The 31-year-old said he would try his best to be present at the eight-man event which takes place from Nov 12-19 at the O2 in London, but his focus was on the long term.
The loss means Pablo Carreno Busta will likely get the final spot.
"When I served for the match my hand was shaking, " Krajinovic said.
Krajinovic's opening service lasted 11 minutes but despite facing a break point he held firm to hold serve before both players dominated behind their serve - Isner won 23 out of 24 points at one stage. "It was mentally really tough because, you know, getting older and older all sponsors said no to me".More news: Rain continues to lash different parts of Tamil Nadu
Krajinovic is the lowest-ranked player in a Masters final since 191st-ranked Andrei Pavel in Paris in 2003.
The first break of the match came in the fifth game of the encounter to see Krajinovic, the world No 77, move 3-2 ahead as a visibly lacklustre Isner struggled from the back of the court.
The 77th-ranked Krajinovic had won only 17 matches in his whole career - thwarted by injuries - before this tournament.
But the giant American, runner-up in Paris to Andy Murray previous year, found a second wind in a second-set tie-break, reeling off the first five points in a row.
First up on this afternoon's schedule, however, is the clash between Isner and Krajinovic, with the big-serving American - finalist past year - a heavy favourite at [1.31] to dispatch the in-form Krajinovic.More news: Jimmy Kimmel, Channing Tatum Play Halloween-Candy Prank on Their Kids
He closed it out with two massive aces to take his tally for the match to 16. Sock can still qualify for London if he wins the tournament.
The second set saw Isner regain some measure of control behind his serve but was relieved to see the Serbian miss a gilt-edged volley which would have brought up a break point at 2-2.
"To be completely honest, I had no idea I could still make London even if I was to win the tournament", a surprised Sock, who was 24th in the points standings at the start of the week, said.
Everything could have been much different if John converted any of the 3 break points he had in the opening return game, but Filip repelled them all with some fine groundstrokes, especially from the backhand side, to avoid an early setback.
The world number 22 was by far the stronger player and completed victory with a run of four straight games.More news: Justin Bieber and Selena Gomez are back together? Here's what sources claim
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