0°C was added
sequentially silver sulfate (3.740 mmol, 1.166 g) and iodine (3.740 mmol, 949 mg). The reaction mixture
was stirred at room temperature for 1 h. A solution of 10% (w/w) sodium thiosulfate was added till the
reaction turned pale yellow. Most of methanol was evaporated by rotary evaporation then saturated sodium
bicarbonate and ethyl acetate were added. The aqueous layer was extracted twice with ethyl acetate. The
combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue
was purified on silica, eluting with 0 to 3% MeOH in DCM to afford compound 561-2 (1.393 g, 77.2%).
(MS+1) m/z 507.1
Step 3: ((S)((tert-butoxycarbonyl)(methyl)amino)(3-iodomethoxyphenyl)acetyl)-L-alanine
O N OH
To a solution of compound 561-2 (2.751 mmol, 1.393 g) in THF (16mL) at 0°C was added
lithium hydroxide, 0.5M in water (2.751 mmol, 5.50 mL). The reaction was stirred at room temperature for
2 h. The reaction mixture was cooled to 0°C and adjusted to pH2-3 by addition of 0.5M HCl. Extracted
with EtOAc, washed with brine, dried with MgSO4, concentrated in vacuo to afford crude compound 561-
3 (1.353 g, 99.9%) as a light tan solid, which was used without further purification. (MS+1) m/z 493.0
Step 4: methyl (S)((tert-butoxycarbonyl)amino)(3,5-diiodomethoxyphenyl)propanoate
To a solution of methyl (S)((tert-butoxycarbonyl)amino)(4-hydroxy-3,5-
diiodophenyl)propanoate (1.10 mmol, 5.471g) in acetone (50 mL) was added potassium carbonate (4.40
mmol, 5.528 g) and iodomethane (4.40 mmol, 5.677 g, 2.49 mL) and the reaction was stirred at room
temperature overnight. The solvent was evaporated. EtOAc was added and the mixture was filtered. The
filtrate was washed by water and brine, dried over Na SO and concentrated. The residue was purified on
silica eluted with 0 to 40% EtOAc in heptanes to give compound 561-4 (95.321 g, 94.82%) as a white
foam. (MS+1) m/z 561.8
Step 5: methyl (S)((tert-butoxycarbonyl)amino)(3-hydroxyiodomethoxyphenyl)propanoate
18253141_1 (GHMatters) P111789.NZ
O OH
A mixture of compound 561-4 (16.7 mmol, 9.40 g) and trimethyl borate (83.7 mmol, 8.7 g, 9.53
mL) in diethyl ether (100 mL) was cooled to -70°C. n-butyllithium (2.5 mol/L) in hexanes (41.9 mmol,
11.00 g, 17 mL) was added drop-wise while keeping internal temperature below -65°C. The reaction
mixture was allowed warming to room temperature and stirred overnight.
The reaction mixture was cooled to 0°C, and treated with acetic acid (167 mmol, 10.0 g, 9.6 mL)
and hydrogen peroxide (30%w/w) in water (17.1 mL). The reaction mixture was stirred overnight allowing
warm to room temperature. The reaction was quenched with saturated NH4Cl (aq.) and extracted with
isopropyl acetate. The organic layer was washed with brine, dried with MgSO4, and concentrated. The
residue was purified on silica eluted with 0 to 50% EtOAc in heptanes afforded compound 561-5 (2.45 g,
32.5%) as a white foam. (MS+1) m/z 452.3
Step 6: methyl (S)((tert-butoxycarbonyl)amino)(3-hydroxymethoxy(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)phenyl)propanoate
[001203] compound 561-5 (4.63 mmol, 2.09 g), bis(pinacolato)diboron (10.2 mmol, 2.59 g), potassium
acetate (18.5 mmol, 1.82 g), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride
dichloromethane complex (0.463 mmol, 386 mg) were suspended in dry dimethyl sulfoxide (50 mL)
(degassed by sparging with nitrogen), and heated to 85 ºC under nitrogen overnight. The reaction mixture
was cooled to room temperature, and then filtered through Celite. The filtrate was diluted with 1:1
isopropyl acetate and water, and filtered through Celite. The layers were separated, and the aqueous layer
was extracted 3x with isopropyl acetate. The combined organic layer was dried with MgSO4, and
concentrated in vacuo. The dark brown residue was purification by flash chromatography (silica, 20 to
60% EtOAc in heptanes) provided compound 561-6 (1.743 g, 83.4%) as a white solid. (MS+1) m/z 452.1
Step 7: methyl (S)amino(3-hydroxymethoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)phenyl)propanoate
18253141_1 (GHMatters) P111789.NZ
compound 561-6 (1.405 mmol, 634 mg) in dichloromethane (4 mL) was cooled to 0°C and
treated with trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 2 h. The
mixture was concentrated. To the residue was added Et O, and then concentrated. Repeat the process 2
more times. The residue was dried on high vacuum to afford compound 561-7 (493.4 mg, 100.0%), which
was used as is. (MS+1) m/z 352.1
Step 8: methyl (6S,9S,12S)(3-hydroxymethoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)benzyl)(3-iodomethoxyphenyl)-2,2,5,9-tetramethyl-4,7,10-trioxooxa-5,8,11-triazatridecan
oate
O N O
[001205] To a solution of compound 561-7 (1.405 mmol, 493.4 mg) in acetonitrile (5 mL) and N,N-
dimethylformamide (3 mL) was added 1-hydroxybenzotriazole hydrate (1.532 mmol, 234.6 mg),
compound 561-3 (1.277 mmol, 672 mg), TEA (0.38 mL, 0.38 mmol) and 1-(3-dimethylaminopropyl)
ethylcarbodiimide hydrochloride (3.192 mmol, 611.9 mg) at 0 °C. The resulting mixture was allowed to
warm to room temperature and stirred overnight. The reaction mixture was partitioned between EtOAc and
water. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with
water, saturated NaHCO , and brine, dried with MgSO and concentrated under reduced pressure to afford
crude compound 561-8 as an off-white solid, which was used without further purification. (MS+1) m/z
826.1
Step 9: methyl (4S,7S,10S)((tert-butoxycarbonyl)(methyl)amino)hydroxy-16,26-dimethoxy
methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphanecarboxylate
O N O
A mixture of compound 561-8 (2.000 mmol, 1.651 g), potassium phosphate tribasic (7.000
mmol, 1.53g), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane
complex (0.2000 mmol, 165 mg) in degassed acetonitrile under nitrogen was heated at 65 °C for 2 h. The
reaction mixture was cooled to room temperature and partitioned between EtOAc and a dilute aqueous
NH4Cl solution. The aqueous phase was extracted twice with EtOAc. The combined organic layers were
washed with water and brine, dried and concentrated under reduced pressure. Purification by flash column
chromatography (SiO2; 0-100% EtOAc in DCM), afforded compound 561-9 (276 mg, 17.14%) as an off-
white solid. (MS+1) m/z 572.1
18253141_1 (GHMatters) P111789.NZ
Step 10: methyl (4S,7S,10S)(2-(((benzyloxy)carbonyl)amino)ethoxy)((tert-
butoxycarbonyl)(methyl)amino)-16,26-dimethoxymethyl-6,9-dioxo-5,8-diaza-1,2(1,3)-
dibenzenacyclodecaphanecarboxylate
O N O
[001207] To a solution of compound 561-9 (0.249 mmol, 142 mg) and benzyl (2-bromoethyl)carbamate
(0.746 mmol, 203 mg) in N,N-dimethylformamide (5 mL) was added cesium carbonate (1.243 mmol, 405
mg). The reaction mixture was stirred at room temperature overnight. The reaction was diluted with
EtOAc and washed with water. The organic layer was washed with brine and concentrated. The residue
was purified on silica eluted with 0 to 2% MeOH in DCM to afford compound 561-10 (124 mg, 47.96%).
(MS+1) m/z 749.3
Step 11: methyl (4S,7S,10S)(2-(((benzyloxy)carbonyl)amino)ethoxy)-16,26-dimethoxymethyl
(methylamino)-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphanecarboxylate
HN O
10 (0.1416 mmol, 106 mg) in dichloromethane (8 mL) was cooled to 0°C and treated with
trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was
concentrated. To the residue was added Et O, and then concentrated again. Repeat the process 2 more
times. The residue was dried on high vacuum to afford crude compound 561-11 (91.8 mg, 100%), which
was carried forward without purification. (MS+1) m/z 649.1
Step 12: methyl (4S,7S,10S)((S)(((benzyloxy)carbonyl)amino)((tert-butoxycarbonyl)amino)-N-
methylbutanamido)(2-(((benzyloxy)carbonyl)amino)ethoxy)-16,26-dimethoxymethyl-6,9-dioxo-
,8-diaza-1,2(1,3)-dibenzenacyclodecaphanecarboxylate
18253141_1 (GHMatters) P111789.NZ
O HN
HN O
To a mixture of (2S)(benzyloxycarbonylamino)(tert-butoxycarbonylamino)butanoic acid
(0.2127 mmol, 74.97 mg) and compound 561-11 (0.1418 mmol, 92 mg) in N,N-dimethylformamide (5
mL) was added N,N-diisopropylethylamine (1.418 mmol, 183 mg, 0.247 mL) and HATU (0.284 mmol,
110 mg). After stirred at room temperature for 15 min, the reaction mixture was partitioned between
EtOAc and water. The organic layer was washed with brine, dried with MgSO4, and concentrated. The
residue was purified on silica eluted with 0-5% MeOH in DCM to afford compound 561-12 (128 mg,
85.4%). (MS+1) m/z 983.4
Step 13: methyl (4S,7S,10S)((S)amino(((benzyloxy)carbonyl)amino)-N-methylbutanamido)
(2-(((benzyloxy)carbonyl)amino)ethoxy)-16,26-dimethoxymethyl-6,9-dioxo-5,8-diaza-1,2(1,3)-
dibenzenacyclodecaphanecarboxylate
O HN
H N N O
HN O
compound 561-12 (0.2360 mmol, 232 mg) in dichloromethane (10 mL) was cooled to 0°C and
treated with trifluoroacetic acid (4 mL). The reaction mixture was stirred at room temperature for 0.5 h,
and then concentrated. To the residue was added Et O, and re-concentrated. Repeat the process 2 more
times. The residue was dried under high vacuum to afford compound 561-13, which was carried forward
without purification. (MS+1) m/z 883.3
18253141_1 (GHMatters) P111789.NZ
Step 14: methyl (4S,7S,10S)((S)(((benzyloxy)carbonyl)amino)(2-(4-(tert-butyl)phenyl)-4,6-
dimethylpyrimidinecarboxamido)-N-methylbutanamido)(2-(((benzyloxy)carbonyl)amino)ethoxy)-
16,26-dimethoxymethyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphanecarboxylate
O HN
N N N O
HN O
[001211] To a mixture of 2-(4-tert-butylphenyl)-4,6-dimethyl-pyrimidinecarboxylic acid (0.355 mmol,
101 mg) and compound 561-13 (0.237 mmol, 209 mg) in N,N-dimethylformamide (8 mL) was added
N,N-diisopropylethylamine (2.367 mmol, 306 mg, 0.413 mL) and HATU (0.473 mmol, 1834 mg). After
stirring at room temperature for 15 min, the reaction mixture was partitioned between EtOAc and water.
The organic layer was washed with brine, dried with MgSO4, and concentrated. The residue was purified
on silica eluted with 0-10% MeOH in DCM to afford compound 561-14 (138 mg, 51%). (MS+1) m/z
1149.5
Step 15: (4S,7S,10S)((S)amino(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine
carboxamido)-N-methylbutanamido)(2-aminoethoxy)-16,26-dihydroxymethyl-6,9-dioxo-5,8-diaza-
1,2(1,3)-dibenzenacyclodecaphanecarboxylic acid
N OH
N N N O
Aluminum chloride (7.233 mmol, 965 mg) and 1-dodecanethiol (7.233 mmol, 1.464 mg, 1.73
mL) in dichloromethane (15 mL) was stirred at room temperature for 0.5 h. 14 (0.120 mmol, 156 mg) in
dichloromethane (15 mL) was added gradually. The resulting mixture was stirred at room temperature
overnight. The reaction mixture was concentrated, and the residue dried on high vacuum to afford crude
compound 561-15 which was carried forward without purification. (MS+1) m/z 839.4
18253141_1 (GHMatters) P111789.NZ
Step 16: methyl (4S,7S,10S)((S)amino(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine
carboxamido)-N-methylbutanamido)(2-aminoethoxy)-16,26-dihydroxymethyl-6,9-dioxo-5,8-diaza-
1,2(1,3)-dibenzenacyclodecaphanecarboxylate
O HN
N N N O
[001213] To compound 561-15 (0.1204 mmol, 101 mg) in anhydrous methanol (15 mL) was added
thionyl chloride (1 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was
concentrated to provide crude compound 561-16, which was carried forward without purification.
Step 17: methyl (4S,7S,10S)((S)((tert-butoxycarbonyl)amino)(2-(4-(tert-butyl)phenyl)-4,6-
dimethylpyrimidinecarboxamido)-N-methylbutanamido)(2-((tert-butoxycarbonyl)amino)ethoxy)-
16,26-dihydroxymethyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphanecarboxylate
16 (0.1184 mmol, 101 mg) in acetone (15 mL) and water (5 mL) was treated with saturated
K2CO3 in water to pH 9-10. Di-tert-butyl dicarbonate (1.184 mmol, 266.4 mg) was then added and the
reaction mixture was stirred at room temperature for 1h. The reaction mixture was extracted with EtOAc
and the organic layer was concentrated. The residue was purified on silica eluted with 0 to 10% MeOH in
DCM provided compound 561-17 (124.7 mg, 100.0%). (MS+1) m/z 1053.6
Step 18: methyl (4S,7S,10S)((S)((tert-butoxycarbonyl)amino)(2-(4-(tert-butyl)phenyl)-4,6-
dimethylpyrimidinecarboxamido)-N-methylbutanamido)(2-((tert-butoxycarbonyl)amino)ethoxy)-
16-((tert-butoxycarbonyl)oxy)hydroxymethyl-6,9-dioxo-5,8-diaza-1,2(1,3)-
dibenzenacyclodecaphanecarboxylate
18253141_1 (GHMatters) P111789.NZ
HN O
A mixture of compound 561-17 (0.1184 mmol, 124.7 mg), N,N-diisopropylethylamine (0.5920
mmol, 76 mg, 0.103 mL), and di-tert-butyl dicarbonate (0.5920 mmol, 133 mg) in dichloromethane (20
mL) was stirred at room temperature overnight. The reaction mixture was concentrated and the residue
purified on silica eluted with 0 to 10% MeOH in DCM afforded compound 561-18 (117 mg, 86%).
(MS+1) m/z 1154.2
Step 19: (4S,7S,10S)((S)((tert-butoxycarbonyl)amino)(2-(4-(tert-butyl)phenyl)-4,6-
dimethylpyrimidinecarboxamido)-N-methylbutanamido)(2-((tert-butoxycarbonyl)amino)ethoxy)-
16-((tert-butoxycarbonyl)oxy)hydroxymethyl-6,9-dioxo-5,8-diaza-1,2(1,3)-
dibenzenacyclodecaphanecarboxylic acid
N N N
HN O
compound 561-18 (0.101 mmol, 116 mg) was dissolved in 1,4-dioxane (6 mL) and water (3
mL). Lithium hydroxide (0.5 M, 0.304 mmol, 0.61 mL) was added at 0°C drop-wise, and the reaction
mixture was stirred at room temperature for 1h. Water (6 mL) was added and the reaction mixture, and the
mixture was acidified with 0.5 M HCl to pH~3. The resultant white precipitate was extracted with EtOAc,
dried with MgSO4, filtered, and concentrated to afford crude compound 561-19 (106.8 mg, 92.64%) as a
white solid, which was used as is. (MS+1) m/z 1140.4
Step 20: tert-butyl (2-(((3S,6S,9S)((S)((tert-butoxycarbonyl)amino)(2-(4-(tert-butyl)phenyl)-4,6-
dimethylpyrimidinecarboxamido)-N-methylbutanamido)((tert-butoxycarbonyl)oxy)
((cyanomethyl)carbamoyl)hydroxymethyl-4,7-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-
-yl)oxy)ethyl)carbamate
18253141_1 (GHMatters) P111789.NZ
HN O
To a mixture of compound 561-19 (0.035 mmol, 40 mg), aminoacetonitrile hydrochloride (0.35
mmol, 33mg) in N,N-dimethylformamide (5 mL) was added N,N-diisopropylethylamine (0.526 mmol, 68
mg, 0.092 mL) and HATU (0.0526 mmol, 21 mg). The reaction was stirred at room temperature for 1h.
The reaction mixture was diluted with EtOAc, and washed with water. The organic layer was dried with
Na SO and concentrated. The residue was purified on silica eluted with 0 to 10% MeOH in DCM
provided compound 561-20 (17.1 mg, 41.4%). (MS+1) m/z 1177.8
Step 21: (4S,7S,10S)((S)amino(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine
carboxamido)-N-methylbutanamido)(2-aminoethoxy)-N-(cyanomethyl)-16,26-dihydroxymethyl-
6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphanecarboxamide
compound 561-20 (0.0145 mmol, 17.1 mg) in trifluoroacetic Acid (0.25 mL) and 1,1,1,3,3,3-
hexafluoropropanol (4.75 mL) was stirred at room temperature for 1h. The reaction mixture was
concentrated. To the residue was added Et O, and re-concentrated; repeated the process 2 more times. The
residue was dried on high vacuum and then purified by reverse phase HPLC provided Compound 561 (6
mg, 47.1%) as a white powder. (MS+1) m/z 877.4
H NMR (400 MHz, Methanol-d4) δ 8.34 (dd, J = 8.7, 2.2 Hz, 2H), 7.59 – 7.52 (m, 2H), 7.18 (dd, J = 8.2,
2.3 Hz, 1H), 7.07 (d, J = 2.4 Hz, 1H), 7.01 (d, J = 8.5 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H), 6.43 (s, 1H), 5.26
– 5.19 (m, 2H), 4.28 (td, J = 8.7, 7.5, 4.2 Hz, 2H), 4.20 (d, J = 7.3 Hz, 1H), 3.46 (s, 1H), 3.41 (t, J = 5.1 Hz,
3H), 3.15 (d, J = 7.5 Hz, 3H), 3.04 (s, 1H), 2.99 (s, 3H), 2.30 (dq, J = 14.2, 7.2 Hz, 1H), 2.16 (dq, J = 14.3,
7.5 Hz, 1H), 1.38 – 1.33 (m, 9H).
Example 362: Synthesis of Compound 562
O HN
N N N O
18253141_1 (GHMatters) P111789.NZ
Step 1: methyl (S)amino(3-bromohydroxyphenyl)propanoate hydrochloride
To a solution of (2S)amino(3-bromohydroxy-phenyl)propanoic acid (39.32 mmol, 10.3
g) in methanol (100 mL) was slowly added thionyl chloride (86.5 mmol, 10,29 g, 6.30 mL) at 0 °C. The
resulting mixture was stirred at room temperature. The reaction mixture was concentrated under reduced
pressure, and the residue dried on high vacuum to afford the title compound (12.21 g, 100%), which was
used without further purification. (MS+1) m/z 272.0
Step 2: methyl (S)(3-bromohydroxyphenyl)((tert-butoxycarbonyl)amino)propanoate
HN O
[001220] To a mixture of methyl (S)amino(3-bromohydroxyphenyl)propanoate hydrochloride
(39.32 mmol, 12.21 g) in 1:1 acetone/water (100mL) was added sodium bicarbonate (118 mmol, 9.91 g)
and di-tert-butyl dicarbonate (58.98 mmol, 13.27 g). The resulting reaction mixture was stirred at room
temperature overnight. The reaction mixture was quenched by addition of 1 N HCl to pH 3-4. The aqueous
layer was extracted twice with EtOAc (2x100mL) and the combined organic layers were washed with
brine, dried over Na SO and concentrated to afford crude methyl (S)(3-bromohydroxyphenyl)
((tert-butoxycarbonyl)amino)propanoate, which was carried forward without further purification. (MS+1)
m/z 372.0
Step 3: methyl (S)(3-bromohydroxyiodophenyl)((tert-butoxycarbonyl)amino)propanoate
HN O
[001221] To a solution of (S)(3-bromohydroxyphenyl)((tert-butoxycarbonyl)amino)propanoate
(18.95 mmol, 7.09 g) in N,N-dimethylformamide (50 mL) was added N-iodosuccinimide (22.74 mmol,
.22 g). The reaction was stirred at room temperature for 1 h. The reaction mixture was partitioned
between EtOAc and water. The organic layer was washed with saturated NaHCO and brine, dried with
Na SO , and concentrated. The residue was purified on silica eluted with 15 to 30% EtOAc in heptanes
provided the title compound (6.86 g, 72.4%) as a white solid. (MS+1) m/z 499.9
Step 4: methyl (S)(3-bromoiodomethoxyphenyl)((tert-butoxycarbonyl)amino)propanoate
HN O
18253141_1 (GHMatters) P111789.NZ
Methyl (S)(3-bromohydroxyiodophenyl)((tert-butoxycarbonyl)amino)propanoate
(6.24 mmol, 3.12 g) was dissolved in acetone (50 mL) and treated sequentially with potassium carbonate
(31.2 mmol, 4.31 g) and iodomethane (7.49 mmol, 1.06 g, 0.466 mL). The solution was stirred at room
temperature overnight. The solvent was evaporated under reduced pressure and the residue was dissolved
in EtOAc, which was washed with water and brine, dried over Na SO and concentrated. The residue was
purified by flash chromatography (0 to 40% EtOAc in heptanes) provided the title compound (2.28 g,
71.1%) as a white foam. (MS+1) m/z 513.9
Step 5: methyl (S)(3-bromohydroxymethoxyphenyl)((tert-butoxycarbonyl)amino)propanoate
[001223] Bis(pinacolato)diboron (8.046 mmol, 2.04 g), methyl (S)(3-bromoiodomethoxyphenyl)-
2-((tert-butoxycarbonyl)amino)propanoate (5.364 mmol, 2.76 g), potassium acetate (13.41 mmol, 1.32 g),
and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.2682
mmol, 223 mg) were suspended in dry dimethyl sulfoxide (50 mL) (degassed by sparging with nitrogen),
and heated to 65 ºC under nitrogen overnight. The mixture was cooled to room temperature, and filtered
through Celite. The filtrate was diluted with 1:1 EtOAc and water, and filtered through Celite. The layers
were separated, and the aqueous layer was extracted 3x with EtOAc. The combined organic layer was
dried with MgSO4, and concentrated in vacuo to afford crude methyl (S)(3-bromomethoxy
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl)((tert-butoxycarbonyl)amino)propanoate as a dark
brown gum, which was carried forward without further purification. (MS+1) m/z 514.1
[001224] The above methyl (S)(3-bromomethoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)phenyl)((tert-butoxycarbonyl)amino)propanoate (5.364 mmol, 2.76 g) was dissolved in methanol
( 24 mL) and hydrogen peroxide (30% in water) (8 mL) and was stirred at room temperature for 1 h.
MeOH was removed under reduced pressure. To the residue was added EtOAc and brine. The organic
layer was separated, dried with Na SO , filtered, and concentrated. The residue was purified on silica
eluted with 0 to 50% EtOAc in heptanes provided the title compound (1.15 g, 53% over 2 steps). (MS+1)
m/z 404.0
Step 6: tert-butyl ((S)(((benzyloxy)carbonyl)(methyl)amino)(4-hydroxy(4,4,5,5-tetramethyl-
1,3,2-dioxaborolanyl)phenyl)acetyl)-L-alaninate
OH O
O N O
[001225] Bis(pinacolato)diboron (19.22 mmol, 4.88 g), tert-butyl (2S)[[(2S)
[benzyloxycarbonyl(methyl)amino](4-hydroxyiodo-phenyl)acetyl]amino]propanoate (12.01 mmol,
18253141_1 (GHMatters) P111789.NZ
6.827 g), potassium acetate (36.03 mmol, 3.536 g), and 1,1'-bis(diphenylphosphino)ferrocene-
palladium(II)dichloride dichloromethane complex (0.6005 mmol, 500 mg) were suspended in dry dimethyl
sulfoxide (120 mL) (degassed by sparging with nitrogen), and heated to 85 ºC under nitrogen overnight.
The mixture was cooled to room temperature, and then filtered through Celite. The filtrate was diluted with
1:1 EtOAc and water, and filtered through Celite. The layers were separated, and the aqueous layer was
extracted 3 times with EtOAc. The combined organic layer was dried with MgSO4, and concentrated in
vacuum and the residue was run through a quick silica column eluted with 20 to 80% EtOAc in heptanes
provided the title compound (3.85 g, 56.4%). (MS+1) m/z 569.2
Step 7: methyl (S)((tert-butoxycarbonyl)amino)(2',5-dihydroxymethoxy-5'-((5S,8S)-4,8,11,11-
tetramethyl-3,6,9-trioxophenyl-2,10-dioxa-4,7-diazadodecanyl)-[1,1'-biphenyl]yl)propanoate
O N O
A mixture of tert-butyl ((S)(((benzyloxy)carbonyl)(methyl)amino)(4-hydroxy(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)phenyl)acetyl)-L-alaninate (3.42 mmol, 1.94 g), methyl (S)(3-
bromohydroxymethoxyphenyl)((tert-butoxycarbonyl)amino)propanoate (2.85 mmol, 1.92 g),
potassium phosphate tribasic (11.4 mmol, 2.49 g and chloro(crotyl)(tri-tert-butylphosphine)palladium(II)
(0.285 mmol, 120 mg) in degassed acetonitrile (60 mL) and water (4 mL) under nitrogen was heated at 85
°C for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by
silica gel column chromatography (0-50% EtOAc in DCM) provided the title compound (2.64 g, 60.5%).
(MS+1) m/z 766.3
Step 8: ((S)(5'-((S)aminomethoxyoxopropyl)-3',6-dihydroxy-2'-methoxy-[1,1'-biphenyl]yl)-
2-(((benzyloxy)carbonyl)(methyl)amino)acetyl)-L-alanine
O O O
O OH
methyl (S)((tert-butoxycarbonyl)amino)(2',5-dihydroxymethoxy-5'-((5S,8S)-4,8,11,11-
tetramethyl-3,6,9-trioxophenyl-2,10-dioxa-4,7-diazadodecanyl)-[1,1'-biphenyl]yl)propanoate
(1.72 mmol, 2.64 g) in TFA (8mL) and DCM (32mL) was stirred at room temperature overnight. The
reaction mixture was concentrated. To the residue was added Et O and re-concentrated and the process
was repeated two more times. The residue was dried on high vacuum to afford the crude title compound
(1.05 g, 100%), which was carried forward without further purification. (MS+1) m/z 610.2
18253141_1 (GHMatters) P111789.NZ
Step 9: methyl (4S,7S,10S)(((benzyloxy)carbonyl)(methyl)amino)-16,25-dihydroxymethoxy
methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphanecarboxylate
O HN
To a solution of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide, 50% in DMF
(3.79 mmol, 2.41 g, 2.21 mL) and N,N-diisopropylethylamine (8.61 mmol, 1.11 g, 1.50 mL) in N,N-
dimethylformamide (42 mL) at room temperature was added a solution of ((S)(5'-((S)amino
methoxyoxopropyl)-3',6-dihydroxy-2'-methoxy-[1,1'-biphenyl]yl)
(((benzyloxy)carbonyl)(methyl)amino)acetyl)-L-alanine (1.72 mmol, 1.05 g) in N,N-dimethylformamide
(43 mL). The resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was
diluted with EtOAc, washed with saturated NaHCO (aq.) and brine. The organic layer was dried with
MgSO4, and concentrated. The residue was purified on silica eluted with 0 to 5% MeOH in DCM to
provide the title compound (747 mg, 49.1%). (MS+1) m/z 592.2
Step 10: methyl (4S,7S,10S)(((benzyloxy)carbonyl)(methyl)amino)-16,25-bis(2-((tert-
butoxycarbonyl)amino)ethoxy)methoxymethyl-6,9-dioxo-5,8-diaza-1,2(1,3)-
dibenzenacyclodecaphanecarboxylate
O O NH
To a solution of methyl (4S,7S,10S)(((benzyloxy)carbonyl)(methyl)amino)-16,25-
dihydroxymethoxymethyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphanecarboxylate
(0.3222 mmol, 373.7 mg) and tert-butyl n-(2-bromoethyl)carbamate (1.611 mmol, 380 mg) in N,N-
dimethylformamide (10 mL) was added cesium carbonate (1.611 mmol, 524.8 mg). The reaction mixture
was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, and washed with
water. The organic layer was washed with brine and concentrated. The residue was purified on silica eluted
with 0 to 5% MeOH in DCM to afford the title compound (266 mg, 48%). (MS+1) m/z 878.0
Step 11: methyl (4S,7S,10S)-16,25-bis(2-((tert-butoxycarbonyl)amino)ethoxy)methoxymethyl
(methylamino)-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphanecarboxylate
18253141_1 (GHMatters) P111789.NZ
To a solution of methyl (4S,7S,10S)(((benzyloxy)carbonyl)(methyl)amino)-16,25-bis(2-
((tert-butoxycarbonyl)amino)ethoxy)methoxymethyl-6,9-dioxo-5,8-diaza-1,2(1,3)-
dibenzenacyclodecaphanecarboxylate (0.1545 mmol, 266 mg) in isopropyl alcohol (50mL) was added
20% Pd(OH) (50mg) and the reaction was placed under an atmosphere of hydrogen. The reaction mixture
was stirred at room temperature overnight. The reaction mixture was filtered through Celite and the filtrate
concentrated to afford crude methyl (4S,7S,10S)-16,25-bis(2-((tert-butoxycarbonyl)amino)ethoxy)
methoxymethyl(methylamino)-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane
carboxylate (114.9 mg, 100%), which was carried forward without further purification. (MS+1) m/z 744.0
Step 12: methyl (4S,7S,10S)((S)((((9H-fluorenyl)methoxy)carbonyl)amino)((tert-
butoxycarbonyl)amino)-N-methylbutanamido)-16,25-bis(2-((tert-butoxycarbonyl)amino)ethoxy)
methoxymethyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphanecarboxylate
HN O
To a mixture of (2S)(tert-butoxycarbonylamino)(9H-fluoren
ylmethoxycarbonylamino)butanoic acid (0.232 mmol, 102 mg) and methyl (4S,7S,10S)-16,25-bis(2-((tert-
butoxycarbonyl)amino)ethoxy)methoxymethyl(methylamino)-6,9-dioxo-5,8-diaza-1,2(1,3)-
dibenzenacyclodecaphanecarboxylate (0.154 mmol, 114 mg) in N,N-dimethylformamide (5 mL) was
added N,N-diisopropylethylamine (0.7724 mmol, 99.8 mg, 0.135 mL) and HATU (0.3862 mmol, 149.8
mg). After stirring at room temperature for 0.5 h, the reaction mixture was partitioned between EtOAc and
water, washed with brine, and the organic layer was concentrated. The residue was purified on silica eluted
with 0 to 10% MeOH in DCM to provide the title compound (286 mg, 95%). (MS+1) m/z 1167.4
18253141_1 (GHMatters) P111789.NZ
Step 13: methyl (4S,7S,10S)((S)amino((tert-butoxycarbonyl)amino)-N-methylbutanamido)-
16,25-bis(2-((tert-butoxycarbonyl)amino)ethoxy)methoxymethyl-6,9-dioxo-5,8-diaza-1,2(1,3)-
dibenzenacyclodecaphanecarboxylate
H N N
HN O
[001232] A mixture of methyl (4S,7S,10S)((S)((((9H-fluorenyl)methoxy)carbonyl)amino)
((tert-butoxycarbonyl)amino)-N-methylbutanamido)-16,25-bis(2-((tert-butoxycarbonyl)amino)ethoxy)
methoxymethyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphanecarboxylate (0.1471 mmol,
286 mg) in 10% piperidine in DMF (10mL) was stirred at room temperature for 10 min, then concentrated
and dried under high vacuum to provide the crude title compound (138.9 mg, 100%), which was carried
forward without further purification. (MS+1) m/z 944.6
Step 14: methyl (4S,7S,10S)((S)((tert-butoxycarbonyl)amino)(2-(4-(tert-butyl)phenyl)-4,6-
dimethylpyrimidinecarboxamido)-N-methylbutanamido)-16,25-bis(2-((tert-
butoxycarbonyl)amino)ethoxy)methoxymethyl-6,9-dioxo-5,8-diaza-1,2(1,3)-
dibenzenacyclodecaphanecarboxylate
O N O
N N N O
To a solution of methyl (4S,7S,10S)((S)amino((tert-butoxycarbonyl)amino)-N-
methylbutanamido)-16,25-bis(2-((tert-butoxycarbonyl)amino)ethoxy)methoxymethyl-6,9-dioxo-
,8-diaza-1,2(1,3)-dibenzenacyclodecaphanecarboxylate (0.1471 mmol, 138.9 mg) in N,N-
dimethylformamide (5 mL) was added 2-(4-tert-butylphenyl)-4,6-dimethyl-pyrimidinecarboxylic acid
(0.1765 mmol, 50.2 mg) , N,N-diisopropylethylamine (0.7356 mmol, 95 mg, 0.128 mL), and HATU
(0.2207 mmol, 85.6 mg). After stirring at room temperature for 0.5 h, the reaction mixture was diluted
18253141_1 (GHMatters) P111789.NZ
with EtOAc, washed 3 times with water. The combined organic layers were concentrated and the residue
was purified using silica gel chromatography, eluting with 0 to 10% MeOH in DCM to provide the title
compound (93 mg, 52%). (MS+1) m/z 1211.5
Step 15: (4S,7S,10S)((S)amino(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine
carboxamido)-N-methylbutanamido)-16,25-bis(2-aminoethoxy)hydroxymethyl-6,9-dioxo-5,8-
diaza-1,2(1,3)-dibenzenacyclodecaphanecarboxylic acid
N OH
O HN
N N N O
Aluminum chloride (12.0 mmol, 1.60 g) and 1-dodecanethiol (12.0 mmol, 2.43 g, 2.88 mL) in
dichloromethane (10 mL) was stirred at room temperature for 0.5h, then added to a solution of methyl
(4S,7S,10S)((S)((tert-butoxycarbonyl)amino)(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine-
-carboxamido)-N-methylbutanamido)-16,25-bis(2-((tert-butoxycarbonyl)amino)ethoxy)methoxy
methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphanecarboxylate (0.077032 mmol, 148 mg) in
dichloromethane (10 mL). The resulting mixture was stirred at room temperature overnight. The mixture
was concentrated, and the residue dried under high vacuum provided the crude title compound, which was
carried forward without further purification. (MS+1) m/z 883.4
Step 16: methyl (4S,7S,10S)((S)amino(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine
carboxamido)-N-methylbutanamido)-16,25-bis(2-aminoethoxy)hydroxymethyl-6,9-dioxo-5,8-
diaza-1,2(1,3)-dibenzenacyclodecaphanecarboxylate
O HN
N N N
[001235] To a solution of (4S,7S,10S)((S)amino(2-(4-(tert-butyl)phenyl)-4,6-
dimethylpyrimidinecarboxamido)-N-methylbutanamido)-16,25-bis(2-aminoethoxy)hydroxy
methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphanecarboxylic acid (0.07596 mmol, 67 mg)
in anhydrous methanol (10 mL) was added thionyl chloride (15 mmol, 1.80 g, 1.1 mL). The reaction
mixture was stirred at room temperature for 1 h. The mixture was concentrated to provide the crude title
compound, which was used immediately in the next step without further purification. (MS+1) m/z 896.8
18253141_1 (GHMatters) P111789.NZ
Step 17: methyl (4S,7S,10S)((S)((tert-butoxycarbonyl)amino)(2-(4-(tert-butyl)phenyl)-4,6-
dimethylpyrimidinecarboxamido)-N-methylbutanamido)-16,25-bis(2-((tert-
butoxycarbonyl)amino)ethoxy)hydroxymethyl-6,9-dioxo-5,8-diaza-1,2(1,3)-
dibenzenacyclodecaphanecarboxylate
O O NH
O HN
N N N
HN O
A mixture of methyl (4S,7S,10S)((S)amino(2-(4-(tert-butyl)phenyl)-4,6-
dimethylpyrimidinecarboxamido)-N-methylbutanamido)-16,25-bis(2-aminoethoxy)hydroxy
methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphanecarboxylate (0.07589 mmol, 68 mg)
suspended in acetone (10 mL) and water (5 mL) was treated with saturated NaHCO in water to pH 9-10.
A large excess di-tert-butyl dicarbonate (1.518 mmol, 341.5 mg) was then added and the reaction mixture
was stirred at room for 0.5 h until complete conversion was observed. The reaction mixture was diluted
with EtOAc and filtered through Celite. The organic layer was concentrated. The residue was purified on
silica eluted with 0 to 10% MeOH in DCM to provide the title compound (51.3 mg, 56.5%). (MS+1) m/z
1196.8
Step 18: (4S,7S,10S)((S)((tert-butoxycarbonyl)amino)(2-(4-(tert-butyl)phenyl)-4,6-
dimethylpyrimidinecarboxamido)-N-methylbutanamido)-16,25-bis(2-((tert-
butoxycarbonyl)amino)ethoxy)hydroxymethyl-6,9-dioxo-5,8-diaza-1,2(1,3)-
dibenzenacyclodecaphanecarboxylic acid
O O NH
O HN
N N N O
HN O
18253141_1 (GHMatters) P111789.NZ
methyl (4S,7S,10S)((S)((tert-butoxycarbonyl)amino)(2-(4-(tert-butyl)phenyl)-4,6-
dimethylpyrimidinecarboxamido)-N-methylbutanamido)-16,25-bis(2-((tert-
butoxycarbonyl)amino)ethoxy)hydroxymethyl-6,9-dioxo-5,8-diaza-1,2(1,3)-
dibenzenacyclodecaphanecarboxylate (0.0524 mmol, 114 mg) was dissolved in 1,4-dioxane (3 mL) and
water (1 mL), and lithium hydroxide (0.5 M, 0.26204 mmol, 0.524 mL) was added dropwise at 0°C and
the reaction mixture was stirred at room temperature for 0.5 h. Water (3 mL) was added and the reaction
mixture was acidified with 0.5 M HCl to pH 3-4. The resultant white precipitate was extracted with EtOAc,
dried with MgSO4, filtered, and concentrated to afford the crude title compound (105 mg, 93%) as a white
solid, which was used in the next step without further purification. (MS+1) m/z 1183.5
Step 19: tert-butyl ((S)(((3S,6S,9S)-15,26-bis(2-((tert-butoxycarbonyl)amino)ethoxy)
((cyanomethyl)carbamoyl)hydroxymethyl-4,7-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-
3-yl)(methyl)amino)(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidinecarboxamido)
oxobutyl)carbamate
O HN
N N N O
HN O
[001238] To a mixture of (4S,7S,10S)((S)((tert-butoxycarbonyl)amino)(2-(4-(tert-butyl)phenyl)-
4,6-dimethylpyrimidinecarboxamido)-N-methylbutanamido)-16,25-bis(2-((tert-
butoxycarbonyl)amino)ethoxy)hydroxymethyl-6,9-dioxo-5,8-diaza-1,2(1,3)-
dibenzenacyclodecaphanecarboxylic acid (0.03721 mmol, 80 mg) and aminoacetonitrile hydrochloride
(0.1861 mmol, 17.2 mg) in N,N-dimethylformamide (5 mL) was added N,N-diisopropylethylamine
(0.3721 mmol, 48.1 mg, 0.0649 mL) and HATU (0.05582 mmol, 21.7 mg). The reaction was stirred at
room temperature for 0.5 h. The reaction mixture was diluted with EtOAc, and washed with water. The
organic layer was dried with Na SO and concentrated. The residue was purified using silica gel
chromatography, eluting with 0 to 10% MeOH in DCM to provide the title compound (36 mg, 63.4%).
(MS+1) m/z 1221.8
Step 20: (4S,7S,10S)((S)amino(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidine
carboxamido)-N-methylbutanamido)-16,25-bis(2-aminoethoxy)-N-(cyanomethyl)hydroxymethyl-
6,9-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphanecarboxamide
tert-butyl ((S)(((3S,6S,9S)-15,26-bis(2-((tert-butoxycarbonyl)amino)ethoxy)
((cyanomethyl)carbamoyl)hydroxymethyl-4,7-dioxo-5,8-diaza-1,2(1,3)-dibenzenacyclodecaphane-
18253141_1 (GHMatters) P111789.NZ
3-yl)(methyl)amino)(2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidinecarboxamido)
oxobutyl)carbamate (0.0236 mmol, 36 mg) was dissolved in TFA (0.1 mL) and 1,1,1,3,3,3-hexafluoro
propanol (4.9 mL) and stirred at room temperature for 1.5 h. The reaction mixture was concentrated. To
the residue was added Et O and re-concentrated. This process was repeated twice more, and the residue
was purified by reverse phase HPLC to provide the title compound (23.4 mg, 92.1%) as a white powder.
(MS+1) m/z 921.4
H NMR (400 MHz, Methanol-d4) δ 8.39 – 8.30 (m, 2H), 7.59 – 7.49 (m, 2H), 7.30 (dd, J = 8.8, 2.4 Hz,
1H), 7.17 (d, J = 8.6 Hz, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.87 (d, J = 2.0 Hz, 1H), 6.47 (s, 1H), 6.42 (s, 1H),
.22 (dd, J = 7.5, 6.0 Hz, 1H), 4.83 (d, J = 19.6 Hz, 3H), 4.45 – 4.32 (m, 2H), 4.36 – 4.22 (m, 2H), 4.26 –
4.09 (m, 2H), 3.47 – 3.22 (m, 6H), 3.19 – 3.04 (m, 2H), 2.99 (s, 3H), 2.65 (s, 1H), 2.57(s, 6H), 2.30 (dq, J
= 14.1, 7.3 Hz, 1H), 2.16 (dq, J = 14.7, 7.6 Hz, 1H), 1.38 (s, 12H).
Example 363: Synthesis of Compound 563
N OH
O HN
N N N O
[001240] (4S,7S,10S)((S)((tert-butoxycarbonyl)amino)(2-(4-(tert-butyl)phenyl)-4,6-
dimethylpyrimidinecarboxamido)-N-methylbutanamido)-16,25-bis(2-((tert-
butoxycarbonyl)amino)ethoxy)hydroxymethyl-6,9-dioxo-5,8-diaza-1,2(1,3)-
dibenzenacyclodecaphanecarboxylic acid (0.01269 mmol, 25 mg) was dissolved in TFA (0.1 mL) and
1,1,1,3,3,3-hexafluoropropanol (4.9 mL) and stirred at room temperature for 4 h. The reaction mixture
was concentrated and the residue purified by reverse phase HPLC to provide the title compound (12.4 mg,
98.1%) as a white powder. m/z 883.4
H NMR (400 MHz, Methanol-d4) δ 8.39 – 8.30 (m, 2H), 7.59 – 7.49 (m, 2H), 7.29 (dd, J = 8.9, 2.5 Hz,
1H), 7.17 (d, J = 8.6 Hz, 1H), 6.95 (s, 1H), 6.50 (s, 1H), 6.43 (s, 1H), 5.22 (t, J = 6.8 Hz, 1H), 4.86 (s, 2H),
4.43 – 4.21 (m, 3H), 3.48 – 3.29 (m, 5H), 3.28 (dd, J = 3.4, 1.7 Hz, 2H), 3.20 – 3.03 (m, 2H), 3.00 (s, 3H),
2.65 (s, 1H), 2.57 (s, 5H), 2.30 (dq, J = 14.1, 7.5, 7.1 Hz, 1H), 2.16 (dq, J = 14.6, 7.6 Hz, 1H), 1.38 (s, 9H),
1.43 – 1.26 (m, 4H).
18253141_1 (GHMatters) P111789.NZ
Example 364: Synthesis of Compound 564
HO ,
DMF O 2
1 C CO
) 2 3
2 Pd dppf Cl KOA N
) ( ) O
B pi DMF
2( )2
H N O
NH N CN
O HN
H N N N O
z ( )
b N O
101E
Step 1: Starting from 4-bromophenol and bromocycloheptane, S 2 reaction conditions
(described in example 44) and Suzuki borylation (described in example 10) were applied to give 2-(4-
(cycloheptyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as colorless oil. H NMR (400 MHz,
CDCl ) δ 7.73(d, J=8.8 Hz, 2H), 6.86(d, J=8.8 Hz, 2H), 4.51-4.45 (m, 1H), 2.05-1.98 (m, 2H), 1.82-1.72
(m, 4H), 1.60-1.57 (m, 4H), 1.51-1.44 (m, 2H), 1.34 (s, 12H).
tert-Butyl (3-bromopropyl)carbamate and 4-amino(4-(cycloheptyloxy)phenyl)methyl nicotinic acid
was prepared as a white solid by utilizing methods analogous to those described in example 213. LCMS
(Method 5-95 AB, ESI): t = 0.791 min, [M + H] = 341.0
Compound 564 (FA salt) was prepared as a white solid from 101E, tert-butyl (3-bromo
propyl)carbamate and 4-amino(4-(cycloheptyloxy)phenyl)methylnicotinic acid by utilizing methods
analogous to those described in example 53. LCMS (Method 5-95 AB, ESI): t = 0.703 min, [M/2 + H] =
495.1; H NMR (400 MHz, MeOH-d ) δ 8.45 (br s, 1H), 7.68-7.65 (m, 2H), 7.28-7.16 (m, 2H), 7.10-7.07
(m, 1H), 7.03-6.95 (m, 4H), 6.89-6.87 (m, 1H), 6.81-6.72 (m, 1H), 6.43-6.37 (m, 1H), 5.07-5.02 (m, 1H),
4.74-4.71 (m, 1H), 4.59-4.53 (m, 1H), 4.20-4.15 (m, 4H), 4.08-4.02 (m, 2H), 3.20-3.01 (m, 4H), 2.98-2.93
(m, 7H), 2.51 (d, J = 3.2 Hz, 3H), 2.21-2.09 (m, 2H), 2.04-1.99 (m, 6H), 1.82-1.70 (m, 4H), 1.62-1.60 (m,
4H), 1.52-1.51 (m, 2H), 1.39-1.31 (m, 3H).
Example 365: Synthesis of Compound 565
H N O
NH N N
O HN
N N N O
Compound 565 (FA salt) was prepared as a white solid from 101E and bromocyclohexane
utilizing methods analogous to those described in example 364. LCMS (Method 5-95 AB, ESI): t = 0.692
min, [M + H] = 974.5; H NMR (400 MHz, MeOH-d ) δ 8.40 (br s, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.26-
7.14 (m, 2H), 7.07-6.93 (m, 5H), 6.89 (br s, 1H), 6.78-6.70 (m, 1H), 6.41-6.33 (m, 1H), 5.02-4.99 (m, 1H),
18253141_1 (GHMatters) P111789.NZ
4.72-4.69 (m, 2H), 4.41-4.36 (m, 1H), 4.19-4.13 (m, 4H), 4.04-4.00 (m, 2H), 3.17-3.05 (m, 3H), 2.99-2.90
(m, 7H), 2.51 (br s, 3H), 2.20 (br s, 1H), 2.14-2.11 (m, 1H), 1.98 (br s, 6H), 1.75 (br s, 2H), 1.54-1.20 (m,
9H).
Example 366: Synthesis of Compound 566
DIAD, PPh LiHMDS
OH NH
Toluene, 80 C 2)
N NH CN
N NH
O HN
N N O
N (S)
N OH
Step 1: To a solution of 4-hydroxybenzonitrile (5.00 g, 43.8 mmol), cycloheptanol (11.7 g, 98.5
mmol) and triphenylphosphine (27.6 g, 105 mmol) in toluene (50 mL) was added DIAD (21.3 g, 105
mmol) at 25 C under N . The reaction was stirred at 80 C for 2 h. The volatiles were removed and the
residue was purified by chromatography on silica, eluting with 0-5% EtOAc in petroleum ether, to afford
4-(cycloheptyloxy)benzonitrile (6.1 g, 65% yield) as a white solid.
Step 2: To a solution of 4-(cycloheptyloxy)benzonitrile (3.8 g, 17.6 mmol) in THF (40 mL) was
added LiHMDS (1 M in THF, 70.6 mL) at 0 C. The reaction was stirred at 25 C for 40 h. After that, HCl
(4 M in H O, 60 mL) was added and the mixture was stirred for 10 min, which was then adjusted to pH =
12 using NaOH and extracted with DCM (100 mL). The organic layer was dried over Na SO and
concentrated to afford 4-(cycloheptyloxy) benzimidamide (2.6 g, 63% yield) as brown oil.
4-Amino(4-(cycloheptyloxy)phenyl)methylpyrimidinecarboxylic acid was prepared as a white
solid by utilizing methods analogous to those described in example 221 and example 213. LCMS (Method
-95 AB, ESI): t = 0.671 min, [M + H] = 342.5
Compound 566 (FA salt) was prepared as a white solid from 101E and 4-Amino(4-(cyclo
heptyloxy)phenyl)methylpyrimidinecarboxylic acid utilizing methods analogous to those described
in example 364. LCMS (Method 5-95 AB, ESI): t = 0.589 min, [M + H] = 989.6; H NMR (400 MHz,
MeOH-d ) δ 8.53 (br s, 1H), 8.11 (d, J=8.0 Hz, 2H), 7.28-7.06 (m, 4H), 6.89 (d, J =8.0 Hz, 2H), 6.83 (s,
1H), 6.64-6.61 (m, 2H), 4.79-4.67 (m, 3H), 4.61-4.60 (m, 1H), 4.39-4.09 (m, 6H), 3.28-3.01 (m,
10H), 2.31 (s, 3H), 2.23-2.08 (m, 7H), 1.88-1.80 (m, 5H), 1.75-1.60 (m, 4H), 1.58 (s, 2H), 1.43-1.32 (m,
4H).
18253141_1 (GHMatters) P111789.NZ
Example 367: Synthesis of Compound 567
HO O
NaN , CeCl
1) 3 3
OH O
O O O PPh H O
2) 3 2
SOCl , MeOH
3) 2
K CO DMF
, Boc NaHCO
2 3 O,
4) 2 3
Cbz N O
O Cbz N O
567-1
101E
NHBoc
H N O
BocHN O
N CN
O HN
N N N O
Cbz N O
567-2
Step 1: A solution of 101E (1.0 g, 1.78 mmol), K CO (4.4 g, 32 mmol) and [(2R)-oxiran yl]
methyl 3-nitrobenzenesulfonate (6.9 g, 26.7 mmol) in DMF (10 mL) was stirred at 50 C for 24 h. The
reaction mixture was added with EtOAc (150 mL), which was washed with brine (150 mL x 3), dried over
Na SO , concentrated and the residue was purified by column (2% MeOH in DCM) to give compound
567-1 (1.0 g, 83% yield) as a white solid. LCMS (10-80AB_7min, ESI): t = 3.611 min, [M + Na] =
696.1
Step 2: A solution of compound 567-1 (1.0 g, 1.48 mmol) in acetonitrile (20 mL) and Water (5
mL) was added CeCl (183 mg, 0.74 mmol) and NaN (1.45 g, 22 mmol) and the mixture was stirred at
75 C for 24 h. Water (100 mL) was added to the above solution and the mixture was stirred for 5 min. The
resulting precipitate was collected for next step. The filtrate was treated with aq HCl (1 mol/L) until
pH=6, which was extracted with EtOAc (50 mL x 2). The organic layers were combined, dried over
Na SO and concentrated. The resulting residue together with aforementioned precipitate was treated with
PPh (2.0 g, 7.9 mmol), H O (0.3 mL) in THF (20 mL) at 50 C for 15 h. The volatiles were removed and
the residue was treated with SOCl (230 mg, 2 mmol) in MeOH (6 mL) at 75 C for 1 h. After
concentration under vacuum, the residue was dissolved in THF/H2O (20 mL, v/v=7:1), to which NaHCO
(415 mg, 4.9 mmol) and Boc O (925 mg, 4.2 mmol) were added. The mixture was stirred at 30 C for 2 h.
The reaction mixture was added with water (50 mL), which was extracted with EtOAc (100 mL x 2). The
combined organic layers were dried over Na SO , concentrated and the residue was purified by column,
eluting with 30% acetone in petroleum ether to remove PPh O, then 70% EtOAc in petroleum ether) to
give compound 567-2 (860 mg, 67% yield) as a white solid. LCMS (Method 5-95 AB, ESI): t = 0.878
min, [M + Na] = 930.2
Compound 567 (FA salt) was prepared as a white solid from Compound 567-2 by utilizing
methods analogous to those described in example 53. LCMS (Method 5-95 AB, ESI): t = 0.708 min, [M +
H] = 964.8; H NMR (400 MHz, MeOH-d ) δ 8.51 (br s, 1H), 8.20 (d, J=8.0 Hz, 2H), 7.47 (d, J=8.0 Hz,
18253141_1 (GHMatters) P111789.NZ
2H), 7.29-7.15 (m, 2H), 7.02 (s, 1H), 6.80 (s, 1H), 6.59 (s, 1H), 6.50 (s, 1H), 5.36-5.23 (m, 1H), 4.81-4.70
(m, 2H), 4.32-4.04 (m, 7H), 4.02-3.90 (m, 1H), 3.20-3.04 (m, 4H), 3.03-2.87 (m, 6H), 2.46 (s, 6H), 2.31-
2.10 (m, 2H), 1.38 (s, 9H), 1.33 (d, J=6.4 Hz, 3H).
Example 368: Synthesis of Compound 568
H N O
O OH
N N CN
O HN
N N N O
Compound 568 (FA salt) was prepared as a white solid from 2-(4-(cyclohexyloxy)phenyl) -4,6-
dimethylpyrimidinecarboxylic acid (described in example 137) by utilizing methods analogous to those
described in example 367. LCMS (Method 5-95 AB, ESI): t = 0.742 min, [M/2 + H] = 504.0; H NMR
(400 MHz, MeOH-d ) δ 8.54 (br s,1H), 8.19-8.01 (m, 2H), 7.22 (br s, 2H), 7.08-6.85 (m, 4H), 6.77 (s, 1H),
6.71 (s, 1H), 6.36 (br s, 1H), 5.40-5.30 (m, 1H), 4.82-4.68 (m, 2H), 4.51-3.86 (m, 10H), 3.28-2.64 (m,
10H), 2.58-2.22 (m, 7H), 2.21-2.08 (m, 1H), 2.07-1.98 (m, 2H), 1.90-1.79 (m, 2H), 1.68-1.26 (m, 9H).
Example 369: Synthesis of Compound 569
H N O
O OH
N N CN
O HN
N N N O
Compound 569 (FA salt) was prepared as a white solid from 2-(4-isopropoxyphenyl)-4,6-
dimethylpyrimidinecarboxylic acid by utilizing methods analogous to those described in example 367.
LCMS (Method 5-95 AB, ESI): t = 0.679 min, [M + H] = 966.5; H NMR (400 MHz, MeOH-d ) δ 8.54
(br s, 1H), 8.10-8.04 (m, 2H), 7.24 (br s, 2H), 7.02 (d, J=8.8 Hz, 1H), 6.94-6.87 (m, 3H), 6.76 (s, 2H), 6.30
(s, 1H), 5.38-5.36 (m, 1H), 4.77-4.69 (m, 2H), 4.34-4.16 (m, 7H), 3.98-3.95 (m, 1H), 3.31-3.26 (m, 1H),
3.16-3.06 (m, 4H), 3.01 (s, 3H), 2.95-2.92 (m, 2H), 2.76-2.48 (m, 2H), 2.35 (s, 6H), 2.30-2.12 (m, 2H),
1.38 (d, J=6.0 Hz, 6H), 1.33 (d, J=6.8 Hz, 3H).
Example 370: Synthesis of Compound 570
H N O
N N CN
O HN
N N N O
( ) ( )
18253141_1 (GHMatters) P111789.NZ
Compound 570 (FA salt) was prepared as a white solid from 101E and [(2S)-oxiran yl]
methyl 3-nitrobenzenesulfonate by utilizing methods analogous to those described in example 367. LCMS
(Method 5-95 AB, ESI): t = 0.720 min, [M + H] = 964.6; H NMR (400 MHz, MeOH-d ) δ 8.53 (br s,
1H), 8.14 (d, J=8.0 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 7.27-7.16 (m, 2H), 7.06-6.92 (m, 2H), 6.78 (s, 1H),
6.67 (s, 1H), 6.41 (s, 1H), 5.41-5.18 (m, 1H), 4.83-4.70 (m, 2H), 4.41-3.90 (m, 9H), 3.23-2.82 (m, 10H),
2.43 (s, 6H), 2.33-2.08 (m, 2H), 1.39 (s, 9H), 1.33 (d, J=6.4 Hz, 3H).
Example 371: Synthesis of Compound 571
NHBoc NHBoc
H N O
Boc O O
O OH
% TFA in HFIP
2) Boc NaHCO N N CN
O HN
OMe OMe
THF/H O
HN HN H
N N O
N O N O N O
Cbz Cbz
N O N O
571-1 571-2
Step 1: A solution of compound 571-1 (from example V (compound 106-B1), 300 mg, 0.37
mmol) in 10% TFA in DCM (30 mL) was stirred at 25 C for 5 h. The volatiles were removed and the
residue was re-dissolved in THF (12 mL), to which Boc O (93 mg, 0.43 mmol) was added. The resulting
mixture was added with sat. NaHCO solution until pH=8 and the reaction was stirred at 25 C for 2 h. The
reaction was added with water (30 mL), which was extracted with EtOAc (30 mL x 3). The combined
organic layers were washed with brine (50 mL x 2), dried over Na SO , concentrated and the residue was
purified by prep-TLC (10% MeOH in DCM, Rf =0.4) to get compound 571-2 (251 mg, 96% yield) as a
white solid. LCMS (Method 5-95 AB, ESI): t = 0.907 min, [M + Na] = 727.5
Compound 571 (FA salt) was prepared as a white solid from compound 571-2 by utilizing
methods analogous to those described in example 367. LCMS (Method 10-80 AB, ESI, 7 min): t = 1.756
min, [M + H] = 935.6; H NMR (400 MHz, MeOH-d ) δ 8.52 (br s, 2H), 8.28-8.14 (m, 2H), 7.50-7.45 (m,
2H), 7.32-7.18 (m, 2H), 7.10-6.96 (m, 2H), 6.83 (s, 1H), 6.65-6.40 (m, 2H), 5.30 (m, 1H), 4.85-4.77 (m,
2H), 4.46-4.29 (m, 3H), 4.25-4.00 (m, 4H), 3.30-3.26 (m, 2H), 3.14 (br s, 3H), 3.07-3.01 (m, 3H), 3.00-
2.86 (m, 3H), 2.45 (s, 6H), 2.35-2.23 (m, 1H), 2.22-2.09 (m, 1H), 1.39 (s, 9H), 1.34 (d, J=6.0 Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 372: Synthesis of Compound 572
CbzHN COOH
CbzHN COOH
TMS NH
O N 2
Et DCM O Et DMF
O N, 3N,
O O TMS
O Cl
NHBoc NHBoc
NHBoc
BocHN O
BocHN O
BocHN O
(S) TBAF, DMF
N N CN 1) (S)
N N CN
O O HN
(S) H H
OMe (S) ClSO2NCO, t-BuOH,
N N O 2) (S)
N (S) (S) N N N O
(S) (S)
DIEA/DCM N O
Pyr,
N (S) O
HN O
O S O
NHBoc
101G
572-1 572-2
H N O
N N CN
O HN
N N O
N (S) (S)
O S O
Step 1: To a solution of 2-(trimethylsilyl)ethanol (7.0 g, 60 mmol) and Et N (10 g, 100 mmol) in
DCM (15 mL) was added 4-nitro-phenylchloroformate (10 g, 50 mmol) and the mixture was stirred at
30 C for 1 h. The reaction was quenched with water (50 mL), and then extracted with DCM (50 mL x 3).
The combined organic layers were dried with Na SO , concentrated and the residue was purified by
column, eluting with 2% EtOAc in petroleum ether, to give (4-nitrophenyl) 2-trimethylsilylethyl carbonate
(10 g, 71% yield) as colorless oil.
Step 2: To a solution of (4-nitrophenyl) 2-trimethylsilylethyl carbonate (5.0 g, 17.6 mmol) in
DMF (45 mL) was added (2S)amino(benzyloxycarbonylamino)propanoic acid (3.5 g, 14.7 mmol)
and Et N (3.0 g, 29.4 mmol) at 25 C and the mixture was stirred at the same temperature for 3 h. The
volatiles were removed and the residue was partitioned between DCM and H O (200 mL each). The
organic layer was washed with brine (100 mL x 2), dried over Na SO , concentrated and the residue
was purified by silica-gel column, eluting with 10%-30% MeOH in DCM to give (2S)
(benzyloxycarbonylamino)(2-trimethylsilyl ethoxycarbonylamino)propanoic acid (3.4 g, 61% yield) as
a white solid.
Compound 572-1 was prepared as a white solid by utilizing methods analogous to those
described in example 53. LCMS (Method 5-95 AB, ESI): t = 1.146 min, [M + H] = 1235.4.
Step 3: To a solution of compound 572-1 (120 mg, 0.097 mmol) in DMF (2 mL) was added
TBAF (1 M in THF, 40 μL) at 20 C and the reaction was stirred at 50 C for 2h. The mixture was diluted
with water (20 mL), which was extracted with EtOAc (20 mL x 2). The combined organic layers were
washed with brine (40 mL), dried over Na SO and concentrated to have INT-A.
Another solution of chlorosulfonyl isocyanate (17 mg, 0.11 mmol) in DCM (2 mL) at 0 C was
added t-BuOH (13 μL, 0.11 mmol) and the mixture was stirred for 30 min, followed by the addition of
pyridine (26 μL, 0.22 mmol). The resulting mixture was stirred for 40min during which time precipitate
formed, which was added via pipette to a mixture of INT-A and DIEA (40 mg, 0.30 mmol) in DCM (2 mL)
18253141_1 (GHMatters) P111789.NZ
at 0 C. The reaction was stirred at 0 C for 0.5 h. After that, the mixture was diluted with DCM (10 mL),
which was washed with brine (10 mL). The organic layer was dried over Na SO , concentrated and the
residue was purified by prep-TLC (10% MeOH in DCM) to get compound 572-2 (40 mg, 33% yield)
Compound 572 (FA salt) was prepared as a white solid from compound 572-2 by utilizing
methods analogous to those described in example 53. LCMS (Method 5-95 AB, ESI): t = 0.756 min, [M +
H] = 969.7; H NMR (400 MHz, MeOH-d ) δ 8.54 (br s, 2H), 8.01 (d, J=8.0 Hz, 2H), 7.37 (d, J=8.0 Hz,
2H), 7.28-7.21 (m, 2H), 7.05 (d, J=8.0 Hz, 1H), 6.90-9.84 (m, 2H), 6.76 (s, 1H), 6.27 (s, 1H), 5.51-5.47 (m,
1H), 4.76-4.71 (m, 1H), 4.43 (s, 1H), 4.29-4.20 (m, 5H), 4.09 (s, 1H), 3.56-3.51 (m, 1H), 3.40-3.34 (m,
2H), 3.21 (s, 2H), 3.09 (s, 3H), 2.87-2.77 (m, 1H), 2.61-2.53 (m, 1H), 2.35 (s, 6H), 1.39 (s, 9H), 1.33 (d,
J=6.4 Hz, 3H).
Example 373: Synthesis of Compound 573
N N CN
O HN
N N N O
Compound 573 (FA salt) was prepared as a white solid from 2-(4-(cyclohexyloxy)phenyl) -4,6-
dimethylpyrimidinecarboxylic acid (described in example 137) by utilizing methods analogous to those
described in example 372. LCMS (Method 5-95 AB, ESI): t = 0.801 min, [M + H] = 997.4; H NMR
(400 MHz, DMSO-d ) δ 8.40 (br s, 3H), 8.12 (d, J=8.0 Hz, 1H), 7.28-7.15 (m, 2H), 7.06-7.04 (m, 3H),
7.00-6.94 (m, 2H), 6.74-6.64 (m, 3H), 5.76-5.72 (m, 1H), 4.93-4.60 (m, 2H), 4.45-4.35 (m, 2H), 4.20-4.16
(m, 2H), 4.05 (s, 5H), 3.77 (s, 12H), 2.97 (m, 4H), 2.42 (s, 2H),1.94 (s, 2H), 1.74-1.72 (m, 2H), 1.56-1.36
(m, 6H), 1.25-1.21 (m, 3H).
Example 374: Synthesis of Compound 574
N N CN
O HN
N N N O
HN NH
Compound 574 (FA salt) was prepared as a white solid from (S)amino(((benzyloxy)
carbonyl) amino) butanoic acid by utilizing methods analogous to those described in example 372. LCMS
(Method 5-95 AB, ESI): t = 0.782 min, [M + H] = 983.7; H NMR (400 MHz, MeOH-d ) δ 8.51 (br s,
1H), 8.12-8.06 (m, 2H), 7.43 (d, J=8.4 Hz, 2H), 7.27-7.23 (m, 2H), 7.07 (d, J=8.4 Hz, 1H), 7.00-6.96 (m,
1H), 6.83 (s, 1H), 6.81 (s, 1H), 6.40 (s, 1H), 5.33-5.32 (m, 1H), 4.90-4.85 (m, 1H), 4.78-4.73 (m, 1H),
4.45-4.41 (m, 2H), 4.32-4.22 (m, 4H), 3.35 (m, 3H), 3.27-3.17 (m, 4H), 3.07 (m, 3H), 2.91 (m, 1H), 2.43
(s, 6H), 2.04-1.98 (m, 1H), 2.07-1.95 (m, 1H), 1.39 (s, 9H), 1.34 (d, J=6.8 Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 375: Synthesis of Compound 575
N N CN
O HN
N N N O
O S NH
Compound 575 (FA salt) was prepared as a white solid from 101E and tert-butyl (3-bromo
propyl)carbamate by utilizing methods analogous to those described in example 372. LCMS (Method 5-95
AB, ESI): t = 0.772 min, [M + H] = 997.6; H NMR (400 MHz, MeOH-d ) δ 8.42 (br s, 1H), 7.99 (d,
J=8.0Hz, 2H), 7.35 (d, J=8.4Hz, 2H), 7.27-7.12 (m, 2H), 7.07-6.93 (m, 2H), 6.87-6.75 (m, 1H), 6.69 (s,
1H), 6.19 (br s, 1H), 5.58-5.48 (m, 1H), 4.78-4.62 (m, 1H), 4.50-4.15(m, 5H), 4.13-3.77 (m, 2H), 3.60-
3.47 (m, 1H), 3.41-3.32 (m, 1H), 3.28-3.16 (m, 2H), 3.15-2.93 (m, 5H), 2.83-2.68 (m, 1H), 2.60-2.46 (m,
1H), 2.31 (s, 6H), 2.20-1.90 (m, 4H), 1.39 (s, 9H), 1.34 (d, J=6.8 Hz, 3H).
Example 376: Synthesis of Compound 576
H N O
N CN
N N N O
(S) (S)
O S O
Compound 576 (FA salt) was prepared as a white solid from 101E, tert-butyl (3-bromo
propyl)carbamate and 2-(4-(cyclohexyloxy)phenyl) -4,6-dimethylpyrimidinecarboxylic acid (described
in example 137) by utilizing methods analogous to those described in example 372. LCMS (Method 5-95
AB, ESI): t = 0.771 min, [M + H] = 1039.9; H NMR (400 MHz, MeOH-d ) δ 8.41 (br s, 3H), 8.11 (d,
J=6.4 Hz, 2H), 7.22 (br s, 2H), 7.11-6.95 (m, 3H), 6.90 (d, J=8.4 Hz, 2H), 6.77 (s, 1H), 6.40 (br s, 1H),
.52-5.45 (m, 1H), 4.84-4.74 (m, 2H), 4.48-4.24 (m, 6H), 4.13-4.05 (m, 1H), 3.61-3.49 (m, 1H), 3.42-3.35
(m, 1H), 3.22-2.97 (m, 8H), 2.96-2.85 (m, 1H), 2.39 (s, 6H), 2.22 (br s, 2H), 2.09-2.02 (m, 4H), 1.89-1.80
(m, 2H), 1.69-1.44 (m, 6H), 1.38 (d, J=6.8 Hz, 3H).
Example 377: Synthesis of Compound 577
NHBoc
H N O
(R) O
BocHN O
N N CN
O HN
N N O
Cbz N O
O S NH
577-1
18253141_1 (GHMatters) P111789.NZ
Compound 577 (FA salt) was prepared as a white solid from compound 577-1 (synthesis
described in example 367) by utilizing methods analogous to those described in example 372. LCMS
(Method 10-80 AB, ESI, 7 min): t = 2.329 min, [M + H] = 1029.4; H NMR (400 M Hz, MeOH-d ) δ
8.54 (br s, 1H), 7.98 (d, J=8.4 Hz, 2H), 7.34 (d, J =8.4 Hz, 2H), 7.27-7.09 (m, 2H), 6.99 (d, J =8.8 Hz, 2H),
6.87-6.75 (m, 1H), 6.69 (s, 1H), 6.16 (br s, 1H), 5.52-5.95 (m, 1H), 4.55-4.52 (m, 1H), 4.45-4.10 (m, 8H),
4.00-3.70 (m, 2H), 3.60-3.45 (m, 1H), 3.40-3.25 (m, 5H), 3.17-3.08 (m, 2H), 3.00-2.90 (m, 1H), 2.81-2.65
(m, 1H), 2.30 (s, 6H), 1.40 (s, 9H), 1.34 (d, J=6.4 Hz, 3H).
Example 378: Synthesis of Compound 578
NHBoc
OH (R)
H N O
BocHN O O OH
N N CN
O HN
OMe H H
HN N N N O
Cbz N O
N O O
O S NH
578-1
[001266] Compound 578 (FA salt) was prepared as a white solid from compound 578-1 (synthesis
described in example 367) and 2-(4-(cyclohexyloxy)phenyl) -4,6-dimethylpyrimidine carboxylic acid
(described in example 137) by utilizing methods analogous to those described in example 372. LCMS
(Method 5-95 AB, ESI): t = 0.776 min, [M + H] = 1072.0; H NMR (400 MHz, MeOH-d ) δ 8.54 (br s,
1H), 8.08-7.88 (m, 2H), 7.29-7.11 (m, 2H), 7.08-6.80 (m, 5H), 6.72 (s, 1H), 6.24 (br s, 1H), 5.55-5.46 (m,
1H), 4.83-4.62 (m, 2H), 4.49-3.83 (m, 10H), 3.59-3.48 (m, 1H), 3.41-3.34 (m, 1H), 3.30-3.18 (m, 1H),
3.16-2.71 (m, 7H), 2.54-2.15 (m, 6H), 2.09-1.98 (m, 2H), 1.90-1.80 (m, 2H), 1.70-1.31 (m, 9H).
Example 379: Synthesis of Compound 579
NHBoc (R)
H N O
O OH
BocHN O
N N CN
O HN
N N N O
Cbz N O
H N S O
579-1
Compound 579 (FA salt) was prepared as a white solid from compound 579-1 (synthesis
described in example 367) and 2-(4-isopropoxyphenyl)-4,6- dimethylpyrimidinecarboxylic acid by
utilizing methods analogous to those described in example 372. LCMS (Method 5-95 AB, ESI): t = 0.582
min, [M + H] = 1031.4; H NMR (400 MHz, MeOH-d ) δ 8.54 (br s, 1H), 8.14-7.94 (m, 2H), 7.26-7.16
(m, 2H), 7.06-7.01 (m, 1H), 7.01-6.90 (m, 2H), 6.86 (d, J=8.4 Hz, 2H), 6.75 (br s, 1H), 6.34 (s, 1H), 5.54-
.45 (m, 1H), 4.78-4.67 (m, 2H), 4.38-4.08 (m, 8H), 4.00-3.92 (m, 1H), 3.58-3.50 (m, 1H), 3.41-3.33 (m,
2H), 3.30-3.22 (m, 1H), 3.14-2.99 (m, 5H), 2.95-2.81 (m, 2H), 2.34 (s, 6H), 1.39 (d, J=5.6 Hz, 6H), 1.37
(d, J=6.4 Hz, 3H)
18253141_1 (GHMatters) P111789.NZ
Example 380: Synthesis of Compound 580
H N O
N N CN
O HN
N N N O
HN NH
Compound 580 (FA salt) was prepared as a white solid from (S)amino(((benzyloxy)
carbonyl) amino) butanoic acid by utilizing methods analogous to those described in example 377. LCMS
(Method 5-95 AB, ESI): t = 0.776 min, [M + H] = 1043.8; H NMR (400 MHz, MeOH-d ) δ 8.55 (s, 1H),
8.08 (d, J=6.8 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 7.26-7.14 (m, 2H), 7.05-6.82 (m, 3H), 6.75 (s, 1H), 6.28
(br s, 1H), 5.41-5.32 (m, 1H), 4.77-4.67 (m, 1H), 4.42-3.88 (m, 10H), 3.28-3.15 (m, 3H), 3.12-2.98 (m,
5H), 2.95-2.74 (m, 2H), 2.38 (s, 6H), 2.26-2.15 (m, 1H), 2.08-1.95 (m, 1H), 1.39 (s, 9H), 1.32 (d, J=6.8 Hz,
3H).
Example 381: Synthesis of Compound 581
H N O
N N CN
O HN
N N N O
H N S O
Compound 581 (TFA salt) was prepared as a white solid from [(2S)-oxiran yl] methyl 3-
nitrobenzenesulfonate by utilizing methods analogous to those described in example 377. LCMS (Method
-95 AB, ESI): t = 0.772 min, [M + H] = 1029.3; H NMR (400 MHz, MeOH-d ) δ 7.98 (d , J=8.0 Hz,
2H), 7.36 (d, J=8.0 Hz, 2H), 7.25 (d, J=8.8 Hz, 1H), 7.16 (d, J=8.8 Hz, 1H), 7.05-6.95 (m, 2H), 6.89-6.79
(m, 1H), 6.70 (br s, 1H), 6.19 (br s, 1H), 5.58-5.48 (m, 1H), 4.83-4.61 (m, 2H), 4.44-3.99 (m, 8H), 3.59-
3.48 (m, 1H), 3.41-3.31 (m, 2H), 3.29-3.14 (m, 2H), 3.10 (s, 3H), 3.08-3.02 (m, 1H), 3.00-2.92 (m, 1H),
2.82-2.69 (m, 1H), 2.32 (s, 6H), 1.40 (s, 9H), 1.36(d, J=7.2 Hz, 3H).
Example 382: Synthesis of Compound 582
O O Bn
Bn Bn
B B SEM HO
O SEM O SEM O
OH O
Pd/C, H , DMA HO
Pd 1)
PCy , 2
I 1) 3 2(dba)3 HO
CbzOSu, DMA
DMSO, KOAc 2)
1) 2/AgSO4
OMe OMe HN
H O , MeOH HN
HN SEM-Cl, DIEA HN 2) 2 2
2) H
H H Cbz N O
Cbz N O Cbz N O Cbz N O
N O N O
582-4
582-2 582-3
582-1
NHBoc
H N NH
OH (R)
HO OH
BocHN O
N N CN
O HN
OMe H
N N N O
H N O
Cbz N O
N O O
O S NH
582-5 2
18253141_1 (GHMatters) P111789.NZ
Step 1: To a solution of compound 582-1 (from example V (compound 106-A2), 13.0 g, 20
mmol) in MeOH (100 mL), AgSO (4.35 g, 14.0 mmol) and I (5.57 g, 22 mmol) was added at 20 C and
the reaction mixture was stirred for at 20 C for 2 h. After filtration, the filtrate was concentrated and the
residue was purified by silica-gel column, eluting with 5% MeOH in DCM. The resulting material was
dissolved in DCM (130 mL), to which DIEA (6.5 g, 50 mmol) and SEM-Cl (4.45 mL, 25 mmol) was
added. The reaction was stirred for 4h at 25 C. The mixture was added with DCM (300 mL), which was
washed with saturated NH Cl solution and brine (250 mL each). The organic layer was dried over Na SO ,
4 2 4
concentrated and the residue was purified by silica-gel column to give compound 582-2 (15 g, 83% yield)
as a off-white solid. LCMS (Method 5-95 AB, ESI): t = 1.088 min, [M + Na] = 930.0
[001271] Step 2: A mixture of KOAc (7.57 g, 77 mmol), compound 582-2 (10.0 g, 11 mmol), Pin B
(14.0 g, 55 mmol), Pd (dba) (504 mg, 0.55 mmol) and PCy (309 mg, 1.1 mmol) in DMSO (150 mL) was
2 3 3
stirred at 80 C overnight under N . The mixture was diluted with EtOAc (500 mL), which was washed
with saturated NaHCO solution and brine (each 500 mL). The organic layer was dried over Na SO ,
3 2 4
concentrated and the residue was purified by silica-gel column, eluting with 5% MeOH in DCM. The
resulting material was re-dissolved in MeOH (100 mL), to which was added H O (30% w/w, 20 mL). The
reaction was stirred for 6 h at 30 C. The mixture was diluted with EtOAc (200 mL), which was washed
with water and brine (100 mL each). The organic layer was dried over Na SO , concentrated and the
residue was purified by silica-gel column, eluting with 5% MeOH in DCM, to obtain the desire product
compound 582-3 (7.2 g, 9.0 mmol, 82% yield) as a white solid. LCMS (Method 5-95 AB, ESI): t = 0.996
min, [M + Na] = 820.0
Step 3: A solution of compound 582-3 (2.4 g, 3.0 mmol) and 10% Pd/C (1.6 g, 1.5 mmol) in
DMA (20 mL) was stirred under H (50 psi) at 50 C for 20 h. After filtration, the filtrate was added with
CbzOSu (749 mg, 3.0 mmol) and the resulting mixture was stirred at 25 C for 1 h. After that, the mixture
was added with EtOAc (120 mL), which was washed with brine (100 mL x 3). The organic layer was dried
over Na SO , concentrated and the residue was purified by silica-gel column, eluting with 50% EtOAc in
petroleum ether, to give compound 582-4 (1.9 g, 90% yield) as a white solid. LCMS (Method 5-95 AB,
ESI): t = 0.904 min, [M + Na] = 730.2
Compound 582-4 was prepared as a white solid by utilizing methods analogous to those
described in example 367 (SEM was removed under methyl ester formation condition). LCMS (Method 5-
95 AB, ESI): t = 0.863 min, [M + Na] = 946.3
Compound 582 (TFA salt) was prepared by utilizing methods analogous to those described in
example 377 (over-acylation on un-protected phenol occurred during each amide coupling step, which can
be converted back to the desired product by treating with 3% ammonia in MeOH for 1 h). LCMS (Method
-80 AB, ESI, 7 min): t = 2.331 min, [M + H] = 1045.6; 1H NMR (400MHz, DMSO-d6, T=80 C) δ
8.84-8.58 (m, 2H), 8.52 (br s, 1H), 8.32 (d, J=7.6 Hz, 2H), 8.07 (d, J=8.4 Hz, 1H), 7.54 (d, J=7.6 Hz, 2H),
7.18 (d, J=8.4 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 6.83 (br s, 1H), 6.77 (br s, 1H), 6.46 (br s, 1H), 6.34 (s,
18253141_1 (GHMatters) P111789.NZ
1H), 5.20-5.09 (m, 1H), 4.81-4.68 (m, 2H), 4.22-4.06 (m, 8H), 3.45-3.35 (m, 1H), 3.26-3.15 (m, 2H), 3.10-
2.92 (m, 6H), 2.88-2.72 (m, 2H), 2.53 (s, 6H), 1.35 (s, 9H), 1.24 (d, J=6.0 Hz, 3H)
Example 383: Synthesis of Compound 583
SEM HO
N CN
O HN
HN H
N N N O
Cbz N O
582-4 2
[001275] Compound 583 (TFA salt) was prepared from compound 582-4 (described in example 382) by
utilizing methods analogous to those described in example 53. LCMS (Method 5-95 AB, ESI): t = 0.706
min, [M + H] = 920.4; H NMR (400 MHz, MeOH-d ) δ 8.35 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H),
7.23 (d, J=7.6 Hz, 1H), 7.08 (d, J=8.0 Hz, 1H), 6.91 (s, 1H), 6.84 (s, 1H), 6.58 (s, 1H), 6.42 (s, 1H), 5.25-
.15 (m, 1H), 4.85-4.80 (m, 2H), 4.48-4.15 (m, 6H), 3.45-3.35 (m, 4H), 3.27-3.07 (m, 4H), 3.07-3.00 (m,
3H), 2.59 (s, 6H), 2.35-2.25 (m, 1H), 2.25-2.15 (m, 1H), 1.40 (s, 9H), 1.38 (d, J=7.2 Hz, 3H).
Example 384: Synthesis of Compound 584
SEM HO O
O H N
HO N
N CN
O HN
OMe N N N O
HN N O
Cbz N O
O NH
O O S NH
582-4
Compound 584 (TFA salt) was prepared from compound 582-4 (described in example 382) by
utilizing methods analogous to those described in example 372. LCMS (Method 5-95 AB, ESI): t = 0.767
min, [M + H] = 985.6; H NMR (400 MHz, MeOH-d ) δ 8.34-8.16 (m, 2H), 7.54-7.26 (m, 2H), 7.12-7.05
(m, 2H), 6.85 (s, 1H), 6.71-6.37 (m, 3H), 5.33 (m, 1H), 4.80-4.78 (m, 2H), 4.38-4.20 (m, 6H), 3.61-3.38
(m, 6H), 3.20-2.90 (m, 2H), 3.02 (s, 3H), 2.53 (s, 6H), 1.36 (s, 9H), 1.27 (d, J=6.8 Hz, 3H).
Example 385: Synthesis of Compound 585
Bn O
OH O
N N CN
O HN
OMe H
N N N O
H N O
Cbz N O
O S NH
585-1
[001277] Compound 585 (FA salt) was prepared from compound 585-1 (from example V (compound
106-A2), iodomethane, and tert-butyl (2-bromoethyl)carbamate, by utilizing methods analogous to those
described in example 382. LCMS (Method 5-95 AB, ESI): t = 0.758 min, [M + Na] = 1021.1; H NMR
(400 MHz, DMSO-d ) δ 8.51 (s, 2H), 8.32 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.09-7.00 (m, 3H),
6.54 (br s, 1H), 6.52 (br s, 1H), 6.39 (s, 1H), 5.24-5.08 (m, 1H), 4.88-4.67 (m, 2H), 4.39-4.20 (m, 7H),
18253141_1 (GHMatters) P111789.NZ
3.91 (s, 3H), 3.68-3.31 (m, 6H), 3.19 (s, 3H), 2.94-2.79 (m, 2H), 2.45 (s, 6H), 1.36 (s, 9H), 1.23 (d, J=6.8
Hz, 3H).
Example 386: Synthesis of Compound 586
N N CN
O HN
N N N O
Cbz O
586-1 2
[001278] Compound 586 (FA salt) was prepared from compound 586-1 (from example V (compound
106-A2), iodomethane, and (S)(((benzyloxy)carbonyl)amino)((tert-butoxycarbonyl) amino)
oxopentanoic acid, by utilizing methods analogous to those described in example 382. LCMS (Method 5-
95 AB, ESI): t = 0.749 min, [M + Na] = 1016.3; H NMR (400 MHz, MeOH-d ) δ 8.50 (br s, 2H), 8.29
(d, J=8.8 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 7.06 (d, J=8.4 Hz, 2H), 6.75 (s, 1H), 6.58 (s, 1H), 6.56 (s, 1H),
5.23-5.21(m, 1H), 4.82-4.77 (m, 1H), 4.26-4.04 (m, 8H), 3.80 (s, 3H), 3.29-3.00 (m, 8H), 3.07 (s, 3H),
2.55 (s, 6H), 2.33-2.17 (m, 2H), 1.40 (s, 9H), 1.38 (d, J=7.2 Hz, 3H).
Example 387: Synthesis of Compound 587
NHBoc Bn
O OH
OH O
O H N
N N CN
OMe O HN
HN HN H
H N N N O
N N O
Cbz N O Cbz O
N O N O
587-2
587-1
Compound 587-2 was prepared from compound 587-1 ((from example V (compound 106-A2)),
iodomethane and tert-butyl (2-bromoethyl)carbamate, by utilizing methods analogous to those described
in example 382. LCMS (Method 5-95 AB, ESI): t = 0.854 min, [M + Na] = 847.2
Compound 587 (FA salt) was prepared from compound 587-2 and (S)(((benzyloxy) carbonyl)amino)-
-((tert-butoxycarbonyl)amino)oxopentanoic acid, by utilizing methods analogous to those described in
example 382. LCMS (Method 5-95 AB, ESI): t = 0.706 min, [M + H] = 964.3; H NMR (400 MHz,
MeOH-d ) δ 8.49 (br s, 2H), 8.35 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.28-7.21 (m, 1H), 7.08-6.96
(m, 2H), 6.86 (s, 1H), 6.62-6.55 (m, 1H), 6.43 (s, 1H), 5.20-5.09 (m, 1H), 4.84-4.72 (m, 2H), 4.38-4.02 (m,
7H), 3.66 (s, 3H), 3.37-3.31 (m, 3H), 3.21-2.95 (m, 8H), 2.59 (s, 6H), 2.33-2.07 (m, 2H), 1.38 (s, 9H), 1.36
(d, J=6.8 Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 388: Synthesis of Compound 588
NHBoc BocHN
NHBoc
NHBoc
HO OBn
N OMe
N OMe
O HN
H O HN
OMe H
N N O H
HN N
N O N O
Cbz N O
N O O
NHBoc
NHBoc
588-2
588-1 588-3
BocHN H N
NHBoc
HO OH HO OH
Pd/C,
N OMe N N CN
EtOH O HN O HN
N N O N N
N N O
N O N O
O O O O
NHBoc NH
588-4 2
Compound 588-2 was prepared from compound 588-1 ((from example V (compound 106-B1)),
by utilizing methods analogous to those described in example 54. LCMS (Method 5-95 AB, ESI): t =
1.042 min, [M + Na] = 1059.1
Compound 588-3 was prepared from compound 588-2 and benzyl bromide (synthesis
described in example 391), by utilizing methods analogous to those described in example 382. LCMS
(Method 5-95 AB, ESI): t = 1.083 min, [M + Na] = 1338.6
Compound 588-4 was prepared hydrogenation of compound 588-3 (described in example 414). LCMS
(Method 5-95 AB, ESI): t = 1.017 min, [M + Na] = 1249.6
Compound 588 (FA salt) was prepared by utilizing methods analogous to those described in
example 382. LCMS (Method 5-95 AB, ESI): t = 0.704 min, [M + H] = 950.6; H NMR (400 MHz,
MeOH-d ) δ 8.50 (br s, 2H), 8.31 (d, J=7.6 Hz, 2H), 7.53 (d, J=8.0 Hz, 2H), 7.16 (s, 1H), 7.07 (d, J=8.8
Hz, 1H), 6.83 (s, 1H), 6.77 (s, 1H), 6.54 (s, 2H), 5.22-5.21 (t, J=6.4 Hz, 1H), 4.81 (q, J=6.4 Hz, 1H), 4.41-
4.34 (m, 2H), 4.25 (s, 3H), 4.07-4.05 (m, 2H), 3.43-3.34 (m, 2H), 3.22-3.05 (m, 9H), 2.56 (s, 6H), 2.32-
2.17 (m, 2H), 1.40 (s, 9H), 1.38 (d, J=6.8 Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 389: Synthesis of Compound 589
FmocCl, Na CO
FmocHN
H N CHO
FmocHN
EtOAc
NHBoc
NHBoc
HNO /HOAc
1) 3
N OMe
N OMe
O HN
Boc O, NaHCO O HN
2) 2 3
N N O
N N N O
NHBoc
NHBoc
589-2
589-1
NHBoc
FmocHN TEAF, DMF
Pd/C, H
1) 2
N OMe
Boc NaHCO
HN 2) 2O, 3
FmocHN
N N O
NaBH
CN, HOAc
NHBoc
589-3
NHBoc
BocHN
N N CN
N OMe
O HN
O HN
N N N O
N N N O (S)
NHBoc
589-4
Step 1: To a solution of 2-aminoethanol (2.0 g, 32.7 mmol) and Na CO (10.4 g, 98.2 mmol) in
H O (35 mL) was added FmocCl (9.3 g, 36.0 mmol) at 20 C and the mixture was stirred at the same
temperature for 2 h. The mixture was extracted with DCM (100 mL x 3). The combined organic layers
were dried over Na SO , concentrated and the residue was purified by silica-gel column, eluting with 50%
EtOAc in petroleum ether, to give (9H-fluorenyl) methyl (2-hydroxyethyl)carbamate (5.6 g, 60.4%
yield) as a white solid.
Step 2: A solution of (9H-fluorenyl) methyl (2-hydroxyethyl)carbamate (1.0 g, 3.5 mmol)
and 2-iodoxybenzoic acid (3.0 g, 10.5 mmol) in EtOAc (100mL) was stirred at 80 C under N for 16 h.
After filtration, the filtrate was concentrated to afford (9H-fluorenyl)methyl (2-oxoethyl)carbamate (1.0
g, quantitative yield) as a white solid. H NMR (400 MHz, CDCl ) δ 9.67 (s, 1H), 7.78 (d, J=8.0 Hz, 2H),
7.60 (d, J=8.0 Hz, 2H), 7.43-7.39 (m, 2H), 7.34-7.31 (m, 2H), 5.50-5.44 (m, 1H), 4.43 (d, J=6.8 Hz, 2H),
4.24 (t, J=6.8 Hz, 1H), 4.20-4.00 (m, 2H).
[001285] Step 3: A solution of compound 589-1 (synthesis described in example 388, 200 mg, 0.19
mmol) in HOAc (2 mL) was added fume nitric acid (30 μL) at 0 C. The mixture was gradually warmed up
to 25 C while stirring and stirred at the same temperature for 3.5 h. The above mixture was added with
saturated NaHCO solution (40 mL), Boc O (84 mg, 0.39 mmol) and THF (12 mL) and the resulting
C for 1.5 h. The mixture was extracted with EtOAc (30 mL x 3). The combined
mixture was stirred at 25
organic layers were washed with brine (50 mL x 2), dried over Na SO , concentrated and the residue was
18253141_1 (GHMatters) P111789.NZ
purified on silica-gel column, eluting with 5% MeOH in DCM, to afford compound 589-2 (140 mg, 67%
yield) as a yellow solid. LCMS (Method 5-95 AB, ESI): t = 1.131 min, [M + H] = 1082.7
Step 4: A solution of compound 589-2 (140 mg, 0.13 mmol) and 10% Pd/C (134 mg, 0.13
mmol) in Ethanol (10mL) was stirred at 30 C under H (15 psi) for 1 h. After filtration, the filtrate was
concentrated and the residue was re-dissolved in MeOH (4 mL), to which (9H-fluorenyl)methyl (2-
oxoethyl)carbamate (43 mg, 0.15 mmol) and HOAc (50 μL) were added. The resulting mixture was stirred
at 25 C for 6 h. After that, the mixture was added with EtOAc (40 mL), which was washed with brine (50
mL), dried over Na SO and concentrated. The residue was purified by pre-TLC, eluting with 7%MeOH in
DCM, to give compound 589-3 (140 mg, 83% yield) as a white solid. LCMS (Method 5-95 AB, ESI): t =
1.136 min, [M + H] = 1318.2
Step 5: A solution of compound 589-3 (140 mg, 0.11 mmol) and TEAF·4H O (47 mg, 0.21
mmol) in DMF (2 mL) was stirred at 30 C for 30 min. The mixture was added with EtOAc (30 mL), which
was washed with brine (30 mL), dried over Na SO and concentrated. The resulting residue was re-
disssolved in THF (3 mL), to which Boc2O (24 mg, 0.12 mmol) and saturated NaHCO (2 mL) was added.
The resulting mixture was stirred at 25 C for 1 h. The reaction was partitioned between EtOAc and water
(50 mL each) and the organic layer was washed with brine (40 mL), dried over Na SO and concentrated.
The residue was purified by pre-TLC, eluting with 5% MeOH in DCM, to afford compound 589-4 (50 mg,
38% yield) as a white solid. LCMS (Method 5-95 AB, ESI): t = 1.052 min, [M + H] = 1195.4
Compound 589 (TFA salt) was prepared by utilizing methods analogous to those described in
example 382. LCMS (Method 5-95 AB, ESI): t = 0.733 min, [M + H] = 919.6; H NMR (400 MHz,
MeOH-d ) δ 8.29 (d, J=8.0 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 7.18 (d, J=8.8 Hz, 1H), 7.04 (d, J=8.8 Hz,
1H), 6.91 (s, 1H), 6.52 (s, 1H), 6.41 (s, 1H), 6.21 (s, 1H), 5.15-5.12 (m, 1H), 4.80-4.76 (m, 2H), 4.31-4.26
(m, 2H), 4.19 (s, 2H), 3.45-3.43 (m, 2H), 3.30-3.28 (m, 3H), 3.15-3.09 (m, 5H), 3.02 (s, 3H), 2.55 (s, 6H),
2.26-2.12 (m, 2H), 1.36 (s, 9H), 1.34 (d, J=6.8 Hz, 3H).
Example 390: Synthesis of Compound 590
18253141_1 (GHMatters) P111789.NZ
Et DMF
Br TMS
NHBoc
NHBoc
Bn O
NHBoc OH O
O HO
N OMe
N OMe
O HN
O HN
N N O
OMe N N N O
N O N
HN O
Cbz N O O O
N O NBn
O S NHBoc
O O S NBnBoc
O 590-2
590-1
590-3
NBoc
NH NH
NH NHBoc
BocHN
H N NH
O OH
N N CN
N OMe O HN
HN H
H N N O
H N (S)
N N N O N O
O S NH
O S NBnBoc
590-4
2-(trimethylsilyl)ethyl (2-bromoethyl)carbamate was prepared from 2-bromoethanamine and 4-
nitrophenyl (2-(trimethylsilyl)ethyl) carbonate (synthesis described in example 372) as pale-yellow oil by
applying the same method described in example 372.
Compound 590-2 was prepared from compound 590-1 ((from example V (compound 106-B1)) as a white
solid by utilizing methods analogous to those described in example 372. LCMS (Method 5-95 AB, ESI): t
= 0.973 min, [M + H] = 1124.1
Compound 590-3 was prepared from compound 590-2 and benzyl bromide (synthesis
described in example 391) as a white solid by utilizing methods analogous to those described in example
382. LCMS (Method 5-95 AB, ESI): t = 1.224 min, [M + H] = 1388.8
Compound 590-4 was prepared from compound 590-3 and 2-(trimethylsilyl)ethyl (2-
bromoethyl)carbamate as a white solid by utilizing methods analogous to those described in example 395.
LCMS (Method 5-95 AB, ESI): t = 1.252 min, [M/2 + H] = 837.9
Compound 590 (TFA salt) was prepared by utilizing methods analogous to those described in
example 388. LCMS (Method 5-95 AB, ESI): t = 0.769 min, [M + H] = 1027.7; H NMR (400 MHz,
MeOH-d ) δ 8.38-8.18 (m, 2H), 7.57-7.43 (m, 2H), 7.28-6.99 (m, 3H), 6.86 (br s, 1H), 6.71 (br s, 1H),
6.52 (s, 1H), 5.37-5.26 (m, 1H), 4.83-4.56 (m, 2H), 4.37 (s, 2H), 4.30-4.02 (m, 3H), 3.70-3.45 (m, 3H),
3.43-3.32 (m, 2H), 3.18-2.96 (m, 1H), 3.08 (s, 3H), 2.52 (s, 6H), 1.40 (s, 9H), 1.38 (d, J=6.8 Hz, 3H).
Example 391: Synthesis of Compound 591
H N (R)
O NH
O OH
OH HO O
N N CN
O HN
HN H
Cbz N O
N N N O
N O N O
Cbz N O
O O O
101E
591-1 NH
18253141_1 (GHMatters) P111789.NZ
Step 1: A solution of NBS (634 mg, 3.56 mmol) and 101E (1.0 g, 1.78 mmol) in DCM (5
mL) was stirred at 30 C for 3h. The volatiles were removed and the residue was purified by silica-gel
column, eluting with 5% MeOH in DCM. The resulting residue was re-dissolved in DMF (6 mL), to which
K CO (1.15 g, 8.34 mmol) and iodomethane (0.7 mL, 11.3 mmol) were added. The reaction was stirred at
25 C for 16 h. The mixture was added with EtOAc (60 mL), followed by the filtration. The filtrate was
washed with brine (50 mL x 3), dried over Na SO , concentrated and the residue was purified by silica-gel
column, eluting with 40% EtOAc in petroleum ether, to give compound 591-1 (1.2 g, 96% yield) as a
white solid. LCMS (Method 5-95 AB, ESI): t = 1.023 min, [M + H] = 746.0.
Compound 591 (TFA salt) was prepared from compound 591-1 and (S)(((benzyloxy)
carbonyl)amino)((tert-butoxycarbonyl)amino)oxopentanoic acid, by utilizing methods analogous to
those described in example 382. LCMS (Method 5-95 AB, ESI): t = 0.696 min, [M + H] = 1024.8; H
NMR (400 MHz, MeOH-d ) δ 8.31 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 6.92 (d, J=7.6 Hz, 2H), 6.52
(s, 1H), 6.42 (s, 2H), 5.20-5.10 (m, 1H), 4.78-4.72 (m, 2H), 4.28-4.16 (m, 8H), 3.78-3.66 (m, 3H), 3.30-
3.20 (m, 3H), 3.19-3.00 (m, 11H), 2.56 (s, 6H), 2.25-2.15 (m, 1H), 2.15-2.05 (m, 1H), 1.36 (s, 9H), 1.33 (d,
J=6.8 Hz, 3H).
Example 392: Synthesis of Compound 592
O OMe
N N CN
OMe O HN
HN H
N N N O
H (S)
Cbz N O N O
591-1 NH
Compound 592 (FA salt) was prepared from compound 591-1 (synthesis described in example
391) and tert-butyl (2-bromoethyl)carbamate, by utilizing methods analogous to those described in
example 391. LCMS (Method 5-95 AB, ESI): t = 0.703 min, [M + Na] = 986.6; H NMR (400 MHz,
MeOH-d ) δ 8.50 (br s, 3H), 8.33 (d, J=8.8 Hz, 2H), 7.52 (d, J=8.8 Hz, 2H), 7.00 (s, 1H), 6.96 (s, 1H),
6.57 (br s, 1H), 6.49 (br s, 1H), 6.41 (s, 1H), 5.14-5.11 (m, 1H), 4.77-4.75 (m, 2H), 4.32-4.19 (m, 6H),
3.73 (s, 3H), 3.69 (s, 3H), 3.39-3.34 (m, 6H), 3.14-3.05 (m, 2H), 3.01 (s, 3H), 2.57 (s, 6H), 2.26-2.12 (m,
2H), 1.36 (s, 9H), 1.33 (d, J=6.8 Hz, 3H).
Example 393: Synthesis of Compound 593
2 (R)
O NH
O OH
HO O
Br H
N CN
O HN
OMe H
HN N N N O
Cbz N O
O S O
591-1
Compound 593 (FA salt) was prepared from compound 591-1 (synthesis described in example
391) by utilizing methods analogous to those described in example 391. LCMS (Method 5-95 AB, ESI): t
= 0.736 min, [M + H] = 1089.6; H NMR (400 MHz, MeOH-d ) δ 8.51 (br s, 1H), 8.18-8.12 (m, 2H),
18253141_1 (GHMatters) P111789.NZ
7.44-7.38 (m, 2H), 6.86 (br s, 1H), 6.71 (br s, 2H), 6.44 (s, 1H), 6.14 (s, 1H), 5.39-5.30 (m, 1H), 4.79-4.67
(m, 2H), 4.25-4.03 (m, 8H), 4.02-3.88 (m, 4H), 3.76 (s, 3H), 3.59-3.50 (m, 1H), 3.39-3.30 (m, 2H), 3.29-
3.20 (m, 2H), 3.11-3.00 (m, 2H), 3.05 (s, 3H), 2.41 (s, 6H), 1.36 (s, 9H), 1.35 (d, J=6.4 Hz, 3H)
Example 394: Synthesis of Compound 594
NHBoc
Bn HO
H N O
OH OH
N OMe
N N CN
O HN
OMe H
N N N O
HN N N
Cbz N O
N O O O
NHBoc
594-1
594-2
Compound 594-2 was prepared from compound 594-1 (from example V (compound 106-A2)) by
utilizing methods analogous to those described in example 395. LCMS (Method 5-95 AB, ESI): t = 0.950
min, [M + H] = 1067.5
Compound 594 (FA salt) was prepared from compound 594-2 and tert-butyl (2-bromoethyl)
carbamate by utilizing methods analogous to those described in example 382. LCMS (Method 5-95 AB,
ESI): t = 0.729 min, [M + H] = 950.4; H NMR (400 MHz, MeOH-d ) δ 8.56 (br s, 2H), 8.35 (d, J=8.0
Hz, 2H), 7.56 (d, J=8.0 Hz, 2H), 7.29 (d, J=8.4 Hz, 1H), 7.16 (d, J=8.4 Hz, 1H), 6.95 (d, J=1.2 Hz, 1H),
6.85 (s, 1H), 6.46 (s, 1H), 6.41 (s, 2H), 5.26-5.22 (m, 1H), 4.84-4.77 (m, 2H), 4.30-4.10 (m, 7H), 3.50 -
3.40 (m, 2H), 3.25-3.05 (m, 6H), 3.01 (s, 3H), 2.58 (s, 6H), 2.30-2.27 (m, 1H), 2.18-2.14 (m, 1H), 1.36 (s,
9H), 1.34 (d, J=6.8 Hz, 3H).
Example 395: Synthesis of Compound 595
BocN NHBoc
BocHN BocO
HN HO
TFA in HFIP
BocN OMe
NHBoc
Cbz N O
N O N
N Cbz N O
2) N O
595-1
595-2
HN NH
NHBoc
BocN
HN HO
HN BocO
Boc O, N N CN
O HN
N N N
(S) O
Cbz N O
595-3
Step 1: A solution of compound 595-1 (from example V (compound 106-B2), 300 mg, 0.37
mmol) in 5% TFA in HFIP (15 mL) was stirred at room temperature for 1 h. The mixture was concentrated
and the residue was re-dissolved in THF (8 mL), which was added tert-butyl (((tert-butoxycarbonyl)amino)
(1H-pyrazol-1 -yl)methylene)carbamate (158 mg, 0.51 mmol). The resulting mixture was stirred at room
temperature for another 3 h. The reaction was added with water (15 mL), which was extracted with EtOAc
(15 mL x 3). The combined organic layers were washed with brine (30 mL), dried with Na SO ,
18253141_1 (GHMatters) P111789.NZ
concentrated and purified by column (5% MeOH/DCM) to give Compound 595-2 (280 mg, 97.5% yield
over two steps) as a white solid. LCMS (Method 5-95 AB, ESI): t = 0.825 min, [M + H] = 847.1
Step 2: To a solution of Compound 595-2 (280 mg, 0.33 mmol) in DCM (15 mL), Et N (100
mg, 0.99 mmol) and Boc O (2.16 g, 9.92 mmol) was added at room temperature and the reaction was
stirred for 72 hours at the same temperature. The reaction was added with water (15 mL), which was
extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (30 mL), dried
with Na SO , concentrated and purified by column (5% MeOH/DCM) to give Compound 595-3 (300 mg,
96% yield) as a white solid. LCMS (Method 5-95 AB, ESI): t = 0.875 min, [M + H] = 947.4
Compound 595 (TFA salt) was prepared as a white solid from Compound 595-3 by utilizing
methods analogous to those described in example 54. LCMS (Method 5-95 AB, ESI): t = 0.749 min, [M +
H] = 903.6; H NMR (400 MHz, MeOH-d4) δ 8.30 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.0 Hz, 2H), 7.27 (d,
J=8.4 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 6.92-6.86 (m, 2H), 6.85 (d, J=8.4 Hz, 1H), 6.62 (br s, 1H), 6.41 (s,
1H), 5.35-5.26 (m, 1H), 4.83-4.78 (m, 1H), 4.62 (br s, 1H), 4.42-4.32 (m, 2H), 4.30-4.23 (m, 2H), 3.74-
3.61 (m, 2H), 3.14 (t, J=8.0 Hz, 2H), 3.05-2.72 (m, 5H), 2.44 (s, 6H), 2.29-2.10 (m, 2H), 1.38 (s, 9H),
1.34(d, J=6.4Hz, 3H).
Example 396: Synthesis of Compound 596
H N N O
BocHN O
N N CN
OMe O
HN H H
HN N N N O
H N O
Cbz N O
Cbz N O
O O O
101E 2
596-1
Compound 596-1 was prepared as a white solid from 101E and tert-butyl (3-bromopropyl)
carbamateby utilizing methods analogous to those described in example 54.
[001302] Compound 596 (FA salt) was prepared as a white solid from Compound 596-1 by utilizing
methods analogous to those described in example 395. LCMS (Method 5-95 AB, ESI): t = 0.634 min, [M
+ H] = 917.5; H NMR (400MHz,MeOH-d4) δ 8.52 (br s, 1H), 8.37-8.23 (m, 2H), 7.57-7.46 (m, 2H),
8.33-8.22 (m, 1H), 7.20-6.89 (m, 3H), 6.87-6.75 (m, 1H), 6.62 (br s, 1H), 6.50 (s, 1H), 5.30-5.18 (m, 1H),
4.83-4.79 (m, 2H), 4.33-4.01 (m, 4H), 3.54-3.35 (m, 2H), 3.26-2.91 (m, 7H), 2.56-2.49 (s, 6H), 2.35-1.95
(m, 4H), 1.42 (s, 9H), 1.38 (d, J=6.8 Hz, 3H).
Example 397: Synthesis of Compound 597
NHBoc
Boc O
N NH
N NH(S) NH O
H N O
Cbz N O
597-1
Compound 597 (FA salt) was prepared as a white solid from Compound 597-1 (side product
during the synthesis of compound 596-1 in example 396 synthesis) by utilizing methods analogous to
18253141_1 (GHMatters) P111789.NZ
those described in example 54. LCMS (Method 5-95 AB, ESI): t = 0.758min, [M + H] = 875.4; H NMR
(400 MHz, MeOH-d4) δ 8.50 (br s, 2H), 8.19 (d, J=8.0 Hz, 2H), 7.47 (d, J=8.0 Hz, 2H), 7.11-7.06 (m, 1H),
7.05-6.95 (m, 3H), 6.79 (br s, 1H), 6.64 (br s, 1H), 6.54 (s, 1H), 5.35-5.29 (m, 1H), 4.82-4.75 (m, 2H),
4.35-4.25 (m, 3H), 4.20-4.10 (m, 1H), 3.27-3.10 (m, 5H), 3.11(s, 3H), 3.05-2.90 (m, 1H), 2.45 (s, 6H),
2.35-2.25 (m, 1H), 2.20-2.10 (m, 3H), 1.39 (s, 9H), 1.35 (d, J=7.2Hz, 3H).
Example 398: Synthesis of Compound 598
O HN
N N N O
Compound 598 (FA salt) was prepared as a white solid from 4,6-dimethyl(4-(pentyloxy)
phenyl)pyrimidinecarboxylic acid (described in example 128) by utilizing methods analogous to those
described in example 396 and example 54. LCMS (Method 5-95 AB, ESI): t = 0.777min, [M + H] =
905.8; H NMR (400 MHz, MeOH-d4) δ 8.52 (br s, 2H), 8.28 (d, J=8.4 Hz, 2H), 7.60-7.25 (m, 2H), 7.05-
7.00 (m, 1H), 6.98 (d, J=8.4Hz, 2H), 6.91 (d, J=2.4 Hz, 1H), 6.83 (br s, 1H), 6.62 (br s, 1H), 6.51 (s, 1H),
.30-5.20 (m, 1H), 4.82-4.75 (m, 2H), 4.41-4.29 (m, 2H), 4.22 (s, 2H), 4.06 (t, J = 6.4 Hz, 2H), 3.27-2.95
(m, 9H), 2.49 (s, 6H), 2.35-2.24 (m, 1H), 2.20-2.10 (m, 3H), 1.90-1.80 (m, 2H), 1.55-1.40 (m, 4H), 1.35 (d,
J=6.4 Hz, 3H), 0.98 (t, J=6.8 Hz, 3H).
Example 399: Synthesis of Compound 599
BocO
Br HO
Br O
K CO , DMF
2 3 CH NH
1) 3 2
TFA/DCM
OMe 2)
Cbz N O
Cbz N O
599-1 599-3
599-2
N CN
O HN
Step 1: A solution of compound 599-1 (from example V (compound 106-A2), 300 mg, 0.45
mmol), 1,2-dibromoethane (852 mg, 4.5 mmol) and K CO (627 mg, 4.5 mmol) in DMF (10 mL) was
stirred at 25 C for 12 h. The reaction was taken up in EtOAc (100 mL), which was washed brine (50 mL
x3), dried over Na2SO4, concentrated and the residue was purified by prep-TLC (10% MeOH in DCM) to
give compound 599-2 (275 mg, 79% yield) as a white solid.
18253141_1 (GHMatters) P111789.NZ
Step 2: A solution of compound 599-2 (275 mg, 0.36 mmol), methylamine (2M in THF, 1.8
mL), K CO (494 mg, 3.6 mmol) in DMF (10 mL) was stirred at 25 C for 12 h. The reaction mixture was
taken up in EtOAc (100 ml), which was washed with brine (50 mL x 2), dried over Na2SO4, concentrated.
The residue was treated with 10% TFA/DCM (10 mL) for 1 h. The volatiles were removed and the residue
was purified by prep-TLC to give compound 599-3 (160 mg, 72% yield) as a off-white solid. LCMS
(Method 5-95 AB, ESI): t = 0.745 min, [M + H] = 619.6
The title compound (FA salt) was prepared as white solids from compound 599-3 by utilizing
methods analogous to those described in example 395. LCMS (Method 5-95 AB, ESI): t = 0.758 min, [M
+ H] = 917.4; H NMR (400 MHz, MeOH-d4) δ 8.54 (br s, 1H), 8.22 (d, J=8.0Hz, 2H), 7.50 (d, J=8.0Hz,
2H), 7.29-7.15 (m, 2H), 6.96-6.80 (m, 3H), 6.57 (s, 1H), 6.53 (s, 1H), 5.30-5.26 (m, 1H), 4.81-4.60 (m,
2H), 4.46-4.24 (m, 2H), 4.24 (s, 2H), 3.87-3.74(m, 2H), 3.15-2.89 (m, 10H), 2.49 (s, 6H), 2.30-2.12 (m,
2H), 1.39 (s, 9H), 1.36-1.20 (m, 3H).
Example 400: Synthesis of Compound 600
BocO
BocO
Boc Et N
O, H
N N CN
O HN
OMe H
HN N N O
N (S)
H N O
Cbz N O
Cbz N O
N O O O
599-3
600-2
[001308] Step 1: A solution of compound 599-3 (synthesis described in example 399, 210 mg, 0.3 mmol),
Boc O (273 mg, 1.25 mmol) and Et N (127 mg, 1.25 mmol) in DCM (20 mL) was stirred at 25 C for 12 h.
The volatiles were removed and the residue was taken up in EtOAc (30 mL), which was washed with brine
(30 mL x 2). The organic layer was dried over Na SO , concentrated and the residue was purified by prep-
TLC (10% MeOH in DCM) to give compound 600-2 (143 mg, 70% yield) as a white solid.
[001309] Compound 600 (FA salt) was prepared as a white solid from compound 600-2 by utilizing
methods analogous to those described in example 54. LCMS (Method 5-95 AB, ESI): t = 0.740min, [M +
H] = 875.4; H NMR (400 MHz,MeOH-d4) δ 8.52 (br s, 1H), 8.10 (d, J=7.6Hz, 2H), 7.43 (d, J=7.6 Hz,
2H), 7.30-7.19 (m, 2H), 7.06-6.74 (m, 3H), 6.73 (br s, 1H), 6.32 (s, 1H), 5.40-5.31 (m, 1H), 4.82-4.65 (m,
2H), 4.53 (s, 2H), 4.35-4.18 (m, 2H), 3.52-3.44 (m, 2H), 3.14 (t, J=7.6 Hz, 2H), 3.01 (s, 3H), 2.95-2.84 (m,
1H), 2.80 (s, 3H), 2.66-2.52 (m, 1H), 2.41 (s, 6H), 2.31-2.13 (m, 1H), 1.39 (s, 9H), 1.34 (d, J=6.4Hz, 3H).
Example 401: Synthesis of Compound 601
N HO
H N O
Br BocO
N N CN
O HN
N N N O
601-1
Compound 601 (FA salt) was prepared as a white solid from compound 601-1 (described in
example 399) and tert-butyl (2-aminoethyl)carbamate by utilizing methods analogous to those described in
18253141_1 (GHMatters) P111789.NZ
example 399 and example 600. LCMS (Method 5-95 AB, ESI): t = 0.716min, [M + H] = 904.5; H NMR
(400 MHz, MeOH-d4) δ 8.49 (br s, 1H), 8.24 (d, J=8.0 Hz, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.53-7.41 (m, 2H),
7.26-7.15 (m, 2H), 7.10-6.99 (m, 1H), 6.85-6.74 (m, 2H), 6.67 (br s, 1H), 6.34 (s, 1H), 5.33-5.23 (m, 1H),
4.79-4.76 (m, 2H), 4.38-4.30 (m, 2H), 4.26-4.18 (m, 2H), 3.17-3.03 (m, 5H), 2.99-2.88 (m, 6H), 2.51 (s,
3H), 2.39 (s, 3H), 2.30-2.13 (m, 2H), 1.40 (s, 9H), 1.37 (d, J=6.4 Hz, 3H).
Example 402: Synthesis of Compound 602
H N HO
Br BocO
N N CN
O HN
N N O
Cbz N O
602-1
Compound 602 (FA salt) was prepared as a white solid from compound 602-1 (described in
example 399) and tert-butyl (3-aminopropyl)carbamate by utilizing methods analogous to those described
in example 399 and example 600. LCMS (Method 10-80 AB_7min, ESI): t = 2.087min, [M + H] = 918.6;
H NMR (400 MHz,MeOH-d4) 8.57 (br s, 2H), 8.13 (d, J=8.0 Hz, 2H), 7.44 (d, J=8.0 Hz, 2H), 7.28-7.19
(m, 2H), 6.91-6.78 (m, 3H), 6.64 (br s, 1H), 6.38 (s, 1H), 5.33-5.18 (m, 1H), 4.82-4.50 (m, 2H), 4.46 (s,
2H), 4.31-4.17 (m, 2H), 3.61-3.55 (m, 4H), 3.26-3.08 (m, 4H), 3.02 (s, 3H), 2.92-2.51 (m, 2H), 2.41 (s,
6H), 2.33-2.05 (m, 2H), 2.02-1.87 (m, 2H), 1.39 (s, 9H), 1.35 (d, J=6.8Hz, 3H).
Example 403: Synthesis of Compound 603
O N O N
O HO O
TEA/DCM TMS
O Cl O O
BocHN BocO
TeocHN BocO
TFA/HFIP
2 HN
Cbz N O
Cbz N O
Teoc
N 2)
603-1 603-2
N BocO
Teoc O
HN N HO
TBAF/THF
H 1)
N N CN
O HN
N N CN
NH HCl
O HN
N N N O
N O O
N N N O
O DIPEA,
O MeCN
%TFA in HFIP
NHBoc
603-3
Step 1: To a solution of 4-nitro-phenyl-chloroformate (3.0 g, 14.9 mmol) and 2-(trimethylsilyl)
ethanol (2.1 g, 17.9 mmol) in DCM (15 mL) was added Et N (3.0 g, 29.8 mmol) and the mixture was
stirred at 30 C for 1 h. The reaction was quenched with water (15 mL), which was extracted with DCM (30
mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried with Na SO ,
18253141_1 (GHMatters) P111789.NZ
concentrated and the residue was purified by silica-gel column, eluting with 5% EtOAc in petroleum ether,
to give (4-nitrophenyl) 2-trimethylsilylethyl carbonate (2.8 g, 68% yield) as colorless oil.
Step 2: A solution of compound 603-1 (from example V (compound 106-B2), 400 mg, 0.50
mmol) in 5% TFA in HFIP (15 mL) was stirred at 30 C for 1 h. The reaction was concentrated and the
residue was re-dissolved in DMF (15 mL), to which DIEA (577 mg, 4.5 mmol) and (4-nitrophenyl) 2-
trimethyl silylethyl carbonate (253 mg, 0.89 mmol) was added sequentially at 0 C. The resulting mixture
was stirred for 16 h at 30 C. The reaction was quenched with water (30 mL), which was extracted with
EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL x 2), concentrated and
the residue was purified by silica-gel column, eluting with 0-5% MeOH in DCM, to obtain compound
603-2 (310 mg, 93% yield) as a white solid. LCMS (Method 5-95 AB, ESI): t = 0.964 min, [M + Na] =
771.3
Step 3: compound 603-3 (130 mg) was prepared as white solids from compound 603-2 by
utilizing methods analogous to those described in example 54. LCMS (Method 5-95 AB, ESI): t = 1.054
min, [M + Na] = 1227.6
[001315] Step 4: To a solution of compound 603-3 (110 mg, 0.09 mmol) in DMF (3 mL) was added
TBAF (95 mg, 0.36 mmol) and the mixture was stirred at 50 C for 3 h. The reaction was added with water
(15 mL), which was exacted with EtOAc (15 mL x 3). The combined organic layers were washed with
brine (50 mL x 2), dried over Na SO and concentrated. The residue was re-dissolved with acetonitrile (5
mL), to which ethyl ethanimidate (24 mg, 0.27 mmol) and DIEA (58 mg, 0.45 mmol) was added. The
mixture was stirred at 25 C for 2 h. The reaction was concentrated to dryness and the residue was taken up
in EtOAc (30 mL), which was washed with brine (30 mL). The organic layer was dried over Na SO and
concentrated and the resulting residue was treated with 5% TFA/HFIP (5 mL) at 25 C for 3 h. The reaction
was concentrated and the residue was purified by prep-HPLC (acetonitrile 10-35/0.225%FA in water) to
afford the title compound (TFA salt, 13.6 mg, 16% yield over three steps) as a white solid. LCMS (Method
5-95 AB, ESI): t = 0.764 min, [M + H] = 902.4; HNMR (400 MHz, MeOH-d4) δ 8.24 (d, J=8.0Hz, 1H),
7.49 (d, J=8.0 Hz, 2H), 7.33-7.15 (m, 2H), 7.03-6.81 (m, 3H), 6.60-6.50 (m, 2H), 5.29-5.21 (m, 1H), 4.82-
4.75 (m, 2H), 4.44-4.30 (m, 2H), 4.23 (s, 2H), 3.75-3.63(m, 2H), 3.21-2.82 (m, 7H), 2.50 (s, 6H), 2.31-
2.05 (m, 2H), 2.21 (s, 3H), 1.38 (s, 9H), 1.35 (d, J=6.8Hz, 3H).
Examples 404 and 405: Synthesis of Compound 604 and 605
18253141_1 (GHMatters) P111789.NZ
BocN
BocN Br
K CO , DMF
HN O
H HN
Cbz N O
O Cbz N O
101E
604-1
A mixture
regio-isomers
N N CN
N N CN
O HN
O HN
N N N O
N N N O
NH 604
2 NH
Step 1: A mixture of 101E (320 mg, 0.58 mmol), K CO (394 mg, 2.85 mmol) and tert-butyl 3-
bromoazetidinecarboxylate (672 mg, 2.85 mmol) in DMF (5 mL) was stirred at 50 C for 5 days. The
reaction mixture was taken up in EtOAc (50 mL), which was washed with saturated brine solution (30 mL
SO , concentrated and the residue was purified by HPLC(water(0.225%FA)-ACN) to
x 2), dried over Na
give compound 604-1 (120 mg, 29% yield) as a white solid. LCMS (Method 5-95 AB, ESI): t = 0.895
min, [M + Na] = 739.5
Both title compounds (TFA salt) were prepared as white solids from Compound 604-1 by
utilizing methods analogous to those described in example 395 and they were separated at the final step by
HPLC.
Compound 604: LCMS (Method 5-95 AB, ESI): t = 0.753 min, [M + H] = 873.9; H NMR (400
MHz,Methanol-d4) δ 8.25 (d, J=8.4 Hz, 2H),7.49 (d, J=8.4Hz, 2H), 7.13-6.96 (m, 3H), 6.80 (br s, 1H),
6.74 (d, J=8.4 Hz, 2H), 6.54 (br s, 1H), 5.31-5.10 (m, 2H), 4.80-4.78 (m, 2H), 4.50-4.35 (m, 2H), 4.26-
4.18 (m, 3H), 4.08-4.00 (m, 1H), 3.35-3.33 (m, 1H), 3.11 (t, J=7.2Hz, 2H), 3.05-2.98 (m, 4H), 2.49 (s, 6H),
2.30-2.11 (m, 2H), 1.39 (s, 9H), 1.35 (d, J=6.8Hz, 3H). Compound 605: LCMS (Method 5-95 AB, ESI):
t = 0.740 min, [M + H] = 873.4; H NMR (400 MHz,MeOH-d4) δ 8.55 (br s, 1H), 8.26 (d, J=8.0 Hz, 2H),
7.49 (d, J=8.0 Hz, 2H), 7.25-7.22 (m, 1H), 6.93-6.81 (m, 4H), 6.54 (br s, 2H), 5.32-5.24 (m, 2H), 4.82-
4.78 (m, 2H), 4.47-4.44 (m, 2H), 4.30-4.10 (m, 2H), 4.24 (s, 2H), 3.22-3.09 (m, 4H), 3.00 (s, 3H), 2.49 (s,
6H), 2.34-2.10 (m, 2H), 1.39 (s, 9H), 1.35 (d, J=7.2Hz, 3H).
Examples 406 and 407: Synthesis of Compound 606 and 607
18253141_1 (GHMatters) P111789.NZ
OH Me
BocHN
BocHN HO
K CO
Cbz N O O
N O HN
Cbz N O
101E
A mixture of
regio-isomers
H N HO
N N CN
H O HN
N CN
N N N O
O HN (S)
H N O
N N N O
NH 607
2 606
Both title compounds (FA salt) were prepared as white solids from 101E and tert-butyl (2-
bromopropyl)carbamate by utilizing methods analogous to those described in examples 404/405 and they
were separated at the final step by HPLC.
[001319] Compound 606: LCMS (Method 5-95 AB, ESI): t = 0.751 min, [M + H] = 875.5; H NMR
(400 MHz,MeOH-d4) δ 8.54 (br s, 1H), 8.12-8.06 (m, 2H), 7.46-7.40 (m, 2H), 7.25-7.20 (m, 1H), 7.06-
6.84 (m, 1H), 6.79-6.74 (m, 3H), 6.43 (br s, 1H), 5.36-5.32 (m, 1H), 4.80-4.75 (m, 4H), 4.32-4.24 (m,
2H),3.28-3.00 (m, 8H), 2.42-1.93 (m, 8H), 1.52-1.26 (m, 15H).
Compound 607: LCMS (Method 5-95 AB, ESI): t = 0.753 min, [M + H] = 875.5; H NMR
(400 MHz,MeOH-d4) δ 8.52 (br s, 1H), 8.21-8.14 (m, 2H), 7.46-7.40 (m, 2H), 7.25-7.21(m, 1H), 7.06-
7.01 (m, 1H), 6.85-6.61 (m, 3H), 6.43 (br s, 1H), 5.35-5.28 (m, 1H), 4.81-4.76 (m, 4H), 4.30-4.24 (m, 2H),
3.35-3.30 (m, 1H), 3.18-2.93 (m, 7H), 2.45-1.93 (m, 8H), 1.48-1.32 (m, 15H).
Examples 408 and 409: Synthesis of Compound 608 and 609
BocN
BocO
BocN
K CO
,DMF
Cbz N O NH
Cbz O
101E
A mixture of N
regio-isomers
HO O
N N N N CN
O HN
O HN
N N N O
N N N O
(S) (S)
N O N O
NH 609
[001321] Both title compounds (FA salt) were prepared as white solids from 101E and tert-butyl 4-
bromopiperidinecarboxylate by utilizing methods analogous to those described in examples 404/405
and they were separated at the final step by HPLC.
18253141_1 (GHMatters) P111789.NZ
Compound 608: LCMS (Method 5-95 AB, ESI): t = 0.751 min, [M + H] = 901.5; H NMR (400
MHz,MeOH-d4) δ 8.50 (br s,2H), 8.13 (d, J=8.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 7.10-7.03 (m, 3H), 6.91
(br s, 1H), 6.80 (s, 1H), 6.78 (s, 1H), 6.43 (br s, 1H), 5.38-5.33 (m, 1H), 4.81-4.60 (m, 1H), 4.34-4.12 (m,
4H), 3.57-3.50 (m, 2H), 3.28-3.07 (m, 10H), 2.69-2.10 (m, 4H), 2.41 (s, 6H), 2.00-1.93 (m, 1H), 1.81-1.75
(m, 1H), 1.80 (s, 9H), 1.35 (d, J=6.8Hz, 3H).
Compound 609: LCMS (Method 5-95 AB, ESI): t = 0.748min, [M + H] = 901.5; H NMR (400
MHz,MeOH-d4) 8.54 (br s, 1H), 8.15 (d, J=8.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 7.28-7.19 (m, 2H), 6.89
(br s, 1H), 6.86-6.73 (m, 2H), 6.64 (br s, 1H), 6.38 (s, 1H), 5.33-5.18 (m, 1H), 4.82-4.50 (m, 2H), 4.32-
4.15 (m, 3H), 3.61-3.55 (m, 1H), 3.28-2.86 (m, 10H), 2.41 (s, 6H), 2.48-2.09 (m, 6H), 1.38 (s, 9H), 1.34 (d,
J=6.8Hz, 3H).
Examples 410 and 411: Synthesis of Compound 610 and 611
BrBn, NaH NaN
PTSA
MsCl, TEA 3
BnO OMs
MeOH DCM DMF
HO O BnO O BnO OH
/C, H
1) Pd(OH)
NHBoc
NHBoc
Pd/C,H
1) 2
BnO N
Boc Et DMAP
3 O, N,
2) 2 3
MsO NHBoc
MsCl, Et N
BnO NHBoc 2)
2 HO
H N O
N N CN
O HN
N N CN
N N N O
O HN
N N N O
Step 1: To a solution of (2,2-dimethyl-1,3-dioxanyl)methanol (1.0 g, 6.84 mmol) and NaH
(60% in oil, 0.41 g, 10.3 mmol) in THF (30 mL) was added BnBr (1.62 mL, 13.7 mmol). The reaction was
stirred at 20 C for 16 h. The reaction was taken up in EtOAc (50 mL), which was washed with brine (30
mL x 2), dried over Na SO , concentrated and the residue was purified by silica gel column, eluting with
% EtOAc in petroleum ether, to obtain 5-(benzyloxy methyl)-2,2-dimethyl-1,3-dioxane (1.6 g, 99%
yield) as colorless oil.
Step 2: To a solution of 5-(benzyloxymethyl)-2,2-dimethyl-1,3-dioxane (1.5 g, 6.35 mmol) in
MeOH (20 mL) was added TsOH (109 mg, 0.63 mmol). The reaction mixture was stirred at 20 C for 1 h.
The reaction was taken up in EtOAc (50 mL), which was washed with brine (20 mL x 3), dried over
Na SO , concentrated and the crude was purified by silica gel column, eluting with 50% EtOAc in
petroleum ether, to obtain 2-(benzyloxymethyl)propane-1,3-diol (1.0 g, 80% yield) as colorless oil.
Step 3: A solution of 2-(benzyloxymethyl)propane-1,3-diol (1.0 g, 5.1 mmol) and Et N (2.86
mL, 20.4 mmol) in DCM (20 mL) was stirred at 0 C for 30 min, followed by the slow addition of MsCl
(1.22 mL, 15.7 mmol). The mixture was stirred for another 3 h at 0 C. After filtration, the filtrate was
concentrated and the residue was purified by silica gel column, eluting with 10% EtOAc in petroleum
18253141_1 (GHMatters) P111789.NZ
ether, to obtain [2-(benzyloxymethyl)methyl sulfonyloxy-propyl] methanesulfonate (1.5 g, 84% yield)
as colorless oil. H NMR (400 MHz, CDCl ) δ 7.35-7.27 (m, 5H), 4.50 (s, 2H), 4.36-4.29 (m, 4H), 3.55 (d,
J=6.0 Hz, 2H), 2.99 (s, 6H), 2.55-2.46 (m, 1H).
Step 4: A solution of [2-(benzyloxymethyl)methylsulfonyloxy-propyl] methanesulfonate (1.5
g, 4.3 mmol) and NaN (2.84 g, 43.7 mmol) in DMF (20 mL) was stirred at 80 C for 16 h. After filtration,
the filtrate was taken up in EtOAc (200 mL), which was washed with brine (100 mL x 3 ), dried over
Na SO , concentrated and the residue was purified by silica-gel column, eluting with 7% MeOH in
DCM, to give [3-azido(azidomethyl)propoxy]methyl benzene (1.0 g, 95.4% yield) as colorless oil.
Step 5: To a solution of [3-azido(azidomethyl)propoxy]methylbenzene (1.0 g, 4.1 mmol) in
MeOH (20 mL) was added 10% Pd(OH) /C (432 mg, 0.41 mmol). The reaction mixture was stirred
at 15 C for 5 h under H (15 psi). The mixture was filtered and the filtrate was concentrated. The residue
was re-dissolved in THF (10 mL), to which was added Boc O (4.04 g, 18.5 mmol), Et N (2.81 g, 27.8
mmol) and DMAP (142 mg, 1.2 mmol). The reaction mixture was stirred at 20 C for 16 h. After that, the
reaction was taken up in EtOAc (200 mL), which was washed with brine (100 mL x 3), dried over
Na SO , concentrated and the residue was purified by silica gel column, eluting with 20% EtOAc in
petroleum ether, to give tert-butyl N-[2-(benzyloxymethyl)(tert-butoxycarbonylamino)propyl]carbamate
(1.3 g, 71% yield) as colorless oil.
Step 6: To a solution of tert-butyl N-[2-(benzyloxymethyl)(tert-butoxycarbonylamino)
propyl]carbamate (1.3 g, 3.3 mmol) in MeOH (20 mL) was added 10% Pd/C (351 mg, 0.33 mmol) and the
reaction mixture was stirred at 60 C for 5 h under H (40 psi). The mixture was filtered and the filtrate was
concentrated. The residue was re-dissolved in DCM, to which Et N (740 μL, 5.3 mmol) was added at 0 C
for 30 min. MsCl (150 μL, 2.0 mmol) in DCM (2 mL) was then added dropwise to the above solution and
the resulting mixture was stirred for another 3 h at 0 C. After filtration, the filtrate was concentrated to
obtain [3-(tert-butoxy carbonylamino)[(tert-butoxycarbonylamino)methyl]propyl] methanesulfonate
(500 mg, quantitative yield) as colorless oil, which was used directly without further purification.
Both title compounds (FA salt) were prepared as white solids from 101E and [3-(tert-butoxy
carbonylamino)[(tert-butoxycarbonylamino)methyl]propyl] methanesulfonate by utilizing methods
analogous to those described in examples 404/405 and they were separated at the final step by HPLC.
Compound 610: LCMS (Method 5-95 AB, ESI): t = 0.743 min, [M + H] = 904.4; H NMR
(400 MHz, MeOH-d4) δ 8.48 (br s, 2H), 8.35 (d, J=8.0 Hz, 2H), 7.56 (d, J=8.0 Hz, 2H), 7.35-6.90 (m, 4H),
6.89-6.75 (m, 2H), 6.43 (s, 1H), 5.26-5.25 (m, 1H), 4.80-4.70 (m, 2H), 4.60-4.25 (m, 2H), 4.22 (s, 2H),
3.50 -3.40 (m, 1H), 3.25-2.95 (m, 10H), 2.57 (s, 6H), 2.45-2.35 (m, 1H), 2.30-2.20 (m, 1H), 2.19-2.10 (m,
1H), 1.40 (s, 9H), 1.37 (d, J=6.8 Hz, 3H).
Compound 611: LCMS (Method 5-95 AB, ESI): t = 0.740min, [M + H] = 905.0; H NMR
(400 MHz, MeOH-d4) δ 8.57 (br s, 1H), 8.40 - 8.20 (m, 2H), 7.56-7.54 (m, 2H), 7.35-7.00 (m, 3H), 6.98-
6.75 (m, 2H), 6.69 (br s, 1H), 6.47 (s, 1H), 5.30-5.15 (m, 1H), 4.80 - 4.70 (m, 2H), 4.41-4.31 (m, 2H), 4.22
18253141_1 (GHMatters) P111789.NZ
(s, 2H), 3.50-3.40 (m, 1H), 3.25-3.04 (m, 7H), 3.05 (s, 3H), 2.57 (s, 6H), 2.45-2.35 (m, 1H), 2.30-2.20 (m,
1H), 2.19-2.10 (m, 1H), 1.40 (s, 9H), 1.38-1.25 (m, 3H).
Example 412: Synthesis of Compound 612
O MeO
Boc Boc
TsCl, Et DMAP
PTSA LiAlH4 N,
HO O O O
Toluene DCM
OH OTs
CO Me
NHBoc
N N CN
N N N O
[001331] Step 1: A solution of (R)-methyl 2-((tert-butoxycarbonyl)amino)hydroxypropanoate (7.77 g,
.4 mmol) in toluene (80 mL) was added 2,2-dimethoxypropane (7.38 g, 70.9 mmol) and TsOH (610 mg,
3.54 mmol) was stirred at 110 C for 0.5 h. The volatiles were distilled under 1 atm and the residue was re-
dissolved with EtOAc (100 mL), which was washed with saturated NaHCO and brine (100 mL each). The
organic layer was dried over Na SO , concentrated and the residue was purified by chromatography on
silica, eluting with 10% EtOAc in petroleum ether, to afford (R)tert-butyl 4-methyl 2,2-
dimethyloxazolidine- 3,4- dicarboxylate (7.60 g, 83% yield) as yellow oil.
Step 2: To a suspension of lithium aluminium hydride (3.34 g, 87.9 mmol) in tetrahydrofuran
(80 mL) was added a solution of (R)tert-butyl 4-methyl 2,2-dimethyloxazolidine- 3,4- dicarboxylate
(7.60 g, 29.3 mmol) in tetrahydrofuran (5 mL) dropwise at 0 C under N . The reaction was then gradually
warmed up to 25 C while stirring and stirred at the same temperature for 2 h. The reaction was quenched
with 10% NaOH solution (3.5 mL). After filtration, the filtrate was concentrated and the residue was
partitioned between EtOAc and water (300 mL each). The organic layer was washed with brine (300 mL),
dried over Na SO , concentrated to give (S)-tert-butyl 4-(hydroxymethyl)-2,2-dimethyloxazolidine
carboxylate (5.51 g, 81% yield) as colorless oil.
[001333] Step 3: To a solution of (S)-tert-butyl 4-(hydroxymethyl)-2,2-dimethyloxazolidine
carboxylate (4.90 g, 21.2 mmol) and TsCl (6.06 g, 31.8 mmol) in dichloromethane (50 mL) was added
Et N (5.91 mL, 42.4 mmol) and DMAP (259 mg, 2.12 mmol) and the reaction was stirred at 25 C for 16 h.
The reaction mixture was added with water and DCM (100 mL each). The organic layer was washed with
brine (100 mL x 2), concentrated and the residue was purified by silica-gel column, eluting with 20-50%
EtOAc in petroleum ether, to afford (R)-tert-butyl 2,2-dimethyl((tosyloxy)methyl)oxazolidine
carboxylate (4.73 g, 58% yield) as a white solid.
Compound 612 (FA salt) was prepared as a white solid from 101E and (R)-tert-butyl 2,2-
dimethyl((tosyloxy)methyl)oxazolidinecarboxylate by utilizing methods analogous to those
described in example 404. LCMS (Method 5-95 AB, ESI): t = 0.611 min, [M + H] = 891.4; H NMR
(400 MHz, MeOH-d4) δ 8.60 (br s, 1H), 8.28-8.12 (m, 2H), 7.54-7.48 (m, 2H), 7.29-7.02 (m, 3H), 6.88-
18253141_1 (GHMatters) P111789.NZ
6.81 (m, 2H), 6.65 (br s, 1H), 6.54 (s, 1H), 5.37-5.30 (m, 1H), 4.84-4.80 (m, 2H), 4.73-4.20 (m, 4H), 4.25
(s, 2H), 4.28-4.23 (m, 3H), 3.92-3.77 (m, 2H), 3.64-3.60 (m, 1H), 3.15-3.11 (m, 2H), 3.03 (s, 3H), 2.48 (s,
6H), 2.33-2.29 (m, 1H), 2.21-2.14 (m, 1H), 1.41 (s, 9H), 1.37 (d, J = 6.4 Hz, 3H).
Example 413: Synthesis of Compound 613
N N CN
N N N O
Compound 613 (TFA salt) was prepared as a white solid from (S)-methyl 2-((tert-butoxy
carbonyl)amino)hydroxypropanoate by utilizing methods analogous to those described in example 412.
LCMS (Method 5-95 AB, ESI): t = 0.609 min, [M + H] = 891.4; H NMR (400 MHz, MeOH-d4) δ 8.36
(d, J=8.4 Hz, 2H), 7.56 (d, J=8.4 Hz, 2H), 7.33-7.30 (m, 1H), 7.20-7.15 (m, 1H), 7.12-7.05 (m, 1H), 6.72-
6.93 (m, 2H), 6.91-6.85 (m, 1H), 6.78 (br s, 1H), 6.46 (s, 1H), 5.26-5.22 (m, 2H), 4.43-4.29 (m, 3H), 4.22
(s, 2H), 4.07-4.02 (m, 2H), 3.85-3.73 (m, 2H), 3.03 (s, 3H), 2.52 (s, 6H), 2.30-2.00 (m, 2H), 1.42 (s, 9H),
1.37 (d, J = 6.8 Hz, 3H).
Example 414: Synthesis of Compound 614
Bn Bn
SEM HO
O O O
OH O
SEMCl, DIEA Pd/C, H
OMe OMe HN
EtOH
HN HN
H H N O
Cbz N O Cbz N O HN O
N O N O
614-1 614-2 614-3
SEM HO
O HN
N N N O
NHBoc
614-4
NHBoc
(R) NH
SEM O
N CN
N OMe
O HN
O HN
N N O
N N N O
NHBoc 614-5 2
[001336] Step 1: To a solution of compound 614-1 (from example V (compound 106-A2)) 200 mg, 0.31
mmol) and DIEA (507 μL, 3.1 mmol) in DMF (5 mL) was added SEM-Cl (543 μL, 3.1 mmol) and the
reaction was stirred at 50 C for 16 h. The mixture was partitioned between EtOAc and H O (each 100 mL).
The organic layer was washed with brine, dried over Na SO , concentrated and the residue was purified by
18253141_1 (GHMatters) P111789.NZ
silica-gel column, eluting with 10% MeOH in DCM, to afford compound 614-2 (200 mg, 83% yield) as
yellow oil. LCMS (Method 5-95 AB, ESI): t = 1.038 min, [M + Na] = 804.0
Step 2: To a solution of compound 614-2 (200 mg, 0.26 mmol) in EtOH (20 mL) was added 10% Pd/C
(272 mg, 0.26 mmol) and a drop of ammonia and the mixture was stirred at 30 C under H (15 psi) for 3 h.
After filtration, the volatiles were concentrate to afford compound 614-3 (96 mg, 67% yield) as a white
solid. LCMS (Method 5-95 AB, ESI): t = 0.758 min, [M + Na] = 580.0
Compound 614-4 was prepared as a white solid from compound 614-3 by utilizing methods
analogous to those described in example 54. LCMS (Method 5-95 AB, ESI): t = 1.125 min, [M + Na] =
1046.3
Compound 614-5 was prepared from compound 614-4 as a white solid by utilizing methods analogous to
those described in example 367. LCMS (Method 5-95 AB, ESI): t = 1.117 min, [M + Na] = 1219.2
Compound 614 (FA salt) was prepared as a white solid from compound 614-5 by utilizing
methods analogous to those described in example 54. LCMS (Method 5-95 AB, ESI): t = 0.728min, [M +
H] = 891.4; H NMR (400 MHz, MeOH-d4) δ 8.55 (br s, 1H), 8.27 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.0
Hz, 2H), 7.14-6.99 (m, 4H), 6.85 (br s, 1H), 6.69 (br s, 1H), 6.58 (s, 1H), 5.35-5.25 (m, 1H), 5.35-5.25
(m, 2H), 4.71-4.40 (m, 2H), 4.31-4.06 (m, 3H), 3.21-3.17 (m, 1H), 3.15-3.07 (m, 5H), 3.03 (s, 3H), 2.51 (s,
6H), 2.33-2.24 (m, 1H), 2.20-2.11 (m, 1H), 1.41 (s, 9H), 1.37 (d, J = 6.4 Hz, 3H).
Example 415: Synthesis of Compound 615
H N HO
BocHN O
N N CN
O HN
N N N O
Cbz N O
615-1 O
[001339] Compound 615 (TFA salt) was prepared as a white solid from compound 615-1 (from example
V (compound 106-B2)) and 2-(4-(cyclohexyloxy)phenyl)-4,6-dimethylpyrimidinecarboxylic acid
(described in example 137) by utilizing methods analogous to those described in example 374. LCMS
(Method 5-95 AB, ESI): t = 0.702 min, [M + H] = 982.4; H NMR (400 MHz, MeOH-d4) δ 8.24-8.08
(m, 2H), 7.27-7.14 (m, 2H), 6.97-6.69 (m, 6H), 6.45 (s, 1H), 5.33-5.24 (m, 1H), 4.81-4.74 (m, 2H), 4.57-
4.37 (m, 4H), 4.28-4.20 (m, 1H), 3.42-3.35 (m, 2H), 3.29-3.19 (m, 2H), 3.05 (s,3H), 2.99-2.74 (m, 2H),
2.44 (s, 6H), 2.24-2.14 (m, 1H), 2.09-1.97 (m, 3H), 1.89-1.79 (m, 2H), 1.66-1.41 (m, 6H), 1.35 (d,
J=6.8Hz, 3H).
Example 416: Synthesis of Compound 616
18253141_1 (GHMatters) P111789.NZ
NHBoc
OBoc
N N CN
O HN
HN N N N O
Cbz N O
N O O O
O S NH
616-1
Compound 616 (TFA salt) was prepared as a white solid from compound 616-1 (from example
V (compound 106-B1)) and 2-(4-(cyclohexyloxy)phenyl)-4,6-dimethylpyrimidine carboxylic acid
(described in example 137) by utilizing methods analogous to those described in example 374. LCMS
(Method 5-95 AB, ESI): t = 0.831 min, [M + H] = 968.4; H NMR (400 MHz, MeOH-d4) δ 8.10-7.93
(m, 2H), 7.17-6.97 (m, 4H), 6.97-6.81 (m, 3H), 6.72 (br s, 1H), 6.26 (br s, 1H), 5.54-5.50 (m, 1H), 4.83-
4.72 (m, 2H), 4.51-4.34 (m, 3H), 4.29 (s, 2H), 4.02-3.74 (m, 1H), 3.58-3.37 (m, 4H), 3.12 (s, 3H), 2.85-
2.75 (m, 1H), 2.33 (s, 6H), 2.09-2.02 (m, 2H), 1.89-1.85 (m, 2H), 1.67-1.38 (m, 9H).
Example 417: Synthesis of Compound 617
NHBoc
Bn OH
H N O
OH O
N N CN
O HN
HN OMe
N N N O
Cbz O H
N O Cbz N O
617-1
617-2
Compound 617-2 was prepared as a white solid from compound 617-1 (from example V
(compound 106-A2)) by utilizing methods analogous to those described in example 367. LCMS (Method
-95 AB, ESI): t = 0.817 min, [M + Na] = 847.2
Compound 617 (FA salt) was prepared as a white solid from compound 617-2 and (S)
(((benzyloxy)carbonyl)amino)((tert-butoxycarbonyl)amino)butanoic acid by utilizing methods
analogous to those described in example 414 and example 382. LCMS (Method 5-95 AB, ESI): t = 0.617
min, [M + H] = 891.3; H NMR (400MHz, MeOH-d4) δ 8.45 (br s, 1H), 8.21 (d, J=7.6Hz, 2H), 7.48 (d,
J=7.6 Hz, 2H), 7.31-7.15 (m, 2H), 6.93-6.86 (m, 2H), 6.85-6.81 (m, 1H), 6.59 (br s, 1H), 6.48 (s, 1H),
.34-5.26 (m, 1H), 4.85-4.76 (m, 2H), 4.30-4.19 (m, 3H), 4.21 (s, 2H), 3.28-3.08 (m, 4H), 3.00 (s, 3H),
2.97-2.70 (m, 2H), 2.47 (s, 6H), 2.36-2.25 (m, 1H), 2.21-2.11 (m, 1H), 1.39 (s, 9H), 1.34 (d, J=6.8Hz, 3H).
Example 418: Synthesis of Compound 618
18253141_1 (GHMatters) P111789.NZ
BocHN
BocHN
BocHN
Boc 2
O HN
O HN
H H N N N O
N N N O
N N N O
NHBoc
NHBoc
NHBoc
618-3
618-2
618-1
BocHN
HN NH
NH NH
TMSNCO
N N CN
O HN
O HN
H H N N N O
N N N O
NHBoc
618-4
Compound 618-2 was prepared as a white solid from compound 618-1 (from example V
(compound 106-B2)) by utilizing methods analogous to those described in example 371. LCMS (Method
-95 AB, ESI): t = 0.944 min, [M + H] = 1038.9
[001344] Compound 618-3 was prepared as a white solid from compound 618-2 by utilizing methods
analogous to those described in example 389. LCMS (Method 5-95 AB, ESI): t = 0.795 min, [M + H] =
1052.8
A solution of compound 618-3 (70 mg, 0.07 mmol), trimethylsilyl isocyanate (153 mg, 1.3
mmol) in DCM (5 mL) was stirred for 5 h at 25 C. The reaction was added with DCM (30 mL), which was
washed with 0.1 M HCl solution and brine (30 mL each). The organic layer was dried over Na SO ,
concentrated and the residue was purified by prep-TLC, eluting with 10% MeOH in DCM, to give
compound 618-4 (20 mg, 27% yield) as a white solid. LCMS (Method 5-95 AB, ESI): t = 0.989 min, [M
+ H] = 1095.6
Compound 618 (TFA salt) was prepared as a white solid by utilizing methods analogous to
those described in example 382. LCMS (Method 5-95 AB, ESI): t = 0.715 min, [M + H] = 919.8; H
NMR (400 MHz, MeOH-d ) δ 8.21 (d, J=7.6 Hz, 2H), 7.51 (d, J=7.6 Hz, 2H), 7.29 (d, J=7.2 Hz, 1H), 7.22
(d, J=7.2 Hz, 1H), 7.03 (br s, 1H), 6.95 (br s, 1H), 6.61 (br s, 1H), 6.34 (s, 1H), 5.35-5.27 (m, 1H), 4.63-
4.33 (m, 4H), 4.26 (s, 2H), 3.43-3.31 (m, 3H), 3.20-3.08 (m, 2H), 3.03 (s, 3H), 2.99-2.92 (m, 1H), 2.49 (s,
6H), 2.40-2.28 (m, 1H), 2.21-2.10 (m, 1H), 1.40 (s, 9H), 1.37 (d, J=6.8 Hz, 3H).
Example 419: Synthesis of Compound 619
NH O
NHBoc 2
BocHN
BocHN
2 HN NH
H N O
NHBoc O
K CO , DMF
N OMe
N N CN
N OMe
O HN HN
O HN
H H H
N N N H H
O N N
N N N O N (S) O
NHBoc
NHBoc 2
619-1
619-2
Step 1: A solution of compound 619-1 (134 mg, 0.12 mmol), K CO (86 mg, 0.62 mmol) and
tert-butyl (2-bromoethyl)carbamate (139 mg, 0.62 mmol) in DMF (5 mL) was stirred at 50 C for 48 h
while four portions of K CO (86 mg, 0.62 mmol) and tert-butyl (2-bromoethyl) carbamate (139 mg, 0.62
mmol) were added every 12 h. After filtration, the filtrate was partitioned between EtOAc and water (40
18253141_1 (GHMatters) P111789.NZ
mL each). The organic layer was washed with brine (30 mL x 2), dried over Na SO , concentrated and the
residue was purified by prep-TLC, eluting with 5% MeOH in DCM, to afford compound 619-2 (131 mg,
86% yield) as a white solid. LCMS (Method 5-95 AB, ESI): t = 1.214 min, [M + H] = 1225.8
Compound 619 (FA salt) was prepared as a white solid by utilizing methods analogous to those
described in example 418. LCMS (Method 10-80 AB, ESI, 7 min): t = 1.749 min, [M + H] = 962.5; H
NMR (400 MHz, MeOH-d ) δ 8.53 (br s, 1H), 8.05 (s, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.34-7.23 (m, 2H),
7.20-7.08 (m, 1H), 6.91 (s, 1H), 6.76 (br s, 1H), 6.09 (br s, 1H), 5.42-5.27 (m, 1H), 4.87-4.72 (m, 2H),
4.59-4.40 (m, 2H), 4.23 (s, 2H), 3.74 (t, J=5.2 Hz, 2H), 3.49-3.45 (m, 2H), 3.32-3.31 (m, 1H), 3.14 (t,
J=8.4 Hz, 2H), 3.07-3.03 (m, 2H), 3.02 (s, 3H), 2.92-2.77 (m, 1H), 2.38 (s, 6H), 2.30-2.24 (m, 1H), 2.21-
2.07 (m, 1H), 1.38 (s, 9H), 1.35 (d, J=6.8 Hz, 3H).
Example 420: Synthesis of Compound 620
NHBoc
NHBoc
NHBoc
OBoc
O OH
OBoc
N OMe
N OMe
O HN
OMe O HN
HN H
N N N O
N N N O
Cbz N O N O
NHBoc
620-1 NHBoc
620-2
620-3
NHBoc NH
OH OH
Ac O, Py N N
DCM N O OMe N O N CN
O HN O HN
N N N O N N N O
N O N O
O O O O
NHBoc NH
620-4
Compound 620-2 was prepared as a white solid from compound 620-1 (from example V
(compound 106-B1)) by utilizing methods analogous to those described in example 54. LCMS (Method 5-
95 AB, ESI): t = 1.161 min, [M + H] = 1138.1
Compound 620-3 was prepared as a white solid by utilizing methods analogous to those
described in example 418. LCMS (Method 5-95 AB, ESI): t = 0.986 min, [M + Na] = 1074.7
A solution of compound 620-3 (100 mg, 0.10 mmol), Ac O (30 μL, 0.29 mmol) and pyridine
(50 μL, 0.57 mmol) in DCM (2 mL) was stirred for 2 h at 25 C. The mixture was added EtOAc (50 mL),
which washed with brine (50 mL), dried over Na SO and concentrated. The residue was purified by pre-
TLC, eluting with 5% MeOH in DCM, to afford compound 620-4 (108 mg, 97% yield) as a white solid.
LCMS (Method 5-95 AB, ESI): t = 1.059 min, [M + H] = 1094.8
Compound 620 (FA salt) was prepared as a white solid by utilizing methods analogous to those
described in example 382. LCMS (Method 20-80 AB, ESI, 7 min): t = 2.366 min, [M/2 + H] = 459.9; H
NMR (400 MHz, MeOH-d ) δ 8.55 (br s, 1H), 8.21 (d, J=8.0 Hz, 2H), 7.54 (s, 1H), 7.46 (d, J=8.0 Hz, 2H),
7.00-6.90 (m, 2H), 6.66 (s, 1H), 6.48 (s, 1H), 6.31 (s, 1H), 5.34-5.31 (m, 1H), 4.86-4.74 (m, 2H), 4.40-4.28
(m, 4H), 3.42-3.32 (m, 2H), 3.31-3.26 (m, 1H), 3.12 (t, J=7.8 Hz, 2H), 2.98 (s, 3H), 2.95-2.89 (m, 1H),
2.43 (s, 6H), 2.36-2.27 (m, 1H), 2.15 (m, 1H), 2.17-2.11 (s, 3H), 1.39 (s , 9H), 1.36 (d, J=6.8 Hz, 3H).
18253141_1 (GHMatters) P111789.NZ
Example 421: Synthesis of Compound 621
NHBoc
H N N
N OMe
N O N CN
O HN
O HN
N N O
N N O
NHBoc
621-1
Compound 621 (FA salt) was prepared from compound 621-1 (synthesis described in example
418) as a white solid by utilizing methods analogous to those described in example 418. LCMS (Method
20-80 AB, ESI, 7 min): t = 2.372 min, [M + H] = 919.5; H NMR (400 MHz, MeOH-d ) δ 8.70 (br s, 1H),
8.10 (d, J=7.6 Hz, 2H), 7.55-7.40 (m, 3H), 6.99 (d, J=8.4 Hz, 1H), 6.90 (br s, 1H), 6.62 (s, 1H), 6.44 (s,
1H), 6.33 (s, 1H), 5.43-5.32 (m, 1H), 4.87-4.70 (m, 2H), 4.44-4.27 (m, 4H), 3.45-3.34 (m, 2H), 3.21-3.04
(m, 2H), 2.98 (s, 3H), 2.93-2.79 (m, 1H), 2.62-2.51 (m, 1H), 2.41 (s, 6H), 2.36-2.28 (m, 1H), 2.22-2.09 (m,
1H), 1.41 (s, 9H), 1.30 (d, J=6.4 Hz, 3H).
Example 422: Synthesis of Compound 622
NHBoc
H N O
2 H N N
N O N CN
O HN
H H H
N N N O
N N O
N (S)
NHBoc
622-1 2
Compound 622 (FA salt) was prepared from compound 622-1 (synthesis described in example
418) as a white solid by utilizing methods analogous to those described in example 419. LCMS (Method
-80 AB, ESI, 7 min): t = 1.930 min, [M + H] = 962.6; H NMR (400 MHz, MeOH-d ) δ 8.49 (br s, 1H),
8.26 (d, J=8.0 Hz, 2H), 7.68 (s, 1H), 7.50 (d, J=8.0 Hz, 2H), 7.20 (d, J=8.4 Hz, 1H), 7.08 (d, J=8.4 Hz,
1H), 6.85 (s, 1H), 6.64 (s, 1H), 6.47 (s, 1H), 5.43-5.32 (m, 1H), 4.87-4.70 (m, 2H), 4.44-4.27 (m, 2H), 4.22
(s, 2H), 4.00-3.80 (m, 2H), 3.45-3.34 (m, 2H), 3.21-3.04 (m, 2H), 2.98 (s, 3H), 2.62-2.40 (m, 2H), 2.51 (s,
6H), 2.36-2.28 (m, 1H), 2.22-2.09 (m, 1H), 1.38 (s, 9H), 1.36 (d, J=6.8 Hz, 3H).
Example 423: Synthesis of Compound 623
NHBoc NH
NHBoc 2
OH O
CDI, THF
N N CN
N OMe N OMe
O HN
O HN O HN
H H H
N N N O
N N N O N N O
N N O
O N O
O O O O
NHBoc NHBoc 2
623-1
623-2
Step 1: A solution of compound 623-1 (synthesis described in example 418, 110 mg, 0.10
mmol), 1,1’-carbonyldiimidazole (339 mg, 2.1 mmol) in anhydrous THF (6 mL) was stirred at 25 C for 16
h. The mixture was partitioned between EtOAc and water (40 mL each) and the organic layer was washed
with brine (30 mL x 2), dried over Na SO and concentrated. The residue was purified by pre-TLC, eluting
18253141_1 (GHMatters) P111789.NZ
with 5% MeOH in DCM, to obtain compound 623-2 (91 mg, 81% yield) as a white solid. LCMS (Method
-95 AB, ESI): t = 1.047 min, [M + H] = 1078.7
Compound 623 (FA salt) was prepared from compound 623-2 as a white solid by utilizing
methods analogous to those described in example 54. LCMS (Method 10-80 AB, ESI, 7 min): t = 2.188
min, [M + H] = 902.5; H NMR (400 MHz, MeOH-d ) δ 8.52 (br s, 1H), 8.34 (d, J=8.4Hz, 2H), 7.53 (d,
J=8.4Hz, 2H), 7.29-7.19 (m, 1H), 7.14 (d, J=8.4Hz, 1H), 6.96 (s, 1H), 6.81 (br s, 1H), 6.75 (s, 1H), 6.55 (s,
1H), 5.22-5.18 (m, 1H), 4.73-4.56 (m, 2H), 4.51-4.40 (m, 1H), 3.39-4.27 (m, 1H), 4.22 (s, 2H), 3.47-3.38
(m, 2H), 3.38-3.34 (m, 2H), 3.15-3.11 (m, 2H), 3.00 (s, 3H), 2.57 (s, 6H), 2.33-2.22 (m, 2H), 1.41 (s, 9H),
1.37 (d, J=6.0 Hz, 3H).
Example 424: Synthesis of Compound 624
O N O N
I O N
O 2 2
Tf Py
NHBoc BBr DCM 1) O,
1) , 2
O N N
K CO , MeI Zn, Pd 5% TFA/HFIP
2 3 , s-phos MeOH/HCl 2)
2(dba)3 2) HO TfO
Boc NaHCO
DMF O, OMe OMe
DMF 3) 2 3
HO Br Br
MeO BocHN H N
BocHN 2
NHBoc
NHBoc
NHBoc
O BocHN O N
2 AgSO4
Cbz N
Cbz N
N OMe
N OMe Cbz N O
Cbz N
N OMe
624-1
624-2
624-4
624-3
H N H N
BocHN BocHN
SnCl EtOAc
1) 2
Boc Et N
2) 2O, 3
N N CN
O HN
HN H
H N N N O
Cbz N O
624-5
Step 1: 4-bromomethoxynitrobenzene was prepared as a yellow solid from 5-bromo
nitrophenol by utilizing methylation procedure described in example 391.
Step 2: A solution of methyl 2-((tert-butoxycarbonyl)amino)iodopropanoate (4.26 g, 12.9
mmol), zinc (1.69 g, 25.8 mmol) and I (100 mg) in DMF (10mL) was stirred at 20 C under N for 30 min,
followed by the addition of 4-bromomethoxynitrobenzene (2.0 g, 8.6 mmol), sphos (354 mg, 0.86
mmol) and Pd (dba) (395 mg, 0.43 mmol) under N . The mixture was then warmed to 60 C while stirring
2 3 2
and stirred for at 60 C for 3 h. The mixture was taken up in EtOAc (200 mL), which was washed with
brine (150 mL x 2), dried over MgSO and concentrated. The residue was purified by silica-gel column,
eluting with 0-20% EtOAc in petroleum ether, to give (S)-methyl 2-((tert-butoxycarbonyl)amino)(3-
methoxy nitrophenyl)propanoate (2.0 g, 66% yield) as yellow oil.
Step 3: A solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)(3-methoxynitrophenyl)
propanoate (2.0 g, 5.6 mmol) in DCM (10 mL), BBr (3.2 mL, 33.9 mmol) was added at 0 C. The mixture
was warmed to 25 C slowly while stirring and stirred at the same temperature for 16 h. The reaction was
added into MeOH (20mL) slowly and the resulting mixture was concentrated. The residue was re-
dissolved in saturated HCl/MeOH (50 mL) and the mixture was stirred at 25 C for 5 h. The volatiles were
18253141_1 (GHMatters) P111789.NZ
removed and the resulting residue was re-dissolved in THF (15 mL), to which Boc O (1.44 mL, 6.3 mmol)
and 15 mL saturated NaHCO solution were added. The reaction mixture was stirred at 25 C for 16
h. After that, the mixture was diluted with EtOAc (100mL), which was washed with brine (100 mL), dried
over Na SO and concentrated. The residue was purified by silica-gel column, eluting with 0-30% EtOAc
in petroleum ether, to obtain (S)-methyl 2-((tert-butoxycarbonyl)amino) (3-hydroxy
nitrophenyl)propanoate (1.44 g, 74% yield) as a yellow solid. NMR (400 MHz, CDCl ): δ 10.59 (s, 1H),
8.04 (d, J=8.0 Hz, 1H), 6.94 (s, 1H), 6.78 (d, J=8.0 Hz, 1H), 5.07 (d, J=7.6 Hz, 1H, NH), 4.62 (br s, 1H,
phenol-OH), 3.76 (s, 3H), 3.27-3.05 (m, 2H), 1.43 (s, 9H).
Step 4: (S)-methyl 2-amino(4-nitro(((trifluoromethyl)sulfonyl)oxy)phenyl)propanoate was
prepared as a white solid from (S)-methyl 2-((tert-butoxycarbonyl)amino)(3-hydroxy
nitrophenyl)propanoate by utilizing triflate formation procedure (described in example 10) and Boc
removal procedure (described in example 53).
Step 5: To a solution of compound 624-1 (10.0 g, 18.4 mmol) in DCM/MeOH (150 mL,
v/v=1:2) was added Ag SO (4.0 g, 12.9 mmol) and iodine (5.1 g, 20.2 mmol). The mixture was stirred at
25 C for 3 h. The mixture was partitioned betwen EtOAc and saturated NaHCO solution (300 mL each)
and the organic layer was washed by 5% Na2S2O3 and brine (300 mL each), dried over Na SO and
concentrated. The residue was purified by silica-gel column, eluting with 40-60% EtOAc in petroleum
ether, to give compound 624-2 (12.0 g, 97% yield) as a yellow solid. LCMS (Method 5-95 AB, ESI): t =
0.959 min, [M + Na] = 692.1
[001362] Step 6: A solution of compound 624-2 (12.0 g, 18 mmol), Pd(PPh3)2Cl2 (1.26 g, 1.8 mmol),
bis(pinacolato)diboron (22.7 g, 90 mmol), KOAc (12.3 g, 126 mmol) in DMSO (40 mL) was stirred at
60 C for 3 h under N . The mixture was taken up in EtOAc (500 mL), which was washed with brine (500
mL x 3), dried over Na SO , concentrated and the residue was purified by silica-gel column, eluting 40-
60% EtOAc in petroleum ether, to give compound 624-3 (9.0 g, 75% yield) as a white solid.
Step 7: Compound 624-4 was prepared from compound 624-3 and (S)-methylamino(4- nitro
(((trifluoromethyl)sulfonyl)oxy)phenyl)propanoate by utilizing methods analogous to those described in
101B. LCMS (Method 5-95 AB, ESI): t = 0.927 min, [M + Na] = 756.3
Step 8: A solution of compound 624-4 (100 mg, 0.14mmol) and SnCl ·2H O (308 mg, 1.4
mmol) in EtOAc (10 mL) was stirred at 75 C for 2 h. The mixture was added with EtOAc (30 mL), which
was washed with saturated Na CO solution and brine (40 mL each), dried over MgSO and concentrated.
2 3 4
The resulting residue was re-dissolved in DCM (10 mL), to which Boc O (152 μL, 0.66 mmol) and Et N
(147μL, 1.1 mmol) were added. The mixture was stirred at 25 C for 32 h. The volatiles were removed and
the residue was purified by prep-TLC, eluting with 10% MeOH in DCM, to give compound 624-5 (100
mg, 94% yield) as a white solid. LCMS (Method 5-95 AB, ESI): t = 0.994 min, [M + Na] = 826.5
[001364] Compound 624 (FA salt) was prepared from compound 624-5 as a white solid by utilizing
methods analogous to those described in example 54. LCMS (Method 5-95 AB, ESI): t = 0.730 min, [M +
H] = 860.4; H NMR (400 MHz, MeOH-d ) δ 8.55 (br s, 3H), 8.14 (d, J=8.0 Hz, 2H), 7.44 (d, J=8.0 Hz,
18253141_1 (GHMatters) P111789.NZ
2H), 7.30-7.22 (m, 2H), 6.89-6.71 (m, 4H), 6.33 (s, 1H), 5.30 (m, 1H), 4.60-4.50 (m, 2H), 4.39-4.20 (m,
2H), 4.26 (s, 2H), 3.08-2.54 (m, 8H), 3.01 (s, 3H), 2.42 (s, 6H), 2.24-2.11 (m, 2H), 1.38 (s, 9H), 1.35 (d,
J=6.4 Hz, 3H).
Example 425: Synthesis of Compound 625
BocHN MeO OBn
MeO OBn
MeO OBn
BnBr, K Ag SO , I
CO 1) 2 4 2
1) 2 3
MeO OH
% TFA/HFIP OMe
O HN
Br NHBoc
BocHN 2
Cbz N O
Zn, Pd , N O
2) (dba) s-phos
2 3 O
625-1
BocHN MeO OH H N MeO
N OMe N N
O HN
O HN
H H H
N N N O
(S) N N (S) N O
NHBoc 625-2 NH
Step 1: (S)-methyl 3-(2-(benzyloxy)methoxyphenyl)((tert-butoxycarbonyl)amino)
propanoate was prepared as a white solid from 2-bromomethoxyphenol and benzyl bromide by utilizing
methods analogous to those described in example 424. H NMR (400 MHz, CDCl ) δ 7.47-7.31 (m, 5H),
7.02 (d, J=8.4 Hz, 1H), 6.51 (d, J=2.0 Hz, 1H), 6.44 (dd, J=8.4, 2.0 Hz, 1H), 5.12-5.03 (m, 2H), 4.50-4.45
(m, 1H), 3.77(s, 3H), 3.61 (s, 3H), 3.12-2.98 (m, 2H), 1.39 (s, 9H).
Step 2: Compound 625-1 was prepared as a white solid by utilizing methods analogous to those
described in example 424. LCMS (Method 5-95 AB, ESI): t = 0.991 min, [M + Na] = 847.5
Step 3: Compound 625-2 was prepared as a white solid from (S)(((benzyloxy)carbonyl)
amino)((tert-butoxycarbonyl)amino)butanoic acid by utilizing methods analogous to those described in
example 382. LCMS (Method 5-95 AB, ESI): t = 0.896 min, [M + H] = 1068.3
Compound 625 (FA salt) was prepared as a white solid by utilizing methods analogous to those
described in example 382. LCMS (Method 5-95 AB, ESI): t = 0.743 min, [M + Na] = 913.5; H NMR
(400 MHz, MeOH-d ) δ 8.56 (br s, 2H), 8.08 (d, J=7.6 Hz, 2H), 7.43(d, J=7.6 Hz, 2H), 7.18 (br s,
2H), 6.77 (br s, 1H), 6.73 (s, 1H), 6.52 (s, 1H), 6.17 (s, 1H), 5.37-5.35 (m, 1H), 4.79-4.74 (m, 2H), 4.39-
4.25 (m, 2H), 4.31 (s, 2H), 3.83 (s, 3H), 3.27-3.15 (m, 2H), 3.10-2.95 (m, 2H), 3.02 (s, 3H), 2.79-2.71 (m,
2H), 2.38 (s, 6H), 2.28-2.08 (m, 2H), 1.40 (s, 9H), 1.34 (d, J=6.8 Hz, 2H).
Example 426: Synthesis of Compound 626
18253141_1 (GHMatters) P111789.NZ
BocHN MeO OH BocHN MeO OTf
Zn(CN)2
Tf Py Pd
O, (dba) ,dppf
2 2 3
N OMe N OMe
O HN DCM O HN
N N N O N N N O
(S) (S)
N O N O
O O O O
NHBoc NHBoc
626-2
626-1
BocHN MeO CN
O BocHN BocO CN
BBr , DCM
1) 3
HCl, MeOH
Et N
Boc O,
3) 2 3
N OMe
NaBH , NiCl , Boc O
O HN 2 2
H O HN
N N N O
(S) H
N O N N N O
NHBoc
NHBoc
626-3
626-4
BocHN BocO H N HO
NHBoc O
N OMe N N CN
O HN O HN
N N N N N N O
(S) O (S)
N O N O
O O O O
NHBoc NH
626-5
Step 1: Compound 626-2 was prepared as a white solid from compound 626-1 (synthesis
described in example 425) by utilizing triflate formation procedure described in example 10). LCMS
(Method 5-95 AB, ESI): t = 1.054 min, [M + H] = 1199.6
[001370] Step 2: A solution of compound 626-2 (240 mg, 0.20 mmol), Zn(CN) (48 mg, 0.40
mmol), dppf (44 mg, 0.08 mmol) and Pd (dba) (17 mg, 0.04 mmol) in DMF (8 mL) was stirred at 100 C
in 16 h under N . The mixture was added with EtOAc (80 mL), which was washed with brine (50 mL x 2),
dried over Na SO and concentrated. The residue was purified by prep-TLC, eluting with 10% MeOH in
DCM, to give compound 626-3 (160 mg, 74% yield) as a white solid. LCMS (Method 5-95 AB, ESI): t =
1.148 min, [M + H] = 1077.0
Step 3: Compound 626-4 was prepared as a white solid from compound 626-3 by utilizing the
methods described in example 424 except Boc addition procedure where Boc O, Et N were used
(described in example 395). LCMS (Method 5-95 AB, ESI): t = 1.174 min, [M + Na] = 1184.3
Step 4: To a solution of compound 626-4 (50 mg, 0.04 mmol), Boc O (57 mg, 0.26 mmol) and
NiCl ·6H O (15 mg, 0.06 mmol) in MeOH (4 mL) was added NaBH (11 mg, 0.30 mmol) slowly at 0 C.
2 2 4
The reaction was gradually warmed to 25 C while stirring and stirred at the same temperature
overnight. The mixture was added with EtOAc (40 mL), which was washed with brine (40 mL), dried over
Na SO and concentrated. The residue was purified by prep-TLC, eluting with 10% MeOH in DCM, to
give compound 626-5 (30 mg, 55% yield) as a white solid. LCMS (Method 5-95 AB, ESI): t = 1.133 min,
= 1288.3
[M + Na]
Compound 626 (FA salt) was prepared from compound 626-5 as a white solid by utilizing
methods analogous to those described in example 54. LCMS (Method 5-95 AB, ESI): t = 0.760 min, [M +
H] = 891.0; H NMR (400 MHz, MeOH-d ) δ 8.49 (br s, 2H), 8.32 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.4 Hz,
18253141_1 (GHMatters) P111789.NZ
1H), 7.30 (d, J=8.4 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.01 (s, 1H), 6.92 (s, 1H), 6.81 (s, 1H), 6.45 (s, 1H),
.24-5.21 (m, 2H), 4.85-4.80 (m, 1H), 4.40-4.32 (m, 2H), 4.22 (s, 2H), 4.10-4.04 (m, 2H), 3.35-3.11 (m,
6H), 2.98 (s, 3H), 2.55 (s, 6H), 2.29-2.13 (m, 2H), 1.38 (s, 9H), 1.35 (d, J=6.8 Hz, 3H).
Example 427: Synthesis of Compound 627
NHBoc
BocHN MeO O
H N MeO O
BocHN MeO OBn
N CN
N N CN
O HN 5% TFA/HFIP
O HN
OMe H H
N N N O
N N N O
HN N (S)
Cbz N O
N O O O
O S NHBoc
O S NH
627-1
627-2 O
Compound 627-2 was prepared from compound 627-1 (described in example 425) and tert-
butyl (2-bromoethyl)carbamate, by utilizing methods analogous to those described in example 382. LCMS
(Method 5-95 AB, ESI): t = 1.011 min, [M + H] = 1299.6
Compound 631 (FA salt) was prepared from compound 627-2 as a white solid by utilizing Boc
removal condition described in example 53. LCMS (Method 5-95 AB, ESI): t = 0.785 min, [M + H] =
999.6; H NMR (400 MHz, MeOH-d ) δ 8.53 (br s, 3H), 8.19 (d, J=7.6 Hz, 2H), 7.47 (d, J=7.6 Hz, 2H),
7.24-7.16 (m, 3H), 6.77 (s, 1H), 6.72 (s, 1H), 6.62 (br s, 1H), 6.52 (s, 1H), 5.42-5.40 (m, 1H), 4.78-4.62 (m,
2H), 4.27-4.22 (m, 6H), 3.88 (s, 3H), 3.58-3.53 (m, 2H), 3.40-3.38 (m, 1H), 3.05 (s, 3H), 2.99-2.96 (m,
2H), 2.90-2.75 (m, 3H), 2.49 (s, 6H), 1.38 (s, 9H), 1.37 (d, J=6.4 Hz, 3H).
Example 428: Synthesis of Compound 628
NHBoc
BocHN MeO O
O H N HO O
BBr /DCM
N N 3
O HN
N N CN
H H O HN
N N N O
(S) H H
N O N N N O
NHBoc
O S NH
628-1
To a solution of compound 628-1 (synthesis described in example 427, 50 mg, 0.04 mmol) in
DCM (4 mL) was added BBr (36 μL, 0.38 mmol) at 0 C. The reaction was gradually warmed to 25 C
while stirring and stirred at the same temperature for 16 h. The reaction was quenched by water and the
resulting mixture was lyophilized immediately. The residue was purified by Prep-HPLC (acetonitrile 23-
33/0.225%FA in water) to afford compound 628 (FA salt) as a white solid (2.3 mg, 5.9% yield). LCMS
(Method 5-95 AB, ESI): t = 0.793 min, [M + Na] = 1007.8; H NMR (400 MHz, MeOH-d ) δ 8.53 (br s,
3H), 8.22 (d, J=7.6 Hz, 2H), 7.48 (d, J=7.6 Hz, 2H), 7.21 (d, J=8.0 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 6.82
(s, 1H), 6.63 (br s, 1H), 6.53 (s, 1H), 6.50 (br s, 1H), 5.39-5.35 (m, 2H), 4.81-4.77 (m, 1H), 4.65-4.15 (m,
6H), 4.21 (s, 2H), 3.58-3.53 (m, 2H), 3.39-3.33 (m, 4H), 3.10 (s, 3H), 3.05-2.98 (m, 2H), 2.50 (s, 6H), 1.36
(s, 9H), 1.35 (d, J=6.4 Hz, 3H).
Example 429: Synthesis of Compound 629
18253141_1 (GHMatters) P111789.NZ
NHBoc
NHBoc
BocHN BF K
Ag I
SO ,
2 4 2
S-Phos, K PO
OMe Pd , toluene
OMe (dba)
Cbz N O
Cbz N O
629-1
629-2
NHBoc
N N CN
BocHN
O HN
N N N O
Cbz N O
O S NH
629-3
Step 1: Compound 629-2 was prepared from compound 629-1 (synthesis described in example
371), by utilizing iodination condition described in example 382. LCMS (Method 5-95 AB, ESI): t =
0.925 min, [M + Na] = 853.1
[001378] Step 2: A solution of compound 629-2 (200 mg, 0.24 mmol), Pd dba (11 mg, 0.01 mmol),
SPhos (10 mg, 0.02 mmol), potassium tert-butyl N-(difluoroboranylmethyl)carbamate fluoride (63 mg,
0.26 mmol) and K PO (153 mg, 0.72 mmol) in toluene (2 mL) and H O (0.10 mL) at 85 C for 16 h under
3 4 2
N . The volatiles were removed and the residue was added with EtOAc (30 mL). After filtration, the
filtrate was washed with brine (35 mL x 3), dried over Na SO , concentrated and the residue was purified
by prep-TLC, eluting with 10% MeOH in DCM, to give compound 629-3 (110 mg, 55% yield) as a
yellow solid. LCMS (Method 5-95 AB, ESI): t = 0.926 min, [M + Na] = 856.1
Compound 629 (FA salt) was prepared as a white solid by utilizing methods analogous to those
described in example 382. LCMS (Method 5-95 AB, ESI): t = 0.785 min, [M + H] = 955.5; H NMR
(400 MHz, MeOH-d ) δ 8.44 (brs, 1H), 8.32 (d, J=8.0 Hz, 1H), 7.53 (d, J=8.4 Hz, 2H), 7.23 (d, J=8.0 Hz,
1H), 7.15 (s, 1H), 7.07 (d, J=8.0 Hz, 1H), 6.93 (brs, 1H), 6.86 (s, 1H), 6.79 (s, 1H), 6.48 (s, 1H), 5.30-5.27
(m, 1H), 4.90-4.81 (m, 2H), 4.35 (s, 2H), 4.21 (s, 2H), 4.10-4.00 (m, 2H), 3.60-3.55 (m, 2H), 3.25-3.10 (m,
4H), 3.06 (s, 3H), 2.59 (s, 6H), 1.38 (s, 9H), 1.36 (d, J=6.0 Hz, 3H).
Examples 430-437: Synthesis of compounds 630-637
[001380] The following compounds in table 4 were prepared by utilizing methods analogous to those
previously described.
18253141_1 (GHMatters) P111789.NZ
Table 4
Comp. # Structure
Chiral
O HN
N N N
H N HO
Chiral
O HN
N N N O
Chiral
O HN
N N N O
H N HO
Chiral
O HN
N N N O
H N O
O HN
N N N O
O HN
N N N O
18253141_1 (GHMatters) P111789.NZ
Comp. # Structure
O HN
N N N O
O S NH
Example 438-449: Synthesis of compounds 638-649
The following compounds in table 5 were prepared by utilizing methods analogous to those
previously described.
Table 5
Comp. # Structure
N OH
O HN
N N N O
N OH
N N N O
N OH
O HN
N N N O
H N O
O HN
N N N
18253141_1 (GHMatters) P111789.NZ
Comp. # Structure
N OH
O HN
N N N O
N OH
N N N O
N OH
N N O
O HN
N N N O
O HN
N N N O
648 H
O HN
N N N O
18253141_1 (GHMatters) P111789.NZ
Comp. # Structure
O HN
N N N O
Biological Assays
Example B1: Determination of Minimum Inhibitory Concentration
In vitro antimicrobial activity of each compound was determined by measuring minimal
inhibitor concentrations (MICs) using the broth micro-dilution technique as approved by the Clinical and
Laboratory Standards Institute (CLSI) (Methods for Dilution Antimicrobial Susceptibility Tests for
Bacteria that Grow Aerobically; Approved Standard - Eighth Edition. CLSI document M07-A8. Wayne,
PA: Clinical and Laboratroy Standards; 2009). Antibacterial activity was measure against two strains of
bacteria: a Methicillin Resistant Staphylococcus aureus strain USA 200, (S. aureus) and Escherichia coli
ATCC 25922 (E. coli), a clinically relevant Gram-negative strain. Cells were inoculated onto plates of
Trypyticase Soy Agar or Luria Agar respectively and grown at 35°C for 20 hours. Inocula suspensions
were prepared by scraping cells into 1 mL of testing media (cation adjusted Mueller Hinton Broth
supplemented with 0.002% v/v Tween-80) and diluting to a final OD of 0.01.
600nm
Test compounds were prepared in DMSO at a concentration of 10 mg/mL. The compounds were
tested under several different dilution formats and the data are reported in Tables 6, 7 and 8. In protocol 1,
the compound stocks were diluted into testing media at a concentration of 64 μg/ml and serial 2-fold
dilutions were made in the same media, in 96-well U bottom microtiter dishes, for a total of 10 compound
concentrations. In protocol 2, the compound stocks were diluted into testing media at a concentration of 4
μg/mL and serial 2-fold dilutions were made in the same media, in 96-well U bottom microtiter dishes, for
a total of 10 compound concentrations. In protocol 3, compound stocks were diluted into testing media at a
concentration of 0.5 μg/mL, with serial 2-fold dilutions conducted as described above. In protocol 4,
compound stocks were diluted into testing media at a concentration of 0.13 μg/mL, with serial 2-fold
dilutions conducted as described above. Inocula suspensions were added to the 2-fold serial dilutions of
test compounds to a final density of OD OD of 0.0005 and incubated at 35°C for 22 hours. After
600nm
incubation the plates were examined visually and the lowest concentration of test compound that
completely prevented bacterial growth were recorded as the MICs. The results are listed in Table 6, 7, and
18253141_1 (GHMatters) P111789.NZ
Table 6
Comp. # MIC S. MIC E. Comp. # MIC S. MIC E.
aureus µM coli µM aureus µM coli µM
201 0.062 0.42 381 0.067 4.3
202 0.023 0.37 382 0.4 4.3
203 0.031 0.13 383 0.1 1.1
204 0.032 2.1 384 0.033 0.4
205 0.012 0.066 385 0.017 0.27
206 0.025 0.13 386 0.75 8
207 0.017 0.1 387 0.25 8
208 0.017 0.14 388 0.031 1
209 0.26 2.1 389 0.13 4
210 0.022 0.35 390 0.094 8
211 0.026 0.17 391 0.031 0.25
212 0.017 0.067 392 0.063 3
213 0.28 1.1 393 0.021 8.2
214 0.034 0.41 394 0.0083 0.2
215 0.017 0.13 395 0.013 0.27
216 0.0084 0.2 396 0.016 0.5
217 0.0082 0.099 397 0.023 0.38
218 0.012 0.097 398 0.025 0.27
219 0.012 0.13 399 0.0078 0.5
220 0.0062 0.099 400 0.047 0.25
221 0.024 1 401 0.016 0.25
222 0.033 0.53 402 0.031 0.38
223 0.016 0.26 403 0.016 0.5
224 0.017 0.13 404 0.094 0.38
225 0.016 0.19 405 0.063 0.38
226 0.0082 0.099 406 0.023 0.25
227 0.017 0.077 407 0.016 0.13
228 0.57 2.3 408 0.023 0.38
229 0.57 4.6 409 0.13 0.75
230 0.012 0.066 410 0.016 0.3
231 0.35 1.4 411 0.016 0.25
232 0.015 0.16 412 0.023 0.5
233 0.016 0.13 413 0.016 0.13
234 0.0082 0.066 414 0.016 0.25
235 0.016 0.26 415 0.063 1.5
236 0.016 0.13 416 0.094 3
237 0.0083 0.27 417 0.0062 0.13
238 0.53 2.1 418 0.008 0.064
239 0.015 0.12 419 0.063 8
240 0.012 0.13 420 0.75 3
241 0.0081 0.097 421 0.031 0.19
242 0.016 0.39 422 0.031 0.38
243 0.008 0.13 423 0.13 2
244 0.012 0.13 424 0.023 0.19
245 0.0081 0.097 425 0.016 0.19
246 0.067 0.4 426 0.023 0.12
247 0.016 0.19 427 NT 0.094
248 0.016 0.13 428 NT 0.5
249 0.043 0.35 429 0.023 1
250 0.066 0.35 430 0.15 4.7
18253141_1 (GHMatters) P111789.NZ
Comp. # MIC S. MIC E. Comp. # MIC S. MIC E.
aureus µM coli µM aureus µM coli µM
251 0.067 1.1 431 0.18 3.9
252 0.0081 0.097 432 0.045 1.4
253 0.012 0.14 433 0.016 0.096
254 0.061 0.24 434 0.023 0.21
255 0.0082 0.066 435 0.012 0.094
256 0.0078 0.1 436 NT 0.063
257 0.016 0.13 437 0.031 0.38
258 0.012 0.13 438 0.012 0.16
259 0.025 0.26 439 0.016 0.076
260 0.079 0.45 440 NT 1
261 0.014 0.1 441 NT 0.38
262 0.0081 0.097 442 0.042 0.91
263 0.016 0.53 443 0.27 4.2
264 0.52 1.6 444 0.064 4.1
265 0.068 0.41 445 0.13 4.1
266 0.033 0.2 446 0.032 4.1
267 0.39 1 447 0.033 4.2
268 0.016 0.12 448 0.13 4.1
269 0.016 0.094 449 0.016 0.5
270 0.012 0.064 450 0.016 2.1
271 0.032 0.26 451 0.047 0.76
272 0.012 0.065 452 0.13 1.3
273 0.0082 0.099 453 0.026 1.1
274 0.023 0.063 454 0.55 4.4
275 0.012 0.094 455 NT NT
276 0.016 0.063 456 0.56 3.3
277 0.016 0.13 457 0.025 0.27
278 0.0078 0.094 458 0.033 1.1
279 0.023 0.13 459 0.083 0.71
280 0.031 0.13 460 0.13 4.1
281 0.016 0.065 461 0.051 1.1
282 0.016 0.094 462 0.027 5.4
283 0.012 0.094 463 NT NT
284 0.016 0.13 464 0.063 4
285 0.047 0.19 465 0.047 4
286 0.016 0.13 466 0.047 1.5
287 0.065 1 467 0.19 8
288 0.023 1.5 468 0.063 1
289 0.016 0.75 469 0.13 6
290 0.19 0.75 470 0.047 4
291 0.094 0.25 471 0.04 5.1
292 0.13 0.75 472 0.0085 0.11
293 0.13 1.5 473 0.31 4.9
294 0.031 0.19 474 0.11 4.8
295 0.0078 0.063 475 0.6 4.8
296 0.016 0.38 476 0.025 1.1
297 0.016 0.75 477 0.26 3.2
298 0.016 0.13 478 0.071 1.1
299 0.047 0.38 479 0.027 0.77
300 0.031 0.25 480 0.061 1.6
301 0.016 0.094 481 0.037 2.3
302 NT 0.5 482 0.036 0.24
18253141_1 (GHMatters) P111789.NZ
Comp. # MIC S. MIC E. Comp. # MIC S. MIC E.
aureus µM coli µM aureus µM coli µM
303 NT 0.13 483 0.036 0.29
304 NT 0.13 484 NT NT
305 NT 0.13 485 0.023 0.5
306 0.84 14 486 0.023 0.38
307 0.033 0.2 487 0.016 0.38
308 0.012 0.096 488 NT 0.5
309 0.27 1.1 489 0.016 0.38
310 0.066 0.53 490 0.023 1
311 1 8.2 491 0.049 3.1
312 0.024 0.063 492 0.016 2
313 0.016 0.13 493 0.047 1
314 0.033 0.2 494 0.068 1.1
315 0.016 0.25 495 0.031 1
316 0.38 1.5 496 0.094 1
317 0.047 0.5 497 0.047 0.75
318 0.016 0.38 498 0.063 1
319 1 8 499 0.063 1.5
320 0.016 0.19 500 0.031 0.48
321 0.047 0.38 501 0.063 1
322 0.15 0.6 502 0.078 0.24
323 0.38 1 503 0.047 1
324 0.047 0.13 504 0.063 0.75
325 0.016 0.13 505 0.094 1.5
326 0.031 0.13 506 0.094 0.83
327 NT 0.13 507 0.063 0.38
328 0.0093 0.07 508 1 6
329 0.011 0.11 509 0.047 0.5
330 0.033 0.26 510 0.023 1.5
331 0.0081 0.13 511 NT 2
332 0.0078 0.063 512 NT 1
333 1 2 513 0.0061 0.097
334 0.5 4 514 0.031 0.19
335 0.032 0.19 516 0.19 2
336 0.016 0.15 517 0.19 0.75
337 0.012 0.11 518 0.028 0.16
338 0.012 0.13 519 NT 0.13
339 0.047 0.25 520 NT 1
340 0.023 0.063 521 0.047 0.2
341 0.016 0.13 522 NT 0.13
342 0.097 0.39 523 0.044 0.28
343 0.13 0.75 524 0.56 4.5
344 0.063 0.38 525 0.053 0.56
345 0.023 0.25 526 0.047 0.33
346 0.016 0.13 527 NT 0.38
347 0.047 0.25 528 NT 0.063
348 0.023 0.19 529 NT 4
349 0.023 0.094 530 0.063 0.35
350 0.016 0.094 531 0.047 0.25
351 NT 0.25 532 NT 0.063
352 0.023 0.094 533 NT 1.5
353 0.047 2 534 NT 0.5
354 0.016 1.5 535 0.029 0.23
18253141_1 (GHMatters) P111789.NZ
Comp. # MIC S. MIC E. Comp. # MIC S. MIC E.
aureus µM coli µM aureus µM coli µM
355 0.094 4 536 0.016 0.13
356 NT 0.13 537 NT 0.25
357 NT 0.19 538 NT 0.063
358 0.033 0.2 539 0.023 0.15
359 0.008 0.064 540 NT 1.5
360 0.066 0.26 541 NT 0.75
361 0.016 0.13 542 0.55 4.4
362 0.063 0.25 543 0.063 0.35
363 0.016 0.19 544 NT 0.13
364 0.016 0.25 545 NT 1
365 0.063 0.31 546 NT 0.38
366 0.016 0.13 547 NT 0.094
367 NT 0.5 548 0.047 0.46
368 0.047 0.5 549 0.035 0.21
369 0.047 0.75 550 NT 2
370 0.031 0.19 551 NT 1
371 0.031 0.19 552 0.25 1.4
372 0.023 0.38 553 0.055 0.21
373 NT 0.13 554 NT 0.094
374 0.016 0.25 555 NT 0.19
375 0.031 0.5 556 NT 0.19
376 0.016 0.25 557 NT 0.25
377 0.031 0.5 558 0.046 0.73
378 0.031 0.38
379 0.26 1
380 0.045 0.48
Table 7
Cp# MIC S. MIC E. Cp# MIC S. MIC E.
aureus µM coli µM aureus µM coli µM
559 NT 0.38 597 NT 0.26
560 NT 0.25 598 NT 0.094
561 NT 0.75 599 NT 0.58
562 NT 0.094 600 NT 0.38
563 NT 0.25 601 NT 0.50
564 NT 0.063 602 NT 0.063
565 NT 0.13 603 NT 0.44
566 NT 0.094 604 NT 0.75
567 NT 0.094 605 NT 0.75
568 NT 0.063 606 NT 0.50
569 NT 0.50 607 NT 0.50
570 NT 0.063 608 NT 0.38
571 NT 0.094 609 NT 0.50
572 NT 0.28 610 NT 0.19
573 NT 0.50 611 NT 0.19
574 NT 0.50 612 NT 0.25
575 NT 0.31 613 NT 0.75
576 NT 0.50 614 NT 0.19
577 NT 0.21 615 NT 1.0
578 NT 0.19 616 NT 0.50
579 NT 0.75 617 NT 0.19
18253141_1 (GHMatters) P111789.NZ
580 NT 0.58 618 NT 0.19
581 NT 0.25 619 NT 0.13
582 NT 0.75 620 NT 0.50
583 NT 0.17 621 NT 0.25
584 NT 0.50 622 NT 0.50
585 NT 0.38 623 NT 0.50
586 NT 0.19 624 NT 0.38
587 NT 0.094 625 NT 0.38
588 NT 0.094 626 NT 0.25
589 NT 1.0 627 NT 0.50
590 NT 0.38 628 NT 0.44
591 NT 0.25 630 NT 0.25
592 NT 0.19 631 NT 0.19
593 NT 1.5 632 NT 0.50
594 NT 0.13 633 NT 0.047
595 NT 0.33 634 NT 0.25
596 NT 0.50
Table 8
Comp. # MIC S. MIC E.
aureus µM coli µM
638 0.19 0.22
639 0.75 0.38
640 NT 0.25
641 0.047 0.094
642 0.21 0.23
643 1.1 2.3
644 1.2 0.58
645 0.52 0.4
646 1.1 0.37
647 0.19 0.25
648 0.28 0.1
NT = not tested
Example B2: Whole-cell SpsB Biochemical Screening Assay
A kinetic fluorogenic enzyme activity assay is used to assess inhibition of SpsB (Staphylococcus
aureus signal peptidase) activity and IC s are determined. This assay uses a suspension of Staphylococcus
aureus cells as a source of SpsB instead of recombinant SpsB protein.
Cell preparation: Luria broth (LB) is inoculated with S. aureus (USA300 background,
overexpressing SpsB) and shaken at 37°C until an OD of 1.5-2.0 is reached (~4 hr). The culture is
600nm
then diluted to an OD of 1.0 with LB, aliquoted and centrifuged at 10,000x g for 2 mins. The
600nm
supernatant is removed and the pellet is resuspended in phosphate buffer (1x PBS, 12.5 mg/L MgCl , 25
mg/L CaCl , 0.1% Tween-80) to an OD of 0.5, then centrifuged again at 10,000x g for 2 mins. The
2 600nm
supernatant is removed and the pellets are frozen at -20 C.
[001386] Test compounds are prepared in DMSO at a concentration of 10 mg/mL. These compound
stocks are diluted into DMSO to a concentration of 25 μg/mL and serial 3-fold dilutions are made in
18253141_1 (GHMatters) P111789.NZ
DMSO, for a total of 11 compound concentrations. 20 nL of each compound solution is pre-spotted into a
white 384-well plate (50 µL/well polypropylene, Nunc) using acoustic fluid transfer (Echo).
Frozen S. aureus pellets are resuspended in assay buffer (1x PBS, 12.5 mg/L MgCl2, 25 mg/L
CaCl2, 0.1% Tween-80) to an OD600nm of 0.05, then mixed 1:1 (v/v) with 20 µM substrate
((Dabcyl)βAla-KPAKAAE(Edans)) in assay buffer, and this solution is added (20 μL/well) to the 384-well
plate that has been pre-spotted with compound. Fluorescence intensity is then immediately read kinetically
for 30 minutes with 2 minute read intervals to monitor cleavage of the internally quenched peptide
substrate (excitation wavelength = 340 nm, emission wavelength = 490nm, Molecular Devices Spectramax
M5). Reaction rate (slope) is plotted against inhibitor concentration to derive the IC .
Example B3: Activity in a neutropenic thigh infection model
The ability of a compound to inhibit an infection of a bacterial pathogen can be measured using
a murine neutropenic thigh infection model. The reduction of bacterial burden is a measure of antibacterial
activity in vivo.
Jugular vein cannulated CD-1 mice are subjected to induced neutropenia (<100 cells/mm ) by
injecting 150 mg/kg and 100 mg/kg cyclophosphamide at day -5 and day -2 respectively. At day -1, saline
is infused at 20 µL/hour for 12 hours using Harvard Apparatus PHD 2000 Infusion pumps. At day 0, mice
are infected in the thigh muscle with with 1X10 CFU/ 50 µL of Escherichia coli strain ATCC 25922.
There are four test groups and one vehicle group that begin dosing at 1 hour post infection:
Group 1 - vehicle control (3% HP-beta-cyclodextrin in PBS)
Group 2 - Compound disclosed herein group dosed at a concentration of 0.62 mg/mL solution,
infused at 80µL/hour for 23 hours, with a target steady-state concentration (Css) of 13 µg/mL.
Group 3 - Compound disclosed herein group dosed at a concentration of 0.21 mg/mL solution,
infused at 80µL/hour for 23 hours to achieve a steady state concentration (Css) of 3.4 µg/mL.
Group 4 - Compound disclosed herein group dosed at 0.07 mg/mL solution (Css 1.2 ug/mL)
infused at 80µL/hour for 23 hours.
Group 5 - Compound disclosed herein group dosed at 0.02 mg/mL solution (Css 0.31 ug/mL)
infused at 80µL/hour for 23 hours.
At 24 hours post infection, bacterial burden in the thigh muscle is determined by plating the
tissue homogenate in serial dilutions on blood agar plates.
Example B4: Clinical Trial of the Safety and Efficacy of Compounds of Formula (I), (Ia)-(If), (II),
(IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc) in Patients with C. Difficile-
Associated Diarrhea
Purpose: This study aims to determine the safety and efficacy of compounds presented herein
for the treatment of symptoms of C. difficile-associated diarrhea and lowering the risk of repeat episodes
of diarrhea. The compounds are evaluated in comparison to current standard antibiotic treatment, so all
patients will receive active medication. All study-related care is provided including doctor visits, physical
exams, laboratory tests and study medication. Total length of participation is approximately 10 weeks.
18253141_1 (GHMatters) P111789.NZ
Patients: Eligible subjects will be men and women 18 years and older.
Criteria:
Inclusion Criteria:
Be at least 18 years old;
Have active mild to moderate C. difficile- Associated Diarrhea (CDAD);
Be able to tolerate oral medication;
Not be pregnant or breast-feeding; and
Sign and date an informed consent form.
Study Design: This is a randomized, double-blind, active control study of the efficacy, safety,
and tolerability of a compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-
(IVc), (V), or (Va)-(Vc) in patients with C. difficile-associated diarrhea.
Example B5: Clinical Trial Comparing a Compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III),
(IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc) with Vancomycin for the Treatment of MRSA
Osteomyleitis
[001395] Purpose: This study aims to determine the efficacy of compounds presented herein as compared
to vancomycin for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis.
Patients: Eligible subjects will be men and women 18 years and older.
Criteria:
Inclusion Criteria:
Culture-proven MRSA, obtained in operating room or sterile biopsy procedure from bone site. The
infection and sampling site is either within the bone or a deep soft-tissue site that is contiguous with bone;
OR radiographic abnormality consistent with osteomyelitis in conjunction with a positive blood culture for
MRSA;
Surgical debridement of infection site, as needed;
Subject is capable of providing written informed consent; and
Subject capable of receiving outpatient parenteral therapy for 12 weeks.
Exclusion Criteria:
Hypersensitivity to a compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-
(IVc), (V), or (Va)-(Vc) or vancomycin;
S. aureus resistant to a compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-
(IVc), (V), or (Va)-(Vc) or vancomycin;
Osteomyelitis that develops directly from a chronic, open wound;
Polymicrobial culture (the only exception is if coagulase-negative staphylococcus is present in the culture
and the clinical assessment is that it is a contaminant);
Subject has a positive pregnancy test at study enrollment;
Baseline renal or hepatic insufficiency that would preclude administration of study drugs;
Active injection drug use without safe conditions to administer intravenous antibiotics for 3 months; and
18253141_1 (GHMatters) P111789.NZ
Anticipated use of antibiotics for greater than 14 days for an infection other than osteomyelitis.
Study Design: This is a randomized, open-label, active control, efficacy trial comparing
vancomycin with a compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc),
(V), or (Va)-(Vc) for the treatment of MRSA Osteomyelitis.
Example B5: Clinical Trial Evaluating a Compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III),
(IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc) in Selected Serious Infections Caused by
Vancomycin-Resistant Enterococcus (VRE)
Purpose: This study aims to determine the safety and efficacy of a compound of Formula (I),
(Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc) in the treatment of selected
serious infections caused by VRE.
Patients: Eligible subjects will be men and women 18 years and older.
Criteria:
Inclusion Criteria:
Isolation of one of the following multi-antibiotic resistant bacteria: vancomycin-resistant Enterococcus
faecium, vancomycin-resistant Enterococcus faecalis alone or as part of a polymicrobial infection; and
Have a confirmed diagnosis of a serious infection (eg, bacteremia [unless due to an excluded infection],
complicated intra-abdominal infection, complicated skin and skin structure infection, or pneumonia)
requiring administration of intravenous (IV) antibiotic therapy.
Exclusion Criteria:
Subjects with any concomitant condition or taking any concomitant medication that, in the opinion of the
investigator, could preclude an evaluation of a response or make it unlikely that the contemplated course of
therapy or follow-up assessment will be completed or that will substantially increase the risk associated
with the subject’s participation in this study.
Anticipated length of antibiotic therapy less than 7 days.
[001403] Study Design: This is a randomized, double-blind, safety and efficacy study of a compound of
Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc) in the
treatment of selected serious infections caused by VRE.
Pharmaceutical Compositions
Example C1: Parenteral Composition
[001404] To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100
mg of a compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or
(Va)-(Vc) is dissolved in DMSO and then mixed with 10 mL of 0.9% sterile saline. The mixture is
incorporated into a dosage unit form suitable for administration by injection.
In another embodiment, the following ingredients are mixed to form an injectable formulation:
Ingredient Amount
Compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), 1.2 g
(IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc)
18253141_1 (GHMatters) P111789.NZ
sodium acetate buffer solution (0.4 M) 2.0 mL
HCl (1 N) or NaOH (1 M) q.s. to suitable pH
water (distilled, sterile) q.s.to 20 mL
All of the above ingredients, except water, are combined and stirred and if necessary, with slight
heating if necessary. A sufficient quantity of water is then added.
Example C2: Oral Composition
To prepare a pharmaceutical composition for oral delivery, 100 mg of a compound of Formula
(I), (Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc) is mixed with 750 mg
of starch. The mixture is incorporated into an oral dosage unit, such as a hard gelatin capsule, which is
suitable for oral administration.
In another embodiment, the following ingredients are mixed intimately and pressed into single
scored tablets.
Ingredient Quantity per tablet, mg
compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), 200
(IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc)
Cornstarch 50
croscarmellose sodium 25
Lactose 120
magnesium stearate 5
In yet another embodiment, the following ingredients are mixed intimately and loaded into a
hard-shell gelatin capsule.
Ingredient Quantity per tablet, mg
compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), (III), 200
(IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc)
lactose, spray-dried 148
magnesium stearate 2
In yet another embodiment, the following ingredients are mixed to form a solution/suspension
for oral administration:
Ingredient Amount
Compound of Formula (I), (Ia)-(If), (II), (IIa)-(IIe), 1 g
(III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc) 0.1 g
Anhydrous Sodium Carbonate
Ethanol (200 proof), USP 10 mL
Purified Water, USP 90 mL
18253141_1 (GHMatters) P111789.NZ
Aspartame 0.003g
Example C3: Topical Gel Composition
To prepare a pharmaceutical topical gel composition, 100 mg of a compound of Formula (I),
(Ia)-(If), (II), (IIa)-(IIe), (III), (IIIa)-(IIIc), (IV), (IVa)-(IVc), (V), or (Va)-(Vc) is mixed with 1.75 g of
hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of purified
alcohol USP. The resulting gel mixture is then incorporated into containers, such as tubes, which are
suitable for topical administration.
While preferred embodiments of the present disclosure have been shown and described herein, it
will be obvious to those skilled in the art that such embodiments are provided by way of example only.
Numerous variations, changes, and substitutions will now occur to those skilled in the art without
departing from the invention. It should be understood that various alternatives to the embodiments
described herein may be employed in practicing the invention. It is intended that the following claims
define the scope of the invention and that methods and structures within the scope of these claims and their
equivalents be covered thereby.
18253141_1 (GHMatters) P111789.NZ
Claims (125)
1. A compound of Formula (I): (R ) (R ) 18 16 R R N O CN Z X N 17 9 R 11 12 Formula (I); wherein: 1 2 23 R and R are each independently H, -(C -C )alkyl, -(C -C )alkyl-OR , -CH CH(OH)CH NH , - 1 6 1 6 2 2 2 CH CH(heterocycloalkyl)CH NH , -CH C(O)NH , -CH C(O)N(H)CH CN, -(C -C )alkyl-C(O)OR , - 2 2 2 2 2 2 2 1 6 21 22 25 26 23 21 22 10 (C -C )alkyl-NR R , -(C -C )alkyl-C(O)NR R , -(C -C )alkyl-N(R )C(O)(C -C )alkylNR R , - 1 6 1 6 1 6 1 6 23 23 (C -C )alkyl-N(R )C(O)(C -C )alkyl, -(C -C )alkyl-C(O)N(R )(C -C )alkyl, -(C -C )alkyl- 1 6 1 6 1 6 1 6 1 6 23 23 21 22 C(O)N(R )(C -C )alkyl-heterocycloalkyl, -(C -C )alkyl-NR C(=NH)NR R , -(C -C )alkyl- 1 6 1 6 1 6 23 23 21 22 NR C(=NH)R , -(C -C )alkyl-[(C -C )alkyl-NR R ] , -(C -C )heteroalkyl, or optionally substituted 1 6 1 6 2 1 6 heterocycloalkyl; 15 or R and R and the atoms to which they are attached form an optionally substituted heterocycloalkyl ring; R is H or -(C -C )alkyl; R is H, -(C -C )alkyl, -(C -C )alkyl-OH, -(C -C )cycloalkyl, or -C(O)NH ; 1 6 1 6 3 6 2 or R and R are combined to form a heterocycloalkyl ring; R is H or -(C -C )alkyl; 20 or R and R and the carbon atom to which they are attached form a cyclopropyl ring; 6 7 8 R , R , and R are each independently H, fluoro, hydroxyl, amino, optionally substituted alkyl, optionally substituted heteroalkyl, or -(C -C )alkyl; R is H, -(C -C )alkyl, -(C -C )haloalkyl, or -(C -C )cycloalkyl; 1 6 1 6 3 6 R is H, -(C -C )alkyl, -(C -C )haloalkyl, or -(C -C )cycloalkyl; 1 6 1 6 3 6 9 10 25 or R and R are combined to form a heterocycloalkyl or cycloalkyl ring 11 12 23 23 R and R are each independently H, -NH , -(C -C )alkyl, -(C -C )alkyl-OR , -(C -C )alkyl-SR , -(C - 2 1 6 1 6 1 6 1 23 21 22 23 23 C )alkyl-C(O)OR , -(C -C )alkyl-NR R , -(C -C )alkyl-NR OR , -(C -C )alkyl- 6 1 6 1 6 1 6 23 23 25 26 NHC(O)NR OR , -(C -C )alkyl-O-(C -C )alkyl-NR R , -(C -C )alkyl-CN, -(C -C )alkyl- 1 6 1 6 1 6 1 6 23 23 25 26 NR C(O)R , -(C -C )alkyl-C(O)NR R , -(C -C )heteroalkyl-CO H, -(C -C )alkyl-S(O)(C -C )alkyl, 1 6 1 6 2 1 6 1 6 30 -(C -C )alkyl-N(H)CH=NH, -(C -C )alkyl-C(NH )=NH, -(C -C )alkyl-N(H)C(=NH)NH , -(C - 1 6 1 6 2 1 6 2 1 18253141_1 (GHMatters) P111789.NZ 25 26 25 26 C )alkyl-N(H)S(O) NR R , -(C -C )alkyl-N(H)S(O) (C -C )alkyl, -(C -C )alkyl-N(H)-C(O)NR R , 6 2 1 6 2 1 6 1 6 -(C -C )alkylC(O)N(H)[optionally substituted(C -C )alkyl]-OR , -(C -C )alkylN(H)C(O)(C - 1 6 2 6 1 6 1 23 25 26 C )alkyl-OR , -(C -C )alkylC(O)N(H)heterocycloalkyl, -(C -C )alkylC(O)NR R , -(C -C )alkyl- 6 1 6 1 6 1 6 25 26 25 26 N(H)-C(O)-(C -C )alkyl-NR R , -(C -C )alkyl-N(H)-(C -C )alkylC(O)NR R , -(C -C )alkyl- 1 6 1 6 1 6 1 6 5 heterocycloalkyl, optionally substituted -(C -C )alkyl-N(H)heterocycloalkyl, or -(C -C )alkyl- 1 6 1 6 heteroaryl; 11 18 12 or R and R are combined to form an optionally substituted heterocycloalkyl ring; and R is H; 15 16 17 18 23 R , R , R , and R are each independently H, -(C -C )alkyl, -(C -C )cycloalkyl, -(C -C )alkyl-OR , - 1 6 3 6 1 6 23 21 22 (C -C )alkyl-C(O)OR , or -(C -C )alkyl-NR R ; 1 6 1 6 10 X is optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, optionally substituted -(C - 1 6 2 6 2 6 3 C )cycloalkyl-, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally 24 24 substituted heteroaryl, -O-(C -C )alkyl-, -N(R )(C -C )alkyl-, -N(R )(C -C )aryl-, or -SO (C - 1 6 1 6 6 10 2 1 C )alkyl-; Y is a bond, -O-, -S-, optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, -(C - 1 6 2 6 2 6 1 24 24 24 15 C )alkyl-N(R )(C -C )alkyl-, -O-(C -C )alkyl-, -Oaryl-, -N(R )(C -C )alkyl-, -N(R )SO (C - 6 1 6 1 6 1 6 2 1 C )alkyl-, -N(R )C(O)(C -C )alkyl-, -C(O)(C -C )alkyl-, -S(C -C )alkyl-, -SO (C -C )alkyl-, - 6 1 6 1 6 1 6 2 1 6 C(O)NH(C -C )alkyl-, optionally substituted -(C -C )cycloalkyl-, optionally substituted - 1 6 3 7 24 24 24 C(O)N(R )aryl-, optionally substituted -N(R )C(O)aryl-, optionally substituted -N(R )SO aryl-, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; 20 Z is H, halogen, -NH , -CN, -CF , -CO H, -(C -C )alkyl, -(C -C )alkenyl, -CH=((C -C )cycloalkyl), - 2 3 2 1 12 2 12 3 7 25 26 (C -C )alkynyl, -C(O)NR R , -O-(C -C )alkyl, -S-(C -C )alkyl, -O-(C -C )[optionally substituted 2 12 1 12 1 12 3 10 23 23 (C -C )cycloalkyl], -O-(C -C )alkyl-OR , -(C -C )alkyl-OR , -(C -C )alkyl-CN, -S-(C -C )alkyl, - 3 7 1 6 1 12 1 12 1 12 24 24 )(C -C )alkyl, -N(R )C(O)(C -C )alkyl, optionally substituted -(C -C )cycloalkyl, -(C - 1 12 1 12 3 7 1 C )alkyl-(C -C )cycloalkyl, -(C -C )alkyl-heterocycloalkyl, optionally substituted heterocycloalkyl, 6 3 7 1 6 25 optionally substituted aryl, or optionally substituted heteroaryl; 21 22 each R and R is independently H, -(C -C )alkyl, -(C -C )heteroalkyl, -(C -C )alkyl-CO H, -C(O)(C - 1 6 1 6 1 6 2 1 C )alkyl, -C(O)O(C -C )alkyl, -C(O)O(C -C )haloalkyl, -C(=NH)(C -C )alkyl, -C(=NH)N(R ) , - 6 1 6 1 6 1 6 2 31 31 21 22 C(O)N(R ) , or -SO N(R ) ; or R and R and the nitrogen atom to which they are attached form a 2 2 2 heterocycloalkyl ring; 31 31 30 each R is independently H or -(C -C )alkyl; or two R and the nitrogen atom to which they are attached form a heterocycloalkyl ring; each R is independently H or -(C -C )alkyl; each R is independently H or -(C -C )alkyl; 25 26 each R and R is independently H or optionally substituted -(C -C )alkyl; 25 26 35 or R and R and the nitrogen atom to which they are attached form a heterocycloalkyl ring; 27 23 24 23 23 24 each R is independently halogen, -NR R , -NHC(O)R , -NHC(O)NR R , nitro, hydroxyl, optionally substituted -(C -C )alkyl, optionally substituted -(C -C )heteroalkyl, optionally substituted -(C - 1 6 1 6 1 18253141_1 (GHMatters) P111789.NZ C )heteroalkyloxy, optionally substituted -(C -C )heteroalkylamino, -(C -C )alkoxy, -C(O)(C - 6 1 6 1 6 1 C )alkyl, or -S(O) (C -C )alkyl; 6 2 1 6 1 27 or R and R and the atoms to which they are attached form an optionally substituted 5- or 6-membered heterocycloalkyl ring; 28 23 24 23 23 24 5 each R is independently halogen, -NR R , -NHC(O)R , -NHC(O)NR R , nitro, hydroxyl, optionally substituted -(C -C )alkyl, optionally substituted -(C -C )heteroalkyl, optionally substituted -(C - 1 6 1 6 1 C )heteroalkyloxy, optionally substituted -(C -C )heteroalkylamino, -(C -C )alkoxy, -C(O)(C - 6 1 6 1 6 1 C )alkyl, or -S(O) (C -C )alkyl; 6 2 1 6
2 28 or R and R and the atoms to which they are attached form an optionally substituted 5- or 6-membered 10 heterocycloalkyl ring; p is 1 or 2 and q is 0, 1, or 2; or q is 1 or 2 and p is 0, 1, or 2; and wherein the optional substituents, in each instance, are selected from the group consisting of -(C - C )alkyl, halogen, hydroxy, amine, carboxylic acid, and -O-(C -C )alkyl-; 10 1 6 or a pharmaceutically acceptable salt or solvate thereof. 15 2. The compound of claim 1 having the structure of Formula (Ia): (R ) (R ) R R N O CN Z X N 17 9 O R R 11 12 Formula (Ia). 6 7 8
3. The compound of claim 1 or 2, wherein R , R , and R are H. 15 16
4. The compound of any one of claims 1-3, wherein R and R are H. 20 is -CH .
5. The compound of any one of claims 1-4, wherein R
6. The compound of any one of claims 1-5, wherein R is H.
7. The compound of any one of claims 1-6, wherein R is H.
8. The compound of any one of claims 1-7, wherein R is H.
9. The compound of any one of claims 1-7, wherein R is -(C -C )alkyl. 25
10. The compound of any one of claims 1-7, wherein R is -(C -C )cycloalkyl.
11. The compound of any one of claims 1-7, wherein R and R and the carbon atom to which they are attached form a cyclopropyl ring.
12. The compound of any one of claims 1-11, wherein R is -(C -C )alkyl.
13. The compound of claim 12, wherein R is -CH . 11 23 30
14. The compound of any one of claims 1-13, wherein R is -(C -C )alkyl-OR . 18253141_1 (GHMatters) P111789.NZ
15. The compound of claim 14, wherein R is -CH CH OH.
16. The compound of any one of claims 1-13, wherein R is -(C -C )alkyl. 11 21 22
17. The compound of any one of claims 1-13, wherein R is -(C -C )alkyl-NR R .
18. The compound of any one of claims 1-13, wherein R is -(C -C )alkyl-NH . 1 6 2 5
19. The compound of claim 18 wherein R is -CH NH .
20. The compound of claim 18, wherein R is -CH CH NH . 2 2 2
21. The compound of claim 18, wherein R is -CH CH CH NH . 2 2 2 2
22. The compound of claim 18, wherein R is -CH CH CH CH NH . 2 2 2 2 2
23. The compound of any one of claims 1-22, wherein R and R are each independently H or -(C - 21 22 10 C )alkyl-NR R .
24. The compound of any one of claims 1-22, wherein R and R are each independently -(C -C )alkyl- 21 22 NR R .
25. The compound of any one of claims 1-22, wherein R and R are each -CH CH NH . 2 2 2 1 21 22 2
26. The compound of any one of claims 1-22, wherein R is -(C -C )alkyl-NR R and R is H. 15
27. The compound of any one of claims 1-22, wherein R is -CH CH NH and R is H. 2 2 2 1 2 21 22
28. The compound of any one of claims 1-22, wherein R is H and R is -(C -C )alkyl-NR R .
29. The compound of any one of claims 1-22, wherein R is H and R is -CH CH NH . 2 2 2
30. The compound of any one of claims 1-22, wherein R is H and R is H.
31. A compound of Formula (II): (R ) (R ) 13 14 N 18 16 O R R Z X N 17 9 R 11 12 Formula (II); wherein: 1 2 23 R and R are each independently H, -(C -C )alkyl, -(C -C )alkyl-OR , -CH CH(OH)CH NH , - 1 6 1 6 2 2 2 CH CH(heterocycloalkyl)CH NH , -CH C(O)NH , -CH C(O)N(H)CH CN, -(C -C )alkyl-C(O)OR , - 2 2 2 2 2 2 2 1 6 21 22 25 26 23 21 22 25 (C -C )alkyl-NR R , -(C -C )alkyl-C(O)NR R , -(C -C )alkyl-N(R )C(O)(C -C )alkylNR R , - 1 6 1 6 1 6 1 6 23 23 (C -C )alkyl-N(R )C(O)(C -C )alkyl, -(C -C )alkyl-C(O)N(R )(C -C )alkyl, -(C -C )alkyl- 1 6 1 6 1 6 1 6 1 6 23 23 21 22 C(O)N(R )(C -C )alkyl-heterocycloalkyl, -(C -C )alkyl-NR C(=NH)NR R , -(C -C )alkyl- 1 6 1 6 1 6 23 23 21 22 NR C(=NH)R , -(C -C )alkyl-[(C -C )alkyl-NR R ] , -(C -C )heteroalkyl, or optionally substituted 1 6 1 6 2 1 6 heterocycloalkyl; 18253141_1 (GHMatters) P111789.NZ or R and R and the atoms to which they are attached form an optionally substituted heterocycloalkyl ring; R is H or -(C -C )alkyl; R is H, -(C -C )alkyl, -(C -C )alkyl-OH, -(C -C )cycloalkyl, or -C(O)NH ; 1 6 1 6 3 6 2 or R and R are combined to form a heterocycloalkyl ring; 5 R is H or -(C -C )alkyl; or R and R and the carbon atom to which they are attached form a cyclopropyl ring; 6 7 8 R , R , and R are each independently H or -(C -C )alkyl; R is H, -(C -C )alkyl, -(C -C )haloalkyl, or -(C -C )cycloalkyl; 1 6 1 6 3 6 R is H or -(C -C )alkyl; 11 12 23 23 10 R and R are each independently H, -NH , -(C -C )alkyl, -(C -C )alkyl-OR , -(C -C )alkyl-SR , -(C - 2 1 6 1 6 1 6 1 23 21 22 23 23 C )alkyl-C(O)OR , -(C -C )alkyl-NR R , -(C -C )alkyl-NR OR , -(C -C )alkyl- 6 1 6 1 6 1 6 23 23 25 26 NHC(O)NR OR , -(C -C )alkyl-O-(C -C )alkyl-NR R , -(C -C )alkyl-CN, -(C -C )alkyl- 1 6 1 6 1 6 1 6 23 23 25 26 NR C(O)R , -(C -C )alkyl-C(O)NR R , -(C -C )heteroalkyl-CO H, -(C -C )alkyl-S(O)(C -C )alkyl, 1 6 1 6 2 1 6 1 6 -(C -C )alkyl-N(H)CH=NH, -(C -C )alkyl-C(NH )=NH, -(C -C )alkyl-N(H)C(=NH)NH , -(C - 1 6 1 6 2 1 6 2 1 25 26 25 26 15 C )alkyl-N(H)S(O) NR R , -(C -C )alkyl-N(H)S(O) (C -C )alkyl, -(C -C )alkyl-N(H)-C(O)NR R , 6 2 1 6 2 1 6 1 6 -(C -C )alkylC(O)N(H)[optionally substituted(C -C )alkyl]-OR , -(C -C )alkylN(H)C(O)(C - 1 6 2 6 1 6 1 23 25 26 C )alkyl-OR , -(C -C )alkylC(O)N(H)heterocycloalkyl, -(C -C )alkylC(O)NR R , -(C -C )alkyl- 6 1 6 1 6 1 6 25 26 25 26 N(H)-C(O)-(C -C )alkyl-NR R , -(C -C )alkyl-N(H)-(C -C )alkylC(O)NR R , -(C -C )alkyl- 1 6 1 6 1 6 1 6 heterocycloalkyl, optionally substituted -(C -C )alkyl-N(H)heterocycloalkyl, or -(C -C )alkyl- 1 6 1 6 20 heteroaryl; 13 14 23 23 R and R are each independently H, -NH , -(C -C )alkyl, -(C -C )alkyl-OR , -(C -C )alkyl-SR , -(C - 2 1 6 1 6 1 6 1 23 21 22 25 26 C )alkyl-C(O)OR , -(C -C )alkyl-NR R , -(C -C )alkyl-CN, -(C -C )alkyl-C(O)NR R , -(C - 6 1 6 1 6 1 6 1 )alkyl-N(H)C(NH)NH , -(C -C )alkyl-heterocycloalkyl, or -(C -C )alkyl-heteroaryl; 6 2 1 6 1 6 13 19 14 or R and R are combined to form an optionally substituted heterocycloalkyl ring; and R is H; 15 16 17 18 19 25 R , R , R , R , and R are each independently H, -(C -C )alkyl, -(C -C )cycloalkyl, -(C -C )alkyl- 1 6 3 6 1 6 23 23 21 22 OR , -(C -C )alkyl-C(O)OR , or -(C -C )alkyl-NR R ; 1 6 1 6 X is optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, optionally substituted -(C - 1 6 2 6 2 6 3 C )cycloalkyl-, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally 24 24 substituted heteroaryl, -O-(C -C )alkyl-, -N(R )(C -C )alkyl-, -N(R )(C -C )aryl-, or -SO (C - 1 6 1 6 6 10 2 1 30 C )alkyl-; Y is a bond, -O-, -S-, optionally substituted -(C -C )alkyl-, -(C -C )alkenyl-, -(C -C )alkynyl, -(C - 1 6 2 6 2 6 1 24 24 C )alkyl-N(R )(C -C )alkyl-, -O-(C -C )alkyl-, -O(C -C )aryl-, -N(R )(C -C )alkyl-, - 6 1 6 1 6 6 10 1 6 24 24 N(R )SO (C -C )alkyl-, -N(R )C(O)(C -C )alkyl-, -C(O)(C -C )alkyl-, -S(C -C )alkyl-, -SO (C - 2 1 6 1 6 1 6 1 6 2 1 C )alkyl-, -C(O)NH(C -C )alkyl-, optionally substituted -(C -C )cycloalkyl-, optionally substituted - 6 1 6 3 7 24 24 24 35 C(O)N(R )aryl-, optionally substituted -N(R )C(O)aryl-, optionally substituted -N(R )SO aryl-, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; 18253141_1 (GHMatters) P111789.NZ Z is H, halogen, -NH , -CN, -CF , -CO H, -(C -C )alkyl, -(C -C )alkenyl, -CH=((C -C )cycloalkyl), - 2 3 2 1 12 2 12 3 7 25 26 (C -C )alkynyl, -C(O)NR R , -O-(C -C )alkyl, -S-(C -C )alkyl, -O-(C -C )[optionally substituted 2 12 1 12 1 12 3 10 23 23 (C -C )cycloalkyl], -O-(C -C )alkyl-OR , -(C -C )alkyl-OR , -(C -C )alkyl-CN, -S-(C -C )alkyl, - 3 7 1 6 1 12 1 12 1 12 24 24 N(R )(C -C )alkyl, -N(R )C(O)(C -C )alkyl, optionally substituted -(C -C )cycloalkyl, -(C - 1 12 1 12 3 7 1 5 C )alkyl-(C -C )cycloalkyl, -(C -C )alkyl-heterocycloalkyl, optionally substituted heterocycloalkyl, 6 3 7 1 6 optionally substituted aryl, or optionally substituted heteroaryl; 21 22 each R and R is independently H, -(C -C )alkyl, -(C -C )heteroalkyl, -(C -C )alkyl-CO H, -C(O)(C - 1 6 1 6 1 6 2 1 31 31 21 22 C )alkyl, -C(O)N(R ) , or -SO N(R ) ; or R and R and the nitrogen atom to which they are 6 2 2 2 attached form a heterocycloalkyl ring; 31 31 10 each R is independently H or -(C -C )alkyl; or two R and the nitrogen atom to which they are attached form a heterocycloalkyl ring; each R is independently H or -(C -C )alkyl; each R is independently H or -(C -C )alkyl; 25 26 each R and R is independently H or optionally substituted -(C -C )alkyl; 25 26 15 or R and R and the nitrogen atom to which they are attached form a heterocycloalkyl ring; 27 23 24 23 23 24 each R is independently halogen, -NR R , -NHC(O)R , -NHC(O)NR R , nitro, hydroxyl, optionally substituted -(C -C )alkyl, optionally substituted -(C -C )heteroalkyl, optionally substituted -(C - 1 6 1 6 1 C )heteroalkyloxy, optionally substituted -(C -C )heteroalkylamino, -(C -C )alkoxy, -C(O)(C - 6 1 6 1 6 1 C )alkyl, or -S(O) (C -C )alkyl; 6 2 1 6 1 27 20 or R and R and the atoms to which they are attached form an optionally substituted 5- or 6-membered heterocycloalkyl ring; 28 23 24 23 23 24 each R is independently halogen, -NR R , -NHC(O)R , -NHC(O)NR R , nitro, hydroxyl, optionally -C )alkyl, optionally substituted -(C -C )heteroalkyl, optionally substituted -(C - substituted -(C 1 6 1 6 1 C )heteroalkyloxy, optionally substituted -(C -C )heteroalkylamino, -(C -C )alkoxy, -C(O)(C - 6 1 6 1 6 1 25 C )alkyl, or -S(O) (C -C )alkyl; 6 2 1 6 2 28 or R and R and the atoms to which they are attached form an optionally substituted 5- or 6-membered heterocycloalkyl ring; n is 0 or 1; p is 1 or 2 and q is 0, 1, or 2; or q is 1 or 2 and p is 0, 1, or 2; and 30 wherein the optional substituents, in each instance, are selected from the group consisting of -(C - C )alkyl, halogen, hydroxy, amine, carboxylic acid, and -O-(C -C )alkyl-; 10 1 6 or a pharmaceutically acceptable salt or solvate thereof. 6 7 8
32. The compound of claim 31, wherein R , R , and R are H. 15 16
33. The compound of claim 31 or 32, wherein R and R are H. 35
34. The compound of any one of claims 31-33, wherein R is H.
35. The compound of any one of claims 31-34, wherein R is H.
36. The compound of any one of claims 31-35, wherein R is -CH . 18253141_1 (GHMatters) P111789.NZ
37. The compound of any one of claims 31-36, wherein R is H.
38. The compound of any one of claims 31-37, wherein R is H.
39. The compound of any one of claims 31-37, wherein R is -(C -C )alkyl.
40. The compound of any one of claims 31-37, wherein R is -(C -C )cycloalkyl. 5
41. The compound of any one of claims 31-36, wherein R and R and the carbon atom to which they are attached form a cyclopropyl ring.
42. The compound of any one of claims 31-41, wherein R is -(C -C )alkyl.
43. The compound of claim 42, wherein R is -CH . 11 23
44. The compound of any one of claims 31-43, wherein R is -(C -C )alkyl-OR . 10
45. The compound of claim 44, wherein R is -CH CH OH.
46. The compound of any one of claims 31-43, wherein R is -(C -C )alkyl. 11 21 22
47. The compound of any one of claims 31-43, wherein R is -(C -C )alkyl-NR R .
48. The compound of any one of claims 31-43, wherein R is -(C -C )alkyl-NH . 1 6 2
49. The compound of claim 48, wherein R is -CH NH . 15
50. The compound of claim 48, wherein R is -CH CH NH . 2 2 2
51. The compound of claim 48, wherein R is -CH CH CH NH . 2 2 2 2
52. The compound of claim 48, wherein R is -CH CH CH CH NH . 2 2 2 2 2 13 23
53. The compound of any one of claims 31-52, wherein R is -(C -C )alkyl-OR .
54. The compound of claim 53, wherein R is -CH OH. 20
55. The compound of claim 53, wherein R is -CH CH OH.
56. The compound of claim 55, wherein R is -CH .
57. The compound of claim 55 or 56, wherein R is H. is H.
58. The compound of any one of claims 55-57, wherein R
59. The compound of any one of claims 55-57, wherein R is -(C -C )alkyl. 25
60. The compound of any one of claims 55-57, wherein R is -(C -C )cycloalkyl.
61. The compound of claim 55 or 56, wherein R and R and the carbon atom to which they are attached form a cyclopropyl ring.
62. The compound of any one of claims 55-61, wherein R is -(C -C )alkyl.
63. The compound of claim 62, wherein R is -CH . 30
64. The compound of any one of claims 31-63, wherein R and R are each independently H or -(C - 21 22 C )alkyl-NR R .
65. The compound of any one of claims 31-63, wherein R and R are each independently -(C -C )alkyl- 21 22 NR R .
66. The compound of any one of claims 31-63, wherein R and R are each -CH CH NH . 2 2 2 1 21 22 2 35
67. The compound of any one of claims 31-63, wherein R is -(C -C )alkyl-NR R and R is H.
68. The compound of any one of claims 31-63, wherein R is -CH CH NH and R is H. 2 2 2 1 2 21 22
69. The compound of any one of claims 31-63, wherein R is H and R is -(C -C )alkyl-NR R . 18253141_1 (GHMatters) P111789.NZ
70. The compound of any one of claims 31-63, wherein R is H and R is -CH CH NH . 2 2 2
71. The compound of any one of claims 1-70, wherein X is optionally substituted aryl.
72. The compound of any one of claims 1-70, wherein X is optionally substituted phenyl.
73. The compound of any one of claims 1-70, wherein X is optionally substituted heteroaryl. 5
74. The compound of claim 73, wherein X is disubstituted heteroaryl.
75. The compound of claim 73, wherein X is heteroaryl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally 23 25 26 substituted -O-(C -C )alkyl, OR , -NR R , and -NO . 1 6 2
76. The compound of claim 73, wherein X is heteroaryl disubstituted with substituents each 10 independently selected from -(C -C )alkyl.
77. The compound of claim 73, wherein X is heteroaryl disubstituted with methyl.
78. The compound of claim 73, wherein X is pyridinyl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally 23 25 26 substituted -O-(C -C )alkyl, OR , -NR R , or -NO . 1 6 2 15
79. The compound of claim 73, wherein X is pyridinyl disubstituted with substituents each independently selected from -(C -C )alkyl.
80. The compound of claim 73, wherein X is pyridinyl disubstituted with methyl.
81. The compound of claim 73, wherein X is pyrimidinyl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted -(C -C )alkyl, optionally 23 25 26 20 substituted -O-(C -C )alkyl, OR , -NR R , or -NO . 1 6 2
82. The compound of claim 73, wherein X is pyrimidinyl disubstituted with substituents each independently selected from -(C -C )alkyl.
83. The compound of claim 73, wherein X is pyrimidinyl disubstituted with methyl.
84. The compound of any one of claims 1-70, wherein X is optionally substituted -(C -C )alkyl-. 25
85. The compound of any one of claims 1-84, wherein Y is optionally substituted aryl.
86. The compound of any one of claims 85, wherein Y is optionally substituted phenyl.
87. The compound of any one of claims 1-84, wherein Y is optionally substituted heteroaryl.
88. The compound of any one of claims 1-84, wherein Y is optionally substituted -(C -C )alkyl-.
89. The compound of any one of claims 1-84, wherein Y is optionally substituted (C -C )cycloalkyl-. 30
90. The compound of any one of claims 1-84, wherein Y is optionally substituted heterocycloalkyl.
91. The compound of any one of claims 1-84, wherein Y is -O-.
92. The compound of any one of claims 1-84, wherein Y is -(C -C )alkynyl.
93. The compound of any one of claims 1-84, wherein Y is -O-(C -C )alkyl-.
94. The compound of any one of claims 1-84, wherein Y is a bond. 35
95. The compound of any one of claims 1-94, wherein Z is -(C -C )alkyl. 1 12
96. The compound of any one of claims 1-94, wherein Z is n-butyl, isobutyl, or tert-butyl.
97. The compound of any one of claims 1-94, wherein Z is -O-(C -C )alkyl. 1 12 18253141_1 (GHMatters) P111789.NZ
98. The compound of any one of claims 1-94, wherein Z is -O-(C -C )cycloalkyl.
99. The compound of any one of claims 1-94, wherein Z is -(C -C )alkenyl. 2 12
100. The compound of any one of claims 1-94, wherein Z is optionally substituted aryl.
101. The compound of any one of claims 1-94, wherein Z is optionally substituted phenyl. 5
102. The compound of any one of claims 1-94, wherein Z is phenyl monsubstituted or disubstituted with a substituent independently selected from -(C -C )alkyl.
103. The compound of any one of claims 1-94, wherein Z is phenyl monosubstituted with n-butyl, isobutyl, or tert-butyl.
104. The compound of any one of claims 1-94, wherein Z is phenyl monosubstituted with n-butyl. 10
105. The compound of any one of claims 1-94, wherein Z is phenyl monosubstituted with isobutyl.
106. The compound of any one of claims 1-94, wherein Z is phenyl monosubstituted with tert-butyl.
107. The compound of any one of claims 1-94, wherein Z is optionally substituted heteroaryl.
108. The compound of any one of claims 1-94, wherein Z is optionally substituted -(C -C )cycloalkyl.
109. The compound of any one of claims 1-94, wherein Z is optionally substituted heterocycloalkyl. 15
110. The compound of any one of claims 1-94, wherein Z is halogen.
111. The compound of any one of claims 1-94, wherein Z-Y-X- is not .
112. A compound selected from the group consisting of Cp. # Structure H N O O HN N N O H N O N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure H N O O HN N N O O HN N N O H N O O HN N N O H N O N N O H N O N N O H N O O HN N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure H N O N N N O HN N N O N N CN O HN N N O O HN N N O N N CN O HN N N O N N CN N N O N N CN O HN N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure H N O N CN O HN N N O H N O N N CN O HN N N N O H N O N N CN O HN N N N O H N O N N CN O HN N N N O H N O N N CN O HN N N N O H N O N CN O HN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure H N O N CN N N N O H N O N N CN O HN N N (S) N O H N O N N CN N N N O H N O N N CN O HN N N N (S) O H N O N N CN O HN N N N (S) O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure H N O N N CN O HN N N N O H N O N N CN N N N O H N O N N CN N N N O N N CN O HN N N N O H N O N N CN O HN N N (S) N O H N O N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure N N N O HN N N N O O HN N N N N N N O HN N N N O O HN N N N O HN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure O HN N N N O HN N N N O O HN N N N N N N O O HN N N N O O HN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure N N CN O HN N N N O N N CN O HN N N N O N N CN O HN N N N Cl O N N CN O HN N N N N N CN O HN N N N N N CN O HN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure O HN N N N O O HN N N N O N N CN N N N O N N CN O HN N N N O H N HO N N N O N N CN O HN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure N N CN O HN N N N N N CN O HN N N N O O HN N N N O N N CN O HN N N N O N N CN N N N O N N CN O HN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure N N CN O HN N N N O N N N N N N O HN N N N O O HN N N N O O HN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure O HN N N N O N N N O O HN N N N O HN N N N O O O HN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure O HN N N N O O HN N N N O O HN N N N O O HN N N N O HN N N N O O HN N N N 18253141_1 (GHMatters) P111789.NZ Cp. # Structure N N N O N N N O O HN N N N O O HN N N N O O HN N N N O O HN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure O HN N N N O O O HN N N N O O HN N N N O HN N N N O O HN N N N O O HN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure O HN N N N O O HN N N N O O N N O HN N N N O N O HN N N N O N N N O N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure O HN N N N N N N O O HN OH N N N O O HN F N N N O N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure N N N O N N N O O HN N N N O O HN N N N O O HN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure O HN N N N O HN N N N O O HN N N N O O HN N N N O O HN N N N O O HN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure O HN N N N O O HN N N N O O HN N N N O N N N O HN N N N O N N N O HN N N N O N N N O HN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure N N N N N N O N N N O HN N N N O O HN N N N O N N N O O HN N N N O O HN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure O HN N N N O O HN N N N O O HN N N N N N N O O HN N N N O O HN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure O HN N N N O O HN N N N O O HN N N N O HN N N N O O O HN N N N O HN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure O HN N N N O O HN N N N O O HN N N N O O HN N N N O HN N N N O O HN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure O HN N N N O N N N O O HN N N N O O HN N N N O O HN N N N O O HN N N N 18253141_1 (GHMatters) P111789.NZ Cp. # Structure O HN N N N O HN N N N O O HN N N N O F HN F N N N O N N N O O N N O HN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure O N N N N N O O N N O HN N N N O O HN N N N O O HN N N N O HN N N O O HN N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure O HN N N O O HN N N O O HN F N N O O HN N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure N N O F O HN F N N O O HN - N N N O O O N O NH N N O H N O N CN N (S) N O H N O Cl N CN N (S) N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure H N O NH N CN O HN N N O H N O NH N CN (S) O H N O N (S) N O H N O O HN N N O H N O O Cl N N N O H N O O Cl O HN N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure H N O O Cl N O HN H N O O HN N N O H N O N N O H N O N CN O O HN N H H N (S) N O H N O N CN N H H N N O H N O N HN N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure H N O N O HN N N N O H N O N O HN N N N O N HN N N N O N O HN N N N O F O HN N N O N O HN N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure H N O O HN N N N O H N O N N O H N O N CN O HN N N O H N O O HN N N O H N O O HN N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure H N O O HN N N O H N O O HN N N O O N O H N O O HN N N O O N O H N O O HN N N O N N O H N O O HN N N O H N O N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure H N O H N O O HN O HN N N O N N O Br N O Br N O H N O O HN N N O H N O N N O MeO O H N O O HN N N O HO N O H N O O HN N N O H N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure H N O O HN N N O O N N O O HN N N O Cl N O H N O O HN N N O N N O H N O O HN N N O N N O H N O O HN N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure H N O NH N O HN N N N O H N O N NH N N N O O HN N N N O H N O N NH N O HN N N O H N O N NH N O HN 18253141_1 (GHMatters) P111789.NZ Cp. # Structure H N O N NH N O HN N N O H N N O HN N N N O H N O N CHF N N N N O H N O N N N O H N O HOOC N O N CN O HN N N N O H N O N Cl N O HN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure H N O N OMe N O HN N N N O H N O N OH N O HN N N N O H N O N NMe N O HN N N N O H N O N NHMe N O HN N N N O H N O N NH N O HN N N N O H N O N NH N N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure H N O N CF N O HN N N N O H N O N NH N CN O HN N N N O NH O O O HN N N O O HN N N N O HN N N N O O HN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure N N N O H N O O HN N N N O H N O N NH N O HN N N O 437 2 H N O O HN N N N O H N (S) N N N H N O N N CN O HN N N N 18253141_1 (GHMatters) P111789.NZ Cp. # Structure N N CN O HN N N N O HN NH HN N O N N CN O HN N N N O N N CN O HN N N N O O HN 18253141_1 (GHMatters) P111789.NZ Cp. # Structure O HN O HN H N O C H N CN 8 17 O HN N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure H N O N CN N N O N NH H N O N N CN O HN N N (S) N O HN NH H N O N N CN O HN N N N O HN NH N CN O NH N NH O H N O C H N CN 7 15 N N O N CN O HN N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure N CN O HN N N CN O HN N N N O H N O N N CN O HN N N N O H N O N N CN O HN N N N O N N CN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure H N O O N CN H N O N N CN O HN N N N O HN NH OH N O O HN N N O O O HN N N O N N N O OH N O O HN N N O N N N 18253141_1 (GHMatters) P111789.NZ Cp. # Structure Ot-Bu O O HN N N O N N O OH N O O HN N N O N N N O Ot-Bu N N N O N N N O O HN N N N O N N O N N O C CH 6 13 3 O HN O O CH 18253141_1 (GHMatters) P111789.NZ Cp. # Structure O HN N N N O O CH CH N O HN O O CH CH N O HN O O CH NH NH CH N O HN N N O CH N O O O CH NH OH O HN N N N O O HN N N N 18253141_1 (GHMatters) P111789.NZ Cp. # Structure H N O N N O H N O O HN N N O O HN N N O H N O O HN N N O H N O O HN O HN N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure H N O O HN N N O O HN N N N O N N N O O HN N N N O HN N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure O HN N N N O NH O O O HN N N N O N O O 491 2 O HN N N N O HN N N N O 493 2 O HN N N N O O NH 18253141_1 (GHMatters) P111789.NZ Cp. # Structure 494 2 O HN N N N O HN N N N O N CN O HN N N N HN O O HN N N N O O HN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure O HN N N N O O NH O HN N N N O N N N O O NH N N N O S O O HN N N N O S O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure O HN N N N O O HN N N N H N O O HN N N N O O HN N N N O O HN N N N O O HN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure N CN O HN N N O N N O O HN N N N HN O O HN N N N O N N CN O HN N N N O O HN N N N O O HN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure O HN N N N O O HN N N N O O HN N N N O H N O N NH N O HN N N O NH O O O HN N N N O O HN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure H N HO O HN N N N O O HN N N N O H N HO O HN N N N O H N HO N N O H N O N N N O HN N N N O O HN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure O HN N N O NH O O O HN N N N O N N N O H N O N NH N O HN N N N O H N O O HN N N O HN N O H N O N NH N O HN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure H N HO O HN N N N N N N O H N O O HN F N N O F O O NH N O HN N N N O H N HO 539 O O HN N N N O H N O N N N O HN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure H N HO O HN N N O O HN N N N O O HN N N N O H N O NH N O HN N N N O H N O NH N O HN N N N O H N O O HN N N O NH O O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure H N O N NH N O HN N N N O H OH N NH N O HN N N N O O HN N N N O H N O N N N N N N O H N O O HN N N N O O HN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure N N N O H N O N Cl N O HN N N O NH O O H N O O HN N N N O H N HO O HN N N O NH O O NH N O HN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure O HN N N N O H N HO O HN N N N O H N HO O HN N N N N N N N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure NH N CN O HN N N N O H N O NH N CN O HN N N N O H N O N NH N CN N N N O N CN O HN N N N O H N O O OH N N CN O HN N N N O H N O N N CN O HN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure H N O N N CN O HN N N N O ( ) ( ) H N O N N CN O HN N N N O H N O N N CN O HN N N N O (S) (S) O S O N N CN O HN N N N N N CN O HN N N N O HN NH 18253141_1 (GHMatters) P111789.NZ Cp. # Structure N N CN O HN N N N O O S NH H N O N N CN N N N O (S) (S) O S O H N O N N CN O HN N N N O O S NH (R) O H N O O OH N N CN O HN N N N O O S NH H N O O OH N N CN O HN N N N O H N S O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure H N O N N CN O HN N N N O H N O N N CN O HN N N N O H N S O H N NH N N CN N N N O O S NH N CN O HN N N N O 584 2 N N CN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure N N CN N N N O H N NH N N CN O HN N N N O N N CN O HN N N N O HO OH N N CN O HN N N N O N N CN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure NH NH 590 2 H N NH OH N N CN N N N O O S NH O NH O OH HO O N N CN O HN N N N O NH O N N CN N N N O 2 (R) O NH O OH HO O N N CN O HN N N N O O S O N N CN O HN N N N O HN NH HN HO N N CN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure H N N O N N CN N N N O N NH O NH N NH NH O 598 2 O HN N N N O O HN N N CN O HN N N N O N HO H N O N N CN O HN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure H N N HO N N CN N N N O HN N HO N N CN O HN N N N O O HN N N N O N N CN O HN N N N N CN O HN N N N O H N HO N N CN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure N N CN O HN N N N N N CN O HN N N N O N N CN H N O N N CN O HN N N N O N N CN O HN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure N N CN N N N O O HN N N N O H N HO 615 O N N CN O HN N N N O N N CN N N N O O S NH 617 H N O N N CN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure HN NH N N CN O HN N N N O NH O HN NH H N O N N CN O HN N N N O N O N CN O HN N N N O H N N N O N O HN N N N O H N O H N N N O N CN O HN N N N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure N N N O H N H N N N CN O HN N N N O H N MeO OH N N CN N N N O H N HO N N CN N N N O H N MeO O N N CN O HN N N N O S NH H N HO O N N CN O HN N N N O O S NH 18253141_1 (GHMatters) P111789.NZ Cp. # Structure 629 2 N N CN N N N O O S NH Chiral O HN N N N O H N HO Chiral N N N O Chiral O HN N N N O H N HO Chiral O HN N N N O H N O 18253141_1 (GHMatters) P111789.NZ Cp. # Structure O HN N N N O HN N N N O , and N N N O O S NH or a pharmaceutically acceptable salt or solvate thereof.
113. A pharmaceutical composition comprising the compound of any one of claims 1-112, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable excipient. 5
114. Use of a compound of any one of claims 1-112, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, for preparation of a medicament for treatment of a bacterial infection in a patient.
115. Use of a compound of any one of claims 1-112, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, for preparation of a medicament for treatment of a lepB- 10 mediated infection in a mammal.
116. The use of claim 114 or 115, wherein the bacterial infection or lepB-mediated infection is an infection involving Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, 15 Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter baumannii, Acinetobacter 18253141_1 (GHMatters) P111789.NZ calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, 5 Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, 10 Bacteroides splanchnicus, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus 15 haemolyticus, Staphylococcus hominis, or Staphylococcus saccharolyticus.
117. The use of any one of claims 114-116, wherein the bacterial infection or lepB-mediated infection is an infection involving a Gram-negative bacteria.
118. The use of any one of claims 114-117, wherein the medicament is suitable for topical administration. 20
119. The use of any one of claims 114-118, wherein the treatment further comprises administration of a second therapeutic agent.
120. The use of claim 119, wherein the second therapeutic agent is not an SpsB inhibitor.
121. The use of claim 119, wherein the second therapeutic agent is an aminoglycoside antibiotic, fluoroquinolone antibiotic, β-lactam antibiotic, macrolide antibiotic, glycopeptide antibiotic, rifampicin, 25 chloramphenicol, fluoramphenicol, colistin, mupirocin, bacitracin, daptomycin, or linezolid.
122. The use of claim 121, wherein the second therapeutic agent is a β-lactam antibiotic.
123. The use of claim 122, wherein the β-lactam antibiotic is selected from penicillins, monobactams, cephalosporins, cephamycins, and carbapenems.
124. The use of claim 122, wherein the β-lactam antibiotic is selected from Azlocillin, Amoxicillin, 30 Ampicillin, Doripenem, Meropenem, Biapenem, Cefamandole, Imipenem, Mezlocillin, Cefmetazole, Cefprozil, Piperacillin/tazobactam, Carbenicillin, Cefaclor, Cephalothin, Ertapenem, Cefazolin, Cefepime, Cefonicid, Cefoxitin, Ceftazidime, Oxacillin, Cefdinir, Cefixime, Cefotaxime, Cefotetan, Cefpodoxime, Ceftizoxime, Ceftriaxone, Faropenem, Mecillinam, Methicillin, Moxalactam, Ticarcillin, Tomopenem, Ceftobiprole, Ceftaroline, Flomoxef, Cefiprome, and Cefozopran. 35
125. The use of any one of claims 122-124, wherein the treatment further comprises administration of a β-lactamase inhibitor. 18253141_1 (GHMatters) P111789.NZ
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNPCT/CN2017/073575 | 2017-02-15 | ||
| CNPCT/CN2017/073575 | 2017-02-15 | ||
| CNPCT/CN2017/085075 | 2017-05-19 | ||
| CNPCT/CN2017/085075 | 2017-05-19 | ||
| PCT/CN2018/076957 WO2018149419A1 (en) | 2017-02-15 | 2018-02-22 | Macrocyclic broad spectrum antibiotics |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NZ756220A NZ756220A (en) | 2021-09-24 |
| NZ756220B2 true NZ756220B2 (en) | 2022-01-26 |
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