Processes For The Preparation Of Anti-Viral Compounds And Compositions Containing Them

• US 20100029655A1
• Filed: 07/09/2009
• Published: 02/04/2010
• Est. Priority Date: 07/11/2008
• Status: Abandoned Application

• Current Assignee: Martin Robert Leivers, Ryan Lauchli
• Original Assignee: Martin Robert Leivers, Ryan Lauchli
• Inventors: Leivers, Martin Robert, Lauchli, Ryan
• Application Number:
  US12/499,828
• Publication Number:
  US 20100029655A1
• Time in Patent Office: Days
• US Class Current: 514/248
• CPC Class Codes: A61K 31/41 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

Disclosed are processes for the preparation of compounds of formula I and compositions that comprise said compounds of formula I.

Also disclosed are processes for the preparation of compounds of formula III and compositions that comprise said compounds of formula III.

Claims

1. A process of preparing a compound of formula I

comprising converting a compound of formula 1.1

a compound of formula 2.1

a compound of formula 3.1

or a compound of formula II

to the compound of formula I,

wherein

a) when X is CR² or N, one of Y or Z is O and the other of Y or Z is N;

or one of Y or Z is N and the other of Y or Z is NR^a;

b) when X is O, NR^a, or S(O)_p wherein p is 0 or 1, one of Y or Z is N and the other of Y or Z is N or CR²;

L¹ is L³;

L² is a bond or L³;

L³ is independently C_3-6 cycloalkylene or is C_1-5 alkylene where one or two —

CH₂—

groups of said C_1-5 alkylene are optionally replaced with —

NR^b—

, —

S—

, —

(C═

O)—

, or —

O— and

optionally two —

CH₂—

groups together form a double bond or triple bond provided that L³ does not contain an —

O—

O—

, —

S—

O—

, or —

S—

S—

group, and wherein said C₁ to C₅ alkylene is optionally substituted with one to three groups independently selected from halo, alkyl, and spirocycloalkyl;

R^a and R^b are independently H, alkyl, or substituted alkyl;

R¹ and R³ are independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, cycloalkyl, and substituted cycloalkyl;

R² is independently selected from hydrogen, halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted amino, acylamino, hydroxy, alkoxy, substituted alkoxy, carboxy, carboxy ester, cycloalkyl, substituted cycloalkyl, and cyano;

CP is a substituent that can undergo a coupling reaction; and

LG is a leaving group

2. The process of claim 1, wherein the compound of formula I

is prepared by a process comprising

reacting the compound of formula 1.1

with a desulfurizing reagent.

3. The process of claim 2, wherein the compound of formula 1.1

is prepared by a process comprising

reacting a compound of formula 1.2

with a sulfurizing reagent.

4. The process of claim 3, wherein the compound of formula 1.2

is prepared by cyclizing a compound of formula 1.3

wherein

each LG is independently chosen and each is a leaving group.

5. The process of claim 4, wherein the cyclization of the compound of formula 1.3

occurs with a compound of formula 1.4

6. The process of claim 5, wherein at least one LG of formula 1.3 is a halogen.

7. The process of claim 5, wherein the compound of formula 1.3

is prepared by a process comprising

cyclizing a compound of formula 1.5

8. The process of claim 7, wherein the compound of formula 1.5

is prepared by a process comprising

reacting a compound of formula 1.6

with hydrazine,

wherein

LG is a leaving group.

9. The process of claim 8, wherein LG of formula 1.6 is a halogen, hydroxy, alkoxy, substituted alkoxy, or sulfonyloxy.

10. The process of claim 1, wherein the compound of formula I

is prepared by a process comprising

coupling a compound of formula 2.1

under conditions appropriate to form a new carbon-carbon bond.

11. The process of claim 10, wherein the compound of formula 2.1 is coupled with a compound of formula 2.2

M-L²-R³  

 

2.2

wherein

M is a substituent that can undergo a coupling reaction.

12. The process of claim 11, wherein the compound of formula 2.2

M-L²-R³  

 

2.2

is selected from an organotin, organozinc, organomagnesium, organosilyl, organoboron, and organotrifluoroborate compound.

13. The process of claim 12, wherein the organoboron is a boronic acid or boronic ester of formula 2.3

wherein

each R^x is independently selected from hydrogen, alkyl, or substituted alkyl and,

wherein

the R^x groups, if alkyl or substituted alkyl, can optionally be connected.

14. The process of claim 10, wherein CP is a halogen or sulfonlyoxy.

15. The process of claim 10, wherein the compound of formula 2.1

is prepared by a process comprising

reacting a compound of formula 2.5

with the compound of formula 1.6

wherein LG is a leaving group.

16. The process of claim 15, wherein LG of formula 1.6 is a halogen, hydroxy, substituted alkoxy, or sulfonyloxy.

17. The process of claim 15, wherein the compound of formula 2.5

is prepared by a process comprising

a) reacting a compound of formula 2.6

with a reducing reagent

and

b) cyclizing the resulting product to form the compound of formula 2.5.

18. The process of claim 1, wherein the compound of Formula I is prepared by converting the compound of formula 3.1

to the compound of formula I

by a process that comprises reacting the compound of formula 3.1 with a compound comprising nitrogen, oxygen or sulfur.

19. The process of claim 18, wherein LG is a halogen, hydroxy, alkoxy, substituted alkoxy, or sulfonyloxy.

20. The process of claim 18, wherein the compound comprising nitrogen is chosen from aniline, morpholine, piperidine, phenylmethanamine, N-methyl(phenyl)methanamine, 1,2,3,4-tetrahydroquinoline, (2-fluorophenyl)methanamine, (2,3-diflurophenyl)methanamine, 2-phenylethanamine, 1-phenylethanamine, 1,2,3,4-tetrahydroisoquinoline, 2,3-dihydro-1H-inden-1-amine, 1,2,3,4-tetrahydronaphthalen-1-amine, and isoindoline.

21. The process of claim 18, wherein the compound of formula 3.1

is prepared by a process comprising

reacting a compound of formula 3.2

with the compound of formula 1.6

wherein

each LG of formula 3.1 and 1.6 is independently chosen and each is a leaving group.

22. The process of claim 21, wherein at least one LG of formula 3.1 and 1.6 is halogen, hydroxy, alkoxy, substituted alkoxy, or sulfonyloxy.

23. The process of claim 21, wherein the compound of formula 3.2

is prepared by a process comprising

a) reacting a compound of formula 3.3

with a reducing reagent

and

b) cyclizing the resulting product to form the compound of formula 3.2.

24. The process of claim 1, wherein the compound of formula I is prepared by converting the compound of formula II

to the compound of formula I

by a process that comprises reacting the compound of formula II with a compound of formula 1.6

wherein

LG of formula 1.6 is a leaving group.

25. The process of claim 24, wherein LG of formula 1.6 is a halogen, hydroxy, alkoxy, substituted alkoxy, or sulfonyloxy.

26. The process of claim 24, wherein the compound of formula II

is prepared by a process comprising

a) reacting a compound of formula 4.1

with a reducing reagent

and

b) cyclizing the resulting product to form the compound of formula II.

27. The process of claim 26, wherein the compound of formula 4.1

is prepared by a process comprising

cyclizing a compound of formula 4.2

28. The process of claim 27, wherein the compound of formula 4.2

is prepared by a process comprising

reacting a compound of formula 4.3

with a compound of formula 4.4

29. The process of claim 24, wherein the compound of formula II

is prepared by a process comprising

a) saponifying a compound of formula 5.1

to form a compound of formula 5.2

and

b) decarboxylating the compound of formula 5.2 to form the compound of formula II,

wherein

each Alk is independently chosen and each is an alkyl or substituted alkyl.

30. The process of claim 29, wherein Alk is CH₃.

31. The process of claim 29, wherein the compound of formula 5.1

is prepared by a process comprising

reacting a compound of formula 5.3

with a compound of formula 5.4

to form the compound of formula 5.1.

32. The process of claim 31, wherein the compound of formula 5.3

is prepared by a process comprising

reacting a compound of formula 4.4

with glyoxal and ammonia.

33. The process of claim 1, wherein the compound of formula I is prepared by converting the compound of formula II

to the compound of formula I

by a process that comprises

a) reacting the compound of formula II with a compound of formula 6.1

to form a compound of formula 6.2

and

b) coupling the compound of formula 6.2 under conditions appropriate to form a carbon-carbon bond,

wherein

LG is a leaving group

and

CP is a substituent that can undergo a coupling reaction.

34. The process of claim 33, wherein LG of formula 6.1 is a halogen, hydroxy, alkoxy, substituted alkoxy, or sulfonyloxy.

35. The process of claim 33, wherein the compound of formula 6.2 is coupled with a compound of formula 6.3

M-R¹  

 

6.3

wherein

M is a substituent that can undergo a coupling reaction.

36. The process of claim 35, wherein the compound of formula 6.3

M-R¹  

 

6.3

is selected from an organotin, organozinc, organomagnesium, organosilyl, organoboron, and organotrifluoroborate compound.

37. The process of claim 36, wherein the organoboron is a boronic acid or boronic ester of formula 6.4

wherein

each R^x is independently selected from hydrogen, alkyl, or substituted alkyl

and,

wherein

the R^x groups, if alkyl or substituted alkyl, can optionally be connected.

38. The process of claim 33, wherein CP of formula 6.2 is a halogen or sulfonlyoxy.

39. The process of claim 1, wherein the compound of formula I is prepared by converting the compound of formula II

to the compound of formula I

by a process that comprises

a) reacting the compound of formula II with a compound of formula 7.1

to form a compound of formula 7.2

b) reacting the compound of formula 7.2 with a suitable reagent to form a compound of formula 7.3

and

c) coupling the compound of formula 7.3 with a compound of formula 7.4

CP—

R¹  

 

7.4

under conditions appropriate to form a carbon-carbon bond,

wherein

LG is a leaving group,

R^y is a halogen or sulfonyloxy,

and

M and CP are each substituents that can undergo a coupling reaction.

40. The process of claim 39, wherein LG of formula 7.1 is a halogen, hydroxy, alkoxy, substituted alkoxy, or sulfonyloxy.

41. The process of claim 39, wherein R^y is a halogen.

42. The process of claim 39, wherein M comprises tin, zinc, magnesium, silicon, or boron.

43. The process of claim 39, wherein CP of formula 7.4 is a halogen or sulfonlyoxy.

44. A process of preparing a compound of formula III

comprising converting a compound of formula 8.1

a compound of formula 9.1

a compound of formula 10.1

to the compound of formula III,

wherein

ring B is a 6-membered aromatic ring wherein 1 to 3 ring carbon atoms are optionally replaced by nitrogen, wherein each nitrogen is optionally oxidized, and wherein ring B may be optionally fused to a 5- or 6-membered aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle to form a 9- or 10-membered bicyclic ring;

L⁴is L⁶;

L⁵ is a bond or L⁶;

L⁶ is independently C_3-6 cycloalkylene or is C_1-5 alkyene where one or two —

CH₂—

groups of said C_1-5 alkylene are optionally replaced with —

NR⁷—

, —

S—

, —

(C═

O)—

, or —

O— and

optionally two —

CH₂—

groups together form a double bond or triple bond provided that L⁶ does not contain an —

O—

O—

, —

S—

O—

, or —

S—

S—

group, and wherein said C₁ to C₅ alkylene is optionally substituted with one to two groups independently selected from spirocycloalkyl and R⁵;

R⁴ is independently selected from R⁵, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, stabilized alkenyloxyaryl, and stabilized alkenyloxyheteroaryl;

R⁵ is independently selected from hydrogen, halo, amino, substituted amino, acylamino, aminocarbonyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, azido, hydroxy, alkoxy, substituted alkoxy, oxo, carboxy, carboxy ester, acyloxy, cyano, thiol, alkylthio, substituted alkylthio, and substituted sulfonyl;

R⁶ is independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, stabilized alkenyloxyaryl, and stabilized alkenyloxyheteroaryl;

R⁷ is independently H, alkyl, or substituted alkyl;

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

CP is a group that can undergo a coupling reaction; and

LG is a leaving group;

provided that the compound of Formula I is not 4′

-(2-butyl-imidazo[4,5-d]-pyridazin-5-ylmethyl)-biphenyl-2-carboxylic acid.

45. The process of claim 44, wherein the compound of formula III is prepared by converting the compound of formula 8.3

to the compound of formula III

by a process that comprises desulfurization of the compound of formula 8.1.

46. The process of claim 45, wherein the compound of formula 8.1

is prepared by a process comprising

reacting a compound of formula 8.2

with a sulfurizing reagent.

47. The process of claim 46, wherein the compound of formula 8.2

is prepared by a process comprising

cyclizing a compound of formula 8.3

wherein

each LG of formula 8.3 is independently chosen and each is a leaving group.

48. The process of claim 47, wherein the cyclization of the compound of formula 8.3

occurs with a compound of formula 8.4

49. The process of claim 48, wherein at least one LG of formula 8.3 is a halogen.

50. The process of claim 48, wherein the compound of formula 8.3

is prepared by a process comprising

cyclizing a compound of formula 8.5

51. The process of claim 50, wherein the compound of formula 8.5

is prepared by a process comprising

reacting a compound of formula 8.6

with hydrazine.

wherein

LG is a leaving group.

52. The process of claim 51, wherein LG of formula 8.6 is a halogen, hydroxy, alkoxy, substituted alkoxy, or sulfonyloxy.

53. The process of claim 44, wherein the compound of formula III

is prepared by a process comprising

coupling a compound of formula 9.1

under conditions appropriate to form a new carbon-carbon bond.

54. The process of claim 53, wherein the compound of formula 9.1 is coupled with a compound of formula 9.2

M-L⁵-R⁶  

 

9.2

wherein

M is a substituent that can undergo a coupling reaction.

55. The process of claim 54, wherein the compound of formula 9.2

M-L⁵-R⁶  

 

9.2

comprises tin, zinc, magnesium, silicon, or boron.

56. The process of claim 55, wherein the compound of formula 9.2

M-L⁵-R⁶  

 

9.2

is selected from an organotin, organozinc, organomagnesium, organosilyl, organoboron, or organotrifluoroborate compound.

57. The process of claim 56, wherein the organoboron is a boronic acid or boronic ester of formula 9.3

wherein

each R^x is independently selected from hydrogen, alkyl, or substituted alkyl

and,

wherein

the R^x groups, if alkyl or substituted alkyl, can optionally be connected.

58. The process of claim 53, wherein CP of formula 9.1 is a halogen or sulfonlyoxy.

59. The process of claim 53, wherein the coupling reaction occurs in the presence of at least one compound comprising palladium, nickel, iron, or copper.

60. The process of claim 53, wherein the compound of formula 9.1

is prepared by a process comprising

reacting a compound of formula 2.5

with a compound of formula 9.5

wherein LG is a leaving group.

61. The process of claim 60, wherein LG of formula 9.5 is a halogen, hydroxy, alkoxy, substituted alkoxy, or sulfonyloxy.

62. The process of claim 44, wherein the compound of formula III is prepared by converting the compound of formula 10.1

to the compound of formula III

by a process that comprises reacting the compound of formula 10.1 with a compound comprising nitrogen, oxygen or sulfur.

63. The process of claim 62, wherein LG is a hydrogen, hydroxyl, alkoxy, substituted alkoxy, or sulfonyloxy.

64. The process of claim 62, wherein the compound comprising nitrogen is chosen from aniline, morpholine, piperidine, phenylmethanamine, N-methyl(phenyl)methanamine, 1,2,3,4-tetrahydroquinoline, (2-fluorophenyl)methanamine, (2,3-diflurophenyl)methanamine, 2-phenylethanamine, 1-phenylethanamine, 1,2,3,4-tetrahydroisoquinoline, 2,3-dihydro-1H-inden-1-amine, 1,2,3,4-tetrahydronaphthalen-1-amine, and isoindoline.

65. The process of claim 62, wherein the compound of formula 10.1

is prepared by a process comprising

reacting the compound of formula 3.2

with the compound of formula 9.5

wherein

each LG of formula 3.2 and 9.5 is independently chosen and each is a leaving group.

66. The process of claim 65, wherein at least one LG formula 3.2 and 9.5 is halogen, hydroxy, alkoxy, substituted alkoxy, or sulfonyloxy.

67. A process of preparing a compound of formula III

comprising converting a compound of formula IV

to the compound of formula III,

wherein

ring B is a 6-membered aromatic ring wherein 1 to 3 ring carbon atoms are optionally replaced by nitrogen, wherein each nitrogen is optionally oxidized, and wherein ring B may be optionally fused to a 5- or 6-membered aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle to form a 9- or 10-membered bicyclic ring;

L⁴ is L⁶;

L⁵ is a bond or L⁶;

L⁶ is independently C_3-6 cycloalkylene or is C_1-5 alkylene where one or two —

CH₂—

groups of said C_1-5 alkylene are optionally replaced with —

NR⁷—

, —

S—

, —

(C═

O)—

, or —

O— and

optionally two —

CH₂—

groups together form a double bond or triple bond provided that L⁶ does not contain an —

O—

O—

, —

S—

O—

, or —

S—

S—

group, and wherein said C₁ to C₅ alkylene is optionally substituted with one to two groups independently selected from spirocycloalkyl and R⁵,

R⁴ is independently selected from R⁵, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, stabilized alkenyloxyaryl, and stabilized alkenyloxyheteroaryl;

R⁵ is independently selected from hydrogen, halo, amino, substituted amino, acylamino, aminocarbonyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, azido, hydroxy, alkoxy, substituted alkoxy, oxo, carboxy, carboxy ester, acyloxy, cyano, thiol, alkylthio, substituted alkylthio, and substituted sulfonyl;

R⁶ is independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, stabilized alkenyloxyaryl, and stabilized alkenyloxyheteroaryl;

R⁷ is independently H, alkyl, or substituted alkyl;

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

provided that the compound of Formula I is not 4′

-(2-butyl-imidazo[4,5-d]-pyridazin-5-ylmethyl)-biphenyl-2-carboxylic acid.

68. The process of claim 67, wherein converting the compound of formula IV

to the compound of formula III

comprises reacting the compound of formula IV with a compound of formula 9.5

wherein

LG is a leaving group.

69. The process of claim 68, wherein LG is a halogen, hydroxy, alkoxy, substituted alkoxy, or sulfonyloxy.

70. The process of claim 68, wherein the compound of formula IV

is prepared by a process comprising

a) reacting a compound of formula 10.1

with a reducing reagent

and

b) cyclizing the resulting product to form the compound of formula IV.

71. The process of claim 70, wherein the reducing reagent is diisobutylaluminum hydride.

72. The process of claim 70, wherein the cyclization occurs with hydrazine.

73. The process of claim 70, wherein the compound of formula 10.1

is prepared by a process comprising

cyclizing a compound of formula 10.2

74. The process of claim 73, wherein the cyclization occurs with N-chlorosuccinimide and nicotinamide.

75. The process of claim 73, wherein the compound of formula 10.2

is prepared by a process comprising

reacting a compound of formula 4.3

with a compound of formula 10.3

76. The process of claim 67, wherein the compound of formula IV

is prepared by a process comprising

a) saponifying a compound of formula 11.1

to form a compound of formula 11.2

and

b) decarboxylating the compound of formula 11.2 to form the compound of formula IV,

wherein

each Alk is independently chosen and each is an alkyl or substituted alkyl.

77. The process of claim 76, wherein the saponification and decarboxylation occur in the presence of hydrochloric acid and water.

78. The process of claim 76, wherein Alk is CH₃.

79. The process of claim 76, wherein the compound of formula 11.1

is prepared by a process comprising

reacting a compound of formula 11.3

with a compound of formula 11.4

to form the compound of formula 11.1.

80. The process of claim 79, wherein the reaction is heated.

81. The process of claim 79, wherein the compound of formula 11.3

is prepared by a process comprising

reacting a compound of formula 10.3

with glyoxal and ammonia.

82. The process of claim 81, wherein converting the compound of formula IV

to the compound of formula III

comprises

a) reacting the compound of formula IV with a compound of formula 12.1

to form a compound of formula 12.2

and

b) coupling the compound of formula 12.2 under conditions appropriate to form a new carbon-carbon bond,

wherein

LG is a leaving group

and

CP is a substituent that can undergo a coupling reaction.

83. The process of claim 82, wherein LG is a halogen, hydroxy, alkoxy, substituted alkoxy, or sulfonyloxy.

84. The process of claim 82, wherein the compound of formula 12.2

is coupled with a compound of formula 12.3

M-R⁴  

 

12.3

wherein

M is a substituent that can undergo a coupling reaction.

85. The process of claim 84, wherein the compound of formula 12.3

M-R⁴  

 

12.3

comprises tin, zinc, magnesium, silicon, or boron.

86. The process of claim 84, wherein the compound of formula 12.3

M-R⁴  

 

12.3

is selected from an organotin, organozinc, organomagnesium, organosilyl, organoboron, and organotrifluoroborate compound.

87. The process of claim 86, wherein the organoboron is a boronic acid or boronic ester of formula 12.4

wherein

each R^x is independently selected from hydrogen, alkyl, or substituted alkyl

and,

wherein

the R^x groups, if alkyl or substituted alky, can optionally be connected.

88. The process of claim 87, wherein the boronic acid is a compound of formula 12.5

89. The process of claim 82, wherein CP is a halogen or sulfonlyoxy.

90. The process of claim 82, wherein the coupling reaction occurs in the presence of at least one compound comprising palladium, nickel, iron, or copper.

91. The process of claim 90, wherein the coupling reaction occurs in the presence of tetrakistriphenylphosphine palladium.

92. The process of claim 67, wherein converting the compound of formula IV

to the compound of formula III

comprises

a) reacting the compound of formula IV with a compound of formula 13.1

to form a compound of formula 13.2

b) reacting the compound of formula 13.2 with a suitable reagent to form a compound of formula 13.3

and

c) coupling the compound of formula 13.3 with a compound of formula 13.4

CP—

R⁴  

 

13.4

under conditions appropriate to form a new carbon-carbon bond,

wherein

LG is a leaving group,

R^y is a halogen or sulfonyloxy,

and

M and CP are each substituents that can undergo a coupling reaction,

93. The process of claim 92, wherein LG is a halogen, hydroxy, alkoxy, substituted alkoxy, or sulfonyloxy.

94. The process of claim 92, wherein R^y is a halogen or sulfonyloxy.

95. The process of claim 92, wherein M comprises tin, zinc, magnesium, silicon, or boron.

96. The process of claim 92, wherein CP is a halogen or sulfonlyoxy.

97. The process of claim 92, wherein the coupling reaction of step (c) occurs in the presence of at least one compound comprising palladium, nickel, iron, or copper.

98. The process of claim 97, wherein the coupling reaction of step (c) occurs in the presence of tetrakistriphenylphosphine palladium.

99. The process of claim 68, wherein the compound of formula 9.5 is 5-(Chloromethyl)-2-[4-propyloxy)-2-(trifluoromethyl)phenyl]pyrimidine.

100. The process of claim 68, wherein the compound of formula 9.5

is prepared by a process comprising reacting a compound of formula 16.1

with a compound containing LG to form the compound of formula 9.5.

101. The process of claim 100, wherein the compound containing LG is a chlorinated compound.

102. The process of claim 100, wherein the chlorinated compound is thionyl chloride.

103. The process of claim 100, wherein the compound of formula 16.1 is {2-[4-(Propyloxy)-2-(trifluoromethyl)phenyl]-5-pyrimidinyl}methanol.

104. The process of claim 100, wherein the compound of formula 16.1 is prepared by a process comprising reacting a compound of formula 16.2

with a reducing reagent to form the compound of formula 16.1, wherein Alk is alkyl or substituted alkyl.

105. The process of claim 104, wherein Alk in the compound of formula 16.2 is CH₃.

106. The process of claim 104, wherein the reducing agent is selected from the group consisting of lithium aluminum hydride, sodium borohydride and diisobutylaluminum hydride.

107. The process of claim 104, wherein the compound of formula 16.2 is Methyl 2-[4-(Propyloxy)-2-(trifluoromethyl)phenyl]-5-pyrimidinecarboxylate.

108. The process of claim 104, wherein the compound of formula 16.2 is prepared by a process comprising reacting a compound of formula 16.3

or a salt thereof, with an alkoxy ester to form the compound of formula 16.2.

109. The process of claim 108, wherein reaction of the compound of formula 16.3 or salt thereof with the alkoxy ester occurs in the presence of nitrogen and optionally heat.

110. The process of claim 108, wherein the alkoxy ester is methyl-2-[bis(methyloxy)methyl]-3-hydroxy-2-propenoate or a salt thereof.

111. The process of claim 108, wherein the compound of formula 16.3 or salt thereof is 4-(Propyloxy)-2-(trifluoromethyl)benzenecarboximidamide hydrochloride.

112. The process of claim 108, wherein the compound of formula 16.3 or salt thereof is prepared by a process comprising reacting a compound of formula 16.4

with a nucleophilic base to form the compound of formula 16.3 or a salt thereof.

113. The process of claim 112, wherein reaction of the compound of formula 16.4 occurs in the presence of nitrogen and optionally heat.

114. The process of claim 112, wherein the nucleophilic base is a salt of hexamethyldisilazide.

115. The process of claim 112, wherein the compound of formula 16.4 is 4-(Propyloxy)-2-(trifluoromethyl)benzonitrile.

116. A composition comprising

(1) a compound of formula I or a salt or solvate thereof

wherein

a) when X is CR² or N, one of Y or Z is O and the other of Y or Z is N;

or one of Y or Z is N and the other of Y or Z is NR^a;

b) when X is O, NR^a, or S(O)_p wherein p is 0 or 1, one of Y or Z is N and the other of Y or Z is Nor CR²;

L¹ is L³;

L² is a bond or L³;

L³ is independently C_3-6 cycloalkylene or is C_1-5 alkylene where one or two —

CH₂—

groups of said C_1-5 alkylene are optionally replaced with —

NR^b—

, —

S—

, —

(C═

O)—

, or —

O— and

optionally two —

CH₂—

groups together form a double bond or triple bond provided that L³ does not contain an —

O—

O—

, —

S—

O—

, or —

S—

S—

group, and wherein said C₁ to C₅ alkylene is optionally substituted with one to three groups independently selected from halo, alkyl, and spirocycloalkyl;

R^a and R^b are independently H, alkyl, or substituted alkyl;

R¹ and R³ are independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, cycloalkyl, and substituted cycloalkyl;

and

R² is independently selected from hydrogen, halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted amino, acylamino, hydroxy, alkoxy, substituted alkoxy, carboxy, carboxy ester, cycloalkyl, substituted cycloalkyl, and cyano; and

(2) a detectable amount of one or more compounds selected from;

a compound of formula 1.1

or a salt thereof;

P₂S₅;

a compound of formula 2.1

or a salt thereof, wherein CP is a group that can undergo a coupling reaction;

a compound of formula 14.1

or a salt thereof, wherein L¹, L², R¹, R³, X, Y, and Z are as defined above;

a compound comprising tin, zinc, magnesium, silicon, or boron;

a compound comprising palladium, nickel, iron, or copper;

hydrazine;

and

Cs₂CO₃.

117. A composition comprising

(1) a compound of formula III or a salt or solvate thereof

wherein

ring B is a 6-membered aromatic ring wherein 1 to 3 ring carbon atoms are optionally replaced by nitrogen, wherein each nitrogen is optionally oxidized, and wherein ring B may be optionally fused to a 5- or 6-membered aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle to form a 9- or 10-membered bicyclic ring;

L⁴ is L⁶;

L⁵ is a bond or L⁶;

L⁶ is independently C_3-6 cycloalkylene or is C_1-5 alkylene where one or two —

CH₂—

groups of said C_1-5 alkylene are optionally replaced with —

NR⁷—

, —

S—

, —

(C═

O)—

, or —

O— and

optionally two —

CH₂—

groups together form a double bond or triple bond provided that L⁶ does not contain an —

O—

O—

, —

S—

O—

, or —

S—

S—

group, and wherein said C₁ to C₅ alkylene is optionally substituted with one to two groups independently selected from spirocycloalkyl and R⁵;

R⁴ is independently selected from R⁵, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, stabilized alkenyloxyaryl, and stabilized alkenyloxyheteroaryl;

R⁵ is independently selected from hydrogen, halo, amino, substituted amino, acylamino, aminocarbonyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, azido, hydroxy, alkoxy, substituted alkoxy, oxo, carboxy, carboxy ester, acyloxy, cyano, thiol, alkylthio, substituted alkylthio, and substituted sulfonyl;

R⁶ is independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, stabilized alkenyloxyaryl, and stabilized alkenyloxyheteroaryl;

R⁷ is independently H, alkyl, or substituted alkyl;

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

provided that the compound of Formula I is not 4′

-(2-butyl-imidazo[4,5-d]-pyridazin-5-ylmethyl)-biphenyl-2-carboxylic acid.

and

(2) a detectable amount of one or more compounds selected from;

a compound of formula 6.1

or a salt thereof;

P₂S₅;

a compound of formula 7.1

or a salt thereof, wherein CP is a group that can undergo a coupling reaction;

a compound of formula 15.1

or a salt thereof, wherein L⁴, L⁵, R⁴, R⁵, R⁶, and m are as defined above;

a compound comprising tin, zinc, magnesium, silicon, or boron;

a compound comprising palladium, nickel, iron, or copper;

hydrazine;

and

Cs₂CO₃.