AZETIDINE AND CYCLOBUTANE DERIVATIVES AS JAK INHIBITORS

• US 20090233903A1
• Filed: 03/10/2009
• Published: 09/17/2009
• Est. Priority Date: 03/11/2008
• Status: Active Grant

• Current Assignee: Incyte Holdings Corporation And Incyte Corporation
• Original Assignee: Incyte Corporation
• Inventors: Li, Yun-Long, Shepard, Stacey, Rodgers, James D., Xia, Michael, Zhou, Jiacheng, Liu, Pingli, Meloni, David
• Granted Patent: US 8,158,616 B2
• Time in Patent Office: Days
• US Class Current: 514/210.210
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 41/00 Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: B60Q 3/76 : for spotlighting, e.g. reading lamps spotlighting on or for specific fittings B60Q3/20; spotlighting in mass transit vehicles B60Q3/44
• CPC Class Codes: B60Q 3/80 : Circuits; Control arrangements for dashboards B60Q3/16; for mass transit vehicles B60Q3/47
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: Y10S 362/80 : Light emitting diode
• CPC Class Codes: Y10S 362/802 : Position or condition responsive switch

Abstract

The present invention relates to azetidine and cyclobutane derivatives, as well as their compositions, methods of use, and processes for preparation, which are JAK inhibitors useful in the treatment of JAK-associated diseases including, for example, inflammatory and autoimmune disorders, as well as cancer.

Claims

1. A compound of Formula I:

or pharmaceutically acceptable salt thereof, wherein;

L is SO₂ or CO;

R¹ is C_1-6 alkyl, C_3-7 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, indolyl, NR²R³, or OR⁴, wherein said alkyl, cycloalkyl, phenyl, or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from F, CN, and C_1-4 alkyl;

R² and R³ are independently selected from H, C_1-4 alkyl, and phenyl; and

R⁴ is C_1-6 alkyl, phenyl, or benzyl;

wherein when L is SO₂, R¹ is other than OR⁴.

2. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein L is SO₂.

3. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein L is CO.

4. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, 2-methylprop-1-yl, 1-methylprop-1-yl, each optionally substituted with 1, 2, or 3 F.

5. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R¹ is C_1-4 alkyl.

6. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R¹ is ethyl.

7. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R¹ is C_3-7 cycloalkyl optionally substituted by C_1-4 alkyl.

8. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R¹ is phenyl optionally substituted with F, methyl, or CN.

9. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R¹ is 5-membered heteroaryl selected from thienyl, pyrazolyl, pyrrolyl, 1,2,4-oxadiazolyl, and isoxazolyl, each optionally substituted with C_1-4 alkyl.

10. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R¹ is pyridinyl.

11. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R¹ is NR²R³ or OR⁴.

12. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein L is SO₂ and R¹ is C_1-6 alkyl.

13. The compound of claim 1 selected from:

{1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

1-(cyclopropylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-ylacetonitrile;

1-[(1-methylcyclopropyl)carbonyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-ylacetonitrile;

1-[(1-methylcyclopropyl)sulfonyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-ylacetonitrile;

1-(methylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(phenylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]acetonitrile;

{1-(isopropylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1yl]azetidin-3-yl}acetonitrile;

{1-(propylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(butylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(tert-butylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1yl]azetidin-3-yl}acetonitrile;

3-(cyanomethyl)-N,N-dimethyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidine-1-sulfonamide;

{1-[(1-methyl-1H-pyrazol-3-yl)sulfonyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo 1-1-yl]-1-[(3,3,3-trifluoropropyl)sulfonyl]azetidin-3-yl}acetonitrile;

{1-(isobutylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(sec-butylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-[(5-methyl-2-thienyl)sulfonyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-[(4-fluorophenyl)sulfonyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-[(3-fluorophenyl)sulfonyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-[(2-fluorophenyl)sulfonyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1yl]azetidin-3-yl}acetonitrile;

{1-(pyridin-3-ylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(pyridin-2-ylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cyclopropylcarbonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

1-[(1-methylcyclopropyl)carbonyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-ylacetonitrile;

{1-benzoyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-[(6-methylpyridin-2-yl)carbonyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(pyridin-3-ylcarbonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(3-methylbenzoyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(4-methylbenzoyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

3-({3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}carbonyl)benzonitrile;

[3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazo 1-1-yl]-1-(2-thienylcarbonyl)azetidin-3-yl]acetonitrile;

[3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(1H-pyrrol-2-ylcarbonyl)azetidin-3-yl]acetonitrile;

{1-(1H-indol-2-ylcarbonyl)-3-[4-(7H-pyrrolo[2,3-d ]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(isoxazol-5-ylcarbonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(1H-pyrazol-3-ylcarbonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

isobutyl 3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate;

phenyl 3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate;

benzyl 3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate; and

3-(cyanomethyl)-N-phenyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxamide;

or a pharmaceutically acceptable salt of any of the aforementioned.

16. A composition comprising a compound of claim 1, or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

17. The composition of claim 16 which is suitable for topical administration.

28. A method of treating an autoimmune disease in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1 or claim 18, or pharmaceutically acceptable salt thereof.

29. The method of claim 28 wherein said autoimmune disease is a skin disorder, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, type I diabetes, lupus, inflammatory bowel disease, Crohn'"'"'s disease, myasthenia gravis, immunoglobulin nephropathies, myocarditis, or autoimmune thyroid disorder.

30. The method of claim 29 wherein said autoimmune disease is rheumatoid arthritis.

31. The method of claim 29 wherein said autoimmune diseases is a skin disorder.

32. The method of claim 31 wherein said skin disorder is atopic dermatitis, psoriasis, skin sensitization, skin irritation, skin rash, contact dermatitis or allergic contact sensitization.

33. A method of treating cancer in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1 or claim 18, or pharmaceutically acceptable salt thereof.

34. The method of claim 33 wherein said cancer is a solid tumor.

35. The method of claim 33 wherein said cancer is prostate cancer, renal cancer, hepatic cancer, breast cancer, lung cancer, thyroid cancer, Kaposi'"'"'s sarcoma, Castleman'"'"'s disease or pancreatic cancer.

36. The method of claim 33 wherein said cancer is lymphoma, leukemia, or multiple myeloma.

37. A method of treating a myeloproliferative disorder in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1 or claim 18, or pharmaceutically acceptable salt thereof.

38. The method of claim 37 wherein said myeloproliferative disorder (MPD) is polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), idiopathic myelofibrosis (IMF), or systemic mast cell disease (SMCD).

39. A method of treating an inflammatory disease in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1 or claim 18, or pharmaceutically acceptable salt thereof.

40. A method of treating organ transplant rejection in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1 or claim 18, or pharmaceutically acceptable salt thereof.

45. A method for preparing a compound of claim 1, comprising treating a compound of Formula Ia:

to remove the R⁷ moiety;

wherein;

L is SO₂ or CO;

R¹ is C_1-6 alkyl, C_3-7 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, indolyl, NR²R³, or OR⁴, wherein said alkyl, cycloalkyl, phenyl, or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from F, CN, and C_1-4 alkyl;

R² and R³ are independently selected from H, C_1-4 alkyl, and phenyl;

R⁴ is C_1-6 alkyl, phenyl, or benzyl; and

R⁷ is a protecting group;

wherein when L is SO₂, R¹ is other than OR⁴.

46. The method of claim 45, wherein R⁷ is a group which is resistant to room temperature acidic conditions.

47. The method of claim 45, wherein R⁷ is 2-(trimethylsilyl)ethoxymethyl.

48. The method of claim 46 or 47, wherein said treating comprises treating with lithium tetrafluoroborate or trifluoroborate etherate, followed by treating with ammonium hydroxide.

49. The method of claim 45, wherein R⁷ is N-pivaloyloxymethyl.

50. The method of claim 46 or 49, wherein said treating comprises treating with base.

51. The method of claim 50, wherein said base is sodium hydroxide or lithium hydroxide.

52. The method of claim 45, further comprising reacting said compound of Formula I with phosphoric acid to form the phosphate salt.

53. The method of claim 45, further comprising reacting a compound of Formula Ib:

with a compound of Formula Ic;

to form said compound of Formula Ia.

54. The method of claim 53, wherein said reacting of said compound of Formula Ib and said compound of Formula Ic is performed in the presence of a Michael addition catalyst.

55. The method of claim 54, wherein said Michael addition catalyst is a tetraalkylammonium halide, tetraalkylammonium hydroxide, guanidine, amidine, hydroxide, alkoxide, silicate, alkali metal phosphate, oxide, tertiary amine, alkali metal carbonate, alkali metal bicarbonate, alkali metal hydrogen phosphate, phosphine, or alkali metal salt of a carboxylic acid.

56. The method of claim 54, wherein said Michael addition catalyst is tetramethyl guanidine, 1,8-diazabicyclo(5.4.0)undec-7-ene, 1,5-diazabicyclo(4.3.0)non-5-ene, 1,4-diazabicyclo(2.2.2)octane, tert-butyl ammonium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, tripotassium phosphate, sodium silicate, calcium oxide, triethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydrogen phosphate, triphenyl phosphine, triethyl phosphine, potassium acetate, or potassium acrylate.

57. The method of claim 54, wherein said Michael addition catalyst is 1,8-diazabicyclo(5.4.0)undec-7-ene.

58. The method of claim 45, further comprising reacting a compound of Formula Id:

with a compound of formula R⁸-L-R¹ to form said compound of Formula Ia;

wherein R⁸ is a leaving group.

59. The method of claim 58, wherein R⁸ is halogen or C_1-4 alkoxy.

60. The method of claim 58, wherein R⁸ is chloro.

61. The method of any one of claims 58 to 60, wherein said reacting of said compound of Formula Id with said compound of formula R⁸-L-R¹ is performed in the presence of a base.

62. The method of claim 61, wherein said base is a tertiary amine.

63. The method of claim 61 wherein said base is diisopropylethylamine.

64. The method of claim 58, further comprising treating a compound of Formula Ie:

to remove the R⁹ group thereby forming said compound of Formula Id;

wherein R⁹ is a protecting group.

65. The method of claim 64, wherein R⁹ is C_1-6 alkoxycarbonyl.

66. The method of claim 64, wherein R⁹ is tert-butoxycarbonyl.

67. The method of claim 64, wherein said treating of said compound of Formula Ie comprises treating with hydrochloric acid in 1,4-dioxane.

68. The method claim 64, further comprising reacting a compound of Formula Ib:

with a compound of Formula If;

to form said compound of Formula Ie.

69. The method of claim 68, wherein said reacting of said compound of Formula Ib and said compound of Formula If is performed in the presence of a Michael addition catalyst.

70. The method of claim 69, wherein said Michael addition catalyst is a tetraalkylammonium halide, tetraalkylammonium hydroxide, guanidine, amidine, hydroxide, alkoxide, silicate, alkali metal phosphate, oxide, tertiary amine, alkali metal carbonate, alkali metal bicarbonate, alkali metal hydrogen phosphate, phosphine, or alkali metal salt of a carboxylic acid.

71. The method of claim 69, wherein said Michael addition catalyst is tetramethyl guanidine, 1,8-diazabicyclo(5.4.0)undec-7-ene, 1,5-diazabicyclo(4.3.0)non-5-ene, 1,4-diazabicyclo(2.2.2)octane, tert-butyl ammonium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, tripotassium phosphate, sodium silicate, calcium oxide, triethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydrogen phosphate, triphenyl phosphine, triethyl phosphine, potassium acetate, or potassium acrylate.

72. The method of claim 69, wherein said Michael addition catalyst is 1,8-diazabicyclo(5.4.0)undec-7-ene.

73. The method of claim 53 or claim 68, further comprising treating a compound of Formula Ig:

to remove the R¹⁰ group thereby forming said compound of Formula Ib;

wherein R¹⁰ is a protecting group.

74. The method of claim 73, wherein R¹⁰ is a group which is deprotected under room temperature acidic conditions.

75. The method of claim 73, wherein R¹⁰ is 1-(ethoxy)ethyl.

76. The method of claim 73, wherein said treating of said compound of Formula Ig comprises treating with an aqueous solution of from about 1 N to about 5 N hydrochloric acid at a temperature of from about 10°

C. to about 30°

C.

77. The method of claim 73, further comprising reacting a compound of Formula Ih:

with a compound of Formula Il;

in the presence of a palladium catalyst and a base to form said compound of Formula Ig;

wherein;

X is a tosylate group, a triflate group, iodo, chloro, or bromo; and

R^a and R^b are each independently H or C_1-6 alkyl;

or

R^a and R^b, together with the oxygen atoms to which they are attached and the boron atom, form a 5- to 6-membered heterocyclic ring, which is optionally substituted with 1, 2, 3, or 4 C_1-4 alkyl groups.

78. The method of claim 77, wherein R^a and R^b, together with the oxygen atoms to which they are attached and the boron atom, form the moiety:

79. The method of claim 77, wherein X is chloro, bromo, or iodo.

80. The method of claim 77, wherein X is chloro.

81. The method of claim 77, wherein said palladium catalyst is tetrakis(triphenylphosphine)palladium(0) or tetrakis(tri(o-tolyl)phosphine)palladium(0).

82. The method of claim 77, wherein said palladium catalyst is tetrakis(triphenylphosphine)palladium(0).

83. The method of claim 77, wherein said base is an alkali metal carbonate.

84. The method of claim 77, wherein said base is potassium carbonate.

85. The method of claim 77, comprising protecting a compound of Formula Ir:

with a R⁷ group.

86. The method of claim 85, wherein R⁷ is 2-(trimethylsilyl)ethoxymethyl.

87. The method of claim 85, wherein R⁷ is N-pivaloyloxymethyl.

88. The method of claim 53, further comprising reacting the compound of Formula Ik:

or salt thereof, with a compound of formula R⁸-L-R¹ in the presence of a base to form said compound of Formula Ic;

wherein R⁸ is a leaving group.

89. The method of claim 88, wherein R⁸ is halogen or C_1-4 alkoxy.

90. The method of claim 88, wherein R⁸ is chloro.

91. The method of claim 88, wherein said base is a tertiary amine.

92. The method of claim 88, wherein said base is diisopropylethylamine.

93. The method of claim 88, wherein said salt of said compound of Formula Ik is the hydrochloride salt.

94. The method of claim 88, further comprising treating a compound of Formula Im:

to remove said —

C(═

O)OR¹¹ moiety thereby forming said compound of Formula Ik;

wherein R¹¹ is C_1-6 alkoxycarbonyl.

95. The method of claim 94, wherein R¹¹ is tert-butoxycarbonyl.

96. The method of claim 94, wherein said treating of said compound of Formula Im comprises treating with aqueous hydrochloric acid.

97. The method of claim 94, further comprising reacting a compound of Formula In:

with a Wittig-type reagent containing a cyanomethyl or cyanomethyl ylide group to form said compound of Formula Im.

98. The method of claim 97, wherein said Wittig reagent is diethyl cyanomethyl phosphonate.

99. The method of claim 97, further comprising treating a compound of Formula To:

with an oxidizing agent component to form said compound of Formula In.

100. The method of claim 99, wherein said oxidizing agent component comprises 2,2,6,6-tetramethylpiperidine-1-oxyl and sodium hypochlorite.

101. The method of claim 99, further comprising treating a compound of Formula Ip:

with a compound of Formula Iq;

under catalytic hydrogenation conditions to form said compound of Formula Io.

102. The method according to claim 101, wherein said catalytic hydrogenation conditions comprises hydrogen gas and a palladium on carbon catalyst.

103. The method according to claim 101, further comprising the steps of:

(a) reacting a compound of Formula Ir;

with a compound of Formula Is;

to form the halide salt of said compound of Formula Ip; and

(b) treating said salt of said compound of Formula Ip with a base to form said compound of Formula Ip;

wherein X¹ is halogen.

104. The method according to claim 103, wherein X¹ is chloro.

105. A method for preparing a compound of claim 1, comprising:

(a) reacting a compound of Formula Ih;

with a compound of formula;

in the presence of tetrakis(triphenylphosphine)palladium(0) and an alkali metal carbonate base to form a compound of Formula Ig;

(b) treating said compound of Formula Ig to remove the R¹⁰ group to form a compound of Formula Ib;

(c) reacting said compound of Formula Ib with a compound of Formula Ic;

in the presence of a catalytic or stoichiometric amount of 1,8-diazabicyclo(5.4.0)undec-7-ene to form said compound of Formula Ia;

(d) treating said compound of Formula Ia to remove the R⁷ moiety to form a compound of Formula I;

wherein;

L is SO₂;

R¹ is C_1-6 alkyl;

R⁷ is 2-(trimethylsilyl)ethoxyethyl or 2-pivaloyloxymethyl;

R¹⁰ is 1-(ethoxy)ethyl; and

X is chloro.

106. A method for preparing a compound of claim 1, comprising:

(a) reacting a compound of Formula Ih;

with a compound of formula;

in the presence of tetrakis(triphenylphosphine)palladium(0) and an alkali metal carbonate or alkali metal hydrogen carbonate base to form a compound of Formula Ig;

(b) treating said compound of Formula Ig to remove the R¹⁰ group to form a compound of Formula Ib;

(c) reacting a compound of Formula Ib;

with a compound of Formula If;

in the presence of a catalytic or stoichiometric amount of 1,8-diazabicyclo(5.4.0)undec-7-ene to form a compound of Formula Ie;

(d) treating said compound of Formula Ie to remove the R⁹ group thereby forming a compound of Formula Id;

(e) reacting said compound of Formula Id with a compound of formula R⁸-L-R¹ to form a compound of Formula Ia;

(f) treating said compound of Formula Ia to remove the R⁷ moiety to form a compound of Formula I;

wherein;

L is SO₂;

R¹ is C_1-6 alkyl;

R⁷ is 2-(trimethylsilyl)ethoxyethyl or 2-pivaloyloxymethyl;

R⁸ is chloro;

R⁹ is tert-butoxycarbonyl;

R¹⁰ is 1-(ethoxy)ethyl; and

X is chloro.

107. The method of claim 105 or 106, wherein said compound is {1-(Ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile.

108. The method of claim 105 or 106, further comprising reacting said compound of Formula I with phosphoric acid to form the phosphate salt.

109. The method of claim 108, wherein said compound is {1-(Ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile phosphoric acid salt.

14. {1-(Ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, or pharmaceutically acceptable salt thereof.

15. {1-(Ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile phosphoric acid salt.

18. A compound of Formula II:

or pharmaceutically acceptable salt thereof, wherein;

R⁵ and R⁶ are independently selected from H, F, CN, OH, C_1-4 alkyl, benzyloxy, C_2-8 dialkylaminosulfonyl, and 5-membered heteroaryl, wherein said alkyl is optionally substituted by 1, 2, or 3 substituents selected from F, OH, CN, and C_1-4 alkoxy, and wherein said 5-membered heteroaryl is optionally substituted with C_1-4 alkyl,

wherein when one of R⁵ and R⁶ is OH, then the other of R⁵ and R⁶ is other than CN or F.

19. The compound of claim 18, or pharmaceutically acceptable salt thereof, wherein one of R⁵ and R⁶ is H and the other is selected from H, F, CN, OH, C_1-4 alkyl, benzyloxy, C_2-8 dialkylaminosulfonyl, and 5-membered heteroaryl, wherein said alkyl is optionally substituted by 1, 2, or 3 substituents selected from F, OH, CN, and C_1-4 alkoxy, and wherein said 5-membered heteroaryl is optionally substituted with C_1-4 alkyl.

20. The compound of claim 18, or pharmaceutically acceptable salt thereof, wherein R⁵ and R⁶ are independently selected from H, F, CN, OH, and methyl.

21. The compound of claim 18, or pharmaceutically acceptable salt thereof, R⁵ and R⁶ are independently selected from H and CN.

22. The compound of claim 18 selected from:

3-(cyanomethyl)-N,N-dimethyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutanesulfonamide;

3-isoxazol-3-yl-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile;

{3-(3-methyl-1,2,4-oxadiazol-5-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidn-4-yl)-1H-pyrazol-1yl]cyclobutyl}acetonitrile;

{3-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile;

3-(hydroxymethyl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile;

3-(fluoromethyl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile;

3-(difluoromethyl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile;

2,2′

-[1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutane-1,3-diyl]diacetonitrile;

3-(cyanomethyl)-1-methyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutanecarbonitrile;

3-(cyanomethyl)-1-(methoxymethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutanecarbonitrile;

3-(cyanomethyl)-1-(fluoromethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutanecarbonitrile;

1,3-bis(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutanecarbonitrile;

3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutanecarbonitrile;

3,3-bis(hydroxymethyl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile;

3,3-bis(fluoromethyl)-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile;

2,2′

,2″

-[1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutane-1,3,3-triyl]triacetonitrile;

3-hydroxy-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile;

3-fluoro-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile;

3-methyl-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile;

3,3-dimethyl-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile; and

3-(benzyloxy)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile;

or a pharmaceutically acceptable salt of any of the aforementioned.

26. A composition comprising a compound of claim 18, or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

27. The composition of claim 26 which is suitable for topical administration.

23. 3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutanecarbonitrile, or a pharmaceutically acceptable salt thereof.

24. cis-3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutanecarbonitrile, or a pharmaceutically acceptable salt thereof.

25. trans-3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutanecarbonitrile, or a pharmaceutically acceptable salt thereof.

41. A method of treating rheumatoid arthritis in a patient comprising administering to said patient a therapeutically effective amount of {1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, or pharmaceutically acceptable salt thereof.

42. A method of treating rheumatoid arthritis in a patient comprising administering to said patient a therapeutically effective amount of 3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutanecarbonitrile, or a pharmaceutically acceptable salt thereof.

43. A method of treating primary myelofibrosis (PMF) in a patient comprising administering to said patient a therapeutically effective amount of {1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, or pharmaceutically acceptable salt thereof.

44. A method of treating primary myelofibrosis (PMF) in a patient comprising administering to said patient a therapeutically effective amount of 3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutanecarbonitrile, or a pharmaceutically acceptable salt thereof.

110. A compound of Formula III or IV:

or pharmaceutically acceptable salt thereof, wherein;

L is SO₂ or CO;

R¹ is C_1-6 alkyl, C_3-7 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, indolyl, NR²R³, or OR⁴, wherein said alkyl, cycloalkyl, phenyl, or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from F, CN, and C_1-4 alkyl;

R² and R³ are independently selected from H, C_1-4 alkyl, and phenyl; and

R⁴ is C_1-6 alkyl, phenyl, or benzyl;

wherein when L is SO₂, R¹ is other than OR⁴.

111. The compound of claim 110, or pharmaceutically acceptable salt thereof, wherein L is SO₂.

112. The compound of claim 110, or pharmaceutically acceptable salt thereof, wherein L is CO.

113. The compound of claim 110, or pharmaceutically acceptable salt thereof, wherein R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, 2-methylprop-1-yl, 1-methylprop-1-yl, each optionally substituted with 1, 2, or 3 F.

114. The compound of claim 110, or pharmaceutically acceptable salt thereof, wherein R¹ is C_1-4 alkyl.

115. The compound of claim 110, or pharmaceutically acceptable salt thereof, wherein R¹ is ethyl.

116. The compound of claim 110, or pharmaceutically acceptable salt thereof, wherein R¹ is C_3-7 cycloalkyl optionally substituted by C_1-4 alkyl.

117. The compound of claim 110, or pharmaceutically acceptable salt thereof, wherein R¹ is phenyl optionally substituted with F, methyl, or CN.

118. The compound of claim 110, or pharmaceutically acceptable salt thereof, wherein R¹ is 5-membered heteroaryl selected from thienyl, pyrazolyl, pyrrolyl, 1,2,4-oxadiazolyl, and isoxazolyl, each optionally substituted with C_1-4 alkyl.

119. The compound of claim 110, or pharmaceutically acceptable salt thereof, wherein R¹ is pyridinyl.

120. The compound of claim 110, or pharmaceutically acceptable salt thereof, wherein R¹ is NR²R³ or OR⁴.

121. The compound of claim 110, or pharmaceutically acceptable salt thereof, wherein L is SO₂ and R¹ is C_1-6 alkyl.

122. The compound of claim 110 which is selected from:

{1-(ethylsulfonyl)-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile; and

4-{1-[1-(Ethylsulfonyl)-3-(fluoromethyl)azetidin-3-yl]-1H-pyrazol-4-yl}-7H-pyrrolo[2,3-yl]pyrimidine;

or a pharmaceutically acceptable salt thereof.

123. A composition comprising a compound of claim 110, or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

124. The composition of claim 123 which is suitable for topical administration.

125. A method of treating an autoimmune disease in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 110, or pharmaceutically acceptable salt thereof.

126. The method of claim 125 wherein said autoimmune disease is rheumatoid arthritis.

127. The method of claim 125 wherein said autoimmune diseases is a skin disorder.

128. A method of treating cancer in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 110, or pharmaceutically acceptable salt thereof.

129. A method of treating a myeloproliferative disorder in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 110, or pharmaceutically acceptable salt thereof.

130. The method of claim 129 wherein said myeloproliferative disorder (MPD) is polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), idiopathic myelofibrosis (IMF), or systemic mast cell disease (SMCD).