| HAI LALA AT MATALUL DE UMA

| HAI LALA AT MATALUL DE UMA US009879019B2

( 12 ) United States Patent Nordstroem et al .

( 10 ) Patent No . : ( 45 ) Date of Patent :

US 9 , 879 , 019 B2 Jan . 30 , 2018

( 54 ) PROCESSES FOR THE PREPARATION OF ( 3S , 4R ) - 3 - ETHYL - 4 - ( 3H - IMIDAZO [ 1 , 2 - a ] PYRROLO [ 2 , 3 - E ] - PYRAZIN - 8 - YL ) - N - ( 2 , 2 , 2 TRIFLUOROETHYL ) PYRROLIDINE - 1 CARBOXAMIDE AND SOLID STATE FORMS THEREOF

( 71 ) Applicant : AbbVie Inc . , North Chicago , IL ( US )

( 72 ) Inventors : Lars Frederick Nordstroem , Evanston , IL ( US ) ; Ahmad Y . Sheikh , Deerfield , IL ( US )

( 73 ) Assignee : ABBVIE INC . , North Chicago , IL ( US )

( * ) Notice : Subject to any disclaimer , the term of this patent is extended or adjusted under 35 U . S . C . 154 ( b ) by 0 days .

5 , 693 , 801 A 5 , 703 , 244 A 5 , 733 , 905 A 5 , 736 , 540 A 5 , 753 , 648 A 5 , 763 , 137 A 5 , 840 , 888 A 5 , 990 , 109 A 6 , 090 , 382 A 6 , 245 , 801 B1 6 , 262 , 241 B1 6 , 653 , 471 B2 6 , 949 , 562 B2 7 , 169 , 926 B1 7 , 452 , 981 B2 7 , 593 , 820 B2 7 , 772 , 231 B2 7 , 902 , 197 B2 8 , 039 , 009 B2 8 , 168 , 624 B2 8 , 361 , 962 B2 8 , 426 , 411 B2 8 , 637 , 529 B2 8 , 785 , 639 B2 8 , 962 , 629 B2 9 , 365 , 579 B2

2003 / 0078277 A1 2004 / 0023992 A1 2005 / 0176796 A1 2006 / 0160806 A1 2006 / 0183758 A1 2007 / 0232653 AL 2008 / 0070914 Al 2009 / 02 15724 Al 2009 / 0215750 A1 2009 / 0215788 Al 2009 / 0264399 Al

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11 / 2008 Wijdenes et al . 9 / 2009 Wilks et al . 8 / 2010 Sheppard et al . 3 / 2011 Elworthy et al .

10 / 2011 Rastogi et al . 5 / 2012 Agarwal et al . 1 / 2013 Billedeau 4 / 2013 Wishart et al . 1 / 2014 Woller et al . 7 / 2014 Wishart et al . 2 / 2015 Wishart et al . 6 / 2016 Wishart et al . 4 / 2003 Hibi et al . 2 / 2004 Das et al . 8 / 2005 D ' Alessio et al . 7 / 2006 Haviv et al . 8 / 2006 Beard et al .

10 / 2007 Bachmann et al . 3 / 2008 Freyne et al . 8 / 2009 Dubois et al . 8 / 2009 Bamberg et al . 8 / 2009 Elworthy et al .

10 / 2009 Inoue et al . ( Continued )

( 21 ) Appl . No . : 15 / 682 , 457

( 22 ) Filed : Aug . 21 , 2017 ( 65 ) Prior Publication Data

US 2017 / 0342083 A1 Nov . 30 , 2017

Related U . S . Application Data ( 63 ) Continuation of application No . 15 / 295 , 561 , filed on

Oct . 17 , 2016 .

( 60 ) Provisional application No . 62 / 242 , 797 , filed on Oct . 16 , 2015 , provisional application No . 62 / 267 , 672 , filed on Dec . 15 , 2015 , provisional application No . 62 / 301 , 537 , filed on Feb . 29 , 2016 , provisional application No . 62 / 352 , 380 , filed on Jun . 20 , 2016 .

FOREIGN PATENT DOCUMENTS ?? EA

2675288 A1 7 / 2008 007415 B1 10 / 2006

( Continued )

OTHER PUBLICATIONS ( 51 ) Int . CI .

C07D 487 / 14 ( 2006 . 01 ) A61K 47 / 12 ( 2006 . 01 ) A61K 4738 ( 2006 . 01 ) A61K 314985 ( 2006 . 01 ) A61K 9 / 00 ( 2006 . 01 )

( 52 ) U . S . CI . CPC . . . . . . . . . . C07D 487 / 14 ( 2013 . 01 ) ; A61K 9 / 0053

( 2013 . 01 ) ; A61K 31 / 4985 ( 2013 . 01 ) ; A61K 47 / 12 ( 2013 . 01 ) ; A61K 47 / 38 ( 2013 . 01 ) ; C07B

2200 / 13 ( 2013 . 01 ) ( 58 ) Field of Classification Search

CPC CO7D 487 / 14 ; A61K 9 / 0053 ; A61K 31 / 4985 ; A61K 47 / 12 ; A61K 47 / 38 ; C07B 2200 / 13

USPC . . . . . . . . . 514 / 250 See application file for complete search history .

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( Continued ) Primary Examiner — Kristin Vajda ( 74 ) Attorney , Agent , or Firm — Sterne , Kessler , Goldstein & Fox P . L . L . C . ( 57 ) ABSTRACT The present disclosure relates to processes for preparing ( 3S , 4R ) - 3 - ethyl - 4 - ( 3H - imidazo [ 1 , 2 - a ] pyrrolo [ 2 , 3 - e ] pyrazin - 8 - yl ) - N - ( 2 , 2 , 2 - trifluoroethyl ) pyrrolidine - 1 - carbox amide , solid state forms thereof , and corresponding phar maceutical compositions , methods of treatment ( including treatment of rheumatoid arthritis ) , kits , methods of synthe sis , and products - by - process .

30 Claims , 77 Drawing Sheets

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Journal of Heterocyclic Chemistry 12 : 1021 - 1023 , Journal of Het erocyclic Chemistry , United States ( 1975 ) . Schwartz , D . M . , et al . , “ Type I / II Cytokines , JAKs , and New Strategies for Treating Autoimmune Diseases , ” Nature Reviews . Rheumatology 12 ( 1 ) : 25 - 36 , Macmillan Publishers Limited , United States ( Jan . 2016 ) . Scott , I . C . and Scott , D . , “ Joint Counts in Inflammatory Arthritis , " Clinical and Experimental Rheumatology 32 ( 85 ) : S7 - S12 , ( 2014 ) . Semerano , L . , et al . , “ Developments with Investigational Janus Kinase Inhibitors for Rheumatoid Arthritis , " Expert Opinion on Investigational Drugs 25 ( 12 ) : 1355 - 1359 , Informa UK Limited , England ( Oct . 2016 ) . Semerano , L . , et al . , “ Novel Immunotherapeutic Avenues for Rheu matoid Arthritis , ” Trends in Molecular Medicine 22 ( 3 ) : 214 - 229 , Elsevier Science Ltd . , England ( Mar . 2016 ) . Singh , J . A . , et al . , “ 2012 Update of the 2008 American College of Rheumatology Recommendations for the Use of Disease - Modify ing Antirheumatic Drugs and Biologic Agents in the Treatment of Rheumatoid Arthritis , " Arthritis Care & Research 64 ( 5 ) : 625 - 639 , John Wiley & Sons , United States ( 2012 ) . Sivaraman , P . and Cohen , S . B . , “ Malignancy and Janus Kinase Inhibition , ” Rheumatic Diseases Clinics of North America 43 ( 1 ) : 79 - 93 , Elsevier Inc . , United States ( Feb . 2017 ) . Smolen , J . , et al . , “ EULAR recommendation for the management of rheumatoid arthritis with synthetic and biological disease - modify ing antirheumatic drugs , ” Annals of the Rheumatic Diseases 69 ( 6 ) : 964 - 975 , BMJ , England ( 2010 ) . Smolen , J . S . , et al . , “ Eular Reconnnendations for the Management of Rheumatoid Arthritis With Synthetic and Biological Disease modifying Antirheumatic Drugs : 2013 Update , ” Annals of the Rheumatic Diseases 73 ( 3 ) : 492 - 509 , H . K . Lewis , England ( 2014 ) . Solomon , D . H . and Bucala , R . J . , “ The Enduring Value of Reporting Randomized Controlled Clinical Trials in Arthritis & Rheumatol ogy : 2016 and Beyond , ” Arthritis & Rheumatology 68 ( 12 ) : 2831 2833 , American College of Rheumatology , United States ( Aug . 2016 ) . Stahl , et al . , Editors " IUPAC Handbook of Pharmaceutical Salts : Properties , Selection , and Use , " Wiley - VCH , Weinheim , Geffilany , 5 pages ( 2002 ) ( Table of Contents ) . Stella , V . J . , et al . , “ A Case for Prodrugs , ” in Prodrugs : Challenges and Rewards Part 1 , p . 24 , American Association of Pharmaceutical Sciences , United States ( 2007 ) . Strand , V . , et al . , “ Sustained Benefit in Rheumatoid Arthritis Fol lowing One Course of Rituximab : Improvements in Physical Func tion Over 2 Years , ” Rheumatology 45 ( 12 ) : 1505 - 1513 , Mercury International , England ( 2006 ) . Trost , B . M . , et al . , “ Palladium - catalyzed DYKAT of Vinyl Epoxides : Enantioselective Total Synthesis and Assignment of the Configuration of ( + ) - Broussonetine G , " Angewandte Chemie 42 ( 48 ) : 5987 - 5990 , Wiley - VCH , Germany ( 2003 ) . Van Epps , S . , et al . , “ Design and synthesis of tricyclic cores for kinase inhibition , ” Bioorg Med Chem Lett . 23 ( 3 ) : 693 - 698 , Elsevier Ltd . , England ( 2013 ) . Van Vollenhoven , R . F . , et al . , “ THU0178 Relationship between NK Cell Count and Important Safety Events in Rheumatoid Arthritis Patients Treated with Tofacitinib , ” Annals of the Rheumatic Dis eases 74 ( 2 ) : 258 - 259 , H . K . Lewis , England ( 2015 ) . Voss , J . , et al . , “ THU0127 Pharmacodynamics of a Novel JAK1 Selective Inhibitor in Rat Arthritis and Anemia Models and in Healthy Human Subjects , ” Annals of the Rheumatic Diseases 73 ( 2 ) : 222 , H . K . Lewis , England ( 2014 ) . Wang , G . T . , et al . , “ Design , Synthesis , and Structural Analysis of Influenza Neuraminidase Inhibitors Containing Pyrrolidine Cores , ” Journal of Medicinal Chemistry 44 ( 8 ) : 1192 - 1201 , American Chemical Society , United States ( 2001 ) . Winthrop , K . L . , “ The Emerging Safety Profile of JAK Inhibitors in Rheumatic Disease , ” Nature Reviews . Rheumatology 13 ( 4 ) : 234 243 , Macmillan Publishers Limited , United States ( Apr . 2017 ) . Wolff , M . E . , " Some Considerations for Prodrug Design , " in Burg er ' s Medicinal Chemistry and Drug Discovery , Fifth Edition , vol . 1 : Principles and Practices , pp . 975 - 977 , John Wiley and Sons , United States ( 1995 ) .

US 9 , 879 , 019 B2 Page 5

( 56 ) References Cited

OTHER PUBLICATIONS Woodworth , T . , et al . , " Standardizing Assessment and Reporting of Adverse Effects in Rheumatology Clinical Trials II : the Rheumatol ogy Common Toxicity Criteria V . 2 . 0 . , ” The Journal of Rheumatol ogy 34 ( 6 ) : 1401 - 1414 , Journal of Rheumatology Publishing Co , Canada ( 2007 ) . Wormser , H . C . , " Synthesis of Azabiotin Analogs as Potential Cofactors for Biotin - dependent Enzymes , ” Journal of Pharmaceu tical Sciences 59 ( 12 ) : 1732 - 1737 , Elsevier , United States ( 1970 ) .

MANUFACTURING OF AMORPHOUS FREEBASE VIA FREEBASE HYDRATE FORM B

U . S . Patent

TARTRATE

FREEBASING STEP

FREEBASE IN SOLUTION -

EXTRACTIONS

H20

HYDRATE FORM B SEEDS ( AS A SLURRY )

CRYSTALLIZATION OF HYDRATE FORM B IN EVOH / H20

FREEBASE DISSOLVED IN ELOH IN ETOH

SOLVENT SWITCH ( DISTILLATION )

Jan . 30 , 2018

FILTRATION FILTRATE ( DISCARDED )

Sheet 1 of 77

FILTER CAKE

DRYING ( HYDRATE FORM B DEHYDRATES TO AMORPHOUS )

WASH H20

FINAL API ( AMPRPHOUS FREEBASE )

MILLING ( DELUMPING )

FIG . 1A

US 9 , 879 , 019 B2

MANUFACTURING FREEBASE HYDRATE FORM C ( HEMIHYDRATE )

U . S . Patent

HYDRATE C SEEDS

H2O , HEPTANE

API REACTION

FREEBASE DISSOLVED IN ETOAC

CRYSTALLIZATION OF HYDRATE C IN EtOAC / H20 / HEPTANE

Jan . 30 , 2018

FILTRATION

DRYING

WASH ( EtOAC / H2O / HEPTANE )

FILTER CAKE

FILTRATE ( DISCARDED )

Sheet 2 of 77

MILLING ( PSD REDUCTION )

FINAL API ( HYDRATE C )

FIG . 1B

US 9 , 879 , 019 B2

U . S . Patent

API REACTION

TARTRATE SEEDS

FREEBASE IN IPA AND IPAC

CRYSTALLIZATION OF TARTRATE

L - TARTARIC ACID IN H2O

Jan . 30 , 2018

FILTRATION

WASH 2 MTBE / H20

WASH 1 IPAC / H20

WET FILTER CAKE

FILTRATE ( DISCARDED )

Sheet 3 of 77

HUMIDIFIED DRYING AT 10°C

UNLOADING AND FREEZING OF TARTRATE

MILLING

FINAL API ( TARTRATE )

FIG . 1C

US 9 , 879 , 019 B2

atent Jan . 30 , 2018 Sheet 4 of 77 US 9 , 879 , 019 B2

PXRD : AMORPHOUS FREEBASE ( VIA PRECIPITATION

INTENSITY ( COUNTS ) .

L

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5 10 30 35 15 20 25 TWO - THETA ( DEG ) FIG . 2A

PXRD : AMORPHOUS FREEBASE ( VIA DEHYDRATION )

Se INTENSITY ( COUNTS )

o 5 10 15 20 25 TWO - THETA ( DEG )

30 35 FIG . 2B

U . S . Patent Jan . 30 , 2018 Sheet 5 of 77 US 9 , 879 , 019 B2

PXRD : FREEBASE SOLVATE FORM A ( ISOPROPYL ACETATE / WATER SOLVATE )

1500

INTENSITY ( COUNTS )

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TWO - THETA ( DEG ) 35

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2000 INTENSITY ( COUNTS )

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PXRD : HYDROCHLORIDE SOLVATE FORM BB

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5 10 15 20 25 TWO - THETA ( DEG )

30 35 FIG . 3G

PXRD : L - MALEATE FORM AAA 2000


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TWO - THETA ( DEG ) 30 35

FIG . 3 )

TGA : AMORPHOUS FREEBASE ( VIA PRECIPITATION )

U . S . Patent

mg 12 . 50 12 . 45

STEP

12 . 40 12 . 35 12 . 30 12 . 25

- 3 . 6795 % - 0 . 4606 mg 30 . 82 °C 159 . 05 °C

10 . 00 °Cmin ^ - 1

Jan . 30 , 2018

LEFT LIMIT RIGHT LIMIT HEATING RATE

12 . 20

Sheet 10 of 77

12 . 15 12 . 10 12 . 09

30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 °C o i ? 3 4 5 ? 8 9 10 11 12 13 14 15 16 17 min FIG . 4A

US 9 , 879 , 019 B2

TGA : AMORPHOUS FREEBASE ( VIA DEHYDRATION )

U . S . Patent atent

mg

STEP

6 . 96 6 . 94


- 0 . 7952 %

- 55 . 3541 e - 03 mg 32 . 76 °C 108 . 81°C

10 . 00 °Cmin ^ - 1

Jan . 30 , 2018

6 . 92

Jan . 30 , 2018

6 . 90 6 . 88 6 . 86 6 . 84 6 . 82 6 . 80

Sheet 11 of 77

40 2

60 4

0

80 6

100 120 8 10

LLL 140 160 180 200 220 240 260 °C 12 14 16 18 20 22 24 min

FIG . 4B

US 9 , 879 , 019 B2

TGA : FREEBASE SOLVATE FORM A ( ISOPROPYL ACETATE / WATER SOLVATE )

U . S . Patent

19

STEP

5 . 4

- 6 . 9179 % - 0 . 3723 mg 34 . 71 °C 87 . 53°C

10 . 00 °Cmin ^ - 1


5 . 3

Jan . 30 , 2018

5 . 2 5 . 1

STEP

se


- 5 . 2037 % - 0 . 2801 mg 87 . 39°C 126 . 12 °C

10 . 00 °Cmin ^ - 1

Sheet 12 of 77

4 . 8 4 . 7

30 0 . 5

40 1 . 5

50 2 . 5

60 3 . 5

70 4 . 5

80 5 . 5

90 6 . 5

100 7 . 5 110 8 . 5

120 °C 9 . 5 10 . 5 min

FIG . 4C

US 9 , 879 , 019 B2

TGA : FREEBASE HYDRATE FORM B

U . S . Patent

mg 4 . 7 4 . 6

STEP

4 . 5


- 12 . 0438 % - 0 . 5600 mg 33 . 35 °C 102 . 48 °C

10 . 00 °Cmin ^ - 1

4 . 4 .

Jan . 30 , 2018

4 . 3 4 . 2

STEP

4 . 1 4 . 0 o o


- 5 . 4835 % - 0 . 2550 mg 102 . 48°C 141 . 91 °C 10 . 00 °Cmin ^ - 1

Sheet 13 of 77

3 . 9 3 . 8

3 . 71 40

0 2

60 4

80 6

100 8 120 10

140 160 180 200 12 14 16 18

220 240 20 22

260 °C 24 min

FIG . 4D

US 9 , 879 , 019 B2

TGA : FREEBASE HYDRATE FORM C

mg

atent

6 . 22 6 . 20 6 . 18

Jan . 30 , 2018

STEP

6 . 16

- 2 . 3269 % - 0 . 1447 mg 114 . 52 °C 168 . 15 °C

10 . 00 °Cmin 1 - 1


6 . 14 6 . 12

Sheet 14 of 77

6 . 10 6 . 08

w

0 . 067 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 °C

0 1 2 3 4 5 6 Ž 8 9 10 11 12 13 14 15 16 17 min FIG . 4E

US 9 , 879 , 019 B2

TGA : TARTRATE HYDRATE

U . S . Patent

3 mg

STEP

4 . 6

- 11 . 9227 % - 0 . 5536 mg 32 . 98 °C 159 . 76 °C 10 . 00 °Cmin ^ - 1


4 . 4 4 . 2

Jan . 30 , 2018

ZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZ 4 . 0 3 . 8 3 . 6

Sheet 15 of 77

3 . 4 3 . 2 3 . 0

| 40 0 2

60 4

80 6

100 120 140 160 8 10 12 14

180 200 220 240 260 °C 16 18 20 22 24 min

FIG . 4F

US 9 , 879 , 019 B2

TGA : HYDROCHLORIDE SOLVATE FORM AA

U . S . Patent

mg . 2 . 15

STEP

2 . 10

- 14 . 9573 % - 0 . 3267 mg 32 . 29 °C 178 . 85 °C

10 . 00 °Cmin ^ - 1


Jan . 30 , 2018

2 . 05 2 . 00 1 . 95

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Sheet 16 of 77 .

1 . 90 1 . 85

1 . 80 - L . 40

0 2

1 . OU III

60 4

80 6

LLL 100 120 140 8 10 12

FIG . 4G

160 14

180 16

200 18

°C min

US 9 , 879 , 019 B2

TGA : L - MALEATE FORM BBB

U . S . Patent

mg

STEP

1 . 21


- 1 . 6310 %

- 19 . 7841e - 03 mg 35 . 99 °C 124 . 57 °C

10 . 00 °Cmin ^ - 1

1 . 20 1 . 19

Jan . 30 , 2018

1 . 18 1 . 17

Sheet 17 of 77

1 . 16 1 . 15 1 . 14

1 30

40 i

50 §

60 3

_

_

_

70 80 90 4 5 6

FIG . 4H

100 ?

_ _

110 8

120 125 9 10

°C 11 min

US 9 , 879 , 019 B2

TGA : FREEBASE ANHYDRATE FORMD

U . S . Patent

mg

STEP

4 . 80

- 0 . 6879 %

- 32 . 9485e - 03 mg

LEFT LIMIT 41 . 36 °C RIGHT LIMIT 190 . 48 °C HEATING RATE 10 . 00 °Cmin ^ - 1

4 . 78 4 . 76 4 . 74

Jan . 30 , 2018

4 . 72 4 . 70 4 . 68

Sheet 18 of 77 .

4 . 66 4 . 64 4 . 62 4 . 60 +

0

40 2

60 4

80 6

100 8

120 10

140 12

160 14

180 16

200 18 220 20 240

22

260 24

oC min

US 9 , 879 , 019 B2

FIG . 41

U . S . Patent

de med A

Jan . 30 , 2018

DSC : AMORPHOUS FREEBASE ( VIA DEHYDRATION OF FREEBASE HYDRATE FORM B )

mW - 0 . 05

GLASS TRANSITION

- 0 . 10

ONSET

118 . 96 °C

MIDPOINT ISO 121 . 51 °C

- 0 . 15

LEFT LIMIT

114 . 01 °C

- 0 . 20

RIGHT LIMIT 141 . 60 °C

- 0 . 25

HEATING RATE 10 . 00 °Cmin 1 - 1

- 0 . 30 - 0 . 35 - 0 . 40 - 0 . 45 - 0 . 50 - 0 . 55 - 0 . 60

- 0 . 65 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 °C

0 1 2 3 4 5 6 9 8 9 10 11 12 13 14 15 16 17 min

Sheet 19 of 77

TT

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FIG . 5A

US 9 , 879 , 019 B2

DSC : FREEBASE HYDRATE FORM B

U . S . Patent

INTEGRAL NORMALIZED ONSET LEFT LIMIT RIGHT LIMIT HEATING RATE

- 1058 . 32 m ) - 194 . 58 Jg ^ - 1

59 . 90 °C 34 . 61 °C 98 . 79 °C

10 . 00 °Cmin 1 - 1

0 - ?

Jan . 30 , 2018

?


- 475 . 57 m ) - 87 . 44 Jg ^ - 1

109 . 31 °C 106 . 57 °C 132 . 94 °C 10 . 00 °Cmin ^ - 1

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Sheet 20 of 77

14

| 40 0 2

60 4

80 6

100 8

120 140 10 12

160 180 200 220 240 260 °C 14 16 18 20 22 24 min

US 9 , 879 , 019 B2

FIG . 5B

mW 0 . 0 - 0 . 5

U . S . Patent

DSC : FREEBASE HYDRATE FORM C

- 1 . 0 - 1 . 5 - 2 . 0

- - - -

Jan . 30 , 2018

- 2 . 5 -

- - - - - - - - -

- 3 . 0


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134 . 70 °C 110 . 34 °C 167 . 53 °C

10 . 00 °Cmin 4 - 1

- - - - - - - - -

- 3 . 5

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Sheet 21 of 77

- 5 . 0

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- 5 . 5 - 6 . 0 - 6 . 5 - 7 . 0

30

40 i

50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 3 4 5 6 Ž 8 9 10 11 12 13 14 15 16 i7

°C min

FIG . 5C

US 9 , 879 , 019 B2

DSC : TARTRATE HYDRATE

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INTEGRAL NORMALIZED ONSET PEAK LEFT LIMIT RIGHT LIMIT HEATING RATE

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Jan . 30 , 2018 Sheet 22 of 77

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200

20 2

40 4

60 6

80 8

H 100 10

120 12

140 14

-

160 16 -

-

180 18

0

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FIG . 5D

US 9 , 879 , 019 B2

DSC : FREEBASE ANHYDRATE FORM D

U . S . Patent

mg - 7 - 10

INTEGRAL - 406 . 85 m ) NORMALIZED - 85 . 36 Jg ^ - 1 ONSET 199 . 55 °C LEFT LIMIT 183 . 59 °C RIGHT LIMIT 217 . 41 °C

HEATING RATE 10 . 00 °Cmin 1 - 1

Jan . 30 , 2018

- 11 - 1 - 12 - 14 - 15

Sheet 23 of 77

- 16 - 17 - 18 - 20 + 207 0

200

40 2

60 4

80 6

100 8

120 10

140 160 12 14 FIG . 5E

180 16

220 20 240 22 260

24

°C min

US 9 , 879 , 019 B2

MOSITURE VAPOR ISOTHERM : AMORPHOUS FREEBASE ( VIA DEHYDRATION OF FREEBASE HYDRATE FORM B )

U . S . Patent

fonske

mom +

DVS ISOTHERM PLOT CYCLE 1 SORP CYCLE 1 DESORP CYCLE 2 SORP CYCLE 2 DESORP

de nd

+

Jan . 30 , 2018

fo fun

CHANGE IN MASS ( % ) - REF

Sheet 24 of 77

10

20

30

70

80

90

100

40 50 60 SAMPLE % P / PO FIG . 6A

US 9 , 879 , 019 B2

MOSITURE VAPOR ISOTHERM : FREEBASE HYDRATE FORM C

U . S . Patent

DVS ISOTHERM PLOT

TEMP : 21 . 5 °C

men -

CYCLE 1 SORP CYCLE 1 DESORP CYCLE 2 SORP CYCLE 2 DESORP

Jan . 30 , 2018


Sheet 25 of 77

20

80

100

40 60 TARGET % P / PO FIG . 6B

US 9 , 879 , 019 B2

MOSITURE VAPOR ISOTHERM : TARTRATE HYDRATE

U . S . Patent

DVS ISOTHERM PLOT CYCLE 1 SORP CYCLE 1 DESORP CYCLE 2 SORP CYCLE 2 DESORP

TEMP : 24 . 5 °C

METH : 30 _ 90 _ 10 _ 90 _ 3dmdt _ 001 _ 25C _ 360 max _ SC . sao

MRef : 9 . 8972

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Jan . 30 , 2018

1 . 2 1 . 0


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Sheet 26 of 77

0 . 4 0 . 2

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20

30

70

80

90

100

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40 50 60 SAMPLE % P / PO FIG . 6C

- 0 . 4

US 9 , 879 , 019 B2

MOISTURE VAPOR ISOTHERM : FREEBASE ANHYDRATE FORM D

U . S . Patent

DVS ISOTHERM PLOT

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Jan . 30 , 2018


+ - - om +

CYCLE 1 SORP CYCLE 1 DESORP CYCLE 2 SORP CYCLE 2 DESORP

Sheet 27 of 77

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20

30

70

80

90

100

40 50 60 SAMPLE % P / PO FIG . 6D

US 9 , 879 , 019 B2

U . S . Patent Jan . 30 , 2018 Sheet 28 of 77 . US 9 , 879 , 019 B2

8 muy pH 6 . 8 - AMORPHOUS FREEBASE

pH 6 . 8 - FREEBASE HYDRATE FORMC - - - - - TARGET

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Jan . 30 , 2018

% LA RELEASED

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Sheet 29 of 77

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% LA RELEASED Promo -

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5 15 20 10 TIME ( HOURS ) FIG . 11


- # - ER4 wa ERZ

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% LA RELEASED wwwwwwwwwwww Š Šo

5 20 25 10 15 TIME ( HOURS )

FIG . 12 - ER4

+ ER8 À

§

% LA RELEASED

ö 5 20 25 10 15 TIME ( HOURS )

FIG . 13


* ER3 DUAL PH ER1 DUAL PH ER4 DUAL PH

- - - - - TARGET

% LA RELEASED gö ö f o

20 10 15 TIME ( HOURS ) FIG . 14


( HPMC + TARTARIC ACID ) 8

? ???? ?? ? ? .

?

% LA RELEASED - - - -

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- - - - TARGET

Ko me me me

m

O 15 10

TIME ( HOURS ) FIG . 15A

( HPMC + CITRIC ACID ) 8

- -

8

or the 8

% LA RELEASED 8 - - - - - cover would come more news concom meum f + pH 1 . 2

pH 6 . 8 - - - - - - TARGET 8

en como

o Y OT 5 10 15 15 TIME ( HOURS ) FIG . 15B


( HPMC + SUCCINIC ACID ) - - - - - - -

-

% LA RELEASED & 0 - - - - - pH 1 . 2

- - - - wamefilim pH 6 . 8 - - - TARGET

- -

5 15 15 20 10 10 TIME ( HOURS ) FIG . 15C

( HPMC + FUMARIC ACID )

- - - - - -

- - - - -

-

% LA RELEASED – pH 1 . 2 of - -

pH 6 . 8 - - - - - - - - - - - . TARGET

- - - -

0 O 15 20 10

TIME ( HOURS ) FIG . 15D


( CARBOPOL + TARTARIC ACID ) umida

men -

see ons mens nie -

-

% LA RELEASED go fão -

+ pH 1 . 2 mutta pH 6 . 8 - - - TARGET

- -

*

-

5 10 15 15 20 TIME ( HOURS ) FIG . 15E

( CARBOPOL + CITRIC ACID ) $

. apa - -

- - -

;

% LA RELEASED - - - + pH 1 . 2

- $ w -

- - pH 6 . 8 - - - TARGET -

- Å pie manis

10 15 TIME ( HOURS ) FIG . 15F


( CARBOPOL + SUCCINIC ACID ) 8

-

www

% LA RELEASED was PH 1 . 2 f me pH 6 . 8

- - - TARGET - r -

- - -

o 10 15 20

TIME ( HOURS ) FIG . 15G

( CARBOPOL + FUMARIC ACID ) 8

- 7

% LA RELEASED ce moment - - - - - - - - - - f

+ pH 1 . 2 - pH 6 . 8 - - - TARGET pe con

ö

form o

15 20 10 TIME ( HOURS ) FIG . 15H


8

www . cm

REGIMEN A : 12 mg IR CAPSULE ( N = 11 ) REGIMEN B : 15 mg ONCE - DAILY TABLÉT ( N = 11 )

8

8 COMPOUND 1 PLASMA CONCENTRATION ( ng / mL )

8

o

0 8 16 56 64 72 24 32 40 48 TIME ( hr )

FIG . 16A

. REGIMEN A : 12 mg IR CAPSULE ( N = 11 ) REGIMEN B : 15 mg ONCE - DAILY TABLET ( N = 11 )

COMPOUND 1 PLASMA CONCENTRATION ( ng / mL )

1 0 8 16 56 64 72 24 32 40 48

TIME ( hr ) FIG . 16B


REGIMEN C : 24 mg IR CAPSULES FASTING ( N = 12 ) REGIMEN D : 30 mg ONCE - DAILY TABLETS FASTING ( N = 12 )

* * * * * * * * *

Low COMPOUND 1 PLASMA CONCENTRATION ( ng / mL ) * * * * * * * * *

0 8 16 56 64 72 24 32 40 48 TIME ( hr )

FIG . 17A 7 ma

mmpunan REGIMEN C : 24 mg IR CAPSULES FASTING ( N = 12 ) REGIMEN D : 30 mg ONCE - DAILY TABLETS FASTING ( N = 12 )

100 DE COMPOUND 1 PLASMA CONCENTRATION ( ng / mL )

ó 16 56 64 72 24 32 40 48 TIME ( hr )

FIG . 17B


REGIMEN D : 30 mg ONCE - DAILY TABLETS FASTING ( N = 12 ) REGIMEN E : 30 mg ONCE - DAILY TABLETS HIGH - FAT ( N = 12 ) s

COMPOUND 1 PLASMA CONCENTRATION ( ng / mL ) 7 ,

o

0 8 16 56 64 72 24 32 40 48 TIME ( hr )

FIG . 18A

wananchi COMPOUND 1 PLASMA CONCENTRATION ( ng / mL ) Ö

REGIMEN D : 30 mg ONCE - DAILY TABLETS FASTING ( N = 12 ) REGIMEN E : 30 mg ONCE - DAILY TABLETS HIGH - FAT ( N = 12 )

0 8 16 24 32 40 48 56 64 72 TIME ( hr )

FIG . 18B

DAY 1

DAYS 3 - 6

DAY 7

atent

A

ROGIMLIV

REGIMEN F : 15 mg ONCE - DAILY TABLET ( N = 8 ) A - REGIMEN G : 30 mg ONCE - DAILY TABLET ( N = 8 )

- - Ban chammbondoomboommmmmmmmmmmmmm kommend

menanaman

Jan . 30 , 2018


& Room ä ä oo

ang Anna Damansara

Lancamentowanewed

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the lo

0 6 12 18 24 48

72

96

120 144 156

168 180

192 204 216

TIME ( hr ) FIG . 19

US 9 , 879 , 019 B2

U . S . Patent

DAY 1

DAYS 3 - 6

DAY 7

- O

REGIMEN K : 6 mg IR CAPSULES ( N = 11 ) REGIMEN L : 15 mg ONCE - DAILY TABLET ( N = 12 )

Å så

Jan . 30 , 2018


po na mama

Sheet 41 of 77

de

TTT

-

0 5 12 18 24 48

92

120 144 156

168 180 192 204 216

96


US 9 , 879 , 019 B2


6 mg BID 15 mg QD

8

Ž

6

FIG . 21 5 DAY 4

. .

.

. 1

3

2

CONCENTRATION ( ng / mL ) COMPOUND 1 PRE - MORNING DOSE TROUGH

U . S . Patent

DAY 1

DAYS 3 - 6

DAY 7

atent

10

+ REGIMEN M : 12 mg IR CAPSULES ( N = 11 ) - A REGIMEN N : 30 mg ONCE - DAILY TABLET ( N = 12 )

Jan . 30 , 2018

COMPOUND 1 CONCENTRATION ( ng / mL )

www

Astana ft

Sheet 43 of 77

TI 04 8 12 16 20 24 48

72

120 144 156

168 180 192 204 216

96


US 9 , 879 , 019 B2

U , S , Patent

303 COMPOUND 1 PRE - MORNING DOSE TROUGH

CONCENFRATION ( ng / mL ) 6

Jan . 30 , 2018

$ 12 mg BID $ 30 mg QD

?

Sheet 44 0f77

• • •

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_ 2

_ 3

_ 4

_ 6 5

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DAY FIG . 23

US 9 , 879 , 019 B2

U . S . Patent

Om REGIMEN A : 30 mg TABLET ER8 - FASTING ( N = 36 ) ? REGIMEN B : 30 mg TABLET ER10 - FASTING ( N = 24 ) A REGIMEN D : 30 mg TABLET ER11 - FASTING ( N = 24 ) - REGIMEN F : 30 mg TABLET ER12 - FASTING ( N = 24 )

Home 2

COMPOUND 1 PLASMA CONCENTRATION ( ng / mL ) O? ? ? ç

Jan . 30 , 2018

140 - 180oolo

Sheet 45 of 77

Thes

4

8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72

TIME ( hr ) FIG . 24A

US 9 , 879 , 019 B2

U . S . Patent

O A

REGIMEN A : 30 mg TABLET ER8 - FASTING ( N = 36 ) REGIMEN B : 30 mg TABLET ER10 - FASTING ( N = 24 ) REGIMEN D : 30 mg TABLET ER11 - FASTING ( N = 24 ) REGIMEN F : 30 mg TABLET ER12 - FASTING ( N = 24 )

10

?


Jan . 30 , 2018

- 0 . 1

Sheet 46 of 77

0

4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 TIME ( hr )

FIG . 24B

US 9 , 879 , 019 B2

8

U . S . Patent

*

REGIMEN B : 30 mg TABLET ER10 - FASTING ( N = 24 ) REGIMEN C : 30 mg TABLET ER10 - HIGH - FAT MEAL ( N = 12 )

8 KE

Jan . 30 , 2018

COMPOUND 1 PLASMA CONCENTRATIO

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Atsa

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|

= - - prow

- - napomenumpanomp - vong

0 4

8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72


US 9 , 879 , 019 B2

?

U . S . Patent

* A

REGIMEN B : 30 mg TABLET ER10 - FASTING ( N = 24 ) REGIMEN C : 30 mg TABLET ER10 - HIGH - FAT MEAL ( N = 12 )

DDDD

Jan . 30 , 2018

? COMPOUND 1 PLASMA CONCENTRATI

Sheet 48 of 77

o 0

4

8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72

TIME ( hr ) FIG . 25B

US 9 , 879 , 019 B2


160 ver

140 120

Cmax ( ng / mL )

to tatt

+

ER10 FASTING ER10 HIGH - FAT

FIG . 26A

o

AUC in ( ng . h / mL ) g

go to


FIG . 26B

§

U . S . Patent

- - REGIMEN D : 30 mg TABLET ER11 - FASTING ( N = 24 )

REGIMEN E : 30 mg TABLET ER11 - HIGH - FAT MEAL ( N = 12 )

§

Jan . 30 , 2018

§ COMPOUND 1 PLASMA CONCENTRATI

od

Ô

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- - -

0 4

8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72


US 9 , 879 , 019 B2

U . S . Patent

-

Hhh .

REGIMEN D : 30 mg TABLET ER11 - FASTING ( N = 24 ) REGIMEN E : 30 mg TABLET ER11 - HIGH - FAT MEAL ( N = 12 )

Jan . 30 , 2018

COMPOUND 1 PLASMA CONCENTRATIO

Sheet 51 of 77

pengawasan persoon perempuanny passa pewno

prong . . .

- - - -

0

4

8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72

TIME ( hr )

US 9 , 879 , 019 B2

FIG . 27B


el

mb

( 79 / bu ) xeling

• Ø Å


FIG . 28A

1100 ,

AUC in ( ng . h / mL )

ga XX XXXX 2001


FIG . 28B

8

U . S . Patent

a

-

REGIMEN F : 30 mg TABLET ER12 - FASTING ( N = 24 ) REGIMEN G : 30 mg TABLET ER12 - HIGH - FAT MEAL ( N = 12 )

8 COMPOUND 1 PLASMA CONCENTRATION ( ng / mL )

Jan . 30 , 2018

8 8 Ethilo

Sheet 53 of 77

8

quam ngang

0

4

8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72


US 9 , 879 , 019 B2

U . S . Patent

mamy m REGIMEN F : 30 mg TABLET ER12 - FASTING ( N = 24 )

- REGIMEN G : 30 mg TABLET ER12 - HIGH - FAT MEAL ( N = 12 )

Jan . 30 , 2018

–

Ihmad

COMPOUND 1 PLASMA CONCENTRATION

?

Sheet 54 of 77

H

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 TIME ( hr )

FIG . 29B

US 9 , 879 , 019 B2

U . S . Patent Jan . 30 , 2018 Sheet s5 of 77 US 9 , 879 , 019 B2

*

*

( Tu / 6u ) Xeu ????? ? ? ? ? ? ? ?

? ER12 FASTING ER12 HIGH - FAT

FIG . 30A

1100 ?

.

1 AUC inf ( ng . h / mL ) ?? ? ? ? ? ? ? ?

ER12 FASTING | ER12 HIGH - FAT

FIG . 30B


30

R2 = 0 . 961

20

TARTARIC % FIG . 31

10

.

mammofon o o

pH

- 1 mg mm Omn 3 mg 6 mg II 12 mg A 24 mg com a 36 mg

48 mg

U . S . Patent


Jan . 30 , 2018 Sheet 57 of 77

12 0 6

12

18

24

42 48

54

60 66

72

30 36 TIME ( hr ) FIG . 32A

US 9 , 879 , 019 B2

bu Imam O

bu E

bwg the 6? 7 | - - - -

U . S . Patent

1000

* *

24 mg 36 mg

100 -

A

bu 8t

10 -

co NADO

Jan . 30 , 2018

- COMPOUND 1 PLASMA CONCENTRATIO

0 . 1

Sheet 58 of 77 .

0 . 01 . 001

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6

12

18

24

42

48

54

60

66

72

30 36 TIME ( hr )

US 9 , 879 , 019 B2

FIG . 32B

140

DAY 1

DAY 5 , 6 , 7 , 13

DAY 14

U . S . Patent

- o

3 mg 6 mg 12 mg 36 mg

-

Jan . 30 , 2018


mes

Sheet 59 of 77

Dista A

As

an

DDD

wo

0

12

348

360

372

384

96 192 288 312 324 336

TIME ( hr )

FIG . 33

US 9 , 879 , 019 B2

U . S . Patent

HEALTHY SUBJECTS A SUBJECTS WITH RA

head

Cmax / DOSE ( ng / mL ) / mg

Cmax / DOSE ( ng / mL ) / mg

Jan . 30 , 2018 Sheet 60 of 77

48

24

13 6 12 24 36

COMPOUND 1 DOSE ( mg )

3 6 12


FIG . 34A

FIG . 34B

US 9 , 879 , 019 B2

U . S . Patent

• HEALTHY SUBJECTS A SUBJECTS WITH RA

Jan . 30 , 2018

AUC inf / DOSE ( ng . h / mL ) / mg Á sam jó

AUC0 - 12 / DOSE ( ng . h / mL ) / mg jo

Sheet 61 of 77

TT

1

3 6 12 24 36


48

3 6 12 24


FIG . 34C

FIG . 34D

US 9 , 879 , 019 B2


A COMPOUND 1 6 mg BID - - - - COMPOUND 1 12 mg BID . . . COMPOUND 1 24 mg BID is

COMPOUND 1 AUC0 - 12 ( ng . h / mL ) / mg

Á = =

- - - - - - -

DAY 28 WITHOUT

METHOTREXATE

DAY 29 WITH

METHOTREXATE

FIG . 35A

- - -

11

IIIIIIII

METHOTREXATE AUC inf / DOSE ( ng . h / mL ) / mg og si www

DAY 1 WITHOUT

COMPOUND 1

DAY 29 WITH

OMPOUND 1

FIG . 35B

ACR RESPONSE AT WEEK 12

U . S . Patent

A * * * * * *

A PLACEBO J3 mg BID 6 mg BID 12 mg BID ] 18 mg BID

W W

Jan . 30 , 2018

SA

RESPONSE RATE ( % )

* * * * 22 22

Sheet 63 of 77

ACR20

ACR50

ACR70

FIG . 36A

US 9 , 879 , 019 B2


LAPLACEBO 13 mg BID 6 mg BID 12 mg BID 18 mg BID

In = 13 n = 16 n = 16 n = 15 n = 17 | 22

FIG . 36B

ACR20 RESPONSES AT WEEK 12 BY NUMBER OF PRIOR ANTI - TNF AGENTS NUMBER OF PRIOR ANTI - TNFS

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

( n = 421 n = 39 n = 38 n = 38 n = 38 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1007 FO

ACR20 RESPONSE RA


ACR20 RESPONSES OVER TIME IN SUBJECTS WITH ACTIVE RHEUMATOID ARTHRITIS AND PRIOR

INADEQUATE RESPONSE OR INTOLERANCE TO AN ANTI - TNF BIOLOGIC AGENT 100 , 5 PLACEBO

Am 3 mg BID on 6 mg BID

my 12 mg BID Ø 18 mg BID

* * * * * *

58 * * * * * * * *

71 * * * 67 * * * 58 * * A 53 *

* * * 3 * Q *

* * * * - ACR20 RESPONSE RATE ( % )

- ] 34

O BASELINE 2 8 10 12 4 6

WEEK FIG . 37A

100 m PLACEBO 3 mg BID 6 mg BID

C 80 - 12 mg BID 18 mg BID


INADEQUATE RESPONSE OR INTOLERANCE TO AN ANTI - TNF BIOLOGIC AGENT

ACR50 RESPONSE RATE ( % ) * * * * * * * * * * *

42 * * 38 * * 35 * 24 * * *

16 28 16

BASELINE 8 10 12 4

WEEK FIG . 37B



INADEQUATE RESPONSE OR INTOLERANCE TO AN ANTI - TNF BIOLOGIC AGENT

§ + PLACEBO Am 3 mg BID * 6 mg BID h 12 mg BID

18 mg BID 8 ACR70 RESPONSE RATE ( % ) ó

25 * * 22 * * * *

22 * * 13 WNNU 4

BASELINE § 10 6 WEEK

FIG . 370 DAS28 ( CRP ) MEAN CHANGE FORM BASELINE IN SUBJECTS WITH ACTIVE RHEUMATOID ARTHRITIS

AND PRIOR INADEQUATE RESPONSE OR INTOLERANCE TO AN ANTI - TNF BIOLOGIC AGENT WEEK

BASELINE ? 4 6 8 10 12

- 0 . 9 - - - - - 1 . 1

* * * * * * * * *

? á

DAS28 ( CRP ) CHANGE FROM BASELINE Š in

ü

* * * * * * * * *

* * * * * * * * * 1 . 8

* * * * * *

- 1 . 9 * * - 2 . 2 * * * - 2 . 3 * * *

moto - 2 . 5 * * * * * * * * *

* * * * PLACEBO - 3 mg BID + 6 mg BID + 12 mg BID

- 18 mg BID

FIG . 37D


PATIENTS ACHIEVING DAS28 ( CRP ) < 3 . 2 OR < 2 . 5 AT WEEK 12 IN SUBJECTS WITH ACTIVE RHEUMATOID ARTHRITIS AND PRIOR INADEQUATE RESPONSE OR INTOLERANCE TO AN

ANTI - TNF BIOLOGICAL AGENT

50 DAS 28 ( CRP ) 53 . 2 DAS28 ( CRP ) < 2 . 6

33 Response Rate ( % ) 25 25

nr . .

-

-

" . - .

* * - . .

* . . . . .

. . . . .

. . . . -

.

Placebo 3 mg BID 18 mg BID 6 mg BID 12 mg BID COMPOUND 1

FIG . 37E

50 PATIENTS ACHIEVING CDAI LDA OR CR AT WEEK 12 IN SUBJECTS WITH ACTIVE RHEUMATOID ARTHRITIS AND PRIOR INADEQUATE RESPONSE OR INTOLERANCE TO AN ANIT - TNF BIOLOGICAL AGENT

D CDAI 510 40

CDAI S2 . 8 40

31 Response Rate ( % )

Placebo 3 mg BID 18 mg BID YYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYY

6 mg BID 12 mg BID COMPOUND 1

FIG . 37F


MEAN HEMOGLOBIN LEVELS OVER TIME ( ALL SUBJECTS WITH ACTIVE RHEUMATOID ARTHRITIS AND PRIOR INADEQUATE RESPONSE OR INTOLERANCE TO AN ANTI - TNF BIOLOGIC

AGENT ) 15 , + PLACEBO

+ 3 mg BID within 6 mg BID

- 12 mg BID 18 mg BID

MEAN HEMOGLOBIN ( g / dL )

2NE RG BASELINE 2 4

WEEK 6 Š 10 12

FIG . 38A

MEAN HEMOGLOBIN CHANGE FROM BASELINE OVER TIME ( ALL SUBJECTS WITH ACTIVE RHEUMATOID ARTHRITIS AND PRIOR INADEQUATE RESPONSE OR INTOLERANCE TO AN ANTI - TNF

BIOLOGIC AGENT WITH HSCRP > ULN )

O men

MEAN CHANGE IN HEMOGLOBIN FROM BASELINE ( g / dL )

- 0 . 4 - 0 . 6 - 0 . 8

# PLACEBO + 3 mg BID

mithin 6 mg BID + 12 mg BID

min 18 mg BID BASELINE 8 10 12 4 6

WEEK

FIG . 38B

PATIENT DISPOSITION

RANDOMIZED n = 276

U . S . Patent

DOSED n = 276

PLACEBO n = 56

3 mg BID n = 55

6 mg BID 1 omg BID n = 55

12 mg BID n = 55 12 mg BID

18 mg BID n = 55

Jan . 30 , 2018

DISCONTINUED n = 11 ( 20 % )

• AE , 2 . • WITHDREW CONSENT , 3

LOST TO FOLLOW - UP , 2

LACK OF EFFICACY , 1

NOT COMPLIANT , 1

OTHER , 2

DISCONTINUED n = 4 ( 7 % ) WITHDREW CONSENT , 1 • LOST TO

FOLLOW - UP , 1

LACK OF EFFICACY , 1 OTHER , 2


| AE , 6 • WITHDREW CONSENT , 2 OTHER , 1

DISCONTINUED n = 4 ( 7 % ) • AE , 2 . WITHDREW CONSENT , 1 • OTHER , 1

DISCONTINUED n = 5 ( 9 % ) • AE , 3 .

. WITHDREW CONSENT , 1

LOST TO FOLLOW - UP , 1

Sheet 69 of 77

COMPLETED n = 45 ( 80 % )


COMPLETED = 46 ( 84 % )



FIG . 39

US 9 , 879 , 019 B2

PATIENT DISPOSITION

RANDOMIZED n = 300

U . S . Patent

NOT DOSED n = 1

RANDOMIZED AND DOSED n = 299

PLACEBO n = 50

3 mg BID n = 50

6 mg BID n = 50

12 mg BID n = 50

met een

Jan . 30 , 2018


AE , 1 WITHDREW CONSENT , 4

DISCONTINUED n = 1 ( 2 % ) AE , 1 . •


AE , { WITHDREW CONSENT , 4 • NOT COMPLIANT ,

DISCONTINUED n = 3 ( 6 % ) AE , 1 WITHDREW CONSENT , 1 LOST TO

FOLLOW - UP , 1

Sheet 70 of 77





US 9 , 879 , 019 B2

FIG . 40A

U . S . Patent

18 mg BID n = 50 open enda

24 mg QD n = 49 poco

Jan . 30 , 2018


AE , 5 WITHDREW CONSENT , 1 LOST TO

FOLLOW - UP , 1


AE , 1 • WITHDREW CONSENT , 2 • LOST TO

FOLLOW - UP , 1

• OTHER , 1

Sheet 71 of 77



FIG . 40B

US 9 , 879 , 019 B2

1001

ACR RESPONSES IN SUBJECTS WITH ACTIVE RHEUMATOID ARTHRITIS AND INADEQUATE RESPONSE TO METHOTREXATE ACR20 , ACR50 , AND ACR70 AT

WEEK 12 ( NONRESPONDER IMPUTATION ANALYSIS )

.

U . S . Patent

* * * 80

* *

80

Jan . 30 , 2018

* * *

* * 50 46 X

PLACEBO COMPOUND 1 3 mg BID COMPOUND 1 6 mg BID O COMPOUND 1 12 mg BID COMPOUND 1 18 mg BID COMPOUND 1 24 mg QD

3 RESPONSE RATE ( % ) @ @

* * 40 39

. . . . . .

* * De

.

* * * *

. .

28

. . .

26

*

Sheet 72 of 77

. . . . . . . . .

ACR20

ACR50

ACR70

FIG . 41

US 9 , 879 , 019 B2


+ PLACEBO COMPOUND 1 3 mg BID

* COMPOUND 1 6 mg BID * COMPOUND 1 12 mg BID + COMPOUND 1 18 mg BID

maten COMPOUND 1 24 mg OD ACR20 RESPONSES OVER TIME ( NRI ANALYSIS ) IN SUBJECTS WITH ACTIVE RHEUMATOID ARTHRITIS AND INADEQUATE RESPONSE TO METHOTREXATE

* * * * *

* * * *

76 * * * * * * *

* * * * * * * 8

44 * * * / ACR20 RESPONSE RATE ( % )

34 * *

BASELINE 2 4 6 WEEK

8 10 12

FIG . 42A + PLACEBO # COMPOUND 1 3 mg BID

- COMPOUND 16 mg BID + COMPOUND 1 12 ing BID + COMPOUND 1 18 mg BID * COMPOUND 1 24 mg QD ACRE - 4 mg QD ACR50 RESPONSES OVER TIME ( NRI ANALYSIS ) IN

SUBJECTS WITH ACTIVE RHEUMATOID ARTHRITIS AND INADEQUATE RESPONSE TO METHOTREXATE

Y * * * * *

À * * ACR50 RESPONSE RATE ( % ) 50 * * * 46 * * 40 * * * * * * * * *

* mamamman 38 * *

Ooo 18 - 18 *

4 6 WEEK

FIG . 42B

- 8 BASELINE 10 12


ACR70 RESPONSES OVER TIME ( NRI ANALYSIS ) IN SUBJECTS WITH ACTIVE RHEUMATOID ARTHRITIS AND INADEQUATE RESPONSE TO METHOTREXATE &

S

I PLACEBO + COMPOUND 1 3 mg BID * COMPOUND 1 6 mg BID - COMPOUND 1 12 mg BID * COMPOUND 1 18 mg BID

- COMPOUND 1 24 mg QD ACR70 RESPONSE RATE ( % ) Š

* * * * * * * 44

20 + 004

NNNN ONNO Š

* 0

BASELINE 2 10 12 4 6 8 WEEK

FIG . 420 DAS28 ( CRP ) MEAN CHANGE FROM BASELINE OVER TIME ( OBSERVED CASES ) IN SUBJECTS WITH ACTIVE RHEMATOID ARTHRITIS AND INADEQUATE RESPONSE TO METHOTREXATE

BASELINE 2 4 WEEK

6 8 10 12 - 0 . 4

1 - 1 . 0 * * - 1 . 0 * *

- 1 . 3 * * * 1 . 3 *

- 1 . 4 * * * * * * * 0 * * * 0 *

= 5 :

DAS28 ( CRP ) CHANGE FROM BASELINE is

* * * * * * * - 2 . 2 * * - 2 . 3 * * * - 2 . 4 * * * - 2 . 5 * * * * - 2 . 6 * * *

* * * * * * * 0

2 . 0

* * * PLACEBO

+ COMPOUND 1 3 mg BID COMPOUND 1 6 mg BID COMPOUND 1 12 mg BID

A COMPOUND 1 18 mg BID A COMPOUND 1 24 mg QD

FIG . 42D


807 D

DAS28 ( CRP ) < 3 . 2 DAS28 ( CRP ) < 2 . 6

SUBJECTS WITH ACTIVE RHEUMATOID ARTHRITIS AND PRIOR INADEQUATE RESPONSE TO

METHOTREXATE ACHIEVING DAS28 ( CRP ) < 3 . 2 or < 2 . 6

* * * 52 * *

48 * * * * * 46

* * $

SA 36 RESPONSE RATE ( % ) o

PLACEBO 3 mg BID 6 mg BID 12 mg BID 18 mg BID 24 mg QD COMPOUND 1

FIG . 43A M CDAI < 10

601 GCDAI < 2 . 8 SUBJECTS WITH ACTIVE RHEUMATOID ARTHRITIS

AND PRIOR INADEQUATE RESPONSE TO METHOTREXATE ACHIEVING CDAI < 10 or < 2 . 8 AT

WEEK 12 * *

*

* * 35 29

20 RESPONSE RATE ( % ) 16

II . . . .

PLACEBO 3 mg BID 6 mg BID 12 mg BID 18 mg BID 24 mg QD COMPOUND 1

FIG . 43B


* PLACEBO + COMPOUND 1 3 mg BID + COMPOUND 1 6 mg BID + COMPOUND 1 12 mg BID

men COMPOUND 1 18 mg BID - COMPOUND 1 24 mg QD 0 . 81

???

MEAN HEMOGLOBIN CHANGE FROM BASELINE OVER TIME BY TREATMENT GROUP IN SUBJECTS WITH ACTIVE RHEUMATOID ARTHRITIS AND INADEQUATE RESPONSE TO METHOTREXATE 0 . 6

t - - LLLLLL MEAN CHANGE IN HEMOGLOBIN FROM BASELINE ( g / dL ) SS e o en

the

BASELINE 2 4 6 WEEK

8 10 12 B

FIG . 44A

+ PLACEBO * COMPOUND 1 3 mg BID

- COMPOUND 1 6 mg BID ngh COMPOUND 1 12 mg BID

COMPOUND 1 18 mg BID V . hoftium COMPOUND 1 24 mg QD

MEAN HEMOGLOBIN CHANGE FROM BASELINE OVER TIME BY TREATMENT GROUP IN SUBJECTS WITH ACTIVE RHEUMATOID ARTHRITIS AND INADEQUATE RESPONSE TO METHOTREXATE

WITH ISCRP < 5mg / mL AT BASELINE


:

BASELINE 2 8 10 12 4 6 WEEK

FIG . 44B


MEAN HEMOGLOBIN CHANGE FROM BASELINE OVER TIME BY TREATMENT GROUP IN SUBJECTS WITH ACTIVE RHEUMATOID ARTHRITIS AND INADEQUATE

0 . 8 7 RESPONSE TO METHOTREXATE WITH ISCRP < 5mg / mL AT BASELINE 0 . 6

ten ?? ?? ?? w - www ww mwen - - - - - - -


???? ??? ???

+ * + PLACEBO + COMPOUND 1 3 mg BID

COMPOUND 16 mg BID - COMPOUND 1 12 mg BID

COMPOUND 1 18 mg BID antingen COMPOUND 1 24 mg QD BASELINE 4 6

WEEK 8 10 12

FIG . 44C

US 9 , 879 , 019 B2

PROCESSES FOR THE PREPARATION OF Additionally , currently known processes for the prepara ( 3S , 4R ) - 3 - ETHYL - 4 - ( 3H - IMIDAZO [ 1 , 2 - a ] tion of Compound 1 involve the use of particularly hazard

PYRROLO [ 2 , 3 - E1 - PYRAZIN - 8 - YL ) - N - ( 2 , 2 , 2 ous reagents , such as trimethylsilyldiazomethane or diaz TRIFLUOROETHYL ) PYRROLIDINE - 1 omethane , and do not produce a crystalline product . There is

CARBOXAMIDE AND SOLID STATE FORMS 5 thus also a need for a process for preparing Compound 1 , THEREOF and pharmaceutically acceptable salts thereof , that avoids

the use of particularly hazardous reagents , and can produce CROSS - REFERENCE TO RELATED a crystalline product and crystalline intermediates .

APPLICATIONS 10 Additionally , sustained peak plasma concentrations can

This application is a continuation of U . S . application Ser . theoretically be achieved by means of sustained release No . 15 / 295 , 561 , filed Oct . 17 , 2016 , which claims the matrix systems . However , when such systems are made of benefit of U . S . Provisional Application No . 62 / 242 , 797 , filed hydrophilic polymers , such as HPMC , they seldom provide Oct . 16 , 2015 ; and claims the benefit of U . S . Provisional pH independent drug release of pH - dependent soluble drugs , Application No . 62 / 267 . 672 , filed Dec . 15 . 2015 : and claims 15 and they are normally incapable of attaining zero - order the benefit of U . S . Provisional Application No . 62 / 301 , 537 , release except for practically insoluble drugs . Unexpectedly , filed Feb . 29 , 2016 ; and claims the benefit of U . S . Provi - is has been discovered that when tartaric acid is used as a sional Application No . 62 / 352 , 380 , filed Jun . 20 , 2016 ; all of pH - modifier in such a system , it allows Compound 1 to be which are herein incorporated by reference in their entirety . released at a steady rate regardless of the pH of the envi

20 ronment . FIELD OF THE INVENTION In an unexpected finding , it was discovered that as a tablet

The present disclosure relates to : ( a ) processes for the containing the hydrophilic polymer matrix system erodes , preparation of ( 3S , 4R ) - 3 - ethyl - 4 - ( 3H - imidazo [ 1 , 2 - a ] pyrrolo Compound 1 reacts with the HPMC , creating a thicker gel [ 2 , 3 - e ] pyrazin - 8 - yl ) - N - ( 2 , 2 , 2 - trifluoroethyl ) pyrrolidine - 1 - 1 25 layer which slows the release of Compound 1 from the 25 l carboxamide ( referred to herein as “ Compound 1 ” ) . ( b ) tablet . The resulting gel layer provided an environment intermediates used in the preparation of Compound 1 and suitable for Compound 1 to dissolve . processes for preparing the intermediates ; ( c ) solid state forms of Compound 1 , ( d ) pharmaceutical compositions SUMMARY OF THE INVENTION comprising one or more solid state forms of Compound 1 , 30 and , optionally , one or more additional therapeutic agents ; ( e ) methods of treating Janus kinase - associated conditions In one aspect , the present disclosure relates to a process ( including rheumatoid arthritis ) by administering one or for preparing Compound 1 , or a pharmaceutically acceptable more solid state forms of Compound 1 to a subject in need salt thereof . The process comprises : thereof ; ( f ) kits comprising a first pharmaceutical composi - 35 a ) reacting a compound of formula ( 1 ) tion comprising a solid state form of Compound 1 , and , optionally , a second pharmaceutical composition compris ing one or more additional therapeutic agents ; ( g ) methods for the preparation of solid state forms of Compound 1 ; and ( h ) solid state forms of Compound 1 prepared in accordance 40 with such methods .

BACKGROUND OF THE INVENTION > 10ml

OH ( 3S , 4R ) - 3 - ethyl - 4 - ( 3H - imidazo [ 1 , 2 - a ] pyrrolo [ 2 , 3 - e ] 45 pyrazin - 8 - yl ) - N - ( 2 , 2 , 2 - trifluoroethyl ) pyrrolidine - 1 - carbox amide ( “ Compound 1 ” ) was first disclosed in International Application WO2011 / 068881A1 , which is herein incorpo rated by reference in its entirety . The compound has activity or a pharmaceutically acceptable salt thereof with trim as a Janus kinase ( “ JAK ” ) inhibitor , particularly as a JAK - 1 50 ethylsulfoxonium chloride to form a compound of formula inhibitor . Clinical trials are ongoing to evaluate the use of ( II ) the compound to treat rheumatoid arthritis .

The isolation and commercial - scale preparation of a solid state form of Compound 1 and corresponding pharmaceu tical formulations having acceptable solid state properties 55 ( including chemical stability , thermal stability , solubility , hygroscopicity , and / or particle size ) , compound manufac turability ( including yield , impurity rejection during crys tallization , filtration properties , drying properties , and mill ing properties ) , and formulation feasibility ( including 60 stability with respect to pressure or compression forces during tableting ) present a number of challenges that are discussed in greater detail below . Accordingly , there is a current need for one or more solid state forms of Compound 1 that have an acceptable balance of these properties and can 65 be used in the preparation of pharmaceutically acceptable solid dosage forms .

PG

un

G =

=

US 9 , 879 , 019 B2 wherein PG is a protecting group ; b ) contacting the compound of formula ( II ) with LiX and

a sulfonic acid to form a compound of formula ( III )

e ) deprotecting the compound of formula ( VI ) and form ing a pharmaceutically acceptable salt of the compound of formula ( VII ) :

5 ( III ) ( VII )

111nu PG

VH

10

Un

15

wherein X is Br or Cl ; c ) reacting the compound of formula ( III ) with a com

pound of formula ( IV ) 20

f ) reacting the pharmaceutically acceptable salt of the compound of formula ( VII ) with 2 , 2 , 2 - trifluoroethylamine to produce Compound 1 .

In another aspect , the present disclosure relates to a process for preparing Compound 1 , or a pharmaceutically acceptable salt thereof . The process comprises :

a ) reacting a compound of formula ( lb ) ( IV )

IZ

25 ( Ib )

Cbz

to produce a compound of formula ( V ) HN . HN 1111111 - OH

PG

35 with trimethylsulfoxonium chloride in the presence of

carbonyldiimidazole and a strong base to form a compound of formula ( IIa )

40

( IIIa ) Cbz Teme RU

45

1111111 wherein R , is selected from the group consisting of alkyl ,

aryl , and OR2 ; R2 is alkyl ; and Ts is tosyl ; d ) contacting the compound of formula ( V ) with a per - 50

fluoro acid anhydride and an organic base to form a com pound of formula ( VI ) wherein Cbz is carboxybenzyl ;

b ) contacting the compound of formula ( IIa ) with lithium bromide and a sulfonic acid to form a compound of formula

55 ( IIIa ) ( VI )

11111011 ( IIIa ) VPG Cbz

> > 11111111

1110 W01011 Br

US 9 , 879 , 019 B2 6

c ) reacting the compound of formula ( IIIa ) with a com pound of formula ( IVA )

f ) contacting the compound of formula ( VII ) with hydro chloric acid to form a compound of formula ( VIIa )

( IV ) 5 ( VIIa ) Un

NH

> Illlll 2HCI

10

in the presence of lithium tert - butoxide to produce a compound of formula ( Va ) 15 15

( Va ) Cbz

20

g ) reacting the compound of formula ( VIIa ) with 2 , 2 , 2 trifluoroethylamine in the presence of carbonyldiimidazole to produce Compound 1 .

In another aspect , the present disclosure relates to a process for preparing Compound 1 . The process comprises :

a ) reacting a compound of formula ( 1 ) Mits

25 PG 2 - ?

. R2

- OH

wherein R , is methyl or ethyl ; and Ts is tosyl ; d ) contacting the compound of formula ( Va ) with a

perfluoro acid anhydride and an organic base to form a 3 compound of formula ( VIa )

or a pharmaceutically acceptable salt thereof with trim ethylsulfoxonium chloride to form a compound of formula ( II )

( Vla ) 40 TIMI - Cbz WIN > 111111

.

11

N

50

una o formula ya no Brasia e ) deprotecting the compound of formula ( VIa ) to form a compound of formula ( VII ) wherein PG is a protecting group ;

b ) contacting the compound of formula ( II ) with LiX and a sulfonic acid to form a compound of formula ( III ) no n a su Ss

( VII ) 1111 ( III )

PG

IUNI

ill

US 9 , 879 , 019 B2

wherein X is Br or Cl ; c ) reacting the compound of formula ( III ) with a com

pound of formula ( IV ) ( VII )

uma NH

i

( IV ) > 11111111 HCl

Ri 10

NH

to produce a compound of formula ( V )

( V ) PG

f ) contacting the compound of formula ( VIIb ) with a base 15 to form the compound of formula ( VII ) ;

g ) reacting the compound of formula ( VII ) with 2 , 2 , 2 trifluoroethylamine to produce Compound 1 ;

h ) contacting Compound 1 with L - tartaric acid to produce a tartrate salt of Compound 1 ; and

20 i ) contacting the tartrate salt with sodium carbonate and sodium bicarbonate to produce Compound 1 .

In another aspect , the present disclosure relates to a process for preparing Compound 1 , or a pharmaceutically acceptable salt thereof . The process comprises :

25 a ) converting a compound of formula ( Xla ) :

( XIa )

30 N PG — PG HO .

wherein R , is selected from the group consisting of alkyl , aryl , and — OR , ; R , is alkyl ; and Ts is tosyl ;

d ) contacting the compound of formula ( V ) with a per fluoro acid anhydride and an organic base to produce a 35 compound of formula ( VI ) to a compound of formula ( 1 ) :

110111 PG -

7 N - PG

11111 45 - OH

DZ

50 wherein PG is a protecting group ; b ) reacting the compound of formula ( I ) with trimethyl

sulfoxonium chloride to form a compound of formula ( II ) e ) deprotecting the compound of formula ( VI ) to form a compound of formula ( VII )

( VII ) 55

PG -

Z

05 and contacting the compound of formula ( VII ) with

hydrochloric acid to form the compound of formula ( VIIb )

US 9 , 879 , 019 B2 10

c ) contacting the compound of formula ( II ) with an f ) deprotecting the compound of formula ( VI ) and form anhydrous source of HBr or HCl to form a compound of ing a pharmaceutically acceptable salt of the compound of formula ( III ) formula ( VII ) :

5 ( III ) ( VII )

PG 100mm

01111 10

T

wherein X is Br or Cl ; d ) reacting the compound of formula ( III ) with a com -

pound of formula ( IV ) de and

g ) reacting the pharmaceutically acceptable salt of the 20 compound of formula ( VII ) with 2 , 2 , 2 - trifluoroethylamine

to produce Compound 1 . In another aspect , the present disclosure relates to a

compound of formula ( II ) : ( IV )

25 ( II )

PG

to produce a compound of formula ( V ) 30

1110 0111111 PG

35

wherein PG is a protecting group . In another aspect , the disclosure relates to a process for

preparing a compound of formula ( II ) : 40

E

PG R

45

ut 4100 wherein R , is selected from the group consisting of alkyl , aryl , and - - OR2 ; R2 is alkyl ; and Ts is tosyl ;

e ) contacting the compound of formula ( V ) with a per - 50 fluoro acid anhydride and an organic base to form a com pound of formula ( VI )

wherein PG is a protecting group , the process comprising 55 reacting a compound of formula ( 1 )

( VI ) 11u

NPG PG

110 MUM - OH

N

US 9 , 879 , 019 B2 11 12

In another aspect , the present disclosure relates to a process for preparing a compound of formula ( V )

or a pharmaceutically acceptable salt thereof with trimeth ylsulfoxonium chloride to form the compound of formula ( II ) .

In another aspect , the present disclosure is directed to a process for the preparation of a compound of formula ( III ) : PG

( III ) llies . PG

10 - Z

. IIllI

1110

the process comprising contacting a compound of formula 20 the process comprising : ( II )

a ) converting a compound of formula ( Xla ) : ( II ) 25 PG

( Xla )

— PG

HO 30

to a compound of formula ( 1 ) 35 35

with LiX and a sulfonic acid to form the compound of formula ( III ) ; wherein PG is a protecting group ; and X is Br or Cl .

40 PG - In another aspect , the present disclosure relates to a

compound of formula ( Va ) Z

45

timu Man - OH ;

( Va ) 50

b ) reacting the compound of formula ( I ) with trimethyl sulfoxonium chloride to form a compound of formula ( II )

55

( II ) PG

11th

wherein R2 is methyl or ethyl ; and Ts is tosyl .

US 9 , 879 , 019 B2 13 14

with a compound of formula ( IV ) : c ) contacting the compound of formula ( II ) with an anhydrous source of HBr or HCl to form a compound of formula ( III )

( IV ) 5

PG

Ts . 10

110 unt

15 d ) reacting the compound of formula ( III ) with a com

pound of formula ( IV )

to produce the compound of formula ( V ) ; wherein : PG is a protecting group ; X is Br or Cl ; R is OR ; R2 is methyl or ethyl ; and Ts is tosyl . In another aspect , the present disclosure relates to a

20 compound of formula ( IVa ) :

( IVa )

25

to produce the compound of formula ( V ) ; wherein : PG is a protecting group ; 30 X is Br or Cl ; R , is selected from the group consisting of alkyl , aryl , and OR ; R , is alkyl ; and Ts is tosyl . In another aspect , the disclosure is directed to a process 35

for preparing a crystalline compound of formula ( V )

wherein R , is methyl or ethyl , and Ts is tosyl . In another aspect , the present disclosure relates to a

process for preparing a compound of formula ( IVa ) :

( IVa )

( V ) ten PG

40

wherein R , is methyl or ethyl , and Ts is tosyl , the process comprising :

a ) reacting a compound of formula ( XVII ) 45

RI ( XVII ) Br N Br

50

' N NH2 the process comprising : a ) reacting a compound of formula ( III )

55 with trimethylsilylacetylene in the presence of a catalyst to form a compound of formula ( XVIII ) :

PG ( XVIII ) TMS TMS

Br

111111 NH2

wherein TMS is trimethylsilyl ;

15 US 9 , 879 , 019 B2

16 b ) contacting the compound of formula ( XVIII ) with ( ii ) protecting the compound of formula ( VIII ) to form a

p - toluenesulfonyl chloride in the presence of a base to form compound of formula ( IX ) : a compound of formula ( XIX )

( IX ) R30

( XIX ) Br - Cbz

10

wherein Ts is tosyl ; and c ) reacting the compound of formula ( XIX ) with a car - 13

bamate in the presence of a catalyst and a ligand to form the compound of formula ( IVA ) , wherein the carbamate is selected from the group consisting of methyl carbamate and ethyl carbamate . 20

In another aspect , the present disclosure relates to a compound of formula ( VII ) :

wherein R3 is selected from the group consisting of CF3S02 — ; CH2S02 — ; and tosyl ;

( iii ) contacting the compound of formula ( IX ) with one of ethyl boronic acid , ethyl magnesium bromide , or ethyl zinc chloride in the presence of a catalyst to form a compound of formula ( X ) :

20

N - Cbz

( VII ) 25 11111

( iv ) hydrolyzing the compound of formula ( X ) to produce 30 the compound of formula ( XI ) :

( XI ) 35 - Cbz

HO .

or a pharmaceutically acceptable salt thereof . In another aspect , the present disclosure relates to a

process for preparing a compound of formula ( lb ) 40 ( v ) converting the compound of formula ( XI ) to the

compound of formula ( XII ) : Cbz

45 ( XII ) HN • HN

N - Cbz H11111 - OH ??

50

wherein Cbz is carboxybenzyl , the process comprising : ( vi ) contacting the compound of formula ( XII ) with ( i ) reacting carboxybenzyl - glycine ethyl ester with ethyl se dicyclohexylamine to form the compound of formula ( Ib ) .

55 In another aspect , the present disclosure relates to the acrylate to form a compound of formula ( VIII ) : dicyclohexylamine salt of ( 3R , 4S ) - 1 - ( ( benzyloxy ) carbo nyl ) - 4 - ethylpyrrolidine - 3 - carboxylate .

In one aspect , the present disclosure relates to pharma ceutically acceptable solid state forms of Compound 1 .

1 ) 60 In another aspect , the present disclosure relates to Amor phous Freebase of Compound 1 .

N - Cbz In another aspect , the present disclosure relates to crys talline Compound 1 .

In another aspect , the present disclosure relates to crys 65 talline hydrates of Compound 1 .

In another aspect , the present disclosure relates to crys talline tartrates of Compound 1 .

HO .

US 9 , 879 , 019 B2 18

In another aspect , the present disclosure relates to the In another aspect , the present disclosure relates to meth Freebase Hydrate Form C of Compound 1 . ods of treating a JAK - associated condition ( such as rheu

In another aspect , the present disclosure relates to the matoid arthritis ) in a human subject suffering from or Freebase Hydrate Form B of Compound 1 . susceptible to such a condition comprising administering to

In another aspect , the present disclosure relates to crys - 5 the subject a solid state form of Compound 1 , in combina talline anhydrates of Compound 1 . tion with one or more additional therapeutic agents ( e . g . , a

In another aspect , the present disclosure relates to the therapeutic agent for treating rheumatoid arthritis that is not Freebase Anhydrate Form D of Compound 1 . a JAK inhibitor ) . In another aspect , the disclosure relates to

In another aspect , the present disclosure relates to phar - a pharmaceutical composition comprising a solid state form maceutical compositions comprising one or more solid state 10 of Compound 1 , as described in the present disclosure , in forms of Compound 1 , and a pharmaceutically acceptable combination with one or more additional therapeutic agents carrier . ( e . g . , a therapeutic agent for treating rheumatoid arthritis

In another aspect , the present disclosure is directed to a that is not a JAK inhibitor ) , for use in treatment of a pharmaceutical composition comprising one or more solid JAK - associated condition ( such as rheumatoid arthritis ) in a state forms of Compound 1 , from about 10 w / w % to about 15 subject , particularly in a human subject suffering from or 35 w / w % of an organic acid selected from the group susceptible to the condition . consisting of tartaric acid , fumaric acid , citric acid , succinic In another aspect , the present disclosure relates to a acid , malic acid , and combinations thereof , and a pharma - method of treating moderate to severely active rheumatoid ceutically acceptable carrier . In one embodiment , the solid arthritis , the method comprising administering a therapeu state form is Tartrate Hydrate . In one embodiment , the solid 20 tically effective amount of Compound 1 in one or more state form is Freebase Hydrate Form C . forms as disclosed herein to a subject suffering from or

In another aspect , the present disclosure relates to phar susceptible to the condition . In a particular aspect , such a maceutical compositions comprising one or more solid state method may comprise administering 7 . 5 mg once daily or 15 forms of Compound 1 , and , optionally , one or more addi - mg once daily , or 30 mg once daily , or 45 mg once daily of tional therapeutic agents . 25 the Compound 1 , in one or more forms as disclosed herein ,

In another aspect , the present disclosure relates to meth to the subject . In this or another particular aspect , the subject ods of treating a JAK - associated condition ( such as rheu - may be administered the Compound 1 in Freebase Form C . matoid arthritis ) in a human subject suffering from or In this or yet another particular aspect , the subject may have susceptible to such a condition comprising administering to an inadequate response to methotrexate . In this or yet the subject a therapeutically effective amount of a solid state 30 another particular aspect , the subject may have an inad form of Compound 1 . In another aspect , the disclosure equate response to biologics medicines approved for rheu relates to a pharmaceutical composition comprising a thera - matoid arthritis . In this or yet another particular aspect , the peutically effective amount of a solid state form of Com - subject may have not previously been administered biolog pound 1 as described in the present disclosure , for use in ics medicines approved for rheumatoid arthritis . treatment of a JAK - associated condition ( such as rheuma - 35 In another aspect , the present disclosure relates to a toid arthritis ) in a subject , particularly in a human subject method of treating an adult subject having moderate to suffering from or susceptible to the condition . severely active rheumatoid arthritis , the method comprising

In another aspect , the present disclosure relates to meth - administering to the subject : a ) about 7 . 5 mg of Compound ods of treating rheumatoid arthritis , wherein the term “ rheu - 1 freebase , or a pharmaceutically acceptable salt thereof , or matoid arthritis ” includes juveline rheumatoid arthritis , 40 a crystalline hydrate or a crystalline anhydrate of Compound juvenile idiopathic arthritis , ankylosing spondylitis disease , 1 in an amount sufficient to deliver to the subject about 7 . 5 Sjogren ' s syndrome , psoriatic arthritis . mg of Compound 1 freebase equivalent ; or b ) about 15 mg

In another aspect , the present disclosure relates to meth - of Compound 1 freebase , or a pharmaceutically acceptable ods of treating inflammatory bowel disease , wherein the salt thereof , or a crystalline hydrate or a crystalline anhy term “ inflammatory bowel disease " includes Crohn ' s dis - 45 drate of Compound 1 in an amount sufficient to deliver to the ease , pediatric Crohn ' s disease and ulcerative colitis . subject about 15 mg of Compound 1 freebase equivalent ; or

In another aspect , the present disclosure relates to a c ) about 30 mg of Compound 1 freebase , or a pharmaceu method of treating a condition selected from the group tically acceptable salt thereof , or a crystalline hydrate or a consisting of rheumatoid arthritis , juvenile idiopathic arthri - crystalline anhydrate of Compound 1 in an amount sufficient tis , Crohn ' s disease , ulcerative colitis , psoriasis , plaque 50 to deliver to the subject about 30 mg of Compound 1 psoriasis , nail psoriasis , psoriatic arthritis , ankylosing spon - freebase equivalent ; or d ) about 45 mg of Compound 1 dylitis , alopecia areata , hidradenitis suppurativa , atopic der - freebase , or a pharmaceutically acceptable salt thereof , or a matitis and systemic lupus erythematosus in a human subject crystalline hydrate or a crystalline anhydrate of Compound suffering from or susceptible to such a condition , the method 1 in an amount sufficient to deliver to the subject about 45 comprising administering to the subject a therapeutically 55 mg of Compound 1 freebase equivalent . In one embodiment , effective amount a solid state form of Compound 1 . In the present disclosure is directed to a pharmaceutical com another aspect , the disclosure relates to a pharmaceutical position for use in treating an adult subject having moderate composition comprising a therapeutically effective amount to severely active rheumatoid arthritis , the use comprising of a solid state form of Compound 1 as described in the administering the pharmaceutical composition to the sub present disclosure , for use in treatment of a condition 60 ject , wherein the pharmaceutical composition comprises a ) selected from the group consisting of rheumatoid arthritis , about 7 . 5 mg of Compound 1 freebase , or a pharmaceuti juvenile idiopathic arthritis , Crohn ' s disease , ulcerative coli - cally acceptable salt thereof , or a crystalline hydrate or a tis , psoriasis , plaque psoriasis , nail psoriasis , psoriatic arthri crystalline anhydrate of Compound 1 in an amount sufficient tis , ankylosing spondylitis , alopecia areata , hidradenitis sup - to deliver to the subject about 7 . 5 mg of Compound 1 purativa , atopic dermatitis , and systemic lupus 65 freebase equivalent ; or b ) about 15 mg of Compound 1 erythematosus in a subject , particularly in a human subject freebase , or a pharmaceutically acceptable salt thereof , or a suffering from or susceptible to the condition . crystalline hydrate or a crystalline anhydrate of Compound

19 US 9 , 879 , 019 B2

20 1 in an amount sufficient to deliver to the subject about 15 per day of Compound 1 freebase or a pharmaceutically mg of Compound 1 freebase equivalent ; or c ) about 30 mg acceptable salt thereof , or a crystalline hydrate or crystalline of Compound 1 freebase , or a pharmaceutically acceptable anhydrate of Compound 1 in an amount sufficient to deliver salt thereof , or a crystalline hydrate or a crystalline anhy to the subject about 15 mg per day of Compound 1 freebase drate of Compound 1 in an amount sufficient to deliver to the 5 equivalent ; or c ) about 30 mg per day of Compound 1 subject about 30 mg of Compound 1 freebase equivalent ; or freebase or a pharmaceutically acceptable salt thereof , or a d ) about 45 mg of Compound 1 freebase , or a pharmaceu - crystalline hydrate or crystalline anhydrate of Compound 1 tically acceptable salt thereof , or a crystalline hydrate or a in an amount sufficient to deliver to the subject about 30 mg crystalline anhydrate of Compound 1 in an amount sufficient per day of Compound 1 freebase equivalent ; or d ) about 45 to deliver to the subject about 45 mg of Compound 1 10 mg per day of Compound 1 freebase or a pharmaceutically freebase equivalent . acceptable salt thereof , or a crystalline hydrate or crystalline

In another embodiment , the present disclosure relates to a anhydrate of Compound 1 in an amount sufficient to deliver method of treating structural damage associated with rheu - to the subject about 45 mg per day of Compound 1 freebase matoid arthritis in an adult subject , the method comprising equivalent ; wherein the subject has symptoms selected from administering to the subject : a ) about 7 . 5 mg per day of 15 the group consisting of at least 6 swollen joints , at least 6 Compound 1 freebase or a pharmaceutically acceptable salt tender joints , and combinations thereof prior to treating . In thereof , or a crystalline hydrate or crystalline anhydrate of one embodiment , the disclosure is directed to a pharmaceu Compound 1 in an amount sufficient to deliver to the subject tical composition for use in treating moderate to severely about 7 . 5 mg per day of Compound 1 freebase equivalent ; active rheumatoid arthritis in an adult subject , the use or b ) about 15 mg per day of Compound 1 freebase or a 20 comprising administering the pharmaceutical composition pharmaceutically acceptable salt thereof , or a crystalline to the subject , wherein the pharmaceutical composition hydrate or crystalline anhydrate of Compound 1 in an comprises : a ) about 7 . 5 mg per day of Compound 1 freebase amount sufficient to deliver to the subject about 15 mg per or a pharmaceutically acceptable salt thereof , or a crystalline day of Compound 1 freebase equivalent ; or c ) about 30 mg hydrate or crystalline anhydrate of Compound 1 in an per day of Compound 1 freebase or a pharmaceutically 25 amount sufficient to deliver to the subject about 7 . 5 mg per acceptable salt thereof , or a crystalline hydrate or crystalline day of Compound 1 freebase equivalent ; or b ) about 15 mg anhydrate of Compound 1 in an amount sufficient to deliver per day of Compound 1 freebase or a pharmaceutically to the subject about 30 mg per day of Compound 1 freebase acceptable salt thereof , or a crystalline hydrate or crystalline equivalent ; or d ) about 45 mg per day of Compound 1 anhydrate of Compound 1 in an amount sufficient to deliver freebase or a pharmaceutically acceptable salt thereof , or a 30 to the subject about 15 mg per day of Compound 1 freebase crystalline hydrate or crystalline anhydrate of Compound 1 equivalent ; or c ) about 30 mg per day of Compound 1 in an amount sufficient to deliver to the subject about 45 mg freebase or a pharmaceutically acceptable salt thereof , or a per day of Compound 1 freebase equivalent ; such that the crystalline hydrate or crystalline anhydrate of Compound 1 structural damage in the adult subject is inhibited or less - in an amount sufficient to deliver to the subject about 30 mg ened . In one embodiment , the disclosure relates to a phar - 35 per day of Compound 1 freebase equivalent ; or d ) about 45 maceutical composition for use in treating structural damage mg per day of Compound 1 freebase or a pharmaceutically associated with rheumatoid arthritis in an adult subject , the acceptable salt thereof , or a crystalline hydrate or crystalline use comprising administering the pharmaceutical composi - anhydrate of Compound 1 in an amount sufficient to deliver tion to the subject , wherein the pharmaceutical composition to the subject about 45 mg per day of Compound 1 freebase comprises : a ) about 7 . 5 mg per day of Compound 1 freebase 40 equivalent ; wherein the subject has symptoms selected from or a pharmaceutically acceptable salt thereof , or a crystalline the group consisting of at least 6 swollen joints , at least 6 hydrate or crystalline anhydrate of Compound 1 in an t ender joints , and combinations thereof prior to treating . amount sufficient to deliver to the subject about 7 . 5 mg per I n another aspect , the disclosure is directed to a method of day of Compound 1 freebase equivalent ; or b ) about 15 mg reducing signs and symptoms of rheumatoid arthritis in an per day of Compound 1 freebase or a pharmaceutically 45 adult subject with moderately to severely active rheumatoid acceptable salt thereof , or a crystalline hydrate or crystalline arthritis , the method comprising administering to the sub anhydrate of Compound 1 in an amount sufficient to deliver ject : a ) about 7 . 5 mg per day of Compound 1 freebase or a to the subject about 15 mg per day of Compound 1 freebase pharmaceutically acceptable salt thereof , or a crystalline equivalent ; or c ) about 30 mg per day of Compound 1 hydrate or crystalline anhydrate of Compound 1 in an freebase or a pharmaceutically acceptable salt thereof , or a 50 amount sufficient to deliver to the subject about 7 . 5 mg of crystalline hydrate or crystalline anhydrate of Compound 1 Compound 1 freebase equivalent ; or b ) about 15 mg per day in an amount sufficient to deliver to the subject about 30 mg of Compound 1 freebase or a pharmaceutically acceptable per day of Compound 1 freebase equivalent ; or d ) about 45 salt thereof , or a crystalline hydrate or crystalline anhydrate mg per day of Compound 1 freebase or a pharmaceutically of Compound 1 in an amount sufficient to deliver to the acceptable salt thereof , or a crystalline hydrate or crystalline 55 subject about 15 mg of Compound 1 freebase equivalent ; or anhydrate of Compound 1 in an amount sufficient to deliver c ) about 30 mg per day of Compound 1 freebase or a to the subject about 45 mg per day of Compound 1 freebase pharmaceutically acceptable salt thereof , or a crystalline equivalent ; such that the structural damage in the adult hydrate or crystalline anhydrate of Compound 1 in an subject is inhibited or lessened . amount sufficient to deliver to the subject about 30 mg of

In another aspect , the disclosure is directed to a method of 60 Compound 1 freebase equivalent ; or d ) about 45 mg per day treating moderate to severely active rheumatoid arthritis in of Compound 1 freebase or a pharmaceutically acceptable an adult subject , the method comprising administering to the salt thereof , or a crystalline hydrate or crystalline anhydrate subject : a ) about 7 . 5 mg per day of Compound 1 freebase or of Compound 1 in an amount sufficient to deliver to the a pharmaceutically acceptable salt thereof , or a crystalline subject about 45 mg of Compound 1 freebase equivalent . In hydrate or crystalline anhydrate of Compound 1 in an 65 one embodiment , the disclosure is directed to a pharmaceu amount sufficient to deliver to the subject about 7 . 5 mg per tical composition for use in reducing signs and symptoms of day of Compound 1 freebase equivalent ; or b ) about 15 mg rheumatoid arthritis in an adult subject with moderately to

21 US 9 , 879 , 019 B2

22 severely active rheumatoid arthritis , the use comprising 30 mg , or about 45 mg per day of Compound 1 freebase or administering the pharmaceutical composition to the sub - a crystalline hydrate of Compound 1 in an amount sufficient ject , wherein the pharmaceutical composition comprises : a ) to deliver to the subject about 7 . 5 mg , or about 15 mg , or about 7 . 5 mg per day of Compound 1 freebase or a phar about 30 mg , or about 45 mg per day of Compound 1 maceutically acceptable salt thereof , or a crystalline hydrate 5 freebase equivalent , wherein the subject has symptoms or crystalline anhydrate of Compound 1 in an amount selected from the group consisting of at least 6 swollen sufficient to deliver to the subject about 7 . 5 mg of Com - joints , at least 6 tender joints , and combinations thereof prior pound 1 freebase equivalent ; or b ) about 15 mg per day of to treating . In this or another particular aspect , the hydrate Compound 1 freebase or a pharmaceutically acceptable salt may be a hemihydrate . In this or another aspect , the hemi thereof , or a crystalline hydrate or crystalline anhydrate of 10 hydrate may be Freebase Hydrate Form C . Compound 1 in an amount sufficient to deliver to the subject in another aspect , the present disclosure relates to a about 15 mg of Compound 1 freebase equivalent ; or c ) about method of reducing signs and symptoms of rheumatoid 30 mg per day of Compound 1 freebase or a pharmaceuti - arthritis in an adult subject with moderately to severely cally acceptable salt thereof , or a crystalline hydrate or active rheumatoid arthritis , the method comprising admin crystalline anhydrate of Compound 1 in an amount sufficient 15 istering to the subject about 7 . 5 mg per day of Compound 1 to deliver to the subject about 30 mg of Compound 1 freebase or a crystalline hydrate of Compound 1 in an freebase equivalent ; or d ) about 45 mg per day of Compound amount sufficient to deliver to the subject about 7 . 5 mg of 1 freebase or a pharmaceutically acceptable salt thereof , or Compound 1 freebase equivalent . In this or another particu a crystalline hydrate or crystalline anhydrate of Compound lar aspect , the hydrate may be a hemihydrate . In this or 1 in an amount sufficient to deliver to the subject about 45 20 another aspect , the hemihydrate may be Freebase Hydrate mg of Compound 1 freebase equivalent . Form C .

In another aspect , the present disclosure relates to kits In another aspect , the present disclosure relates to a comprising one or more pharmaceutical compositions com - method of reducing signs and symptoms of rheumatoid prising a solid state form of Compound 1 . The kit optionally arthritis in an adult subject with moderately to severely can comprise another pharmaceutical composition compris - 25 active rheumatoid arthritis , the method comprising admin ing one or more additional therapeutic agents and / or instruc - istering to the subject about 15 mg per day of Compound 1 tions , for example , instructions for using the kit . freebase or a crystalline hydrate of Compound 1 in an

In another aspect , the present disclosure relates to meth - amount sufficient to deliver to the subject about 15 mg of ods for the preparation of a solid state form of Compound 1 . Compound 1 freebase equivalent . In this or another particu

In another aspect , the present disclosure relates to solid 30 lar aspect , the hydrate may be a hemihydrate . In this or state forms of Compound 1 prepared in accordance with another aspect , the hemihydrate may be Freebase Hydrate such methods . Form C .

In another aspect , the present disclosure relates to a In another aspect , the present disclosure relates to a method of treating an adult subject having moderate to method of reducing signs and symptoms of rheumatoid severely active rheumatoid arthritis , the method comprising 35 arthritis in an adult subject with moderately to severely administering to the subject about 7 . 5 mg , or about 15 mg , active rheumatoid arthritis , the method comprising admin or about 30 mg , or about 45 mg of Compound 1 freebase , or istering to the subject about 30 mg per day of Compound 1 a crystalline hydrate of Compound 1 in an amount sufficient freebase or a crystalline hydrate of Compound 1 in an to deliver to the subject about 7 . 5 mg , or about 15 mg , or amount sufficient to deliver to the subject about 30 mg of about 30 mg , or about 45 mg of Compound 1 freebase 40 Compound 1 freebase equivalent . In this or another particu equivalent . In this or another particular aspect , the hydrate lar aspect , the hydrate may be a hemihydrate . In this or may be a hemihydrate . In this or another aspect , the hemi another aspect , the hemihydrate may be Freebase Hydrate hydrate may be Freebase Hydrate Form C . In this or yet Form C . another particular aspect , the subject may have an inad - In another aspect , the present disclosure relates to a equate response or tolerance to one or more disease - modi - 45 method of reducing signs and symptoms of rheumatoid fying antirheumatic drugs ( DMARDS ) , such as methotrex - arthritis in an adult subject with moderately to severely ate . In this or yet another particular aspect , the subject may active rheumatoid arthritis , the method comprising admin have not previously been administered DMARDS . In this or istering to the subject about 45 mg per day of Compound 1 yet another particular aspect , the subject may further be freebase or a crystalline hydrate of Compound 1 in an administered one or more DMARD . 50 amount sufficient to deliver to the subject about 45 mg of

In another aspect , the present disclosure relates to a Compound 1 freebase equivalent . In this or another particu method of treating structural damage associated with rheu - lar aspect , the hydrate may be a hemihydrate . In this or matoid arthritis in an adult subject , the method comprising another aspect , the hemihydrate may be Freebase Hydrate administering to the subject about 7 . 5 mg , or about 15 mg , Form C . or about 30 mg , or about 45 mg per day of Compound 1 55 In another aspect , the present disclosure relates to a freebase or a crystalline hydrate of Compound 1 in an pharmaceutical composition comprising a crystalline amount sufficient to deliver to the subject about 7 . 5 mg , or hydrate of Compound 1 and a pharmaceutically acceptable about 15 mg , or about 30 mg , or about 45 mg per day of carrier , wherein the composition comprises the crystalline Compound 1 freebase equivalent , such that the structural hydrate in an amount sufficient to deliver about 7 . 5 mg of damage in the adult subject is inhibited or lessened . In this 60 Compound 1 freebase equivalent . In this or another particu or another particular aspect , the hydrate may be a hemihy - lar aspect , the hydrate may be a hemihydrate . In this or drate . In this or another aspect , the hemihydrate may be another aspect , the hemihydrate may be Freebase Hydrate Freebase Hydrate Form C . Form C .

In another aspect , the present disclosure relates to a In another aspect , the present disclosure relates to a method of treating moderate to severely active rheumatoid 65 pharmaceutical composition comprising a crystalline arthritis in an adult subject , the method comprising admin - hydrate of Compound 1 and a pharmaceutically acceptable istering to the subject about 7 . 5 mg , or about 15 mg , or about carrier , wherein the composition comprises the crystalline

24 US 9 , 879 , 019 B2

23 hydrate in an amount sufficient to deliver about 15 mg of layer that provides an environment suitable for Compound 1 Compound 1 freebase equivalent . In this or another particu - and the pH modifier to dissolve . lar aspect , the hydrate may be a hemihydrate . In this or In another aspect , the present disclosure is directed to a another aspect , the hemihydrate may be Freebase Hydrate process for preparing a pharmaceutical composition , the Form C . process comprising : ( a ) combining Compound 1 or a phar

In another aspect , the present disclosure relates to a maceutically acceptable salt thereof , or a solid state form of pharmaceutical composition comprising a crystalline Compound 1 , and at least a portion of one additional hydrate of Compound 1 and a pharmaceutically acceptable composition component to form a dry granulation mixture ; carrier , wherein the composition comprises the crystalline ( b ) contacting the dry granulation mixture with a granulation hydrate in an amount sufficient to deliver about 30 mg of fluid to form a wet granulation mixture ; ( c ) drying the wet Compound 1 freebase equivalent . In this or another particu - granulation mixture to form a granulated material ; ( d ) mill lar aspect , the hydrate may be a hemihydrate . In this or ing the granulated material to form a milled granulated another aspect , the hemihydrate may be Freebase Hydrate material ; ( e ) combining the milled granulation material with Form C . 15 any remaining composition components ; and ( f ) compress

In another aspect , the present disclosure relates to a ing the composition to form the pharmaceutical composi pharmaceutical composition comprising a crystalline tion . hydrate of Compound 1 and a pharmaceutically acceptable carrier , wherein the composition comprises the crystalline BRIEF DESCRIPTION OF THE DRAWINGS hydrate in an amount sufficient to deliver about 45 mg of 20 Compound 1 freebase equivalent . In this or another particu - FIG . 1A schematically illustrates one method of preparing lar aspect , the hydrate may be a hemihydrate . In this or the Amorphous Freebase . another aspect , the hemihydrate may be Freebase Hydrate FIG . 1B schematically illustrates one method of preparing Form C . the Freebase Hydrate Form C .

In another aspect , the present disclosure relates to a 25 FIG . 1C schematically illustrates one method of preparing method of treating an adult subject having moderate to the Tartrate Hydrate . severely active rheumatoid arthritis , the method comprising FIGS . 2A and 2B are powder X - ray diffraction patterns administering to the subject about 7 . 5 mg , or about 15 mg , corresponding to the Amorphous Freebase ( via precipita or about 30 mg , or about 45 mg of a crystalline hydrate of tion ) and the Amorphous Freebase ( via dehydration ) , respec Compound 1 . In this or another particular aspect , the hydrate 30 tively . may be a hemihydrate . In this or another aspect , the hemi - FIG . 3A is a powder X - ray diffraction pattern correspond hydrate may be Freebase Hydrate Form C . ing to the Freebase Solvate Form A ( Isopropyl Acetate /

In another aspect , the present disclosure relates to a Water Solvate ) . method of treating structural damage associated with rheu - FIG . 3B is a powder X - ray diffraction pattern correspond matoid arthritis in an adult subject , the method comprising 35 ing to the Freebase Hydrate Form B . administering to the subject about 7 . 5 mg , or about 15 mg , FIG . 3C is a powder X - ray diffraction pattern correspond or about 30 mg , or about 45 mg per day of a crystalline ing to the Freebase Hydrate Form C . hydrate of Compound 1 , such that the structural damage in FIG . 3D is a powder X - ray diffraction pattern correspond the adult subject is inhibited or lessened . In this or another ing to the Tartrate Hydrate . The experimental PXRD pattern particular aspect , the hydrate may be a hemihydrate . In this 40 is shown at the bottom of FIG . 3D and the calculated PXRD or another aspect , the hemihydrate may be Freebase Hydrate pattern is shown at the top of FIG . 3D . Form C . FIG . 3E is a powder X - ray diffraction pattern correspond

In another aspect , the present disclosure relates to a ing to the Hydrochloride Solvate Form AA . method of treating moderate to severely active rheumatoid FIG . 3F is powder X - ray diffraction pattern corresponding arthritis in an adult subject , the method comprising admin - 45 to the Hydrochloride Solvate Form BB . istering to the subject about 7 . 5 mg , or about 15 mg , or about FIG . 3G is a powder X - ray diffraction pattern correspond 30 mg , or about 45 mg per day of a crystalline hydrate of ing to the Hydrochloride Solvate Form CC . Compound 1 , wherein the subject has symptoms selected FIG . 3H is a powder X - ray diffraction pattern correspond from the group consisting of at least 6 swollen joints , at least ing to L - Maleate Form AAA . 6 tender joints , and combinations thereof prior to treating . In 50 FIG . 31 is a powder X - ray diffraction pattern correspond this or another particular aspect , the hydrate may be a ing to L - Maleate Form BBB . hemihydrate . In this or another aspect , the hemihydrate may F IG . 3J is a powder X - ray diffraction pattern correspond be Freebase Hydrate Form C . ing to Freebase Anhydrate Form D .

In another aspect , the present disclosure relates to a FIGS . 4A and 4B are thermogravimetric analysis thermo method of reducing signs and symptoms of rheumatoid 55 grams corresponding to the Amorphous Freebase ( via pre arthritis in an adult subject with moderately to severely cipitation ) and the Amorphous Freebase ( via dehydration ) , active rheumatoid arthritis , the method comprising admin respectively . istering to the subject about 7 . 5 mg , or about 15 mg , or about FIG . 4C is a thermogravimetric analysis thermogram 30 mg , or about 45 mg per day of a crystalline hydrate of corresponding to the Freebase Solvate Form A . Compound 1 . In this or another particular aspect , the hydrate 60 FIG . 4D is a thermogravimetric analysis thermogram may be a hemihydrate . In this or another aspect , the hemi - corresponding to the Freebase Hydrate Form B . hydrate may be Freebase Hydrate Form C . FIG . 4E is a thermogravimetric analysis thermogram

In another aspect , the present disclosure is directed to an corresponding to the Freebase Hydrate Form C . extended release formulation for oral administration com - FIG . 4F is a thermogravimetric analysis thermogram prising Compound 1 or a pharmaceutically acceptable salt 65 corresponding to the Tartrate Hydrate . thereof , a hydrophilic polymer , and a pH modifier , wherein FIG . 4G is a thermogravimetric analysis thermogram the hydrophilic polymer , in contact with water , forms a gel corresponding to the Hydrochloride Solvate Form AA .

25 US 9 , 879 , 019 B2

26 FIG . 4H is a thermogravimetric analysis thermogram C ) or a 30 mg once - daily extended release tablet ( Regimen

corresponding to L - Maleate Form BBB . D ) under fasting conditions using a linear ( FIG . 17A ) or FIG . 41 is a thermogravimetric analysis thermogram cor - semi - log ( FIG . 17B ) scale .

responding to Freebase Anhydrate Form D . FIGS . 18A and 18B show the Compound 1 mean plasma FIG . 5A is a differential scanning calorimetry thermogram 5 concentration versus time following administration of a 30

corresponding to the Amorphous Freebase ( via dehydra mg once - daily extended release tablet under fasting condi tion ) . tions ( Regimen D ) or a 30 mg once - daily extended release

FIG . 5B is a differential scanning calorimetry thermogram tablet after consumption of a high - fat meal ( Regimen E ) corresponding to the Freebase Hydrate Form B . using a linear ( FIG . 18A ) or semi - log ( FIG . 18B ) scale .

FIG . 5C is a differential scanning calorimetry thermogram FIG . 19 shows the Compound 1 mean plasma concentra corresponding to the Freebase Hydrate Form C . tion versus time following administration of a 15 mg once

FIG . 5D is a differential scanning calorimetry thermo - daily extended release tablet ( Regimen F ) or a 30 mg gram corresponding to the Tartrate Hydrate . once - daily extended release tablet ( Regimen G ) for seven

FIG . 5E is a differential scanning calorimetry thermogram 15 days under non - fasting conditions . corresponding to the Freebase Anhydrate Form D . FIG . 20 shows the Compound 1 mean plasma concentra

FIG . 6A is a moisture sorption isotherm corresponding to tion versus time following administration of 6 mg twice the Amorphous Freebase ( via dehydration ) . daily immediate release capsules ( Regimen K ) or a 15 mg

FIG . 6B is a moisture sorption isotherm corresponding to once - daily extended release tablet ( Regimen L ) for seven the Freebase Hydrate Form C . 20 days under fasting conditions .

FIG . 6C is a moisture sorption isotherm corresponding to FIG . 21 shows the Compound 1 pre - morning dose trough the Tartrate Hydrate . concentration ( Ctrowoh ) following administration of 6 mg

FIG . 6D is a moisture sorption isotherm corresponding to twice daily immediate release capsules or a 15 mg once the Freebase Anhydrate Form D . daily extended release tablet over seven days under fasting

FIG . 7 is a comparison of the dissolution profile of the 25 conditions . extended release tablets from Example 26 ( Freebase Hydrate FIG . 22 shows the Compound 1 mean plasma concentra Form C ) and Example 27 ( Amorphous Freebase ) at pH 6 . 8 . tion versus time following administration of 12 mg twice

FIG . 8 is a comparison of the dissolution profile of the daily immediate release capsules ( Regimen M ) or a 30 mg extended release tablets from Example 24 ( ER1 ) , Example once - daily extended release tablet ( Regimen N ) for seven 25 ( ER2 ) , and Example 26 ( ER3 ) in a dual pH system and so and 30 days under fasting conditions .

FIG . 23 shows the Compound 1 pre - morning dose trough at pH 6 . 8 . FIG . 9 is a comparison of the dissolution profile of the concentration ( Ctrough ) following administration of 12 mg

twice daily immediate release capsules or a 30 mg once extended release tablet from Example 32 ( ER4 ) and daily extended release tablet over seven days under fasting Example 33 ( ER4 , no mannitol ) at pH 1 . 2 , pH 6 . 8 , or a dual 35 con * , 10 mamW ) a PTT 1 . 4 , PT . , Via uudi 35 conditions . pH system . FIGS . 24A and 24B show the Compound 1 mean plasma FIG . 10 is a comparison of the dissolution profile of the concentration versus time following administration under extended release tablet from Example 34 ( ER5 ) at pH 1 . 2 , fasting conditions of various 30 mg once - daily extended pH 6 . 8 , and a dual pH system . release tablets having varying concentrations of tartaric acid ,

FIG . 11 is a comparison of the dissolution profile of the 40 using a linear ( FIG . 24A ) or log - linear ( FIG . 24B ) scale . extended release tablet from Example 35 ( ER6 ) at pH 1 . 2 , FIGS . 25A and 25B show the Compound 1 mean plasma pH 6 . 8 , and a dual pH system . concentration versus time following administration under

FIG . 12 is a comparison of the dissolution profile of the fasting conditions or after a high - fat meal ( non - fasting ) of a extended release tablet from Example 28 ( ERT ) and 30 mg once - daily extended release tablet ( ER10 ) using a Example 32 ( ER4 ) in a dual pH system . 45 linear ( FIG . 25A ) or log - linear ( FIG . 25B ) scale .

FIG . 13 is a comparison of the dissolution profile of the FIGS . 26A and 26B show the individual change in Com extended release tablet from Example 31 ( ERS ) and pound 1 Cmor ( FIG . 26A ) and AUC ; F ( FIG . 26B ) following Example 32 ( ER4 ) in a dual pH system . administration under fasting conditions or after a high - fat

FIG . 14 is comparison of the dissolution profile of the meal ( non - fasting ) of a 30 mg once - daily extended release extended release tablets from Example 24 ( ER1 ) , Example 50 tablet ( ER10 ) . 26 ( ER3 ) , and Example 32 ( ER4 ) in a dual pH system . FIGS . 27A and 27B show the Compound 1 mean plasma FIGS . 15A - 15H are comparisons of the dissolution profile concentration versus time following administration under

at pH 1 . 2 and 6 . 8 for the extended release tablets from fasting conditions or after a high - fat meal ( non - fasting ) of a Example 43 , which contain either HPMC ( FIGS . 15A - 15D ) 30 mg once - daily extended release tablet ( ER11 ) using a or Carbopol ( FIGS . 15E - 15H ) as release control polymers , 55 linear ( FIG . 27A ) or log - linear ( FIG . 27B ) scale . and tartaric acid ( FIGS . 15A and 15E ) , citric acid ( FIGS . FIGS . 28A and 28B show the individual change in Com 15B and 15F ) , succinic acid ( FIGS . 15C and 15G ) , or pound 1 Cmor ( FIG . 28A ) and AUCinf ( FIG . 28B ) following fumaric acid ( FIGS . 15D and 15H ) as a pH modifier . administration under fasting conditions or after a high - fat FIGS . 16A and 16B show the Compound 1 mean plasma meal ( non - fasting ) of a 30 mg once - daily extended release

concentration versus time following administration of a 12 60 tablet ( ER11 ) . mg immediate release capsule ( Regimen A ) or a 15 mg FIGS . 29A and 29B show the Compound 1 mean plasma once - daily extended release tablet ( Regimen B ) under fast concentration versus time following administration under ing conditions using a linear ( FIG . 16A ) or semi - log ( FIG . fasting conditions or after a high - fat meal ( non - fasting ) of a 16B ) scale . 30 mg once - daily extended release tablet ( ER12 ) using a FIGS . 17A and 17B show the Compound 1 mean plasma 65 linear ( FIG . 29A ) or log - linear ( FIG . 29B ) scale .

concentration versus time following administration of a 24 FIGS . 30A and 30B show the individual change in Com mg dose ( 2x12 mg ) of immediate release capsule ( Regimen pound 1 Cmax ( FIG . 30A ) and AUCinf ( FIG . 30B ) following

US 9 , 879 , 019 B2 27 28

administration under fasting conditions or after a high - fat ( * P < 0 . 05 ; * * P < 0 . 01 ; * * * P < 0 . 001 relative to placebo ; modi meal ( non - fasting ) of a 30 mg once - daily extended release fied intent - to - treat population with NRI of missing values ) . tablet ( ER12 ) . FIGS . 42A - 42D show the ACR20 ( FIG . 42A , NRI analy

FIG . 31 shows a plot of the pH of the gel formed on sis ) , ACR50 ( FIG . 42B , NRI analysis ) , and ACR70 ( FIG . tablets comprising varying amounts of tartaric acid . 5 42C , NRI analysis ) responses or DAS28 ( CRP ) mean change FIGS . 32A and 32B show the Compound 1 mean plasma from baseline ( FIG . 42D , observed cases ) over time follow concentrations versus time profiles following administration ing administration of placebo or various doses of Compound

of single oral doses of Compound 1 immediate release 1 to subjects with active rheumatoid arthritis and inadequate capsules to healthy subjects using a linear ( FIG . 32A ) or response to methotrexate ( * P < 0 . 05 ; * * P < 0 . 01 ; * * * P < 0 . 001 log - linear ( FIG . 32B ) scales . 10 relative to placebo ; modified intent - to - treat population ) .

FIG . 33 shows the Compound 1 mean plasma concentra FIGS . 43A and 43B show subjects achieving a DAS28 tion versus time profiles following administration of mul ( CRP ) score of 53 . 2 or < 2 . 6 ( FIG . 44A ) or CDAI of s10 or tiple twice - daily oral doses of Compound 1 immediate 52 . 8 ) at week 12 following administration of placebo or release capsules to healthy subjects . various doses of Compound 1 to subjects with active rheu

FIG . 34A - 34D shows the dose - normalized Compound 1 15 matoid arthritis and inadequate response to methotrexate mean Cmor and AUC after administration of single doses in ( * P < 0 . 05 ; * * P < 0 . 01 ; * * * P < 0 . 001 relative to placebo : modi healthy subjects ( FIG . 34A - single dose , Cmar ; FIG . 34C fied intent - to - treat population ( NRI ) ) . For FIGS . 43A and single dose , AUC . ) and multiple - doses in healthy subjects 43B , the bottom number indicates the percentage of subjects and subjects with rheumatoid arthritis ( FIG . 34B — multiple who achieved both cutoff values , the middle number indi doses , C . ; FIG . 34D multiple - doses , AUC0 - 12 ) . 20 cates the percentage of subjects who achieved the less FIGS . 35A and 35B show the lack of effect of concomi stringent cutoff but not the more stringent cutoff value , and

tant methotrexate administration on Compound 1 dose the top number indicates the percentage of patients who normalized AUC ( FIG . 35A ) and lack of effect of concomi achieved either cutoff value . tant Compound 1 administration on methotrexate dose FIGS . 44A - 44C show the mean change in hemoglobin normalized AUC ( FIG . 35B ) . 25 from baseline over time by treatment group in all subjects

FIG . 36A shows the ACR20 , ACR50 , and ACR70 ( FIG . 44A ) , subjects with hsCRP55 mg / mL at baseline response rate at week 12 following administration of pla ( FIG . 44B ) , and subjects with hsCRP > 5 mg / mL at baseline cebo or various doses of Compound 1 to subjects with active ( FIG . 44C ) following administration of placebo or various rheumatoid arthritis and prior inadequate response or intol - doses of Compound 1 to subjects with active rheumatoid erance to an anti - TNF biologic agent ( * P < 0 . 05 ; * * P < 0 . 01 ; 30 arthritis and inadequate response to methotrexate ( safety * * * P < 0 . 001 relative to placebo ; modified intent - to - treat population with observed data ( no imputation of missing population ( NRI ) ) . FIG . 36B shows the ACR20 response rate at week 12 in the same population , broken down by number of prior anti - TNF biologic agents . DETAILED DESCRIPTION OF THE

FIGS . 37A - 37D show the ACR20 ( FIG . 37A ) , ACR50 35 INVENTION ( FIG . 37B ) , and ACR70 ( FIG . 37C ) responses or DAS28 ( CRP ) mean change from baseline ( FIG . 37D ) over time This written description uses examples to disclose the following administration of placebo or various doses of invention and also to enable any person skilled in the art to Compound 1 to subjects with active rheumatoid arthritis and practice the invention , including making and using any of prior inadequate response or intolerance to an anti - TNF 40 the disclosed solid state forms or compositions , and per biologic agent ( * P < 0 . 05 ; * * P < 0 . 01 ; * * * P < 0 . 001 relative to forming any of the disclosed methods or processes . The placebo ; modified intent - to - treat population ( NRI ) ) . FIG . patentable scope of the invention is defined by the claims , 37E shows the subjects achieving a DAS28 ( CRP ) score of and may include other examples that occur to those skilled 53 . 2 or < 2 . 6 at week 12 in the same population . FIG . 37F in the art . Such other examples are intended to be within the shows the subjects achieving low disease activity ( LDA ) or 45 scope of the claims if they have elements that do not differ clinical remission ( CR ) based on clinical disease activity from the literal language of the claims , or if they include index ( CDAI ) criteria ( LDA is CDAI < 10 ; CR is CDAls2 . 8 ) equivalent elements . at week 12 in the same population .

FIG . 38A shows the mean hemoglobin levels over time I . Definitions for all subjects following administration of placebo or 50 various doses of Compound 1 to subjects with active rheu Section headings as used in this section and the entire matoid arthritis and prior inadequate response or intolerance disclosure are not intended to be limiting . to an anti - TNF biologic agent ( safety population with Where a numeric range is recited , each intervening num observed data ( no imputation of missing values ) ) . FIG . 38B ber within the range is explicitly contemplated with the same shows the mean hemoglobin change from baseline over time 55 degree of precision . For example , for the range 6 to 9 , the in subjects with high - sensitivity C - reactive protein ( hsCRP ) numbers 7 and 8 are contemplated in addition to 6 and 9 , and greater than the upper limit of normal ( ULN ) ( normal ranges for the range 6 . 0 to 7 . 0 , the numbers 6 . 0 , 6 . 1 , 6 . 2 , 6 . 3 , 6 . 4 , for hemoglobin : 11 . 5 - 15 . 5 g / dL in females and 13 . 2 - 17 . 0 6 . 5 , 6 . 6 , 6 . 7 , 6 . 8 , 6 . 9 and 7 . 0 are explicitly contemplated . In g / dL in males ; ULN for hsCRP = 5 mg / L ) . the same manner , all recited ratios also include all sub - ratios

FIG . 39 shows the subject disposition for the study 60 falling within the broader ratio . described in Example 55 . The singular forms “ a , " " an ” and “ the ” include plural FIGS . 40A and 40B show the subject disposition for the referents unless the context clearly dictates otherwise .

study described in Example 56 . The term “ about ” generally refers to a range of numbers FIG . 41 shows the ACR20 , ACR50 , and ACR70 that one of skill in the art would consider equivalent to the

responses at week 12 following administration of placebo or 65 recited value ( i . e . , having the same function or result ) . In various doses of Compound 1 to subjects with active rheu - many instances , the term “ about " may include numbers that matoid arthritis and inadequate response to methotrexate are rounded to the nearest significant figure .

24 . ss

US 9 , 879 , 019 B2 29 30

The term “ alkyl ” refers to straight chained or branched or delaying the onset of the condition or improving the hydrocarbons which are completely saturated . For purposes quality of life of a patient suffering from the condition . of exemplification , which should not be construed as limit - The term “ Xantphos ” refers to 4 , 5 - Bis ( diphenylphos ing the scope of this invention , examples of alkyls include phino ) - 9 , 9 - dimethylxanthene . methyl , ethyl , propyl , isopropyl , butyl , pentyl , hexyl , and 5 The abbreviation “ 2 - Me THF ” refers to 2 - methyl tetra isomers thereof . hydrofuran .

The term “ alkenyl ” refers to a hydrocarbon moiety con The abbreviation " ACN ” refers to acetonitrile . taining two to eight carbons , including straight chained or The abbreviation “ AcOH ” refers to acetic acid .

As used herein , the term “ AUC24 , " refers to the steady branched hydrocarbons which contain one or more double bonds . Non - limiting examples of alkenyls are ethenyl , pro 10 state area under the plasma concentration time curve from

time zero to twenty - four hours after administration of the penyl , and butenyl . referent drug . The term “ AUC125 $ ” refers to the steady - state The term “ amorphous ” as applied to a compound refers to area under the plasma concentration time curve from time a state in which the material lacks long range order at the zero to twelve hours after administration of the referent molecular level and , depending upon temperature , may 15 drug exhibit the physical properties of a solid or a liquid . Typi As used herein , the term “ AUCint ” refers to the area under cally such materials do not give distinctive X - ray diffraction the plasma concentration time curve from time zero to patterns and , while exhibiting the properties of a solid , are infinity following a single dose , calculated using the trap more formally described as a liquid . Upon heating , a change ezoidal rule . AUCinF - AUC , + Cjas / k , where Cast is the last from solid to liquid properties occurs which is characterized 20 measured concentration and k is the calculated terminal by a change of state , typically second order ( " glass transi elimination rate constant . tion ” ) . As used herein , the term " AUC ; ” refers to the area under

The term “ anhydrate ” as applied to a compound refers to the plasma concentration time curve from the time of a solid state wherein the compound contains no structural administration of the referent drug to the time of the last water within the crystal lattice . 25 measured concentration calculated using the trapezoidal

The term “ aryl ” refers to a mono - , bi - , or tricyclic rule . “ AUC24 ” refers to the area under the plasma concen aromatic hydrocarbon radical . Examples include phenyl , tration time curve from time zero to twenty - four hours after naphthyl , biphenyl , and 1 , 2 , 3 , 4 - tetrahydronaphthyl . administration of the referent drug following a single dose .

Unless the context requires otherwise , the terms " com - The abbreviation " Bn ” refers to benzyl . prise , " " comprises , ” and “ comprising ” are used on the basis 30 As used herein , the term " C _ 2 " is the plasma concentra and clear understanding that they are to be interpreted tion of the referent drug observed 12 hours after adminis inclusively , rather than exclusively , and that Applicant tration of a single dose , or the indicated number of doses , of intends each of those words to be so interpreted in constru - the referent drug . The term “ C , 2 . ” refers to the C , as ing this patent , including the claims below . measured at a steady - state .

The term " crystalline ” as applied to a compound refers to 35 As used herein , the term “ C24 " is the plasma concentra a solid phase in which the material has a regular ordered tion of the referent drug observed 24 hours after adminis internal structure at the molecular level and gives a distinc t ration of a single dose , or the indicated number of doses , of tive X - ray diffraction pattern with defined peaks . Such the referent drug . The term “ C24 , 55 ” refers to the C24 as materials when heated sufficiently will also exhibit the measured at a steady - state . properties of a liquid , but the change from solid to liquid is 40 The abbreviation “ Cbz ” refers to carboxybenzyl . characterized by a phase change , typically first order ( “ melt - The abbreviation “ CDI ” refers to carbonyldiimidazole . ing point ” ) . The abbreviation “ % CV ” refers to the coefficient of

The term “ crystalline purity ” means the crystalline purity variation , expressed as a percent . % CV is calculated accord of a compound with regard to a particular crystalline form of ing to the following equation : % CV = ( SD / x ) * 100 , wherein the compound as determined by the powder X - ray diffrac - 45 x is the mean value and SD is the standard deviation . tion analytical methods described in this application . As used herein , the term “ Cmax ” refers to the plasma

The term “ crystallization ” as used throughout this appli - concentration of the referent drug at Tmax , expressed herein cation can refer to crystallization and / or recrystallization as ng / mL , produced by the oral ingestion of a single dose , or depending upon the applicable circumstances relating to the indicated number of doses , of the dosage form or pharma preparation of the compound . 50 ceutical composition , such as the dosage forms and compo

The term “ pharmaceutically acceptable ” ( such as in the sitions of the present disclosure . Unless specifically indi recitation of a “ pharmaceutically acceptable salt ” or a " phar cated , Cmax refers to the overall maximum observed maceutically acceptable diluent ” ) refers to a material that is concentration . compatible with administration to a human subject , e . g . , the As used herein , the term “ Cmoriss refers to the steady material does not cause an undesirable biological effect . 55 state Cmar of the referent drug during a dosage interval . Examples of pharmaceutically acceptable salts are described As used herein , the term “ Cmine ” refers to the minimum in " Handbook of Pharmaceutical Salts : Properties , Selec - steady - state plasma concentration of the referent drug during tion , and Use ” by Stahl and Wermuth ( Wiley - VCH , Wein a dosage interval . heim , Germany , 2002 ) . Examples of pharmaceutically As used herein , the term " Ctrough ” refers to the trough acceptable excipients are described in the “ Handbook of 60 plasma concentration of the referent drug , as measured at the Pharmaceutical Excipients , " Rowe et al . , Ed . ( Pharmaceu - end of a dosing interval at steady state . tical Press , 7th Ed . , 2012 ) . The abbreviation “ DBU ” refers to 1 , 8 - diazabicyclo [ 5 . 4 . 0 ]

The term “ subject ” refers to a human subject . undec - 7 - ene . The terms " treating ” and “ treatment ” refer to ameliorat The abbreviation “ DCHA ” refers to dicyclohexylamine .

ing , suppressing , eradicating , reducing the severity of , 65 The abbreviation “ DCM ” refers to dichloromethane . decreasing the frequency of incidence of , preventing , reduc - The abbreviation “ DIPEA ” refers to diisopropylethylam ing the risk of , slowing the progression of damage caused by ine .

771 AX

max , SS

min , ss

32

- max , ss

25

US 9 , 879 , 019 B2 31

The abbreviation “ DMA ” refers to dimethylacetamide , or The abbreviation " TGA - MS ” means thermogravimetric N . N - dimethylacetamide . analysis - mass spectrometer .

The abbreviation “ DMAP ” refers to 4 - dimethylamin The abbreviation “ THF ” refers to tetrahydrofuran . opyridine . As used herein , the term “ Tmax ” refers to the time to peak

The abbreviation " DSC ” means differential scanning 5 plasma concentration of the referent drug after oral ingestion calorimetry . of a single dose , or indicated number of doses , of the referent As used herein , the term " entry into a use environment ” drug . means contact of a formulation of the disclosure with the As used herein , the term “ Tmax . ss ” refers to the time to gastric fluids of the subject to whom it is administered , or peak plasma concentration of the referent drug after oral with a fluid intended to simulate gastric fluid . 10 ingestion of the referent drug at steady - state . The abbreviation “ EtB ( OH ) ” refers to ethyl boronic acid . The abbreviation " TMS ” refers to trimethylsilyl . The abbreviation “ EtOAc ” refers to ethyl acetate . The term “ triflate ” refers to trifluoromethanesulfonate . The abbreviation “ Fe ( acac ) z ” refers to iron ( III ) acetylac The abbreviation “ v / v ” refers to volume / volume . etonate . The abbreviation “ w / w ” refers to weight / weight . The abbreviation “ HDPE ” refers to high - density polyeth - 15 For clarity and convenience purposes only , the convention ylene .

The abbreviation “ HOAC ” refers to acetic acid . is utilized herein of designating the time of drug adminis

The abbreviation “ HPMC ” refers to hydroxypropyl meth tration or initiation of dissolution testing as zero ( 0 ) hours ( t = 0 hours ) and times following administration in appropri ylcellulose . ate time units , for example , t = 30 minutes or t = 2 hours , etc . The abbreviation “ IPAc ” refers to isopropyl acetate . 20°

The abbreviation “ KOtBu ” refers to potassium tert - bu II . Processes for Preparing ( 3S , 4R ) - 3 - ethyl - 4 - ( 3H toxide . imidazo [ 1 , 2 - a ] pyrrolo [ 2 , 3 - e ] pyrazin - 8 - yl ) - N - ( 2 , 2 , 2 The abbreviation LiOtBu ” refers to lithium tert - butoxide . trifluoroethyl ) pyrrolidine - 1 - carboxamide ( Com The abbreviation “ Me SOCI ” refers to trim ethyl sulfoxo pound 1 ) and Intermediates nium chloride . 25

The abbreviations “ MeOH ” and “ EtOH ” refer to metha The present disclosure relates to improved processes for nol and ethanol , respectively . The abbreviation “ MS ” means mass spectrometry . preparing ( 3S , 4R ) - 3 - ethyl - 4 - ( 3H - imidazo [ 1 , 2 - a ] pyrrolo [ 2 ,

3 - e ] pyrazin - 8 - yl ) - N - ( 2 , 2 , 2 - trifluoroethyl ) pyrrolidine - 1 - car The abbreviation “ MTBE ” refers to methyl tert - butyl boxamide ( referred to herein as “ Compound 1 ” or as “ Com ether . pound 1 freebase ” ) , to pharmaceutically acceptable salts of The abbreviation “ MTX ” refers to methotrexate . Compound 1 , and to intermediates used in the preparation of The abbreviations “ Nat?Bu ” or “ NaOtBu ” refer to Compound 1 . Compound 1 has the structure shown below : sodium tert - butoxide .

The abbreviation “ Ni?acac ) ” refers to nickel ( II ) acety lacetonate . 35

The abbreviation " NMM ” refers to N - methyl morpholine . The abbreviation “ Pd / C ” refers to palladium on carbon . The abbreviation “ PdC12 ( dppf ) ” refers to [ 1 , 1 ' - Bis ( diphe

nylphosphino ) ferrocene ] dichloropalladium ( II ) . The abbreviation “ PdC12 ( Ph3P ) ” refers to bis ( triphenyl - 40

phosphine ) palladium ( II ) dichloride . The abbreviation “ Pd ( OAc ) ” refers to palladium ( II )

acetate . The abbreviation “ Pd ( OH ) / C ” refers to palladium

hydroxide on carbon . 45 The abbreviation “ PFPAA ” refers to pentafluoropropionic

anhydride . Methods for making and using this compound are described , The abbreviation “ pTSOH ” refers to p - toluenesulfonic for example , in International Application WO 2011 /

acid . 068881A1 , which is incorporated by reference in this appli The abbreviation “ PVA ” refers to polyvinyl acetate . 50 cation . The abbreviation “ PXRD ” means powder X - ray diffrac Previously disclosed processes for preparing Compound

1 , and pharmaceutically acceptable salts thereof suffer from The abbreviation “ ( S ) - Segphos Ru ( OAc ) ” or several drawbacks . In particular , these processes involve the

“ Ru ( OAc ) , - Segphos ” refers to diacetato [ ( S ) - ( - ) 5 , 5 ' - bis ( di - use of particularly hazardous reagents , such as trimethylsi phenylphosphino ) - 4 , 4 ' - bi - 1 , 3 - benzodioxole ] ruthenium ( II ) . 55 lyldiazomethane or diazomethane , and / or do not produce a As used herein , the term “ t12 ” refers to the terminal crystalline product . The processes of the present disclosure

half - life of the referent drug after oral ingestion of a single overcome these drawbacks by avoiding the use of these dose , or indicated number of doses , of the referent drug . The hazardous reagents , and producing crystalline intermediates , term “ 41 / 2 . 55 ” refers to the terminal half - life as measured at a which aid in purification . steady - state . 60 Compounds of the present disclosure may be prepared

The abbreviation " TEA ” refers to triethylamine . ” using synthetic transformations such as those illustrated in The abbreviation “ TFAA ” refers to trifluoroacetic anhy - Schemes I - XVI . Starting materials are commercially avail

dride . able , may be prepared by the procedures described herein , The abbreviation " TF20 ” refers to trifluoromethanesul - by literature procedures , or by procedures that would be well

fonic anhydride . 65 known to one skilled in the art of organic chemistry ( see , for The abbreviation “ TGA ” means thermogravimetric analy - example , Larock , R . C . “ Comprehensive Organic Transfor

sis . mations : A Guide to Functional Group Preparations , 2nd

H3C CF N

HII

tion .

US 9 , 879 , 019 B2 33 34

- continued edition ” , 1999 , Wiley - VCH or Greene , T . W . and Wuts , P . G . M . “ Protective Groups in Organic Synthesis , 3rd Edition ” , 1999 , Wiley - Interscience ) .

PG

A . Preparation of Compound 1

In one aspect , the present disclosure is directed to a process for preparing Compound 1 , or a pharmaceutically acceptable salt thereof . A process for preparing Compound 10 1 is illustrated in Scheme I . Reaction of protected ( 3R , 4S ) 4 - ethylpyrrolidine - 3 - carboxylic acid ( I ) or a pharmaceuti cally acceptable salt thereof with trimethylsulfoxonium chloride gives sulfur ylide ( II ) . Contacting sulfur ylide ( II ) with LiX and a sulfonic acid yields the corresponding 15 halomethyl ketone ( III ) . Reaction of ( III ) with ( IV ) in the presence of a base yields ( V ) . Cyclization of ( V ) in the presence of a perfluoro acid anhydride and an organic base produces ( VI ) . Removal of the protecting group and con tacting the deprotected compound with an acid yields a 20 pharmaceutically acceptable salt of ( VII ) . Reacting the phar maceutically acceptable salt of ( VII ) with 2 , 2 , 2 - trifluoroeth ylamine produces Compound 1 .

N - PG

25

Scheme I ( VI ) PG PG

NH H2N CF3

f

OH Bo . . .

( VII ) ( II ) 11111 * *

CF3 NH

ya 50 wherein : PG is a protecting group ; X is Br or Cl ; Rj is selected from the group consisting of alkyl , aryl , and

TS

=

55 OR ; +

PG

Ir .

R , is alkyl ; and Ts is tosyl . The protecting group may be any suitable protecting

60 group known in the art . In some embodiments , the protect ing group is selected from the group consisting of carboxy benzyl , p - methoxybenzyl carbonyl , benzyl , p - methoxyben zyl , and 3 , 4 - dimethoxybenzyl . In another embodiment , the protecting group is carboxybenzyl .

65 In another embodiment , R , is OR2 , and R , is methyl or ethyl . In such embodiments , the compound of formula ( IV ) is a compound of formula ( IVA ) :

1111th

( III )

US 9 , 879 , 019 B2 35 35 36

- continued ( IV ) ( VIII )

1110 NH

5 1111011 HCI .

10

110

NH

> 1111111

wherein R2 is methyl or ethyl . It has surprisingly been discovered that when R2 is ethyl or methyl , the compound of formula ( V ) and subsequent downstream compounds can be ( VIIC ) isolated as crystalline solids , which aids in purification of these intermediates . In contrast , previously known pro - 15 cesses , which use compounds where R , is t - butyl , result in pTsOH . formation of compounds of formula ( V ) which are isolated as amorphous solids .

In certain embodiments , a pharmaceutically acceptable salt of a compound of the compound of formula ( I ) is used 20 in the reaction of step ( a ) . In one embodiment , the pharma ceutically acceptable salt of the compound of formula ( I ) is selected from the group consisting of the naphthalenethane amine salt ( la ) and the dicyclohexylamine salt ( lb ) Another process for preparing Compound 1 is illustrated 25 . in Scheme la . Reaction of ( 3R , 4S ) - 1 - ( ( benzyloxy ) carbonyl )

4 - ethylpyrrolidine - 3 - carboxylate dicyclohexylamine salt ( lb ) with trimethylsulfoxonium chloride in the presence of carbonyldiimidazole and a strong base gives sulfur ylide

30 ( Ila ) . Contacting sulfur ylide ( IIa ) with lithium bromide and a sulfonic acid yields the corresponding bromomethyl ketone ( IIIa ) . Reaction of ( IIIa ) with alkyl 5 - tosyl - 5H pyrrolo [ 2 , 3 - b ] pyrazin - 2 - ylcarbamate ( IVa ) in the presence of lithium tert - butoxide yields ( Va ) . Cyclization of ( Va ) in

35 the presence of a perfluoro acid anhydride and an organic base produces ( Vla ) . Removal of the carboxybenzyl pro tecting group and contacting the deprotected compound with hydrochloric acid yields the pharmaceutically acceptable salt ( VIIa ) . Reacting the pharmaceutically acceptable salt

( Ib ) 40 ( VIIa ) with 2 , 2 , 2 - trifluoroethylamine produces Compound

( la ) Cbz

HON > 11111111

th ??

Cbz

. HN HN Scheme la 45

10100 Cbz H

50

OH wherein Cbz is carboxybenzyl . In one embodiment , the pharmaceutically acceptable salt

of compound ( VII ) is selected from the group consisting of ( VIIa ) , ( VIIb ) , and ( VIIC )

55 ( Ib ) Cbz

( VIIa ) 1111111

NH NH 11111111 2HCI ,

H11

( IIa )

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