IP Library › Granted Patent US 8,450,326

Granted Patent B2

US 8,450,326 · App. 12/564,582 · Granted May 28, 2013

Multiheteroaryl compounds as inhibitors of H-PGDS and their use for treating prostaglandin D2 mediated diseases

Inventors: Gregory W. Endres (Saline, MI); Pil Heui Lee (Chelsea, MI); Kirk Lang Olson (Canton, MI); James Bernard Kramer (Sylvania, OH); Fred Lawrence Ciske (Dexter, MI); Stephen Douglas Barrett (Hartland, MI)

Assignee: Cayman Chemical Company, Incorporated

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Quick Facts

Patent No.: US 8,450,326
App. No.: 12/564,582
Granted: May 28, 2013
Kind: B2

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Abstract

Multiheteroaryl compounds, their preparation, pharmaceutical compositions comprising these compounds, and their pharmaceutical use in the prevention and treatment of prostaglandin D 2 mediated diseases and conditions that may be modulated by the inhibition of hematopoietic prostaglandin D synthase (H-PGDS).

Claims (472)

1. A compound of Formula (I):

wherein:

R 1 is (C 1 -C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl, phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl; wherein each phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl of R 1 may be optionally substituted with no more than two of each or a combination of fluoro, hydroxy, —CH 2 OH, carboxy, carboxymethyl, or carboxyethyl;

R 2 is —(CH 2 )Z 1 or —(CH 2 ) n Z 2 ;

n is 0, 1, 2, 3, or 4;

Z 1 is hydrogen, OR 3 , C(O)R 3 , CO 2 R 3 , C(O)NR 4 R 5 , SO 2 NR 4 R 5 , SO 2 R 3 , (C 1 -C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl, (C 3 -C 6 )-alkenyl, (C 3 -C 6 )-alkynyl, (C 6 -C 14 )-aryl, (CH 2 ) p CF 3 , a five- to ten-membered heteroaryl,

or a three- to ten-membered heterocycle; wherein any one nitrogen atom of any heterocycle containing one or more nitrogen atoms that may be substituted with a non-ring atom are substituted with —(CH 2 ) q Q;

Z 2 is cyano, trifluoromethyl, (CF 2 ) p CF 3 , SR 3 , NR 4 R 5 , N(H)C(O)R 3 , N(H)CO 2 R 3 , N(H)C(O)NR 4 R 5 , N(H)SO 2 R 3 , vinyl, or ethynyl when n is 1, 2, 3 or 4;

Z 2 may also be cyano, trifluoromethyl, (CF 2 ) p CF 3 , SR 3 , NR 4 R 5 , N(H)C(O)R 3 , N(H)CO 2 R 3 , N(H)C(O)NR 4 R 5 , N(H)SO 2 R 3 , vinyl, or ethynyl when n is 0, except when R 2 is covalently bonded to a U 1 , U 2 , U 3 , or U 4 that is a nitrogen atom;

R 3 is hydrogen, (C 1 -C 6 )-alkyl, trifluoromethyl, (C 3 -C 6 )-alkenyl, (C 3 -C 6 )-alkynyl, (CH 2 ) m (C 3 -C 6 )-cycloalkyl, (CH 2 ) m phenyl, (CH 2 ) m -(five- to ten-membered heteroaryl), or (CH 2 ) m (three- to ten-membered heterocycle), wherein any one nitrogen atom of any heterocycle containing one or more nitrogen atoms that may be substituted with a non-ring atom are substituted with —(CH 2 ) q Q;

m is 0, 1, 2, 3, or 4;

q is 0, 1, 2, 3, or 4;

Q is hydrogen, (C 1 -C 6 )-alkyl, (CH 2 ) p CF 3 , (C 3 -C 6 )- alkenyl, (C 3 -C 6 )-alkynyl, (C 3 -C 6 )-cycloalkyl, (C 6 -C 14 )-aryl, C(O)R 3 , CO 2 R 3 , C(O)NR 4 R 5 , a three- to six-membered heterocycle, or a five- to ten-membered heteroaryl when q is 0, 1, 2, 3, or 4;

Q may also be cyano, trifluoromethyl, or SO 2 NR 4 R 5 when q is 1, 2, 3, or 4;

Q may also be hydroxy, (C 1 -C 6 )-alkoxy, sulfhydryl, —S—(C 1 -C 6 )-alkyl, or NR 4 R 5 when q is 2, 3, or 4;

p is 1, 2, or 3;

R 3 may also be vinyl or ethynyl when R 3 is not covalently bonded to an N or O atom;

R 3 may also be vinyl or ethynyl when R 3 is not covalently bonded to an S atom possessing a −2 (minus 2) oxidation state;

R 4 and R 5 are independently hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 6 )-alkenyl, (C 3 -C 6 )-alkynyl, (CH 2 ) m (C 3 -C 6 )-cycloalkyl, (CH 2 ) m phenyl, (CH 2 ) m -(three- to ten-membered heterocycyl), or (CH 2 ) m -(five- to ten-membered heteroaryl);

the NR 4 R 5 group of any C(O)NR 4 R 5 , SO 2 NR 4 R 5 , NR 4 R 5 , or N(H)C(O)NR 4 R 5 may also form a pyrrolidine, a piperidine, a morpholine, a thiomorpholine, or a thiomorpholine S-dioxide;

the NR 4 R 5 group of any C(O)NR 4 R 5 , SO 2 NR 4 R 5 , NR 4 R 5 , or N(H)C(O)NR 4 R 5 may also form a piperazine ring, wherein the other nitrogen atom of the piperazine ring is substituted with hydrogen, (C 1 -C 6 )-alkyl, CH 2 CF 3 , (C 3 -C 6 )-cycloalkyl, CH 2 (C 3 -C 6 )-cycloalkyl, phenyl, benzyl, hydroxyethyl, or hydroxypropyl;

phenyl or heteroaryl rings of Z 1 and Z 2 are optionally substituted with one-to-three of any one or combination of the following: halo, hydroxy, sulfhydryl, (C 1 -C 3 )-alkoxy, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-alkylthio, trifluoromethyl, trifluoromethoxy, cyano, carboxy, carboxy (C 1 -C 3 )-alkyl, carbamoyl, or sulfamoyl;

W is a covalent bond, O, S, SO, SO 2 , CH 2 , CHOH, or CO;

U 1 , U 2 , U 3 , U 4 , and a carbon atom form a five-membered heteroaryl ring; wherein one of U 1 , U 2 , U 3 , and U 4 of the five-membered heteroaryl ring is covalently bonded to the R 2 group; wherein the U 1 , U 2 , U 3 , or U 4 that is covalently bonded to the R 2 group is a carbon atom or a nitrogen atom; wherein when the U 1 , U 2 , U 3 , or U 4 that is covalently bonded to the R 2 group is a nitrogen atom, one, two, or all of the other three of the group consisting of U 1 , U 2 , U 3 , and U 4 is N and each remaining of the group consisting of U 1 , U 2 , U 3 , and U 4 that is not N is C—R 6 ; wherein when the U 1 , U 2 , U 3 , or U 4 that is covalently bonded to the R 2 group is a carbon atom, one of the other three of the group consisting of U 1 , U 2 , U 3 , and U 4 is N—R 6 , O, or S, and each of remaining of the group consisting of U 1 , U 2 , U 3 , and U 4 is C—R 6 or N with the further proviso that when Z 2 is SR 3 and n is 0,then at most one of the other three of the group consisting of U 1 , U 2 , U 3 , and U 4 is N-R 6 ;

Y 2 is a CH 2 ;

Y 1 , Y 2 , Y 3 , a nitrogen atom, and two carbon atoms form a six-membered heteroaryl ring; wherein no more than one of the group consisting of Y 1 and Y 3 is N; and wherein all Y 1 and Y 3 that are not N are C—R 6 ;

each R 6 is independently hydrogen, methyl, trifluoromethyl, or amino; and

each R 7 is independently hydrogen or methyl.

2. A compound of claim 1 , wherein the compound according to Formula (I) comprises a compound according to Formula (III):

wherein:

each X 1 , X 2 , X 3 , X 4 , and X 5 is independently hydrogen or fluoro, with no more than two of X 1 , X 2 , X 3 , X 4 , and X 5 being fluoro;

Y 3 is CH or N;

each R 6 is independently hydrogen, methyl, trifluoromethyl, or amino;

n is 0, 1, 2, 3, or 4;

Z 1 is hydrogen, OR 3 , C(O)R 3 , CO 2 R 3 , C(O)NR 4 R 5 , SO2NR 4 R 5 , SO2R 3 , (C 1 -C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl, (C 3 -C 6 )-alkenyl, (C 3 -C 6 )-alkynyl, (C 6 -C 14 )-aryl, (CH 2 ) p CF 3 , a five- to ten-membered heteroaryl,

or a three- to ten-membered heterocycle, wherein any one nitrogen atom of any heterocycle containing one or more nitrogen atoms that may be substituted with a non-ring atom are substituted with —(CH 2 ) q Q;

p is 1, 2, or 3;

R 3 is hydrogen, (C 1 -C 6 )-alkyl, trifluoromethyl, (C 3 -C 6 )-alkenyl, (C 3 -C 6 )-alkynyl, (CH 2 ) m (C 3 -C 6 )-cycloalkyl, (CH 2 ) m phenyl, (CH 2 ) m -(five- to ten-membered heteroaryl), or (CH 2 ) m -(three- to ten-membered heterocycle) wherein any one nitrogen atom of any heterocycle containing one or more nitrogen atoms that may be substituted with a non-ring atom are substituted with —(CH 2 ) q Q;

the NR 4 R 5 group of any C(O)NR 4 R 5 , SO 2 NR 4 R 5 , NR 4 R 5 , or N(H)C(O)NR 4 R 5 may also form a pyrrolidine, a piperidine, a morpholine, a thiomorpholine, or a thiomorpholine S-dioxide;

m is 0, 1, 2, 3, or 4;

q is 0, 1, 2, 3, or 4;

Q is hydrogen, (C 1 -C 6 )-alkyl, (CH 2 ) p CF 3 , (C 3 -C 6 )-alkenyl, (C 3 -C 6 )-alkynyl, (C 3 -C 6 )-cycloalkyl, (C 6 -C 14 )-aryl, C(O)R 3 , CO 2 R 3 , C(O)NR 4 R 5 , a three- to six-membered heterocycle, or a five- to ten-membered heteroaryl;

Q may also be cyano, trifluoromethyl, or SO 2 NR 4 R 5 when q is 1, 2, 3, or 4;

Q may also be hydroxy, sulfhydryl, or NR 4 R 5 when q is 2, 3, or 4;

phenyl or heteroaryl rings of Z 1 are optionally substituted with one-to-three of any one or combination of the following: halo, hydroxy, sulfhydryl, (C 1 -C 3 )-alkoxy, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-alkylthio, trifluoromethyl, trifluoromethoxy, cyano, carboxy, carboxy(C 1 -C 3 )-alkyl, carbamoyl, or sulfamoyl; and

R 7 is hydrogen or methyl.

3. A compound of claim 2 , wherein the compound according to Formula (III) comprises a compound according to Formula (IV):

wherein:

each X 1 , X 2 , X 3 , X 4 , and X 5 is independently hydrogen or fluoro, with no more than two of X 1 , X 2 , X 3 , X 4 , and X 5 being fluoro;

Y 3 is CH or N;

each R 6 is independently hydrogen, methyl, trifluoromethyl, or amino;

n is 0, 1, 2, 3, or 4;

R 3 is hydrogen, (C 1 -C 6 )-alkyl, trifluoromethyl, (C 3 -C 6 )-alkenyl, (C 3 -C 6 )-alkynyl, (CH 2 ) m (C 3 -C 6 )-cycloalkyl, (CH 2 ) m phenyl, (CH 2 ) m -(five- to ten-membered heteroaryl), or (CH 2 ) m -(three- to ten-membered heterocycle); wherein any one nitrogen atom of any heterocycle containing one or more nitrogen atoms that may be substituted with a non-ring atom are substituted with —(CH 2 ) q Q;

the NR 4 R 5 group of any C(O)NR 4 R 5 , SO 2 NR 4 R 5 , NR 4 R 5 , or N(H)C(O)NR 4 R 5 may also form a pyrrolidine, a piperidine, a morpholine, a thiomorpholine, or a thiomorpholine S-dioxide;

the NR 4 R 5 group of any C(O)NR 4 R 5 , SO 2 NR 4 R 5 , NR 4 R 5 , or N(H)C(O)NR 4 R 5 may also form a piperazine ring, wherein the other nitrogen atom of the piperazine ring is substituted with hydrogen, (C 1 -C 6 )-alkyl, CH 2 CF 3 ,(C 3 -C 6 )-cycloalkyl, CH 2 (C 3 -C 6 )-cycloalkyl, phenyl, benzyl, hydroxyethyl, or hydroxypropyl;

m is 0, 1, 2, 3, or 4;

q is 0, 1, 2, 3, or 4;

Q is hydrogen, (C 1 -C 6 )-alkyl, (CH 2 ) p CF 3 , (C 3 -C 6 )-alkenyl, (C 3 -C 6 )-alkynyl, (C 3 -C 6 )-cycloalkyl, (C 6 -C 14 )-aryl, C(O)R 3 , CO 2 R 3 , C(O)NR 4 R 5 , a three- to six-membered heterocycle, or a five- to ten-membered heteroaryl;

Q may also be cyano, trifluoromethyl, or SO 2 NR 4 R 5 when q is 1, 2, 3, or 4;

Q may also be hydroxy, (C 1 -C 6 )-alkoxy, sulfhydryl, —S—(C 1 -C 6 )-alkyl, or NR 4 R 5 when q is 2, 3, or 4;

p is 1, 2, or 3;

R 7 is hydrogen or methyl.

4. A compound of claim 2 , wherein the compound according to Formula (III) comprises a compound according to Formula (V):

wherein:

each X 1 , X 2 , X 3 , X 4 , and X 5 is independently hydrogen or fluoro, with no more than two of X 1 , X 2 , X 3 , X 4 , and X 5 being fluoro;

Y 3 is CH or N;

each R 6 is independently hydrogen, methyl, trifluoromethyl, or amino;

n is 0, 1, 2, 3, or 4;

R 3 is hydrogen, (C 1 -C 6 )-alkyl, trifluoromethyl, (C 3 -C 6 )-alkenyl, (C 3 -C 6 )-alkynyl, (CH 2 ) m (C 3 -C 6 )-cycloalkyl, (CH 2 ) m phenyl, (CH 2 ) m -(five- to ten-membered heteroaryl), or (CH 2 ) m -(three- to ten-membered heterocycle); wherein any one nitrogen atom of any heterocycle containing one or more nitrogen atoms that may be substituted with a non-ring atom are substituted with —(CH 2 ) q Q;

the NR 4 R 5 group of any C(O)NR 4 R 5 , SO 2 NR 4 R 5 , NR 4 R 5 , or N(H)C(O)NR 4 R 5 may also form a pyrrolidine, a piperidine, a morpholine, a thiomorpholine, or a thiomorpholine S-dioxide;

m is 0, 1, 2, 3, or 4;

q is 0, 1, 2, 3, or 4;

Q is hydrogen, (C 1 -C 6 )-alkyl, (CH 2 ) p CF 3 , (C 3 -C 6 )-alkenyl, (C 3 -C 6 )-alkynyl, (C 3 -C 6 )-cycloalkyl, (C 6 -C 14 )-aryl, C(O)R 3 , CO 2 R 3 , C(O)NR 4 R 5 , a three- to six-membered heterocycle, or a five- to ten-membered heteroaryl;

Q may also be cyano, trifluoromethyl, or SO 2 NR 4 R 5 when q is 1, 2, 3, or 4;

Q may also be hydroxy, (C 1 -C 6 )-alkoxy, sulfhydryl, —S—(C 1 -C 6 )-alkyl, or NR 4 R 5 when q is 2, 3, or 4;

p is 1, 2, or 3;

R 7 is hydrogen or methyl.

5. A compound of claim 4 , wherein Y 3 is N.

6. A compound of claim 5 , wherein:

each X 1 , X 3 , X 4 , and X 5 is hydrogen;

X 2 is hydrogen or fluoro;

each R 6 is independently hydrogen, methyl, or trifluoromethyl;

n is 0, 1, or 2;

Z 1 is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, piperidin-4-yl, piperidin-3-yl, piperidin-3(R)-yl, piperidin-3(S)-yl, piperidin-2-yl, piperidin-2(R)-yl, piperidin-2(S)-yl, pyrrolidin-3-yl, pyrrolidin-3(R)-yl, pyrrolidin-3(S)-yl, pyrrolidin-2-yl, pyrrolidin-2(R)-yl, pyrrolidin-2(S)-yl, or azetidin-3-yl;

the nitrogen atom of a piperidinyl, a pyrrolidinyl, or a azetidinyl ring is substituted with —(CH 2 ) q Q;

q is 0, 1, or 2;

Q is hydrogen, (C 1 -C 6 )-alkyl, —CH 2 CF 3 , (C 3 -C 6 )-alkenyl, (C 3 -C 6 )-alkynyl, (C 3 -C 6 )-cycloalkyl, phenyl, naphthyl, C(O)R 3 , CO 2 R 3 , C(O)NR 4 R 5 , a three- to six-membered heterocycle, or a five- to ten-membered heteroaryl;

R 3 is hydrogen, (C 1 -C 6 )-alkyl, trifluoromethyl, (C 3 -C 6 )-alkenyl, (C 3 -C 6 )-alkynyl, (CH 2 ) m (C 3 -C 6 )-cycloalkyl, (CH 2 ) m phenyl, or (CH 2 ) m -(five- to ten-membered heteroaryl); and

m is 0, 1, or 2.

7. A compound of claim 6 , wherein:

Z 1 is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl; and

wherein said phenyl or pyridyl rings of Z 1 are optionally substituted with one or two of any one or combination of the following: halo, hydroxy, methoxy, methyl, or trifluoromethyl.

8. A compound of claim 7 , wherein:

Z 1 is phenyl; and

wherein said phenyl ring of Z 1 is substituted with one or two of any one or combination of the following: halo, hydroxy, methoxy, methyl, or trifluoromethyl.

9. A compound of claim 8 , wherein said phenyl ring of Z 1 is substituted with one or two of any one or combination of the following: halo or methoxy.

10. A compound of claim 7 , wherein Z 1 is 2-pyridyl, 3-pyridyl, or 4-pyridyl.

11. A compound of claim 6 , wherein Z 1 is piperidin-4-yl, piperidin-3-yl, piperidin-3(R)-yl, piperidin-3(S)-yl, piperidin-2-yl, piperidin-2(R)-yl, piperidin-2(S)-yl, pyrrolidin-3-yl, pyrrolidin-3(R)-yl, pyrrolidin-3(S)-yl, pyrrolidin-2-yl, pyrrolidin-2(R)-yl, pyrrolidin-2(S)-yl, or azetidin-3-yl.

12. A compound of claim 11 , wherein:

q is 0 or 1;

Q is (C 1 -C 4 )-alkyl, —CH 2 CF 3 , (C 3 -C 6 )-cycloalkyl, phenyl, C(O)R 3 , CO 2 R 3 , C(O)NHR 5 , a five- to six-membered heterocycle, or a five- to ten-membered heteroaryl;

R 3 is hydrogen, (C 1 -C 4 )-alkyl, trifluoromethyl, (CH 2 ) m (C 3 -C 6 )-cycloalkyl, (CH 2 ) m phenyl, or (CH 2 ) m -(five- to six-membered heteroaryl); and

m is 0, 1, or 2.

13. A compound of claim 12 , wherein

q is 1; and

Q is (C 1 -C 4 )-alkyl, —CH 2 CF 3 , (C 3 -C 6 )-cycloalkyl, phenyl, a five- to six-membered heterocycle, or a five- to ten-membered heteroaryl.

14. A compound of claim 12 , wherein q is 0.

15. A compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein Y 3 is CH.

16. A compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein:

each X 1 , X 3 , X 4 , and X 5 is hydrogen;

X 2 is hydrogen or fluoro;

R 6 is hydrogen, methyl, or trifluoromethyl;

n is 0, 1, or 2;

the nitrogen atom of a piperidinyl, a pyrrolidinyl, or a azetidinyl ring of Z 1 is substituted with —(CH 2 ) q Q;

q is 0, 1, or 2;

m is 0, 1, or 2.

17. A compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein:

Z 1 is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl; and

said phenyl or pyridyl rings may be optionally substituted with one or two of any one or combination of the following: halo, hydroxy, methoxy, methyl, or trifluoromethyl.

18. A compound of claim 17 , wherein:

Z 1 is phenyl; and

said phenyl ring of Z 1 is substituted with one or two of any one or combination of the following: halo, hydroxy, methoxy, methyl, or trifluoromethyl.

19. A compound of claim 18 , wherein said phenyl ring of Z 1 is substituted with one or two of any one or combination of the following: halo or methoxy.

20. A compound of claim 17 , wherein Z 1 is 2-pyridyl, 3-pyridyl, or 4-pyridyl.

21. A compound of claim 16 , wherein Z 1 is piperidin-4-yl, piperidin-3-yl, piperidin-3(R)-yl, piperidin-3(S)-yl, piperidin-2-yl, piperidin-2(R)-yl, piperidin-2(S)-yl, pyrrolidin-3-yl, pyrrolidin-3(R)-yl, pyrrolidin-3(S)-yl, pyrrolidin-2-yl, pyrrolidin-2(R)-yl, pyrrolidin-2(S)-yl, or azetidin-3-yl.

22. A compound of claim 21 , wherein:

q is 0 or 1;

Q is (C 1 -C 4 )-alkyl, —CH 2 CF 3 , (C 3 -C 6 )-cycloalkyl, phenyl, C(O)R 3 , CO 2 R 3 , C(O)NHR 5 , a five- to six-membered heterocycle, or a five- to ten-membered heteroaryl;

R 3 is hydrogen, (C 1 -C 4 )-alkyl, trifluoromethyl, (CH 2 ) m (C 3 -C 6 )-cycloalkyl, (CH 2 ) m phenyl, or (CH 2 ) m -(five- to six-membered heteroaryl); and

m is 0, 1, or 2.

23. A compound of claim 22 , wherein:

q is 1; and

Q is (C 1 -C 4 )-alkyl, —CH 2 CF 3 , (C 3 -C 6 )-cycloalkyl, phenyl, a five- to six-membered heterocycle, or a five- to ten-membered heteroaryl.

24. A compound of claim 22 , wherein:

q is 0;

Q is hydrogen, (C 1 -C 6 )-alkyl, (CH 2 ) p CF 3 , (C 3 -C 6 )- alkenyl, (C 3 -C 6 )-alkynyl, (C 3 -C 6 )-cycloalkyl, (C 6 -C 14 )-aryl, C(O)R 3 , CO 2 R 3 , C(O)NHR 5 , a three- to six-membered heterocycle, or a five- to ten-membered heteroaryl;

phenyl or heteroaryl rings are optionally substituted with one-to-three of any one or combination of the following: halo, hydroxy, sulfhydryl, (C 1 -C 3 )-alkoxy, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-alkylthio, trifluoromethyl, trifluoromethoxy, cyano, carboxy, carboxy(C 1 -C 3 )-alkyl, carbamoyl, or sulfamoyl.

25. A compound of claim 1 , wherein the compound according to Formula (I) comprises a compound according to Formula (VI):

wherein:

each X 1 , X 2 , X 3 , X 4 , and X 5 is independently hydrogen or fluoro, with no more than two of X 1 , X 2 , X 3 , X 4 , and X 5 being fluoro;

n is 0, 1, 2, 3, or 4;

m is 0, 1, 2, 3, or 4;

q is 0, 1, 2, 3, or 4;

Q may also be cyano, trifluoromethyl, or SO 2 NR 4 R 5 when q is 1, 2, 3, or 4;

Q may also be hydroxy, (C 1 -C 6 )-alkoxy, sulfhydryl, —S—(C 1 -C 6 )-alkyl, or NR 4 R 5 when q is 2, 3, or 4;

p is 1, 2, or 3;

R 3 may also be vinyl or ethynyl when R 3 is not covalently bonded to an N or O atom;

R 3 may also be vinyl or ethynyl when R 3 is not covalently bonded to an S atom possessing a −2 (minus 2) oxidation state;

the NR 4 R 5 group of any C(O)NR 4 R 5 , SO 2 NR 4 R 5 , NR 4 R 5 , or N(H)C(O)NR 4 R 5 may also form a pyrrolidine, a piperidine, a morpholine, a thiomorpholine, or a thiomorpholine S-dioxide;

each R 6 is independently hydrogen, methyl, trifluoromethyl, or amino; and

each R 7 is independently hydrogen or methyl.

26. A compound of claim 25 , wherein the compound according to Formula (VI) comprises a compound according to Formula (VII):

wherein:

each X 1 , X 2 , X 3 , X 4 , and X 5 is independently hydrogen or fluoro, with no more than two of X 1 , X 2 , X 3 , X 4 , and X 5 being fluoro;

n is 0, 1, 2, 3, or 4;

m is 0, 1, 2, 3, or 4;

q is 0, 1, 2, 3, or 4;

Q may also be cyano, trifluoromethyl, or SO 2 NR 4 R 5 when q is 1, 2, 3, or 4;

Q may also be hydroxy, (C 1 -C 6 )-alkoxy, sulfhydryl, —S—(C 1 -C 6 )-alkyl, or NR 4 R 5 when q is 2, 3, or 4;

p is 1, 2, or 3;

R 3 may also be vinyl or ethynyl when R 3 is not covalently bonded to an N or O atom;

R 3 may also be vinyl or ethynyl when R 3 is not covalently bonded to an S atom possessing a −2 (minus 2) oxidation state;

the NR 4 R 5 group of any C(O)NR 4 R 5 , SO 2 NR 4 R 5 , NR 4 R 5 , or N(H)C(O)NR 4 R 5 may also form a pyrrolidine, a piperidine, a morpholine, a thiomorpholine, or a thiomorpholine S-dioxide;

each R 6 is independently hydrogen, methyl, trifluoromethyl, or amino; and

each R 7 is independently hydrogen or methyl.

27. A compound of claim 25 , wherein the compound according to Formula (VI) comprises a compound according to Formula (VIII):

wherein:

each X 1 , X 2 , X 3 , X 4 , and X 5 is independently hydrogen or fluoro, with no more than two of X 1 , X 2 , X 3 , X 4 , and X 5 being fluoro;

n is 0, 1, 2, 3, or 4;

m is 0, 1, 2, 3, or 4;

q is 0, 1, 2, 3, or 4;

Q may also be cyano, trifluoromethyl, or SO 2 NR 4 R 5 when q is 1, 2, 3, or 4;

Q may also be hydroxy, (C 1 -C 6 )-alkoxy, sulfhydryl, —S—(C 1 -C 6 )-alkyl, or NR 4 R 5 when q is 2, 3, or 4;

p is 1, 2, or 3;

R 3 may also be vinyl or ethynyl when R 3 is not covalently bonded to an N or O atom;

R 3 may also be vinyl or ethynyl when R 3 is not covalently bonded to an S atom possessing a −2 (minus 2) oxidation state;

the NR 4 R 5 group of any C(O)NR 4 R 5 , SO 2 NR 4 R 5 , NR 4 R 5 , or N(H)C(O)NR 4 R 5 may also form a pyrrolidine, a piperidine, a morpholine, a thiomorpholine, or a thiomorpholine S-dioxide;

each R 6 is independently hydrogen, methyl, trifluoromethyl, or amino; and

each R 7 is independently hydrogen or methyl.

28. A compound of claim 27 , wherein Y 3 is N and each R 6 is independently hydrogen, methyl, or trifluoromethyl.

29. A compound of claim 27 , wherein Y 3 is CH and each R 6 is independently hydrogen, methyl, or trifluoromethyl.

30. A compound of claim 1 , wherein the compound according to Formula (I) comprises a compound according to Formula (IX):

wherein:

each X 1 , X 2 , X 3 , X 4 , and X 5 is independently hydrogen or fluoro, with no more than two of X 1 , X 2 , X 3 , X 4 , and X 5 being fluoro;

n is 0, 1, 2, 3, or 4;

m is 0, 1, 2, 3, or 4;

q is 0, 1, 2, 3, or 4;

Q may also be cyano, trifluoromethyl, or SO 2 NR 4 R 5 when q is 1, 2, 3, or 4;

Q may also be hydroxy, (C 1 -C 6 )-alkoxy, sulfhydryl, —S—(C 1 -C 6 )-alkyl, or NR 4 R 5 when q is 2, 3, or 4;

p is 1, 2, or 3;

R 3 may also be vinyl or ethynyl when R 3 is not covalently bonded to an N or O atom;

R 3 may also be vinyl or ethynyl when R 3 is not covalently bonded to an S atom possessing a −2 (minus 2) oxidation state;

the NR 4 R 5 group of any C(O)NR 4 R 5 , SO 2 NR 4 R 5 , NR 4 R 5 , or N(H)C(O)NR 4 R 5 may also form a pyrrolidine, a piperidine, a morpholine, a thiomorpholine, or a thiomorpholine S-dioxide;

each R 6 is independently hydrogen, methyl, trifluoromethyl, or amino; and

each R 7 is independently hydrogen or methyl.

31. A compound of claim 30 , wherein the compound according to Formula (IX) comprises a compound according to Formula (X):

wherein:

each X 1 , X 2 , X 3 , X 4 , and X 5 is independently hydrogen or fluoro, with no more than two of X 1 , X 2 , X 3 , X 4 , and X 5 being fluoro;

n is 0, 1, 2, 3, or 4;

m is 0, 1, 2, 3, or 4;

q is 0, 1, 2, 3, or 4;

Q is hydrogen, (C 1 -C 6 )-alkyl, (CH 2 ) p CF 3 , (C 3 -C 6 )-alkenyl, (C 3 -C 6 )-alkynyl, (C 3 -C 6 )-cycloalkyl, (C 6 -C 14 )-aryl, C(O)R 3 , CO 2 R 3 , C(O)NR 4 R 5 , a three- to six-membered heterocycle, or a five- to ten-membered heteroaryl when q is 0, 1, 2, 3, or 4;

Q may also be cyano, trifluoromethyl, or SO 2 NR 4 R 5 when q is 1, 2, 3, or 4;

Q may also be hydroxy, (C 1 -C 6 )-alkoxy, sulfhydryl, —S—(C 1 -C 6 )-alkyl, or NR 4 R 5 when q is 2, 3, or 4;

p is 1, 2, or 3;

R 3 may also be vinyl or ethynyl when R 3 is not covalently bonded to an N or O atom;

R 3 may also be vinyl or ethynyl when R 3 is not covalently bonded to an S atom possessing a −2 (minus 2) oxidation state;

the NR 4 R 5 group of any C(O)NR 4 R 5 , SO 2 NR 4 R 5 , NR 4 R 5 , or N(H)C(O)NR 4 R 5 may also form a pyrrolidine, a piperidine, a morpholine, a thiomorpholine, or a thiomorpholine S-dioxide;

each R 6 is independently hydrogen, methyl, trifluoromethyl, or amino; and

each R 7 is independently hydrogen or methyl.

32. A compound of claim 31 , wherein Y 3 is N and each R 6 is independently hydrogen, methyl, or trifluoromethyl.

33. A compound of claim 31 , wherein Y 3 is CH and each R 6 is independently hydrogen, methyl, or trifluoromethyl.

34. A compound of claim 30 , wherein the compound according to Formula (IX) comprises a compound according to Formula (XI):

wherein:

each X 1 , X 2 , X 3 , X 4 , and X 5 is independently hydrogen or fluoro, with no more than two of X 1 , X 2 , X 3 , X 4 , and X 5 being fluoro;

n is 0, 1, 2, 3, or 4;

m is 0, 1, 2, 3, or 4;

q is 0, 1, 2, 3, or 4;

Q may also be cyano, trifluoromethyl, or SO 2 NR 4 R 5 when q is 1, 2, 3, or 4;

Q may also be hydroxy, (C 1 -C 6 )-alkoxy, sulfhydryl, —S—(C 1 -C 6 )-alkyl, or NR 4 R 5 when q is 2, 3, or 4;

p is 1, 2, or 3;

R 3 may also be vinyl or ethynyl when R 3 is not covalently bonded to an N or O atom;

R 3 may also be vinyl or ethynyl when R 3 is not covalently bonded to an S atom possessing a −2 (minus 2) oxidation state;

the NR 4 R 5 group of any C(O)NR 4 R 5 , SO 2 NR 4 R 5 , NR 4 R 5 , or N(H)C(O)NR 4 R 5 may also form a pyrrolidine, a piperidine, a morpholine, a thiomorpholine, or a thiomorpholine S-dioxide;

each R 6 is independently hydrogen, methyl, trifluoromethyl, or amino; and

each R 7 is independently hydrogen or methyl.

35. A compound of claim 34 , wherein Y 3 is N and each R 6 is independently hydrogen, methyl, or trifluoromethyl.

36. A compound of claim 34 , wherein Y 3 is CH and each R 6 is independently hydrogen, methyl, or trifluoromethyl.

37. A compound of claim 1 , wherein the compound according to Formula (I) comprises a compound according to Formula (XII):

wherein:

each X 1 , X 2 , X 3 , X 4 , and X 5 is independently hydrogen or fluoro, with no more than two of X 1 , X 2 , X 3 , X 4 , and X 5 being fluoro;

W is a covalent bond, O, or CO;

n is 0, 1, 2, 3, or 4;

m is 0, 1, 2, 3, or 4;

q is 0, 1, 2, 3, or 4;

Q may also be cyano, trifluoromethyl, or SO 2 NR 4 R 5 when q is 1, 2, 3, or 4;

Q may also be hydroxy, (C 1 -C 6 )-alkoxy, sulfhydryl, —S—(C 1 -C 6 )-alkyl, or NR 4 R 5 when q is 2, 3, or 4;

p is 1, 2, or 3;

R 3 may also be vinyl or ethynyl when R 3 is not covalently bonded to an N or O atom;

R 3 may also be vinyl or ethynyl when R 3 is not covalently bonded to an S atom possessing a −2 (minus 2) oxidation state;

the NR 4 R 5 group of any C(O)NR 4 R 5 , SO 2 NR 4 R 5 , NR 4 R 5 , or N(H)C(O)NR 4 R 5 may also form a pyrrolidine, a piperidine, a morpholine, a thiomorpholine, or a thiomorpholine S-dioxide;

each R 6 is independently hydrogen, methyl, trifluoromethyl, or amino; and

each R 7 is independently hydrogen or methyl.

38. A compound of claim 37 , wherein the compound according to Formula (XII) comprises a compound according to Formula (XIII)

wherein:

each X 1 , X 2 , X 3 , X 4 , and X 5 is independently hydrogen or fluoro, with no more than two of X 1 , X 2 , X 3 , X 4 , and X 5 being fluoro;

W is a covalent bond, O, or CO;

n is 0, 1, 2, 3, or 4;

m is 0, 1, 2, 3, or 4;

q is 0, 1, 2, 3, or 4;

Q may also be cyano, trifluoromethyl, or SO 2 NR 4 R 5 when q is 1, 2, 3, or 4;

Q may also be hydroxy, (C 1 -C 6 )-alkoxy, sulfhydryl, —S—(C 1 -C 6 )-alkyl, or NR 4 R 5 when q is 2, 3, or 4;

p is 1, 2, or 3;

R 3 may also be vinyl or ethynyl when R 3 is not covalently bonded to an N or O atom;

R 3 may also be vinyl or ethynyl when R 3 is not covalently bonded to an S atom possessing a −2 (minus 2) oxidation state;

the NR 4 R 5 group of any C(O)NR 4 R 5 , SO 2 NR 4 R 5 , NR 4 R 5 , or N(H)C(O)NR 4 R 5 may also form a pyrrolidine, a piperidine, a morpholine, a thiomorpholine, or a thiomorpholine S-dioxide;

each R 6 is independently hydrogen, methyl, trifluoromethyl, or amino; and

each R 7 is independently hydrogen or methyl.

39. A compound of claim 38 , wherein Y 3 is N and each R 6 is independently hydrogen, methyl, or trifluoromethyl.

40. A compound of claim 38 , wherein Y 3 is CH and each R 6 is independently hydrogen, methyl, or trifluoromethyl.

41. A compound of claim 37 , wherein the compound according to Formula (XII) comprises a compound according to Formula (XIV):

wherein:

each X 1 , X 2 , X 3 , X 4 , and X 5 is independently hydrogen or fluoro, with no more than two of X 1 , X 2 , X 3 , X 4 , and X 5 being fluoro;

W is a covalent bond, O, or CO;

n is 0, 1, 2, 3, or 4;

m is 0, 1, 2, 3, or 4;

q is 0, 1, 2, 3, or 4;

Q may also be cyano, trifluoromethyl, or SO 2 NR 4 R 5 when q is 1, 2, 3, or 4;

Q may also be hydroxy, (C 1 -C 6 )-alkoxy, sulfhydryl, —S—(C 1 -C 6 )-alkyl, or NR 4 R 5 when q is 2, 3, or 4;

p is 1, 2, or 3;

R 3 may also be vinyl or ethynyl when R 3 is not covalently bonded to an N or O atom;

R 3 may also be vinyl or ethynyl when R 3 is not covalently bonded to an S atom possessing a −2 (minus 2) oxidation state;

the NR 4 R 5 group of any C(O)NR 4 R 5 , SO 2 NR 4 R 5 , NR 4 R 5 , or N(H)C(O)NR 4 R 5 may also form a pyrrolidine, a piperidine, a morpholine, a thiomorpholine, or a thiomorpholine S-dioxide;

each R 6 is independently hydrogen, methyl, trifluoromethyl, or amino; and

each R 7 is independently hydrogen or methyl.

42. A compound of claim 41 , wherein Y 3 is N and each R 6 is independently hydrogen, methyl, or trifluoromethyl.

43. A compound of claim 41 , wherein Y 3 is CH and each R 6 is independently hydrogen, methyl, or trifluoromethyl.

44. A compound of claim 1 , wherein the compound according to Formula (I) comprises a compound according to Formula (XV):

wherein:

each X 1 , X 2 , X 3 , X 4 , and X 5 is independently hydrogen or fluoro, with no more than two of X 1 , X 2 , X 3 , X 4 , and X 5 being fluoro;

W is a covalent bond, O, or CO;

n is 0, 1, 2, 3, or 4;

m is 0, 1, 2, 3, or 4;

q is 0, 1, 2, 3, or 4;

Q is hydrogen, (C 1 -C 6 )-alkyl, (CH 2 ) p CF 3 , (C 3 -C 6 )- alkenyl, (C 3 -C 6 )-alkynyl, (C 3 - C 6 )-cycloalkyl, (C 6 -C 14 )-aryl, C(O)R 3 , CO 2 R 3 , C(O)NR 4 R 5 , a three- to six-membered heterocycle, or a five- to ten-membered heteroaryl when q is 0, 1, 2, 3, or 4;

Q may also be cyano, trifluoromethyl, or SO 2 NR 4 R 5 when q is 1, 2, 3, or 4;

Q may also be hydroxy, (C 1 -C 6 )-alkoxy, sulfhydryl, —S—(C 1 -C 6 )-alkyl, or NR 4 R 5 when q is 2, 3, or 4;

p is 1, 2, or 3;

R 3 may also be vinyl or ethynyl when R 3 is not covalently bonded to an N or O atom;

R 3 may also be vinyl or ethynyl when R 3 is not covalently bonded to an S atom possessing a −2 (minus 2) oxidation state;

the NR 4 R 5 group of any C(O)NR 4 R 5 , SO 2 NR 4 R 5 , NR 4 R 5 , or N(H)C(O)NR 4 R 5 may also form a pyrrolidine, a piperidine, a morpholine, a thiomorpholine, or a thiomorpholine S-dioxide;

each R 6 is independently hydrogen, methyl, trifluoromethyl, or amino; and

each R 7 is independently hydrogen or methyl.

45. A compound of claim 44 , wherein the compound according to Formula (XV) comprises a compound according to Formula (XVI):

wherein:

each X 1 , X 2 , X 3 , X 4 , and X 5 is independently hydrogen or fluoro, with no more than two of X 1 , X 2 , X 3 , X 4 , and X 5 being fluoro;

W is a covalent bond, O, or CO;

n is 0, 1, 2, 3, or 4;

m is 0, 1, 2, 3, or 4;

q is 0, 1, 2, 3, or 4;

Q may also be cyano, trifluoromethyl, or SO 2 NR 4 R 5 when q is 1, 2, 3, or 4;

Q may also be hydroxy, (C 1 -C 6 )-alkoxy, sulfhydryl, —S—(C 1 -C 6 )-alkyl, or NR 4 R 5 when q is 2, 3, or 4;

p is 1, 2, or 3;

R 3 may also be vinyl or ethynyl when R 3 is not covalently bonded to an N or O atom;

R 3 may also be vinyl or ethynyl when R 3 is not covalently bonded to an S atom possessing a −2 (minus 2) oxidation state;

the NR 4 R 5 group of any C(O)NR 4 R 5 , SO 2 NR 4 R 5 , NR 4 R 5 , or N(H)C(O)NR 4 R 5 may also form a pyrrolidine, a piperidine, a morpholine, a thiomorpholine, or a thiomorpholine S-dioxide;

each R 6 is independently hydrogen, methyl, trifluoromethyl, or amino; and

each R 7 is independently hydrogen or methyl.

46. A compound of claim 45 , wherein Y 3 is N and R 6 is hydrogen, methyl, or trifluoromethyl.

47. A compound of claim 45 , wherein Y 3 is CH and R 6 is hydrogen, methyl, or trifluoromethyl.

48. A compound of claim 44 , wherein the compound according to Formula (XV) comprises a compound according to Formula (XVII):

wherein:

each X 1 , X 2 , X 3 , X 4 , and X 5 is independently hydrogen or fluoro, with no more than two of X 1 , X 2 , X 3 , X 4 , and X 5 being fluoro;

W is a covalent bond, O, or CO;

n is 0, 1, 2, 3, or 4;

m is 0, 1, 2, 3, or 4;

q is 0, 1, 2, 3, or 4;

Q may also be cyano, trifluoromethyl, or SO 2 NR 4 R 5 when q is 1, 2, 3, or 4;

Q may also be hydroxy, (C 1 -C 6 )-alkoxy, sulfhydryl, —S—(C 1 -C 6 )-alkyl, or NR 4 R 5 when q is 2, 3, or 4;

p is 1, 2, or 3;

R 3 may also be vinyl or ethynyl when R 3 is not covalently bonded to an N or O atom;

R 3 may also be vinyl or ethynyl when R 3 is not covalently bonded to an S atom possessing a −2 (minus 2) oxidation state;

the NR 4 R 5 group of any C(O)NR 4 R 5 , SO 2 NR 4 R 5 , NR 4 R 5 , or N(H)C(O)NR 4 R 5 may also form a pyrrolidine, a piperidine, a morpholine, a thiomorpholine, or a thiomorpholine S-dioxide;

each R 6 is independently hydrogen, methyl, trifluoromethyl, or amino; and

each R 7 is independently hydrogen or methyl.

49. A compound of claim 48 , wherein Y 3 is N and R 6 is hydrogen or methyl.

50. A compound of claim 48 , wherein Y 3 is CH and R 6 is hydrogen or methyl.

51. A compound of claim 1 , wherein the compound according to Formula (I) comprises a compound according to Formula (XVIII):

wherein:

each X 1 , X 2 , X 3 , X 4 , and X 5 is independently hydrogen or fluoro, with no more than two of X 1 , X 2 , X 3 , X 4 , and X 5 being fluoro;

W is a covalent bond, O, or CO;

n is 0, 1, 2, 3, or 4;

m is 0, 1, 2, 3, or 4;

q is 0, 1, 2, 3, or 4;

Q may also be cyano, trifluoromethyl, or SO 2 NR 4 R 5 when q is 1, 2, 3, or 4;

Q may also be hydroxy, (C 1 -C 6 )-alkoxy, sulfhydryl, —S—(C 1 -C 6 )-alkyl, or NR 4 R 5 when q is 2, 3, or 4;

p is 1, 2, or 3;

R 3 may also be vinyl or ethynyl when R 3 is not covalently bonded to an N or O atom;

R 3 may also be vinyl or ethynyl when R 3 is not covalently bonded to an S atom possessing a −2 (minus 2) oxidation state;

the NR 4 R 5 group of any C(O)NR 4 R 5 , SO 2 NR 4 R 5 , NR 4 R 5 , or N(H)C(O)NR 4 R 5 may also form a pyrrolidine, a piperidine, a morpholine, a thiomorpholine, or a thiomorpholine S-dioxide;

each R 6 is independently hydrogen, methyl, trifluoromethyl, or amino; and

each R 7 is independently hydrogen or methyl.

52. A compound of claim 51 , wherein the compound according to Formula (XVIII) comprises a compound according to Formula (XIX):

wherein:

each X 1 , X 2 , X 3 , X 4 , and X 5 is independently hydrogen or fluoro, with no more than two of X 1 , X 2 , X 3 , X 4 , and X 5 being fluoro;

W is a covalent bond, O, or CO;

n is 0, 1, 2, 3, or 4;

m is 0, 1, 2, 3, or 4;

q is 0, 1, 2, 3, or 4;

Q is hydrogen, (C 1 -C 6 )-alkyl, (CH 2 ) p CF 3 , (C 3 -C 6 )-alkenyl, (C 3 -C 6 )-alkynyl, (C 3 -C 6 )-cycloalkyl, (C 6 -C 14 )-aryl, C(O)R 3 , CO 2 R 3 , C(O)NR 4 R 5 , a three- to six-membered heterocycle, or a five- to ten-membered heteroaryl when q is 0, 1, 2, 3, or 4;

Q may also be cyano, trifluoromethyl, or SO 2 NR 4 R 5 when q is 1, 2, 3, or 4;

Q may also be hydroxy, (C 1 -C 6 )-alkoxy, sulfhydryl, —S—(C 1 -C 6 )-alkyl, or NR 4 R 5 when q is 2, 3, or 4;

p is 1, 2, or 3;

R 3 may also be vinyl or ethynyl when R 3 is not covalently bonded to an N or O atom;

R 3 may also be vinyl or ethynyl when R 3 is not covalently bonded to an S atom possessing a −2 (minus 2) oxidation state;

the NR 4 R 5 group of any C(O)NR 4 R 5 , SO 2 NR 4 R 5 , NR 4 R 5 , or N(H)C(O)NR 4 R 5 may also form a pyrrolidine, a piperidine, a morpholine, a thiomorpholine, or a thiomorpholine S-dioxide;

the NR 4 R 5 group of any C(O)NR 4 R 5 , SO 2 NR 4 R 5 , NR 4 R 5 , or N(H)C(O)NR 4 R 5 may also form a piperazine ring, wherein the other nitrogen atom of the piperazine ring is substituted with hydrogen, (C 1 -C 6 )-alkyl, CH 2 CF 3 ,(C 3 -C 6 )-cycloalkyl, CH 2 (C 3 -C 6 )-cycloalkyl, phenyl, benzyl, hydroxyethyl, or hydroxypropyl;

each R 6 is independently hydrogen, methyl, trifluoromethyl, or amino; and

each R 7 is independently hydrogen or methyl.

53. A compound of claim 52 , wherein Y 3 is N.

54. A compound of claim 52 , wherein Y 3 is CH.

55. A pharmaceutical composition comprising a compound of claim 1 .

56. A method of treating a disease or condition mediated at least in part by prostaglandin D 2 produced by H-PGDS, in a subject in need of such treatment, wherein the disease or condition is allergy or allergic inflammation, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .

57. A pharmaceutical composition comprising a compound of claim 1 and a second pharmacologically active compound.

Assignments (5)

CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNEE ADDRESS TO 1180 E. ELLSWORTH ROAD, AND ADDING SEPTEMBER 22, 2009 AND 12/564,582 PREVIOUSLY RECORDED ON REEL 026436 FRAME 0728. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Recorded Nov 1, 2012

From: ENDRES, GREGORY W.; LEE, PIL HEUI; OLSON, KIRK LANG; KRAMER, JAMES BERNARD; CISKE, FRED LAWRENCE; BARRETT, STEPHEN DOUGLAS

To: CAYMAN CHEMICAL COMPANY, INCORPORATED

Reel/Frame 029229/0001 →

RELEASE OF SECURITY INTEREST Recorded Jul 11, 2011

From: BROADOAK CAPITAL PARTNERS, LLC

To: CAYMAN CHEMICAL COMPANY

Reel/Frame 026574/0808 →

CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNEE NAME TO CAYMAN CHEMICAL COMPANY, INCORPORATED PREVIOUSLY RECORDED ON REEL 023267 FRAME 0819. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Recorded Jun 13, 2011

From: ENDRES, GREGORY W.; LEE, PIL HEUI; OLSON, KIRK LANG; KRAMER, JAMES BERNARD; CISKE, FRED LAWRENCE; BARRETT, STEPHEN DOUGLAS

To: CAYMAN CHEMICAL COMPANY, INCORPORATED

Reel/Frame 026436/0728 →

SECURITY AGREEMENT Recorded Jul 20, 2010

From: CAYMAN CHEMICAL COMPANY, INCORPORATED

To: BROADOAK CAPITAL PARTNERS, LLC, AS AGENT

Reel/Frame 024710/0623 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 22, 2009

From: ENDRES, GREGORY W.; LEE, PIL HEUI; OLSON, KIRK LANG; KRAMER, JAMES BERNARD; CISKE, FRED LAWRENCE; BARRETT, STEPHEN DOUGLAS

To: CAYMAN CHEMICAL COMPANY

Reel/Frame 023267/0819 →

Continuity (2)

Provisional Application 61098942 · Sep 22, 2008

Related Publication 20100075990A1 · Mar 25, 2010