|ANI US010022352B2 (12 ) United States Patent ( 10 ) Patent No. : US 10 ,022 , 352 B2 Hadida Ruah et al. (45 ) Date of Patent : * Jul. 17 , 2018

(54 ) MODULATORS OF ATP - BINDING CO7D 487/ 04 (2006 .01 ) CASSETTE TRANSPORTERS C07D 209 / 08 (2006 .01 ) GOIN 33 /50 (2006 . 01) (71 ) Applicant: Vertex Pharmaceuticals Incorporated , A61K 31/ 47 ( 2006 .01 ) Boston , MA (US ) GOIN 33 / 68 (2006 .01 ) (72 ) Inventors: Sara Sabina Hadida Ruah , La Jolla , ( 52 ) U . S. CI. CA (US ) ; Peter Diederik Jan ??? ...... A61K 31/ 404 ( 2013 .01 ) ; A61K 9 / 28 Grootenhuis , San Diego , CA (US ) ; (2013 .01 ) ; A61K 31/ 405 ( 2013 .01 ); A61K Fredrick F . Van Goor , San Diego , CA 31/ 407 (2013 . 01 ) ; A61K 31/ 4045 (2013 . 01 ); (US ) ; Jinglan Zhou , San Diego , CA A61K 31/ 41 ( 2013 .01 ); A61K 31/ 4184 (US ) ; Brian Richard Bear , Carlsbad , ( 2013 .01 ) ; A61K 31/ 4192 ( 2013 . 01 ) ; A61K CA (US ) ; Mark Thomas Miller , San 31/ 454 (2013 .01 ) ; A61K 31/ 47 ( 2013 .01 ); Diego , CA (US ) ; Jason McCartney , A61K 31/ 5377 ( 2013 .01 ); A6IK 45 / 06 Cardiff by the Sea , CA (US ) ; Mehdi ( 2013 . 01 ) ; C07D 209 / 08 ( 2013 .01 ) ; C07D Michel Djamel Numa , San Diego , CA 233/ 64 ( 2013 .01 ) ; C07D 403/ 12 (2013 .01 ) ; (US ) CO7D 405 / 12 ( 2013 .01 ) ; C07D 405 / 14 ( 2013 .01 ) ; C07D 471/ 04 (2013 .01 ) ; C07D ( 73 ) Assignee : Vertex Pharmaceuticals Incorporated , 487 /04 (2013 .01 ) ; GOIN 33/ 5035 ( 2013. 01 ) ; Boston , MA (US ) GOIN 33 /6893 (2013 .01 ) ; GOIN 2333 /705 ( * ) Notice : Subject to any disclaimer , the term of this (2013 .01 ) ; GOIN 2800 /382 ( 2013. 01 ) patent is extended or adjusted under 35 (58 ) Field of Classification Search U . S .C . 154 (b ) by 0 days . CPC ...... A61K 31 /404 This patent is subject to a terminal dis See application file for complete search history. claimer . (21 ) Appl. No. : 15 /078 , 800 ( 56 ) References Cited (22 ) Filed : Mar. 23 , 2016 U .S . PATENT DOCUMENTS 4 , 138 , 397 A 2 / 1979 Böhme (65 ) Prior Publication Data 5 ,304 , 121 A 4 / 1994 Sahatjian et al. US 2016 /0271105 A1 Sep . 22 , 2016 ( Continued ) FOREIGN PATENT DOCUMENTS Related U . S . Application Data CN 1512987 A 7 /2004 (60 ) Continuation - in -part of application No . 14 /579 , 098 , CN 101151257 A 3 /2008 filed on Dec . 22 , 2014 , which is a continuation of (Continued ) application No . 14 /036 ,286 , filed on Sep . 25 , 2013 , now Pat. No. 8 , 952 , 050 , which is a division of application No. 12 / 948 , 162 , filed on Nov. 17 , 2010 , OTHER PUBLICATIONS now Pat. No . 8 ,575 , 209 , which is a continuation of Aridor et al. , “ Integration of endoplasmic reticulum signaling in application No . 12 /619 ,412 , filed on Nov . 16 , 2009 , health and disease , ” Nature Med ., 5 (7 ): 745 - 751 ( 1999 ). now Pat. No . 8 ,415 , 387 , which is a division of (Continued ) (Continued ) (51 ) Int. Cl. Primary Examiner — Shawquia Jackson A61K 31/ 405 ( 2006 .01 ) A61K 31/ 404 ( 2006 .01 ) (74 ) Attorney , Agent, or Firm — Finnegan , Henderson , A61K 45 / 06 ( 2006 . 01 ) Farabow , Garrett & Dunner, LLP A61K 9 / 28 ( 2006 .01 ) COZD 403 / 12 ( 2006 . 01 ) (57 ) ABSTRACT C07D 405 / 14 ( 2006 .01 ) A61K 31/ 4045 ( 2006 . 01 ) Compounds of the present invention and pharmaceutically A61K 31 /407 ( 2006 . 01 ) acceptable compositions thereof, are useful as modulators of A61K 31/ 41 ( 2006 .01 ) ATP - Binding Cassette (“ ABC ” ) transporters or fragments A61K 31/ 4184 ( 2006 . 01) thereof, including Cystic Fibrosis Transmembrane Conduc A61K 31 /4192 ( 2006 . 01 ) tance Regulator (“ CFTR ” ) . The present invention also A6IK 31 /454 (2006 .01 ) relates to methods of treating ABC transporter mediated A61K 31 /5377 ( 2006 . 01 ) diseases using compounds of the present invention . CO7D 233/ 64 ( 2006 .01 ) CO7D 405 / 12 ( 2006 . 01 ) CO7D 471 /04 ( 2006 .01 ) 20 Claims, No Drawings US 10 ,022 ,352 B2 Page 2

Related U .S . Application Data 8 , 507 , 534 B2 8 / 2013 Keshavarz - Shokri et al . 8 ,507 , 687 B2 8 / 2013 Keshavarz - Shokri et al. application No. 11 / 975 , 297 , filed on Oct. 18 , 2007 . 8 , 513 , 282 B2 8 / 2013 Binch et al . now Pat. No . 7 ,645 , 789 , which is a continuation - in 8 ,524 , 767 B2 9 / 2013 Miller et al . 8 , 524 , 910 B2 9 / 2013 Hadida Ruah et al . part of application No. 11 /786 ,001 , filed on Apr. 9 , 8 , 541, 453 B2 9 / 2013 Hadida -Ruah et al . 2007 , now Pat . No. 7 ,776 , 905 . 8 ,552 , 006 B2 10 /2013 Binch et al. 8 , 552, 034 B2 10 / 2013 Verwijs et al. (60 ) Provisional application No . 60 / 790 ,459 , filed on Apr. 8 ,563 , 573 B2 10 /2013 Ruah et al . 7 , 2006 . 8 , 563 , 593 B2 10 / 2013 Alargova et al. 8 ,575 , 209 B2 11 / 2013 Ruah et al. 8 , 586 ,615 B2 11/ 2013 Hadida - Ruah et al. ( 56 ) References Cited 8 , 592 ,602 B2 11/ 2013 Siesel 8 ,598 , 181 B2 12 / 2013 Hadida Ruah et al. U . S . PATENT DOCUMENTS 8 ,598 , 205 B2 12 / 2013 Binch et al . 8 ,604 , 203 B2 12 / 2013 Binch et al . 5 , 886 , 026 A 3 / 1999 Hunter et al . 8 , 609 , 703 B2 12 / 2013 Ruah et al. 6 ,099 , 562 A 8 / 2000 Ding et al . 8 , 614 , 325 B2 12 /2013 Yang et al . 6 , 426 , 331 B1 . 7 / 2002 McKinney et al. 8 , 614 , 327 B2 12 /2013 Sheth et al . 6 , 777 , 400 B2 8 / 2004 Biggadike et al. 8 , 623 , 894 B2 1 /2014 Demattei et al . 6 , 992 , 096 B2 1/ 2006 Karp et al . 8 , 623 , 905 B2 1 /2014 Ruah et al. 7 ,202 , 262 B2 4 / 2007 Karp et al. 8 , 629 , 162 B2 1 /2014 Hadida -Ruah et al. 7 ,304 , 080 B2 12 / 2007 Karp et al. 8 , 633 , 189 B2 1 / 2014 Binch et al . 7 ,407 , 976 B2 8 /2008 Miller et al. 8 , 642 , 609 B2 2/ 2014 Makings et al. 7 , 419 , 991 B2 9 /2008 Karp et al . 8 , 653 , 103 B2 2 /2014 Keshavarz - Shokri et al. 7 , 495 , 103 B2 2/ 2009 Hadida - Ruah et al . 8 , 674 , 108 B2 3 / 2014 Luisi et al . 7 , 553 , 855 B2 6 / 2009 Young et al . 8 , 710 , 075 B2 4 / 2014 Binch et al. 7 ,582 , 665 B2 9 / 2009 Takemoto et al. 8 , 716 , 338 B2 5 / 2014 Young 7 . 598 .412 B2 10 / 2009 Hadida Ruah et al . 8 , 722 , 704 B2 5 /2014 Hadida Ruah et al. 7 , 645 , 789 B2 1 / 2010 Hadida Ruah et al . 8 , 741 , 922 B2 6 / 2014 Zhang et al . 7 , 659, 268 B2 2 / 2010 Hadida - Ruah et al . 8 , 741, 925 B2 6 / 2014 Hadida -Ruah et al . 7 , 671 , 221 B2 3 / 2010 Hadida Ruah et al . 8 , 741 , 933 B2 6 / 2014 Hadida Ruah et al. 7 , 691 , 902 B2 4 / 2010 Hadida Ruah et al. 8 , 741 , 939 B2 6 / 2014 Hadida Ruah et al . 7 , 728 , 023 B2 6 / 2010 Takeuchi et al . 8 , 742 , 122 B2 6 /2014 Keshavarz - Shokri et al. 7 , 741 , 321 B2 6 / 2010 Hadida Ruah et al . 8 , 748 , 612 B2 6 / 2014 Binch et al. 7 , 754 , 739 B2 7 / 2010 Hadida Ruah et al. 8 , 754, 222 B2 6 /2014 Ambhaikar et al . NNNN.7 ,772 , 259 B2 8 / 2010 Karp et al. 8 , 754 , 224 B2 6 / 2014 Hurter et al. 7 , 776 , 905 B2 8 / 2010 Hadida Ruah et al . 8 , 759 , 335 B2 6 /2014 Hadida Ruah et al. 7 , 846 , 951 B2 12 / 2010 Miller et al . 8 , 765 , 957 B2 7 / 2014 DeMattei et al . 7 , 906 , 516 B2 3 /2011 Tsaklakidis et al . 8 , 785, 476 B2 7 / 2014 Arekar et al. 7 , 956, 052 B2 6 / 2011 Hadida Ruah et al. 8 , 785 , 640 B2 7 / 2014 Binch et al. 7 ,973 , 038 B2 7 / 2011 Hadida Ruah et al . 8 , 796 ,308 B2 8 / 2014 Yang et al . 7 ,973 , 169 B2 7 / 2011 Hadida Ruah et al . 8 , 796 , 312 B2 8 / 2014 Hadida Ruah et al. 7 ,977 , 322 B2 7 / 2011 Ruah et al . 8 , 802 , 700 B2 8 /2014 Sheth et al. 7 , 999 , 113 B2 8 / 2011 Hadida - Ruah et al. 8 , 802 , 844 B2 8 / 2014 Gallardo -Godoy 8 , 012 , 999 B2 9 / 2011 Hadida Ruah et al . 8, 802 ,868 B2 8 / 2014 Keshavarz - Shokri et al. 8 , 039 , 491 B2 10 / 2011 Hadida Ruah et al . 8 , 816, 093 B2 8 / 2014 Siesel 8 , 076 , 357 B2 12 /2011 Young et al. 8 , 822 , 451 B2 9 / 2014 Ruah et al. 8 , 101 , 767 B2 1 / 2012 Ruah et al . 8 , 829 , 204 B2 9 / 2014 Hadida - Ruah et al . 8 , 124 , 781 B2 2 / 2012 Siesel 8 , 835 , 639 B2 9 / 2014 DeMattei et al . 8 ,163 , 772 B2 4 / 2012 DeMattei et al. 8 , 846 , 718 B2 9 / 2014 Keshavarz - Shokri et al. 8 , 188 , 283 B2 5 / 2012 Binch et al . 8 , 846, 753 B2 9 / 2014 Hadida Ruah et al . 8 , 227 , 615 B2 7 / 2012 Hadida - Ruah et al . 8 , 853 , 254 B2 . 10 /2014 Hadida Ruah et al . 8 , 232 , 302 B2 7 / 2012 Miller et al. 8 ,853 ,415 B2 10 / 2014 Hadida Ruah et al. 8 , 242 , 149 B2 8 / 2012 Ruah et al . 8 , 883 , 206 B2 11/ 2014 Dokou et al . 8 , 299 , 099 B2 10 / 2012 Ruah et al . 8 , 884 , 018 B2 11/ 2014 Ambhaikar et al . 8 , 314 , 239 B2 11/ 2012 Binch et al. 8 ,314 ,256 B2 11/ 2012 Ruah et al . 8 , 889 , 875 B2 11 / 2014 Ruah et al . 8 , 318 , 733 B2 11 / 2012 Hadida -Ruah et al . 8 , 912 , 199 B2 12 /2014 Hadida Ruah et al. 8 , 324 ,207 B2 12 / 2012 Hadida Ruah et al . 8 , 952 , 049 B2 2 / 2015 Ruah et al. 8 , 324 , 242 B2 12 / 2012 Ruah et al. 8 , 952 , 050 B2 2 / 2015 Ruah et al. 8 , 344 , 147 B2 1 / 2013 Ambhaikar et al. 8 , 962 , 856 B2 2 / 2015 Hadida - Ruah et al . 8 , 354 , 427 B2 1 / 2013 Van Goor 8 , 969 , 382 B2 3 / 2015 Binch et al . 8 , 362 , 253 B2 1 / 2013 DeMattei et al. 8 , 969 , 386 B2 3 /2015 Hadida -Ruah et al. 8 ,367 , 660 B2 2 /2013 Binch et al. 8 , 969 , 574 B2 3 / 2015 Keshavarz - Shokri et al. 8 , 389 , 727 B2 3 / 2013 Zhang et al. 8 , 993 , 600 B2 3 / 2015 Hadida Ruah et al. 8 ,399 , 479 B2 3 / 2013 Binch et al . 8 , 999 , 976 B2 4 / 2015 Binch et al . 8 ,404 , 849 B2 3 / 2013 Sun et al . 9 , 012 , 473 B2 4 / 2015 Hadida Ruah et al . 8 ,404 , 865 B2 3 / 2013 Ambhaikar et al. 9 , 012 ,496 B2 4 / 2015 Alargova et al. 8 , 410 , 132 B2 4 / 2013 Binch et al. 9 , 012 , 652 B2 4 / 2015 Siesel 8 , 410, 274 B2 4 / 2013 Hurter et al. 9 , 035, 072 B2 5 /2015 Belmont et al . 8 , 415 ,387 B2 4 / 2013 Ruah et al. 9 , 045 , 425 B2 6 / 2015 Luisi et al. 8 , 431 , 605 B2 4 / 2013 Hadida Ruah et al . 9 , 051 , 303 B2 6 / 2015 Keshavarz - Shokri et al. 8 , 436, 014 B2 5 /2013 Zhang et al . 9 , 051, 324 B2 6 /2015 Binch et al . 8 , 461 , 156 B2 6 / 2013 Hadida Ruah et al. 9 , 079 , 916 B2 7 / 2015 Hadida Ruah et al. 8 , 461 , 342 B2 6 / 2013 Siesel 9 , 090 , 619 B2 7 / 2015 Hadida -Ruah et al . 8 , 461 , 352 B2 6 / 2013 Ambhaikar et al . 9 , 102 , 672 B2 8 / 2015 Hadida - Ruah et al . 8 , 471 ,029 B2 6 / 2013 Arekar et al . 9 , 127 ,162 B2 9 / 2015 Harders et al. 8 , 476, 442 B2 7 / 2013 DeMattei et al. 9 , 139, 530 B2 9 /2015 Hurter et al . 8 , 507 ,524 B2 8 / 2013 Ruah et al. 9 , 150 ,552 B2 10 / 2015 Keshavarz -Shokri et al. US 10 ,022 ,352 B2 Page 3

(56 ) References Cited 2013 /0303484 AL 11 /2013 Grootenhuis et al. 2013 /0331567 Al 12 /2013 Hadida - Ruah et al. U . S . PATENT DOCUMENTS 2014 / 0023706 A1 1 / 2014 Verwijs et al. 2014 /0080825 A1 3 / 2014 Hadida - Ruah et al. 9 , 192 ,606 B2 11/ 2015 Young 2014 / 0094499 Al 4 /2014 Alargova et al. 9 ,216 ,969 B2 12 / 2015 Ruah et al . 2014 /0112988 A1 4 /2014 Rowe et al . 9 , 241, 934 B21 / 2016 Verwijs et al . 2014 /0121208 A1 5 / 2014 Van Goor et al. 9 ,249 ,131 B2 2 / 2016 Hadida Ruah et al. 2014 /0142138 Al 5 / 2014 Van Goor et al. 9 ,254 , 291 B2 2 / 2016 Looker et al . 2014 / 0155431 A1 6 / 2014 Hadida -Ruah et al. 9 ,314 , 455 B2 4 / 2016 Keshavarz- Shokri et al. 2014 /0155626 A1 6 / 2014 Hadida Ruah et al. 9 ,321 , 725 B2 4 / 2016 Miller et al. 9 ,351 , 962 B2 5 / 2016 Hadida Ruah et al. 2014 /0163011 A1 6 /2014 Hadida -Ruah et al. 9 , 371 , 287 B2 6 / 2016 DeMattei et al . 2014 /0163068 A1 6 / 2014 Verwijs et al. 9 , 434 , 717 B2 9 / 2016 Keshavarz - Shokri et al . 2014 / 0221424 Al 8 / 2014 Zha 9 , 504, 683 B2 11 / 2016 Hadida Ruah et al. 2014 /0235668 AL 8 /2014 Binch et al . 9 , 522 , 145 B2 12 / 2016 Hadida Ruah et al . 2014 /0243289 Al 8 /2014 Grootenhuis et al. 9 , 550, 761 B2 1 / 2017 Hadida -Ruah et al . 2014 / 0256770 Al 9 / 2014 DeMattei et al . 9 , 670 ,163 B2 6 / 2017 Hurter et al . 2014 / 0303204 Al 10 / 2014 Binch et al . 2003/ 0219489 AL 11/ 2003 Curatolo et al . 2014 / 0303205 Al 10 /2014 Yang et al . 2004 /0105820 AL 6 / 2004 Weers et al . 2014 / 0315948 A1 10 /2014 Rowe et al . 2005 /0113423 Al 5 / 2005 VanGoor et al. 2014 /0323521 Al 10 /2014 Van Goor et al. 2005 / 0164973 A1 7 / 2005 Karp et al. 2014 /0329855 A1 11 /2014 Arekar et al . 2005 / 0215614 A1 * 9 / 2005 Singh ...... CO7D 209 / 08 2014 /0336393 A1 11/ 2014 Ambhaikar et al. 514 /414 2014 /0343098 AL 11/ 2014 Sheth et al . 2005 /0222271 Al 10 /2005 Huang 2014 /0350281 AL 11 /2014 DeMattei et al . 2006 /0003005 A1 1 / 2006 Cao et al. 2015 /0010628 AL 1 / 2015 Dokou et al . 2006 /0004010 A1 1 / 2006 Habashita et al. 2015 / 0024047 AL 1 /2015 Dokou et al . 2006 /0035943 A1 2 / 2006 Karp et al . 2015 / 0031720 A1 1 / 2015 Gallardo -Godoy 2006 /0148863 A1 7 / 2006 Karp et al . 2015 / 0031722 A1 1 / 2015 Hadida - Ruah et al . 2006 /0148864 Al 7 / 2006 Karp et al . 2007 / 0099938 Al 5 / 2007 Ohmoto et al. 2015 / 0065487 A1 3 /2015 Hadida - Ruah et al. 2007 /0218138 A1 9 / 2007 Bittorf et al. 2015 / 0065497 A1 3 / 2015 Hadida Ruah et al. 2008 / 0081814 Al 4 / 2008 Cezanne et al. 2015 /0065500 A1 3 / 2015 Hadida - Ruah et al. 2008 /0097083 A1 4 / 2008 Cho et al . 2015 /0080431 A1 3 /2015 Van Goor et al . 2008/ 0132560 A16 / 2008 Chow et al. 2015 / 0094304 A1 4 / 2015 Ruah et al . 2009 /0105272 A1 4 / 2009 Grootenhuis et al. 2015 /01 19441 A1 4 /2015 Hadida Ruah et al. 2009 /0176839 A1 7 / 2009 Keshavarz - Shokri et al. 2015 /0126566 A1 5 / 2015 Hadida -Ruah et al. 2009 /0246820 AL 10 / 2009 Singh et al. 2015 /0141459 Al 5 / 2015 Van Goor et al . 2009/ 0270465 Al 10 / 2009 Albright et al . 2015 /0164883 A1 6 / 2015 Van Goor et al. 2010 / 0036130 A1 2 / 2010 Siesel 2015 / 0166516 A1 6 / 2015 Hadida -Ruah et al. 2010 / 0074949 Al 3 / 2010 Rowe et al. 2015 /0174089 A1 6 / 2015 Ruah et al. 2010 /0125090 Al 5 / 2010 Hadida Ruah et al . 2015 / 0182517 Al 7 /2015 Alargova et al. 2010 / 0144798 A1 6 / 2010 VanGoor et al. 2015 /0190390 A1 7 /2015 Hadida Ruah et al. 2010 /0249180 A1 9 / 2010 Gallardo -Godoy 2015 / 0203478 A1 7 / 2015 Keshavarz - Shokri et al. 2010 / 0256184 Al 10 / 2010 Rowe et al. 2015 /0218122 A1 8 / 2015 Tanoury et al. 2011 / 0064811 A1 3 / 2011 Hurter et al. 2015 /0231142 A1 8/ 2015 Van Goor et al. 2011 / 0098311 A1 4 / 2011 Van Goor et al. 2011/ 0098484 AL 4 / 2011 Saitoh et al. 2015 /0246031 A1 9 / 2015 Dokou et al . 2011 / 0123449 Al 5 /2011 Zhang et al . 2015 /0265612 A1 9 /2015 Hadida Ruah et al. 2011/ 0177999 Al 7 / 2011 Singh et al. 2015 /0293078 A1 10 / 2015 Singh et al. 2011 /0251253 Al 10 / 2011 Keshavarz - Shokri et al. 2015 /0320736 Al 11/ 2015 Phenix et al . 2011/ 0257223 Al 10 /2011 Goor et al . 2015 / 0336898 A1 11/ 2015 Grootenhuis et al . 2011 / 0288122 Al 11 / 2011 Van Goor et al. 2015 / 0336956 AL 11 / 2015 Hadida - Ruah et al. 2012 / 0035179 A1 2 / 2012 Hadida -Ruah et al. 2016 / 0022664 A2 1 / 2016 Van Goor et al. 2012 /0046330 A1 2 / 2012 Alargova et al . 2016 /0022665 A2 1/ 2016 Van Goor et al. 2012 /0064157 A1 3 / 2012 Dokou et al. 2016 / 0039800 A1 2 / 2016 Young 2012 /0122921 A1 5 / 2012 DeMattei et al . 2016 / 0052916 A1 2 /2016 Keshavarz -Shokri et al. 2012 /0122922 Al 5 / 2012 Young et al. 2016 /0095858 A1 4 /2016 Miller et al. 2012 /0184583 Al 7 /2012 Van Goor et al. 2016 / 0096807 A1 4 / 2016 Strohmeier et al . 2012 /0220625 Al 8 / 2012 Rowe et al . 2016 /0143898 AL 5 /2016 Hadida Ruah et al. 2012 /0232059 AL 9 / 2012 Hadida - Ruah et al . 2012 /0258983 A1 10 / 2012 Rowe et al. 2016 / 0151335 A1 6 / 2016 Tait et al. 2013 / 0012536 AL 1 / 2013 Hadida Ruah et al 2016 /0166540 Al 6 /2016 Looker et al. 2013 /0018071 A1 1 / 2013 Arekar et al. 2016 /0200712 A1 7 /2016 Siesel 2013 / 0085158 A1 4 / 2013 Keshavarz - Shokri et al. 2016 /0221952 A1 8 / 2016 Yang et al. 2013 / 0090354 AL 4 / 2013 Van Goor et al . 2016 /0221995 AL 8 /2016 Keshavarz - Shokri et al . 2013 /0095181 Al 4 / 2013 Verwijs et al. 2016 /0228414 AL 8 /2016 Hadida Ruah et al. 2013 /0131107 A1 5 / 2013 Van Goor et al. 2016 /0237079 AL 8 /2016 Hadida Ruah et al. 2013 /0143919 Al 6 / 2013 Van Goor et al. 2016 /0303096 Al 10 /2016 Verwijs et al. 2013 / 0158071 A1 6 / 2013 Van Goor et al . 2013 /0178496 A1 7 / 2013 Binch et al. 2016 /0318931 A1 11/ 2016 Hadida Ruah et al. 2013 /0184276 A1 7 / 2013 Hadida Ruah et al . 2016 / 0324788 AL 11 /2016 Verwijs 2013 /0186801 Al 7 / 2013 Verwijs 2016 /0324846 A1 11/ 2016 Verwijs et al. 2013 /0196983 A1 8 / 2013 Binch et al . 2016 /0332997 A1 11/ 2016 Hadida Ruah et al . 2013 / 0224293 A1 8/ 2013 Dokou et al. 2016 / 0354316 Al 12 /2016 Swinney et al . 2013 /0231364 Al 9 /2013 Binch et al. 2017 /0087144 A1 3 /2017 Rowe et al . 2013 /0231368 A1 9 / 2013 Zhang et al. 2017 /0096396 AL 4 /2017 DeMattei et al . 2013 / 0245010 AL 9 / 2013 Hadida Ruah et al . 2017 /0100340 A1 4 / 2017 Dokou et al. 2013 /0245011 A1 9 / 2013 Hadida Ruah et al. 2017 /0107205 A14 /2017 Hadida Ruah et al . US 10 ,022 ,352 B2 Page 4

References Cited WO WO 2009 /023509 A2 2 / 2009 ( 56 ) wo WO 2009 /036412 A1 3 / 2009 U . S . PATENT DOCUMENTS WO WO 2009/ 038683 A2 3 / 2009 WO WO 2009 /038913 A2 3 / 2009 2017 /0107206 Al 4 /2017 Hadida Ruah et al. WO WO 2009 / 066775 Al 5 / 2009 2017 /0107225 A14 / 2017 Hadida Ruah et al . WO WO 2009 / 073757 Al 6 / 2009 Wo WO 2009 /076141 A2 6 / 2009 wo WO 2009 / 076593 A1 6 / 2009 FOREIGN PATENT DOCUMENTS wo WO 2010 /037066 A2 4 / 2010 WO WO 2010 /053471 A1 5 / 2010 CN 101287732 A 10 / 2008 WO WO 2010 /054138 A2 5 / 2010 CN 101460489 A 6 / 2009 WO WO 2011 / 050325 A1 4 / 2011 CN 101605543 A 12 /2009 WO WO 2011 / 119984 AL 9 / 2011 DE 27 35 433 Al 2 / 1978 WO WO 2011 / 127290 A2 10 / 2011 EA 4925 B1 . 10 / 2004 WO WO 2011 / 133951 A1 10 /2011 EA 6155 B1 10 / 2005 WO WO 2013 / 185112 AL 12 / 2013 EP 1 380 576 A11 / 2004 WO WO 2014 /014841 Al 1 / 2014 EP 1 864 978 A1 12 / 2007 WO WO 2016 /086103 A1 6 / 2016 61- 103861 A 5 / 1986 WO WO 2016 / 086136 A1 6 / 2016 7 - 45466 B2 5 / 1995 WO 2004 - 131393 A 4 / 2004 WO 2016 / 160945 A1 10 / 2016 JP 2009 - 530416 A 8 / 2009 RU 2005115965 A 1 / 2006 OTHER PUBLICATIONS RU 2005128828 A 5 / 2006 ?? 1244393 B 12 / 2005 Berge et al ., “ Pharmaceutical Salts ,” J. Pharmaceutical Sciences , wo WO 1995 /006046 Al 3 / 1995 Wo WO 1996 /019444 A1 6 / 1996 66 ( 1 ) : 1 - 19 ( 1977 ) . WO WO 1998 /047868 A1 10 / 1998 Bjornsson et al , “ The conduct of in vitro and in vivo drug - drug WO WO 1998 / 58925 A1 12 / 1998 interaction studies : a Pharmaceutical Research and Manufacturers wo WO 2001 / 19830 A1 3 / 2001 of America ( PhRMA ) perspective , " Drug Metab . Dispos ., 31 ( 7 ) : WO WO 2001/ 47916 A1 7 / 2001 815 - 832 ( 2003 ) . WO WO 2002/ 11883 Al 2 /2002 Bruan , J . , “ No association between the deltaF508 cystic fibrosis WO WO 2002 / 12236 A1 2 / 2002 WO WO 2002 / 16349 A1 2 / 2002 mutation and type 2 diabetes mellitus. ” Exp . Clin . Endocrinol WO WO 2003 /002533 Al 1 / 2003 Diabetes . 107 ( 8 ) : 568- 569 ( 1999 ) . WO WO 2003 / 007945 A1 1 / 2003 Bross et al ., " Protein Misfolding and Degradation in Genetic W0 WO 2003/ 055482 A1 7 / 2003 Diseases ,” Human Mut. , 14 : 186 - 189 ( 1999 ) . WO WO 2004 / 028480 A2 4 / 2004 Caira , M . R ., “ Crystalline Polymorphism of Organic Compounds, " WO WO 2004 /035571 A1 4 / 2004 Topics of Current Chemistry , Springer, Berlin , DE. , vol. 198 ( 1998 ), WO WO 2004 / 037806 A1 5 /2004 WO WO 2004 / 041277 Al 5 / 2004 pp . 163 - 208 . WO WO 2004 /056745 A2 7 / 2004 Cecil Textbood ofMedicine , 20th Ed ., 1996 , vol. 2 , pp . 1192 - 1996 . wo WO 2004 /080972 A1 9 / 2004 Cecil Textbook of Medicine , 20th Ed ., 1996 , vol. 2 , pp . 2050 - 2057 . WO WO 2004 /091502 A2 10 / 2004 Cutting et al. , “ A cluster of cystic fibrosis mutations in the first WO WO 2004 / 110352 A2 12 / 2004 nucleotide- binding fold of the cystic fibrosis conductance regulator W0 WO 2004 / 111014 Al 1212 / 2004 protein , ” Nature, 346 : 366 -369 ( 1990 ) . WO WO 2005 /016884 Al 2 / 2005 Dahl et al. , “Markers of early disease and prognosis of COPD , ” WO WO 2005 / 035514 A2 4 / 2005 International Journal of COPD , 4 : 157 - 167 ( 2009 ) . WO WO 2005 /037802 A1 4 / 2005 WO WO 2005 /049018 Al 6 / 2005 Dalemans et al. , " Altered chloride ion channel kinetics associated WO WO 2005 /075435 A1 8 / 2005 with the AF508 cystic fibrosis mutation ,” Nature , 354 : 526 -528 WO WO 2005 /094374 A2 10 / 2005 ( 1991 ) . WO WO 2005 / 120497 A2 12 / 2005 Dean et al. , “ Multiple mutations in highly conserved residues are WO WO 2006 / 002421 A2 1 / 2006 found in mildly affected cystic fibrosis patients, ” Cell ,61 : 863- 870 WO WO 2006 /014012 A2 2 / 2006 ( 1990 ) . WO WO 2006 /044456 A1 4 / 2006 Definition of Amorphous in www .thefreedictionary .com / amorphous wo WO 2006 /044502 A2 4 /2006 p . 1 - 2 ( 2012 ) . WO WO 2006 /044503 A2 4 / 2006 FDA mulls drug to slow late - stage Alzheimer' s [ online ], [ retrieved WO WO 2006 /044505 A2 4 / 2006 Sep . 23 , 2003 ) . Retrieved from the internet, URL : http :/ /www .cnn . WO WO 2006 / 044682 A1 4 / 2006 com /2003 / HEALTH /conditions / 09 /24 / alzheimers .drug . ap / index . WO WO 2006 /099256 A2 9 / 2006 WO WO 2006 / 101740 A2 9 / 2006 html. WO WO 2006 / 110483 Al 10 / 2006 Freireich et al. , “ Quantitative comparison of toxicity of anticancer Wo WO 2006 / 127588 A2 11 / 2006 agents in mouse , rat, hamster , dog , monkey , and man ,” Cancer WO WO 2007/ 017715 A2 2 / 2007 Chemother. Rep ., 50 ( 4 ) : 219 - 244 ( 1966 ) . WO WO 2007 /021982 A2 2 / 2007 Galietta et al. , “ An improved method to obtain highly differentiated WO WO 2007 /044560 A2 4 / 2007 monolayers of human bronchial epithelial cells , ” In Vitro Cell. Dev. WO WO 2007 /056341 A1 5 / 2007 Biol. , 34 : 478 - 481 ( 1998 ) . WO WO 2007/ 075567 Al 7 / 2007 González et al. , “ Cell -based assays and instrumentation for screen WO WO 2007 /075901 A2 7 / 2007 ing ion -channel targets, ” Drug Discov Today , 4 (9 ): 431 -439 ( 1999 ). WO WO 2007 /075946 A1 7 / 2007 González et al, “ Improved indicators of cell membrane potential WO WO 2007 /079139 A2 7 / 2007 WO WO 2007 /087066 A2 8 /2007 that use fluorescence resonance energy transfer, ” Chem Biol , 4 ( 4 ): WO WO 2007/ 109605 A2 9 / 2007 269- 277 ( 1997 ) . WO WO 2007 / 117715 A2 10 / 2007 González et al . , “ Voltage Sensing by Fluorescence Resonance WO WO 2008 /051805 A2 5 / 2008 Energy Transfer in Single Cells ," Biophys J , 69( 4 ) : 1272 - 1280 WO WO 2008 /065732 A1 6 / 2008 ( 1995 ). wo WO 2008 / 127399 A2 10 / 2008 Gregory et al ., " Expression and characterization of the cystic WO WO 2008 / 147952 Al 12 / 2008 fibrosis transmembrane conductance regulator, " Nature , 347 : 382 WO WO 2009 / 006315 A1 1 / 2009 386 ( 1990 ) . US 10 ,022 ,352 B2 Page 5

( 56 ) References Cited Stankovic et al ., “ The CFTR M740V gene variant as a potential modifier of COPD severity : study of Serbian population , ” Genetic OTHER PUBLICATIONS Testing , 12 ( 3 ) : 357 - 362 ( 2008 ) . U . S . Appl. No. 13 /091 ,411 , filed Apr. 21, 2011. International Preliminary Report on Patentability and Writte Opin U . S . Appl. No. 13 /632 , 835 , filed Oct. 1 , 2012 . ion of the International Searching Authority for Internation Appli U . S . Appl. No. 14 /077 , 885 , filed Nov . 12 , 2013 . cation No . PCT/ US2007 /008975 , dated Oct. 8 , 2008 . U . S . Appl. No . 14 / 179 , 762 , filed Feb . 13 , 2014 . International Preliminary Report on Patentability and Written Opin U . S . Appl. No. 14 /444 ,451 , filed Jul. 28 , 2014 . ion of the International Searching Authority for International Appli U . S . Appl. No. 14 / 852 ,892 , filed Sep . 14 , 2015 . cation No. PCT/ US2008 /012689 , dated May 10 , 2011 . U . S . Appl. No. 14 / 870 , 592 , filed Sep . 30 , 2015 . International Preliminary Report on Patentability and Written Opin U . S . Appl. No. 14 / 877 ,860 , filed Oct . 7 , 2015 . ion of the International Search Authority for International Applica U . S . Appl. No . 14 /920 , 836 , filed Oct. 22 , 2015 . tion No . PCT/ US2009 / 063475 , dated May 11 , 2015 . U . S . Appl. No. 14 /925 ,804 , filed Oct . 28 , 2015 . International Search Report for International Application No . PCT/ U . S . Appl. No . 14 /935 ,777 , filed Nov . 9 , 2015 . U . S . Appl. No. 14 /951 , 142 , filed Nov . 24 , 2015 . US2007 /008975 , dated Aug . 22 , 2007 . U . S . Appl. No . 14 / 982 ,973 , filed Dec . 29 , 2015 . International Search Report for International Application No . PCT/ U . S . Appl. No . 14 /985 ,650 , filed Dec . 31, 2015 . US2008 /012689 , dated Aug. 21 , 2009 . U . S . Appl. No. 14 / 992 , 132 , filed Jan . 11 , 2016 . International Search Report for International Application No . PCT/ U . S . Appl. No. 14 /994 ,487 , filed Jan . 13, 2016 . US2009 /063475 , dated Sep . 23 , 2010 . U . S . Appl. No. 14 /996 ,781 , filed Jan . 15 , 2016 . Kerem et al. , “ Identification of mutations in regions corresponding U .S . Appl. No. 15 /001 ,036 , filed Jan . 19 , 2016 . to the two putative nucleotide (ATP ) - binding folds of the cystic U . S . Appl. No. 15 /043 , 049 , filed Feb . 12 , 2016 . fibrosis gene, ” Proc. Natl. Acad. Sci. USA , 87 : 8447 -8451 ( 1990 ) . U . S . Appl . No. 15 /056 ,313 , filed Feb . 29 , 2016 . Kerem et al. , “ Identification of the cystic fibrosis gene: genetic U . S . Appl. No . 15 /056 , 436 , filed Feb . 29 , 2016 . analysis , ” Science, 245 : 1073 - 1080 ( 1989 ). U . S . Appl. No . 15 /064 , 222 , filed Mar. 8 , 2016 . Kerem et al. , " Standards of care for patients with cystic fibrosis : a U . S . Appl . No. 15 /073 ,591 , filed Mar. 17 , 2016 . European consensus, " J Cystic Fibr, 4 : 7 - 26 (2005 ). U . S . Appl. No . 15 / 093 , 582 , filed Apr. 7 , 2016 . Kerns et al. , Drug - like Properties : Concepts , Structure Design and U . S . Appl. No . 15 /097 , 252 , filed Apr. 12 , 2016 . Methods: from ADME to Toxicity Optimization , Academic Press , Van Goor et al. , “ Rescue of deltaF508 -CFTR trafficking and gating UK , pp . 122 - 136 and 197 - 208 (2008 ). in human cystic fibrosis airway primary cultures by small mol Konno et al. , “ Effect of polymer type on the dissolution profile of ecules, ” Am J. Physiol . Lung Cell Mol. Physiol. 290 (6 ): 1117 - 1130 amorphous solid disperions containing felodipine , ” European Jour ( 2006 ). Vertex Pharmaceuticals Incorporated , “ Study of VX -661 Alone and nal of Pharmaceuticals and Biopharmaceutical 70 : 493 -499 ( 2008 ) . in Combination With Ivacaftor in Subjects Homozygous or Krippendorff et al ., “ Optimizing Classification of Drug - Drug Inter Heterozygous to the F508del- Cystic Fibrosis Transmembrane Con action Potential for CYP450 Isoenzyme Inhibition Assays in Early ductance Regulator (CFTR ) Mutation ” , ClinicalTrials . gov Identi Drug Discovery, ” J . Biomol. Screen . , 12 ( 1 ) : 92 - 99 (2007 ) . fier : NCT01531673 , May 5 , 2015 , https: / /clinicaltrials . gov / ct2 / Morello et al . , “ Pharmacological chaperones : a new twist on recep show /NCT01531673 ? term = vx -661 & rank = 3 . tor folding , " TIPS , 21: 466 - 469 ( 2000 ) . Vertex Pharmaceuticals Incorporated , “ Addition of VX -661 to Notice of Allowance and Fee( s ) Due for U . S . Appl. No . 14 /286 ,708 , KALYDECO? ( ivacaftor ) Improves Lung Function in People with dated Feb . 19 , 2016 . CF Who Are Heterozygous for the F508del and G551D Mutations Notice of Allowance and Fee ( s ) Due for U . S . Appl. No. 14 / 317 , 277 , in 28 -day Phase 2 Proof -of - Concept Study ” , May 1 , 2014 , http :/ / dated Feb . 24 , 2016 . investors .vitx .com / releasedetail. cfm ?ReleaseID = 844677 . Notice of Allowance and Fee( s ) Due for U . S . Appl. No . 14 / 334 , 902 , Vertex Pharmaceuticals Incorporated , “ An Open - Label, Phase 1 dated Feb . 18 , 2016 . Study in Healthy Adult Subjects to Examine the Effects of Multiple Notice of Allowance and Fee( s ) Due for U . S . Appl. No. 14 /532 ,791 , Dos Ciprofloxacin on Ivacaftor and VX -661 in Combination With dated Mar. 1 , 2016 . Ivacaftor” , Clinical Trials . gov Identifier: NCT02015507 , Mar. 25 , Notice ofAllowance and Fee( s) Due for U .S .Appl . No. 14 /598 ,560 , 2014 , https: / / clinicaltrials . gov / ct2 / show /NCT02015507 ? term = vx dated Jan . 21 , 2016 . 661 & rank = 4 . Notice of Allowance and Fee( s ) Due for U .S . Appl. No. 14 /687 ,286 , Vertex Pharmaceuticals Incorporated , “ Study to Evaluate Safety and dated Feb . 10 , 2016 . Efficacy of VX -661 in Combination With Ivacaftor in Subjects With Notice ofAllowance and Fee( s) Due for U .S . Appl. No. 14 /730 , 726 , Cystic Fibrosis , Homozygous for the F508del- CFTR Mutation With dated Apr. 12 , 2016 . an Open -Label Expansion ” , Clinical Trials . gov Identifier: Notice of Allowance and Fee( s ) Due for U . S . Appl. No . 14 /841 , 163 , NCT02070744 , Oct . 17 , 2014 , https :/ / clincaltrials . gov / ct2 / show / dated Jan . 11 , 2016 , Issue Fee paid Apr. 8 , 2016 . NCT02070744 ? term = vx -661 & rank = 6 . Pasyk et al. , “Mutant (A F508 ) cystic fibrosis transmembrane Vertex Pharmaceuticals Incorporated , “ Treatment with VX -661 and conductance regulator CT channel is functional when retained in Ivacaftor in a Phase 2 Study Resulted in Statistically significant endoplasmic reticulum of mammalian cells ," J. Biol Biochem , Improvements in Lung Function in People with Cystic Fibrosis Who 270 ( 21 ) : 12347 - 12350 ( 1995 ) . Have Two Copies of the F508del Mutation ” , Apr. 18 , 2013 , http : / / Quintion , " Cystic fibrosis: a disease in electrolyte transport ," investors .vrtx .com /releasedetail .cfm ?ReleaseID = 757597 . FASEB J ., 4 : 2709 - 2717 ( 1990 ) . Vertex Pharmaceuticals Incorporated , “ Vertex Announces Data Rich et al. , “ Expression of cystic fibrosis transmembrane conduc from 12 -Week Phase 2 Safety Study of VX -661 in Combination tance regulator corrects defective chloride channel regulation in with Ivacaftor in People with Cystic Fibrosis Who Have Two Copies cystic fibrosis airway epithelial cells , ” Nature , 347 : 358 - 363 ( 1990 ) . of the F508del Mutation ” , Mar. 23, 2015 , http :/ / investors . vrtx . com / Riley et al, “ Time- dependent CYP inhibitionn , ” Expert Opin Drug releasedetail. cfm ? ReleaseID = 902790 . Metab Toxicol. , 3 : 51 - 66 ( 2007) . Wang et al ., “ Actions of genistein on cystic fibrosis transmembrane Riordan et al. , “ Identification of the cystic fibrosis gene: cloning and conductance regulator channel gating . Evidence for two binding characterization of the complementary DNA ," Science , 245 : 1066 sites with opposite effects , ” J . Gen . Physiol. , 111( 3 ) , 477 -490 1073 (1989 ) . ( 1998 ) . Rutishauser et al ., “ Endoplasmic reticulum storage diseases, ” Swiss Beare , N . A . and J . F . Hartwig ( Jan . 1 , 2002 ) “ Palladium - Catalyzed Med Wkly , 132 : 211 -222 ( 2002 ). Arylation ofMalonates and Cyanoesters Using Sterically Hindered Shastry et al. , “ Neurodegenerative disorders of protein aggrega Trialkyl- and Ferrocenyldialkylphosphine Ligands” J Org Chem , tion , ” Neurochem . International, 43 : 1 - 7 ( 2003 ) . 67 :541 - 555 . US 10 ,022 ,352 B2 Page 6

References Cited Kawakami ( Jan . 2010 ) “ Formulation of a Poorly Water -soluble ( 56 ) Drug by Decrystallization " Chapter 5 in New Development of OTHER PUBLICATIONS Property Evaluation and Formulation Design of Poorly Water Soluble Drugs . CMC Publishing Co ., Ltd .; pp . 212 - 244 . Japanese Bombieri, C . et al . ( 1998 ) “ Complete mutational screening of the with English abstract. CFTR gene in 120 patients with pulmonary disease ” Hum Genet , Levin , M . and A .S . Verkman ( Apr. 2005 ) " CFTR -Regulated Chlo 103 :718 -722 . ride Transport at the Ocular Surface in Living Mice Measured by Brittain , H .G . (Ed .) Polymorphism in Pharmaceutical Solids . Mar Potential Differences” Investigative Ophthalmology & Visual Sci cel Dekker, 1999 ; p . 236 . Chen , R . et al . ( 2004 ) “ Improved Dissolution of an Insoluble Drug ence, 46 : 1428 -1434 . Using a 4 - Fluid Nozzle Spray - Drying Technique Chem Pharm Miyamatsu , H . et al . ( 1974 ) “ A New Nonsteroidal Antiinflammatory Bull , 52 ( 9 ) : 1066 - 1070 . Agent. 3 . Analogs of 2 - Substituted 5 - Benzothiazoleacetic Acids and Chueshov, V .I . (Ed ) (2002 ) Manufacturing Technologies of Drugs . Their Derivatives” J Med Chem , 17 (5 ): 491 - 496 . vol. 2 . Kharkov :MTK -Kniga , Publishing House NPAU ; excerpt , 7 Notice of Allowance and Fee ( s ) Due for U . S . Appl. No . 13 / 290 , 491, pages . dated Oct. 25 , 2012 . Dahl, M . et al. (Oct . 9 , 2005 ) “ Asthma and COPD in cystic fibrosis Notice of Allowance and Fee( s ) Due for U . S . Appl. No. 13 /871 , 349 , intron -8 5T carriers. A population -based study” Respiratory dated Aug . 12 , 2014 . Research , 6 : 113 , doi: 10 . 1186 / 1465 -9921 - 6 - 113 , 9 pages . Notice of Allowance and Fee( s ) Due for U .S . Appl. No . 13/ 871, 349 , Database Registry (Nov . 18 , 1988 ) “ 6 - Quinolineacetic acid , dated Apr. 17 , 2015 . a -cyano -, ethyl ester” RN 117646 - 35 -2 , Retrieved from STN Inter Notice of Allowance and Fee( s ) Due for U . S . Appl. No. 13 / 871, 349 , national [online ]; retrieved on Feb . 13 , 2015 ( 1 page ) . dated Oct. 13 , 2015 . Database REGISTRY (May 19 , 2004 ) “ 1 , 3 - Benzodioxole - 5 - acetic Notice of Allowance and Fee( s ) Due for U . S . Appl. No . 13 /887 ,839 , acid , a -cyano -” RN 683220 -08 - 8 , Retrieved from STN Interna dated Jul. 7 , 2014 . tional [online ]; retrieved on Feb . 13 , 2015 ( 1 page ) . Notice of Allowance and Fee (s ) Due for U .S . Appl. No . 13/ 887 , 839 , Fude, Cui (2002 ) Pharmaceutics . 1st Ed . China Medical Science dated Oct. 16 , 2014 . Press , p . 443 , 445 -446 . Chinese with English translation . Notice of Allowance and Fee( s) Due for U .S . Appl . No. 13/ 887 ,839 , Fude, Cui (Feb . 2004 ) Pharmaceutics. 5th Ed . People ' s Medical dated Feb . 2 , 2015 . Publishing House ; p . 113 - 119 , 334 . Chinese with English transla Notice of Allowance and Fee( s ) Due for U .S . Appl. No . 13/ 887, 839 , tion . dated Sep . 30 , 2015 . Hancock , B . and M . Parks ( 2000 ) “ What Is the True Solubility Notice ofAllowance and Fee( s ) Due for U .S . Appl. No. 14 /031 , 360 , Advantage of Amorphous Pharmaceuticals ? ” Pharm Res , dated Aug . 14 , 2014 . 17 ( 4 ) : 397 - 404 . Notice of Allowance and Fee( s ) Due for U . S . Appl. No. 14 / 298 , 245 , International Patent Application No . PCT/ US2011 / 030032 , filed dated Jul. 21 , 2015 . Mar. 25 , 2011 , by Vertex Pharmaceuticals , Inc . : International Search Notice of Allowance and Fee ( s ) Due for U . S . Appl. No. 14 / 298 , 245 , Report , dated Aug. 2 , 2011 . dated Nov . 12 , 2015 . International Patent Application No . PCT/ US2011 / 030032 , filed Notice of Allowance and Fee ( s ) Due for U . S . Appl. No . 14 /326 ,930 , Mar. 25 , 2011, by Vertex Pharmaceuticals , Inc . : International Pre dated Aug . 14 , 2015 . liminary Report on Patentability , dated Sep . 25 , 2012 . Notice of Allowance and Fee( s ) Due for U . S . Appl. No. 14 / 326 ,930 , International Patent Application No . PCT/ US2011 / 033396 , filed dated Dec . 8 , 2015 . Apr. 21 , 2011, by Vertex Pharmaceuticals , Inc . : International Pre Notice of Allowance and Fee ( s ) Due for U . S . Appl. No . 14 / 334 , 902 , liminary Report on Patentability and Written Opinion , dated Oct. dated Oct. 19 , 2015 . 23 , 2012 Notice of Allowance and Fee ( s ) Due for U . S . Appl. No. 14 / 532, 791 , International Patent Application No. PCT/ US2011 /033396 , filed dated Jul. 24 , 2015 . Apr. 21, 2011, by Vertex Pharmaceuticals , Inc .: International Search Notice of Allowance and Fee( s ) Due for U . S . Appl. No. 14 /532 , 791 , Report, dated Nov . 11 , 2011 . dated Nov . 6 , 2015 . International Patent Application No . PCT/ US2011 / 033687 , filed Notice ofAllowance and Fee( s ) Due for U .S . Appl. No. 14 / 567, 475 , Apr. 22 , 2011 , by Vertex Pharmaceuticals , Inc .: International Search dated Sep . 21 , 2015 . Report and Written Opinion , dated Aug . 30 , 2011. Notice of Allowance and Fee ( s ) Due for U . S . Appl. No. 14 / 567, 475 , International Patent Application No . PCT/ US2011 / 048565 , filed dated Jan . 5 . 2016 . Aug . 22 , 2011 , by Vertex Pharmaceuticals , Inc . : International Notice of Allowance and Fee( s ) Due for U . S . Appl. No. 14 / 579 ,098 , Search Report and Written Opinion , dated Mar. 20 , 2012 . dated Feb . 1, 2016 . International Patent Application No . PCT/ US2011 / 051725 , filed Notice ofAllowability for U . S . Appl. No . 14 /579 ,098 , dated Apr. 18 , Sep . 15 , 2011 , by Vertex Pharmaceuticals , Inc .: International Search 2016 . Report and Written Opinion , dated May 24 , 2012 . Notice of Allowance and Fee ( s ) Due for U . S . Appl. No. 14 / 579 , 098 , International Patent Application No . PCT /US2012 /064217 , filed dated May 12 , 2016 . Nov. 8 , 2012, by Vertex Pharmaceuticals , Inc .: International Search Notice of Allowance and Fee ( s) Due for U . S . Appl .No . 14/ 656 ,043 , Report and Written Opinion , dated Jan . 15 , 2013 . dated Aug . 4 , 2016 . International Patent Application No . PCT/ US2013 /050557 , filed Notice of Allowance and Fee ( s ) Due for U . S . Appl. No. 14 /687 , 286 , Jul . 15 , 2013 , by Vertex Pharmaceuticals Inc: International Search dated May 19 , 2016 . Report and Written Opinion , dated Sep . 30 , 2013 . Notice of Allowance and Fee( s ) Due for U . S . Appl. No . 14 / 687, 286 , International Patent Application No . PCT/ US2015 /025722 , filed dated Sep . 28 , 2016 . Apr. 14 , 2015 , by Vertex Pharmaceuticals Inc: International Search Notice of Allowance and Fee ( s ) Due for U . S . Appl. No. 14 / 877 ,914 , Report and Written Opinion , dated Jul. 3 , 2015 . dated Jul. 27 , 2016 . Ishiguro , H . et al . ( 2006 ) “ Dysfunction of pancreatic HCO3 secre Notice of Allowance and Fee( s ) Due for U . S . Appl. No. 14 / 877 ,914 , tion and pathogenesis of cystic fibrosis /chronic pancreatitis ” J dated Nov . 14 , 2016 . Japan Pancreas Soc, 21( 1) : 13 - 25 . Japanese with English abstract. Notice of Allowance and Fee( s ) Due for U . S . Appl. No. 14 / 925 ,804 , Jenkins , R . and R . L . Snyder ( 1996 ) Introduction to X -Ray Powder dated May 17 , 2016 , Celia C . Chang. Diffractometry . New York , NY : John Wiley & Sons, Inc. : pp . 23 - 26 . Notice of Allowance and Fee ( s ) Due for U . S . Appl. No. 15 / 001, 036 , Jones, A . and J. M . Helm ( Jan . 1, 2009 ) “ Emerging Treatments in dated Feb . 10 , 2017 . Cystic Fibrosis ” Drugs , 69 ( 14 ) : 1903 - 1910 . Notice of Allowance and Fee( s ) Due for U . S . Appl. No. 15 /073 , 591, Kamal, A . et al. (2005 ) “ Ultrasonic activated efficient method for dated Sep . 28 , 2016 , Celia C . Chang . the cleavage of epoxides with aromatic amines” Ultrasonics Notice of Allowance and Fee( s ) Due for U . S . Appl. No. 15 / 160 , 100 , Sonochemistry , 12 (6 ) :429 - 431 . dated May 3 , 2017 . US 10 ,022 ,352 B2 Page 7

( 56 ) References Cited U . S . Appl . No. 15 / 342 ,999 , filed Nov . 3 , 2016 , by Alargova et al. Vehring , R . (May 2008 ) “ Pharmaceutical Particle Engineering via OTHER PUBLICATIONS Spray Drying” Pharm Res, 25 (5 ): 999 - 1022 . Vertex Pharmaceuticals , Inc. (Apr . 5 , 2012) “ A phase 2 , multicenter , Notice of Allowance and Fee( s ) Due for U . S . Appl. No. 15 / 162 ,887 , double -blinded , placebo controlled , 3 - part study to evaluate safety , dated Apr. 28 , 2017 . efficacy , pharmacokinetics , and pharmacodynamics of VX -661 Notice of Allowance and Fee( s) Due for U . S . Appl . No . 15 / 297, 983 , monotherapy and VX -661 / VX - 770 cotherapy in subjects with cystic dated May 18 , 2017 . fibrosis , homozygous for the F508del -CFTR mutation ” [ online ] . Pettit , R . S . (2012 ) " Cystic Fibrosis Transmembrane Conductance Clinicaltrials .gov . Retrieved from : http : / / clinicaltrials . gov / archive / Regulator — Modifying Medications : The Future of Cystic Fibrosis NCT01531673 / 2012 _ 04 -05 ; Identifier: NCT01531673 . Treatment" Annals of Pharmacotherapy , 46 : 1065- 1075 . Vertex Pharmaceuticals , Inc . ( Jul. 18 , 2013 ) “ A Phase 2 , Multi Satoshi ( 2005 ) “ Advances in male infertility therapy ” Urology center, Double -Blinded , Placebo Controlled , 3 - Part Study to Evalu View , 3 ( 6 ) :58 -61 . Japanese with English abstract. ate Safety , Efficacy , Pharmacokinetics , and Pharmacodynamics of Stauffer , S . R . et al . ( Jan . 1 , 2001 ) “ Palladium - Catalyzed Arylation VX -661 Monotherapy and VX -661 /VX - 770 Cotherapy in Subjects of Ethyl Cyanoacetate . Fluorescence Resonance Energy Transfer as With Cystic Fibrosis , Homozygous for the F508del -CFTR Muta a Tool for Reaction Discovery ” J Am Chem Soc , 123 ( 19 ) :4641 - tion ” [online ] . Clinical Trials . gov . Retrieved from : http :/ / clinicaltri 4642 . als .gov / archive/ NCT01531673 /2013 _ 07 _ 18 ; Identifier : Suzuki, H . et al. ( 1983 ) “ A simple one -pot conversion of aryl halides NCT01531673 . into arylacetonitriles " Chem Lett, p . 193 - 194 . Yu , H . et al . (2010 ) “ VX -770 , an investigational CFTR potentiator, Tzetis , M . et al. (2001 ) “ CFTR gene mutations including three acts on multiple CFTR forms in vitro ” Pediatric Pulmonology , novel nucleotide substitutions — and haplotype background in 45 ( 33 ) : 318 - 319 , Abstract 280 . patients with asthma, disseminated bronchiectasis and chronic Yu , H . et al . (2012 ) “ Ivacaftor potentiation of multiple CFTR obstructive pulmonary disease ” Hum Genet, 108: 216 - 221. channels with gating mutations” J Cystic Fibrosis , 11 ( 3 ) : 237 - 245 . U . S . Appl. No . 15 /234 ,877 , filed Aug. 11, 2016 , by Hadida- Ruah et al. * cited by examiner US 10 ,022 , 352 B2 MODULATORS OF ATP - BINDING a large, polar , regulatory ( R ) -domain with multiple phos CASSETTE TRANSPORTERS phorylation sites that regulate channel activity and cellular trafficking. CROSS REFERENCE TO RELATED The gene encoding CFTR has been identified and APPLICATIONS 5 sequenced ( See Gregory, R . J . et al. ( 1990 ) Nature 347 : 382 386 ; Rich , D . P . et al . ( 1990 ) Nature 347 : 358 -362 ) , (Riordan , This application is a continuation - in -part of U . S . appli - J . R . et al. (1989 ) Science 245 : 1066 - 1073 ) . A defect in this cation Ser . No . 14 /579 , 098 , filed Dec . 22 , 2014 , which is a gene causes mutations in CFTR resulting in Cystic Fibrosis continuation of U . S . application Ser. No . 14 /036 , 286 , filed (“ CF " ) , the most common fatal genetic disease in humans . Sep . 25 , 2013 , which is a division of U . S . application Ser . 1 Cystic Fibrosis affects approximately one in every 2 , 500 No. 12 /948 , 162, filed Nov . 17 , 2010 , which is a continuation infants in the United States . Within the general United States of U . S . application Ser . No . 12 /619 ,412 , filed Nov. 16 , 2009 , population , up to 10 million people carry a single copy of the which is a division of U .S . application Ser . No . 11/ 975, 297, defective gene without apparent ill effects . In contrast, filed Oct. 18 , 2007, which is a continuation - in - part of U . S . 1 individuals with two copies of the CF associated gene suffer application Ser. No . 11/ 786 ,001 , filed Apr. 9 , 2007 , which from the debilitating and fatal effects of CF, including claims the benefit under 35 U . S . C . $ 119 of U . S . Provisional chronic lung disease . Application No. 60 /790 , 459 , filed Apr. 7 , 2006 , the entire In patients with cystic fibrosis ,mutations in CFTR endog contents of all applications being incorporated herein by enously expressed in respiratory epithelia leads to reduced reference . 20 apical anion secretion causing an imbalance in ion and fluid transport . The resulting decrease in anion transport contrib TECHNICAL FIELD OF THE INVENTION utes to enhanced mucus accumulation in the lung and the accompanying microbial infections that ultimately cause The present invention relates to modulators of ATP - death in CF patients . In addition to respiratory disease , CF Binding Cassette (" ABC ” ) transporters or fragments thereof, 25 patients typically suffer from gastrointestinal problems and including Cystic Fibrosis Transmembrane Conductance pancreatic insufficiency that , if left untreated , results in Regulator (" CFTR ” ) , compositions thereof and methods death . In addition , the majority of males with cystic fibrosis therewith . The present invention also relates to methods of are infertile and fertility is decreased among females with treating ABC transporter mediated diseases using such cystic fibrosis . In contrast to the severe effects of two copies modulators . 30 of the CF associated gene, individuals with a single copy of the CF associated gene exhibit increased resistance to chol BACKGROUND OF THE INVENTION era and to dehydration resulting from diarrhea - perhaps explaining the relatively high frequency of the CF gene ABC transporters are a family of membrane transporter ety of 35 Sequence analysis of the CFTR gene of CF chromosomes proteins that regulate the transport of a wide variety of 3 has revealed a variety of disease causing mutations (Cutting , pharmacological agents , potentially toxic drugs , and xeno G . R . et al . ( 1990 ) Nature 346 : 366 - 369 ; Dean , M . et al . biotics, as well as anions. ABC transporters are homologous ( 1990 ) Cell 61: 863 : 870 ; and Kerem , B -S . et al. ( 1989 ) membrane proteins that bind and use cellular adenosine Science 245 : 1073 - 1080 ; Kerem , B - S et al. ( 1990 ) Proc . triphosphate ( ATP ) for their specific activities. Some of 40 Natl .Acad . Sci. USA 87 :8447 -8451 ). To date, > 1000 disease these transporters were discovered as multidrug resistance causing mutations in the CF gene have been identified proteins ( like the MDR1- P glycoprotein , or the multidrug ( http : / /www . genet . sickkids .on . ca / cftr / ) . The most prevalent resistance protein , MRP1) , defending malignant cancer cells mutation is a deletion of phenylalanine at position 508 of the against chemotherapeutic agents . To date , 48 ABC Trans CFTR amino acid sequence , and is commonly referred to as porters have been identified and grouped into 7 families 45 AF508 -CFTR . This mutation occurs in approximately 70 % based on their sequence identity and function . of the cases of cystic fibrosis and is associated with a severe ABC transporters regulate a variety of important physi- disease . ological roles within the body and provide defense against The deletion of residue 508 in AF508 -CFTR prevents the harmful environmental compounds . Because of this , they nascent protein from folding correctly . This results in the represent important potential drug targets for the treatment 50 inability of the mutant protein to exit the ER , and traffic to of diseases associated with defects in the transporter , pre - the plasma membrane. As a result , the number of channels vention of drug transport out of the target cell , and inter - present in the membrane is far less than observed in cells vention in other diseases in which modulation of ABC expressing wild - type CFTR . In addition to impaired traf transporter activity may be beneficial . ficking , the mutation results in defective channel gating . One member of the ABC transporter family commonly 55 Together , the reduced number of channels in the membrane associated with disease is the CAMP / ATP -mediated anion and the defective gating lead to reduced anion transport channel , CFTR . CFTR is expressed in a variety of cells across epithelia leading to defective ion and fluid transport . types, including absorptive and secretory epithelia cells , ( Quinton , P . M . ( 1990 ) , FASEB J . 4 : 2709 - 2727 ) . Studies where it regulates anion flux across the membrane , as well have shown , however , that the reduced numbers of AF508 as the activity of other ion channels and proteins . In epithelia 60 CFTR in the membrane are functional , albeit less than cells , normal functioning of CFTR is critical for the main - wild - type CFTR . ( Dalemans et al . ( 1991 ) , Nature Lond . 354 : tenance of electrolyte transport throughout the body, includ - 526 - 528 ; Denning et al. , supra ; Pasyk and Foskett ( 1995 ) , J . ing respiratory and digestive tissue. CFTR is composed of Cell . Biochem . 270 : 12347 - 50 ) . In addition to AF508 approximately 1480 amino acids that encode a protein made CFTR , other disease causing mutations in CFTR that result up of a tandem repeat of transmembrane domains, each 65 in defective trafficking, synthesis , and / or channel gating containing six transmembrane helices and a nucleotide bind - could be up - or down - regulated to alter anion secretion and ing domain . The two transmembrane domains are linked by modify disease progression and /or severity . US 10 ,022 , 352 B2 Although CFTR transports a variety of molecules in membrane . As a result, insufficient amounts of the mature addition to anions, it is clear that this role ( the transport of protein are present at the plasma membrane and chloride anions ) represents one element in an important mechanism transport within epithelial tissues is significantly reduced . In of transporting ions and water across the epithelium . The fact , this cellular phenomenon of defective ER processing of other elements include the epithelial Na + channel, ENAC , 5 ABC transporters by the ER machinery has been shown to Na + / 2017 / K * co - transporter, Na * — K * - ATPase pump and be the underlying basis not only for CF disease , but for a the basolateral membrane K + channels , that are responsible wide range of other isolated and inherited diseases. The two for the uptake of chloride into the cell . These elements work together to achieve directional ways that the ER machinery can malfunction is either by loss transport across the epithelium via their selective expression 10 of coupling to ER export of the proteins leading to degra and localization within the cell . Chloride absorption takes dation , or by the ER accumulation of these defective) place by the coordinated activity of ENaC and CFTR present misfolded proteins [ Aridor M , et al. , Nature Med . , 5 ( 7 ) , pp on the apical membrane and the Nat - K + - ATPase pump and 745 - 751 ( 1999 ) ; Shastry , B . S . , et al. , Neurochem . Interna Cl - channels expressed on the basolateral surface of the cell. tional, 43 , pp 1 - 7 (2003 ) ; Rutishauser, J . , et al. , Swiss Med Secondary active transport of chloride from the luminal side 15 Wkly , 132, pp 211 -222 (2002 ) ; Morello , J Pet al. , TIPS , 21, leads to the accumulation of intracellular chloride, which pp . 466 -469 ( 2000 ) ; Bross P ., et al. , Human Mut. , 14 , pp . can then passively leave the cell via Cl- channels , resulting 186 - 198 ( 1999) ] . The diseases associated with the first class in a vectorial transport . Arrangement of Na+ /2C1 - / K + co of ER malfunction are Cystic fibrosis ( due to misfolded transporter, Na + K + -ATPase pump and the basolateral AF508 -CFTR as discussed above ) , Hereditary emphysema membrane K * channels on the basolateral surface and CFTR 20 (due to al -antitrypsin ; non Piz variants ) , Hereditary on the luminal side coordinate the secretion of chloride via hemochromatosis , Coagulation - Fibrinolysis deficiencies , CFTR on the luminal side. Because water is probably never such as Protein C deficiency, Type 1 hereditary angioedema, actively transported itself , its flow across epithelia depends Lipid processing deficiencies, such as Familial hypercho on tiny transepithelial osmotic gradients generated by the lesterolemia , Type 1 chylomicronemia , Abetalipoproteine bulk flow of sodium and chloride . 25 mia , Lysosomal storage diseases, such as l - cell disease In addition to Cystic Fibrosis , modulation of CFTR activ - Pseudo -Hurler , Mucopolysaccharidoses (due to Lysosomal ity may be beneficial for other diseases not directly caused processing enzymes ), Sandhoffray - Sachs (due to by mutations in CFTR , such as secretory diseases and other 1 -Hexosaminidase ), Crigler- Naijjar type II (due to UDP protein folding diseases mediated by CFTR . These include , glucuronyl- sialyc - transferase ), Polyendocrinopathy /Hyper but are not limited to , chronic obstructive pulmonary disease 30 insi (COPD ) , dry eye disease , and Sjögren ' s Syndrome. insulemia , Diabetes mellitus ( due to Insulin receptor ), Laron COPD is characterized by airflow limitation that is pro dwarfism ( due to Growth hormone receptor) , Myleoperoxi gressive and not fully reversible . The airflow limitation is dase deficiency, Primary hypoparathyroidism (due to Pre due to mucus hypersecretion , emphysema, and bronchiolitis . proparathyroid hormone ), Melanoma (due to Tyrosinase ) . Activators of mutant or wild - type CFTR offer a potential 355 The diseases associated with the latter class of ER malfunc treatment of mucus hypersecretion and impaired mucocili tion are Glycanosis CDG type 1 , Hereditary emphysema ary clearance that is common in COPD . Specifically . (due to al- Antitrypsin (Piz variant) , Congenital hyperthy increasing anion secretion across CFTR may facilitate fluid roidism , Osteogenesis imperfecta (due to Type I, II , IV transport into the airway surface liquid to hydrate the mucus procollagen ), Hereditary hypofibrinogenemia (due to and optimized periciliary fluid viscosity. This would lead to 40 Fibrinogen ) , ACT deficiency (due to al - Antichymotrypsin ) , enhanced mucociliary clearance and a reduction in the Diabetes insipidus (DI ) , Neurophyseal DI ( due to Vasopves symptoms associated with COPD . Dry eye disease is char- sin hormone /V2 - receptor) , Neprogenic DI (due to Aqua acterized by a decrease in tear aqueous production and porin II ), Charcot -Marie Tooth syndrome (due to Peripheral abnormal tear film lipid , protein and mucin profiles. There myelin protein 22 ) , Perlizaeus- Merzbacher disease, neuro are many causes of dry eye , some of which include age , 45 degenerative diseases such as Alzheimer ' s disease (due to Lasik eye surgery , arthritis , medications , chemical/ thermal BAPP and presenilins ) , Parkinson ' s disease , Amyotrophic burns, allergies , and diseases , such as Cystic Fibrosis and lateral sclerosis , Progressive supranuclear plasy , Pick ' s dis Sjögrens ' s syndrome. Increasing anion secretion via CFTR ease , several polyglutamine neurological disorders such as would enhance fluid transport from the corneal endothelial Huntington , Spinocerebullar ataxia type I , Spinal and bulbar cells and secretory glands surrounding the eye to increase 50 muscular atrophy, Dentatorubal pallidoluysian , and Myo corneal hydration . This would help to alleviate the symp - tonic dystrophy , as well as Spongiform encephalopathies , toms associated with dry eye disease . Sjögrens' s syndrome such as Hereditary Creutzfeldt- Jakob disease ( due to Prion is an autoimmune disease in which the immune system protein processing defect ) , Fabry disease (due to lysosomal attacks moisture -producing glands throughout the body, a - galactosidase A ) and Straussler- Scheinker syndrome (due including the eye , mouth , skin , respiratory tissue , liver, 55 to Prp processing defect) . vagina, and gut. Symptoms, include, dry eye , mouth , and In addition to up - regulation of CFTR activity , reducing vagina , as well as lung disease. The disease is also associ anion secretion by CFTR modulators may be beneficial for ated with rheumatoid arthritis , systemic lupus , systemic the treatment of secretory diarrheas , in which epithelial sclerosis , and polymypositis /dermatomyositis . Defective water transport is dramatically increased as a result of protein trafficking is believed to cause the disease , for which 60 secretagogue activated chloride transport . The mechanism treatment options are limited . Modulators of CFTR activity involves elevation of CAMP and stimulation of CFTR . may hydrate the various organs afflicted by the disease and Although there are numerous causes of diarrhea , the help to elevate the associated symptoms. major consequences of diarrheal diseases, resulting from As discussed above , it is believed that the deletion of excessive chloride transport are common to all , and include residue 508 in AF508 -CFTR prevents the nascent protein 65 dehydration , acidosis , impaired growth and death . from folding correctly , resulting in the inability of this Acute and chronic diarrheas represent a major medical mutant protein to exit the ER , and traffic to the plasma problem in many areas of the world . Diarrhea is both a US 10 , 022 , 352 B2 significant factor in malnutrition and the leading cause of or a pharmaceutically acceptable salt thereof, wherein R?, death (5 ,000 ,000 deaths/ year ) in children less than five years R2, ring A , ring B , and n are defined below . old . It has also now been found that compounds of this Secretory diarrheas are also a dangerous condition in invention , and pharmaceutically acceptable compositions patients of acquired immunodeficiency syndrome ( AIDS) 5 thereof , are useful as modulators of ABC transporter activ and chronic inflammatory bowel disease ( IBD ) . 16 million ity . These compounds have the general formula II : travelers to developing countries from industrialized nations every year develop diarrhea , with the severity and number of II cases of diarrhea varying depending on the country and area 10 of travel. Ri Ri Diarrhea in barn animals and pets such as cows, pigs and Ri Ri horses , sheep , goats , cats and dogs, also known as scours , is R3 a major cause of death in these animals . Diarrhea can result R from any major transition , such as weaning or physical 15 movement, as well as in response to a variety of bacterial or viral infections and generally occurs within the first few hours of the animal' s life . The most common diarrhea causing bacteria is entero toxogenic E - coli (ETEC ) having the K99 pilus antigen . 20 Common viral causes of diarrhea include rotavirus and or a pharmaceutically acceptable salt thereof, wherein R , R1, coronavirus. Other infectious agents include cryptospo - R2, R3 , R4, and R , are defined below . ridium , giardia lamblia , and salmonella , among others . These compounds and pharmaceutically acceptable com Symptoms of rotaviral infection include excretion of positions are useful for treating or lessening the severity of watery feces , dehydration and weakness . Coronavirus 25 a variety of diseases , disorders , or conditions, including , but causes a more severe illness in the newborn animals , and has not limited to , cystic fibrosis , hereditary emphysema, heredi a higher mortality rate than rotaviral infection . Often , how - tary hemochromatosis , coagulation - fibrinolysis deficiencies , ever, a young animal may be infected with more than one such as protein C deficiency , Type 1 hereditary angioedema, virus or with a combination of viral and bacterial microor - lipid processing deficiencies, such as familial hypercholes ganisms at one time. This dramatically increases the severity 30 terolemia , Type 1 chylomicronemia , abetalipoproteinemia, of the disease . lysosomal storage diseases , such as I -cell disease /pseudo Accordingly , there is a need for modulators of an ABC Hurler , mucopolysaccharidoses , Sandhof/ fay - Sachs, Cri transporter activity , and compositions thereof, that can be gler -Najjar type II, polyendocrinopathy /hyperinsulemia , used to modulate the activity of the ABC transporter in the diabetes mellitus, laron dwarfism , myleoperoxidase defi cell membrane of a mammal. 35 ciency , primary hypoparathyroidism , melanoma, glycanosis There is a need for methods of treating ABC transporter CDG type 1 , hereditary emphysema, congenital hyperthy mediated diseases using such modulators of ABC transporter roidism , osteogenesis imperfecta , hereditary hypofibrino activity . genemia , ACT deficiency, diabetes insipidus , neurophysiol, There is a need for methods of modulating an ABC nephrogenic , Charcot- Marie Tooth syndrome, Perlizaeus transporter activity in an ex vivo cell membranee 01of a 40 Merzbacher disease , neurodegenerative diseases such as mammal. Alzheimer ' s disease , Parkinson ' s disease , amyotrophic lat There is a need for modulators of CFTR activity that can eral sclerosis , progressive supranuclear plasy , Pick 's dis be used to modulate the activity of CFTR in the cell ease , several polyglutamine neurological disorders asuch as membrane of a mammal. Huntington , spinocerebullar ataxia type I , spinal and bulbar There is a need for methods of treating CFTR -mediated 4 45 muscularmin atrophy, dentatorubal pallidoluysian , and myo diseases using such modulators of CFTR activity . tonic dystrophy, as well as spongiform encephalopathies, There is a need formethods ofmodulating CFTR activity such as hereditary Creutzfeldt - Jakob disease, Fabry disease , in an ex vivo cell membrane of a mammal. Straussler -Scheinker syndrome, COPD , dry - eye disease , and Sjögren ' s disease . SUMMARY OF THE INVENTION 50 It has now been found that compounds of this invention , DETAILED DESCRIPTION OF THE and pharmaceutically acceptable compositions thereof, are INVENTION useful as modulators of ABC transporter activity , particu larly CTFR activity . These compounds have the general ss . I . Definitions formula I : As used herein , the following definitions shall apply unless otherwise indicated . The term “ ABC - transporter” as used herein means an ABC - transporter protein or a fragment thereof comprising at 60 least one binding domain , wherein said protein or fragment thereof is present in vivo or in vitro . The term “ binding E domain ” as used herein means a domain on the ABC n ( R ) transporter that can bind to a modulator. See , e . g ., Hwang , T . C . et al. , J . Gen . Physiol . ( 1998 ) : 111 ( 3 ) , 477 - 90 . 65 The term “ CFTR ” as used herein means cystic fibrosis transmembrane conductance regulator or a mutation thereof capable of regulator activity , including , but not limited to , US 10 , 022 , 352 B2 AF508 CFTR and G551D CFTR ( see , e. g . , http :/ / www .gen As used herein the term “ aliphatic ” encompasses the et. sickkids. on . ca /cftr / , for CFTR mutations) . terms alkyl, alkenyl, alkynyl, each of which being optionally The term “ modulating ” as used herein means increasing substituted as set forth below . or decreasing , e . g . activity , by a measurable amount. Com As used herein , an “ alkyl" group refers to a saturated pounds that modulate ABC Transporter activity , such as 5 aliphatic hydrocarbon group containing 1 - 12 ( e . g ., 1 - 8 , 1 - 6 , CFTR activity , by increasingsing the activityactivity ofof the ABC Trans - or 1 - 4 ) carbon atoms. An alkyl group can be straight or branched . Examples of alkyl groups include, but are not porter, e . g . , a CFTR anion channel , are called agonists . limited to , methyl, ethyl , propyl, isopropyl, butyl, isobutyl, Compounds that modulate ABC Transporter activity , such as sec - butyl, tert- butyl , n -pentyl , n -heptyl , or 2 - ethylhexyl. An CFTR activity, by decreasing the activity of the ABC 10 alkyl group can be substituted (i . e ., optionally substituted ) Transporter , e . g ., CFTR anion channel , are called antago with one or more substituents such as halo , phospho , cycloa nists . An agonist interacts with an ABC Transporter , such as liphatic [ e . g ., cycloalkyl or cycloalkenyl] , heterocycloali CFTR anion channel, to increase the ability of the receptor phatic [ e . g . , heterocycloalkyl or heterocycloalkenyl ], aryl, to transduce an intracellular signal in response to endog heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [ e . g . , ( aliphatic ) enous ligand binding. An antagonist interacts with an ABCC 15 carbonyl , (cycloaliphatic )carbonyl , or (heterocycloaliphatic ) Transporter, such as CFTR , and competes with the endog - carbonyl] , nitro , cyano , amido ?e. g . , ( cycloalkylalkyl) carbo enous ligand ( s ) or substrate ( s ) for binding site ( s ) on the nylamino , arylcarbonylamino , aralkylcarbonylamino , receptor to decrease the ability of the receptor to transduce (heterocycloalkyl ) carbonylamino , (heterocycloalkylalkyl ) an intracellular signal in response to endogenous ligand carbonylamino , heteroarylcarbonylamino , heteroaralkylcar binding . 20 bonylamino alkylaminocarbonyl , cycloalkylaminocarbonyl , The phrase “ treating or reducing the severity of an ABC heterocycloalkylaminocarbonyl , arylaminocarbonyl, or het Transporter mediated disease ” refers both to treatments for eroarylaminocarbonyl] , amino [ e . g . , aliphaticamino , cycloa diseases that are directly caused by ABC Transporter and /or liphaticamino , or heterocycloaliphaticamino ) , sulfonyl [ e. g. , CFTR activities and alleviation of symptoms of diseases not aliphatic - SO , – ], sulfinyl, sulfanyl, sulfoxy , urea , thiourea , directly caused by ABC Transporter and / or CFTR anion 25 sulfamoyl, sulfamide , oxo , carboxy , carbamoyl, cycloali channel activities. Examples of diseases whose symptoms phaticoxy , heterocycloaliphaticoxy , aryloxy , heteroaryloxy , may be affected by ABC Transporter and /or CFTR activity aralkyloxy , heteroarylalkoxy, alkoxycarbonyl, alkylcarbo nyloxy , or hydroxy . Without limitation , some examples of include, but are not limited to , Cystic fibrosis , Hereditary substituted alkyls include carboxyalkyl (such as HOOC emphysema, Hereditary hemochromatosis , Coagulation ve-Fi 30 alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl) , brinolysis deficiencies, such as Protein C deficiency, Type 1 30 cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, aralkyl, hereditary angioedema , Lipid processing deficiencies, such (alkoxyaryl ) alkyl, (sulfonylamino )alkyl (such as (alkyl as Familial hypercholesterolemia , Type 1 chylomicronemia , SO2- amino ) alkyl) , aminoalkyl, amidoalkyl, ( cycloaliphatic ) Abetalipoproteinemia , Lysosomal storage diseases , such as alkyl, or haloalkyl. I - cell disease/ Pseudo -Hurler , Mucopolysaccharidosesndoses , 235 As used herein , an " alkenyl” group refers to an aliphatic Sandhof / Tay - Sachs , Crigler -Najjar type IL Polyendocrin carbon group that contains 2 - 8 ( e . g ., 2 - 12 , 2 -6 , or 2 - 4 ) opathy /Hyperinsulemia , Diabetes mellitus, Laron dwarfism , carbon atoms and at least one double bond . Like an alkyl Myleoperoxidase deficiency , Primary hypoparathyroidism , group , an alkenyl group can be straight or branched . Melanoma, Glycanosis CDG type 1, Hereditary emphy - Examples of an alkenyl group include , but are not limited to sema, Congenital hyperthyroidism , Osteogenesis imper - 40 allyl, isoprenyl, 2 -butenyl , and 2 -hexenyl . An alkenyl group fecta , Hereditary hypofibrinogenemia , ACT deficiency, Dia can be optionally substituted with one or more substituents betes insipidus (DI ) , Neurophysiol DI, Nephrogenic DI, such as halo , phospho , cycloaliphatic [e .g ., cycloalkyl or Charcot- Marie Tooth syndrome , Perlizaeus- Merzbacher dis cycloalkenyl] , heterocycloaliphatic [ e . g . , heterocycloalkyl ease, neurodegenerative diseases such as Alzheimer 's dis or heterocycloalkenyl ], aryl, heteroaryl, alkoxy, aroyl, het ease , Parkinson ' s disease , Amyotrophic lateral sclerosis , 45 eroaroyl, acyl [ e . g . , (aliphatic ) carbonyl, ( cycloaliphatic ) car Progressive supranuclear plasy, Pick ' s disease , several poly - bonyl, or (heterocycloaliphatic )carbonyl ] , nitro , cyano , glutamine neurological disorders such as Huntington , Spi- amido [ e . g . , (cycloalkylalkyl carbonylamino , arylcarbo nocerebullar ataxia type I, Spinal and bulbar muscular nylamino , aralkylcarbonylamino , (heterocycloalkyl ) carbo atrophy, Dentatorubal pallidoluysian , and Myotonic dystro nylamino , (heterocycloalkylalkyl ) carbonylamino , het phy, as well as Spongiform encephalopathies, such as 50 eroarylcarbonylamino , heteroaralkylcarbonylamino Hereditary Creutzfeldt- Jakob disease , Fabry disease , alkylaminocarbonyl , cycloalkylaminocarbonyl, heterocy Straussler - Scheinker syndrome, COPD , dry -eye disease, and cloalkylaminocarbonyl, arylaminocarbonyl, or heteroary Sjögren ' s disease . laminocarbonyl ], amino [ e. g ., aliphaticamino , cycloaliphati For purposes of this invention , the chemical elements are camino , heterocycloaliphaticamino , identified in accordance with the Periodic Table of the 55 aliphaticsulfonylamino ) , sulfonyl [ e . g ., alkyl- S02 — , Elements , CAS version , Handbook of Chemistry and Phys cycloaliphatic - S02 — , or aryl- S02 – ), sulfinyl, sulfanyl, ics , 75th Ed . Additionally, general principles of organic sulfoxy , urea , thiourea , sulfamoyl, sulfamide, oxo , carboxy , chemistry are described in “ Organic Chemistry ” , Thomas carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy, ary Sorrell , University Science Books , Sausolito : 1999 , and loxy , heteroaryloxy , aralkyloxy , heteroaralkoxy , alkoxycar “ March ' s Advanced Organic Chemistry ” , 5th Ed ., Ed. : 60 bonyl, alkylcarbonyloxy, or hydroxy . Without limitation , Smith , M . B . and March , J. , John Wiley & Sons, New York : some examples of substituted alkenyls include cyanoalk 2001, the entire contents of which are hereby incorporated enyl, alkoxyalkenyl, acylalkenyl, hydroxyalkenyl, aralk by reference . enyl, ( alkoxyaryl) alkenyl, ( sulfonylamino ) alkenyl (such as As described herein , compounds of the invention may (alkyl - S0 , - amino Jalkenyl) , aminoalkenyl, amidoalkenyl, optionally be substituted with one or more substituents , such 65 (cycloaliphatic )alkenyl , or haloalkenyl. as are illustrated generally above , or as exemplified by As used herein , an " alkynyl" group refers to an aliphatic particular classes , subclasses, and species of the invention . carbon group that contains 2 -8 (e . g. , 2 -12 , 2 -6 , or 2 -4 ) US 10 ,022 , 352 B2 10 carbon atoms and has at least one triple bond . An alkynyl carbocyclic ring of a benzofused bicyclic or tricyclic aryl) ; group can be straight or branched . Examples of an alkynyl nitro ; carboxy , amido ; acyl [ e . g . , ( aliphatic ) carbonyl ; (cy group include, but are not limited to , propargyl and butynyl. cloaliphatic )carbonyl ; (( cycloaliphatic ) aliphatic ) carbonyl ; An alkynyl group can be optionally substituted with one or (araliphatic ) carbonyl; (heterocycloaliphatic ) carbonyl; ( het more substituents such as aroyl, heteroaroyl, alkoxy, 5 erocycloaliphatic Jaliphatic )carbonyl ; or (heteroaraliphatic ) cycloalkyloxy , heterocycloalkyloxy , aryloxy , heteroaryloxy , carbonyl ]; sulfonyl ?e . g ., aliphatic - SO , — or amino -S0 , 41; aralkyloxy, nitro , carboxy , cyano , halo , hydroxy , sulfo ,mer sulfinyl [ e .g ., aliphatic - S ( O ) or cycloaliphatic - S ( O ) _ ] ; capto , sulfanyl [e .g . , aliphaticsulfanyl or cycloaliphaticsul- sulfanyl [ e. g ., aliphatic - S — ]; cyano ; halo ; hydroxy ; mer fanyl] , sulfinyl [ e . g . , aliphaticsulfinyl or cycloaliphaticsulfi - capto ; sulfoxy ; urea ; thiourea ; sulfamoyl; sulfamide; or nyl ], sulfonyl [ e . g . , aliphatic -SO2 - , aliphaticamino - S02 , 10 carbamoyl. Alternatively , an aryl can be unsubstituted . or cycloaliphatic -S02 – ) , amido [ e . g ., aminocarbonyl, alky - Non - limiting examples of substituted aryls include laminocarbonyl, alkylcarbonylamino , cycloalkylaminocar haloaryl [ e . g. , mono -, di ( such as p , m - dihaloaryl ), and bonyl, heterocycloalkylaminocarbonyl, cycloalkylcarbo - ( trihalo ) aryl] ; (carboxy ) aryl [ e . g ., alkoxycarbonyl) aryl , nylamino , arylaminocarbonyl, arylcarbonylamino , (( aralkyl) carbonyloxy ) aryl, and (alkoxycarbonyl ) aryl ] ; aralkylcarbonylamino , (heterocycloalkyl ) carbonylamino , 15 (amido ) aryl [e . g. , (aminocarbonyl )aryl , (( ( alkylamino ) alkyl) ( cycloalkylalkyl) carbonylamino , heteroaralkylcarbo - aminocarbonyl ) aryl, ( alkylcarbonyl) aminoaryl, Carylamin nylamino , heteroarylcarbonylamino or heteroarylaminocar - ocarbonyl) aryl , and ( (( heteroaryl ) amino ) carbonyl) aryl ]; bonyl] , urea , thiourea, sulfamoyl, sulfamide, alkoxycarbo - aminoaryl [e . g. , ( (alkylsulfonyl )amino )aryl or ( (dialkyl ) am nyl, alkylcarbonyloxy , cycloaliphatic , heterocycloaliphatic , ino )aryl ]; (cyanoalkyl ) aryl ; ( alkoxy ) aryl; (sulfamoyl ) aryl aryl, heteroaryl, acyl [ e. g ., (cycloaliphatic )carbonyl or (het - 20 [e .g ., (aminosulfonyl ) aryl ] ; (alkylsulfonyl ) aryl ; ( cyano )aryl ; erocycloaliphatic )carbonyl ] , amino [ e . g ., aliphaticamino ], (hydroxyalkyl ) aryl; ( alkoxy )alkyl ) aryl; (hydroxy ) aryl, sulfoxy, oxo , carboxy , carbamoyl, (cycloaliphatic ) oxy, (het - (( carboxy ) alkyl ) aryl; ( ( ( dialkyl) amino ) alkyl ) aryl; ( ni erocycloaliphatic ) oxy , or (heteroaryl ) alkoxy . troalkyl) aryl; ( ( ( alkylsulfonyl) amino ) alkyl) aryl; ( (heterocy As used herein , an “ amido ” encompasses both “ aminocar - cloaliphatic )carbonyl )aryl ; ( (alkylsulfonyl ) alkyl) aryl ; (cya bonyl ” and “ carbonylamino " . These terms when used alone 25 noalkyl) aryl ; (hydroxyalkyl ) aryl; (alkylcarbonyl ) aryl; or in connection with another group refer to an amido group alkylaryl; ( trihaloalkyl ) aryl; p - amino - m - alkoxycarbo such as — N (R ) C ( 0 ) R ' or C ( O ) - N ( R ) 2, when nylaryl ; p - amino -m - cyanoaryl ; p -halo - m -aminoaryl ; or (m used terminally , and C ( O ) - N ( R ) or — N ( R ) (heterocycloaliphatic ) - o - ( alkyl) ) aryl. (0 ) — when used internally , wherein R * and R ' are defined As used herein , an " araliphatic ” such as an “ aralkyl” below . Examples of amido groups include alkylamido ( such 30 group refers to an aliphatic group ( e . g ., a C1- 4 alkyl group ) as alkylcarbonylamino or alkylaminocarbonyl) , (heterocy - that is substituted with an aryl group . “ Aliphatic , ” “ alkyl, ” cloaliphatic Jamido , (heteroaralkyl ) amido , (heteroaryl ) and " aryl ” are defined herein . An example of an araliphatic amido , (heterocycloalkyl ) alkylamido , arylamido , aralky - such as an aralkyl group is benzyl . lamido , ( cycloalkyl) alkylamido , or cycloalkylamido . As used herein , an “ aralkyl” group refers to an alkyl group As used herein , an “ amino " group refers to — NR ' R ' 35 (e .g ., a C1- 4 alkyl group ) that is substituted with an aryl wherein each of R and R ' is independently hydrogen , group . Both “ alkyl” and “ aryl ” have been defined above. An aliphatic , cycloaliphatic , ( cycloaliphatic ) aliphatic , aryl, ara example of an aralkyl group is benzyl. An aralkyl is option liphatic , heterocycloaliphatic , (heterocycloaliphatic ) ali ally substituted with one or more substituents such as phatic , heteroaryl, carboxy, sulfanyl, sulfinyl, sulfonyl, ( ali aliphatic [ e . g . , alkyl, alkenyl, or alkynyl, including carboxy phatic )carbonyl , ( cycloaliphatic )carbonyl , ( (cycloaliphatic ) 40 alkyl , hydroxyalkyl , or haloalkyl such as trifluoromethyl] , aliphatic ) carbonyl, arylcarbonyl, ( araliphatic )carbonyl , cycloaliphatic [ e . g ., cycloalkyl or cycloalkenyl ], ( cycloalky ( heterocycloaliphatic )carbonyl , ( heterocycloaliphatic )ali - l ) alkyl , heterocycloalkyl , (heterocycloalkyl ) alkyl, aryl, het phatic )carbonyl , ( heteroaryl) carbonyl, or (heteroaraliphatic ) eroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, ary carbonyl, each of which being defined herein and being loxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy , aroyl, optionally substituted . Examples of amino groups include 45 heteroaroyl, nitro , carboxy , alkoxycarbonyl, alkylcarbony alkylamino , dialkylamino , or arylamino . When the term loxy, amido [ e . g ., aminocarbonyl, alkylcarbonylamino , “ amino ” is not the terminal group ( e . g ., alkylcarbo cycloalkylcarbonylamino , ( cycloalkylalkyl) carbonylamino , nylamino ), it is represented by — NR . R has the same arylcarbonylamino , aralkylcarbonylamino , (heterocy meaning as defined above . cloalkyl) carbonylamino , (heterocycloalkylalkyl ) carbo As used herein , an “ aryl” group used alone or as part of 50 nylamino , heteroarylcarbonylamino , or heteroaralkylcarbo a larger moiety as in “ aralkyl” , “ aralkoxy " , or “ aryloxy - nylamino ), cyano , halo , hydroxy , acyl, mercapto , alkyl” refers to monocyclic ( e .g ., phenyl) ; bicyclic ( e. g ., alkylsulfanyl, sulfoxy, urea, thiourea , sulfamoyl, sulfamide, indenyl, naphthalenyl , tetrahydronaphthyl, tetrahydroinde - oxo , or carbamoyl. nyl) ; and tricyclic ( e . g . , fluorenyl tetrahydrofluorenyl, or As used herein , a " bicyclic ring system ” includes 8 - 12 tetrahydroanthracenyl, anthracenyl) ring systems in which 55 ( e . g ., 9 , 10 , or 11 ) membered structures that form two rings, the monocyclic ring system is aromatic or at least one of the wherein the two rings have at least one atom in common rings in a bicyclic or tricyclic ring system is aromatic . The ( e . g ., 2 atoms in common ) . Bicyclic ring systems include bicyclic and tricyclic groups include benzofused 2 -3 mem - bicycloaliphatics (e . g. , bicycloalkyl or bicycloalkenyl) , bered carbocyclic rings . For example , a benzofused group bicycloheteroaliphatics , bicyclic aryls , and bicyclic het includes phenyl fused with two or more C4- 8 carbocyclic 60 eroaryls . moieties. An aryl is optionally substituted with one or more As used herein , a " carbocycle ” or “ cycloaliphatic ” group substituents including aliphatic [ e . g . , alkyl, alkenyl, or alky - encompasses a “ cycloalkyl” group and a “ cycloalkenyl” nyl] ; cycloaliphatic ; (cycloaliphatic ) aliphatic ; heterocycloa group , each of which being optionally substituted as set forth liphatic ; (heterocycloaliphatic )aliphatic ; aryl; heteroaryl; below . alkoxy ; ( cycloaliphatic )oxy , (heterocycloaliphatic )oxy ; ary - 65 As used herein , a “ cycloalkyl” group refers to a saturated loxy ; heteroaryloxy ; ( araliphatic ) oxy ; ( heteroaraliphatic ) carbocyclic mono - or bicyclic ( fused or bridged ) ring of oxy aroyl; heteroaroyl; amino ; oxo ( on a non - aromatic 3 - 10 ( e . g . , 5 - 10 ) carbon atoms. Examples of cycloalkyl US 10 , 022 , 352 B2 11 12 groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclo (heterocycloaliphatic ) aliphatic , aryl, heteroaryl , alkoxy, ( cy hexyl, cycloheptyl, adamantyl, norbornyl, cubyl , octahydro cloaliphatic ) oxy, (heterocycloaliphatic ) oxy, aryloxy, het indenyl, decahydro -naphthyl , bicyclo [ 3 . 2 . 1 ] octyl, bicyclo eroaryloxy, ( araliphatic ) oxy, (heteroaraliphatic )oxy , aroyl , [ 2 .2 .2 ]octyl , bicyclo [ 3 . 3 .1 ]nonyl , bicyclo [ 3 .3 .2 . ]decyl , heteroaroyl, amino , amido [ e. g ., (aliphatic )carbonylamino , bicyclo [ 2 .2 . 2 ] octyl, adamantyl, or (( aminocarbonyl) cy - 5 (cycloaliphatic ) carbonylamino , ( ( cycloaliphatic ) aliphatic ) cloalkyl )cycloalkyl . carbonylamino , (aryl ) carbonylamino , ( araliphatic ) carbo A " cycloalkenyl” group , as used herein , refers to a non - nylamino , (heterocycloaliphatic )carbonylamino , (( heterocy aromatic carbocyclic ring of 3 - 10 ( e. g ., 4 -8 ) carbon atoms cloaliphatic ) aliphatic )carbonylamino , (heteroaryl ) having one or more double bonds. Examples of cycloalkenyl carbonylamino , or (heteroaraliphatic ) carbonylamino ) , nitro , groups include cyclopentenyl, 1, 4 -cyclohbexa -di - enyl, 10 carboxy [ e. g ., HOOC — , alkoxycarbonyl, or alkylcarbony cycloheptenyl, cyclooctenyl, hexahydro - indenyl, octahydro - loxy ) , acyl ?e .g . , (cycloaliphatic )carbonyl , (( cycloaliphatic ) naphthyl, cyclohexenyl, cyclopentenyl, bicyclo [ 2 . 2 . 2 ] octe aliphatic ) carbonyl, ( araliphatic ) carbonyl , (heterocycloali nyl, or bicyclo [ 3 . 3 . 1 ]nonenyl . phatic ) carbonyl, ( heterocycloaliphatic ) aliphatic ) carbonyl, A cycloalkyl or cycloalkenyl group can be optionally or (heteroaraliphatic )carbonyl ] , nitro , cyano , halo , hydroxy , substituted with one or more substituents such as phosphor, 15 mercapto , sulfonyl [e . g. , alkylsulfonyl or arylsulfonyl] , aliphatic [ e . g ., alkyl , alkenyl, or alkynyl ], cycloaliphatic , sulfinyl [ e . g . , alkylsulfinyl] , sulfanyl [ e . g ., alkylsulfanyl] , ( cycloaliphatic ) aliphatic , heterocycloaliphatic , (heterocy - sulfoxy , urea, thiourea , sulfamoyl, sulfamide , oxo , or car cloaliphatic ) aliphatic , aryl, heteroaryl, alkoxy, ( cycloalipha - bamoyl. tic )oxy , (heterocycloaliphatic )oxy , aryloxy, heteroaryloxy, A “ heteroaryl” group , as used herein , refers to a mono (araliphatic )oxy , (heteroaraliphatic )oxy , aroyl, heteroaroyl, 20 cyclic , bicyclic , or tricyclic ring system having 4 to 15 ring amino , amido [ e . g . , ( aliphatic ) carbonylamino , ( cycloaliphat atomswherein one ormore of the ring atoms is a heteroatom ic ) carbonylamino , (( cycloaliphatic ) aliphatic ) carbo - (e . g . , N , O , S , or combinations thereof) and in which the nylamino , Caryl )carbonylamino , (araliphatic )carbo monocyclic ring system is aromatic or at least one of the nylamino , (heterocycloaliphatic ) carbonylamino , rings in the bicyclic or tricyclic ring systems is aromatic . A ( (heterocycloaliphatic )aliphatic )carbonylamino , (het - 25 heteroaryl group includes a benzofused ring system having eroaryl) carbonylamino , or (heteroaraliphatic ) carbo - 2 to 3 rings. For example , a benzofused group includes nylamino ) , nitro , carboxy ( e . g ., HOOC — , alkoxycarbonyl, benzo fused with one or two 4 to 8 membered heterocy or alkylcarbonyloxy ], acyl [e .g . , (cycloaliphatic )carbonyl , cloaliphatic moieties ( e. g ., indolizyl , indolyl, isoindolyl, ( ( cycloaliphatic ) aliphatic ) carbonyl, ( araliphatic )carbonyl , 3H - indolyl, indolinyl , benzo [ b ] furyl, benzo [ b ]thiophenyl , (heterocycloaliphatic ) carbonyl, ( (heterocycloaliphatic ) ali - 30 quinolinyl, or isoquinolinyl) . Some examples of heteroaryl phatic ) carbonyl, or (heteroaraliphatic ) carbonyl] , cyano , are azetidinyl, pyridyl, 1H - indazolyl, furyl, pyrrolyl, thienyl, halo , hydroxy , mercapto , sulfonyl [ e. g ., alkyl- SO2 - and thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, iso aryl- S02 — ], sulfinyl [ e . g ., alkyl- S ( 0 ) ], sulfanyl [ e . g ., quinolinyl , benzthiazolyl, xanthene, thioxanthene, phenothi alkyl- 5 - ], sulfoxy, urea , thiourea, sulfamoyl, sulfamide , oxo , azine , dihydroindole , benzo [ 1 , 3 ] dioxole , benzo [ b ] furyl, or carbamoyl. 35 benzo [ b ] thiophenyl, indazolyl, benzimidazolyl , benzthiaz As used herein , the term " heterocycle ” or “ heterocycloa olyl , puryl , cinnolyl, quinolyl , quinazolyl , cinnolyl, phthala liphatic ” encompasses a heterocycloalkyl group and a het zyl , quinazolyl, quinoxalyl, isoquinolyl, 4H - quinolizyl, erocycloalkenyl group , each of which being optionally sub - benzo - 1 , 2 , 5 - thiadiazolyl, or 1 , 8 - naphthyridyl . stituted as set forth below . Without limitation , monocyclic heteroaryls include furyl, As used herein , a “ heterocycloalkyl” group refers to a 40 thiophenyl, 2H -pyrrolyl , pyrrolyl, oxazolyl, thazolyl, imi 3 - 10 membered mono - or bicylic (fused or bridged ) ( e . g . , 5 - dazolyl, pyrazolyl, isoxazolyl, isothiazolyl , 1 ,3 , 4 - thiadiaz to 10 -membered mono - or bicyclic ) saturated ring structure , olyl, 2H - pyranyl, 4 - H - pranyl, pyridyl , pyridazyl, pyrimidyl , in which one or more of the ring atoms is a heteroatom ( e . g ., pyrazolyl, pyrazyl, or 1 , 3 , 5 - triazyl. Monocyclic heteroaryls N , O , S , or combinations thereof) . Examples of a heterocy - are numbered according to standard chemical nomenclature . cloalkyl group include piperidyl, piperazyl, tetrahydropyra - 45 Without limitation , bicyclic heteroaryls include indolizyl, nyl, tetrahydrofuryl, 1 ,4 -dioxolanyl , 1 , 4 - dithianyl, 1 , 3 - di- indolyl , isoindolyl , 3H - indolyl , indolinyl , benzo [ b ] furyl , oxolanyl, oxazolidyl, isoxazolidyl, morpholinyl , benzo [ b ] thiophenyl, quinolinyl, isoquinolinyl, indolizinyl , thiomorpholyl, octahydrobenzofuryl, octahydrochromenyl, isoindolyl, indolyl, benzo [b ] furyl, bexo [b ] thiophenyl, inda octahydrothiochromenyl, octahydroindolyl, octahydropy - zolyl , benzimidazyl, benzthiazolyl, purinyl , 4H - quinolizyl , rindinyl, decahydroquinolinyl , octahydrobenzo [b ] thio - 50 quinolyl, isoquinolyl, cinnolyl, phthalazyl, quinazolyl, qui pheneyl, 2 -oxa -bicyclo [ 2 . 2. 2 ]octyl , 1 -aza -bicyclo [ 2. 2 .2 ]oc - noxalyl, 1, 8 -naphthyridyl , or pteridyl. Bicyclic heteroaryls tyl , 3 - aza -bicyclo [ 3 . 2 . 1 ] octyl, and 2 , 6 - dioxa- tricyclo a re numbered according to standard chemical nomenclature . [3 . 3 . 1. 09. ? ]nonyl . A monocyclic heterocycloalkyl group can heteroaryl is optionally substituted with one or more be fused with a phenyl moiety to form structures, such as substituents such as aliphatic [ e. g ., alkyl, alkenyl, or alky tetrahydroisoquinoline, which would be categorized as het - 55 nyl ]; cycloaliphatic ; (cycloaliphatic )aliphatic ; heterocycloa eroaryls . liphatic ; (heterocycloaliphatic )aliphatic ; aryl; heteroaryl; A “ heterocycloalkenyl” group , as used herein , refers to a alkoxy, ( cycloaliphatic ) oxy ; ( heterocycloaliphatic ) oxy ; ary mono - or bicylic ( e . g . , 5 - to 10 -membered mono - or bicy - loxy ; heteroaryloxy ; (araliphatic ) oxy ; (heteroaraliphatic ) clic ) non - aromatic ring structure having one or more double oxy ; aroyl; heteroaroyl; amino ; oxo ( on a non - aromatic bonds , and wherein one or more of the ring atoms is a 60 carbocyclic or heterocyclic ring of a bicyclic or tricyclic heteroatom ( e . g ., N , O , or S ) . Monocyclic and bicyclic heteroaryl) ; carboxy ; amido ; acyl [ e . g ., aliphaticcarbonyl; heterocycloaliphatics are numbered according to standard (cycloaliphatic )carbonyl ; ( (cycloaliphatic ) aliphatic ) carbo chemical nomenclature . nyl; ( araliphatic )carbonyl ; (heterocycloaliphatic ) carbonyl; A heterocycloalkyl or heterocycloalkenyl group can be (( heterocycloaliphatic )aliphatic )carbonyl ; or (heteroarali optionally substituted with one ormore substituents such as 65 phatic )carbonyl ] ; sulfonyl [ e .g ., aliphaticsulfonyl or amino phosphor , aliphatic [ e . g . , alkyl, alkenyl, or alkynyl ], cycloa - sulfonyl ] ; sulfinyl [ e . g ., aliphaticsulfinyl ]; sulfanyl [ e . g . , liphatic , ( cycloaliphatic ) aliphatic , heterocycloaliphatic , aliphaticsulfanyl] ; nitro ; cyano ; halo ; hydroxy ; mercapto ; US 10 ,022 , 352 B2 13 14 sulfoxy ; urea ; thiourea ; sulfamoyl; sulfamide ; or carbamoyl. nylamino , aralkylcarbonylamino , (heterocycloalkyl ) Alternatively , a heteroaryl can be unsubstituted . carbonylamino , (heterocycloalkylalkyl ) carbonylamino , Non - limiting examples of substituted heteroaryls include heteroarylcarbonylamino , heteroaralkylcarbonylamino , (halo )heteroaryl [ e . g . , mono - and di- (halo )heteroaryl ] ; (car cyano, halo , hydroxy , acyl, mercapto , alkylsulfanyl, sulfoxy , boxy )heteroaryl [ e . g . , (alkoxycarbonyl )heteroaryl ] ; cyano - 5 urea , thiourea , sulfamoyl, sulfamide , oxo , or carbamoyl . heteroaryl; aminoheteroaryl [ e . g . , ( alkylsulfonyl) amino ) As used herein , an “ acyl” group refers to a formyl group heteroaryland ( (dialkyl ) amino )heteroaryl ] ; (amido ) heteroaryl [ e . g . , aminocarbonyl) heteroaryl, ( (alkylcarbonyl ) or R * _ C ( O ) - ( such as alkyl - C ( O ) - , also referred to as amino )heteroaryl , ( (( ( alkyl) amino )alkyl ) aminocarbonyl fpony ) “ alkylcarbonyl” ) where R * and " alkyl” have been defined heteroaryl, ( (( heteroaryl) amino )carbonyl ) heteroaryl , 10 previously . Acetyl and pivaloyl are examples of acyl groups . ( (heterocycloaliphatic ) carbonyl) heteroaryl , and ( (alkylcar As used herein , an “ aroyl” or “ heteroaroyl” refers to an bonyl) amino )heteroaryl ] ; (cyanoalkyl ) heteroaryl; (alkoxy ) aryl- C (O ) - or a heteroaryl- C ( O ) — . The aryl and heteroaryl heteroaryl; ( sulfamoyl) heteroaryl [e .g . , ( aminosulfonyl )het portion of the aroyl or heteroaroyl is optionally substituted eroaryl] ; (sulfonyl ) heteroaryl [e . g ., (alkylsulfonyl ) as previously defined . heteroarv11 : ( hydroxyalkylheteroaryl: (alkoxvalköl 15 As used herein , an “ alkoxy ” group refers to an alkyl- 0 heteroaryl: ( hydroxy ) heteroaryl: ( ( carboxylalkyl heteroarvi: group where “ alkyl” has been defined previously . ( ( (dialkyl ) amino Jalkyl] heteroaryl ; ( heterocycloaliphatic ) As used herein , a " carbamoyl” group refers to a group heteroaryl; (cycloaliphatic )heteroaryl ; (nitroalkyl ) het - having the structure - O CO - NR R or — NR _ C0 — eroaryl; (( ( alkylsulfonyl) amino Jalkyl) heteroaryl ; (( alkylsul- O - R , wherein R * and R have been defined above and R ? fonyl) alkyl ) heteroaryl ; (cyanoalkyl ) heteroaryl; (acyl ) 20 can be aliphatic, aryl, araliphatic , heterocycloaliphatic , het heteroaryl [ e .g ., (alkylcarbonyl ) heteroaryl ] ; (alkyl ) eroaryl, or heteroaraliphatic . heteroaryl , and (haloalkyl ) heteroaryl [ e . g ., As used herein , a “ carboxy ” group refers to COOH , trihaloalkylbheteroaryl] . COOR " , - OC ( O ) H , OC ( O ) R " , when used as a termi A “ heteroaraliphatic ” ( such as a heteroaralkyl group ) as nal group ; or — OC (O ) - or - C (O )O when used as an used herein , refers to an aliphatic group ( e . g . , a C1- 4 alkyl 25 internal group . group ) that is substituted with a heteroaryl group . “ Ali - As used herein , a " haloaliphatic ” group refers to an phatic ,” “ alkyl ," and " heteroaryl” have been defined above. aliphatic group substituted with 1 - 3 halogen . For instance , A “ heteroaralkyl” group , as used herein , refers to an alkyl the term haloalkyl includes the group _ CF3. group ( e . g ., a C - 4 alkyl group ) that is substituted with a As used herein , a " mercapto " group refers to — SH . heteroaryl group . Both “ alkyl ” and “ heteroaryl” have been 30 As used herein , a " sulfo " group refers to — SO H or defined above . A heteroaralkyl is optionally substituted with SO3R * when used terminally or - S ( O ) 3 — when used one or more substituents such as alkyl ( including carboxy - internally . alkyl, hydroxyalkyl , and haloalkyl such as trifluoromethyl) , As used herein , a " sulfamide” group refers to the structure alkenyl , alkynyl , cycloalkyl, (cycloalkyl ) alkyl , heterocy . - NRX - S ( O ) 2- NR 'R ? when used terminally and — NR * — cloalkyl , (heterocycloalkyl ) alkyl, aryl, heteroaryl, alkoxy, 35 S ( O )2 - NRY — when used internally , wherein RT, R ', and cycloalkyloxy, heterocycloalkyloxy, aryloxy , heteroaryloxy, R2 have been defined above. aralkyloxy, heteroaralkyloxy , aroyl, heteroaroyl , nitro , car As used herein , a " sulfonamide ” group refers to the boxy , alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, structure - S (O )2 - NR ' R ' or NRX _ S ( O )2 - R2 when alkylcarbonylamino , cycloalkylcarbonylamino , (cycloalky - used terminally ; or - S (O )2 - NR — or - NR S (O )2 lalkyl) carbonylamino , arylcarbonylamino , aralkylcarbo - 40 when used internally , wherein R , R " , and R2 are defined nylamino , (heterocycloalkyl ) carbonylamino , (heterocy - above . cloalkylalkyl) carbonylamino , heteroarylcarbonylamino , As used herein a " sulfanyl” group refers to - S R * when heteroaralkylcarbonylamino , cyano , halo , hydroxy, acyl, used terminally and S — when used internally , wherein R * mercapto , alkylsulfanyl, sulfoxy , urea , thiourea , sulfamoyl, has been defined above. Examples of sulfanyls include sulfamide , oxo , or carbamoyl. 45 aliphatic - S — , cycloaliphatic - s , aryl - S — , or the like . As used herein , " cyclic moiety " and " cyclic group” refer As used herein a " sulfinyl ” group refers to S ( 0 ) R * to mono - , bi- , and tri- cyclic ring systems including cycloa - when used terminally and S ( 0 ) - when used internally, liphatic , heterocycloaliphatic , aryl, or heteroaryl, each of wherein R * has been defined above . Exemplary sulfinyl which has been previously defined . groups include aliphatic - S (O ) - , aryl- S ( O ) - , (cycloali As used herein , a “ bridged bicyclic ring system ” refers to 50 phatic ( aliphatic ) ) - S ( O ) - , cycloalkyl- S ( O ) - , heterocycloa a bicyclic heterocyclicaliphatic ring system or bicyclic liphatic - S ( O ) - , heteroaryl- S ( O ) - , or the like . cycloaliphatic ring system in which the rings are bridged . As used herein , a " sulfonyl” group refers to S ( O )2 - R * Examples of bridged bicyclic ring systems include , but are when used terminally and - S (O )2 — when used internally , not limited to, adamantanyl, norbornanyl, bicyclo [3 .2 . 1 ] wherein RX has been defined above . Exemplary sulfonyl octyl, bicyclo [ 2 . 2 . 2 ] octyl, bicyclo [ 3 . 3 . 1 ] nonyl, bicyclo 55 groups include aliphatic - S ( O ) 2 - , aryl- S ( O ) 2 - , ( cycloali [ 3. 2 .3 ]nonyl , 2 -oxabicyclo [ 2 .2 .2 ]octyl , 1 -azabicyclo [2 .2 . 2 ] phatic (aliphatic )) -S ( O ) 2 - , cycloaliphatic - S ( O ) 2 - , hetero octyl , 3 - azabicyclo [ 3 . 2 . 1 ] octyl , and 2 ,6 - dioxa -tricyclo cycloaliphatic - S ( O ) 2 - , heteroaryl- S ( O ) 2 - , ( cycloaliphatic [ 3 . 3 . 1 . 03. ]nonyl . A bridged bicyclic ring system can be ( amido ( aliphatic ) ) ) - S ( O ) 2 - or the like. optionally substituted with one or more substituents such as As used herein , a “ sulfoxy " group refers to O - SO alkyl ( including carboxyalkyl, hydroxyalkyl, and haloalkyl 60 R $ or S0 – 0 - R®, when used terminally and — O - S such as trifluoromethyl) , alkenyl, alkynyl , cycloalkyl, ( cy - ( 0 ) - or - S ( O ) 0 when used internally , where R has cloalkyl alkyl, heterocycloalkyl , (heterocycloalkyl alkyl, been defined above . aryl , heteroaryl , alkoxy , cycloalkyloxy , heterocycloalky - As used herein , a “ halogen ” or “ halo ” group refers to loxy , aryloxy , heteroaryloxy , aralkyloxy , heteroaralkyloxy, fluorine , chlorine , bromine or iodine . aroyl , heteroaroyl, nitro , carboxy, alkoxycarbonyl, alkylcar- 65 As used herein , an “ alkoxycarbonyl, ” which is encom bonyloxy , aminocarbonyl, alkylcarbonylamino , cycloalkyl- passed by the term carboxy , used alone or in connection with carbonylamino , (cycloalkylalkyl ) carbonylamino , arylcarbo - another group refers to a group such as alkyl- 0 _ C (O ) . US 10 ,022 , 352 B2 15 As used herein , an " alkoxyalkyl” refers to an alkyl group herein . Each substituent of a specific group is further option such as alkyl - O - alkyl- , wherein alkyl has been defined ally substituted with one to three of halo , cyano , oxo , alkoxy, above . hydroxy, amino, nitro , aryl , cycloaliphatic , heterocycloali As used herein , a “ carbonyl” refer to - C ( O ) - . phatic , heteroaryl, haloalkyl, and alkyl . For instance , an As used herein , an " oxo ” refers to = 0 . 5 alkyl group can be substituted with alkylsulfanyl and the As used herein , the term “ phospho ” refers to phosphinates alkylsulfanyl can be optionally substituted with one to three and phosphonates. Examples of phosphinates and phospho of halo , cyano , oxo , alkoxy, hydroxy, amino , nitro , aryl, nates include — P (O )( R ) 2 , wherein RP is aliphatic , alkoxy , haloalkyl, and alkyl. As an additional example , the aryloxy, heteroaryloxy , ( cycloaliphatic ) oxy , (heterocycloali - cycloalkyl portion of a ( cycloalkyl) carbonylamino can be phatic )oxy aryl, heteroaryl, cycloaliphatic or amino . 10 optionally substituted with one to three of halo , cyano , As used herein , an " aminoalkyl” refers to the structure alkoxy , hydroxy , nitro , haloalkyl, and alkyl. When two (R4 ) N - alkyl alkoxy groups are bound to the same atom or adjacent As used herein , a " cyanoalkyl” refers to the structure atoms, the two alkoxy groups can form a ring together with (NC )- alkyl - . the atom ( s ) to which they are bound . As used herein , a " urea ” group refers to the structure 15 In general, the term " substituted , ” whether preceded by — NRY _ CO - NR 'R2 and a " thiourea ” group refers to the the term “ optionally ” or not, refers to the replacement of structure — NRY _ CS - NRR2 when used terminally and hydrogen radicals in a given structure with the radical of a - NRY CONRY — or - NRY_ CSNRY — when used specified substituent . Specific substituents are described internally , wherein R , R ' , and R2 have been defined above . above in the definitions and below in the description of As used herein , a " guanidine” group refers to the structure 20 compounds and examples thereof. Unless otherwise indi - N = C ( N ( R + R ) ) N (R + R ) or NR CCNR )NR R cated , an optionally substituted group can have a substituent wherein R * and R ' have been defined above . at each substitutable position of the group , and when more As used herein , the term “ amidino ” group refers to the than one position in any given structure can be substituted structure C = (NR NRR wherein R and R ' have with more than one substituent selected from a specified been defined above. 25 group , the substituent can be either the same or different at In general, the term “ vicinal” refers to the placement of every position . A ring substituent, such as a heterocy substituents on a group that includes two or more carbon cloalkyl, can be bound to another ring , such as a cycloalkyl , atoms, wherein the substituents are attached to adjacent to form a spiro - bicyclic ring system , e . g . , both rings share carbon atoms. one common atom . As one of ordinary skill in the art will In general, the term " geminal” refers to the placement of 30 recognize , combinations of substituents envisioned by this substituents on a group that includes two or more carbon invention are those combinations that result in the formation atoms, wherein the substituents are attached to the same of stable or chemically feasible compounds. carbon atom . The phrase " stable or chemically feasible , " as used herein , The terms “ terminally ” and “ internally ” refer to the refers to compounds that are not substantially altered when location of a group within a substituent. A group is terminal 35 subjected to conditions to allow for their production , detec when the group is present at the end of the substituent not tion , and preferably their recovery , purification , and use for further bonded to the rest of the chemical structure . Car - one or more of the purposes disclosed herein . In some boxyalkyl, i. e ., R ' O ( O ) C - alkyl is an example of a carboxy embodiments , a stable compound or chemically feasible group used terminally . A group is internal when the group is compound is one that is not substantially altered when kept present in the middle of a substituent of the chemical 40 at a temperature of 40° C . or less , in the absence of moisture structure . Alkylcarboxy ( e . g . , alkyl - C ( O ) O - or alkyl- OC or other chemically reactive conditions , for at least a week . ( 0 ) ) and alkylcarboxyaryl ( e . g . , alkyl- C ( O ) O -aryl - or As used herein , an " effective amount” is defined as the alkyl - O (CO ) -aryl - ) are examples of carboxy groups used amount required to confer a therapeutic effect on the treated internally . patient , and is typically determined based on age, surface As used herein , an “ aliphatic chain ” refers to a branched 45 area, weight, and condition of the patient. The interrelation or straight aliphatic group ( e . g ., alkyl groups , alkenyl ship of dosages for animals and humans ( based on milli groups, or alkynyl groups ) . A straight aliphatic chain has the grams per meter squared of body surface ) is described by structure — [CH ] , where v is 1 - 12 . A branched aliphatic Freireich et al. , Cancer Chemother . Rep ., 50 : 219 (1966 ) . chain is a straight aliphatic chain that is substituted with one Body surface area may be approximately determined from or more aliphatic groups . A branched aliphatic chain has the 50 height and weight of the patient. See , e . g ., Scientific Tables , structure — CQQ ) , - where each Q is independently a hydro - Geigy Pharmaceuticals , Ardsley , N . Y ., 537 ( 1970 ). As used gen or an aliphatic group ; however, Q shall be an aliphatic herein , " patient” refers to a mammal, including a human . group in at least one instance . The term aliphatic chain Unless otherwise stated , structures depicted herein are includes alkyl chains , alkenyl chains, and alkynyl chains, also meant to include all isomeric ( e . g ., enantiomeric , diaste where alkyl, alkenyl, and alkynyl are defined above . 55 reomeric , and geometric ( or conformational) ) forms of the The phrase " optionally substituted ” is used interchange - structure ; for example , the R and S configurations for each ably with the phrase " substituted or unsubstituted .” As asymmetric center , ( Z ) and ( E ) double bond isomers, and ( Z ) described herein , compounds of the invention can optionally11v and ( E ) conformational isomers. Therefore , single stereo be substituted with one or more substituents , such as are chemical isomers as well as enantiomeric , diastereomeric , illustrated generally above , or as exemplified by particular 60 and geometric ( or conformational) mixtures of the present classes , subclasses , and species of the invention . As compounds are within the scope of the invention . Unless described herein , the variables R1, R2, and Rz , and other otherwise stated , all tautomeric forms of the compounds of variables contained in formulae described herein encompass the invention are within the scope of the invention . Addi specific groups , such as alkyl and aryl. Unless otherwise tionally , unless otherwise stated , structures depicted herein noted , each of the specific groups for the variables R1, R2, 65 are also meant to include compounds that differ only in the and Rz, and other variables contained therein can be option presence of one or more isotopically enriched atoms. For ally substituted with one or more substituents described example , compounds having the present structures except US 10 , 022 , 352 B2 17 18 for the replacement of hydrogen by deuterium or tritium , or Ring B is a group having formula Ia : the replacement of a carbon by a 13C - or 14C - enriched carbon are within the scope of this invention . Such com pounds are useful, for example , as analytical tools or probes in biological assays, or as therapeutic agents . 5 Compounds of the present invention are useful modula tors of ABC transporters and are useful in the treatment of ABC transporter mediated diseases. (R3 ) 10 II . Compounds or a pharmaceutically acceptable salt thereof, wherein p is A . Generic Compounds 0 - 3 and each Rz and R 'z is independently -- ZºRo, where The present invention relates to compounds of formula I 15 each Zº is independently a bond or an optionally substituted branched or straight C1- 6 aliphatic chain wherein up to two useful as modulators of ABC transporter activity : carbon units of Zº are optionally and independently replaced by — CO — , - CS - , CONR — CONR NRC — C027 , OCO - NRC0 , - , - 0 , - NR CO I NRC , OCONR , NR NRC — NRCO , 20 - S , SO , SO , — — NRC — — SO ,NRC , - NRC80 , - , or NRCSO NRC — . Each Ro is indepen dently RC, halo , OH , - NH2, - NO2, CN , or - OCF3 . Each RC is independently hydrogen , an optionally substi tuted aliphatic , an optionally substituted cycloaliphatic , an DZ optionally substituted heterocycloaliphatic , an optionally 25 substituted aryl, or an optionally substituted heteroaryl. Alternatively , any two adjacent Rz groups together with the atoms to which they are attached form an optionally sub or a pharmaceutically acceptable salt thereof. stituted carbocycle or an optionally substituted heterocycle . Furthermore, R '; and an adjacent R3 group , together with the R is -- Z4R4, wherein each Z4 is independently a bond OFor 3030 atoms to which they are attached, form an optionally sub an optionally substituted branched or straight C1- 6 aliphatic stituted heterocycle . chain wherein up to two carbon units of Z4 are optionally n is 1 - 3 . and independently replaced by CO — , CSS , However , in several embodiments , when ring A is unsub - CONR4 — , - CONR4NR4 — , - C02 - , - OCO , stituted cyclopentyl, n is 1, R2 is 4 -chloro , and R , is - NR4CO2 , 0 , - NR4CONR4 — , - OCONR4 — , 35 hydrogen , then ring B is not 2 -( tertbutyl )indol -5 - yl , or - NR4NR4 — , - NR4CO — , S , - SO — , 50 , , (2 ,6 -dichlorophenyl ( carbonyl ) ) -3 -methyl - 1H - indol -5 -yl ; - NR4 , SONR4 , - NR480 , - , or — NR4SO2NR4 — and when ring A is unsubstituted cyclopentyl, n is 0 , and Ri Each R4 is independently R4, halo , - OH , - NH2, — NO2, is hydrogen , then ring B is not CN , or — OCF3. Each R4 is independently hydrogen , an optionally substituted aliphatic , an optionally substituted 40 cycloaliphatic , an optionally substituted heterocycloali phatic , an optionally substituted aryl, or an optionally sub stituted heteroaryl. R2 is ZPR5, wherein each ZP is independently a bond or an optionally substituted branched or straight C1- 6 aliphatic * . HN chain wherein up to two carbon units of ZP are optionally and independently replaced by C0 , CS , - CONRB , CONRNRB4 , C026 , OCO , mm - NRCO2 , 0 , - NRBCONRB — , - OCONRB , 50 - NRNRB - , NRBCO — , S , - SO - , - SO , - NRB , SONRB NRBS02 — , or FashionOm , or - NRPSO NRB — . Each Rs is independently RB , halo , OH , NH2, NO2, CN , CF3, or OCF3. Each R? 55 is independently hydrogen , an optionally substituted ali phatic , an optionally substituted cycloaliphatic , an option ally substituted heterocycloaliphatic , an optionally substi tuted aryl, or an optionally substituted heteroaryl. 60 Alternatively , any two adjacent R2 groups together with the OH . atoms to which they are attached form an optionally sub stituted carbocycle or an optionally substituted heterocycle . Ring A is an optionally substituted 3 - 7 membered mono - 65 cyclic ring having 0 - 3 heteroatoms selected from N , O , and Bazar US 10 , 022 ,352 B2 19 20 B . Specific Compounds which is optionally substituted with 1 - 3 of hydroxy , aryl, 1 . R , Group heteroaryl, cycloaliphatic , heterocycloaliphatic , or combina R , is Z4R4, wherein each Z4 is independently a bond or tions thereof. an optionally substituted branched or straight C1- 6 aliphatic I n other embodiments , R , is hydroxy , halo , or cyano . chain wherein up to two carbon units of Z4 are optionally 5 In several embodiments , R , is - ZPRs, and zB is inde and independently replaced by CO — , CS — , pendently a bond or an optionally substituted branched or CONR4 , CONR4NR4 — , C0 , - , OCO , straight C1- 4 aliphatic chain wherein up to two carbon units - NR4C02 — , - 04 , - NR CONR4 — , - OCONR4 — , of zB are optionally and independently replaced by - NR4NR4 — , - NR4CO — , - S - , - SO — , - S02 — , C (O ) - , - , - S - , - S (O )2 - , or - NH - , and Rg - NR4 — , - SO , NR4 — , NR4802 — or 10 is RP , halo , OH , — NH , - NO2, — CN , CF3, or - NRASO NR4 — Each R4 is independently R4, halo , OCF3, and RB is hydrogen or arylom . OH , - NH2, - NO2, CN , or OCF3. Each R4 is In several embodiments , two adjacent R2 groups form an independently hydrogen , an optionally substituted aliphatic , optionally substituted carbocycle or an optionally substi an optionally substituted cycloaliphatic , an optionally sub - tuted heterocycle . For example , two adjacent R2 groups form stituted heterocycloaliphatic , an optionally substituted aryl, 15 an optionally substituted carbocycle or an optionally sub or an optionally substituted heteroaryl. stituted heterocycle , either of which is fused to the phenyl of In several embodiments, R , is — Z4R4 , wherein each Z4 formula I, wherein the carbocycle or heterocycle has for is independently a bond or an optionally substituted mula Ib : branched or straight C - , aliphatic chain and each R . is hydrogen . 20 In other embodiments, R , is - Z4R4, wherein each 24 is a bond and each R4 is hydrogen . 2 . R , Group Each R , is independently ZPRs, wherein each ZP is

independently a bond or an optionally substituted branched 25 w or straight C1- 6 aliphatic chain wherein up to two carbon units of z are optionally and independently replaced by - CO , CS , CONRB - , CONRPNRB Z - Zs § - C02 - , - OCO , NRPCO2 - , - O - , - NRP CONRB , OCONRB — , - NRBNRB — , - NRBCO , 30 Each of Z1, Z2, Z3, Z4 , and Zg is independently a bond , - S , SO — , - S02 — , - NRB , SONRB , CR , R ' , , - NR . - , or 0 ; each R , is independently - NRPS02 - , or - NRPSO NR - . Each R , is indepen - ZPR3, wherein each Z is independently an optionally dently RP , halo , OH , — NH , - NO ,, CN , CF3, or substituted branched or straight C1- 6 aliphatic chain wherein - OCF3. Each R is independently hydrogen , an optionally up to two carbon units of ZP are optionally and indepen substituted aliphatic , an optionally substituted cycloali - 35 dently replaced by CO - , CS - , CONR ” — phatic , an optionally substituted heterocycloaliphatic , an C02 — , OCO — , - NRPCO2 - , - 04 , NR ” optionally substituted aryl, or an optionally substituted het CONRD , OCONR ” , NR NRD , NRPCO eroaryl. Alternatively , any two adjacent R2 groups together S , SO , SO2 - , - NRD , SO NRD , with the atoms to which they are attached form an optionally — NRPS02 — , or NR SONR ” — . Each R , is indepen substituted carbocycle or an optionally substituted hetero - 40 dently R ' , halo , OH , - NH2, - NO2, CN , – CF3, or cycle . OCF3 . Each R is independently hydrogen , an optionally In several embodiments , R2 is an optionally substituted substituted cycloaliphatic , an optionally substituted hetero aliphatic . For example , R2 is an optionally substituted cycloaliphatic , an optionally substituted aryl, or an option branched or straight C1- 6 aliphatic chain . In other examples, ally substituted heteroaryl. Each R ' , is independently hydro R2 is an optionally substituted branched or straight C1- 6 alkyl 45 gen , optionally substituted C1- 6 aliphatic , hydroxy, halo , chain , an optionally substituted branched or straight C26 cyano , nitro , or combinations thereof. Alternatively , any two alkenyl chain , or an optionally substituted branched or adjacent R , groups together with the atoms to which they are straight C26 alkynyl chain . In alternative embodiments , R attached form an optionally substituted 3 - 7 membered car is a branched or straight C - , aliphatic chain that is option - bocyclic ring , such as an optionally substituted cyclobutyl ally substituted with 1 - 3 of halo , hydroxy , cyano , cycloali - 50 ring , or any two R , and R ' , groups together with the atom or phatic , heterocycloaliphatic , aryl, heteroaryl, or combina - atoms to which they are attached form an optionally sub tions thereof. For example, R2 is a branched or straight stituted 3 - 7 membered carbocyclic ring or a heterocarbocy C1- talkyl that is optionally substituted with 1 -3 of halo , clic ring . hydroxy , cyano , cycloaliphatic , heterocycloaliphatic , aryl, In several other examples, two adjacentR2 groups form an heteroaryl, or combinations thereof. In still other examples, 55 optionally substituted carbocycle. For example , two adja R2 is a methyl, ethyl, propyl, butyl, isopropyl , or tert -butyl , cent R2 groups form an optionally substituted 5 - 7 membered each of which is optionally substituted with 1 - 3 of halo , carbocycle that is optionally substituted with 1 - 3 of halo , hydroxy , cyano , aryl, heteroaryl, cycloaliphatic , or hetero hydroxy, cyano , oxo , cyano, alkoxy , alkyl , or combinations cycloaliphatic . In still other examples, R2 is a methyl, ethyl, thereof. In another example , two adjacent R2 groups form a propyl, butyl , isopropyl, or tert- butyl , each of which is 60 5 - 6 membered carbocycle that is optionally substituted with unsubstituted . 1 - 3 of halo , hydroxy , cyano , oxo , cyano , alkoxy , alkyl, or In several other embodiments , R , is an optionally substi - combinations thereof. In still another example , two adjacent tuted branched or straight C1- 5 alkoxy . For example , R , is a R2 groups form an unsubstituted 5 -7 membered carbocycle . C1- 5 alkoxy that is optionally substituted with 1 - 3 of In alternative examples, two adjacent R2 groups form an hydroxy , aryl, heteroaryl, cycloaliphatic , heterocycloali - 65 optionally substituted heterocycle . For instance , two adja phatic , or combinations thereof. In other examples , R , is a cent R , groups form an optionally substituted 5 - 7 membered methoxy, ethoxy, propoxy , butoxy, or pentoxy, each of heterocycle having 1 - 3 heteroatoms independently selected US 10 , 022 , 352 B2 21 22 from N , O , and S . In several examples , two adjacent R2 -continued groups form an optionally substituted 5 - 6 membered het erocycle having 1 - 2 oxygen atoms. In other examples , two XAS adjacent R2 groups form an unsubstituted 5 - 7 membered heterocycle having 1 - 2 oxygen atoms. In other embodi - 5 nim ments , two adjacent R2 groups form a heterocyclic ring selected from : min XAL mm XA9 m NH mer XA2

m XA10 win in min XA3 XA11

ma ni pu

XA4 XA12

w

XA5 XA13

w min nim w

XA6 XA14 n Win con for

XAT XA15 9 man mi US 10 ,022 , 352 B2 23 24 -continued In several embodiments , each R , group is independently XA16 selected from hydrogen , halo , OCHZ, OH , CH2OH , CH3, and OCF3, and / or two adjacent R2 groups mu together with the atoms to which they are attached form 5 mino XA1 XA17 10 Nu mun XA2 Meo XA18

y 20 pur XA3 XA19 25 min mi min XA4 XA20

w si

Win XA5 and

XA21 B nin ?

# XA6

In alternative examples, two adjacent R2 groups form an optionally substituted carbocycle or an optionally substi tuted heterocycle , and a third R2 group is attached to any 30 chemically feasible position on the phenyl of formula L For mi instance , an optionally substituted carbocycle or an option XAT ally substituted heterocycle , both of which is formed by two adjacent R2 groups ; a third R2 group ; and the phenyl of formula I form a group having formula Ic :

Z - 21 XAS - Z5 mo Z1, Z2, Z3, Z4, and Zz has been defined above in formula Ib , and R , has been defined above in formula L US 10 , 022 , 352 B2 25 26 -continued -continued XAO XA18 mi NH mm mu XA10 XA19 mi 10 ww À mu 15 XA11 XA20

w

20 and mu mu XA12 XA21 25 min mus XA13 30 mm In other embodiments , R2 is at least one selected from hydrogen , halo , methoxy , phenylmethoxy, hydroxy , ni hydroxymethyl, trifluoromethoxy, and methyl . 35 In some embodiments , two adjacent R2 groups , together mm with the atoms to which they are attached , form XA14

XA1 > or

mun w

XA15 # XA2 num nh win y XA16 min 55 3 . Ring a Ring A is an optionally substituted 3 -7 membered mono cyclic ring having 0 -3 heteroatoms selected from N , O , and In several embodiments , ring A is an optionally substi XA17' 60 tuted 3 - 7 membered monocyclic cycloaliphatic . For example , ring A is a cyclopropyl, cyclobutyl , cyclopentyl , cyclohexyl, or cycloheptyl, each of which is optionally mm substituted with 1 - 3 of halo , hydroxy, C - 5 aliphatic , or combinations thereof. mm 65 In other embodiments , ring A is an optionally substituted MeóMeo OH S 3 - 7 membered monocyclic heterocycloaliphatic . For example , ring A is an optionally substituted 3 - 7 membered US 10 ,022 , 352 B2 27 28 monocyclic heterocycloaliphatic having 1 - 2 heteroatoms - continued independently selected from N , O , and S . In other examples , XB9 ring A is tetrahydrofuran -yl , tetrahydro - 2H - pyran - yl , pyr (Re ) a rolidone - yl, or piperidine -yl , each of which is optionally substituted . In still other examples, ring A is selected from

XB10 XB1 10 H (Rs ) mi mm www XB2 nin (R8 ) ? XB11 (Rs ) a ww mm HN mm XB3 25 (Rs ) mo XB12 man (Re ) a

man ?? XB4 Roa mu VM www XB13 XB5 89 mm mi XB14 www (R8 ) XB6 (R8 ) ? man mies XB15 man mi (Rs ) a XB7 (R HN w mm men mm XB8 60 XB16 HN (R8 )

w wa mun 65 man US 10 , 022 , 352 B2 29 30 - continued - continued XB17 XC2 V (Rs ) a min mm muro XC3 XB18 10 8a wa m w XC4

man ?

XB19 HN - (Rs ) a ingre 20 mu XC5 ni mm

XB20 25 (R8 ) ipino HN man XC6

and 30 mm ni mos ; and XB21 min (Rs ) XC4 35 mm nim men mi 40 In several embodiments , ring A is Each R , is independently ZFR9, wherein each Z is independently a bond or an optionally substituted branched or straight Cl- s aliphatic chain wherein up to two carbon 45 units of z are optionally and independently replaced by - CO — — CS , CONRE — — CO , — , OCO — , mi ma - NRECO , – , 0 , - NRECONRE , - OCONRE , - NRE NRE , - NRECO - , - S , - SO - , - SO - , NRE , SONRE — — NRESO , — or 50 4 . Ring B - NRESO NRE — , each R , is independently RE, - OH , Ring B is a group having formula Ia : - NH2, - NO2, CN , CF3, oxo , or - OCF3. Each RF is independently hydrogen , an optionally substituted cycloali phatic , an optionally substituted heterocycloaliphatic , an Ta optionally substituted aryl, or an optionally substituted het - > eroaryl. q is 0 - 5 . In other embodiments , ring A is one selected from min (R3 )p 60 XC1 or a pharmaceutically acceptable salt thereof , wherein p is 0 - 3 . 65 Each Rz and R ' z is independently - ZºRo, where each Zº is independently a bond or an optionally substituted min men branched or straight C1- 6 aliphatic chain wherein up to two US 10 , 022 , 352 B2 31 32 carbon units of Zº are optionally and independently replaced For example , ring B is by CO , CS , CONRC , - CONR NRC— , - C02 - , - OCO — , - NRCO2 - , O - , - NRCO NRG , OCONRC, - NR NRC , - NRCO - S - , - SO , SO2 - , NRCS , SO NRG , 5 - NRC80 , — , or NRCSO NRC — . Each Ro is indepen min dently RC, halo , OH , - NH2, — NO2, CN , or OCF3. Each RC is independently hydrogen , an optionally substi R3) p tuted aliphatic , an optionally substituted cycloaliphatic , an optionally substituted heterocycloaliphatic , an optionally substituted aryl, or an optionally substituted heteroaryl. Alternatively, any two adjacent R3 groups together with the atoms to which they are attached form an optionally sub w stituted carbocycle or an optionally substituted heterocycle , 15 . or R ' ; and an adjacent Rz, i. e ., attached to the 2 position of the indole of formula la , together with the atoms to which (R3 ) p (R3 ) p , or they are attached form an optionally substituted heterocycle . In several embodiments , ring B is min 20

(R20 ) 9

25

( R3) p ; (R3 ) p , mm 30 In several embodiments , R ' z is hydrogen and Rz is Seteleattached to the 2 , 3 , 4 , 6 , or 7 position of the indole of formula Ia . In several other examples , Rz is attached to the 2 or 3 position of the indole of formula la , and R , is mi independently an optionally substituted aliphatic . For instance , R , is an optionally substituted acyl group . In several instances , R , is an optionally substituted ( alkoxy ) (R3 ) p , (R3 ) p , or carbonyl . In other instances , Rz is (methoxy ) carbonyl, ( ethoxy ) carbonyl, (propoxy carbonyl, or (butoxy ) carbonyl, each of which is optionally substituted with 1 - 3 of halo , mi hydroxy, or combinations thereof. In other instances , R2 is an optionally substituted (aliphatic ) carbonyl. For example, R2 is an optionally substituted (alkyl ) carbonyl that is option ally substituted with 1 - 3 of halo , hydroxy , or combinations thereof. In other examples, Rz is (methyl ) carbonyl, (ethyl ) Y (R20 ) . 45 carbonyl, (propyl ) carbonyl , or (butyl ) carbonyl , each of which is optionally substituted with 1 - 3 of halo , hydroxy, or combinations thereof. y (R3 ) p -1 In several embodiments , Rz is an optionally substituted ( cycloaliphatic ) carbonyl or an optionally substituted (het 50 erocycloaliphatic )carbonyl . In several examples , Rz is an optionally substituted (C2 . 7 cycloaliphatic )carbonyl . For example , Rz is a ( cyclopropyl) carbonyl , (cyclobutyl ) carbo wherein Hosea is 0 - 3 and eachR is -- ZºR , where each zº nyl, ( cyclopentyl) carbonyl , (cyclohexyl ) carbonyl , or ( cyclo heptyl) carbonyl , each of which is optionally substituted with is independently a bond or an optionally substituted 55 aliphatic , halo , hydroxy , nitro , cyano , or combinations branched or straight C1- 5 aliphatic chain wherein up to two thereof. In several alternative examples , Rz is an optionally carbon units of Zº are optionally and independently replaced substituted ( heterocycloaliphatic carbonyl. For example , Rz by CO — , CS , CONRG , CO2- , _ OCO , is an optionally substituted (heterocycloaliphatic ) carbonyl - NRCO , — , - 0 % OCONRG NR NRGe , having 1 - 3 heteroatoms independently selected from N , O , - NRCO , S , SO , SO2- , - NRG - , 60 and S . In other examples , R , is an optionally substituted SO NRG , NR 80 , - , or NRSO NRG — . Each (heterocycloaliphatic ) carbonyl having 1 - 3 heteroatoms R21 is independently RC, halo , OH , NH ,, - NO2, independently selected from N and O . In still other - CN , or OCF3. Each RG is independently hydrogen , an examples, R , is an optionally substituted 4 - 7 membered optionally substituted aliphatic , an optionally substituted monocyclic (heterocycloaliphatic ) carbonyl having 1 - 3 het cycloaliphatic , an optionally substituted heterocycloali - 65 eroatoms independently selected from N and O . Alterna phatic , an optionally substituted aryl, or an optionally sub tively , Rz is (piperidine - 1 -yl ) carbonyl , (pyrrolidine - 1 -yl ) car stituted heteroaryl. bonyl, or (morpholine - 4 - yl) carbonyl, (piperazine - 1 - yl) US 10 , 022 , 352 B2 33 34 carbonyl, each of which is optionally substituted with 1 - 3 of -continued halo , hydroxy , cyano , nitro , or aliphatic . LOH In still other instances , Rz is optionally substituted (ali phatic ) amido such as ( aliphatic (amino ( carbonyl) ) that is attached to the 2 or 3 position on the indole ring of formula 5 Ia . In some embodiments , Rz is an optionally substituted IZ o IZ ( alkyl( amino ) ) carbonyl that is attached to the 2 or 3 position mm on the indole ring of formula Ia . In other embodiments , Rz the theO is an optionally substituted straight or branched ( aliphatic ( amino ) )carbonyl that is attached to the 2 or 3 position on the indole ring of formula Ia . In several examples, R , is ( N , N dimethyl( amino ) ) carbonyl, (methyl ( amino ) ) carbonyl, ( ethyl mi (amino ) carbonyl, (propyl ( amino ) ) carbonyl, (prop - 2 - yl A0M=O ( amino ) )carbonyl , ( dimethyl( but - 2 - yl( amino ) ) )carbonyl , 15 ( tertbutyl( amino ) )carbonyl , (butylamino ) )carbonyl , each of which is optionally substituted with 1 - 3 of halo , hydroxy , NH mi NH cycloaliphatic , heterocycloaliphatic , aryl, heteroaryl, or min OH combinations thereof. In other embodiments , Rz is an optionally substituted 20 Hinthe ( alkoxy ) carbonyl . For example , Rz is (methoxy ) carbonyl, ( ethoxy )carbonyl , (propoxy )carbonyl , or (butoxy )carbonyl , each of which is optionally substituted with 1 - 3 of halo , hydroxy, or combinations thereof. In several instances , R2 is mm an optionally substituted straight or branched C1- 6 aliphatic . 25 For example , Rz is an optionally substituted straight or branched C1- 6 alkyl . In other examples, Rz is independently Hoteo an optionally substituted methyl, ethyl, propyl, butyl, iso propyl, or tertbutyl, each of which is optionally substituted NH with 1 - 3 of halo , hydroxy , cyano , nitro , or combination 303 min thereof. In other embodiments , Rz is an optionally substi tuted C3- 6 cycloaliphatic . Exemplary embodiments include ??? cyclopropyl , 1 -methyl - cycloprop - 1 - yl, etc . In other examples , p is 2 and the two Rz substituents are attached to z w the indole of formula la at the 2 , 4 - or 2 , 6 - or 2 , 7 -positions . Exemplary embodiments include 6 - F , 3 - ( optionally substi tuted C1- 6 aliphatic or C3- 6 cycloaliphatic ) ; 7 - F - 2 - ( - (option ally substituted Cl- aliphatic or C3- 6 cycloaliphatic )) , 4F - 2 # te # F (optionally substituted C1- 6 aliphatic or C3- 6 cycloaliphatic ); 40 7 -CN -2 - (optionally substituted C1-6 aliphatic or C3- 6 cycloa liphatic ) ; 7 -Me - 2 - ( optionally substituted C1- 6 aliphatic or COOCH3 . C3- 6 cycloaliphatic ) and 7 -OMe - 2 -( optionally substituted min C1- 6 aliphatic or C3- 6 cycloaliphatic ). In several embodiments , Rz is hydrogen . 45 In several embodiments , Rz is one selected from : - H , CHz, — CH ,OH , CH CHz, — CH CH , OH , mo - CH2CH2CH3, - NH2, halo , - OCH3, CN , CF3, CONH , C ( O )OCH CHz, - S ( O )2CH3 , CH NH2, C ( O )NH2 , mm 50 min mm mm - NH ktet 55 tette OH ,

w 9 60 min to bothOH . tyt

OH ni OH x NH Xa 65 XIX - US 10 ,022 , 352 B2 35 36 - continued In another embodiment, two adjacent Rz groups form

num OH . NH mm Men 10 In several embodiments , R 'z is independently - ZºR6, where each Zº is independently a bond or an optionally NH , NH substituted branched or straight C1- 6 aliphatic chain wherein Hatimin up to two carbon units of zº are optionally and indepen dently replaced by C0 — , - CS - , CONRC — , - CONR NRC — , C02 - , - OCO , — NRC0 , — - 0 , - NR CONRC — , - OCONR , NR NRC — min NRCO , S , SO , SO2 - , NRC , tritt SONR , NRCS02 , or - NRCSONRC — Each 20 Ro is independently RC, halo , OH , - NH2, - NO2, CN , or — OCF3. Each R is independently hydrogen , an option ally substituted aliphatic , an optionally substituted cycloa mu NH OEt liphatic , an optionally substituted heterocycloaliphatic , or an optionally substituted heteroaryl. In one embodiment , each mm 25 RC is hydrogen , C1- 6 aliphatic , or C3- 6 cycloaliphatic , wherein either of the aliphatic or cycloaliphatic is optionally w Z- the ti?? substituted with up to 4 OH substituents . In another ?? embodiment, Rºis hydrogen , or C1- 6 alkyl optionally sub stituted with up to 4 - OH substituents . wi , 30 For example , in many embodiments , R ' z is independently that to Be- ZºRo, where each Zº is independently a bond or an optionally substituted branched or straight C1- 6 aliphatic CN chain wherein up to two carbon units of Z© are optionally 35 and independently replaced by C ( O ) , C ( O ) NRC — , _ C ( O )O - , - NRC( ) O - , - 0 % , - NRCS ( 0 ) 2 - , or mi - NRC — . Each Ro is independently Rº, - OH , or - NH2. to fatto Each Rº is independently hydrogen , an optionally substi tuted cycloaliphatic , an optionally substituted heterocycloa 40 liphatic , or an optionally substituted heteroaryl. In one embodiment, each Rºis hydrogen , C1- 6 aliphatic , or C3- 6 ZSZ cycloaliphatic , wherein either of the aliphatic or cycloali O = phatic is optionally substituted with up to 4 — OH substitu ents . In another embodiment, Rº is hydrogen , or Cla alkyl 45 optionally substituted with up to 4 - OH substituents . In other embodiments , R ', is hydrogen or teisteNH n R31 IZ 50 minteja R32, mu OH OH 55 wherein R31 is H or a C1- 2 aliphatic that is optionally mm min substituted with 1- 3 ofhalo , OH , or combinations thereof. R32 is - L -R33 , wherein L is a bond , CH2- , - CH20 , to set theCH NHS (O ) 2 - , CH2C (O ) - , - CH2NHC ( O ) - , or 60 CH NH — ; and R33 is hydrogen , or C1- 2 aliphatic , cycloa liphatic , heterocycloaliphatic , or heteroaryl, each of which is optionally substituted with 1 of OH , - NH2, or — CN . For example , in one embodiment , R31 is hydrogen and R32 is - OH min CO2H C1- 2 aliphatic optionally substituted with OH , - NH2, or , and 65 CN . In several embodiments , R 'z is independently selected from one of the following: US 10 , 022 , 352 B2 37 38 -continued

– H , ?CH , = CH- CH , = C( OCH , = CH -CH - OH , HN

in mm www ?? min

NHSO Me COH 10

mi HOOH , HYHO WAY mo * ????? Kontryhamm min min . HO

20 ma HO mi OtatNHCOCH . mult Et 25 HO NHSO Me min NHCO Me mi OH mi ?? mos BarnNHCO , Me NHMe OMe 30 W HN OH HO mu OH NSW

HU ?? mi HN 35 HO IN , xx min ??OH OHOH

40 min HOW www CONHMe 45

mm . HO

tryHO 50 NHCO , Bu www mi NHSO Et mu min HO COH wom 55 OH mo mm HN w ?? min V THN ' CONMer man HO mi - 09

NHCOMe ni 65 HO minn mwin US 10 , 022 , 352 B2 39 40 -continued -continued

min HO NH NH to

w un HN - HO thatN = 0 tode

mi IZ this?? trimin mmputea , and

In several embodiments , ring B is one selected from : 4c, , totsmi jerstmw . Hoemum NH HN min HO Hostinmi IZ . th mintothera pmin eute · NH

mi min US 10 ,022 , 352 B2 41 42 - continued - continued

1 ) ?? ??? ?????

??

20 ? ??? ?????? ???

???25 ??? ? OH ????? ??????? : ????? H0

M

HN ????? ????? ???? ?????? ????

?????? ??? ?? HN ?? ???

66)

H NH2 ????? ?????? 65 ?????? ?? ????? US 10 , 022 , 352 B2 43 44 -continued -continued OH

HN

mi min 10 mun

NH C HN

w HO wi HO 20 ou to

NH F ) - - NHNH 2525 min mm 30

HO ?? HO

35

HN OH

40 min min

?? 45 mm min

50 tbsp.test i 55 HO

wan mi 65 mm mm US 10 , 022 , 352 B2 45 US10. 022 ,352 .82 46 - continued In one embodiment, the present invention provides com OH pounds of formula II , wherein the compounds set forth parte continued below are excluded : recentemente Ik heb how to1010 ni 15 F xoto OH - NH 20 mie mu , and 25 Dogan

NH mmo 3030 8080 5 . n Term 35 F n is 1 - 3 . In several embodiments , n is 1 . In other embodiments , n is 2 . In still other embodiments , n is 3 . In one aspect , the present invention relates to compounds 20 OH , of formula II useful as modulators of ABC transporter Xotant activity : 11

F Ri Ri . uslOH RIRI 2040 OH ,

OH 55 orDosh a pharmaceutically acceptable salt thereof, wherein xox94 independently for each occurrence : OH , R is H , OH , OCHz or two R taken together form OCH20 - or - OCF20 % ; R is H or alkyl; 60 F R2 is H or F ; Rz is H or CN ; R4 is H , CH ,OCH ,CH (OH )CH2OH , CH , CH N ymyOH ( CH3) 3, or CH2CH2OH ; 65 Rs is H , OH , CH2OCH CH (OH )CH ,OH , CH ,OH , OH , or R4 and R , taken together form a secofive membered ring . US 10 , 022 , 352 B2 47 48 - continued - continued Ze

5 F N F

xotiont .10 coriantOH ,

15 HO11111

OH , 04 + 20 xotinn

' HO Dollar OH , 25 HotIZ - 30 X08077704944F 35 OH I

40 F

IZ. OH OH , 45 0040Z cotton

50

OH , L 70820921 55 F HN OH OH X0703th 60 cota

. HO1111 IZ. ? 65 E OH , Sofront? US 10 , 022 , 352 B2 49 50 - continued embodiment, two R taken together form OCF20 - , R , is H , R , is F , and R , is H . In another embodiment, two R taken HO . together form OCF 04 , R , is H , R , is F , Rz is H , and RA is H . In another embodiment, two R taken together form - OCF20 , R is H , R2 is F , Rz is H , and R4 is CH _ CH _ N + ( CH3) 3 . In another embodiment, two R taken pointIZ together form - OCF , 0 , R , is H , R , is F , R2 is H , and RA is _ CH , OCH , CH (OH )CH , OH . In another embodiment, two R taken together form — OCF , 0 % , R , is H , R , is F , Rz is H , and R4 and R , taken together form a five membered 10 ring. In one embodiment of the compounds, two R taken together form — OCH , 0 % , R is H , and R , is F . In another embodiment, two R taken together form - OCH , O , R , is H , R2 is F , and Rz is H . In another embodiment, two R taken 15 together form - OCH , O , R , is H , R , is F , R , is H , and R OH is — CH ,OCH , CH (OH )CH ,OH . In one embodiment of the compounds, R is OH , R , is H , OH , R , is H , R , is H , and R , is CH , OCH , CH (OH ) CH ,OH . otot In one embodiment of the compounds , at least one R is 20 OCHz, at least two R , are methyl, R , is H , R , is H , and RA is H . In another embodiment, at least one R is OCHz, at least two R are methyl, R , is H , R? is H , and R . is _ CH , OCH , CH (OH )CH , OH . In one embodiment of the compounds, two R taken OH 2325 together form — CH ,CH , CH , — , R , is H , R , is H , R , is H , and R4 is _ CHOCH CH ( OH )CH OH . - OH In one embodiment, the compound is represented by NE formula IIa : 30

Ila N N 355 FVYF

tiezt?? OH OH 40 or a pharmaceutically acceptable salt thereof, wherein : R4 is H , CH2OCH _ CH (OH ) CH2OH , CH2CH2N + Oh , and (CH3 ) 3 , or CH2CH2OH ; and Rg is H , OH , CH2OCH CH (OH )CH2OH , CH2OH , us or R4 and Rs taken together form a five membered ring . In one embodiment of the compounds, R4 is CH _ OCH CH (OH )CH2OH , CH2CH2N + (CH3 ) 3, or _ CH , CH ,OH . In another embodiment, R? is OH , OH CH _ OCH ,CH (OH )CH ,OH , or — CH ,OH . In another count embodiment, R4 is CH OCH CH (OH )CH , OH , O CH , CH N + (CH3 ) 2 , or — CH CH2OH ; and R , is OH , CH _ OCH CH (OH )CH OH , or CH2OH . C . Exemplary Compounds of the Present Invention In one embodiment of the compounds, two R taken Exemplary compounds of the present invention include , together form - OCF20 - , R , is H , and R , is F . In another but are not limited to , those illustrated in Table 1 below . TABLE 1 Exemplary compounds of the present invention . Dicast? H US 10 ,022 ,352 B2 51 52 TABLE 1 - continued Exemplary compounds of the present invention .

? netN

? 3 =

N

H ruditZ US 10 ,022 , 352 B2 53 54 TABLE 1 -continued Exemplary compounds of the present invention . ?? ??? 7

aro 2

?

?? 1 ( ) ? N

???H -// o ?? 0H US 10 ,022 , 352 B2 55 56 TABLE 1 -continued Exemplary compounds of the present invention .

12

?] ?? ??? 13 ????N H

H 14

NH

????-?? 15

???? 16 ?? 17 H US 10 , 022 , 352 B2 57 58 TABLE 1 -continued Exemplary compounds of the present invention . ?? 18

19 I ?? 20 ????N 21 =C

|

???

? | ?? 22

???? 23 ???? US 10, 022 , 352 B2 59 60 TABLE 1- continuted Exemplary compounds of the present invention .

24

N . H

DOY 25

NH

Daish 26 HM?

NH

27

NH

28 - N

0 oh DSH H ) 29

NH US 10 , 022 , 352 B2 61 62 TABLE 1 -continued Exemplary compounds of the present invention .

H 30)

H 31

???

???

32

LZ

33

34

???? 35 ????H US 10 ,022 , 352 B2 63 64 TABLE 1 -continued Exemplary compounds of the present invention . N7ANH 3636

1 - ????? ?? 37 38 ????2?? - 39

40 ) ??? N -

H 41 ???Z US 10 , 022 , 352 B2 65 66 TABLE 1 -continued Exemplary compounds of the present invention .

42

???F |

43

?? ???Z

F | F

44 ??H 45

?? US 10 ,022 , 352 B2 67 68 TABLE 1 -continued Exemplary compounds of the present invention .

46

4

48

? LZ

49 =

-

50)

????H 51

LZ

?? 52 ?? " ??? US 10 ,022 , 352 B2 69 US/ TABLE 1 -continued Exemplary compounds of the present invention . 54

55 ???? .????? H FF | F

56 L

Z

57 FF

LZ ???H 58

= ?????HN US 10 ,022 , 352 B2 71 TABLE 1 - continued Exemplary compounds of the present invention .

59

N

Quat 60 Shax

61

? Oost 62 F

63

NH xquotzucit 64 US 10, 022 , 352 B2 73 74 TABLE 1 - continued Exemplary compounds of the present invention .

ZL H

8 H

HN

H ) ??LZ

??

?????LZ US 10 , 022 , 352 B2 7575 16 TABLE 1 -continued Exemplary compounds of the present invention .

=|

? ?? 28-8-83LZ

H0HH US 10 ,022 , 352 B2 77 78 | 7 TABLE 1 ????-continued Exemplary compounds of the present invention .

6 ???? 77

???Z

79

??

?? 8 ( ??LZ ???? 81 US 10 ,022 , 352 B2 79 80 TABLE 1 - continued Exemplary compounds of the present invention . 82 0 $ 0

L

L

???????? 83 ?????

84

?

/

85

H| H 86 ?????? US 10 ,022 , 352 B2 81 TABLE 1 -continued Exemplary compounds of the present invention .

??? 88 ???H 89

N ?? ?90)

91

N ??H US 10 , 022 , 352 B2 83 84 TABLE 1 -continued Exemplary compounds of the present invention . 0H 92

?? 93 ?? 94

?N . Z

95

96 H - C- = N ?????? US 10 ,022 , 352 B2 85 US 100232B2 86 TABLE 1 -continued Exemplary compounds of the present invention .

48

N L H

?? 99

100)

H

F

?? ???H 101

7 LZ

????? 102

????H 13 o

LZ

??? 104 ??????Z US 10, 022 , 352 B2 87 88 TABLE 1 -continued 5 1002892 02 Exemplary compounds of the present invention . 105 V ZL an 106

Ho 107 R

H 108 *??????? ??? HNH

H 19

??????? 110 US 10 ,022 , 352 B2 89 ?? TABLE 1 -continued Exemplary compounds of the present invention . ??? 111 112

113 ??. N

LZ

114 ?? Z

???H 115

??? 116

N ?? 117 ???? US 10 ,022 , 352 B2 91 TABLE 1 -continued Exemplary compounds of the present invention . 118 ?

F " | ??] ??? 119 120)

??? 2 121

??Lz -?? 122 H

??? 123 10????? US 10 ,022 , 352 B2 93 94 TABLE 1 - continued Exemplary"TAHILE compounds Icontinued of the present invention . ????H 124 125 ???

??

* ????126

=

= ???? H " H 12

N

"128

???H 129

N LZ H

?? 130)

H

) ???? 131 ???? US 10 ,022 , 352 B2 95 96 ? TABLE 1 -continued S 10 . 0232 B2 Exemplary compounds of the present invention . 132

Z

? 133 2

H0

134

AH ?? N H H

135

136

L L 1 137

?? 138

H ???? N US 10 ,022 ,352 B2 97 98 TABLE 1 -continued Exemplary compounds of the present invention .

139

ilove- Z 140

NH

141 SaitenN F ? 142

HN

F

143 Dubox?EZ quat? US 10 ,022 , 352 B2 ?? 100 TABLE 1 -continued Exemplary compounds of the present invention .

144

* 145 H

Z

???? 146

?? 147 ?????Lz

H 148

LZ NH

????? 149

??? 150)

??H US 10, 022 , 352 B2 101 USion2 .32 B2 102 101sialkTABLE 1 -onlinecontinued Exemplary compounds of the present invention .

151

??? 152

}

c 153

??? 154 155

??/

156 ???7 US 10, 022 , 352 B2 103 104 TABLE 1 -continued Exemplary compounds of the present invention .

157

H ???LZ

158 ????H ?? 159 ???? 160) ???? 161 US 10 , 022 , 352 B2 105 106 TABLE 1 - continued Exemplary compounds of the present invention .

162

F

??? F

163

164

??? H 165 US 10 ,022 , 352 B2 107 108 TABLE 1 -continued Exemplary compounds of the present invention .

166

| HN

167

168

H

169 0 $ 0 38#AN S ??? 170) US 10 , 022 , 352 B2 109 110 TABLE 1 - continued05 (0092313222 Exemplary" compounds of the present invention . ??? 171 ?? 172

173

?? 174

L L ?? 175

????? 176 Z ?] ?? ??? US 10, 022, 352 B2 111 112 TABLE 1 - continued Exemplary compounds of the present invention .

177

?? 178

F

?? 179 ASNH

?? 180)

?????? 181 US 10 ,022 , 352 B2 113 114 TABLE 1 -continued Exemplary compounds of the present invention . ?? 182 183

HN

184 ????? ???

185

186 ???H US 10 ,022 ,352 B2 115 116 TABLE 1 -continued Exemplary compounds of the present invention .

187

188

OH lesteHvH 189

190 softN

trajeO O 191

NH

QuesteH 192

NH OsetioOI 193

NH C + US 10 ,022 , 352 B2 117 118 TABLE 1 -continued Exemplary compounds of the present invention . 0H 194 HH

LZ ?????? H 195 H 196 ?? N

??? 197

H

H

1

|

198 H ??????? 199 US 10 ,022 , 352 B2 119 120 TABLE 1 - continued Exemplary compounds of the present invention .

200

OxycityNH IZ post 201

H 202 lonOH 203

K

L quartIZ

204

quantN 205

F NH US 10 ,022 , 352 B2 121 122 TABLE 1 -continued Exemplary compounds of the present invention . 206

«

207

L

L LZ

208

(

20 ?

210) ????

?

?

? LZ US 10 ,022 , 352 B2 123 124 TABLE 1 -continued Exemplary compounds of the present invention .

211

???? 212

213 ?? ???

HN

???? 214 H 215

????216 | N US 10 ,022 , 352 B2 125 126 TABLE 1 - continued Exemplary compounds of the present invention . 217

Z

218

219 0 = $ = 0 HNH

??? 220)

H 221 HN?? H

L

???? 222

???H 223 ????N US 10, 022 ,352 B2 127 128 TABLE 1 - continued ases Exemplary" compounds .. of the present invention . 224 ZL * * 225

??? 226

227 ???????H

???H 228

229

|

| LZ

230)

?? 231 ??? US 10 , 022 , 352 B2 129 130 TABLE 1 - continued Exemplary compounds of the present invention .

H 232 N ??LZ 233

?????H 234

LZ OH

??? 235

???? H 236 )???? LZ 237

??? 238 ??? US 10 , 022 , 352 B2 131 132 TABLE 1 -continued Exemplary compounds of the present invention .

239

XestN 240 om NH

241 orØyingToNH

242 OH NH

DetNH 243

N DottetH US 10 ,022 , 352 B2 133 134 TABLE 1 -continued Exemplary compounds of the present invention .

244 Or H

245

246 ???????? N

???? 247 ????? 248

???? 249

????? -250) ???LZ NH US 10 , 022 , 352 B2 135 136 TABLE 1 -continued Exemplary compounds of the present invention . 251

L

- ?? 252

?

???? 253 ??? 254 o= ??? H 255 N - ???LZ 256 N 0 | || | HNo H

L

L

* ?? 257

LZ

?? "258 H ? N US 10 , 022 , 352 B2 137 138 TABLE 1 -continued Exemplary compounds of the present invention .

259

???? 260)

???? 261

Hx

262

?? N ????? 263 US 10 , 022 , 352 B2 139 140 TABLE 1 -continued Exemplary compounds of the present invention . 264

H

265

H ??? 266

??? 267

???? 268

- C = N

???? 269

o=

???? 270) ????? US 10 ,022 , 352 B2 141 142 TABLE 1 -continued Exemplary compounds of the present invention .

271 ??HN 272 ??LZ 273

0H0

?? ??* ????? 274

0 - ??? 0 HN

H

L L ??? US 10 , 022 , 352 B2 143 144 TABLE 1 - continued Exemplary compounds of the present invention .

275

O nome HN Xyle? +

276 OH

NH

TI ZI 277 zlatoN

278 N vorlaxN 279 xotoIZ US 10 , 022 , 352 B2 145 146 TABLE 1 - continued Exemplary compounds of the present invention . IO 280 XecesH 281

F L - F NH

xoucht 282

0 = S= 0 HN

F N xouct 283

HN OHH XatL US 10 , 022 , 352 B2 147 148 TABLE 1 - continued Exemplary compounds of the present invention .

284

? ?

tagooN queI 285 LO 286

NH

287

HN

H xq 40IZ + US 10 , 022 , 352 B2 149 150 TABLE 1 -continued Exemplary compounds of the present invention . OT 288 HOA NEC

F geenH 289

290

H

F F NH

291 xquchoN US 10 , 022 , 352 B2 151 152 ? TABLE 1 - continued Exemplary compounds of the present invention . 292

FF NH

H 293 N ?

S - 0

3:H F1

294 ??

H 295

?C

F ???? US 10 , 022 , 352 B2 153 154 TABLE 1 - continued Exemplary compounds of the present invention . NEC 296 HN

F

297

H ??NH 298

NH OH

299 footN US 10, 022 , 352 B2 155 156 TABLE 1 - continued Exemplary compounds of the present invention .

300 o

QuatN 301

xglotNH

302 0 OH xqibatiNH OH

303 DictOH H 304 N F L - F

L US 10 ,022 , 352 B2 157 158 TABLE 1 - continued Exemplary compounds of the present invention .

H 305

???? . 306

HN

H

xozcht 307

?? 308

OH - ?

FF TV US 10 , 022 , 352 B2 159 160 TABLE 1 - continued Exemplary compounds of the present invention .

309

F | ??? 310) 0 H ??AN

? 311 H

H8 H

F US 10 ,022 ,352 B2 161 162 TABLE 1 - continued Exemplary compounds of the present invention .

312 -OEZ ZI

313

IZ

L

F FF . 314

315

OH

Bxgung OH

PokF US 10 ,022 , 352 B2 163 164 TABLE 1 -continued Exemplary compounds of the present invention .

H 316 N

=

=

?

F

317 ???? N ?? 318 US 10 ,022 , 352 B2 165 166 TABLE 1 - continued Exemplary compounds of the present invention .

319

320) ???? 0H

F |

321

o 0 ???LZ US 10 ,022 , 352 B2 167 168 TABLE 1 -continued Exemplary compounds of the present invention . 322

?

OH

In another aspect, the present invention relates to a Rz is H or CN ; pharmaceutical composition comprising (i ) a compound of R . is H , CH ,OCH , CH (OH )CH ,OH , CH , CH , N + the present invention ; and ( ii ) a pharmaceutically acceptable (CH , ) . . or -- CH . CH , OH : and carrier. In another embodiment, the composition further 30 comprises an additional agent selected from a mucolytic R? is H , OH , CH ,OCH CH (OH )CH2OH , CH OH , agent, bronchodilator, an anti - biotic , an anti - infective agent, or R4 and R , taken together form a five membered ring . an anti- inflammatory agent, CFTR corrector, CFTR poten - In one embodiment of this method , the ABC transporter tiator, or a nutritional agent. In another embodiment, the is CFTR . composition further comprises an additional agent selected » In one embodiment of this method , two R taken together from compounds disclosed in U . S . patent application Ser. form OCF20 , R is H , and R , is F. In another embodi No . 11/ 165 ,818 , published as U . S . Published Patent Appli - ment, two R taken together form - OCF204 , R , is H , R2 cation No . 2006 /0074075 , filed Jun . 24 , 2005 , and hereby is F , and Rz is H . In another embodiment, two R taken incorporated by reference in its entirety . In another embodi- together form — OCF , 0 - R is H , R , is F , R , is H , and R . ment, the composition further comprises N - (5 -hydroxy -2 , 4 - is H . In another embodiment, two R taken together form ditert - butyl- phenyl) - 4 - oxo - 1H - quinoline- 3 - carboxamide. OCF20 , Ry is H , R2 is F , Rz is H , and R4 is These compositions are useful for treating the diseases CH2CH2N + (CH3 ) 3. In another embodiment, two R taken described below including cystic fibrosis . These composi together form - OCF204 , R , is H , R2 is F , Rz is H , and R4 tions are also useful in the kits described below . 45 is CH OCH CH ( OH ) CH OH . In another embodiment, In another aspectspect , the present invention relates to a * two R taken together form OCF20 , R is H , R , is F , Rz method of increasing the number of functional ABC trans is H , and R . and R , taken together form a five membered porters in a membranee of a cell11 , comprisingcomprising the stenstep of ring . contacting said cell with a compound of formula II : In one embodiment of this method , two R taken together 50 form — OCH20 - , R , is H , and R , is F . In another embodi ment , two R taken together form - OCH , O , R is H , R2 ?II is F , and Rz is H . In another embodiment, two R taken Ri Ri together form - OCH O — , R , is H , R , is F , Rz is H , and R4 RR is — CH OCH CH (OH )CH2OH . 55 In one embodiment of this method , R is OH , R is H , R2 is H , Rz is H , and R4 is -- CH2OCH CH (OH ) CH2OH . In one embodiment of this method , at least one R is OCH3, at least two R , are methyl, R , is H , Rz is H , and R4 RsR5. is H . In another embodiment , at least one R is OCHz, at least 6060 two R , are methyl, R , is H , Rz is H , and R . is CH , OCH CH (OH )CH2OH . wherein independently for each occurrence: In one embodiment of this method , two R taken together R is H , OH , OCH , or two R taken together form form - CH2CH2CH2, R , is H , R2 is H , Rz is H , and R4 is CH2CH2CH2- , - OCHO — or — OCF20 % ; 65 _ CH _ OCH _ CH (OH )CH2OH . Rj is H or alkyl; In one embodiment of this method , the compound is R2 is H or F ; represented by formula Ha* : US 10 , 022 , 352 B2 169 170 In one embodiment of this method , two R taken together IlaIIa form OCH O , R , is H , and R , is F . In another embodi ment, two R taken together form — OCH20 , R , is H , R2 is F , and Rz is H . In another embodiment, two R taken N 5 together form - OCH , 0 — , R , is H , R , is F , R2 is H , and RA is — CH ,OCH , CH (OH )CH ,OH . IT Rs In one embodiment of this method , R is OH , R , is H , R2 F is H , Rz is H , and R4 is CH OCH CH (OH ) CH OH . In one embodiment of this method , at least one R is 10 OCHz, at least two R , are methyl, R , is H , R , is H , and RA or a pharmaceutically acceptable salt thereof, wherein : is H . In another embodiment, at least one R is OCHz, at least R4 is H , CH2OCH2CH (OH ) CH2OH , CH2CH2N + two Ri are methyl, R2 is H , Rz is H , and R4 is (CH3 ) 3 , or CH2CH2OH ; and _ CH , OCH , CH (OH )CH ,OH . R , is H , OH , — CH OCH CH (OH ) CH2OH , CH2OH , In one embodiment of this method , two R taken together or R4 and Rs taken together form a five membered ring . form CH ,CH ,CH , — , R , is H , R , is H , Rz is H , and R4 is In one embodiment of this method , R4 is — CHOCH CH CH . OCH . CH (OH )CH . OH . (OH )CH2OH , CH2CH2N + (CH3 ) 3 , or — CH2CH2OH . In In one embodiment of this method , the compound is another embodiment, R , is OH , CHOCH2CH (OH ) represented by formula Ha: CH ,OH , or CH2OH . In another embodiment, R4 is 30 - CH OCH CH (OH )CH2OH , CH CH N + (CH3 ) 3 , or CH CH2OH ; and Rg is OH , CH OCH _ CH (OH ) Ila CH ,OH , or — CH , OH . In one embodiment of this method , the compound is N selected from Table 1 . 25 F In another aspect , the present invention relates to a method of treating a condition , disease , or disorder in a F ' patient implicated by ABC transporter activity , comprising the step of administering to said patient a compound having formula II: 30 or a pharmaceutically acceptable salt thereof, wherein : R4 is H , CH2OCH CH (OH )CH2OH , CH2CH2N + II (CH3 )2 , or — CH ,CH ,OH ; and Ri Ri R , is H , OH , CH OCH CH (OH )CH2OH , CH2OH , RR 35 or R4 and R , taken together form a five membered ring. R3 In one embodiment of this method , R4 is CH OCH CH ( OH ) CH ,OH , _ CH _ CH _ N + ( CH3) 3 , or CH2CH2OH . In another embodiment, R , is OH , CH2OCH CH (OH ) CH ,OH , or — CH ,OH . In another embodiment, R4 is . Rs 40 CH OCH _CH (OH )CH , OH , CH2CH2N + (CH3 ) 3 , or CH2CH2OH ; and R? is OH , CH2CH (OH )CH ,OH , or CH , OH . In one embodiment of this method , the compound is or a pharmaceutically acceptable salt thereof, wherein selected from Table 1. independently for each occurrence : 45 In one embodiment of this method , said condition , dis Ris H , OH , OCHz or two R taken together form ease , or disorder is selected from cystic fibrosis, hereditary CH2CH2CH2 - , - OCH20 - or OCF20 % ; emphysema, hereditary hemochromatosis , coagulation - fi R , is H or alkyl; brinolysis deficiencies, such as protein C deficiency , Type 1 R , is H or F ; hereditary angioedema, lipid processing deficiencies , such R , is H or CN ; 50 as familial hypercholesterolemia , Type 1 chylomicronemia , R4 is H , CHOCH CH (OH ) CH2OH , CH2CH2N + abetalipoproteinemia , lysosomal storage diseases, such as (CH3 ) 3 , or CH2CH2OH ; and I - cell disease/ pseudo - Hurler , mucopolysaccharidoses , Sand Rs is H , OH , CH , OCH CH (OH ) CH2OH , CH2OH , hoffray - Sachs , Crigler -Najjar type II, polyendocrinopathy or R4 and R , taken together form a five membered ring . hyperinsulemia , diabetes mellitus, laron dwarfism , myleop In one embodiment of this method , two R taken together 55 eroxidase deficiency , primary hypoparathyroidism , form OCF20 , R , is H , and R , is F . In another embodi melanoma, glycanosis CDG type 1, hereditary emphysema , ment, two R taken together form - OCF20 - , R , is H , R2 congenital hyperthyroidism , osteogenesis imperfecta , is F , and Rz is H . In another embodiment, two R taken hereditary hypofibrinogenemia , ACT deficiency, diabetes together form OCF , 0 — , R is H , R2 is F , R , is H , and R4 insipidus (di ) , neurophyseal di , neprogenic DI, Charcot is H . In another embodiment, two R taken together form 60 Marie Tooth syndrome, Perlizaeus -Merzbacher disease , - OCF , 0 % R , is H , R , is F, R , is H , and R4 is neurodegenerative diseases such as Alzheimer ' s disease , - CH2CH N (CH3 ) 3 . In another embodiment, two R taken Parkinson ' s disease , amyotrophic lateral sclerosis, progres together form - OCF20 - , R is H , R is F , Rz is H , and RA sive supranuclear plasy , Pick ' s disease , several polygluta is — CH , OCH , CH (OH ) CH , OH . In another embodiment, mine neurological disorders such as Huntington , spinocer two R taken together form — OCF204 , R is H , R , is F , Rz 65 ebullar ataxia type I , spinal and bulbar muscular atrophy , is H , and R . and R , taken together form a five membered dentatorubal pallidoluysian , and myotonic dystrophy, as ring. well as spongiform encephalopathies , such as hereditary US 10 , 022 , 352 B2 171 172 Creutzfeldt- Jakob disease , Fabry disease, Straussler - Schei ( b ) the method results in a statistically significant mean nker syndrome, COPD , dry - eye disease , and Sjögren ’ s dis within - group absolute improvement from baseline in ease . ppFEV , of 3 .0 percentage points at 12 weeks. In another aspect , the present disclosure provides a In some embodiments of Method A , the method results in method for improving the percent predicted forced expira - a mean within - group absolute improvement from baseline in tory volume in one second (ppFEV ) in a patient in recog - ppFEV1 of 4 . 4 percentage points at 4 weeks . nized need thereof, comprising administering to the patient for 12 weeks once daily a pharmaceutical composition In some embodiments of Method A , the method results in comprising 100 mg ( R ) - 1 - ( 2 , 2 - difluorobenzo [ d ] [ 1 , 3 ] di a mean within - group absolute improvement from baseline in oxol -5 -yl ) - N -( 1- ( 2 ,3 -dihydroxypropyl ) -6 - fluoro -2 - (1 -hy 10 ppFEV1 of 3 . 0 percentage points at 12 weeks. droxy - 2 -methylpropan - 2 -yl ) - 1H -indol - 5 -yl ) cyclopropan In some embodiments of Method A , the method results in ecarboxamide ( Compound A ) a mean within - group absolute improvement from baseline in ppFEV1 of 4 . 4 percentage points at 4 weeks and a mean within -group absolute improvement from baseline in ppFEV1 of 3 . 0 percentage points at 12 weeks. 13] In some embodiments ofMethod A , the method results in OH a statistically significant mean within - group absolute F improvement from baseline in ppFEV1 of 4. 4 percentage 20 points at 4 weeks. OH In some embodiments of Method A , the method results in OH a statistically significant mean within - group absolute improvement from baseline in ppFEV1 of 3 . 0 percentage os points at 12 weeks . and In some embodiments of Method A , the method results in a pharmaceutically acceptable carrier, a statistically significant mean within - group absolute wherein the patient has cystic fibrosis ; improvement from baseline in ppFEV1 of 4 . 4 percentage wherein the patient is also administered every 12 hours a points at 4 weeks and a statistically significantmean within pharmaceutical composition comprising 150 mg N - ( 2 , 4 - di- 3030 group absolute improvement from baseline in ppFEV1 of tert- butyl - 5 -hydroxyphenyl ) - 4 - oxo - 1 , 4 - dihydroquinoline - 3 3 . 0 percentage points at 12 weeks. carboxamide ( Compound B ) In some embodiments of Method A , the method results in a statistically significant mean within - group absolute decrease in sweat chloride relative to a dosing regiment N 35 where the patient receives placebo . In some embodiments of Method A , the method numeri cally reduces the rate of serious adverse events compared to a dosing regimen where the patient receives placebo . 40. In another aspect, the present disclosure provides a method for improving the percent predicted forced expira tory volume in one second (ppFEV1 ) in a patient in recog nized need thereof, comprising administering to the patient OH for 12 weeks every 12 hours a pharmaceutical composition 45 comprising 50 mg ( R ) - 1 - ( 2 , 2 - difluorobenzo [ d ] [ 1 , 3 ] dioxol and 5 - yl) - N - ( 1 - ( 2 , 3 - dihydroxypropyl) - 6 - fluoro - 2 - ( 1 -hydroxy - 2 a pharmaceutically acceptable carrier , and methylpropan - 2 - yl) - 1H - indol- 5 -yl ) cyclopropanecarboxam wherein the percent predicted forced expiratory volume in ide (Compound A ) one second ( ppFEV1) is improved relative to a dosing regimen where the patient receives placebo . 50 Herein , the aforementioned method is referred to as N Method A . In some embodiments of Method A , the method satisfies 1) XOH?? at least one of the following conditions: 55 (a ) the method results in a mean within - group absolute OH improvement from baseline in ppFEV1 of 4 . 4 percentage points at 4 weeks ; and OH ( b ) the method results in a mean within - group absolute improvement from baseline in ppFEV , of 3 . 0 percentagee 60 and points at 12 weeks. a pharmaceutically acceptable carrier, In some embodiments of Method A , the method satisfies wherein the patient has cystic fibrosis ; at least one of the following conditions: wherein the patient is also administered every 12 hours a (a ) the method results in a statistically significant mean 65 pharmaceutical composition comprising 150 mg N - (2 , 4 - di within - group absolute improvement from baseline in tert -butyl - 5 -hydroxyphenyl ) - 4 - oxo - 1 , 4 -dihydroquinoline - 3 ppFEV , of 4 . 4 percentage points at 4 weeks; and carboxamide ( Compound B ) US 10 , 022 ,352 B2 173173 174 numerically reduces the rate of cough compared to a dosing regimen where the patient receives placebo . In some embodiments of Method B , the method numeri cally reduces the rate of pulmonary exacerbation compared 5 to a dosing regimen where the patient receives placebo . In some embodiments ofMethod B , the method numeri cally reduces the rate of cough compared to a dosing regimen where the patient receives placebo . OH In some embodiments of Method B , the method numeri 10 cally reduces the rate of pulmonary exacerbation compared and to a dosing regimen where the patient receives placebo and a pharmaceutically acceptable carrier , and numerically reduces the rate of cough compared to a dosing wherein the percent predicted forced expiratory volume in regimen where the patient receives placebo . one second (ppFEV . ) is improved relative to a dosing 155 In another aspect , the present invention relates to a kit for regimen where the patient receives placebo . use in measuring the activity of a ABC transporter or a Herein , the aforementioned method is referred to as fragment thereof in a biological sample in vitro or in vivo , Method B . comprising: In some embodiments of Method B , the method satisfies ( i) a first composition comprising a compound of formula at least one of the following conditions : 20 II: ( a ) the method results in a mean within - group absolute improvement from baseline in ppFEV , of 0. 9 percentage points at 4 weeks; and R1 R . (b ) the method results in a mean within - group absolute 75 Ri LR improvement from baseline in ppFEV , of 0 .6 percentage points at 12 weeks. In some embodiments of Method B , the method results in a mean within - group absolute improvement from baseline in ppFEV , of 0 . 9 percentage points at 4 weeks. 30 R RS In some embodiments ofMethod B , the method results in a mean within -group absolute improvement from baseline in ppFEV , of 0 .6 percentage points at 12 weeks . In some embodiments of Method B , the method results in wherein independently for each occurrence : a mean within - group absolute improvement from baseline in 35 R is H , OH , OCHz or two R taken together form ppFEV , of 0 . 9 percentage points at 4 weeks and a mean CH2CH2CH2 - , - OCH , 0 or OCF20 — ; within - group absolute improvement from baseline in Rj is H or alkyl; ppFEV , of 0 .6 percentage points at 12 weeks. R , is H or F ; In some embodiments of Method B , the method results in Rz is H or CN ; a statistically significant mean within - group absolute 40 R4 is H , — CH OCH CH (OH )CH2OH , CH2CH2N + decrease in sweat chloride relative to a dosing regiment (CH3 ) 2 , or — CH ,CH , OH ; and where the patient receives placebo . Rs is H , OH , CH2OCH CH (OH ) CH2OH , CH2OH , In some embodiments of Method B , the method numeri - or R4 and Rs taken together form a five membered ring ; and cally reduces the rate of serious adverse events compared to ( ii ) instructions for: a ) contacting the composition with the a dosing regimen where the patient receives placebo . 45 biological sample ; and b ) measuring activity of said ABC In some embodiments of Method A or Method B , the transporter or a fragment thereof . patient is age 18 years or older. In one embodiment, the kit further comprises instructions In some embodiments , Method A or Method B satisfies at for a ) contacting an additional composition with the bio least one of the following conditions : logical sample ; b ) measuring the activity of said ABC (a ) the method numerically reduces the rate of serious 50 transporter or a fragment thereof in the presence of said adverse events compared to a dosing regimen where the additional compound , and c ) comparing the activity of the patient receives placebo ; ABC transporter in the presence of the additional compound ( b ) the method numerically reduces the rate of pulmonary with the density of the ABC transporter in the presence of exacerbation compared to a dosing regimen where the said first composition . patient receives placebo ; and 55 In one embodiment, the kit is used to measure the density ( c ) the method numerically reduces the rate of cough of CTFR . compared to a dosing regimen where the patient receives In one embodiment of this kit, two R taken together form placebo . OCF20 R is H , and R , is F . In another embodiment, In some embodiments of Method A , the method numeri- two R taken together form - OCF20 , R is H , R2 is F , and cally reduces the rate of pulmonary exacerbation compared 60 R , is H . to a dosing regimen where the patient receives placebo . In another embodiment, two R taken together form In some embodiments of Method A , the method numeri - OCF , 0 , R is H , R , is F , R , is H , and R , is H . In another cally reduces the rate of cough compared to a dosing embodiment, two R taken together form OCF , 0 — , R , is regimen where the patient receives placebo . H , R2 is F , Rz is H , and R4 is — CH2CH2N * (CH3 ) 3. In In some embodiments of Method A , the method numeri - 65 another embodiment, two R taken together form cally reduces the rate of pulmonary exacerbation compared OCF , 0 % , R , is H , R , is F , R , is H , and R . is to a dosing regimen where the patient receives placebo and CHOCH _ CH (OH )CH2OH . In another embodiment, two US 10 ,022 , 352 B2 175 176 R taken together form OCF204 , R , is H , R2 is F, Rz is H , yl, or (2 ,6 -dichlorophenyl ( carbonyl) )- 3 -methyl - 1H - indol- 5 and R4 and R , taken together form a five membered ring. yl; and when ring A is unsubstituted cyclopentyl, n is 0 , and In one embodiment of this kit, two R taken together form Rj is hydrogen , then ring B is not - OCH204 , Rj is H , and R2 is F . In another embodiment, two R taken together form - OCH , 0 % , R , is H , R , is F, and 5 Rz is H . In another embodiment, two R taken together form - OCH20 , R is H , R2 is F , Rz is H , and R4 is — CH , OCH ,CH (OH )CH , OH . In another embodiment, R is OH , R , is H , R , is H , R , is H , and R . is CH , OCH , CH (OH )CH2OH . In another embodiment, at least one R is HN OCH ,, at least two R , are methyl, R , is H , R , is H , and R . is H . In another embodiment , at least one R is OCH?, at least two R , are methyl, R2 is H , Rz is H , and R4 is - CH OCH CH (OH )CH , OH . In another embodiment, two 15 mua R taken together form CH2CH2CH2 - , R , is H , R , is H , Rz is H , and R4 is CHOCH CH (OH ) CH2OH . In one embodiment of this kit , the compound is repre sented by formula Ha : , or 20

??

25 Yazar OH . F xoxo30 que or a pharmaceutically acceptable salt thereof, wherein : R4 is H , CH2OCH CH (OH ) CH2OH , CH2CH2N + Another aspect of the present invention provides a com ( CH3) 3 , or CH2CH2OH ; and Rs is H , OH , - CH OCH _ CH (OH )CH2OH , CH ,OH , pound that is useful for modulating ABC transporter activity . or R4 and Rs taken together form a five membered ring. 35 The compound has formula Id : In one embodiment of this kit, R4 is CH OCH CH (OH ) CH ,OH , CH2CH2N * (CH3 )3 , or - CH2CH2OH . In Id another embodiment, R , is OH , CH ,OCH CH (OH ) CH ,OH , or — CH ,OH . In another embodiment, R4 is _ CH , OCH , CH (OH )CH , OH , CH , CH , N + (CHZ ) , or 40 CH , CH2OH ; and Rg is OH , CH ,OCH2CH (OH ) n (R2 ) CH , OH , or CH2OH . In one embodiment of this kit , the compound is selected ??Z from Table 1. 45 III . Subgeneric Compounds of the Present or a pharmaceutically acceptable salt thereof. Invention R1, R2, and ring A are defined above in formula I, and ring Another aspect of the present invention provides a com B , Rz and p are defined in formula la . pound that is useful for modulating ABC transporter activity . 50 However, when R , is H , n is 0 , ring A is an unsubstituted The compound has formula Id : cyclopentyl, and ring B is an indole - 5 - yl substituted with 1- 2 of Rz, then each Rz is independently — ZºR12 , where each Zº is independently a bond or an unsubstituted branched or Ic straight C1- 6 aliphatic chain wherein up to two carbon units 55 of Zº are optionally and independently replaced by - CS - , CONRNRO - , - C02 - , - OCO — , - NRC0 , 0 , - NR CONRG , OCONRO - , - NR NRG _ n ( R ) Z- S , SO , S0 , - NRG , SO NRG A - NR 80 , - , or NRCSO NRC , each R12 is indepen 60 dently RG , halo , OH , - NH2, - NO2, CN , or - OCF3, and each R is independently hydrogen , an unsubstituted aliphatic , an optionally substituted cycloaliphatic , an option or a pharmaceutically acceptable salt thereof. ally substituted heterocycloaliphatic , an unsubstituted aryl, R1, R2, and ring A are defined above in formula I, and ring or an optionally substituted heteroaryl; or any two adjacent B , Rz and p are defined in formula la . Furthermore, when 65 Rz groups together with the atoms to which they are attached ring A is unsubstituted cyclopentyl, n is 1 , R , is 4 - chloro , form an optionally substituted heterocycle . Furthermore , and R , is hydrogen , then ring B is not 2 - ( tertbutyl) indol- 5 . when R , is H , n is 1 , R2 is 4 -chloro , ring A is an unsubsti US 10 , 022 , 352 B2 177 178 tuted cyclopentyl, and ring B is an indole - 5 - yl substituted with 1 - 2 of R3, then each Rz is independently — ZHR22 , IIb where each Z is independently a bond or an unsubstituted 2 - 21 branched or straight C1- 3 aliphatic chain wherein up to two 5 carbon units of Z are optionally and independently replaced (R3 ) p by CS , CONRHNRH, C0 , - , OCO , 24 25

- NRHCO , – , 0 , NRWCONRA , OCONRH — , Z - NRHNRH — , - S — , - SO — , - 50 , , NRH — , 10 ??Z - SO NRH , NRHS0 , - , or - NRHSO NRH — , each R22 is independently R ” , halo , OH , NH2, — NO2, - CN , or — OCF3, and each R " is independently hydrogen , or a pharmaceutically acceptable salt thereof. a substituted C4 alkyl, an optionally substituted C2- 6 alkenyl, 15 R1, R2, and ring A , are defined above in formula I; R3, R ' 3, an optionally substituted C2- 6 alkynyl, an optionally substi - and p are defined above in formula Ia ; and Z1, Z2, Z3, Z4, and tuted C4 alkenyl, an optionally substituted C4 alkynyl , an Z , are defined above in formula Ib . optionally substituted cycloaliphatic , an optionally substi Another aspect of the present invention provides a com tuted heterocycloaliphatic , an optionally substituted het pound that is useful for modulating ABC transporter activity . eroaryl, an unsubstituted phenyl, or a mono - substituted - The compound has formula IIc : phenyl, or any two adjacent R3 groups together with the atoms to which they are attached form an optionally sub stituted heterocycle . IIC Another aspect of the present invention provides a com 25 (R2 ) n pound that is useful for modulating ABC transporter activity The compound has formula II :

I 30 Duo groRip (R3 ) Z - 21 zz -4- 2 or a pharmaceutically acceptable salt thereof. 24- 25 35 Z R1, R2 and n are defined above in formula I ; and R3, R 'z , - and p are defined in formula Ia . p (R2 ) Another aspect of the present invention provides a com pound that is useful for modulating ABC transporter activity . or a pharmaceutically acceptable salt thereof. * The compound has formula IId : R1, R2, and ring A are defined above in formula I; R3 , R '3 , and p are defined above in formula la ; and Z1, Z2, Z3, Z4, and Z , are defined above in formula Ib . Illd Another aspect of the present invention provides a com - 45 R2 pound that is useful for modulating ABC transporter activity .

The compound has formula Ha : G “ N Ila 50 R3 Z geheime(R3 ) 0 - 2

24 25 55s or a pharmaceutically acceptable salt thereof . Z Both R , groups , together with the atoms to which they are Oglan(R2 ) attached form a group selected from : or a pharmaceutically acceptable salt thereof. 60 XA1 R1, R2, and ring A are defined above in formula I; R3 , R 'z , and p are defined above in formula la ; and Z1, Z2, Z3, Z4, and Z , are defined above in formula Ib . Another aspect of the present invention provides a com - 65 pound that is useful for modulating ABC transporter activity. The compound has formula IIb : US 10 , 022, 352 B2 179 180 -continued - continued XA2 XA11 | ANNnn NNNN XA3 XA12 ANN ? 10 NNNN ??? 15 XA4 XA13 AN NANA 20 NA XA5 XA14 NMA MC VAN The XA15 XA6 NNN

w www XA16 NNNNN XA7 For w

XA8 45 N XA17 JP wwww ine

Me OHS XA9 XA18 NTN No NNN XA10 60 XA19 NNN or US 10 , 022 , 352 B2 181 781182 - continued - continued XA20 Winn . COH OH min and * Yout ??? CONMe2 , mo min )HO mia contacto XA21 10

M NHCOMP, ** mmty OH due nuto HN ma . NO mm ?? mu R ' z is independently selected from one of the following : OX 20 NHSO2Me, H²00 – H, ?CH , = CH -CH3 , = CH -CH2OH , mu t a motHO min 25 mi OH , minn OH w mi mun HO www y NHSON mi NHCOM HomeM mi OH HO inn NHCOI HN mm min mi OH New ?? NHCOCH3, COH ' m min I HO‘ mi NHMe, OMe mim OH?? HOOH HO HO mu HO mm mm mm OH , mu NH2, mu ?? NHCOotsu , CONHMe , NHSO Et to mitim . . thanmani mi ?? - IZ mi mu mwi HO US 10 , 022 , 352 B2 183 184 -continued -continued mi mi

10 min HO mi mi PurtNH , . Ottimin mi ]

- mu ?? . 20 N - 0 CO , mi

the 25 tutto mi HO and mim Wim NH mo

30 to the truthin and each Rz is independently selected from — H , CH3, NH - CH2OH , CH2CH3, CH CH , OH , CH2CH2CH3, w - NH2, halo , OCH3, CN , CF3, - C ( O )OCH2CH3 , OH . - S (O )2CH3 , CH2NH2, C (O )NH2 , 35 HO' mi mm weWinn mun

O > mi mo OH pak- OH kka mm HN HN

Houthatham Hey in IZ - NH2 min u

min HN EZ min ? mi min

NH HN min a mu minn OH , US 10 , 022 , 352 B2 185 186 -continued Scheme 1 : (R2 ) wa wy 5 a OH ???? to to wwtayo 10 15 min CN , ww tites 20 and 25 )SOCI , DMF( cat .) , DCM ;b ) R5 – – .py :0 )R14 mm HATU , TEA, DCM /DMF . te to Referring to Scheme 1tomto , the acid la may be converted to º the corresponding acid chloride 1b using thionyl chloride in the presence of a catalystic amount of dimethylformamide . Reaction of the acid chloride with the amine 35 R - 17B men provides compounds of the invention I . Alternatively , the 40 acid la may be directly coupled to the amine using known to take coupling reagents such as, for example , HATU in the presence of triethylamine . OH , Preparation of the acids la may be achieved as illustrated in Scheme 2 . 45 a Hith Scheme 2 :

- OH , and COH 50 tyttunim EN CI Br (R2 )n 2a IV . Generic Synthetic Schemes 55 The compounds of formulae (I , Ic , Id , II , IIa , IIb , IIc , and Ild ) may be readily synthesized from commercially avail able or known starting materials by known methods. 60 SNNb Exemplary synthetic routes to produce compounds of ?? formulae ( I, Ic , Id , II , IIa , IIb , IIc , and Ild ) are provided RSNyn ( R ) below in Schemes 1 - 22 below . 2b la Preparation of the compounds of the invention is achieved 65. aa) ) NaOH ,, olBTEAC ; b ) NaOHNaOH , A - of by the coupling of a ring B amine with a ring A carboxylic acid as illustrated in Scheme 1 .